Interventions for fertility preservation in women with cancer undergoing chemotherapy

Maria AJ Weterings; Elizabeth Glanville; Rik Eekelen; Cindy Farquhar

doi:10.1002/14651858.CD012891.pub2

. 2025 Jun 19;2025(6):CD012891. doi: 10.1002/14651858.CD012891.pub2

Interventions for fertility preservation in women with cancer undergoing chemotherapy

Maria AJ Weterings ^1,^✉, Elizabeth Glanville ², Rik Eekelen ³, Cindy Farquhar ⁴

Editor: Cochrane Central Editorial Service

PMCID: PMC12177921 PMID: 40536056

Abstract

Background

Anti‐cancer drugs can be toxic to healthy cells in the body and have the potential to cause irreversible damage to ovarian tissue. This may lead to premature ovarian insufficiency. There are two main strategies to preserve fertility in women undergoing chemotherapy treatment for cancer. One is controlled ovarian hyperstimulation with gonadotropins and a protective agent for safety, followed by freezing of oocytes or embryos; the other is ovarian suppression using gonadotropin‐releasing hormone agonists (GnRH agonists).

This review aims to gain an understanding of the best way to support women with cancer to preserve their fertility. As breast cancer is the most common cancer in women worldwide, it is the primary focus of this review.

Objectives

To determine the effectiveness and safety of the two main fertility preservation strategies used in premenopausal women with cancer undergoing chemotherapy. One strategy is controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos, and the other is ovarian suppression using GnRH agonists.

Search methods

We searched the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO on 27 November 2023. To identify additional studies, we also checked reference lists and contacted study authors and experts in the field.

Selection criteria

We included randomised controlled trials (RCTs) that evaluated protective agents used in combination with controlled ovarian hyperstimulation with gonadotropins and followed by freezing of oocytes or embryos, and RCTs that evaluated the use of GnRH agonists to suppress the ovaries. The comparator could be placebo, usual care, no treatment or another agent in the same group (e.g. ovarian suppression using goserelin versus using leuprolide acetate). We also looked for studies that compared the two main fertility preservation methods against each other.

Data collection and analysis

We used the standard methodological procedures recommended by Cochrane. The primary review outcomes were ovarian insufficiency, live birth and overall survival. We had a number of secondary outcomes, including non‐pregnancy‐related adverse events.

Main results

We included 23 RCTs (2647 women analysed). We judged the certainty of the evidence to be very low to moderate. The main limitations in the evidence were serious risk of bias in multiple domains for several studies, publication bias due to early termination of three studies and very serious imprecision.

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients

There was no evidence available for our primary outcomes: ovarian insufficiency, live birth and overall survival. Nor was there any evidence for disease‐free survival, pregnancy‐related adverse events or non‐pregnancy‐related adverse events.

Compared to standard controlled ovarian hyperstimulation, the evidence is very uncertain about the effect of controlled ovarian hyperstimulation with gonadotropins plus a protective agent on the number of oocytes retrieved (letrozole: mean difference (MD) 0.70 (95% confidence interval (CI) −2.60 to 4.00; 1 study, 108 women); tamoxifen: MD 0.70 (95% CI −3.05 to 4.45; 1 study, 109 women) (both very low‐certainty evidence). There is probably little to no difference between the use of letrozole or tamoxifen as the protective agent added to controlled ovarian hyperstimulation with gonadotropins (MD −0.04, −2.72 to 2.64; 2 studies, 203 women; I² = 0%; moderate‐certainty evidence).

Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients

Ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency (relative risk (RR) 0.43, CI 0.31 to 0.59; P < 0.001; 5 studies, 811 women; I² = 0%; low‐certainty evidence).

The evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on live birth (RR 1.60, CI 0.89 to 2.87; P = 0.12; 3 studies, 599 women; I² = 0%; very low‐certainty evidence). Ovarian suppression using GnRH agonists may have little to no effect on overall survival over 10 years (hazard ratio (HR) 1.17, CI 0.67 to 2.04; P = 0.58; 1 study, 281 women) and disease‐free survival over 10 years (HR 1.16, CI 0.76 to 1.77; P = 0.5; 1 study; 281 women), but the evidence is of low certainty.

Only evidence that we judged to have very low certainty was available for pregnancy‐related adverse events (4 studies, 648 women), including induced abortion, miscarriage, preterm delivery, delivery complications and elective termination.

Moderate‐certainty evidence was available for non‐pregnancy‐related adverse events (4 studies; 744 women), which showed that study participants in both groups experienced chemotherapy‐related adverse events (e.g. fatigue, nausea, leukopenia) and non‐pregnancy‐related adverse events (e.g. sweating, hot flushes, headache); however, ovarian suppression might increase the likelihood of non‐pregnancy‐related adverse events.

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists

No evidence was available for this comparison.

Women with cancers other than breast cancer

For women with other cancers, the evidence is inconclusive and of very low certainty, and it is not possible to draw conclusions and implications for practice.

Authors' conclusions

In women with breast cancer being treated with chemotherapy, the evidence is very uncertain about controlled ovarian hyperstimulation using gonadotropins plus a protective agent (letrozole or tamoxifen) compared to controlled ovarian hyperstimulation with gonadotropins in terms of the number of oocytes obtained. When comparing letrozole versus tamoxifen used as the protective agent, there is probably little to no difference in the number of oocytes retrieved.

There is no evidence available for the long‐term implications of controlled ovarian hyperstimulation protocols, such as their effects on live births or overall survival of women with breast cancer.

In women with breast cancer, ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency caused by chemotherapy, but the certainty of the evidence is low. Evidence for other outcomes is of low or very low certainty.

We are not able to reach any conclusions concerning the choice of controlled ovarian hyperstimulation versus ovarian suppression because there are no data available comparing these fertility preservation interventions.

Plain language summary

How effective and safe are interventions given to protect the ability to get pregnant in women receiving chemotherapy for cancer?

Key messages

• In women with breast cancer, temporarily stopping the function of the ovaries by using hormone therapy might result in a reduction in ovarian insufficiency caused by chemotherapy. This means that the treatment may keep the ovaries working properly, but our certainty in this evidence is low.

• We cannot reach conclusions on what method to use to preserve fertility (the ability to get pregnant) in premenopausal women with breast cancer treated with chemotherapy.

• More research on this topic is needed.

What is fertility preservation, and why is it important?

Women with cancer are often treated with chemotherapy. Chemotherapy can harm the ovaries, reducing fertility or causing infertility. For women with cancer, preserving fertility (their ability to get pregnant) is important for their future family plans. Two methods are commonly used.

1. Stimulating the ovaries and using medication to protect them, followed by freezing eggs or embryos for later use (controlled ovarian hyperstimulation with gonadotropins and a protective agent)

2. Temporarily stopping the ovaries from working by using hormone therapy (ovarian suppression using gonadotropin‐releasing hormone agonists (GnRH agonists)).

What did we want to find out?

We wanted to find out the effects of the two main methods used for preserving fertility in women with cancer, including whether they were associated with any unwanted effects. As breast cancer is the most common cancer in women worldwide, it is the primary focus of this review.

What did we do?

We searched for studies that looked at premenopausal women (women with a regular period) with cancer being treated with chemotherapy.

We investigated studies for three different comparisons.

Comparison 1: stimulating the ovaries and using medication to protect them and then freezing eggs or embryos for later use versus placebo, usual care, no treatment or another protective agent

Comparison 2: temporarily stopping the ovaries from working by using hormone therapy versus placebo, usual care, no treatment or another hormone therapy

Comparison 3: stimulating the ovaries and using medication to protect them and then freezing eggs or embryos for later use versus temporarily stopping the ovaries from working by using hormone therapy

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 23 studies; two studies for comparison 1 and 23 studies for comparison 2. We found no studies for comparison 3.

The studies involved 2647 premenopausal women with cancer treated with chemotherapy; 2366 of the women had breast cancer and 311 of the women had other cancers.

Comparison 1

We are very uncertain about the effect of stimulating the ovaries and using medication to protect them on the number of oocytes retrieved in breast cancer patients. Two studies compared two different protective medications (letrozole versus tamoxifen) and found that there is probably no difference between them in terms of the number of eggs obtained.

We found no evidence about the effects of stimulating the ovaries and using medication to protect them on our other outcomes of interest (e.g. ovary failure, live births, survival and adverse events).

Comparison 2

In women with breast cancer, temporarily stopping the function of the ovaries using hormone therapy may result in a large reduction in ovarian insufficiency. This means that the treatment may keep the ovaries working properly.

Temporarily stopping ovary function using hormone therapy for may make little to no difference to disease‐free (without signs or symptoms of breast cancer) survival or overall survival over 10 years in women with breast cancer. The effect on the rate of live births to women with breast cancer is very uncertain.

We are also very uncertain about the effect of temporarily stopping ovary function using hormone therapy on pregnancy‐related adverse events, including induced abortion, miscarriage, preterm delivery, delivery complications and elective termination.

Both chemotherapy‐related adverse events (e.g. fatigue, nausea, leukopenia (increased risk of infection due to low white blood cell count) and non‐pregnancy‐related adverse events (e.g. sweating, hot flush, headache) were experienced by women in the studies. Temporarily stopping ovary function by using hormone therapy likely increased non‐pregnancy‐related adverse events.

Comparison 3

We found no evidence for this comparison.

Women with cancers other than breast cancer

For women with other cancers, it is not possible to draw any conclusions because we have very low certainty about the evidence.

What are the limitations of the evidence?

For comparison 1, we have moderate to little confidence in the evidence because there were not enough studies and the studies were very small.

For comparison 2, we are not at all confident in the evidence for women with breast cancer because the studies were very small and there were only a few cases of pregnancy and live birth. In addition, some studies did not provide information about everything that we were interested in, and some studies stopped earlier than planned.

How up to date is this evidence?

The evidence is up to date to November 2023.

Summary of findings

Summary of findings 1. Summary of findings table ‐ Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients.

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients
Patient or population: women with breast cancer Setting: hospital Intervention: controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos Comparison: placebo, usual care, no treatment or another agent in the same group
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo, usual care, no treatment or another agent in the same group	Risk with controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos
Ovarian insufficiency	Not measured
Live birth	Not measured
Overall survival	Not measured
Disease‐free survival	Not measured
Pregnancy‐related adverse events	Not measured
Number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins Assessed with: number of meiosis II oocytes, reported as mean and SD Scale from: 0 to 100 Follow‐up: 1 IVF cycle	Controlled ovarian hyperstimulation with gonadotropins and letrozole as protective agent versus standard controlled ovarian hyperstimulation with gonadotropins
	The mean number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins was 10.5 oocytes.	MD 0.7 oocytes higher (2.6 lower to 4 higher)	‐	108 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	The evidence is very uncertain about the effect of controlled ovarian hyperstimulation with gonadotropins and letrozole as protective agent versus standard controlled ovarian hyperstimulation with gonadotropins on the number of oocytes retrieved.
	Controlled ovarian hyperstimulation with gonadotropins and tamoxifen as protective agent versus standard controlled ovarian hyperstimulation with gonadotropins
	The mean number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins was 10.5 oocytes.	MD 0.7 oocytes higher (3.05 lower to 4.45 higher)	‐	109 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	The evidence is very uncertain about the effect of controlled ovarian hyperstimulation with gonadotropins and tamoxifen as protective agent versus standard controlled ovarian hyperstimulation with gonadotropins on the number of oocytes retrieved.
	Controlled ovarian hyperstimulation with gonadotropins and letrozole as protective agent versus controlled ovarian hyperstimulation with gonadotropins and tamoxifen as protective agent
	The mean number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins and letrozole as protective agent ranged from 11.2 to 16.9 oocytes.	MD 0.04 oocytes lower (2.72 lower to 2.64 higher) with tamoxifen as protective agent	‐	203 (2 RCTs)	⊕⊕⊕⊝ Moderate^c	There is probably little to no difference in the number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins and letrozole as protective agent versus controlled ovarian hyperstimulation with gonadotropins and tamoxifen as protective agent.
Non‐pregnancy‐related adverse events	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IVF: in vitro fertilisation; MD: mean difference; RCT: randomised controlled trial; SD: standard deviation
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded one level for indirectness; only one study reported on this outcome. ^bDowngraded two levels for imprecision; total number of participants less than 200 but more than 50 ^cDowngraded one level for imprecision; total number of participants less than 400 but more than 200

Summary of findings 2. Summary of findings table ‐ Ovarian suppression using gonadotropin‐releasing hormone agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients.

Ovarian suppression using gonadotropin‐releasing hormone agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients
Patient or population: breast cancer patients Setting: hospital Intervention: ovarian suppression using GnRH agonists Comparison: placebo, usual care, no treatment or another agent of the same group
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo, usual care, no treatment or each other	Risk with ovarian suppression using GnRH agonists	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Ovarian insufficiency (POI) Assessed with: presence of irreversible amenorrhoea lasting for at least 12 months and FSH levels, measured at least two times with a minimum of one month in between, equal to or higher than 25 MIU/mL in the presence of a negative pregnancy test. Follow‐up: 12 months	254 per 1000	109 per 1000 (79 to 150)	RR 0.43 (0.31 to 0.59)	811 (5 RCTs)	⊕⊕⊝⊝ Low^a,b,c	Ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency.
Live birth Assessed with: any delivery of a live infant after ≥ 20 weeks' gestation. Follow‐up: mean 10 years	5 per 100	9 per 100 (5 to 16)	RR 1.60 (0.89 to 2.87)	599 (3 RCTs)	⊕⊝⊝⊝ Very low^d,e	The evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on live birth.
Overall survival (OS) Assessed with: survival rate measured after over 10 years, using hazard ratio Follow‐up: 12 years	‐	‐	HR1.17 higher (0.67 higher to 2.04 higher)^f	281 (1 RCT)	⊕⊕⊝⊝ Low^g,h	Ovarian suppression using GnRH agonists may have little to no effect on overall survival over 10 years.
Disease‐free survival (DFS) Assessed with: disease‐free (without any signs or symptoms of breast cancer) survival rate measured over 10 years, using the hazard ratio Follow‐up: 12 years	‐	‐	HR 1.16 higher (0.76 higher to 1.77 higher)ⁱ	281 (1 RCT)	⊕⊕⊝⊝ Low^g,h	Ovarian suppression using GnRH agonists may have little to no effect on disease‐free survival over 10 years.
Pregnancy‐related adverse events Assessed with: any reported	One study reported no pregnancy‐related adverse events. One study reported one induced abortion. Two studies reported several pregnancy‐related adverse events, including induced abortion, miscarriage, preterm delivery, delivery complications (not specified) and elective termination.		Pregnancy‐related adverse events were equally distributed between groups but with a very low number of events.	648 (4 RCTs)	⊕⊝⊝⊝ Very low^e,j	The evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on pregnancy‐related adverse events.
Number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins	Not measured
Non‐pregnancy‐related adverse events Assessed with: any reported, either as a composite measure or separately	One study reported fatigue in all participants. Three studies reported on adverse events in part of the participants, including chemotherapy‐related considered adverse events (e.g. leucopenia, neutropenia, anemia, nausea, alopecia and fatigue) and other adverse events (e.g. hot flush, mood swings, urogenital symptoms, decrease of bone density, endometrial thickening, jaundice, diarrhea, irregular menses, decrease in libido, agitation, anxiety, depression, joint pain, muscle pain, headache, sweating and vaginal dryness).		Chemotherapy‐related adverse events were equally distributed between study arms, while other non‐pregnancy‐related adverse events were more prevalent in ovarian suppression groups.	766 (4 RCTs)	⊕⊕⊕⊝ Moderate^j	Ovarian suppression using GnRH agonists probably causes more non‐pregnancy‐related adverse events than control.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FSH: follicle‐stimulating hormone; GnRH: gonadotropin‐releasing hormone; HR: hazard ratio; IVF: in vitro fertilisation; MD: mean difference; POI: premature ovarian insufficiency; RCT: randomised controlled trial; SD: standard deviation
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for risk of bias; out of five studies, three studies were judged as having unclear or high risk for bias in multiple domains, e.g. allocation concealment was not described or no intention‐to‐treat analysis was used.  ^bDowngraded one level for imprecision; total number of events was less than 400.  ^cNote: one study (Li) terminated early because no effect was found and did not publish (only abstract available). This suggests the possibility of more unpublished work if no effect was seen in the first analysis.  ^dDowngraded one level for risk of bias; two out of three studies were judged as unclear or high risk for bias in multiple domains, e.g. eligibility after randomisation.  ^eDowngraded two levels for imprecision; total number of events was less than 50.  ^fThe chance of overall survival goes from 81.3% (control group) to 78.5% (intervention group). ^gDowngraded one level for indirectness; only one study reported on this outcome. ^hDowngraded one level for imprecision; total number of participants less than 400 but more than 200.  ⁱThe chance of disease‐free survival goes from 69.2% (control group) to 65.2% (intervention group) ^jDowngraded one level for risk of bias; none of the studies is blinded. These outcomes are likely to be influenced and therefor the overall risk of bias is judged as serious.

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Summary of findings 3. Summary of findings table ‐ Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists in breast cancer patients.

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists in breast cancer patients
Patient or population: breast cancer patients Setting: hospital Intervention: controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos Comparison: ovarian suppression using GnRH agonists
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with ovarian suppression using GnRH agonists	Risk with controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos
Ovarian insufficiency	Not measured
Live birth	Not measured
Overall survival	Not measured
Disease‐free survival	Not measured
Pregnancy‐related adverse events	Not measured
Number of oocytes retrieved after controlled ovarian hyperstimulation with gonadotropins	Not measured
Non‐pregnancy‐related adverse events	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GnRH: gonadotropin‐releasing hormone
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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Background

Description of the condition

Infertility secondary to premature ovarian insufficiency (menopause) at the time of cancer treatment can be caused by various toxins. Anti‐cancer drugs can be toxic, with the potential to cause irreversible damage to ovarian tissue (Kim 2021). This may lead to premature ovarian insufficiency, characterised by absence of periods (amenorrhoea) and subsequent infertility, hot flushes, sexual dysfunction and osteoporosis (Ishizuka 2021).The effect of anti‐cancer drugs on ovarian function varies widely. Due to their impact on dividing cells, it is expected that the granulosa and theca cells, which play key roles in follicular development, are most affected by anti‐cancer drugs. Cyclophosphamide, an alkylating agent used in almost all breast cancer treatments (Brenner 2017), is one of the most ovarian‐toxic agents. The effects vary by age, dose and drug. Evidence suggests that chemotherapy has a relatively limited impact on the primordial follicle pool, which contains the non‐growing follicles. However, there is a greater reduction in the number and function of growing follicles, including those at the preantral and antral stages, indicating a disruption in the recruitment and development of follicles (Kim 2021). This suggests that, while the pool of primordial follicles may remain relatively intact, the ability of these follicles to progress through normal development is compromised. Clinical observations, especially amenorrhoea, which is often permanent, and develops during chemotherapy, match these findings. Menstrual function and fertility may return once treatment has finished (Kim 2021).

Description of the intervention

There are two main strategies to preserve fertility in women undergoing chemotherapy treatment for cancer: 1) controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos; 2) ovarian suppression using gonadotropin‐releasing hormone agonists (GnRH agonists) (Anderson 2020; Oktay 2018).

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos

This treatment can be offered to women with cancer as a rapid intervention prior to the commencement of the anti‐cancer drugs, and includes embryo cryopreservation, vitrification of oocytes and ovarian tissue freezing with in vitro maturation of oocytes. It is sometimes described as emergency in vitro fertilisation (IVF). Embryo and oocyte cryopreservation methods are widely used and currently considered established methods of fertility preservation in women with cancer (Taylan 2017). All these techniques require ovarian hyperstimulation: a technique used to induce ovulation by multiple ovarian follicles, resulting in meiosis II oocyctes, which are the specific oocytes that need to be used for this method. A conventional IVF cycle requires approximately 10 to 14 days of controlled ovarian hyperstimulation to achieve multi‐follicular development. Normally, this stimulation results in an increase of 10 to 15 times in the level of serum oestradiol. Although there is no evidence for poor outcomes with high oestrogen levels, there are concerns about safety in women with breast cancer (Muñoz 2015). To avoid these high levels, tamoxifen or letrozole are used alongside hyperstimulation. Letrozole is a non‐steroid aromatase inhibitor, which competitively inhibits the aromatase enzyme and thereby reduces the conversion of androgens to oestrogens (Farmacotherapeutisch Kompas 2023a).Tamoxifen, a non‐steroid triphenylethylene, inhibits binding of natural oestrogen to the oestrogen receptor (Farmacotherapeutisch Kompas 2023b).

Ovarian suppression using GnRH agonists

GnRH agonists result in ovarian suppression and have a possible role in fertility preservation (Sonmezer 2017). Endogenous GnRH stimulates the production of luteinising hormone (LH) and follicle‐stimulating hormone (FSH) by binding to the G‐protein‐coupled transmembrane receptor on the gonadotroph cells in the anterior pituitary. After binding, the receptor becomes internalised within the gonadotroph, and after a while, GnRH and the receptor disconnect. The receptor is then recycled back to the surface of the gonadotroph, ready for a new stimulation by GnRH. As long as the receptor is coupled, the cell remains active, allowing for the production of LH and FSH (Kumar 2014; Valsamakis 2022).However, GnRH agonists bind to the GnRH‐receptor for a much longer duration. This prolonged binding leads to the internalisation of the receptor for extended periods, resulting in down‐regulation. As fewer receptors are available on the cell surface, less stimulation can occur. This results in a reduced production (or even cessation) of LH and FSH, leading to suppression of the ovaries (Kumar 2014). GnRH agonists used for this purpose are goserelin, leuprolide acetate and triptorelin (Lambertini 2018; Moore 2015).

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos

To increase the chances of successful IVF treatment, we need to aim for multi‐follicular growth. This can be done by controlled ovarian hyperstimulation, and results in supraphysiological oestradiol levels. The concomitant use of aromatase inhibitors, such as tamoxifen or letrozole, can lower oestrogen levels, which may be important for women with breast cancer. After hyperstimulation, mature oocytes can be retrieved and vitrified (frozen) directly or fertilised and vitrified as an embryo. Fertilisation of oocytes or transfer of embryos can be scheduled at a time when all anti‐cancer drugs are ceased (Nakasuji 2019).

Ovarian suppression using GnRH agonists

The mechanism of ovarian protection by GnRH agonists is unclear. The theory most supported by research findings at the moment is that the ovaries are the least susceptible to damage if they are inactive. So, in theory, temporary elimination of the ovarian function causes temporary protection of the ovaries. GnRH agonists facilitate this temporary elimination. However, it is likely that the ovarian follicles are still exposed to the DNA‐damaging agents. In addition, primordial follicles do not express gonadotropin receptors, so it is not understood how GnRH agonists positively affect these cells (Sonmezer 2017). Following the cessation of the GnRHa, the women and their caregivers hope that a proportion of the follicles have been protected by the treatment and will respond to ovarian stimulation at a later date.

Why it is important to do this review

Many women with cancer are in the reproductive age group, and they face the difficult decision about receiving treatment that may result in complete loss of their fertility. Although we searched for all types of cancer for this review, breast cancer is our primary focus. According to the World Health Organization (WHO), breast cancer is the most common cancer in women worldwide, covering 25% of all cancer cases (WHO 2021). Approximately 7% of women with breast cancer are diagnosed before the age of 40 years (Coughlin 2019).In the last 20 years, improvements in diagnostics and treatment have yielded an important decrease in mortality (Muñoz 2015).Owing to these improvements, more and more women are now surviving cancer and have to deal with the serious long‐term effects of cancer treatment, of which infertility due to irreversible damage to the ovaries is one. Fertility is one of the topics that women are concerned about after surviving cancer (Payne 2020). It is important to address these concerns, because they may affect decisions about cancer treatment or may have a negative impact on the overall health and well‐being of young survivors of breast cancer (Lambertini 2015a). This review aims to gain an understanding of the best way to support women with cancer to help them preserve their fertility.

Oocyte/embryo cryopreservation after IVF following ovarian stimulation is currently considered an established fertility preservation option. However, this technique is not available to everyone, and the delay of a few weeks at the start of cancer treatment is a concern. For this reason, we also need to have the best available evidence for ovarian suppression regimens used during chemotherapy (Arecco 2022; Taylan 2017).

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included published and unpublished randomised controlled trials (RCTs). We excluded non‐randomised studies and quasi‐randomised studies (where allocation to intervention or control is not truly random, e.g. hospital number or day of the week) due to the high risk of bias. Cluster‐RCTs were eligible for inclusion.

Types of participants

We included premenopausal women (i.e. women with regular menstrual cycles) diagnosed with cancer who were undergoing their first course of chemotherapy and were seeking fertility preservation. We included studies with only a subset of the participants if the data were consistently presented separately. If this was not the case, we attempted to contact the study authors to clarify the data. If that was not possible, we did not use the data. While all cancers are of interest in this review and therefore eligible for inclusion, women with breast cancer will be the primary focus.

Types of interventions

Comparison 1: controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos

Different protective agents used in combination with controlled ovarian hyperstimulation with gonadotropins followed by freezing of oocytes/embryos versus placebo, usual care, no treatment, or another agent in the same group (e.g. tamoxifen as a protective agent versus letrozole as a protective agent).

We included protective agents as specified in the trials (these vary according to response):

tamoxifen;
letrozole.

Comparison 2: ovarian suppression during chemotherapy using GnRH agonists

We included different GnRH agonists to suppress the ovaries, versus placebo, usual care, no treatment, or another agent in the same group (e.g. ovarian suppression using goserelin versus ovarian suppression using leuprolide acetate).

We included GnRH agonists as specified in the trials (these vary according to response):

goserelin;
leuprolide acetate;
triptorelin;
buserelin;
dipherelin.

Comparison 3: controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists

Had they been available, we would have included studies in which controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos as described under 'comparison 1' above were compared with ovarian suppression during chemotherapy using GnRH agonists as described under 'comparison 2' above.

Types of outcome measures

Primary outcomes

Ovarian insufficiency: assessed by 1) the presence of irreversible amenorrhoea lasting for at least 12 months and 2) FSH‐level, measured at least once, equal to or higher than 25 MIU/mL in the presence of a negative pregnancy test. We considered other definitions of ovarian insufficiency for subgroup analysis (see Subgroup analysis and investigation of heterogeneity).
Live birth: any delivery of a live infant after 20 weeks' gestation
Overall survival: survival rate measured, using the hazard ratio, at three time points: after 5 years, over 5 years and over 10 years

Secondary outcomes

Clinical pregnancy: a pregnancy diagnosed by ultrasonographic visualisation of one or more gestational sacs or definitive clinical signs of pregnancy. In addition to intrauterine pregnancy, this includes any clinically documented ectopic pregnancy.
Disease‐free survival: disease‐free (i.e. without any signs or symptoms of breast cancer) survival rate measured after 5 years, between 5 and 10 years and over 10 years, using the hazard ratio
Time‐to‐pregnancy: defined as the number of menstrual cycles required to conceive
Pregnancy‐related adverse events: any that are reported. Examples include miscarriage, ectopic pregnancy, or congenital abnormalities.
Number of oocytes retrieved after ovarian stimulation: defined as the number of meiosis II oocytes, reported as mean and standard deviation (SD)
Non‐pregnancy‐related adverse events: any that are reported, either as a composite measure or separately. Examples include hot flashes, sexual dysfunction, headache, and joint pain.

Search methods for identification of studies

We searched, in consultation with the Cochrane Gynaecology and Fertility Group Information Specialist (MS), for all published and unpublished reports that describe RCTs of ovarian suppression or stimulation therapies to preserve fertility in premenopausal women who are being treated with chemotherapy for cancer. We searched for papers in all languages, and we conducted translations where necessary.

Electronic searches

We searched the following electronic databases on 27 November 2023 for relevant trials.

The Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, ProCite platform, searched from inception to 27 November 2023 (Appendix 1)
CENTRAL via the Cochrane Central Register of Studies Online (CRSO), web‐based, searched on 27 November 2023 (Appendix 2)
MEDLINE, via the Ovid platform, searched from 1946 to 27 November 2023 (Appendix 3)
Embase, via the Ovid platform, searched from 1980 to 27 November 2023 (Appendix 4)
PsychINFO, via the Ovid platform, searched from 1806 to 27 November 2023 (Appendix 5)

We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials, which appears in the Cochrane Handbook of Systematic Reviews of Interventions (Lefebvre 2024). The Embase search was combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN; https://www.sign.ac.uk/what-we-do/methodology/search-filters/).

CENTRAL now includes CINAHL and two trial registries: the World Health Organization International Clinical Trials Registry Platform (trialsearch.who.int) and clinicaltrials.gov (www.clinicaltrials.gov). We also manually searched these trial registries to cover the month‐long time lag from the trial going into the registry to being imported into CENTRAL.

We searched the other electronic sources of trials listed below on 10 December 2024, using the keywords "fertility preservation" and "cancer".

PubMed
Google Scholar
LILACS via the Virtual Health Library Regional Portal
Epistemonikos database

Searching other resources

In order to obtain any trials that we may have missed, we manually searched the reference lists of included articles. We also identified reviews and examined their reference lists as sources of potentially relevant studies. We contacted the study authors if necessary. We manually searched the European Society of Human Reproduction and Embryology (ESHRE) conference abstracts from 2024 for potentially relevant unpublished reports.

Data collection and analysis

Selection of studies

One author (MAJW) downloaded all titles and abstracts from our initial search into the reference management database Endnote (Endnote), and removed any duplicate records. We downloaded the remaining studies to Covidence (Covidence). One review author (MAJW) screened the titles and abstracts to assess their eligibility. We retrieved the full text of those records that MAJW thought might fulfil the inclusion criteria, as well as those without abstracts. Two review authors (MAJW, EG) independently assessed the retrieved papers. We resolved disagreements about eligibility for inclusion by discussion between the two authors, and, if necessary, by involving a third review author (CF). We documented reasons for exclusion in the Characteristics of excluded studies table.

Data extraction and management

Two review authors (MAJW, EG) independently extracted data on study characteristics. Differences between the authors were resolved by discussion. We extracted the following data.

Study identification details: country, setting, sponsorship source, author details and contact information, start and end date of study, aim of study, any conflicts of interest
Method characteristics: study design, sample size, outcome definitions, ethical approval and informed consent obtained, total number randomised
Population characteristics: inclusion and exclusion criteria, baseline differences, number and reason for exclusions, subgroups measured and reported, type of chemotherapy regimen and baseline characteristics (age, type of cancer, if breast cancer: stage of breast cancer, hormone‐positive or hormone‐negative breast cancer)
Intervention characteristics: description of the intervention, duration of treatment, timing of treatment, withdrawals and reason for withdrawals, number randomised to each group, duration of follow‐up and co‐interventions
Outcomes: all outcome definition, measurement, timing and data corresponding to the outcome measures of this review

Assessment of risk of bias in included studies

Two review authors (MAJW, EG) independently assessed the risk of bias according to the guidelines stated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). This included assessment of the following risk of bias domains.

Selection bias: random sequence generation and allocation concealment
Performance bias: blinding of participants and personnel
Detection bias: blinding of outcome assessors
Attrition bias: incomplete outcome data
Reporting bias: selective reporting
Other sources of bias

For each domain, we made a judgement of ‘low risk’, ‘high risk’ or ‘unclear risk’. We resolved differences by discussion amongst the review authors.

Our risk of bias assessments are included for each study in the Characteristics of included studies table. For each outcome, all studies included in the comparison contributed to our assessment of the overall certainty of the evidence for that outcome. In addition, the overall risk of bias for each study is shown (see Figure 1 and Figure 2). We incorporated differences in the risk of bias into our interpretation of review findings by means of sensitivity analyses.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Measures of treatment effect

For dichotomous data (e.g. clinical pregnancies), we used the number of events in the controlled ovarian hyperstimulation and ovarian suppression groups to calculate risk ratios (RRs). For continuous outcomes, we used mean differences to compare the mean outcomes of the groups. For survival outcomes, we extracted HRs from studies or calculated them using the log‐rank statistic based on presented information, if available; or if the authors provided us with the relevant data, we used Cox proportional hazards models to directly estimate hazard ratios (HRs). We presented Kaplan‐Meier analyses for all time‐to‐event data. We reversed the direction of the effect in individual studies, if required, to ensure consistency across trials. We presented 95% confidence intervals (CIs) for all outcomes. Where data to calculate RRs or mean differences (MDs) were not available, we used the most detailed numerical data available to facilitate similar analyses of included studies. We assessed whether the estimates calculated in the review for individual studies were compatible in each case with the estimates reported in the study publications.

Unit of analysis issues

For all analyses, the denominator was per woman randomised. If data were unsuitable for valid analysis (e.g. data provided per cycle), we briefly summarised these data in an additional table, and these were not used in meta‐analyses.

We planned to include cluster‐RCTs and multi‐arm studies. If, in future updates of this review, we identify cluster‐RCTs for inclusion, we will use the intraclass correlation coefficient (ICC) in the included study to calculate design effects and effective sample sizes and therefore enable individual‐level pooling according to Cochrane methods (Higgins 2019).

If, in future updates of this review, we identify multi‐arm trials for inclusion, but data provided do not permit pairwise meta‐analysis, we will combine all relevant experimental intervention groups in the trial into a single group and all relevant control intervention groups into a single control group for outcomes of interest.

Dealing with missing data

In the case of missing data or insufficient information being available to calculate effect measures, we attempted to obtain these data from the original authors. If this was not obtainable, we analysed only the available data. We used the intention‐to‐treat principle to analyse the data. If studies reported sufficient detail to calculate MDs but provided no information on associated standard deviation (SD), we assumed the outcome to have an SD equal to the highest SD from the other studies within the same analysis.

Assessment of heterogeneity

We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar that meta‐analysis would provide a clinically meaningful summary. We assessed statistical heterogeneity by the plot, Chi² test and I². We interpreted an I² measurement greater than 50% as indicating substantial heterogeneity.

We used subgroup analysis to assess possible causes for heterogeneity (see Subgroup analysis and investigation of heterogeneity). We used the fixed‐effect model for data pertaining to the review question and fors the subgroups.

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were 10 or more studies in a meta‐analysis, we used a funnel plot to explore the possibility of small‐study effects.

Data synthesis

If the studies were sufficiently similar, we combined the results from primary studies using meta‐analysis within Review Manager Web (RevMan 2024), using the fixed‐effect model. We conducted separate analyses for women with breast cancer and women with any other type of cancer. For each group, we made the following comparisons.

Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent in the same group
Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group
Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists

Subgroup analysis and investigation of heterogeneity

We performed the following subgroup analyses to explore the separate evidence for the following participant subgroups.

Premature ovarian insufficiency defined using strict criteria (our primary outcome) versus premature ovarian insufficiency defined using any criteria. Where studies reported premature ovarian insufficiency in multiple ways, using several separate criteria, we chose one outcome, based on expert opinion.
Age: grouped by age at intervention and grouped by age at the start of the wish to conceive: under 35 years old versus 35 years old and above. We divided the data by age because the chance of getting pregnant naturally (without any complications) decreases with age.
Because breast cancer was our primary focus, we performed additional subgroup analyses for the data that only included women with breast cancer.
1. Grouped by stage of breast cancer: early (defined as stage I to stage III) versus late (defined as stage IV)
2. Grouped by hormone sensitivity of the tumour: hormone‐positive (defined as oestrogen‐receptor‐sensitive and/or progesterone‐receptor‐sensitive breast cancer) versus hormone‐negative breast cancer (defined as oestrogen‐receptor‐insensitive and progesterone‐receptor‐insensitive breast cancer)

When we detected substantial heterogeneity, we explored possible explanations in subgroup analysis or sensitivity analysis. We took any substantial statistical heterogeneity into account when interpreting the results, especially if there was variation in the direction of effect.

Sensitivity analysis

Sensitivity analysis was conducted for all outcome measures to determine whether the conclusions were robust to the decisions we made regarding eligibility criteria and analysis method. These sensitivity analyses allowed us to consider whether the review conclusions would have differed if we had:

restricted eligibility to studies without high risk of bias (defined as studies that are at low risk for selection bias and not at high risk in any domain); or
adopted a random‐effects model; or
used the odds ratio (OR) rather than the RR for the summary effect estimate.

Summary of findings and assessment of the certainty of the evidence

We prepared three summary of findings tables using GRADEpro software and using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2024). In these tables, we presented our evaluation of the overall certainty of the evidence for the most important review outcomes (ovarian insufficiency, live birth, overall survival, disease‐free survival, pregnancy‐related adverse events, number of oocytes retrieved after ovarian stimulation and non‐pregnancy‐related adverse events) for all three comparisons of this review, specifically in breast cancer patients. For people with other cancers, the equivalent information is presented in Table 4. We did not include clinical pregnancy and time‐to‐pregnancy outcomes in the summary of findings tables because how often a woman is pregnant and how long it takes to eventually have a baby is of secondary importance to the outcome of live birth. We assessed the certainty of the evidence using GRADEpro criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence certainty (high, moderate, low or very low) were made by two review authors (MAJW, EG) working independently, with disagreements resolved by discussion. We justified, documented and incorporated these judgements into the reporting of the results for each outcome.

1. Summary of findings table ‐ Ovarian suppression using gonadotrophin‐releasing hormone agonists versus placebo, usual care, no treatment or another agent in the same group, for people with other cancers.

Ovarian suppression using gonadotrophin‐releasing hormone agonists versus placebo, usual care, no treatment or another agent in the same group, in people with other cancers
Patient or population: people with other cancers (i.e. not breast cancer) Setting: hospital Intervention: ovarian suppression Comparison: control
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Relative effect (95% CI)	Certainty of the evidence (GRADE)	Comments
	Risk with control	Risk with ovarian suppression
Ovarian insufficiency (POI) Assessed with: presence of irreversible amenorrhoea lasting for at least 12 months, and FSH levels, measured at least two times with a minimum of one month in between, equal to or higher than 25 MIU/mL in the presence of a negative pregnancy test. Follow‐up: 25 months	250 per 1000	303 per 1000 (208 to 443)	RR 1.21 (0.83 to 1.77)	23 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,c,d	The evidence is very uncertain about the effect of ovarian suppression on ovarian insufficiency.
Live birth Assessed with: any delivery of a live infant at or after 20 weeks' gestation. Follow‐up: 25 months	0 per 1000	0 per 1000 (0 to 0)	Not estimable	23 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,c,d	Relative risk was not calculable because there were no events.
Overall survival	Not measured
Disease‐free survival	Not measured
Pregnancy‐related adverse events	Not reported
Number of oocytes retrieved after ovarian hyperstimulation	Not measured
Non‐pregnancy‐related adverse events	Two studies reported on this outcome. They mentioned sweating, hot flushes, vaginal dryness, headaches, vaginal bleeding, vaginitis and severe adverse events (not specified).		The number of adverse events was comparable in both studies and between study arms.	136  (2 RCTs)	⊕⊝⊝⊝ Very low^e,g	The evidence is very uncertain about the effect of ovarian suppression on non‐pregnancy‐related adverse events.
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FSH:* follicle‐stimulating hormone; MIU/mL: milli‐international units per millilitre; POI: premature ovarian insufficiency; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for risk of bias: we judged the study as unclear risk or high risk for bias on all domains. ^bDowngraded two levels for imprecision: total number of events was less than 50. ^cDowngraded one level for indirectness: only one study reported on this outcome. ^dNote: this study was terminated early because no effect was found. Only an abstract was published. Unpublished study results might suggest the existence of more unpublished work, if no effect was seen in the first result.  ^eDowngraded one level for imprecision: studies with very few participants, high loss to follow‐up, no power calculations and significant differences in baseline characteristics between study arms ^fDowngraded one level for inconsistency: some studies favour ovarian suppression, and some studies favour control. ^gDowngraded one level for imprecision: total number of events was less than 200 but more than 50.

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We undertook study data extraction, formatting of our comparisons in data tables and preparation of the summary of findings tables before writing the results and conclusions of our review.

Results

Description of studies

Results of the search

The electronic search retrieved 3783 articles as 3767 studies. The manual search retrieved 23 additional articles. After removing duplicate records, we screened the remaining 2595 articles. Thirty‐seven articles were potentially eligible, and we retrieved them in full text. We excluded five studies. Thirty‐two studies met our inclusion criteria, of which two are ongoing and seven are awaiting classification. Therefore, we included 23 studies (reported in 42 articles) in the review. One multi‐arm study had data that permitted pairwise meta‐analysis. No studies included subsets of participants requiring separate analyses. See Figure 3 for a depiction of the study selection process, and see tables of Characteristics of included studies, Characteristics of excluded studies, Characteristics of studies awaiting classification and Characteristics of ongoing studies for further information.

Comparisons

Of the 23 included studies, two studies reported on controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or compared with another agent in the same group (comparison 1) (Balkenende 2019; Letourneau 2021). Twenty‐one RCTs reported on ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or compared with another agent in the same group (comparison 2) (Behringer 2010; Demeestere 2016; Elgindy 2013; Falkson 1991; Gerber 2011; Gilani 2007; Giuseppe 2007; Ismail‐Khan 2008; Karimi‐Zarchi 2017; Lambertini 2022; Leonard 2017; Li 2015; Moore 2019; Munster 2012; Rabie 2021; Song 2013; Sun 2021; Sverrisdottir 2009; Waxman 1987; Zhong 2019; Zong 2022). No studies were found that compared controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists (comparison 3).

Study design and setting

The 23 studies were RCTs of parallel design.

Eleven were multicentre studies (Balkenende 2019; Behringer 2010; Demeestere 2016; Elgindy 2013; Gerber 2011; Gilani 2007; Lambertini 2022; Moore 2019; Sverrisdottir 2009; Zhong 2019; Zong 2022), six were single‐centre studies (Giuseppe 2007; Karimi‐Zarchi 2017; Letourneau 2021; Rabie 2021; Song 2013; Sun 2021) and five did not describe this clearly (Falkson 1991; Ismail‐Khan 2008; Leonard 2017; Li 2015; Munster 2012; Waxman 1987).

Nineteen studies were conducted in one country: China (Li 2015; Song 2013; Sun 2021; Zhong 2019; Zong 2022), Egypt (Elgindy 2013; Rabie 2021), Germany (Behringer 2010; Gerber 2011), Iran (Gilani 2007; Karimi‐Zarchi 2017), Italy (Giuseppe 2007; Lambertini 2022), South Africa (Falkson 1991), the UK (Leonard 2017; Waxman 1987) and the USA (Ismail‐Khan 2008; Letourneau 2021; Munster 2012). Four studies were conducted in two or three countries: Balkenende 2019 in Belgium and the Netherlands, Demeestere 2016 in Belgium, France and Italy, Sverrisdottir 2009 in Italy, Sweden and the UK, and Moore 2019 in Australia, New Zealand and the USA.

Participants

The studies included 2647 premenopausal women diagnosed with cancer and undergoing chemotherapy. Their mean age ranged across studies from 18 to 54 years. Age at the start of the wish to conceive was not reported in any study. Age at intervention according to our subgroups of interest, i.e. under 35 years old or 35 years and older, was reported in two studies (Munster 2012; Zong 2022). For the under‐35 subgroup, there were 68 participants and for the 35‐and‐over subgroup, there were 311. The other studies did not report on subgroups by age (15 studies) or used other age groups (6 studies (Demeestere 2016; Giuseppe 2007; Karimi‐Zarchi 2017; Leonard 2017; Song 2013; Zhong 2019)); therefore, their data could not be used for this review.

Seventeen studies included 2366 breast cancer patients (Balkenende 2019; Elgindy 2013; Falkson 1991; Gerber 2011; Ismail‐Khan 2008; Karimi‐Zarchi 2017; Lambertini 2022; Leonard 2017; Letourneau 2021; Li 2015; Moore 2019; Munster 2012; Song 2013; Sun 2021; Sverrisdottir 2009; Zhong 2019; Zong 2022). Of these, 1988 had early‐stage breast cancer (12 studies: Elgindy 2013; Karimi‐Zarchi 2017; Lambertini 2022; Leonard 2017; Letourneau 2021; Li 2015; Moore 2019; Munster 2012; Song 2013; Sverrisdottir 2009; Zhong 2019; Zong 2022); one study (162 participants) reported on both early‐stage and late‐stage breast cancer (Balkenende 2019); and the other four studies did not report participants' breast cancer stage (216 participants) (Falkson 1991; Gerber 2011; Ismail‐Khan 2008; Letourneau 2021).

Seven of the studies on breast cancer patients included both participants with hormone‐positive and participants with hormone‐negative cancer (1390 participants) (Balkenende 2019; Lambertini 2022; Leonard 2017; Song 2013; Sverrisdottir 2009; Zhong 2019; Zong 2022). Three studies included only hormone‐positive patients (352 participants) (Letourneau 2021; Li 2015; Sun 2021), and four studies included only hormone‐negative patients (460 participants) (Elgindy 2013; Gerber 2011; Karimi‐Zarchi 2017; Moore 2019). The other three studies did not report hormone‐receptor status (164 participants) (Falkson 1991; Ismail‐Khan 2008; Munster 2012).

Of the six studies that involved participants with cancers other than breast cancer, five included 281 patients with Hodgkin or non‐Hodgkin lymphoma (Behringer 2010; Demeestere 2016; Giuseppe 2007; Rabie 2021; Waxman 1987), and one included 30 ovarian cancer patients (Gilani 2007).

In three studies, we used only a subset of participants (Falkson 1991; Letourneau 2021; Waxman 1987), because these studies also included participants who were not eligible for this review (e.g. males). All data were consistently presented separately, which is why we were able to include these data in the review.

Interventions

One three‐arm study compared controlled ovarian hyperstimulation with gonadotropins and tamoxifen as a protective agent versus controlled ovarian hyperstimulation with gonadotropins and letrozole as a protective agent versus standard controlled ovarian hyperstimulation with gonadotropins (Balkenende 2019). Another study compared controlled ovarian hyperstimulation with gonadotropins and tamoxifen as a protective agent versus controlled ovarian hyperstimulation with gonadotropins and letrozole as a protective agent (Letourneau 2021).

Seventeen studies compared ovarian suppression using GnRH agonists with no treatment (Falkson 1991; Gerber 2011; Gilani 2007; Giuseppe 2007; Ismail‐Khan 2008; Karimi‐Zarchi 2017; Lambertini 2022; Leonard 2017; Li 2015; Moore 2019; Munster 2012; Rabie 2021; Song 2013; Sun 2021; Waxman 1987; Zhong 2019; Zong 2022). One study compared ovarian suppression using GnRH agonists versus oral contraceptives (Behringer 2010). One study compared ovarian suppression using GnRH agonists with norethisterone versus norethisterone alone (Demeestere 2016). One study compared ovarian suppression using GnRH agonists versus ovarian suppression using GnRH agonists and tamoxifen versus no treatment (Sverrisdottir 2009). One study compared ovarian suppression using GnRH agonists versus ovarian suppression using GnRH agonists in combination with a GnRH antagonist versus no treatment divided into two groups depending on the start of chemotherapy (early versus late) (Elgindy 2013).

The ovarian suppression agents used in the studies were goserelin (eight studies: Behringer 2010; Gerber 2011; Leonard 2017; Li 2015; Moore 2019; Rabie 2021; Sverrisdottir 2009; Zhong 2019), triptorelin (six studies: Demeestere 2016; Elgindy 2013; Giuseppe 2007; Ismail‐Khan 2008; Lambertini 2022, Munster 2012), buserelin (two studies: Falkson 1991; Waxman 1987), dipherelin (two studies: Gilani 2007; Karimi‐Zarchi 2017), and leuprolide acetate (two studies: Song 2013; Sun 2021). One study used goserelin or leuprorelide acetate (Zong 2022).

Outcomes

For breast cancer, five studies reported ovarian insufficiency (Lambertini 2022; Leonard 2017; Li 2015; Moore 2019; Song 2013), using our prespecified definition. In addition, seven studies reported ovarian insufficiency using another definition (Elgindy 2013; Gerber 2011; Karimi‐Zarchi 2017; Munster 2012; Sverrisdottir 2009; Zhong 2019; Zong 2022). We based our decision about which outcome to use on the expert opinion of the review team in co‐operation with a specialist in the field, considering the individual importance of the criteria. We judged FSH levels as more important than AMH (anti‐Müllerian hormone) levels, and the longest follow‐up‐time was chosen. Three studies reported live births (Elgindy 2013; Lambertini 2022; Moore 2019). Overall survival was reported by seven studies (Lambertini 2022; Leonard 2017; Li 2015; Moore 2019; Sun 2021; Zhong 2019; Zong 2022); however, the data of only two studies were usable in our meta‐analysis (Lambertini 2022; Moore 2019). Six studies reported clinical pregnancy (Elgindy 2013; Gerber 2011; Lambertini 2022; Leonard 2017; Moore 2019; Munster 2012). Five studies reported disease‐free survival (Lambertini 2022; Li 2015; Moore 2019; Zhong 2019; Zong 2022). Non‐pregnancy‐related adverse events were reported by five studies (Moore 2019; Song 2013; Sun 2021; Zong 2022; Sverrisdottir 2009), and pregnancy‐related adverse events by four (Gerber 2011; Lambertini 2022; Moore 2019; Munster 2012). One study reported time‐to‐pregnancy (Lambertini 2022). Two studies measured the number of oocytes retrieved after ovarian hyperstimulation (Balkenende 2019; Letourneau 2021).

For other cancers, one study reported ovarian insufficiency using our definition, live birth and overall survival (Demeestere 2016); however, the data on overall survival were not usable for calculating HRs. Five studies reported ovarian insufficiency using other definitions (Demeestere 2016; Gilani 2007; Giuseppe 2007; Rabie 2021; Waxman 1987). Three studies reported clinical pregnancy (Demeestere 2016; Giuseppe 2007; Waxman 1987). Disease‐free survival (Behringer 2010; Demeestere 2016) and non‐pregnancy‐related adverse events (Demeestere 2016; Rabie 2021) were each reported by two studies. No studies reported time‐to‐pregnancy or pregnancy‐related adverse events.

Excluded studies

We excluded five articles: one assessed the wrong setting; three were commentaries; and one was a fraudulent trial. For further details, please refer to the Characteristics of excluded studies table.

Risk of bias in included studies

Overall, the risk of bias in the studies we included in the review was unclear. For detailed information, see the risk of bias tables for included studies in Characteristics of included studies and Figure 1 and Figure 2.

Blinding of outcome assessors

Given the nature of the outcome measures, it is unlikely that the lack of blinding in the studies would have affected the outcomes of ovarian insufficiency, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy and number of oocytes retrieved were affected. In contrast, adverse events (both pregnancy‐related and non‐pregnancy‐related) might have been influenced because the studies were not blinded.

Incomplete outcome data

In 12 studies (Balkenende 2019; Elgindy 2013; Gerber 2011; Gilani 2007; Karimi‐Zarchi 2017; Lambertini 2022; Leonard 2017; Letourneau 2021; Moore 2019; Munster 2012; Rabie 2021; Waxman 1987), the review authors did not observe any incomplete outcome data. In three studies (Behringer 2010; Giuseppe 2007; Ismail‐Khan 2008), attrition bias was unclear because the presentation of withdrawals was unclear and/or unequal between study groups. We judged the other seven studies at high risk of attrition bias because the loss‐to‐follow‐up was very high (over 20% per study arm) and not clearly described, and per‐protocol analyses were used (Demeestere 2016; Falkson 1991; Li 2015; Song 2013; Sun 2021; Sverrisdottir 2009 Zhong 2019; Zong 2022). One of these studies used incomplete data as an exclusion criterion (Sun 2021), which makes this study particularly vulnerable to attrition bias.

Selective reporting

For 17 studies (Balkenende 2019; Demeestere 2016; Elgindy 2013; Gerber 2011; Gilani 2007; Giuseppe 2007; Karimi‐Zarchi 2017; Lambertini 2022; Leonard 2017; Letourneau 2021; Moore 2019; Rabie 2021; Song 2013; Sverrisdottir 2009; Waxman 1987; Zhong 2019; Zong 2022), no signs of reporting bias were observed by the review authors. We assessed these studies as low risk for reporting bias. In two studies (Falkson 1991; Sun 2021), the risk of reporting bias was unclear. For one of these studies (Falkson 1991), no protocol is available. In the other study, there appeared to be some errors in the report, which made us suspect reporting bias; we assessed the risk of bias in this study as unclear (Sun 2021). Three studies were terminated early, so we assessed them at high risk of reporting bias (Ismail‐Khan 2008; Li 2015; Munster 2012). One study reported a different primary outcome than prespecified in the study protocol; we assessed this study at high risk of bias (Behringer 2010).

For all outcomes, there were too few studies reporting results for the construction of a funnel plot to explore the possibility of small‐study effects.

Other potential sources of bias

In seven studies (Balkenende 2019; Lambertini 2022; Leonard 2017; Rabie 2021; Song 2013; Sverrisdottir 2009; Zhong 2019), no other sources of bias were identified. In three studies (Gilani 2007; Moore 2019; Zong 2022), other sources of bias were unclear due to various reasons (e.g. risk of inequality between study arms caused by errors in the randomisation process, low number of participants). We judged the risk of bias from other sources to be high risk in the other 13 studies (Behringer 2010; Demeestere 2016; Elgindy 2013; Falkson 1991; Gerber 2011; Giuseppe 2007; Ismail‐Khan 2008; Karimi‐Zarchi 2017; Letourneau 2021; Li 2015; Munster 2012; Sun 2021; Waxman 1987). The reasons for this were early termination of the study, doubt about true randomisation, imbalances in baseline characteristics, no registration in a trial register, sponsorship issues and conflicts of interest.

Effects of interventions

See: Table 1; Table 2; Table 3

1. Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group

1.1 Women with breast cancer

See Table 1. No trials reported on our primary outcomes (ovarian insufficiency, live birth, overall survival). No trials reported on our secondary outcomes of clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events and non‐pregnancy‐related adverse events.

1.1.1. Number of oocytes retrieved after ovarian stimulation

The only study that investigated controlled ovarian hyperstimulation with gonadotropins and a protective agent versus standard controlled ovarian hyperstimulation was Balkenende 2019. The study authors did not find evidence of a difference in the number of oocytes retrieved between study arms, both for the comparison with letrozole (mean difference (MD) 0.70, 95% confidence interval (CI) −2.60 to 4.00; 1 study, 108 women; Analysis 1.1) and for the comparison with tamoxifen (MD 0.70, 95% CI −3.05 to 4.45; 1 study, 109 women; Analysis 1.2). In addition, Letourneau 2021 investigated controlled ovarian hyperstimulation with letrozole as a protective agent versus controlled ovarian hyperstimulation with tamoxifen as a protective agent. There is probably little to no difference in the number of oocytes retrieved. Pooling of Balkenende 2019 and Letourneau 2021 was possible (MD −0.04, 95% CI −2.72 to 2.64; P = 0.97; 2 studies, 203 women; I² = 0%; Analysis 1.3). We graded the certainty of the evidence as moderate, downgrading for imprecision.

1.1 — Comparison 1: Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos in breast cancer patients, Outcome 1: Standard controlled ovarian hyperstimulation with gonadotropins versus controlled ovarian hyperstimulation with gonadotropins + letrozole: number of oocytes retrieved after ovarian stimulation

1.2 — Comparison 1: Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos in breast cancer patients, Outcome 2: Standard controlled ovarian hyperstimulation with gonadotropins versus controlled ovarian hyperstimulation with gonadotropins + tamoxifen: number of oocytes retrieved after ovarian stimulation

1.3 — Comparison 1: Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos in breast cancer patients, Outcome 3: Standard controlled ovarian hyperstimulation with gonadotropins + letrozole versus standard controlled ovarian hyperstimulation with gonadotropins + tamoxifen: number of oocytes retrieved after ovarian stimulation

1.2 Other cancers

No trials were available of this comparison in women with other cancers.

2. Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent from the same group

2.1 Women with breast cancer

See Table 2.

2.1.1. Ovarian insufficiency

Five studies measured the ovarian insufficiency rate in their study and thereby used the strict definition as set in this review (Lambertini 2022; Leonard 2017; Li 2015; Moore 2019; Song 2013). All five studies favoured ovarian suppression, although the CIs of two studies included results favouring ovarian suppression and results favouring control. The pooled data resulted in a large effect favouring ovarian suppression (RR 0.43, 95% CI 0.31 to 0.59; P < 0.001; 5 studies, 811 women; I² = 0%; Analysis 3.1). Sensitivity analysis did not provide any evidence that conclusions would have been different if we had used other methods (specifically, if we had not included studies at high risk of bias, or if we had used the random‐effects model for our meta‐analysis rather than the fixed‐effect model, or if we had used the odds ratio instead of the risk ratio for the summary effect estimate). We assessed the overall certainty of the evidence as low, downgrading two levels because one study was terminated early, the total number of events was less than 400, and we judged three of the five studies as unclear or at high risk of bias in more than one domain.

3.1 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 1: Ovarian insufficiency grouped by strict or broad definition

2.1.1.1 Ovarian insufficiency, broad definition

If we include all definitions of ovarian insufficiency, seven additional studies reported this outcome (Elgindy 2013; Gerber 2011; Karimi‐Zarchi 2017; Munster 2012; Sverrisdottir 2009; Zhong 2019; Zong 2022). Six studies favoured ovarian suppression, while one favoured the control group. Pooled data revealed an RR of 0.54 (95% CI 0.45 to 0.65; P < 0.001; 7 studies, 713 women; I² = 88%; Analysis 3.1) favouring ovarian suppression. However, when we applied the random‐effects model, the data showed an RR of 0.63, with a 95% CI of 0.38 to 1.05 (P = 0.08). This is because, with a random‐effects model, the larger studies are less influential (e.g. Zong 2022). Considering the broad range of different definitions used for ovarian insufficiency in this analysis, we think that the random‐effects model is more appropriate, and this analysis suggests that there is likely no difference between ovarian suppression groups and the control groups.

2.1.1.3. Ovarian insufficiency, grouped by receptor status

Li 2015 reported outcomes for ovarian insufficiency in hormone‐receptor‐positive patients. The results favoured ovarian suppression (RR 0.18); however, the confidence interval was wide (95% CI 0.02 to 1.37; P = 0.10; 1 study, 102 women; Analysis 3.2). We graded the certainty of this evidence as very low because the study was terminated prematurely and only an abstract is available.

3.2 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 2: Ovarian insufficiency grouped by receptor status

Ovarian insufficiency in hormone‐receptor‐negative patients was reported by Moore 2019. The authors report that the rate of ovarian insufficiency decreases when ovarian suppression is used (RR 0.35, 95% CI 0.13 to 0.90; P = 0.03; 1 study, 135 women; Analysis 3.2). We judged the risk of bias in this study as high because allocation concealment and blinding were not described and the randomisation process was improperly conducted.

The number of studies and the overall certainty of evidence in the available studies are insufficient to draw conclusions about differences in ovarian insufficiency between hormone‐receptor‐positive and hormone‐receptor‐negative patients.

2.1.2. Live birth

Three studies reported on live birth rates (Elgindy 2013; Lambertini 2022; Moore 2019). They all favoured ovarian suppression, but the CI of the studies included results favouring both the ovarian suppression groups and the control groups. This was also observed in the pooled data (RR 1.60, 95% CI 0.89 to 2.87; P = 0.12; 3 studies, 599 women; I² = 0%; Analysis 3.3). Sensitivity analysis corroborated these results. The overall certainty of evidence is very low. We downgraded the certainty because of a very low number of events and a high proportion of unclear or high‐risk judgements in two out of three studies.

3.3 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 3: Live birth

2.1.3. Overall survival

Moore 2019 reports overall survival rates after five years favouring ovarian suppression (HR 0.45, 95% CI 0.21 to 0.95; P = 0.04; 1 study, 257 women; Analysis 3.4). This finding appears to be consistent with the results of Leonard 2017. In this study, after five years, nine out of 106 participants in the ovarian suppression group died (8.5%) versus 15 out of 121 (12.3%) in the control group. Zong 2022 and colleagues agree with Moore 2019 and Leonard 2017. They report favouring ovarian suppression after four years of follow‐up (HR 0.65, 95% CI 0.16 to 2.68; P = 0.546). This was also seen by Sun 2021 after six months of follow‐up. In contrast, at a median follow‐up time of 27.4 months for the ovarian suppression group and 25.7 months for the control group, Li 2015 reports two and zero deaths, respectively, which aligns with the findings of Zhong 2019, who reported, respectively, two and zero deaths after one year. Meanwhile, Lambertini 2022 reports overall survival rates after 12 years favouring control (HR 1.17, 95% CI 0.67 to 2.04; P = 0.58; 1 study, 281 women; Analysis 3.5). Because of differences in time frames, missing HRs and the absence of raw data, it was not possible to further combine these data.

3.4 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 4: Overall survival at 5 years

3.5 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 5: Overall survival at 12 years

2.1.3.1. Overall survival, grouped by receptor status

Lambertini 2022 investigated the survival rates at 12 years, subgrouped by receptor status. No differences were found between hormone‐receptor‐positive and hormone‐receptor‐negative patients (respectively, HR 1.12, 95% CI 0.59 to 2.12; P = 0.73, and HR 1.24, 95% CI 0.41 to 3.77; P = 0.88; 1 study; 281 women; I² = 0%; Analysis 3.6).

3.6 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 6: Overall survival at 12 years grouped by receptor status

2.1.4. Clinical pregnancy

For clinical pregnancy, we included six studies in meta‐analysis. The RR of Gerber 2011 was exactly 1.00 (CI 0.07 to 15.26). One study favoured ovarian suppression (Moore 2019). In four studies, 95% confidence intervals included the value 1.00 (Lambertini 2022; Leonard 2017; Elgindy 2013; Munster 2012), indicating that there was not a clear favoured method. After pooling the data, we found a positive effect of ovarian suppression (RR 1.59; CI 1.01 to 2.49; P = 0.04; 6 studies; 933 women; I² = 0%; Analysis 3.7). Sensitivity analysis did not provide any evidence that we would have reached a different conclusion if we had used other measures. However, the overall certainty of the evidence is very low. We downgraded the certainty of the evidence for early termination of one study, a low number of events, the wide range of RRs in the individual studies and the overall high risk of bias (we judged only two out of six studies as low risk of bias for all domains).

3.7 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 7: Clinical pregnancy

2.1.4.1. Clinical pregnancy, grouped by receptor status

Lambertini 2022 reported clinical pregnancy in hormone‐receptor‐positive patients. The results favour ovarian suppression, but the 95% CI is wide (RR 5.59, CI 0.68 to 45.69; P = 0.11; 1 study, 117 women; Analysis 3.8). The certainty of the evidence in this study is low. We downgraded the certainty of evidence due to the low number of events.

3.8 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 8: Clinical pregnancy grouped by receptor status

Four studies reported clinical pregnancy in hormone‐receptor‐negative patients (Elgindy 2013; Gerber 2011; Lambertini 2022; Moore 2019). Pooled results favour ovarian suppression, but the CI is wide (RR 1.56, CI 0.90 to 2.68; P = 0.11; 4 studies; 214 women; I² = 0%; Analysis 3.8). The overall certainty of the evidence is very low. We downgraded the certainty of evidence due to early termination of one study, a low number of events, the wide range of RRs in the individual studies and the overall high risk of bias (only one out of four studies was assessed as low risk of bias for all domains).

The results in both hormone‐receptor‐positive and hormone‐receptor‐negative patients are comparable (Chi² = 1.33; I² = 25.0%; Analysis 3.8).

2.1.5. Disease‐free survival

Hazard ratios for disease‐free survival rates were reported by Moore 2019 at five years and by Lambertini 2022 at 12 years. Moore 2019 presented an HR of 0.72 (95% CI 0.39 to 1.32; P = 0.29; 1 study; 257 women; Analysis 3.9) in favour of ovarian suppression, although the evidence is not clear due to a confidence interval that includes 1.00. Zong 2022 and Zhong 2019 did not find any differences between groups after four years of follow‐up. Lambertini 2022 found similar results to Moore 2019 after 12 years of follow‐up, seeming to favour ovarian suppression but with a wide confidence interval that includes 1.00 (HR 1.16, 95% CI 0.76 to 1.77; P = 0.5; 1 study, 281 women; Analysis 3.10). These results are uncertain because of the low overall certainty of the evidence. We downgraded the certainty of the evidence because of the lack of studies.

3.9 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 9: Disease‐free survival at 5 years

3.10 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 10: Disease‐free survival at 12 years

2.1.5.1. Disease‐free survival, grouped by receptor status

Lambertini 2022 reported disease‐free survival rates at 12 years subgrouped by receptor status. No differences were found between hormone‐receptor‐positive and hormone‐receptor‐negative patients (respectively, HR 1.02, 95% CI 0.63 to 1.64; P = 0.93, and HR 1.93, 95% CI 0.73 to 5.07; P = 0.18; 1 study, 281 women; I² = 25.4%; Analysis 3.11).

3.11 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 11: Disease‐free survival grouped by receptor status

2.1.6. Time‐to‐pregnancy

Time‐to‐pregnancy defined as the number of menstrual cycles required to conceive was not reported in any study. In Gerber 2011, pregnancies occurred between 8 and 12 months after stopping chemotherapy. Lambertini 2022 reports that the interval from random assignment to first pregnancy ranged between 1.0 and 10.2 years.

2.1.7. Pregnancy‐related adverse events

One study reported no pregnancy‐related adverse events (Munster 2012). One study reported one induced abortion in the control group (Gerber 2011). Two studies reported several pregnancy‐related adverse events, which were equally present in both the ovarian suppression and the control groups (Lambertini 2022; Moore 2019), including induced abortion, miscarriage, preterm delivery, delivery complications (not specified) and elective termination (Analysis 3.13). Due to the low total number of pregnancy‐related adverse events and the high potential that outcomes would have been influenced by the lack of blinding in the studies, we graded the overall certainty of the evidence as very low.

3.13. Analysis.

Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 13: Pregnancy‐related adverse events

Pregnancy‐related adverse events
Study	Total number of pregnancies	Pregnancies in ovarian suppression group	Pregnancies in control group	Ovarian suppression	Control
Gerber 2011	2	1	1	Induced abortion (0)	Induced abortion (1)
Lambertini 2022	13	9	4	Miscarriage (2), induced abortion (1), preterm delivery (1)	Miscarriage (0), induced abortion (0), preterm delivery (1)
Moore 2019	34	22	12	Miscarriage (4), elective termination (2), delivery complication (2)	Miscarriage (5), elective termination (3), delivery complication (2)
Munster 2012	2	0	2	No pregnancy‐related adverse events reported	No pregnancy‐related adverse events reported

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2.1.8. Number of oocytes retrieved after ovarian stimulation

No trials reported on the number of oocytes retrieved.

2.1.9. Non‐pregnancy‐related adverse events

One study reported fatigue in all participants of both study arms (Zong 2022). Four studies reported on adverse events in some of their participants (Moore 2019; Song 2013; Sun 2021; Sverrisdottir 2009), including (likely) chemotherapy‐related adverse events, equally distributed between both groups (e.g. leucopenia, neutropenia, anaemia, nausea, alopecia and fatigue), and other non‐pregnancy‐related adverse events, which were more prevalent in the ovarian suppression group (e.g. hot flushes, mood swings, urogenital symptoms, decrease of bone density, endometrial thickening, jaundice, diarrhoea, irregular menses, decrease in libido, agitation, anxiety, depression, joint pain, muscle pain, headache, sweating and vaginal dryness) (Analysis 3.15). We graded the certainty of the evidence as moderate. None of the studies were blinded, and this outcome is likely to be influenced by the absence of blinding.

3.15. Analysis.

Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 15: Non‐pregnancy‐related adverse events

Non‐pregnancy‐related adverse events
Study	Ovarian suppression group	Control group	Subgroups measured
Moore 2019	N = 103	N = 111
Moore 2019	Diarrhoea (0), fatigue (2), hot flushes (33), irregular menses (7), decrease in libido (9), agitation (6), anxiety (9), depression (9), joint pain (0), muscle pain (1), headache (12), sweating (10), vaginal dryness (12)	Diarrhoea (2), fatigue (1), hot flushes (17), irregular menses (2), decrease in libido (6), agitation (5), anxiety (4), depression (3), joint pain (2), muscle pain (2), headache (2), sweating (7), vaginal dryness (9)	Only early stage and hormone receptor negative patients
Song 2013	N = 89	N = 94
Song 2013	"The majority of adverse effects were considered to be related to chemotherapy, including hematological adverse events (leucopenia, neutropenia and aneamia), nausea, alopecia and fatigue. All patients reported leuprolide‐acetate‐related adverse effects, including hot flushes, mood swings and urogenital symptoms, were Grade I and II cases."	"The majority of adverse effects were considered to be related to chemotherapy, including hematological adverse events (leucopenia, neutropenia and aneamia), nausea, alopecia and fatigue."	Only early stage patients
Sun 2021	N = 20	N = 20
Sun 2021	Decrease of bone density (1), endometrial thickening (1), jaundice (1)	Decrease of bone density (4), endometrial thickening (3), jaundice (2)	Only hormone receptor positive patients
Sverrisdottir 2009	N = 29	N = 28
Sverrisdottir 2009	"The goserelin group reported more problems with vaginal dryness over time compared with each of the three other groups." Endocrine treatment had no effect on the participants' self‐evaluation of memory and concentration problems. "There was no significant main effect of endocrine treatment on fatigue." There was no significant effect on participants' perceived anxiety and depressive symptoms.		No subgroups measured
Zong 2022	N = 165	N = 165	Early stage patients
Zong 2022	Fatigue (165)	Fatigue (165)	Both hormone receptor positive and hormone receptor negative patients; there is no difference between groups.

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2.2. Women with other cancers

See Table 4.

2.2.1. Ovarian insufficiency

Only one study reported on ovarian insufficiency using the strict definition as defined in our review protocol (Behringer 2010). Behringer and colleagues found an effect, with a risk ratio of 1.21 favouring the control group (RR 1.21, 95% CI 0.83 to 1.77; P = 0.32; 1 study, 23 women; Analysis 4.1). However, we graded the evidence as very low, downgrading for imprecision, the very low total number of events, the early termination of the study and our judgements of unclear and/or high risk of bias for all risk of bias domains.

4.1 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 1: Ovarian insufficiency grouped by strict or broad definition

2.2.1.1. Ovarian insufficiency, broad definition

Taking into account the broader definition of ovarian insufficiency, we found a total of five additional studies (Demeestere 2016; Gilani 2007; Giuseppe 2007; Rabie 2021; Waxman 1987), which made it possible to pool the data. We conducted meta‐analysis (RR 1.52, 95% CI 1.26 to 1.84; P < 0.001; 5 studies, 192 women; Analysis 4.1). Gilani 2007, Giuseppe 2007 and Rabie 2021 all reported findings supporting an effect favouring the control group (RR 1.48, RR 1.82 and RR 3.12, respectively), meaning that the use of GnRHa appears to increase the risk for ovarian insufficiency. For all three studies, the confidence interval, both lower limit and upper limit, exceeded the value 1.00 (respectively, 1.02 to 2.13; 1.14 to 2.91 and 1.78 to 5.48; Analysis 4.1). Demeestere 2016 also found evidence favouring control (RR 1.08), but the 95% CI was 0.83 to 1.40.

2.2.2. Live birth

Behringer and colleagues were the only investigators who reported on live birth (Behringer 2010). However, no live births occurred in this study, which is why it was not possible to calculate the RR and 95% CI (Analysis 4.2).

4.2 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 2: Live birth

2.2.3. Overall survival

Demeestere 2016 reported four deaths in the GnRHa group and two deaths in the control group. No data were available to calculate HR or perform meta‐analysis (1 study, 129 women; Analysis 4.3)

4.3 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 3: Overall survival

2.2.4. Clinical pregnancy

Clinical pregnancy was reported in three trials (Demeestere 2016; Giuseppe 2007; Waxman 1987), which we included in a meta‐analysis. Demeestere 2016 reported 17 pregnancies in the GnRHa group and 15 in the control group. The RR was 1.24, favouring ovarian suppression; however, the 95% CI was 0.75 to 2.05. The results of Giuseppe 2007 and Waxman 1987 favoured the control group. Both trials reported no clinical pregnancies in the GnRHa group, and therefore the 95% CI was very broad (respectively, RR 0.21, 95% CI 0.01 to 4.09; RR 0.41, 95% CI 0.02 to 8.84; Analysis 4.4). Overall, an RR of 1.04 (95% CI 0.64 to 1.70; P = 0.87; 3 studies, 114 women; I² = 0%; Analysis 4.4) was found, favouring ovarian suppression, but we graded the certainty of the evidence as very low, and this outcome is very uncertain.

4.4 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 4: Clinical pregnancy

2.2.4.1. Clinical pregnancy, grouped by age

Munster 2012 reported clinical pregnancy for predefined age groups, age < 35 years and age ≥ 35 years. No difference was found between these groups: respectively, RR 0.33 (95% CI 0.02 to 7.02) and RR 0.33 (95% CI 0.01 to 7.72) (1 study; 49 women; I² = 0%; Analysis 4.5).

4.5 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 5: Clinical pregnancy grouped by age

2.2.5. Disease‐free survival

Demeestere 2016 reported overall disease‐free survival rates of 87.5% and 82% for participants in the control and GnRHa groups, respectively (Analysis 4.6). No other data were available.

4.6 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 6: Disease‐free survival

2.2.6. Time‐to‐pregnancy

No studies reported on this outcome.

2.2.7. Pregnancy‐related adverse events

No trials reported on pregnancy‐related adverse events.

2.2.8. Number of oocytes retrieved after ovarian stimulation

No trials reported on number of oocytes retrieved.

2.2.9. Non‐pregnancy‐related adverse events

Two studies reported non‐pregnancy‐related adverse events (Demeestere 2016; Rabie 2021). Adverse events mentioned were sweating, hot flushes, vaginal dryness, vaginal bleeding, vaginitis, headache and severe adverse events. The number of adverse events was comparable across both studies and comparable between study arms (Analysis 4.10).

4.10. Analysis.

Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 10: Non‐pregnancy‐related adverse events

Non‐pregnancy‐related adverse events
Study	Ovarian suppression group	Control group
Demeestere 2016	N = 45	N = 39
Demeestere 2016	Sweating (21), hot flushes (11), vaginal dryness (7), headache (14), vaginal bleeding (7), severe adverse event (2)	Sweating (14), hot flushes (12), vaginal dryness (5), headache (16), vaginal bleeding (15), severe adverse event (0)
Rabie 2021	N = 26	N = 26
Rabie 2021	Sweating (12), hot flushes (18), vaginal dryness (0), headache (12), vaginal bleeding (0), vaginitis (8)	Sweating (12), hot flushes (12), vaginal dryness (0), headache (4), vaginal bleeding (4), vaginitis (8)

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3. Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists

No trials were available for this comparison (see Table 3).

Discussion

Summary of main results

1. Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group

There is no evidence available for our primary outcomes and non‐pregnancy‐related adverse events for this comparison in breast cancer patients or in women with other cancers.

Of our other secondary outcomes, only one was reported; it was measured in two studies of women with breast cancer. Compared to standard controlled ovarian hyperstimulation, the evidence is very uncertain about the effect of controlled ovarian hyperstimulation with gonadotropins plus a protective agent (either letrozole or tamoxifen) on the number of oocytes retrieved. There is probably little to no difference between the use of letrozole or tamoxifen as the protective agent.

2. Ovarian suppression during chemotherapy using GnRH agonists

Ovarian suppression using gonadotropin‐releasing hormone agonists (GnRH) agonists may result in a large reduction in ovarian insufficiency in breast cancer patients, although the certainty of the evidence is low. The evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on live birth in breast cancer patients. Ovarian suppression using GnRH agonists may increase overall survival in breast cancer patients at five years, but the evidence was mixed. Measured at over 10 years, there was low‐certainty evidence that ovarian suppression may have little to no effect on overall or disease‐free survival.

In women with other cancers, the evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on ovarian insufficiency. In women with other cancers, there were no births in either the ovarian suppression arm or the control arm, which is why the RR was not calculable. In women with other cancers, overall survival was not measured.

Moderate‐certainty evidence is available for non‐pregnancy‐related adverse events, which suggests that both chemotherapy‐related adverse events (e.g. fatigue, nausea, leukopenia) and other non‐pregnancy‐related adverse events (e.g. sweating, hot flushes, headache) are experienced by women with breast cancer as well as by women with other cancers. Ovarian suppression using GnRH agonists may increase the incidence of non‐pregnancy‐related other adverse events.

3. Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists

No evidence was available that compared controlled ovarian hyperstimulation with gonadotropins and a protective agent versus ovarian suppression using GnRH agonists.

Overall completeness and applicability of evidence

1. Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group

For the comparison of controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group, only two trials reported the number of oocytes retrieved. One trial was a head‐to‐head trial comparing two different protective agents. One trial included a comparison with standard ovarian hyperstimulation in addition. Live birth, overall survival and non‐pregnancy‐related adverse events were not reported in these studies.

2. Ovarian suppression during chemotherapy using GnRH agonists

For the comparison of ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent from the same group, six out of 23 studies reported ovarian insufficiency as defined in our review as an outcome in their study. However, for women and clinicians, live birth and adverse events might be more important outcomes of fertility preservation. These outcomes were reported by four and six studies respectively. Most studies compared intervention versus no treatment. No head‐to‐head studies were found for this comparison. Two studies did not report any usable outcome for our review (Falkson 1991; Ismail‐Khan 2008).

3. Controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists

No studies were found for the comparison of controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists. This comparison is probably the most important for women and clinicians, in deciding which type of fertility preservation is most likely to help them in the future.

The subgroups of strict versus broad definitions of ovarian insufficiency were reported by seven trials in women with breast cancer and five studies for women with other cancers. There was minimal reporting in the studies for our other subgroups of interest (age group, stage of breast cancer; hormone sensitivity of tumours in breast cancer).

No evidence of statistical heterogeneity was found in the main outcomes, secondary outcomes or subgroups. We could not rule out the effects of clinical heterogeneity on study results.

Quality of the evidence

The included studies were homogeneous in their design.

For the comparison of controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group, the certainty of the evidence is moderate to very low. Limitations in the certainty of the evidence were mainly caused by imprecision, due to the low number of studies reporting outcomes and the low total number of participants.

For the comparison of ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent from the same group in breast cancer patients, the certainty of the evidence is moderate to very low. Limitations include the low total number of participants and low number of total events, the high risk of bias in the included studies, and the early termination of studies, which suggests publication bias and wide CIs. The certainty of the evidence is moderate for non‐pregnancy‐related adverse events, low for ovarian insufficiency and survival outcomes, and very low for pregnancy‐related afverse events.

For women with other cancers, the certainty of the evidence is very low as we downgraded it for the same reasons.

Potential biases in the review process

We aimed to retrieve all eligible studies. However, there may be some studies that were not yet published at the time of our search. Title and abstract screening was conducted by a single author due to time constraints. We attempted to contact all study authors to request additional information and agree on the risk of bias assessment. However, we were unable to contact some authors due to missing contact information or lack of response. We stated in our protocol that we would perform subgroup analyses, but due to insufficient data, most of the planned subgroup analyses were not performed. Similarly, it was not possible to construct a funnel plot for all primary and secondary outcomes to assess potential publication bias due to limited data available.

We identified two ongoing studies. These studies have not reported their results, and we are not aware of any relevant recent publications.

Agreements and disagreements with other studies or reviews

In the past, most systematic reviews and meta‐analysis on fertility preservation in women with cancer undergoing chemotherapy contained observational, case‐control and cohort studies, with very few to no randomised controlled trials (RCTs), especially for the comparison of controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group. In addition, many of these reviews had a different scope compared to our review; for example, the differences between conventional stimulation protocols and random‐start stimulation protocols or the investigation of how many stimulation cycles are necessary.

Chen 2021 reports that co‐administration of letrozole or tamoxifen showed similar results for the number of oocytes retrieved after ovarian stimulation compared to standard stimulation protocols, which is consistent with our findings. They state that co‐administration of letrozole can lead to more desirable outcomes in terms of lower peak serum oestradiol, which might be of special importance for breast cancer patients. Arecco 2022 specifically reports on the safety of controlled ovarian hyperstimulation protocols. In the Arecco 2022 review, such safety outcomes, like overall survival and disease‐free survival, were predefined, but not reported because no included RCTs reported on these outcomes.

Sofiyeva 2019 investigated whether GnRH agonists have a protective role for women treated with chemotherapy, specifically alkylating agents. The results of the Sofiyeva 2019 review indicate that concurrent GnRHa administration decreases gonadotoxicity and thereby protects the ovaries. This is consistent with our review findings and the findings of Lambertini and colleagues (Lambertini 2015b; Lambertini 2018). In contrast, Elgindy 2015 states that administration of GnRH agonists during chemotherapy does not appear to protect the ovaries from gonadal toxicity and is therefore not recommended.

There are no publications available that compare controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists.

Authors' conclusions

Implications for practice.

For women with breast cancer being treated with chemotherapy, this review suggests that there may be no difference in the number of oocytes retrieved between controlled ovarian hyperstimulation with a protective agent and standard controlled ovarian hyperstimulation, but the evidence is of very low certainty. There is moderate‐certainty evidence of no difference in the number of oocytes retrieved when letrozole is used as the protective agent versus when tamoxifen is used as the protective agent.

There is no evidence available on long‐term implications of these different controlled ovarian hyperstimulation protocols, such as live births or overall survival.

In breast cancer patients, ovarian suppression with GnRH agonists might result in a large reduction in ovarian insufficiency caused by chemotherapy, but the certainty of the evidence is low. Ovarian suppression may have little to no effect on overall survival over 10 years and disease‐free survival over 10 years, but the certainty of the evidence is also low. The evidence is very uncertain about the effect of ovarian suppression on live birth.

For women with other cancers, it is not possible to draw conclusions and implications for practice because the evidence is inconclusive and of very low certainty.

We cannot reach any conclusions concerning the best choice from the methods to preserve fertility—controlled ovarian hyperstimulation or ovarian suppression—because there are no data available comparing these methods.

Implications for research.

Good‐quality RCTs with higher numbers of participants (and therefore a higher number of events) are necessary to confirm the current trends. In particular, more research is necessary to investigate long‐term outcome measures like live birth, overall survival, clinical pregnancy and disease‐free survival, because the evidence currently available is sparse and of low to very low certainty, yet these outcomes are most important for the women involved. There is a lack of data for specific subgroups, such as hormone‐receptor‐positive breast cancer versus hormone‐receptor‐negative breast cancer patients, stage of breast cancer and specific age groups. Randomised controlled trials are also needed to compare controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists, in order to inform the advice given to women with breast cancer or other cancers about fertility preservation methods.

History

Protocol first published: Issue 12, 2017

Acknowledgements

We would like to thank Dr Naera Waters, Medical Oncologist at Auckland City Hospital, for her clinical advice for this review.

We also thank Dr Janneke E den Hartog for her help in preparing this review.

We acknowledge the contribution of Marian Showell, who developed the search strategy and conducted the database searches.

Editorial and peer‐reviewer contributions

Cochrane Gynaecology and Fertility Group supported the authors in the development of this intervention review.

The following people conducted the editorial process for this article.

Sign‐off Editor (final editorial decision): Toby Lasserson, Acting Editor‐in‐Chief, Cochrane Library
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Liz Bickerdike, Cochrane Editorial Service
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments and supported editorial team): Jessenia Hernandez, Central Editorial Service
Copy Editor (copy editing and production): Laura MacDonald, Cochrane Central Production Service
Peer reviewers (provided comments and recommended an editorial decision): Allan Covens, University of Toronto (clinical/content review); Dr Lucy Prentice MbCHB FRANZOG, University of Auckland (clinical/content review); Debbi Knauft, Cochrane Consumer (consumer review); Nuala Livingstone, Cochrane Evidence Production and Methods Directorate (methods review); Yuan Chi, Beijing Yealth Technology Co, McMaster University (search review).

Appendices

Appendix 1. Cochrane Gynaecology and Fertility (CGF) specialised register search strategy

Searched 27 November 2023

ProCite platform

Keywords CONTAINS "fertility preservation" or Title CONTAINS "fertility preservation"

(50 records)

Appendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO)

Web platform

Searched from inception to 27 November 2023

#1 MESH DESCRIPTOR Neoplasms EXPLODE ALL TREES 111680 #2 neoplasm*:TI,AB,KY 107653 #3 cancer*:TI,AB,KY 196372 #4 tumo?r*:TI,AB,KY 86282 #5 carcinoma*:TI,AB,KY 48468 #6 #1 OR #2 OR #3 OR #4 OR #5 265733 #7 MESH DESCRIPTOR Fertility Preservation EXPLODE ALL TREES 67 #8 (fertility adj2 preserv*):TI,AB,KY 232 #9 (ovar* adj2 protect*):TI,AB,KY 35 #10 (ovar* adj2 preserv*):TI,AB,KY 63 #11 (premenopaus* or young women):TI,AB,KY 7387 #12 #7 OR #8 OR #9 OR #10 OR #11 7642 #13 MESH DESCRIPTOR Ovulation Induction EXPLODE ALL TREES 1782 #14 (ovulat* adj2 induc*):TI,AB,KY 3275 #15 (ovar* adj2 hyper stimulat*):TI,AB,KY 75 #16 superovulat*:TI,AB,KY 243 #17 (ovar* adj2 stimulat*):TI,AB,KY 2804 #18 MESH DESCRIPTOR Aromatase Inhibitors EXPLODE ALL TREES 1771 #19 MESH DESCRIPTOR Tamoxifen EXPLODE ALL TREES 2760 #20 letrozole:TI,AB,KY 2521 #21 tamoxifen:TI,AB,KY 5186 #22 MESH DESCRIPTOR In Vitro Oocyte Maturation Techniques EXPLODE ALL TREES 19 #23 (in vitro maturation or IVM):TI,AB,KY 325 #24 #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 13000 #25 (ovar* adj2 suppress*):TI,AB,KY 395 #26 (ovulat* adj2 suppress*):TI,AB,KY 51 #27 (endocrine therap*):TI,AB,KY 2777 #28 MESH DESCRIPTOR Gonadotropin‐Releasing Hormone EXPLODE ALL TREES 2968 #29 (gonadotrop?in releasing hormone agonist*):TI,AB,KY 1182 #30 (gonadotrop?in releasing hormone analog*):TI,AB,KY 466 #31 (GnRH a or GnRHa or GnRH agonist*):TI,AB,KY 2597 #32 (goserelin or leuprolide or triptorelin):TI,AB,KY 2963 #33 (lupron or Zoladex):TI,AB,KY 415 #34 (luteinizing hormone releasing hormone agonist*):TI,AB,KY 138 #35 (LHRH agonist*):TI,AB,KY 329 #36 (LHRH a or GnRH analog*):TI,AB,KY 590 #37 #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 8943 #38 #24 OR #37 18890 #39 #6 AND #12 AND #38 1210

Appendix 3. MEDLINE search strategy

Searched from 1946 to 27 November 2023

Ovid platform

1 exp Ovulation Induction/ (14971) 2 (ovulat* adj2 induc*).tw. (8483) 3 (ovar* adj2 hyperstimulat*).tw. (5864) 4 (ovar* adj2 hyper stimulat*).tw. (139) 5 (ovar* adj2 stimulat*).tw. (8896) 6 exp Tamoxifen/ (22829) 7 exp Aromatase Inhibitors/ (10115) 8 letrozole.tw. (3858) 9 tamoxifen.tw. (25398) 10 exp In Vitro Oocyte Maturation Techniques/ (2074) 11 (in vitro maturation or IVM).tw. (6936) 12 or/1‐11 (73784) 13 (ovar* adj2 suppress*).tw. (2222) 14 (ovulat* adj2 suppress*).tw. (684) 15 endocrine therap*.tw. (10593) 16 gonadotropin‐releasing hormone/ or goserelin/ or leuprolide/ or triptorelin pamoate/ (33434) 17 gonadotrop?in releasing hormone agonist*.tw. (3372) 18 (GnRH a or GnRHa or GnRH agonist*).tw. (7367) 19 (goserelin or leuprolide or triptorelin).tw. (3842) 20 (lupron or Zoladex).tw. (575) 21 luteinizing hormone releasing hormone agonist*.tw. (636) 22 LHRH agonist*.tw. (1130) 23 (LHRH a or GnRH analog*).tw. (2915) 24 or/13‐23 (50904) 25 12 or 24 (114722) 26 exp Neoplasms/ (3902288) 27 neoplasm*.tw. (160001) 28 cancer*.tw. (2266452) 29 tumo?r*.tw. (2054106) 30 carcinoma*.tw. (773240) 31 or/26‐30 (5032884) 32 25 and 31 (47915) 33 Fertility Preservation/ (3959) 34 (fertility adj2 preserv*).tw. (7441) 35 (ovar* adj2 protect*).tw. (947) 36 (ovar* adj2 preserv*).tw. (1324) 37 (premenopaus* or young women).tw. (48693) 38 33 or 34 or 35 or 36 or 37 (57929) 39 32 and 38 (3511) 40 randomized controlled trial.pt. (603917) 41 controlled clinical trial.pt. (95471) 42 randomized.ab. (626047) 43 randomised.ab. (123365) 44 placebo.tw. (250091) 45 clinical trials as topic.sh. (201456) 46 randomly.ab. (421727) 47 trial.ti. (297888) 48 (crossover or cross‐over or cross over).tw. (100096) 49 or/40‐48 (1646766) 50 exp animals/ not humans.sh. (5173642) 51 49 not 50 (1517117) 52 39 and 51 (847)

Appendix 4. Embase search strategy

Searched from 1980 to 27 November 2023

Ovid platform

1 exp malignant neoplasm/ (4153622) 2 neoplasm*.tw. (208284) 3 tumo?r*.tw. (2696948) 4 cancer*.tw. (3142059) 5 carcinoma*.tw. (992822) 6 1 or 2 or 3 or 4 or 5 (5878984) 7 exp fertility preservation/ (7957) 8 (fertility adj2 preserv*).tw. (13064) 9 (ovar* adj2 protect*).tw. (1270) 10 (ovar* adj2 preserv*).tw. (2129) 11 (premenopaus* and ovar*).tw. (5419) 12 (premenopaus* and fertil*).tw. (1086) 13 (premenopaus* and ovulat*).tw. (546) 14 (premenopaus* and infertil*).tw. (564) 15 (premenopaus* and protect*).tw. (1817) 16 (premenopaus* and preserv*).tw. (948) 17 (young women and fertil*).tw. (3214) 18 (young women and ovar*).tw. (4369) 19 (young women and ovulat*).tw. (451) 20 (young women and infertil*).tw. (1192) 21 (young women and protect*).tw. (1727) 22 (young women and preserv*).tw. (2059) 23 or/7‐22 (31433) 24 6 and 23 (17004) 25 Clinical Trial/ (1063917) 26 Randomized Controlled Trial/ (786721) 27 exp randomization/ (98979) 28 Single Blind Procedure/ (52216) 29 Double Blind Procedure/ (209208) 30 Crossover Procedure/ (75679) 31 Placebo/ (390647) 32 Randomi?ed controlled trial$.tw. (329611) 33 Rct.tw. (54774) 34 random allocation.tw. (2566) 35 randomly.tw. (554768) 36 randomly allocated.tw. (45768) 37 allocated randomly.tw. (2954) 38 (allocated adj2 random).tw. (873) 39 Single blind$.tw. (31708) 40 Double blind$.tw. (239019) 41 ((treble or triple) adj blind$).tw. (1937) 42 placebo$.tw. (363821) 43 prospective study/ (890941) 44 or/25‐43 (3068167) 45 case study/ (97586) 46 case report.tw. (537391) 47 abstract report/ or letter/ (1257930) 48 or/45‐47 (1877546) 49 44 not 48 (3001695) 50 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6771470) 51 49 not 50 (2801391) 52 24 and 51 (2070)

Appendix 5. PsycINFO search strategy

Searched from 1806 to 27 November 2023

Ovid platform

1 exp Neoplasms/ (62519) 2 neoplasm*.tw. (2717) 3 cancer*.tw. (75005) 4 (carcinoma or tumo?r).tw. (17288) 5 1 or 2 or 3 or 4 (92901) 6 exp Fertility/ (3300) 7 (fertility adj2 preserv*).tw. (324) 8 (ovar* adj2 protect*).tw. (15) 9 (ovar* adj2 preserv*).tw. (13) 10 (fertil* adj2 protect*).tw. (12) 11 6 or 7 or 8 or 9 or 10 (3396) 12 5 and 11 (324) 13 random.tw. (70513) 14 control.tw. (513785) 15 double‐blind.tw. (25220) 16 clinical trials/ (12263) 17 placebo/ (6554) 18 exp Treatment/ (1333927) 19 or/13‐18 (1773206) 20 12 and 19 (187)

Appendix 6. Glossary

Amenorrhoea: the absence of a menstrual period in a women of reproductive age Aromatase enzyme: protein important for the synthesis of oestrogens Bias: a deviation from the expected value, bias refers to systematic error, meaning that multiple replications of the same study would reach the wrong answer on average Composite measure: measurement based on multiple data items Cox proportional hazards model: a regression model used for investigating the association between the survival time of patients and one or more predictor variables Cryopreservation: a process where cells or tissues are preserved by cooling to very low temperatures Granulosa cell: also called follicular cell, somatic, supportive cell of the sec cord that is closely associated with the developing female egg cell Hazard ratio: a measure of an effect of an intervention on an outcome of interest over time indicating the probability that an individual would experience an event at a particular given point in time after the intervention, assuming that this individual has survived to that particular point of time without experiencing any event Heterogeneity: the degree of uniformity Kaplan Meijer analyses: non‐parametric statistic used to estimate the survival function from lifetime data Log‐rank statistic: hypothesis test to compare the survival distribution of two samples Oocyte: immature female egg cell Ovarian failure: the loss of function of the ovaries Primordial follicle: first stage vesicle containing an immature egg cell and granulosa cells PRISMA flow chart: diagram that depicts the flow of information through the different phases of a systematic review RCT: randomised controlled trial, a form of scientific experiment used to control factors not under direct experimental control. Risk ratio: also called relative risk, the ratio of the probability of an event occuring in an exposed group to the probability of the event occuring in a comparison, non‐exposed group Sensitivity analysis: the study of how the uncertainty in the results can be apportioned to different sources of uncertainty in its input data Theca cells: group of endocrine cells in the ovary surrounding the follicle supporting the development of egg cells WHO: World Health Organisation, United Nations agency that connects nations, partners and people to promote health, keep the world safe and serve the vulnerable – so everyone, everywhere can attain the highest level of health

Data and analyses

Comparison 1. Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos in breast cancer patients.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Standard controlled ovarian hyperstimulation with gonadotropins versus controlled ovarian hyperstimulation with gonadotropins + letrozole: number of oocytes retrieved after ovarian stimulation	1	108	Mean Difference (IV, Fixed, 95% CI)	0.70 [‐2.60, 4.00]
1.2 Standard controlled ovarian hyperstimulation with gonadotropins versus controlled ovarian hyperstimulation with gonadotropins + tamoxifen: number of oocytes retrieved after ovarian stimulation	1	109	Mean Difference (IV, Fixed, 95% CI)	0.70 [‐3.05, 4.45]
1.3 Standard controlled ovarian hyperstimulation with gonadotropins + letrozole versus standard controlled ovarian hyperstimulation with gonadotropins + tamoxifen: number of oocytes retrieved after ovarian stimulation	2	203	Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐2.72, 2.64]

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Comparison 3. Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Ovarian insufficiency grouped by strict or broad definition	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1.1 Ovarian insufficiency, strict definition	5	811	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.31, 0.59]
3.1.2 Ovarian insufficiency, broad definition	7	713	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.45, 0.65]
3.2 Ovarian insufficiency grouped by receptor status	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.2.1 Ovarian insufficiency in hormone‐receptor‐positive patients	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.02, 1.37]
3.2.2 Ovarian insufficiency in hormone‐receptor‐negative patients	1	135	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.13, 0.90]
3.3 Live birth	3	599	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.89, 2.87]
3.4 Overall survival at 5 years	1		Hazard Ratio (IV, Fixed, 95% CI)	0.45 [0.21, 0.95]
3.5 Overall survival at 12 years	1		Hazard Ratio (IV, Fixed, 95% CI)	1.17 [0.67, 2.04]
3.6 Overall survival at 12 years grouped by receptor status	1		Hazard Ratio (IV, Fixed, 95% CI)	Subtotals only
3.6.1 Overall survival in hormone‐receptor‐positive patients	1		Hazard Ratio (IV, Fixed, 95% CI)	1.12 [0.59, 2.12]
3.6.2 Overall survival in hormone‐receptor‐negative patients	1		Hazard Ratio (IV, Fixed, 95% CI)	1.24 [0.41, 3.77]
3.7 Clinical pregnancy	6	933	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.01, 2.49]
3.8 Clinical pregnancy grouped by receptor status	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.8.1 Clinical pregnancy in hormone‐receptor‐positive patients	1	226	Risk Ratio (M‐H, Fixed, 95% CI)	5.59 [0.68, 45.69]
3.8.2 Clinical pregnancy in hormone‐receptor‐negative patients	4	429	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.90, 2.68]
3.9 Disease‐free survival at 5 years	1		Hazard Ratio (IV, Fixed, 95% CI)	0.72 [0.39, 1.32]
3.10 Disease‐free survival at 12 years	1		Hazard Ratio (IV, Fixed, 95% CI)	1.16 [0.76, 1.77]
3.11 Disease‐free survival grouped by receptor status	1		Hazard Ratio (IV, Fixed, 95% CI)	1.15 [0.75, 1.77]
3.11.1 Disease‐free survival in hormone‐receptor‐positive patients	1		Hazard Ratio (IV, Fixed, 95% CI)	1.02 [0.63, 1.64]
3.11.2 Disease‐free survival in hormone‐receptor‐negative patients	1		Hazard Ratio (IV, Fixed, 95% CI)	1.93 [0.73, 5.09]
3.12 Time‐to‐pregnancy	0		Hazard Ratio (IV, Fixed, 95% CI)	Not estimable
3.13 Pregnancy‐related adverse events	0		Other data	No numeric data
3.14 Number of oocytes retrieved after ovarian stimulation	0	0	Mean Difference (IV, Fixed, 95% CI)	Not estimable
3.15 Non‐pregnancy‐related adverse events	0		Other data	No numeric data

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3.12 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 12: Time‐to‐pregnancy

3.14 — Comparison 3: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients, Outcome 14: Number of oocytes retrieved after ovarian stimulation

Comparison 4. Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Ovarian insufficiency grouped by strict or broad definition	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1.1 Ovarian insufficiency, strict definition	1	23	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.83, 1.77]
4.1.2 Ovarian insufficiency, any definition	5	192	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [1.26, 1.84]
4.2 Live birth	1	23	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3 Overall survival	1		Hazard Ratio (IV, Fixed, 95% CI)	Not estimable
4.3.1 At 5 years	1		Hazard Ratio (IV, Fixed, 95% CI)	Not estimable
4.4 Clinical pregnancy	3	114	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.64, 1.70]
4.5 Clinical pregnancy grouped by age	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.5.1 Age < 35 years	1	14	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 7.02]
4.5.2 Age ≥ 35 years	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.72]
4.6 Disease‐free survival	1		Hazard Ratio (IV, Fixed, 95% CI)	Not estimable
4.6.1 At 5 years	1		Hazard Ratio (IV, Fixed, 95% CI)	Not estimable
4.7 Time‐to‐pregnancy	0		Hazard Ratio (IV, Fixed, 95% CI)	Not estimable
4.8 Pregnancy‐related adverse events	0		Other data	No numeric data
4.9 Number of oocytes retrieved after ovarian stimulation	0	0	Mean Difference (IV, Fixed, 95% CI)	Not estimable
4.10 Non‐pregnancy‐related adverse events	0		Other data	No numeric data

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4.7 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 7: Time‐to‐pregnancy

4.8. Analysis.

Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 8: Pregnancy‐related adverse events

Pregnancy‐related adverse events
Study	Ovarian suppression group	Control group

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4.9 — Comparison 4: Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in other cancer patients, Outcome 9: Number of oocytes retrieved after ovarian stimulation

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Balkenende 2019.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: yes. The study report states "we aim to prove a two‐sided difference of 4 oocytes with an alpha of 5% and a power of 90%. The sample size is calculated with STATA 14.2, for a two‐sample means test using Satterthwaite's t‐test assuming unequal variances. To compensate for 7% lost to follow‐up we aim to enrol 53 women in each group, i.e. 159 women in total." Blinding: no blinding
Participants	Setting: multicentre: 10 hospitals in the Netherlands and 1 in Belgium Number randomised: 162 Inclusion criteria: women between 18 and 43 years with breast cancer (hormone receptor positive, negative or unknown status), who opted for banking of oocytes or embryos in the course of fertility preservation as approved by referring breast cancer specialists and the fertility clinics the women were referred to Exclusion criteria: contraindication to use of study medication; if women use medication that opposes the effect of study medication, i.e. paroxetine Group differences: baseline characteristics showed a similar distribution amongst groups. Exclusions: not described
Interventions	Comparison: controlled ovarian hyperstimulation with gonadotropins (n = 55; 3 withdrawals) vs controlled ovarian hyperstimulation with gonadotropins and tamoxifen (n = 54; 2 withdrawals) vs controlled ovarian hyperstimulation with gonadotropins and letrozole (n = 53; 3 withdrawals) Controlled ovarian hyperstimulation with gonadotropins Duration of treatment: 1 IVF cycle Number randomised to group: 55  Age (mean, SD): 31.4 years (4.0)  Withdrawals: 3  Reason for withdrawals: 2 low response, 1 psychological issues  Timing of treatment: N/A  Duration of follow‐up: 1 IVF cycle for primary outcome, still ongoing for long‐term outcomes Controlled ovarian hyperstimulation with gonadotropins and tamoxifen Duration of treatment: 1 IVF cycle Number randomised to group: 54  Age (mean, SD): 31.8 years (4.4)  Withdrawals: 2  Reason for withdrawals: 1 low response, 1 did not pursue fertility preservation  Timing of treatment: on diagnosis of breast cancer  Duration of follow‐up: 1 IVF cycle for primary outcome, still ongoing for long‐term outcomes 60 mg tamoxifen (tablets with a dose of 10 to 30 mg) per day orally. Tamoxifen and rFSH are discontinued on the day of GnRH‐a trigger administration. Controlled ovarian hyperstimulation with gonadotropins and letrozole Duration of treatment: 1 IVF cycle Number randomised to group: 53  Age (mean, SD): 32.2 years (3.8)  Withdrawals: 3  Reason for withdrawals: 2 low response, 1 did not pursue fertility preservation  Timing of treatment: on diagnosis of breast cancer  Duration of follow‐up: 1 IVF cycle for primary outcome, still ongoing for long‐term outcomes Letrozole (tablets with a dose of 2.5 mg) 5 mg per day orally, starting on cycle day 2. Women are prescribed to use letrozole between 18.00 and 21.00. Letrozole and rFSH are discontinued on the day of GnRH‐a trigger administration. Women restart letrozole (5 mg per day) at the day of OPU to prevent a rebound increase in E2 levels, and stop after 3 days. Co‐interventions: "On cycle day 2, or the second day of interruption of the contraceptive pill, 225 IU/day rFSH (Follitropin, such as Puregon ®; Organon, Oss, the Netherlands, Gonal‐F ®; Merck Serono, Switserland, Bemfola ®Finox Biotech Benelux, or Ovaleap Teva Nederland) is used as gonadotrophin. On day 5 of rFSH, a GnRH antagonist (Ganirelix, such as Orgalutran® 0,25 mg; Organon, Oss, the Netherlands or Cetrotide® 0,25 mg, Merck‐Serono, Switzerland) is administered to prevent premature LH surge. Gonadotropins should always be administered in the evening (between 18:00 h and 21:00 h). When one follicle or more reaches 18–20 mm, oocyte maturation is triggered by GnRH‐a (Triptorelin, such as Decapeptyl ®, 0,2 mg; Ferring BV, Hoofddorp or Triptofem ®, 0,2 mg; Goodlife BV Lelystad). Gonadotrophins (r‐FSH) are discontinued on the day of the GnRH‐a trigger. GnRH antagonists are continued until the day of the GnRH‐a trigger. The GnRH antagonist injection needs to be given before the GnRH‐a trigger injection. Follicle aspiration is performed 34–36 h after ovulation trigger (see Fig. 1).  Oocytes are frozen in metaphase II or fertilized by ICSI with subsequent embryo banking. (protocol)"
Outcomes	Number of oocytes retrieved after ovarian stimulation Outcome definition: mean number of oocytes retrieved at follicle aspiration, defined as the number of metaphase II oocytes
Identification	Country: the Netherlands and Belgium  Setting: multicentre, 10 hospitals in the Netherlands and one in Belgium  Author's name: Dr EME Balkenende  Institution: Amsterdam University Medical Center  Email: e.m.balkenende@amc.nl  Address: Center for Reproductive Medicine, Amsterdam University Medical Center, 1100 DE Amsterdam, The Netherlands  Aim of study: to evaluate the effectiveness of ovarian stimulation with tamoxifen or letrozole compared to standard ovarian stimulation on the number of oocytes retrieved in women with breast cancer in the course of fertility preservation Possible conflicts of interest: "M.G., C.B.L. and R.S. declared that the Center for ReproductiveMedicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non‐financial support from Agendia, grants, non‐financial support and other from AstraZeneca, grants from Eurocept‐pharmaceuticals, grants and non‐financial support from Genentech/Roche, Novartis, grants from Pfizer, Tesaro, Immunomedics and other from Cergentis, IBM, Bayer, and Daiichi‐Sankyo, outside the submitted work; In addition, SCL has a patent UN23A01/P‐EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme(MSD). KF declared paid lectures for Ferring. DS reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work."  Start and end date: January 2014 to December 2018
Notes	Author contacted by email to confirm risk of bias and ask for raw data; no reply received Ethical approval: this study was approved by the Institutional Review Board (IRB) of the Academic Medical Centre in Amsterdam (MEC 2013_070) and by the board of directors of all participating centres. Study was conducted according to the guidelines for good clinical practice (GCP) as well as the Declaration of Helsinki.  Informed consent obtained: in women fulfilling the inclusion criteria, written informed consent was obtained before randomisation.  Sponsorship source: The Pink Ribbon Foundation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Women are randomised on‐line via a web‐based facility in a 1:1:1 ratio. They are stratified for oral anticonception use at start ovarian stimulation, for positive estrogen receptor status and positive lymph nodes. The allocated treatment, i.e. group 1 group 2 or group 3, appears directly online and an automatic email with allocation code is sent to the data manager." From the study protocol
Allocation concealment (selection bias)	Low risk	Quote: "Allocation concealment was ensured by the use of a web‐based randomization program, as the persons who registered participants for randomization could not see how many participants had already been randomized or what their allocation was."
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "162 women were randomized. Fifty‐four women were assigned to the ovarian stimulation plus tamoxifen arm, 53 women to the ovarian stimulation plus letrozole arm and 55 women to the standard ovarian stimulation arm. Of these, 154 had a follicle aspiration. All 162 women were included in the ITT analysis..."
Selective reporting (reporting bias)	Low risk	Quote: "When designing the trial in 2012, we primarily focused on the safety of controlled ovarian stimulation, with peak estradiol as a proxy for safety. Following new insights, after approval of all investigators and the Medical Ethical Committee, we changed our focus to effectiveness in March 2015, with number of cumulus oocytes retrieved as the ef‐ fectiveness outcome." Comment: all primary outcomes are reported as planned.
Other bias	Low risk	Comment: baseline characteristics equal

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Behringer 2010.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: "the hypothesis that GnRH‐a provide an at least 20% higher ovarian protection rate than oral contraceptive (OC) should be tested in a two‐stage sequential design with a global alpha error level of 0.05. After 2 x 30 participants, an interim analysis with Fisher’s exact test on FSH‐based ovarian protection rates was planned." Blinding: not described
Participants	Setting: Aurich; Bremen, Klinikum Bremen Mitteg GmbH; Emden, Hans‐Susem ihl‐Klinik; Oldenburg, Pius‐Hospital; Recklinghausen, Elisabeth Krankenhaus; Ulm, Department III of Internal Medicine, University hospital Ulm Number randomised: 23 Inclusion criteria: ‐ age 18 to 40 years ‐ biopsy‐proven HL at first diagnosis: advanced stages (clinical stage IIB with risk factor extranodal involvement or large mediastinal mass, all clinical stage III + IV)  ‐ adequate organ function  ‐ history of spontaneous menstrual cycle  ‐ no primary ovarian failure  ‐ FSH levels ≤ 30 U/l at baseline Exclusion criteria: not described
Interventions	Comparison: GnRHa (goserelin acetate) 3.8 mg (supplied by AstraZeneca) administered monthly, subcutaneously, during 8 cycles of BEACOPPesc (see explanation under type of chemotherapy) during 8 cycles of chemotherapy Ovarian suppression with GnRH agonists Number randomised to group: 11  Age (median): 25.26 years Withdrawals: 1  Reason for withdrawal: developed secondary acute myeloid leukaemia  Timing of treatment: the first GnRH‐a dose had to be administered 1 week before the onset of chemotherapy. Duration of follow‐up: the median observation time was 25.4 months after randomisation and 18.2 months after end of therapy (range 12.5 to 33.3 months). Co‐interventions: radiotherapy if not in complete remission after 8 cycles of chemotherapy Comparison:no treatment  Number randomised to group: 12  Age (median) : 25.95 years Withdrawals: 3  Reason for withdrawals: 1 secondary acute myeloid leukaemia, 2 AMH not available after 12 months due to loss to follow‐up  Timing of treatment: not described  Duration of follow‐up: the median observation time was 25.4 months after randomisation and 18.2 months after end of therapy (range 12.5 to 33.3 months). Co‐intervention: daily oral contraceptive (levonorgestrel 0.15 mg + ethinyl oestradiol 0.03 mg), radiotherapy if not in complete remission after 8 cycles of chemotherapy Group differences: the GnRH‐a group seems to have more severe participants (more stage IV, more extranodal disease, more participants with 3 or more lymph node areas involved). Type of chemotherapy: BEACOPPesc chemotherapy: escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone regimen.  Cumulative dose of alkylating agents in this regimen are 10.0 g/m² for cyclophosphamide and 5.6 g/m² for procarbazine.
Outcomes	Live birth (dichotomous outcome) reported as number of participants with event Premature ovarian insufficiency (dichotomous outcome) reported as number of participants with event Notes: not directly reported in the study, but amenorrhoea after 12 months and FSH‐levels are reported separately per participant, so it was possible to combine those data to 'form' our outcome. Outcome definitions: outcomes used included amenorrhoea and FSH‐level 6 and 12 months after end of therapy. Because the data are presented per participant, it is possible to combine these data to use them for the outcome 'ovarian failure' as defined in our study protocol.  "All remaining patients are in continuous first complete remission so far", therefore we can calculate disease‐free survival rates. Subgroups measured: not described  Subgroups reported: not described
Identification	Country: Germany  Author's name: Dr K Behringer  Institution: First Department of Internal Medicine, University Hospital Cologne  Email: karolin.behringer@uk‐koeln.de  Address: Kerpener Str. 62, 50924 Cologne, Germany  Aim of study: we initiated a prospective randomised study of hormonal co‐treatment with OC or GnRH‐a during intensive polychemotherapy consisting of 8 cycles of BEACOPPesc to protect the ovarian reserve in young Hodgkin Lymphoma patients. Possible conflicts of interest: none of the authors declare conflicts of interest.  Start and end date: 2004 to 2007
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: the study was carried out in accordance with the declaration of Helsinki and the International Conference on Harmonization‐guidelines for Good Clinical Practice (ICH‐GCP).  Informed consent obtained: written informed consent on the basis of the institutional review board guidelines had to be given for trial participation.  Sponsorship source: Deutsche Krebshilfe; Kompetenznetz; Maligne Lymphome
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: more lost to follow‐up in oral contraceptive group (2 versus 0). No statistical analysis reported
Selective reporting (reporting bias)	High risk	Quote: "...Primary end point was the protection of the ovarian reserve as determined by FSH levels. However, in the last years, anti‐Mullerian hormone (AMH) has been established as a cycle independent and much more valid indicator for the ovarian follicle reserve [20–29]. Thus, AMH levels (threshold 0.46 lg/l) after at least 12 months were used for this ﬁnal analysis to determine the primary objective." Comment: FSH at 12 months was primary outcome in protocol, but AMH reported.
Other bias	High risk	Quote: "Due to slow enrollment and upcoming concerns about their a priori assumptions, an unplanned interim analyses was carried out after recruitment of 23 patients. The study stopped after this analyses." The GnRH‐a group seems to have more severe patients.

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Demeestere 2016.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: "the original study design mandated the accrual of 157 participants to ensure a power of 80% and a type error I probability of 5%, on the basis of an assumed difference of a premature ovarian failure rate of 40%. After the first interim analysis, enrolment was discontinued after the random assignment of 129 patients, because the study was unlikely to meet the primary end point (similar POF rate in both groups)." Blinding: not described
Participants	Setting: 15 oncological centres in France, Belgium and Italy Number randomised: 129 Inclusion criteria: ‐ premenopausal women  ‐ aged between 18 to 45 years ‐ were being treated for Hodgkin or non‐Hodgkin lymphoma with alkylating agents (regimens consisted of 3 to 8 cycles of chemotherapy or high‐dose therapy with autologous stem‐cell transplantation as the first‐line consolidative treatment)  ‐ FSH < 15 IU/L at the time of random assignment Exclusion criteria: ‐ pelvic irradiation  ‐ history of amenorrhoea (3 months)  ‐ thromboembolic processes  ‐ severe hypertension  ‐ severe obesity  ‐ hepatic or renal insufficiency  ‐ contraindication of intramuscular injection  ‐ prior chemotherapy treatment  ‐ presence of ovarian abnormalities (other than functional cysts)  ‐ ovarian insufficiency defined as FSH 15 IU/L at the time of diagnosis  ‐ the receipt of fewer than 8 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine treatment Group differences: there were no significant differences in the baseline characteristics amongst the groups. There was no significant difference between groups concerning the type of chemotherapy regimens and the cumulative doses of alkylating agents.  Exclusions: 17  Reason for exclusions:  ‐ 11 did not give consent  ‐ 1 advanced age  ‐ 2 previously started chemotherapy  ‐ 1 refused chemotherapy  ‐ 2 low‐dose chemotherapy
Interventions	Ovarian suppression using GnRH agonists Intramuscular injection of 11.25 mg of triptorelin (Decapeptyl LP 11.25 mg; Ipsen Pharma, Merelbeke, Belgium) every 12 weeks in addition to norethisterone acetate at 5 mg once per day (Primolut‐Nor 5 mg; Bayer Schering Pharma, Antwerp, Belgium) Number randomised to group: 65  Age (mean, SEM): 25.84 years (1.00)  Withdrawals:  ‐ 20 at 1‐year follow‐up  ‐ 33 at final follow‐up  Reason for withdrawals:  ‐ 4 deaths  ‐ 1 chemotherapy > 9 months  ‐ 19 lost to follow‐up  ‐ 2 severe adverse events probably related to treatment  ‐ 3 relapse of disease  ‐ 4 non‐compliant/protocol violation  Timing of treatment: the first triptorelin injection occurred 2 ± 0.51 days before chemotherapy initiation in the GnRHa group (range 0 to 19). Duration of follow‐up (median): 5.33 years Comparison: no treatment; only norethisterone acetate at 5 mg once per day (Primolut‐Nor 5 mg; Bayer Schering Pharma, Antwerp, Belgium) No treatment Duration of treatment: during all chemotherapy  Number randomised to group: 64  Age (mean, SEM): 26.55 years (0.82)  Withdrawals:  ‐ 25 at 1‐year follow‐up  ‐ 29 at final follow‐up  Reason for withdrawals:  ‐ 2 deaths  ‐ 3 chemotherapy > 9 months  ‐ 13 lost to follow‐up  ‐ 6 relapse of disease  ‐ 5 non‐compliant/protocol violation  Timing of treatment: initiated 10 days before the start of chemotherapy if possible  Duration of follow‐up (median): 5.58 years Co‐interventions: the participants were allowed to take oral contraception or other hormonal replacement therapy during the follow‐up period. Type of chemotherapy: alkylating agents: regimens consisted of 3 to 8 cycles of chemotherapy or high‐dose therapy with autologous stem‐cell transplantation as the first‐line consolidative treatment.
Outcomes	Premature ovarian insufficiency, any definition, dichotomous outcome reported as number of participants with event Ovarian failure Live birth Overall survival Dichotomous outcome reported as hazard ratio (HR, CI, N, P value). There were 4 deaths reported in GnRHa group and 2 in control group, respectively. Clinical pregnancy 1 additional pregnancy after egg donation in a participant from the GnRHa group Disease‐free survival Dichotomous outcome reported as hazard ratio (HR, CI, N, P value). The overall disease‐free survival rates were 87.5% and 82% for participants in the control and GnRHa groups, respectively. Time‐to‐pregnancy Pregnancy‐related adverse events Non‐pregnancy‐related adverse events (other adverse events): sweating, hot flashes, vaginal dryness, headaches, vaginal bleeding, Severe adverse events Notes: 1 pulmonary thromboembolism, 1 erythema nodosum Outcome definitions Premature ovarian failure: at least one episode of FSH level ≥ 40 IU/L during long‐term follow‐up Disease‐free survival: participants without recurrence or death at the end of the follow‐up Adverse events: incidence of adverse events  Pregnancy: incidence of any pregnancies Subgroups measured: age, conditioning regimen for haematopoietic stem cell transplant, coadministration of GnRHa, type of disease and cumulative dose of cyclophosphamide ("not received cyclophosphamide of had received a cumulative doxe <5 g/m2 and patients who had received a cumulative dose of cyclophophamide ≥ 5 g/m2").  Subgroups reported: age, type of disease, cumulative dose of cyclophosphamide, coadministration of GnRHa
Identification	Country: France, Belgium and Italy  Setting: 15 oncological centres  Author's name: Isabelle Demeestere  Institution: Research Laboratory on Human Reproduction, Campus Erasme  Email: idemeest@ulb.ac.be Address: 808 Route de Lennik, 1070 Brussels, Belgium  Aim of study: to assess the efficacy of gonadotropin‐releasing hormone agonist (GnRHa) in preventing chemotherapy‐induced ovarian failure in patients treated for Hodgkin or non‐Hodgkin lymphoma within the setting of a multicentre, randomised, prospective trial Possible conflicts of interest: I Demeestere, P Brice, FA Peccatori, P Zachee, E van den Neste, J Dechene, V De Maertelaer: no relationship to disclosure  A Kentos: consulting role at Novartis, Roche, Bristol‐Myers Squibb, Celgene, Amgen, Janssen‐Cilag  J Dupuis: consulting role at Abbvie  O Casasnovas: honoraria Genentech, Takeda, Gilead Sciences, Sanofi  D Bron: research funding Celgne, Janssen Pharmaceuticals, Gilead Sciences  Y Englert: research funding Merck Serone, Ferring Pharmaceuticals  Start and end date: July 2002 to April 2010
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval obtained for study: ethical committee approval was obtained for each of the participating centres according to national obligation.  Informed consent obtained: written informed consent was obtained from all participants.  Sponsorship source: The Fonds National de la Recherche Scientifique (FNRS‐Televie) and an unconditional grant from the Ipsen Pharmaceutical Group. Triptorelin was provided by the Ipsen Pharmaceutical Group.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A random allocation sequence was generated using simple random assignment to produce equally sized groups." Comment: Author confirmed sequence generation by random number table.
Allocation concealment (selection bias)	Low risk	Quote: "Allocation concealment was implemented using central telephone or fax systems (Research Laboratory for Human Reproduction)."
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: "Loss to follow‐up balanced between groups, but in both groups >50%. Per‐protocol analyses used."
Selective reporting (reporting bias)	Low risk	Comment: all predefined outcome measures and subgroups are reported.
Other bias	High risk	Comment: baseline characteristics are comparable between groups with respect to age and chemotherapy regimen. However, 55% in GnRHa group versus 41% in control group used oral contraceptives. We think this difference is too big and can cause bias, especially in fertility‐related outcome measures.

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Elgindy 2013.

*Study characteristics*
Methods	Design: parallel‐group 4‐arm RCT Randomisation method: computer randomisation Power calculation: "Previous data indicated that the rate of resumption of menstruation among control group individuals is 35%. If resumption rate for experimental participants is assumed to be 80%, using a continuity‐corrected x2statistic to evaluate this null hypothesis we needed to recruit 22 women in each study arm to be able to reject the null hypothesis that the failure rates are equal with a probability (power) of 0.8 and a type I error probability of 0.05 using the x2 statistic. Because this trial was stratified according to planned time of starting chemotherapy, we intended on enrolling 25 women in each arm to allow for loss to follow‐up and further comparisons within the strata." Blinding: not described
Participants	Setting: 2 university‐affliated oncology centres in Egypt Number randomised: 100 Inclusion criteria: ‐ women 18 to 40 years old  ‐ having primary hormone‐insensitive breast cancer  ‐ scheduled for cyclophosphamide‐based chemotherapy  ‐ history of regular menstrual periods  ‐ transvaginal ultrasound‐confirmed presence of both ovaries  ‐ absence of ovarian tumours or cysts larger than 4 mm Exclusion criteria: ‐ advanced breast cancer (stage IIIb to IV)  ‐ primary ovarian cancer or pelvic metastases  ‐ history of chemotherapy or abdominal or pelvic radiation  ‐ receiving or planning to receive hormone therapy  ‐ pregnant and nursing women Group differences: baseline characteristics were comparable between each intervention group and its respective control individuals.  Exclusions: 76  Reasons for exclusions: 68 did not meet inclusion criteria; 8 declined to participate.
Interventions	4 groups: ovarian suppression using GnRH agonists; ovarian suppression using GnRH agonists + antagonists; no treatment (early chemotherapy); no treatment (delayed chemotherapy) Comparison 1: ovarian suppression using GnRH agonists versus no treatment (early chemotherapy) No treatment (early chemotherapy) Number randomised to group: 25  Age (mean, SD): 32.32 years (± 3.99)  Withdrawals: 2 after 12 months, 8 after 18 months  Reason for withdrawals: 1 death, 1 pregnancy, 1 recurrence, 5 lost to follow‐up  Timing of treatment: chemotherapy at least 10 days after study inclusion  Duration of follow‐up: 18 months Ovarian suppression using GnRH agonists Description: chemotherapy after downregulation with GnRH agonist, which was continued every 4 weeks until the end of chemotherapy Duration of treatment: until the end of chemotherapy Number randomised to group: 25 Age (mean, SD): 33 years (± 3.8)  Withdrawals: 2 after 12 months, 8 after 18 months Reason for withdrawals: 1 death, 1 recurrence, 6 lost to follow‐up Timing of treatment: prior to chemotherapy Duration of follow‐up: 18 months Co‐interventions: regional adjuvant radiotherapy was permitted if indicated by the managing oncologist. Comparison 2: ovarian suppression using GnRH agonists + antagonists versus no treatment (delayed chemotherapy) No treatment (delayed chemotherapy) Chemotherapy after downregulation with GnRH agonist, which was continued every 4 weeks until the end of chemotherapy.  Duration of treatment: until the end of chemotherapy  Number randomised to group: 25 Age (mean, SD): 32.84 years (± 4.3)  Withdrawals: 2 after 12 months, 8 after 18 months Reason for withdrawals: 1 death, 1 pregnancy, 1 recurrence, 5 lost to follow‐up Timing of treatment: chemotherapy at least 10 days after study inclusion Duration of follow‐up: 18 months Ovarian suppression using GnRH agonists + antagonists Cetrorelix 0.25 mg daily and triptorelin 3.75mg until downregulation (E2 less than 50 pg/mL) was confirmed. Then, women were instructed to discontinue the GnRH antagonist and to continue using the GnRH agonist every 4 weeks until the end of chemotherapy.  Duration of treatment: cetrorelix until downregulation and triptorelin until end of chemotherapy  Number randomised to group: 25 Age (mean, SD): 33.28 years (± 3.3)  Withdrawals: 2 after 12 months, 8 after 18 months Reason for withdrawals: 2 deaths, 1 pregnancy, 5 lost to follow‐up Timing of treatment: prior to commencing chemotherapy Duration of follow‐up: 18 months Co‐interventions: regional adjuvant radiotherapy was permitted if indicated by the managing oncologist. Type of chemotherapy: the standard regimen of intravenous 5‐flourouracil (500/m²), adriamycin (50 mg/m²), and cyclophosphamide (500 mg/m²) every 21 days for 6 cycles, in the absence of disease progression or toxicity, was used in all participants.
Outcomes	Clinical pregnancy Premature ovarian insufficiency, any definition Notes: defined as resumed menses after 6 months. Outcome reversed (participants who did not reach the above definition) to obtain a value for premature ovarian insufficiency. Live birth Adverse events: assessed clinically and by means of haematological and biochemical measurements
Identification	Author's name: Eman A Elgindy  Institution: Department of Obstetrics andGynecology, Zagazig University School of Medicine  Email: eman_elgindy2013@hotmail.com  Address: Zagazig, Egypt  Aim of study: to estimate the effectiveness of gonadotropin‐releasing hormone (GnRH) analogues co‐treatment in preventing chemotherapy‐induced amenorrhoea in young breast cancer patients undergoing cyclophosphamide‐based chemotherapy.  Possible conflicts of interest: the authors did not report any potential conflicts of interest.  Start and end date: December 2009 to August 2011
Notes	This study has 4 arms. In all analyses, no treatment (early chemotherapy) was compared to ovarian suppression using GnRH agonists and no treatment (delayed chemotherapy) was compared to ovarian suppression using GnRH agonists + antagonists. Author contacted by email to confirm risk of bias and ask for raw data. No reply received. Ethical approval: Institutional Review Board was obtained.  Informed consent: all participants provided written informed consent.  Sponsorship source: The School of Medicine Zagazig University and the Alexandria Regional Centre for Women’s Health
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants were randomized in a 1:1 ratio using a computer‐generated block randomization scheme with variable block sizes (range from four to eight participants per block) and stratification for the timing of the first cycle of chemotherapy. The randomization list was produced by a statistician not involved with patient recruitment."
Allocation concealment (selection bias)	Low risk	Quote: "Allocation concealment was achieved with sequentially numbered, dark, opaque, sealed envelopes."
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "statistical analysis was performed according to the intention‐to‐treat principle." Comment: low number of withdrawals, balanced in all groups, with the same reasons. ITT analysis used
Selective reporting (reporting bias)	Low risk	Comment: all predefined outcomes are reported.
Other bias	High risk	Quote: "Opting for the type of cotreatment was based on available timeframe until start of chemotherapy." Comment: not truly randomised into late vs early chemotherapy (and therefore GnRH antagonist +agonist vs GnRH agonist and controls)

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Falkson 1991.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: not described Power calculation: not described Blinding: not described
Participants	Setting: single hospital in South Africa Number randomised: 66 Inclusion criteria: ‐ premenopausal women  ‐ having histologically confirmed breast cancer  ‐ receiving chemotherapy Exclusion criteria: not described Group differences: there were no significant differences between baseline values of E2, FSH and LH in the 4 groups of participants.  19 participants (11 in control group, 8 in buserelin group) had a hysterectomy.
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment (chemotherapy alone) No treatment (chemotherapy alone) Number randomised to chemotherapy alone: 32  Age (median, range): 42 years (32 to 50)  Withdrawals: 0 after 1 month, 9 after 6 months, 16 after 9 months, 19 after 12 months, 24 after 18 months, 25 after 24 months  Reason for withdrawals: not described  Duration of follow‐up: not described. 24 months presented in table Ovarian suppression using GnRH agonists Monthly depot buserelin as a 6.6 mg subcutaneous implant continuously for 5 years Number randomised to chemotherapy + GnRHa group: 34  Age (median, range): 40 years (30 to 53)  Withdrawals: 0 after 1 month, 5 after 6 months, 10 after 9 months, 16 after 12 months, 19 after 18 months, 21 after 24 months  Reason for withdrawals: not described  Duration of follow‐up: not described. 24 months presented in table Co‐interventions: chemotherapy Type of chemotherapy: CMF (cyclophosphamide 100 mg/m² orally per day on days 1 to 14, methotrexate 40 mg/m² intravenously on days 1 and 8, 5‐fluorouracil 600 mg/m² intravenously on days 1 and 8 every 28 days) given for 6 cycles
Outcomes	Serial determinations of E2, LH and FSH Outcome definitions: not described This study published the outcomes of several hypotheses in one article. All hypotheses were clearly separated, which is why it was possible to use only the eligible data for this review.
Identification	Country: South Africa  Setting: not described  Comments: none  Author's name: CI Falkson  Institution: University of Pretoria  Email: not described  Address: Department of Medical Oncology, Private Bag X 169, Pretoria 0001, South Africa  Aim of study: to assess the effect of chemotherapy with or without buserelin on ovarian function of premenopausal women with breast cancer Possible conflicts of interest: not described  Start and end date: not described
Notes	Author contacted by letter to confirm risk of bias and ask for raw data. No reply received Ethical approval: not described  Informed consent obtained: not described  Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: does not describe which analysis was used. High amount of loss to follow‐up. Reasons for loss to follow‐up not described
Selective reporting (reporting bias)	Unclear risk	Comment: no protocol available; outcome measures not clearly described
Other bias	High risk	Comment: sponsorship source unknown. No information available about informed consent, ethical approval, setting and start/end date. Trial not registered in a clinical trial register

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Gerber 2011.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: "sample size was determined based on the assumption that the number of patients with intact ovarian function 6 months after anthracycline‐based chemotherapy could be improved by 30%, from 50% without goserelin to 80% with goserelin. The error rate for a false positive was set at 5% using a one‐sided test. The false negative rate was set at 20% (ie, power of trial was 80% for difference of clinical interest). A total of 62 patients (31 in control arm and 31 with proven ovarian suppression in goserelin arm) were required, as calculated using nQuery Advisor." Blinding: not blinded
Participants	Setting: 16 centres in Germany Number randomised: 61 Inclusion criteria: ‐ premenopausal women  ‐ primary hormone‐insensitive breast cancer  ‐ undergoing anthracycline/cyclophosphamide (with or without taxane)‐based neoadjuvant chemotherapy  ‐ between the ages of 18 and 45  ‐ requested preservation of ovarian function  ‐ regular and spontaneous menstrual periods before study entry  ‐ FSH below 15 m lU/mL Exclusion criteria: ‐ treatment with sex hormones  ‐ known hypersensitivity reaction to the investigational compounds  ‐ prior cytotoxic treatment for any reason  ‐ distant metastases  ‐ if primary or secondary ovarian insufficiency was suspected Group differences: the baseline characteristics were comparable between the two arms. Participants in the group with goserelin tended to be younger than those in the group without goserelin (35 vs 38.5 years; P = 0.092).
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Co‐interventions: chemotherapy Ovarian suppression using GnRH agonists Number randomised to GnRHa group: 30 Age (median, range): 35 years (26 to 44)  First injection of 3.6 mg at least 2 weeks before start of chemotherapy, independently of the day of menstrual cycle, and then every 4 weeks (28 ± 3 days) until the end of the last chemotherapy cycle. Before the first administration of chemotherapy, ovarian suppression had to be proven.  Duration of treatment: every 4 weeks (28.3 days) until the end of the last chemotherapy cycle Withdrawals: 2  Reason for withdrawals: 1 adverse events, 1 disease progression  Timing of treatment: at least 2 weeks before start of chemotherapy, independent of the day of menstrual cycle Duration of follow‐up: 2 years No treatment  Number randomised to no treatment group: 31  Age (median, range): 38.5 years (29 to 47)  Withdrawals: 3  Reason for withdrawals: 1 withdrawal of consent after random assignment, 1 adverse events, 1 patient wish  Timing of treatment: N/A  Duration of follow‐up: 2 years Type of chemotherapy: a modern chemotherapy regimen, including at least anthracycline and cyclophosphamide with more than 500 mg/m2 per cycle and more than 2,400 mg/m2 in total per regimen, administered every 3 weeks for 6 or 8 cycles.
Outcomes	Clinical pregnancy Premature ovarian insufficiency, any definition Defined as: 2 consecutive menstrual periods within 21 to 35 days in a timeframe of 5 to 8 months after last administration of goserelin. Outcome reversed (participants who did not reach the above definition) to obtain a value for premature ovarian insufficiency. Time‐to‐pregnancy. pregnancies occurred 8 and 12 months after end of chemotherapy/LH‐releasing hormone agonist Pregnancy‐related adverse events: induced abortion Notes: the woman in the group without goserelin had an abortion during the first trimester, while receiving trastuzumab. Outcome definitions: 2 consecutive menstrual periods within 21 to 35 days in a timeframe of 5 to 8 months after last administration of goserelin
Identification	Author's name: Sibylle Loibl  Institution: German Breast Group, GBG Forschungs GmbH  Email: sibylle.loibl@germanbreastgroup.de  Address: Martin‐Behaim‐Str.12, 63263 Neu‐Isenburg, Germany  Aim of study: to investigate using a randomised controlled design, the preventive effect of the LHRHa goserelin on chemotherapy‐induced ovarian failure in young patients with hormone‐insensitive breast cancer treated with anthracycline/cyclophosphamide (with or without taxane) – based neoadjuvant chemotherapy.  Possible conflicts of interest: employment or leadership position: no consultant or advisory role: none; no stock ownership; no honoraria: Bernd Gerber, Astra Zeneca, Roche, Sanofi‐aventis, Novartis, Glaxo Smith Kline; Olaf Ortmann, Novartis, Pfizer, AstraZeneca; Tanja Fehm, Roche, Novartis Research Funding: Bernd Gerber, Novartis; Gunter von Minckwitz, AstraZeneca; Tanja Fehm, Novartis; expert testimony: none; other remuneration: none Start and end date: March 2005 to December 2007
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval: the study was approved by the ethics' committees.  Informed consent: all participants gave written informed consent.  Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: withdrawals low and balanced between groups. Reasons described. Numbers also balanced between groups
Selective reporting (reporting bias)	Low risk	Comment: protocol available; all predefined outcome measures are reported.
Other bias	High risk	Quote: "There are two clinically relevant confounding factors in our trial. First, the patients in the goserelin group tended to be younger than those in the group without goserelin, because we did not stratify for age, and second, the number of applied chemotherapy cycles was lower in the group with goserelin compared with that in the group without. Therefore, it can be hypothesized that the menstruation rate in the goserelin group could be even lower." Comment: baseline characteristics are not totally comparable in both groups.

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Gilani 2007.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not described Blinding: not blinded
Participants	Setting: 2 medical university centres in Iran Number randomised: 30 Inclusion criteria:  ‐ post‐menarchal women aged 12 to 40 years with history of normal menstrual rhythm  ‐ patients who had one or two ovaries and normal laboratory tests (FSH, LH, oestradiol) after surgery  ‐ alkylating or alkylating‐like MCT  ‐ different histological ovarian tumours and any radiologically stage Exclusion criteria: ‐ patients whose parents refused to allow them to be included in the study protocol  ‐ patients who died during the treatment  ‐ incomplete protocols  ‐ patients who were younger than 12 or older than 40 years  ‐ patients who had received radiotherapy  ‐ patients who had received more than 6 months of chemotherapy  ‐ single agent chemotherapy or‐non‐alkylating or alkylating‐like MCT Group differences: there were no significant differences between the two groups with respect to the stage and histopathological type of tumour, the course and the type of chemotherapy, and the age of the participants in each group.
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment (chemotherapy alone) Ovarian suppression using GnRH agonists Diphereline, intramuscular depot injection of 3.75 mg administered prior to chemotherapy. Ideally, the analogue should be administered on day 24 or 25 of the cycle to interrupt follicular growth for the next cycle without altering present menstruation. Because of the urgency of treating these patients, however, the chemotherapy was started as soon as possible, independent of the day of the cycle and usually leaving only a 7 to 10 day margin. The GnRH agonist was administered every 28 days.  Duration of treatment: medication was discontinued after chemotherapy. Number randomised to group: 15  Age (median, range): 21 years (13 to 33)  Withdrawals: 0  Timing of treatment: prior to chemotherapy  Duration of follow‐up: 6 months Co‐interventions: chemotherapy No treatment Number randomised to group: 15  Age (median, range): 22 years (15 to 35)  Withdrawals: 0  Reason for withdrawals: N/A  Timing of treatment: N/A  Duration of follow‐up: 6 months Co‐interventions: chemotherapy Type of chemotherapy: alkylating or alkylating‐like MCT. The participants received BEP (bleomycin, etoposide, cisplation), TC (Taxol, carboplatin), TP (Taxol, cisplatinum), VAC (vincristin, actinomycin, cyclophosphamide).
Outcomes	Premature ovarian insufficiency, any definition Outcome definitions: premature ovarian failure: the early, permanent cessation of menstruation after 6 months of chemotherapy and a serum FSH level > 20 milli‐international units per milliliter (mIU/mL)
Identification	Country: Iran  Setting: 2 medical university centres (Mashhad and Tehran)  Author's name: Mitra Modares Gilani  Institution: Reproductive Health Research Center, Tehran University of Medical Sciences  Email: Assistant Professor Malihe Hasanzadeh, Research Deputy: malhasanzadeh@yahoo.com  Address: Vali‐e‐Asr, Tehran, Iran Aim of study: to demonstrate the effect of a GnRH analogue as a protecting agent for ovarian function during chemotherapy  Possible conflicts of interest: not described  Start and end date: not described
Notes	Author contacted by email, address not found. No other mail address known Ethical approval: not described  Informed consent: informed consent was obtained from participants. Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to have been influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no loss to follow‐up in either group
Selective reporting (reporting bias)	Low risk	Comment: all prespecified outcomes were reported.
Other bias	Unclear risk	Comment: small numbers and no power calculation, but the baseline characteristics are comparable between groups.

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Giuseppe 2007.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not described Blinding: not described
Participants	Setting: single centre in Italy Number randomised: 29 Inclusion criteria: ‐ women  ‐ aged between 20 and 38 years old  ‐ affected by Hodgkin's disease  ‐ treated with chemotherapy Exclusion criteria: not described Group differences: baseline characteristics are comparable between both groups. Time from chemotherapy to outcomes is higher in not GnRH‐a group compared to GnRH group (5.93 vs 2.42, respectively, P = 0.0541)
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Co‐interventions: supradiaphragmatic radiotherapy, if indicated, for a total dosate of 2900 to 6300 Gray Ovarian suppression using GnRH agonists Monthly (Triptorelin 3.25mg) or depot (Triptorelin 11.25 mg) was administered every 3 months intramuscular, for the duration of chemotherapy, starting immediately after the disease was diagnosed.  Duration of treatment: for the duration of chemotherapy  Number randomised to group: 14  Age (mean, SD): 24.3 years ± 5.3  Withdrawals: not described  Timing of treatment: started immediately after the disease was diagnosed  Duration of follow‐up: 2.42 ± 1.7 years No treatment  Duration of treatment: N/A  Co‐interventions: supradiaphragmatic radiotherapy, if indicated, for a total dosate of 2900 to 6300 Gy  Number randomised to group: 15  Age (mean, SD): 24.26 years ± 7.92  Withdrawals: not described  Reason withdrawals: N/A  Timing of treatment: N/A  Duration of follow‐up: 5.93 (± 4.47) Type of chemotherapy:  "13 participants: 6 courses ABVD regimen (adriamicin, bleomicin, vinblastine, dacarbazine)  13 participants: 6 courses ABVD regimen alternating with C(M)OPP (endoxan, vincristine, procarbazine, prednisone)  3 participants: C(M)OPP 6 courses alternating with ABV (adriamicin, bleomicin, vinblastine), later four courses of DHAP (cisplatinum, cytarabine, dexamethasone)"
Outcomes	Premature ovarian insufficiency, any definition Notes: defined as amenorrhoea Clinical pregnancy Outcome definitions: amenorrhoea, pregnancy, hormonal markers of ovarian reserve Subgroups measured and reported:  Age: 36  Post‐chemotherapy menstrual history: menstrual cycle present (normal or oligomenorrhoic), amenorrhoic  Distance in years from the end of chemotherapy: 4 years or less, more than 4 years
Identification	Country: Italy  Setting: single centre: Haematology, University of Bari  Author's name: G Loverro  Institution: Department of Obstetrics and Gynaecology, Policlinico, University of Bari  Email: g.loverro@gynecology3.uniba.it  Address: Piazza G. Cesare 11, 70124 Bari, Italy  Aim of study: evaluate the best method to assess the ovarian reserve and the ovarian protective effect of GnRH‐analog (GnRH‐a), in 29 women with HD treated with chemotherapy Possible conflicts of interest: not described  Start and end date: 1996 to 2002
Notes	Author contacted by email, address not found. No other mailing address known. Ethical approval: this study has been carried out in accordance with the ethical standards of the responsible committee on human experimentation and the Helsinki Declaration of 1975.  Informed consent: informed consent obtained from the participants.  Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: withdrawals not described
Selective reporting (reporting bias)	Low risk	Comment: protocol is not available. All outcomes predefined in methods section are reported.
Other bias	High risk	Quote: "Before starting CHT, all patients were randomly assigned to receive GnRH‐analog (GnRH‐a) as co‐treatment or not." Quote: "In the present observational study," Outcomes were measured at different points following treatment (distance in years from CHT in GnRHa group 2.42 ± 1.7 and in not GnRHa group 5.93 ± 4.47)".

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Ismail‐Khan 2008.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not stated Blinding: not described
Participants	Setting: not described Number randomised: 49: age (median, range): 39 years (21 to 43) Inclusion criteria: ‐ premenopausal women with breast cancer (type unspecified) ‐ age less than 44 years ‐ FSH39  ‐ ER status  ‐ treatment type Exclusion criteria: not described  Subgroups reported: age
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment GnRHa and no treatment Duration of treatment: not described  Number randomised to each group: not described  Withdrawals: 5 after 6 months, 7 after 12 months, 15 after 18 months (from which group is not described)  Reason for withdrawals: not described  Timing of treatment: not described  Duration of follow‐up: not described Co‐interventions: (neo)adjuvant chemotherapy, not defined
Outcomes	Resumed menses Inhibin B and FSH levels Pregnancy Outcome definitions: not described
Identification	Country: not described  Setting: not described  Comments: only conference abstract available. No clinical trial registration either.  Author's name: R Ismail‐Khan  Institution: Moffitt Cancer Center  Email: Roohi.Ismail‐Khan@moffitt.org  Address: 12902 Magnolia Drive, Tampa, FL 33612 Aim of study: to evaluate the benefit of GnRH use during chemotherapy Possible conflicts of interest: no significant financial relationships to disclose Start and end date: not described
Notes	Author contacted by email, address not found. No other mailing address known Ethical approval needed/obtained for study: not described  Informed consent obtained: not described  Funding: not described Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: binding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: binding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: binding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: binding not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: not enough information available to judge. (withdrawals are presented but only as total numbers (not per intervention group) and without reasons).
Selective reporting (reporting bias)	High risk	Comment: incomplete presentation of outcomes
Other bias	High risk	Comment: "The study was stopped before reaching all endpoints because the differences seen that far were not statistically significant."

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Karimi‐Zarchi 2017.

*Study characteristics*
Methods	Design: parallel group RCT Randomisation method: computer randomisation Power calculation: not described Blinding: not described
Participants	Setting: single institution in Iran Number randomised: 42: age (mean, SD): 37 years (5) Inclusion criteria: ‐ primary Stage to Stage II (T2N/M0) adenocarcinoma  ‐ age ranging from 25 to 45 years  ‐ negative ER/PR  ‐ candidate for cyclophosphamide(600 mg/m2), adriamycin (60 mg/m2), and taxoter (75 mg/m2) chemotherapy regimen Exclusion criteria: ‐ advanced stages of the cancer  ‐ low complaint cases in receiving diphereline monthly  ‐ positive ER/PR  ‐ concurrent malignancies  ‐ FSH ≥ 30 at admission Group differences: not described Participants: hormone negative breast cancer, early stage Subgroups measured: age: 35 or younger, older than 35  Subgroups reported: age: 35 or younger, older than 35
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists 3.75 mg/IM diphereline every 28 days for six months Duration of treatment: 6 months  Number randomised to GnRHa group: 21  Withdrawals: 0  No treatment  Number randomised to no treatment group: 21  Withdrawals: 0  Duration of follow‐up: 6 months after chemotherapy Co‐interventions: chemotherapy Type of chemotherapy: cyclophosphamide (600 mg/m2), adriamycin (60 mg/m2), and taxoter (75 mg/m2) chemotherapy regimens
Outcomes	Premature ovarian insufficiency, any definition
Identification	Country: Iran  Setting: Shahid Sadoughi Hospital  Author's name: M Karimi‐Zarchi  Institution: Shahid Sadoughi University of Medical Science, Gynecology Oncology Department  Email: drkarimi2001@yahoo.com  Address: Shahid Ghandi BLV, Yazd 14194, Iran  Aim of study: to evaluate the effect of GnRH agonist on menstrual reverse in breast cancer cases treated with cyclophosphamide regimen Possible conflicts of interest: not described  Start and end date: 2010 to 2011
Notes	Author contacted by email to confirm risk of bias and ask for raw data, no reply Ethical approval: not described  Informed consent: not described Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no withdrawals, appears to be complete
Selective reporting (reporting bias)	Low risk	Comment: all prespecified outcome measures are reported.
Other bias	High risk	Comment: there is no information available about funding sources, prior registration of the trial, conflicts of interest, informed consent and ethical approval, which makes us suspect that this trial may have other bias.

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Lambertini 2022.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enroled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin, with a power of 90% and a 2‐sided α error of 5%. Blinding: no blinding
Participants	Setting: 16 Italian hospitals Number randomised: 281: age (median, range): 39 years (24 to 45) Inclusion criteria: ‐ women aged 18 to 45 years  ‐ stage I to III breast cancer (either hormone receptor‐positive or hormone receptor‐negative tumours)  ‐ premenopausal at the time of diagnosis, early stage ‐ be candidates for adjuvant or neoadjuvant chemotherapy Exclusion criteria: ‐ previous chemotherapy, radiotherapy, or for both cancer or non‐neoplastic diseases  ‐ evidence of distant metastases  ‐ other malignancies in the previous 5 years, except basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix  ‐ pregnancy or lactation Group differences: baseline patient and tumour characteristics were similar between treatment groups, as well as chemotherapy adherence.
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Triptorelin (3.75 mg) administered intramuscularly at least 1 week before chemotherapy and then every 4 weeks for the duration of chemotherapy, last dose was given before the last cycle of chemotherapy Duration of treatment: for the duration of chemotherapy  Number randomised to GnRHa group: 148  Withdrawals: 47  Reason for withdrawals: 29 disease progression, 18 lost to follow‐up (participants without clinical information after 31 December 2012)  Timing of treatment: at least 1 week before chemotherapy No treatment  Number randomised to no treatment group: 133  Withdrawals: 53  Reason for withdrawals: 36 disease progression, 17 lost to follow‐up (participants without clinical information after 31 December 2012) Co‐interventions: women with hormone receptor–positive disease received adjuvant endocrine therapy (20 mg/d of tamoxifen) for 5 years starting from the end of chemotherapy. In both study groups, participants who resumed their ovarian function during the 12‐month period of observation after the end of chemotherapy or at any time during the following 5 years of follow‐up were allowed to receive LHRHa (3.75 mg of triptorelin every 4 weeks) for at least 2 years as part of their endocrine treatment. Radiation therapy after completion of chemotherapy was mandatory for participants who underwent a lumpectomy. For participants who underwent a mastectomy, radiation therapy was performed according to the guidelines of each participating institution.  Duration of follow‐up: at the study cutoff date (31 December 2013), median follow‐up time overall was 7.3 years (interquartile range 6.3 to 8.2 years) Type of chemotherapy: "anthracycline plus taxane‐based (control group 62; GnRH‐a group 86), anthracycline‐based (control group 57; GnRH‐a group 56), or CMF (100 mg/m2 of oral cyclophosphamide on days 1 to 14 or 600 mg/m2 of intravenous cyclophosphamide on days 1 and 8; 40 mg/m2 of methotrexate on days 1 and 8; and 600 mg/m2 of fluorouracil on days 1 and 8)‐based (control group 8; GnRH‐a group 4)"
Outcomes	Premature ovarian insufficiency  Pregnancy‐related adverse events  Disease‐free survival, subgroup hormone‐receptor positive participants  Disease‐free survival, hormone‐receptor negative participants  Overall survival, hormone‐receptor positive participants  Overall survival, hormone‐receptor negative participants  Time‐to‐pregnancy  Notes: the interval from random assignment to first pregnancy ranged between 1.0 and 10.2 years, being 6.2 to 10.2 years and 1.0 to 6.5 years amongst women with hormone‐receptor positive and negative disease, respectively.  Clinical pregnancy  Live birth  Clinical pregnancy, hormone‐receptor positive participants  Clinical pregnancy, hormone‐receptor negative participants Subgroups measured and reported: hormone‐receptor positive vs hormone‐receptor negative, type of chemotherapy, timing of chemotherapy, stage of breast cancer, age Some of the outcome definitions were further specified as below.  Pregnancy: participants reporting no pregnancy were asked about the reasons (e.g. pregnancy not desired or failed attempt). Participants who reported at‐term or preterm delivery, miscarriage, and/or induced abortion were considered as having a pregnancy.  Overall survival (OS): death from any cause was the definition of an OS event.  Post‐treatment pregnancies; any of the following: at term or preterm delivery, miscarriage, and/or induced abortion. Pregnancy desire was not an inclusion criteria, and this information was not collected as part of the trial.  Time to pregnancy was defined as the interval from random assignment to the start of the first pregnancy, irrespective of its outcome. Disease‐free survival (DFS): DFS events were defined by the occurrence of one of the following: local recurrence, distant metastases, contralateral or ipsilateral breast tumour, second primary malignancy, death from any cause. Adverse events: adverse events were assessed clinically and by means of haematological and biochemical measurements throughout the period of chemotherapy. Adverse events were recorded and graded in accordance with the National Cancer Institute Common Toxicity Criteria version 2.0, but only those related to the study medication are described here. Ovarian failure (early menopause): early menopause was defined as no resumption of menstrual activity and postmenopausal levels of FSH for 1 year after the end of chemotherapy. Because FSH levels may be affected by the use of tamoxifen (administered for 5 years to patients with hormone‐sensitive tumours starting from the end of chemotherapy), the protocol was amended to include E2 levels in the definition of early menopause. The amended definition of early menopause was no resumption of menstrual activity and postmenopausal levels of both FSH and E2 for 1 year after the end of chemotherapy. If FSH and E2 levels were not assessed and menstrual activity did not resume, participants were considered to be in early menopause.
Identification	Country: Italy  Setting: 16 Italian hospitals  Author's name: Lucia Del Mastro  Institution: U. O. Sviluppo Terapie Innovative, RCCS AOUSan Martino—IST  Email: lucia.delmastro@hsanmartino.it  Address: Largo RosannaBenzi 10, 16132 Genova, Italy  Aim of study: to evaluate long‐term results of LHRHa‐induced ovarian suppression during breast cancer chemotherapy Possible conflicts of interest: Dr Lambertini reported receiving a 2014 Conquer Cancer Foundation of American Society of Clinical Oncology (ASCO) Merit Award to present the study at the 2014 ASCO Breast Cancer Symposium; Dr Boni reported receiving research funding from Amgen; Dr Gamucci reported receiving honoraria from GlaxoSmithKline and Eisai for attending advisory board meetings; Dr Del Mastro reported receiving honoraria from Takeda and receiving personal fees from Ipsen and Takeda; no other authors reported disclosures.  Start and end date: 24 October 2003 to 14 January 2008
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: the study was approved by ethics committees of all participating institutions. Informed consent obtained: written informed consent was obtained from all participants before study entry. Sponsorship source: The Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy, and partly supported by a grant from the Associazione Italiana per la Ricerca sul Cancro AIRC), Italy. Triptorelin used in the study was provided by Ipsen, Milan, Italy.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Random assignment in a 1:1 allocation ratio was done centrally, with center being the only stratification factor" Comment: participants were randomly allocated to receive chemotherapy alone or chemotherapy plus triptorelin by faxing the clinical trial unit of NCRI in Genoa, where randomisation lists, stratified by centre, had been prepared.
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed centrally by faxing the Clinical Trials Unit of the National Institute for Cancer Research in Genoa (Italy)."
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding; these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: low number of participants loss to follow‐up, balanced between groups. ITT analysis used
Selective reporting (reporting bias)	Low risk	Comment: protocol is available. All prespecified outcome measures are reported.
Other bias	Low risk	Comment: baseline characteristics are similar between groups with respect to age of participants, type of chemotherapy, timing of chemotherapy and breast cancer stage.

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Leonard 2017.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: for the sample size calculation, it was assumed that the rate of amenorrhoea would be 40% in participants 40 years of age and under and 80% in the over 40s. At the time of conception of the trial, 2 uncontrolled studies had suggested that goserelin might reduce the rate of premature menopause to 20%. A one‐sided test with 5% false‐positive rate was used to calculate the sample size to give an 80% chance of detecting an absolute reduction from 40% to 20% in the 40 years and under group and from 80% to 55% in the older group. The intention was to recruit a total of 250 participants, allowing for a 15% loss to follow‐up. Blinding: not described
Participants	Setting: UK Number randomised: 227 Inclusion criteria: ‐ premenopausal patients (defined as regular menses in the 12 months prior to chemotherapy)  ‐ histologically confirmed breast cancer up to stage IIIB ‐ ER‐negative tumours  ‐ ER‐positive tumours for whom the investigator did not deem ovarian suppression necessary as part of the treatment ‐ complete excision of the tumour before adjuvant chemotherapy or planned after neoadjuvant therapy was required  ‐ to receive adjuvant or neoadjuvant chemotherapy  ‐ early stage cancer, hormone positive and hormone negative Exclusion criteria: ‐ metastatic disease  ‐ patients who had had prior chemotherapy or endocrine therapy Group differences: the age distribution, chemotherapy regimens and ER status for the 221 participants did not differ between the two groups. Eligibility: premenopausal patients with histologically confirmed breast cancer who were to receive adjuvant or neoadjuvant chemotherapy. Subgroups measured and reported: age < or > 40 years Total cyclophosphamide dose  Baseline AMH
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists 3.6‐mg goserelin implant: GnRHa starting at least 1 week, and preferably 2 weeks, prior to the start of the chemotherapy treatment, and continuing goserelin 3 to 4 weekly until the end of the chemotherapy treatment.  Number randomised to GnRHa group: 106 (age median (range): 37.9 (25.9 to 50.0)  Withdrawals: 11  Reason for withdrawals: 3 died before 24 months. 8 menstrual status during the interval between the 12‐month follow‐up visit and the 24‐month follow‐up visit could not be determined from the data available  Timing of treatment: starting at least 1 week, and preferably 2 weeks, prior to the start of the chemotherapy treatment  Duration of follow‐up: 5 years  Type of chemotherapy: chemotherapy regimens included 6 to 8 cycles of cyclophosphamide and/or anthracycline‐containing regimens with or without a taxane. Duration of treatment: until the end of the chemotherapy treatment (6 to 8 cycles of chemotherapy) No treatment  Number randomised to no treatment group: 121 Age median (range): 38.8 years (24.8 to 51.1) Withdrawals: 14  Reason for withdrawals: 3 died before 24 months. 11 menstrual status during the interval between the 12‐month follow‐up visit and the 24‐month follow‐up visit could not be determined from the data available. Duration of follow‐up: 5 years Co‐interventions: radiotherapy per standard protocol for each centre
Outcomes	Premature ovarian insufficiency Clinical pregnancy Notes: 9 pregnancies in GnRH‐a group (including 2 each for 2 women), 6 pregnancies in no‐treatment group (including 2 pregnancies in 1 woman) Outcome definitions: premature ovarian insufficiency (POI): the prevalence of amenorrhoea at 12 to 24 months, secondarily combined with elevated FSH concentration giving the prevalence of POI
Identification	Country: UK  Setting: not described  Comments: none  Author's name: Professor Robert CF Leonard  Institution: Department of Surgery and Oncology, Imperial College, Cancer Services, Charing Cross Hospital  Email: r.leonard@imperial.ac.uk  Address: Fulham Palace Road, London W6 8RF, UK  Aim of study: to establish whether goserelin can reduce the risk of POI in women who require chemotherapy for operable hormone‐insensitive breast cancer or for whom ovarian suppression is not considered a necessary part of treatment Possible conflicts of interest: RL has undertaken consultancy work for Amgen, Pfizer, Novartis, Roche, Teva, Caris; GB has undertaken consultancy work for Eisai, Genomic Health, Pfizer, Novartis; JM has undertaken consultancy work for Puma biotechnology; AY has undertaken consultancy work for Kyowa Kirin, Emergent, Galderma, Immodulan, Ipsen, Leica, Pharmagenesis, ReNeuron, Shield, Tokai; RC received research funding from Bayer, Amgen to his institution; RAA has undertaken consultancy work for Roche Diagnostics. The other authors have no conflicts to disclose.  Start and end date: 26 August 2004 to end of December 2009
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: the study received Ethical Committee approval (South West Multi‐centre Research Ethics Committee, reference MREC/03/6/90).  Informed consent obtained: all participants gave informed consent.  Sponsorship source: Cancer Research UK (CRUK/04/004)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "and treatment was allocated by computer‐generated lists."  Quote: "Randomization was stratiﬁed by age (aged 40 years or younger and those over 40 years) and by center."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was centrally performed by telephone to the trial center"
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: outcome data are missing in both groups, but well balanced. A per‐protocol analysis is performed and an intention‐to‐treat analysis is performed with imputation of worst case data (all patients with missing data were assumed to have amenorrhea) and imputation of best case data (all patients with missing data were assumed to not have amenorrhea).
Selective reporting (reporting bias)	Low risk	Comment: not all predetermined outcome measures are reported, but, in our opinion, the most important outcome measures are reported, even if they were not significant.
Other bias	Low risk	Comment: there were no significant differences between groups with respect to the age of patients, chemotherapy regimens and ER status.

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Letourneau 2021.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Blinding: "the treating physician and the participant could not be blinded to the study drug, for the following reasons: the suppressive effect of letrozole on oestradiol; the absence of such an effect with tamoxifen; the standard need to counsel participants in the stimulation protocol about the progress of their stimulation cycle (based on their oestradiol response). The embryologists who were counting mature oocytes were, importantly, blinded to the study drug." Power: "44 participants in each group in the primary comparison (tamoxifen‐gonadotropin versus letrozole‐gonadotropin) were required to obtain 80% statistical power to demonstrate a clinically meaningful absolute difference of three mature oocytes, assuming a standard deviation of five mature oocytes per cycle with the use of an unpaired t‐test with a two‐sided significance level of 0.05. A difference of three mature oocytes was chosen as this number of oocytes could commonly lead to an additional embryo transfer in the future. For our power calculation, we used ten for the expected mean number of oocytes in the tamoxifen group, with the desired effect size of three[3]. The sample size was increased to 48 per arm for an expected dropout of 10%. We also planned to also enrol an additional approximately 44 patients with ER−breast cancer, to be used for our secondary comparison."
Participants	Setting: Reproductive Endocrinology Clinic at University of California, San Francisco, USA Number randomised: 96 Inclusion criteria: ‐ women 18 to 44 years of age ‐ new breast cancer diagnosis, hormone positive, early stage ‐ had not yet begun chemotherapy ‐ planned to undergo ovarian stimulation and oocyte retrieval prior to cancer treatment Exclusion criteria: ‐ chemotherapy had already commenced or been completed; history of recurrent breast cancer ‐ stage IV breast cancer at diagnosis ‐ if patient’s oncologist advised against the trial ‐any significant concurrent disease, illness, or psychiatric disorder that would have compromised patient safety or compliance and interfere with consent, study participation, follow‐up, or interpretation of study results The study used hormone‐receptor‐negative patients as a control group. However, these patients were not randomised, which is why in this review we included only the randomised hormone‐receptor‐positive patients. Group differences: "the randomised groups in our study were similar for baseline antral follicle count, body mass index and race/ethnicity. However, there was a statistically significant difference in age between the three groups, as determined by one‐way ANOVA (F(2,130=4.61, p=0.01). A Bonferroni post hoc test revealed that age was significantly higher in the tamoxifen‐gonadotropin group than the gonadotropin‐only group (35.4±0.8 vs. 32.5±0.6, p=0.01). The mean age for the tamoxifen‐gonadotropin was 1.7 years less than the letrozole‐gonadotropin group, though this difference was not statistically significant (35.4±0.8 vs. 33.7±0.6, p=0.18). Lastly, age was not statistically significantly different for letrozole‐gonadotropin versus gonadotropin alone (33.7±0.6 vs. 32.5±0.6, p=0.64).  In vitro fertilization (IVF) cycle parameters, including total doses of gonadotropins, duration of stimulation, and trigger shot type, were similar between the three groups.  The one significant difference in IVF parameters was peak estradiol levels, which were much lower in the letrozole group, by design." Exclusions: 44  Reason for exclusions: 42 excluded between prescreening and giving consent (ER‐status not known), of which 38 did not meet inclusion criteria and 4 declined to participate, 2 (ER+) decided to not pursue ovarian stimulation due to financial or logistical reasons related to their cancer care.
Interventions	Comparison: controlled ovarian hyperstimulation with gonadotropins + tamoxifen versus controlled ovarian hyperstimulation with gonadotropins + letrozole Controlled ovarian hyperstimulation with gonadotropins + tamoxifen 20 mg daily, not titrated, for one in‐vitro fertilisation cycle Number randomised to + tamoxifen group: 45  Age (mean, SD): 35.4 years (5)  Withdrawals: 1  Reason for withdrawal: did not freeze oocytes/embryos  Timing of treatment: random‐start GnRH antagonist protocol  Duration of follow‐up: outcomes were only measured in the first cycle of ovarian stimulation. Controlled ovarian hyperstimulation with gonadotropins + letrozole 5 mg letrozole daily beginning at start of ovarian stimulation and titrated up to as much as 10 mg per day with the goal of maintaining oestradiol levels close to that observed during monofollicular development in natural cycles (13 mm) Number randomised to + letrozole group: 51  Age: not stated Withdrawals: 1  Reason for withdrawal: did not freeze oocytes/embryos  Timing of treatment: random‐start GnRH antagonist protocol beginning with the start of ovarian stimulation  Duration of follow‐up: outcomes were only measured in the first cycle of ovarian stimulation. Co‐interventions: "In both the ER+ and ER−groups, ovarian stimulation was performed with a random‐start GnRH antagonist protocol. The starting dose and adjustment of gonadotropins were based on the clinic’s standard of care. The initial dosage of gonadotropins (Follistim, Merck; Gonal‐F, EMD‐Serono;and/or Menopur, Ferring) was determined by the patient’s age, body mass index (BMI), and ovarian reserve, as estimated by antral follicle count (AFC) (which was measured on the day of initial consultation). During the cycle, gonadotropin dosages were adjusted as needed, based on follicle count/size and estradiol levels (in the tamoxifen‐gonadotropin and gonadotropin‐only groups), to maximize response and minimizing the risk of ovarian hyperstimulation syndrome (OHSS). GnRH antagonist (0.25mg ganirelix acetate, Organon; or 0.25 mg cetrotide, EMD‐Serono) was administered daily to prevent premature ovulation when the lead follicle measured≥12‐mm mean diameter. Final oocyte maturation was induced with sliding‐scale hCG (1500 to 10,000 IU subcutaneously) or GnRH agonist (4 mg leuprolide acetate subcutaneously) trigger injection depending upon size of the follicular cohort and perceived risk of OHSS. The trigger injection in the tamoxifen‐gonadotropin (ER+) and gonadotropin‐alone (ER−) groups was administered when the largest follicle attained a mean two‐dimensional diameter of 18 mm with the general cohort of follicles >13 mm."
Outcomes	Adverse events Notes: "No serious adverse events related to the treatments occurred during the study, including no unplanned hospitalizations during the study for any of the three groups. Though we did not collect a specific a priori list of side effects during treatment, our patients did undergo very close monitoring during the 2 weeks of the study, with frequent (every 1 to 3 days) visits for ultrasounds. No one stopped their medications due to self‐report of concerns about side effects." Number of oocytes retrieved after ovarian stimulation Clinical pregnancy rates Outcome definitions:  ‐ Number of mature oocytes obtained from the cycle, defined as the number of meiosis II oocytes seen 2 to 3 hours after oocyte retrieval during cumulus stripping. Some participants underwent more than 1 cycle of ovarian stimulation, so outcomes were only measured in the first cycle after informed consent was obtained.  ‐ Clinical pregnancy rates: pregnancy after succesfull IVF‐cycle ‐ Adverse events, defined as any side effects that resulted in discontinuation of study medication. Serious adverse events were defined as events that were fatal/immediately life‐threatening or required inpatient hospitalisation Subgroups measured: none
Identification	Country: USA  Setting: Reproductive Endocrinology Clinic at University of California, San Francisco, Center for Reproductive Health Author's name: Joseph Letourneau  Institution: University of California, San Francisco School of Medicine  Email: Joseph.letourneau@hsc.utah.edu  Address: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco School of Medicine, San Francisco, CA, US  Aim of study: to assess the impact of tamoxifen‐gonadotropin and letrozole‐gonadotropin on mature oocyte yield Possible conflicts of interest: the authors declare no competing interests.  Start and end date: June 2016 to September 2020
Notes	Author confirmed risk of bias via email. No additional raw data available.  Ethical approval needed/obtained for study: all study procedures were approved by the University of California, San Francisco (UCSF) Committee on Human Research. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.  Informed consent obtained: written, informed consent for study participation was obtained by the recruiting physician after the patient chose to undergo oocyte or embryo cryopreservation.  Sponsorship source: departmental research funding within the University of California, San Francisco Department of Obstetrics, Gynecology, and Reproductive Sciences
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A computer‐generated randomizer was used to determine study drug exposure" Comment: only hormone‐receptor positive patients were randomised. Hormone‐receptor negative patients were not randomised, but they were also not included in this review.
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Quote: "The embryologists who were counting mature oocytes were, importantly, blinded to the study drug." Comment: these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: data are complete. Very small number of withdrawals
Selective reporting (reporting bias)	Low risk	Comment: all predefined outcome measures were reported.
Other bias	High risk	Comment: difference in baseline characteristics (age)

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Li 2015.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not stated Blinding: not described
Participants	Setting: not described, in China Number randomised: 216 Inclusion criteria: ‐ female  ‐ primary invasive breast cancer pathologically proved by core needle or open biopsy, hormone positive, early stage ‐ patients must have undergone standard surgery for primary breast cancer as following: mastectomy, breast conservation surgery followed by whole breast radiation, axillary dissection or sentinel node biopsy  ‐ need adjuvant chemotherapy after surgery  ‐ patients taking neo‐chemotherapy ‐ patients with synchronous bilateral cancers are eligible on the condition that if one side is invasive ductal carcinoma (IDC) and the other side is ductal carcinoma in situ, the IDC side should be of the ER and/or progesterone receptor positive phenotype and if two sides are both IDC, they must be ER and/or PR positive phenotype at the same time  ‐ hormone‐receptor positive is defined as detecting ER or PR expression at any time The situation of only PR positive and ER negative ‐ all patients are required to be premenopausal as defined by menstruating actively less than 6 months since last menstrual period, or patients younger than 40 years of age who became amenorrhoeic not more than 1 year if the serum free E2, FSH and LH level was premenopausal (according to the reference value of local centre) ‐ had previous hysterectomy with one or both ovaries left intact are eligible if the serum free E2, FSH and LH levels are premenopausal (according to the reference value of local centre) ‐ patients must have an ECOG performance status of 0 or 1 (0 ‐ fully active, able to carry on all pre‐disease performance without restriction, 1 ‐ restricted in physical strenuous activity but ambulatory)  ‐ leucocyte count must be ≥ 3.010^9/L and platelet count must be ≥ 10010^9/L  ‐ serum creatinine must be < 2 times the ULN  ‐ pregnancy testing is negative and are willing to use contraception during the treatment period Exclusion criteria: ‐ patients with metastatic malignant tumour  ‐ previous history of asynchronous bilateral breast cancer  ‐ any previous malignancy in the past 5 years, except for those treated with curative intent, such as carcinoma in situ of the cervix, squamous carcinoma of the skin or basal cell carcinoma of the skin  ‐ any non‐malignant systemic disease which interfere long time follow‐up  ‐ history of medical ovarian ablation therapy  ‐ severe liver dysfunction ‐ severe renal dysfunction  ‐ occult breast cancer  ‐ severe heart dysfunction, heart functional classification is above Class III Exclusions: not described  Reason exclusions: N/A  Subgroups measured: neoadjuvant chemotherapy  Subgroups reported: neoadjuvant chemotherapy
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Zoladex (goserelin) 3.6mg once a month up to 2 to 3 years Duration of treatment: up to 2 to 3 years  Co‐interventions: tamoxifen  Number randomised to goserelin group: 108  Age (median): 39.0  Withdrawals: 66  Reason for withdrawals: not described  Timing of treatment: starting 0 to 7 days prior to the first chemotherapy dose Duration of follow‐up: median 27.4 months No treatment Number randomised to no treatment group: 108  Age (median): not described  Withdrawals: 48  Reason for withdrawals: not described  Timing of treatment: N/A  Duration of follow‐up: median 25.7 months Co‐interventions: tamoxifen, chemotherapy Type of chemotherapy: 15 participants (GnRH‐a group) and 21 participants (control group) received neoadjuvant chemotherapy. Group differences: there were no significant difference in age, tumour stage and chemotherapy regimens (P > 0.05).
Outcomes	Premature ovarian insufficieny  Relapse‐free survival Overall survival: after 5 years Other adverse events Outcome definitions:  Premature ovarian failure: amenorrhoea for the prior 12 months and postmenopausal FSH or not assessed after last chemotherapy dose or last goserelin dose Relapse‐free survival: RFS‐related events were defined as local‐regional recurrence, distant metastasis or death, whichever occurred first during follow‐up.  Overall survival: after 5 years Other adverse events: gynaecological events, blood lipids, thrombosis, cardiovascular diseases, etc.
Identification	Country: China  Setting: not described  Comments: used registration in clinical trial register (NCT01712893) to fill in the data extraction. Besides poster session abstract, no other publications available.  Author's name: Zhimin Shao  Institution: Cancer Hospital & Institute, Fudan University, Department of Surgical Oncology  Email: zhiminshao@yahoo.com (found on internet)  Address: not given Aim of study: to compare the efficacy and safety of the adjuvant chemotherapy with simultaneous or sequential application of Zoladex up to 2 to 3 years for ≤ 45‐year‐old women with premenopausal hormone receptor‐positive breast cancer Possible conflicts of interest: not described  Start and end date: February 2009 to May 2013
Notes	Author contacted by email; address not found. No other mailing address known Ethical approval needed/obtained for study: not described  Informed consent obtained: yes Sponsorship source: Fudan University
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: many more withdrawals in GnRH‐a group compared to control group. Reasons for withdrawals are not described. No ITT analysis used
Selective reporting (reporting bias)	High risk	Comment: not all outcome measures described in the clinical trial register are reported in this article.
Other bias	High risk	Comment: limited information available because there is only an abstract.

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Moore 2019.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: "the original target enrolment was 416 eligible patients. We estimated that with this sample size, the study, based on a two‐group binomial design, would have more than 80% power to detect an absolute reduction of 15 percentage points in the rate of ovarian failure, assuming rates of ovarian failure in the chemotherapy‐alone group in the range of 20 to 95% and an expected mortality by year 2 of 10%, at a one‐sided significance level of 0.025. The study closed early owing to loss of funding for study‐drug distribution. Post hoc power calculations that were based on actual enrolment indicated that the study had sufficient power (≥80%) to detect an absolute reduction of 20 percentage points in the rate of ovarian failure under the same design specifications." Blinding: not described
Participants	Setting: multiple centres in the USA, Australia and New Zealand Number randomised: 257 Inclusion criteria: ‐ premenopausal women  ‐ 18 to 49 years of age  ‐ operable stage I to IIIA ER–negative and PR–negative breast cancer  ‐ for which treatment with adjuvant or neoadjuvant cyclophosphamide‐containing chemotherapy was planned  ‐ had taken no oestrogens, anti‐oestrogens, selective oestrogen‐receptor modulators, aromatase inhibitors or hormonal contraceptives within the month before enrolment Exclusion criteria: not described
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Goserelin at a dose of 3.6 mg was administered subcutaneously every 4 weeks beginning 1 week before the initial chemotherapy dose and was continued to within 2 weeks before or after the final chemotherapy dose. Number randomised to GnRHa group: 126  Age (median, range): 37.6 years (26.1 to 48.6)  Withdrawals: 60  Reason for withdrawals: 13 ineligible, 47 not evaluated (2 underwent hysterectomy, 1 underwent oophorectomy, 4 withdrew consent, 3 died, 2 lost to follow‐up, 34 missing data)  Timing of treatment: 1 week before initiation of chemotherapy  Duration of follow‐up (median): 2 years for ovarian failure, 5 years for pregnancy No treatment  Number randomised to the no‐treatment group: 131  Age (median, range): 38.7 years (25.1 to 49.9)  Withdrawals: 62  Reason for withdrawals: 11 ineligible, 51 not evaluated (2 underwent hysterectomy, 5 withdrew consent, 11 died or were lost to follow‐up, 30 missing data)  Timing of treatment: N/A  Duration of follow‐up (median): 2 years for ovarian failure, 5 years for pregnancy Co‐interventions: use of trastuzumab was permitted in patients with HER2–overexpressing tumours. Chemotherapy in both groups Group differences: the characteristics of the participants were well balanced between the two groups.  Exclusions: 24 (11 from chemotherapy group and 13 from chemotherapy + goserelin group). Reason for exclusions: 8 baseline pathological tests with insufficient information, 6 did not submit baseline pathological tests, 1 incorrect stage, 1 no plans for protocol‐described therapy, 8 did not submit prestudy forms. Type of chemotherapy: adjuvant or neoadjuvant cyclophosphamide‐containing chemotherapy
Outcomes	Non‐pregnancy‐related adverse events (other adverse events) Diarrhoea Fatigue Hot flashes Irregular menses Decrease in libido Agitation Anxiety Depression Joint pain Muscle pain Headaches Sweating Thromboembolism Vaginal dryness Premature ovarian insufficiency Notes: defined as: amenorrhoea for the preceding 6 months and FSH levels in the post‐menopausal range at 2 years Clinical pregnancy Live birth Pregnancy‐related adverse events Miscarriage Elective termination Delivery complication Disease‐free survival Overall survival Subgroups measured: none
Identification	Country: UK, USA  Setting: multiple centres via CALGB, ECOG, IBCSG and SWOG  Author's name: Dr Moore  Institution: Cleveland Clinic Foundation, Taussig Cancer Institute  Email: mooreh1@ccf.org  Address: Cleveland Clinic Foundation, Taussig Cancer Institute, R35, 9500 Euclid Ave., Cleveland, OH 44195  Aim of study: to evaluate whether administration of the GnRH agonist goserelin (Zoladex, AstraZeneca) with chemotherapy would reduce the rate of ovarian failure after adjuvant or neoadjuvant treatment of hormone‐receptor negative early breast cancer Possible conflicts of interest: Dr Albain reports her institution, as a member of the Southwest Oncology Group, received accrual credits for the patients enroled on this study and funding as a U10 institution during the conduct of this study (per case reimbursement). Beyond this, there was no specific funding for this study and no difference from the other SWOG and Intergroup trials we had open over the years. Dr Fabian reports grant support from the Oregon Health and Science University during the conduct of the study. Dr Gelber reports grant support from the National Institute of Health and non‐financial support from AstraZeneca during the conduct of the study. Dr Hortobagyi reports grant support and personal fees from Novartis and personal fees from Peregrine Pharmaceuticals, Pfizer, Galena Biopharma, Genentech, Amgen, AstraZeneca, Allergan and Sanofi‐Aventis outside the submitted work. Dr Lombard reports non‐financial support from AstraZeneca outside the submitted work. All other authors have nothing to disclose.  Start and end date: February 2004 to May 2011
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: the protocol of the study was approved by the institutional review board at each participating site.  Informed consent obtained: all participants provided written informed consent for participation.  Sponsorship source: grants from National Cancer Institute at the National Institutes of Health (CA189974, CA180821, CA31946, CA075362, CA180820, CA27525, CA189808, CA180830, CA180801, CA189872, CA189822, CA189953, CA189858, CA180858, 189954, CA189957, CA189972) and by AstraZeneca, the Australia and New Zealand Breast Cancer Trials Group, and the Breast Cancer Institute of Australia.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "stratified 1:1 randomization"  Quote: "Stratification factors were age and chemotherapy regimen."
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: withdrawals are balanced in all groups, for the same reasons. Several analyses (protocol‐specified stratified logistic‐regression, univariate regression and multivariate regression) show the same significant results.
Selective reporting (reporting bias)	Low risk	Comment: protocol is available. All predefined outcome measures and subgroups are reported.
Other bias	Unclear risk	Comment: randomisation was done before the participants were found eligible for this study. Therefore, exclusions were done after randomisation, which causes risk of inequality between study groups. However, the baseline characteristics of the different study groups as presented are comparable between both groups.

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Munster 2012.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: the trial was designed to enrol 124 evaluable participants to detect a 20% difference in amenorrhea rate, from 10% in the triptorelin arm to 30% in the control arm, with 80% power and a two‐sided 5% significance level. Blinding: not described
Participants	Setting: USA Number randomised: 49 Inclusion criteria: ‐ premenopausal patients  ‐ newly diagnosed early‐stage breast cancer (stages I to III), hormone positive and hormone negative ‐ planned adjuvant or neoadjuvant chemotherapy  ‐ younger than 45 years of age  ‐ specific chemotherapy regimen Exclusion criteria: not described
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Triptorelin depot (3.75 mg) every 28 to 30 days by intramuscular injection starting no sooner than 4 weeks and at least 7 days before the first cycle of chemotherapy and continued throughout chemotherapy duration.  Duration of treatment: during chemotherapy  Number randomised to GnRHa group: 27  Withdrawals: 1  Reason for withdrawal: withdrew consent  Timing of treatment: starting no sooner than 4 weeks and at least 7 days before the first cycle of chemotherapy.  Duration of follow‐up: planned for 5 years but stopped early. Median 18 months (range 5 to 43 months) from completion of last chemotherapy and 22 months after initiation of chemotherapy No treatment  Number randomised to group: 22  Age (median, range): 38 years (26 to 44)  Withdrawals: 1  Reason for withdrawal: residual disease  Timing of treatment: N/A  Duration of follow‐up: planned for 5 years but stopped early. Median 18 months (range 5 to 43 months) from completion of last chemotherapy and 22 months after initiation of chemotherapy Co‐interventions: tamoxifen if ER‐positive tumour Type of chemotherapy: 4 cycles of doxorubicin plus cyclophosphamide (AC), 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of a taxane (AC‐>T), or 6 cycles with fluorouracil plus epirubicin (FEC) of doxorubicin plus cyclophosphamide (FAC)
Outcomes	Premature ovarian insufficiency, any definition Notes: defined as: resumptions of at least three menses in 6 months and FSH level of less than 40 mIU/mL. Outcome reversed (participants who did not reach the above definition) to obtain a value for premature ovarian insufficiency Clinical pregnancy Clinical pregnancy, participants < 35 years old Clinical pregnancy, participants ≥ 35 years old Pregnancy‐related adverse events Outcome definitions: resumed menses: resumptions of at least three menses in 6 months and FSH level of less than 40 mIU/mL Subgroups reported: age, chemotherapy regimen, tamoxifen yes or no
Identification	Country: USA  Setting: not described  Comments: none  Author's name: Pamela N Munster  Institution: University of California, Division of Hematology and Oncology  Email: pmunster@medicine.ucsf.edu  Address: University of California, San Francisco, CA94143  Aim of study: to determine the protective effect of chemical ovarian suppression achieved by short‐term use of GnRH‐analogue on the preservation of ovarian function in women treated with chemotherapy.  Possible conflicts of interest: "employment or Leadership Position: none. Consultant or Advisory Role: none. Stock Ownership: None. Honoraria: none. Research Funding: Pamela N. Munster, Pfizer. Expert Testimony: None. Other Remuneration: None." Start and end date: July 2003 to January 2007
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: the trial was initiated after approval was granted by the protocol review committee and institutional review board at Moffitt Cancer Center/University of South Florida and the National Cancer Institute.  Informed consent obtained: informed consent was obtained (confirmed by contact with author)  Sponsorship source: The National Cancer Institute, USA
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computerized randomization and stratiﬁcation in age, treatment, and hormone receptor status" Quote: "computer generated" (email from author)
Allocation concealment (selection bias)	Low risk	Comment: central allocation, information from contact with study author by email
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: low number of missing data; reasons for missing data not related to outcomes and balanced between groups
Selective reporting (reporting bias)	High risk	Comment: different publications of this trial present different results of outcome measures.
Other bias	High risk	Comment: trial analysed early, prior to recruitment being complete. Therefore underpowered to detect difference. Imbalance of numbers between intervention and control.

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Rabie 2021.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: "the sample size was calculated based on previous studies in the field to ensure a power of 80% and a type I error probability of 5%, by calculating the following using statistical GPower software version 3: Effect size d = xt – xc/S pooledwhere d = Cohen’s d effect size = mean (average of treatment or comparison conditions), s = standard deviation, t refers to the treatment condition, and c refers to the comparison condition (or control condition). " Blinding:* no blinding
Participants	Setting: hospital in Egypt Number randomised: 52 Inclusion criteria: ‐ all lymphoma types, stages I to IV  ‐ premenopausal female patients between 17 and 40 years old  ‐ with normal menstruation and normal FSH levels (< 10 IU/L)  ‐ patients of childbearing potential were required to have a negative pregnancy test (urine or serum) in the 14 days prior to starting the study, and had to implement adequate non‐hormonal contraceptive measures with an intrauterine device during the study period  ‐ any use of hormonal contraceptives had to be discontinued in the month before enrolment and prior to the first goserelin injection Exclusion criteria: ‐ patients with primary ovarian dysfunction  ‐ patients with a previous history of amenorrhoea  ‐ patients who were unlikely to comply with trial requirements (e.g. those with confusion, psychological or mood disturbances, alcoholism, vaginitis, vaginal bleeding and cardiac arrhythmia)  ‐ patients who underwent hysterectomy or bilateral oophorectomy were categorised as “unable to be evaluated”. Group differences: there were no significant differences between the two study groups in terms of age, anthropometric measurements and fertility history. There were no significant differences between the two study groups in the basal level of FSH and E2. Moreover, there was no significant difference between the study groups in the type and subtypes of lymphoma (Hodgkin or non‐Hodgkin), tumour staging and chemotherapy regimen at baseline.  Exclusions: 6  Reason for exclusions: 2 advanced age (> 40 years), 1 refused consent, 2 previously started chemotherapy, 1 declined to participate
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Description: goserelin (Zoladex) 3.6 mg subcutaneous injection every 4 weeks (28 ± 3 days) plus standard chemotherapy at the start of the regimen Duration of treatment: 6 months  Co‐interventions: standard chemotherapy  Number randomised to group: 26  Age (mean, SD): 28.7 years (8.2) Withdrawals: 2  Reason for withdrawals: 1 lost to follow‐up, with no data available, 1 non‐compliant  Timing of treatment: the first dose was administered 10 to 14 days before the initiation of chemotherapy.  Duration of follow‐up: 3 months after end of chemotherapy (9 months in total) No treatment  Number randomised to group: 26  Age (mean, SD): 29.8 years (8.3)  Withdrawals: 2  Reason for withdrawals: 2 lost to follow‐up, no data available  Timing of treatment: N/A  Duration of follow‐up: 3 months after end of chemotherapy (9 months in total) Co‐interventions: standard chemotherapy Type of chemotherapy: the regimens consisted of 6 to 8 cycles of polychemotherapy received: "ABVD: Doxorubicin 25 mg/m2, IV, D1, D15 ‐ Bleomycin 10 units/m2, IV, D1, D15 ‐ Vinblastine 6 mg/m2, IV, D1, D15 ‐ Decarbonize 375 mg/m2, IV, D1, D15 ‐ Repeat cycle every 4 weeks for 6–8 cycles  R+/R‐ CHOP: Rituximab 375 mg/m2, IV, D1 ‐ Cyclophosphamide 750 mg/m2, IV, D1 ‐ Doxorubicin 50 mg/m2, IV, D1 ‐ Vincristine 1.4 mg/m2, IV bolus (max dose 2 mg), D1 ‐ Prednisone 100 mg orally, D1–5 ‐ Repeat every 3 weeks for 6–8 cycles  CVP: Cyclophosphamide 750 mg/m2, IV, D1 ‐ Vincristine 1.4 mg/m2, IV bolus (max dose 2 mg), D1 ‐ Prednisone 100 mg orally twice daily, D1–5 ‐ Repeat every 3 weeks for 6–8 cycles"
Outcomes	Premature ovarian insufficiency, any definition Notes: defined as: a serum FSH level > 30 IU/mL at 6 months after chemotherapy Non‐pregnancy‐related adverse events (other adverse events) Hot flashes Vaginal bleeding Headaches Sweating Vaginal dryness Vaginitis Outcome definitions: premature ovarian failure was defined as a serum FSH level > 30 IU/mL  Only adverse events related to goserelin or chemotherapy were routinely assessed, with assessment according to the Common Terminology Criteria for Adverse Events, version 5.02 Subgroups measured and reported: types of lymphoma, stage of cancer
Identification	Country: Egypt  Setting: hospital  Author's name: Al Shaimaa Ibrahim Rabie  Institution: Beni‐Suef University Hospital  Email: Alshaimaa.ph@o6u.edu.eg  Address: not described  Aim of study: to determine the effectiveness of gonadotropin‐releasing hormone agonist (GnRHa) (goserelin acetate) in preserving ovarian function in premenopausal women undergoing combined chemotherapy for Hodgkin or non‐Hodgkin lymphoma by documenting the changes in hormonal levels  Possible conflicts of interest: none  Start and end date: not described
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: the study was performed according to the guidelines of the Declaration of Helsinki, and the study protocol was approved from an ethical point of view and registered under Federal Wide Assurance (FWA) for Protection of Human Subjects. The study was granted local ethics committee approval from the Ethics Committee, Faculty of Medicine, Beni‐Suef University, FWA#: FWA 00015574.  Informed consent obtained: written informed consent was obtained from all patients prior to their participation in the study.  Sponsorship source: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The present study is a randomized‐control, parallel, open‐label study designed by block randomization."
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: relatively low number of withdrawals
Selective reporting (reporting bias)	Low risk	Comment: all predetermined outcomes are reported.
Other bias	Low risk	Comment: baseline characteristics equal between groups. No conflicts of interest or suspicious funding resources

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Song 2013.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: assuming that 50% of patients experienced early menopause following chemotherapy, at least 62 patients were required (31 in each group) to detect a 30% absolute reduction in early menopause rate with leuprolide treatment, with a power of 80% and a one‐sided error of 5%. Blinding: not described
Participants	Setting: clinic in China Number randomised: 220 Inclusion criteria: ‐ premenopausal patients between 18 and 45 years  ‐ proven histological stage I to III breast cancer  ‐ no history of prior chemotherapy or hormone therapy  ‐ no distant metastases or localised cancer relapse  ‐ no prior or concomitant malignancy  ‐ no history of primary or secondary ovarian insufficiency  ‐ no pregnancy or nursing Exclusion criteria: not described Group differences: chemotherapy plus leuprolide acetate group tended to be younger than those in chemotherapy‐only group (mean age 40.3 vs 42.1 years). However, the difference in age is not statistically significant (P > 0.05).  There are no other important baseline differences between the two groups.  Exclusions: not described
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists  Subcutaneous injection of leuprolide acetate 3.75 mg; the serum E2 level was measured 2 weeks after injection. If ovarian suppression was confirmed, participants started to receive chemotherapy; otherwise, chemotherapy was not started until ovarian suppression was proved. During chemotherapy, participants were given leuprolide acetate at same dosage every 4 weeks.  Duration of treatment: during chemotherapy. If a participant resumed menstrual activity during follow‐up, she restarted leuprolide acetate treatment and continued for 24 months to induce therapeutic ovarian suppression.  Number randomised to group: 110 Age (mean, SD): 40.3 years (± 6.5)  Withdrawals: 21  Reason withdrawals: 4 failed to complete at least one cycle of chemotherapy, 17 lost to follow‐up  Timing of treatment: serum E2 level was measured 2 weeks after injection. If ovarian suppression was confirmed (E2 level < 30 pg/ml), participants started to receive chemotherapy; otherwise, chemotherapy was not started until ovarian suppression was proved.  Duration of follow‐up: 12 months after end of chemotherapy Co‐interventions: for all the participants with hormone‐sensitive tumours, tamoxifen was administered at the end of chemotherapy. No treatment  Description: no treatment  Duration of treatment: N/A  Number randomised to group: 110  Age (mean, SD): 42.1 years (± 5.9)  Withdrawals: 16  Reason for withdrawals: 2 failed to complete at least one cycle of chemotherapy, 14 lost to follow‐up  Timing of treatment: N/A  Duration of follow‐up: 12 months after end of chemotherapy Co‐interventions: for all the participants with hormone‐sensitive tumors, tamoxifen was administrated at the end of chemotherapy. Type of chemotherapy: cyclophosphamide–doxorubicin‐based chemotherapy: 1) 600 mg/m² cyclophosphamide and 60 mg/m² doxorubicin (CA) every 3 weeks for 6 cycles and 2) 600 mg/m² cyclophosphamide, 60 mg/m² doxorubicin and 175 mg/m² paclitaxel (CA‐>Taxol) every 3 weeks for 4 cycles.
Outcomes	Premature ovarian insufficiency Non‐pregnancy‐related adverse events (other adverse events) Notes: "All patients reported leuprolide‐acetate‐related adverse effects, including hot flush, mood swings andurogenital symptoms, were Grade I and II cases." Outcome definitions: early menopause: FSH level > 40 mIU/ml and E2 < 20 picogramms per millilitre (pg/ml) in the absence of resumption of menstrual activity within 12 months after the end of chemotherapy Adverse events were graded based on NCI‐CTC version 3.0. Subgroups measured and reported: age (≤ 35 versus >35 years), chemotherapy type (CA versus CA + Taxol), chemotherapy duration (> 4 cycles versus ≤ 4 cycles), tamoxifen treatment
Identification	Country: China  Setting: Jiangyin Hospital  Author's name: G Song  Institution: Department of Pharmacy, Jiangyin Hospital Affiliated to Nanjing University of Traditional Chinese Medicine  Email: drsongguiping@gmail.com  Address: No. 130 Renmingzhong Road, Jiangyin 214400, Jiangsu  Aim of study: to examine the efficacy of leuprolide acetate on ovarian function preservation in patients with breast cancer Possible conflicts of interest: none  Start and end date: February 2010 to March 2012
Notes	Author contacted by email to confirm risk of bias and ask for raw data. No reply received Ethical approval needed/obtained for study: this prospective randomised trial was approved by the Medical Ethics Committee of Jiangyin Hospital Affiliated to Nanjing University of Traditional Chinese Medicine.  Informed consent obtained: written consent forms were obtained from all participants.  Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: missing data balanced between groups, but no ITT analysis (stated to be, but participants lost to follow‐up were not included)
Selective reporting (reporting bias)	Low risk	Comment: all prespecified outcome measures are reported.
Other bias	Low risk	Comment: baseline characteristics balanced between groups

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Sun 2021.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not stated Blinding: not described
Participants	Setting: clinic in China Number randomised: 40 Inclusion criteria: ‐ patients confirmed as breast cancer pathologically  ‐ immunohistochemical results showed that at least one of oestrogen or progesterone receptor is positive  ‐ patients who were not menopausal before treatment  ‐ patients who had received surgery, chemoradiotherapy and other treatments in a standardised manner  ‐ patients and their families had clearly knew the theme of this study, and independently co‐operate with the research content and sign informed consent forms Exclusion criteria: ‐ patients who did not completed routine adjuvant therapy  ‐ patients with a second primary cancer  ‐ incomplete clinical data  ‐ patients with serious neurological diseases, mental state abnormalities or mental classification  ‐ patients with severe heart, kidney, lung and other organ failure diseases  ‐ patients with coagulation dysfunction  ‐ patients who resisted the treatment  ‐ patients who participated in other research Group differences: bioactive FSH higher in control group (15.52 vs 7.13) (they state that, because P > 0.05, the groups are similar, but this is an incorrect interpretation of P value. The P value is irrelevant here; the groups are different).  Exclusions: not described
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Leuprorelin 3.75mg, subcutaneous injection once every 4 weeks Duration of treatment: 1 year  Number randomised to group: 20  Age (mean, SD): 41.45 years (5.8)  Withdrawals: 0  Reason withdrawals: N/A  Timing of treatment: not described  Duration of follow‐up: 30 months Co‐interventions: tamoxifen (SFDA approval number H32021472, specification 10 mg, Yangzijiang Pharmaceutical Group Co Ltd) (10 mg/time, twice a day) No treatment  Number randomised to group: 20  Age (mean, SD): 41.25 years (5.75)  Withdrawals: 0  Timing of treatment: not described  Duration of follow‐up: 30 months Co‐interventions: tamoxifen (SFDA approval number H32021472, specification 10 mg, Yangzijiang Pharmaceutical Group Co., Ltd.) (10 mg/time, twice a day) Type of chemotherapy: not described
Outcomes	Non‐pregnancy‐related adverse events (other adverse events) Decrease of bone density Endometrial thickening Jaundice Outcome definitions: incidence of adverse reactions Subgroups measured: none
Identification	Country: China  Setting: Cangzhou Central Hospital  Author's name: Dan Sun  Institution: Gynecology Department II, Cangzhou Central Hospital, Cangzhou, China  Email: not described  Address: not described  Aim of study: the effect and clinical efficacy of leuprorelin and endocrine drugs on ovarian function in receptor‐positive PBC patients were analysed.  Possible conflicts of interest: not described  Start and end date: January 2018 to October 2020
Notes	Tried to contact the author to confirm risk of bias and ask for raw data; no address available.  Ethical approval needed/obtained for study: this study was approved by the Hospital Ethics Committee of Cangzhou Central Hospital (approval number 2017LC102‐25).  Informed consent obtained: participants and their families clearly knew the theme of this study, and independently co‐operates with the research content and signed informed consent forms.  Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomised comprehensive sequential method was used to divide into control group and observation group.
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: not described; however, these outcomes are unlikely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: not described; however these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: high risk, because incomplete outcome data is used as exclusion criterion, meaning those people were already removed from the study before the analysis were done. There is no ITT analysis. It is not clear why those people had missing data and how many people that applies to.
Selective reporting (reporting bias)	Unclear risk	Comment: no protocol found. The outcome measures stated are also reported. However, there is some uncertainty about the presentation of the outcomes. For example, one table has 3 columns describing 'before treatment' and only 1 column describing 'after treatment', while it compares both groups (so it would be more logical to have 2 columns of both before and after treatment). In addition, in the text they state there is no difference in baseline, but if we look at the numbers in the table, there is quite a big difference.
Other bias	High risk	Comment: whether there are any conflicts of interest is not described. Nor is the study sponsor described. Baseline characteristics of both groups are presented as equal, but they only looked at age and duration of cancer treatment; no other participant characteristics were taken into account.

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Sverrisdottir 2009.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not stated Blinding: not described
Participants	Setting: clinics in UK, Italy and Sweden Number randomised: 123 allocated to chemotherapy treatment of which we used only 2 study arms, with a total of 57 participants Inclusion criteria: ‐ invasive breast cancer ≥ 10 mm  ‐ premenopausal menstrual status  ‐ primary surgery consisting of a mastectomy or a sector resection plus axillary node dissection  ‐ no clinical evidence of distant metastases Exclusion criteria: ‐ inoperable breast cancer ‐ prior radiotherapy or neo‐adjuvant chemotherapy  ‐ prior or concurrent endocrine therapy Group differences: baseline characteristics were well balanced.  Exclusions: 123  Reason for exclusions: 123 patient preference
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment GnRHa  Goserelin 3.6 mg subcutaneously every 28 days Duration of treatment: 2 years  Number randomised to group: 29  Age (median, range): 45 years (36 to 51)  Withdrawals: 5 at 2 years of endocrine treatment, 7 at 1 year after end of endocrine treatment  Reason withdrawals: not described  Timing of treatment: start concomitant to chemotherapy  Duration of follow‐up: 36 months Co‐interventions: participants operated on with breast‐conserving surgery received postoperative radiotherapy 50 Gy to the breast for 5 weeks. Participants with 4 or more positive lymph nodes received additionally locoregional radiotherapy including the chest wall, axillary‐ and supraclavivular lymph nodes 46 Gray through 4.5 weeks. No treatment  Duration of treatment: N/A  Number randomised to group: 28  Age (median, range): 45 years (29 to 53)  Withdrawals: 8 at 2 years of endocrine treatment and 1 year after treatment stopped  Reason withdrawals: not described  Timing of treatment: N/A  Duration of follow‐up: 36 months Co‐interventions: participants operated on with breast‐conserving surgery received postoperative radiotherapy 50 Gy to the breast for 5 weeks. Participants with 4 or more positive lymph nodes received additional locoregional radiotherapy including the chest wall, axillary‐ and supraclavivular lymph nodes 46 Gy through 4.5 weeks. Type of chemotherapy: "adjuvant CMF chemotherapy (6 cycles of cyclophsophamide 600 mg/m², methotrexate 40 mg/m2 and 5‐fluorouracil 600 mg/m² intravenously days 1 and 8, every 28 days)."
Outcomes	Premature ovarian insufficiency, any definition Defined as: amenorrhea at 6 months after stop of endocrine treatment Non‐pregnancy‐related adverse events (other adverse events): Outcome definitions: amenorrhea at 6 months after treatment Subgroups measured: none
Identification	Country: UK, Italy and Sweden  Setting: 4 centres affliated to the following trial groups: the British Cancer Research Campaign (CRC – now Cancer Research UK (CRUK)) Breast Cancer Trials Group (BCTG), the Stockholm Breast Cancer Trials Group, the South East (SE) Sweden Breast Group and the Italian GIVIO collaborative group.  Comments: none  Author's name: A Sverrisdottir  Institution: Landspitali University Hospital  Email: asgerds@landspitali.is  Address: Landspitali University Hospital, Reykjavik, Iceland  Aim of study: to examine if goserelin concomitant to CMF‐chemotherapy as adjuvant treatment for premenopausal breast cancer, protects the ovaries from premature failure.  Possible conflicts of interest: free drug was supplied by AstraZeneca for several trials. Payment towards the cost of immunohistochemical estimation of estrogen receptors in UK patients was also given. In Italy, the co‐ordination of the trial was supported by an educational grant from AstraZeneca. The Stockholm trial received funding from the King Gustaf V Jubilee Fund and an unrestricted research grant from AstraZeneca.  Start and end date: August 1987 to March 1999
Notes	Author confirmed risk of bias via email. No extra raw data available.  Ethical approval needed/obtained for study: the study was designed and conducted according to WHO’s Good Clinical Practice guidelines and was approved by the Karolinska Institute Regional Ethics Committee.  Informed consent obtained: it was the responsibility of each investigator to obtain informed consent from patients in the manner recommended by the local ethics committee.  Sponsorship source: free drug was supplied by ICI (now AstraZeneca) for the CRUK BCTG and GIVIO trials. Payment towards the cost of immunohistochemical estimation of ERs in UK patients was also given. In the UK, the trial was supported by a grant from the CRUK (formally Cancer Research Campaign). In Italy, the coordination of the trial was supported by an educational grant from AstraZeneca. The Stockholm trial received funding from the King Gustaf V Jubilee Fund and an unrestricted research grant from AstraZeneca.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Treatment allocation was based on balanced lists using the permuted block technique."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was carried out by telephone to a central ofﬁce where the patient identiﬁers were recorded before the allocated treatment was revealed to the responsible physician."
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are not likely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	Low risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but these outcomes are not likely to be influenced
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: no blinding; this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: "analysis was described as by intention to treat but appeared to be actual numbers." Number of participants dropping out appeared to be high; however, contact with author confirmed low number of dropouts.
Selective reporting (reporting bias)	Low risk	Comment: all prespecified outcome measures are reported.
Other bias	Low risk	Comment: baseline characteristics similar between groups

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Waxman 1987.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: not stated Blinding: not described
Participants	Setting: clinic in England Number randomised: 18 Inclusion criteria: Hodgkin's lymphoma Exclusion criteria: not described Group differences: not described, only age is presented as patient characteristic. According to age, both groups are similiar.  Exclusions: not described  Population description: patients undergoing chemotherapy for Hodgkin's lymphoma This study also incuded men with Hodgkin's lymphoma. All results were split by sex, which is why it was possible to use only the data for women in this review.
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists  Buserelin 200 µg thrice daily intranasally Duration of treatment: buserelin continued for the duration of chemotherapy and for a further 3 days after its completion.  Number randomised to group: 8  Age (mean, range): 28.5 years (17 to 34) Withdrawals: 1 (not described in which group); author says there were none  Reason withdrawals: death  Timing of treatment: 1 week prior to chemotherapy starting  Duration of follow‐up: up to 3 years after completion treatment, mean 2.3 years No treatment  Number randomised to group: 10  Age (mean, range): 25.9 years (17 to 46)  Withdrawals: 1 (not described in which group), author says there were none  Reason withdrawals: death  Timing of treatment: N/A  Duration of follow‐up: up to 3 years after completion treatment, mean 2 years Co‐interventions: not described Type of chemotherapy: each participant was treated with up to 6 cycles of standard MVPP (mustine 6 mg/m² intravenous on days 1 and 8, vinblastine 6 mg/m² i.v. on days 1 and 8, procarbazine 100 mg/m² per os on days 1 to 14 and prednisone 40 mg on days 1 to 14) chemotherapy.
Outcomes	Premature ovarian insufficiency, any definition Defined as: resumption of menses after chemotherapy. Outcome reversed (participants who did not reach the above definition) to obtain a value for premature ovarian insufficiency Clinical pregnancy Subgroups measured: not described
Identification	Country: England  Setting: not described  Comments: none  Author's name: JH Waxman  Institution: Department of Clinical Oncology, Hammersmith Hospital, London  Email: not described  Address: not described  Aim of study: "it may be that the repeated administration of an agonist analogue of gonadotrophin‐releasing hormone could protect against infertility. This hypothesis has been investigated."  Possible conflicts of interest: not described  Start and end date: not described
Notes	Tried to contact the author to confirm risk of bias and ask for raw data; no address available Ethical approval needed/obtained for study: not described  Informed consent obtained: not described  Sponsorship source: not described
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: contact with author by email: random number tables
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there is only 1 dropout, and the reason (death) is clearly reported.
Selective reporting (reporting bias)	Low risk	Comment: all prespecified outcome measures are reported.
Other bias	High risk	Comment: there was not much information available. Information about, e.g. inclusion and exclusion criteria, start and end date and centre is missing, which made us suspect bias in this article. Moreover, there was no power calculation and a small number of participants and limited description of methods.

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Zhong 2019.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: "we originally aimed to recruit 240 eligible patients. We estimated that with this sample size, and using a two‐group binomial design, our study would have more than 80% power to detect an absolute reduction of 15% points in the rate of ovarian failure, at a one‐sided significance level of 0.025...However, eventually only 98 recruited." Blinding: not described
Participants	Setting: 2 hospitals in China Number randomised: 98 Inclusion criteria: ‐ premenopausal women  ‐ aged 18 to 45 years, were eligible for enrolment if they had operable stage I to IIIA breast cancer, regardless of hormone receptor status  ‐ for which treatment with adjuvant anthracyclines‐containing chemotherapy was planned  ‐ the use of trastuzumab was permitted in patients with tumors which over‐expressed HER2. Exclusion criteria: ‐ stage IV breast cancer or with distant metastasis  ‐ presence of other malignancies over the last 5 years  ‐ undergoing chemotherapy or receiving GnRHa  ‐ fitted with an intrauterine device  ‐ taking ovulation‐promoting drugs or oral contraceptives within the previous three months  ‐ definite diagnosis of polycystic ovarian syndrome  ‐ irregular menstruation  ‐ amenorrhoea  ‐ pregnancy or lactation Group differences: the median age of our participants was 39.0 years (intervention participants on average 3 years younger (37 vs 40 years)). All participants received anthracycline‐based therapy and 79% received therapy featuring either paclitaxel or docetaxel. The clinical characteristics of the two groups were well balanced. All hormone receptor positive patients received endocrine therapy, and the endocrine therapy drug was toremifen. There were no significant differences in the levels of AMH, FSH, LH or E2 between the two groups at baseline.  Exclusions: 2  Reason exclusions: 1 not eligible, 1 not evaluated up to the end point of this study
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists Goserelin 3.6 mg subcutaneously every 4 weeks Duration of treatment: "from within 1 week of the initial chemotherapy dose and was continued to within 2 weeks of, or after, the final of chemotherapy" Eligible participants were administered with tamoxifen if their hormone receptor status was positive.  N randomised to group: 51  Age (mean, SD): 37.0 years Withdrawals: 13  Reason withdrawals: not described  Timing of treatment: from within 1 week of the initial chemotherapy dose and continued to within 2 weeks of, or after, the final chemotherapy Duration of follow‐up: 15 months Co‐interventions: the use of trastuzumab was permitted in patients with tumours which over‐expressed HER2 No treatment  N randomised to group: 45  Age (mean, SD): 40.0 years Withdrawals: 9  Reason withdrawals: not described  Timing of treatment: N/A  Duration of follow‐up: 15 months Co‐interventions: the use of trastuzumab was permitted in participants with tumours which over‐expressed HER2. Eligible participants were administered tamoxifen if their hormone receptor status was positive Type of chemotherapy: all participants received anthracycline‐based therapy and 79% of participants received therapy featuring either paclitaxel or docetaxel.
Outcomes	Premature ovarian insufficiency, any definition Notes: defined as: amenorrhoea for the preceding 6 months Outcome definitions: Ovarian failure: amenorrhoea for the preceding 6 months Patients who became pregnant were considered not to have had ovarian failure. Disease‐free survival Overall survival Events of overall survival included deaths due to any cause while events of disease free survival included breast cancer recurrence and metastasis Subgroups measured Age under 40 years and 40 to 45 years Hormone receptor status positive vs negative
Identification	Country: China  Setting: 2 Chinese hospitals  Comments: none  Author's name: Ying Zhong  Institution: Department of Breast Disease, Peking Union Medical College Hospital  Email: bakenfish@163.com  Address: Shuaifuyuan, Wangfujing, Beijing 100730, China  Aim of study: to examine whether GnRHa can protect ovarian function during chemotherapy, regardless of the state of the HR, to investigate whether AMH levels can reflect changes in ovarian function during chemotherapy and, finally, to investigate whether AMH levels can predict regular menstruation after chemotherapy.  Possible conflicts of interest: the authors have declared that they have no competing interest.  Start and end date: August 2015 to November 2016
Notes	Author contacted by email to confirm risk of bias and ask for raw data; no reply received Ethical approval needed/obtained for study: Peking Union Medical College Hospital ethics committee reviewed the study protocol and deemed the study exempt from full review.  Informed consent obtained: all provided written informed consent for participation.  Sponsorship source: Beijing Science and Technology Commission 2016: Science and Technology Project (Optimization of breast cancer screening program for the right age women in Beijing). The role of the funding consists of collection, analysis and interpretation of data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients were randomly assigned, in a 1:1 ratio," Quote: "Randomization was stratified according to age (< 40 years vs. 40 to 45 years) and hormone receptor" Comment: not described
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of participants and personnel (performance bias) Other adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Unclear risk	Comment: blinding not described
Blinding of outcome assessment (detection bias) Other adverse events	Unclear risk	Comment: blinding not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: only 76 participants left (22% withdrawal). Not explained why the other participants are missing
Selective reporting (reporting bias)	Low risk	Comment: all predefined outcome measures and subgroups are reported.
Other bias	Low risk	Comment: baseline characteristics are comparable between the two groups with respect to age, ER‐status and HER2‐status.

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Zong 2022.

*Study characteristics*
Methods	Design: parallel‐group RCT Randomisation method: computer randomisation Power calculation: a sample size of 368 was required for a 90% chance of detecting an absolute difference of 14 percentage points in the rate of POI between the GnRHa group and the control group at a 2‐sided significance level of 5%. The allowable withdrawing rate was 10%; thus, the maximum sample size estimated was 409. The expected difference in POI incidence was determined by reference to the results of POEMS/S0230. Blinding: all the participants, as well as all investigators who administered treatment and assessed outcomes, were unaware of the trial group assignments until the randomisation had been completed. The allocation was masked from the data analysts. No other blinding reported.
Participants	Setting: two hospitals in China Number randomised: 345 Inclusion criteria: ‐ premenopausal women  ‐ aged 18 to 49 years  ‐ with operable stage I to III breast cancer for which treatment with adjuvant or neoadjuvant cyclofosfamide‐containing chemotherapy was planned  ‐ taken no oestrogens, anti‐oestrogens, selective oestrogenreceptor modulators, aromatase inhibitors or hormonal contraceptives within the month before enrolment  ‐ negative urine test results for human chorionic gonadotropin  Exceptions were made for the use of hormonal contraception in women younger than 35 years that was discontinued before randomisation. Exclusion criteria: ‐ use of hormonal treatment for up to 2 months for the purposes of invitro fertilisation and cryopreservation of embryos or oocytes before randomisation  ‐ history of hysterectomy or oophorectomy, or ovarian radiation  ‐ received previous adjuvant endocrine therapy for breast cancer  ‐ with uterine and/or adnexal diseases needing medical or surgical treatment  ‐ with substantial chronic disease or any organ dysfunction  ‐ had allergies to active or inactive excipients of GnRHa Group differences: the 2 groups were well balanced with respect to all baseline demographic and clinical pathologic characteristics, as well as radiotherapy and chemotherapy adherence.  Exclusions: 60  Reason exclusions: 27 people quit participation voluntarily; 33 did not meet the inclusion criteria and were excluded.
Interventions	Comparison: ovarian suppression using GnRH agonists versus no treatment Ovarian suppression using GnRH agonists 3.6 mg goserelin or 3.75 mg of leuprorelin was injected subcutaneously once every 28 days  Duration of treatment: once every 28 days from 1 to 2 weeks before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy  Number randomised to group: 171  Age (mean, SD): 40.6 years (6.7)  Withdrawals: 6  Reason for withdrawals: lost to follow‐up  Timing of treatment: 1 to 2 weeks before the first cycle of chemotherapy  Duration of follow‐up: 5 years Co‐interventions: "all of the participants with erb‐B2 receptor tyrosine kinase 2 (ERBB2)–positive tumours received trastuzumab (first dose, 8mg/kg, followed by 6mg/kg for 1 year). Women with hormone receptor (HR)–positive disease received adjuvant endocrine therapy for 5 years starting from the end of chemotherapy." No treatment  Number randomised to group: 174 Age (mean, SD): 40.2 years (5.9)  Withdrawals: 9  Reason withdrawals: lost to follow‐up  Timing of treatment: N/A  Duration of follow‐up: 5 years Co‐interventions: "all of the participants with erb‐B2 receptor tyrosine kinase 2 (ERBB2)–positive tumours received trastuzumab (first dose, 8mg/kg, followed by 6mg/kg for 1 year). Women with hormone receptor (HR)–positive disease received adjuvant endocrine therapy for 5 years starting from the end of chemotherapy." Type of chemotherapy: "patients received chemotherapy according to 1 of the following CTX‐containing regimens: TEC (docetaxel + epirubicin + cyclophosphamide), EC‐T(H) (epirubicin + cyclophosphamide for 4 cycles followed with 4 additional cycles of docetaxel ± trastuzumab), TC(H) (docetaxel + cyclophosphamide ± trastuzumab), and FEC (5‐fluorouracil + epirubicin +cyclophosphamide). All of the patients with erb‐B2 receptor tyrosine kinase 2 (ERBB2)–positive tumors received trastuzumab (first dose, 8mg/kg, followed by 6mg/kg for 1 year)"
Outcomes	Premature ovarian insufficiency, any definition Notes: defined as: anti‐Müllerian hormone levels of less than 0.5 ng/mL Disease‐free survival Overall survival Disease‐free survival, hormone‐negative participants Disease‐free survival, hormone‐positive participants Disease‐free survival, participants < 35 years old Notes: 93% vs 62%; P = 0.004 Disease‐free survival, participants ≥ 35 years old Overall survival, hormone‐negative participants Overall survival, hormone‐positive participants Overall survival, participants < 35 years old Notes: 100% vs 81% Overall survival, participants ≥ 35 years old Non‐pregnancy‐related adverse events (other adverse events): fatigue Notes: no severe adverse events occurred. Each woman experienced different degrees of fatigue. Most of the intervention‐related adverse events were grade 1 to 2, and the proportion of grade 3 events was less than 5%. Outcome definitions: Premature ovarian insufficiency was defined as an AMH level of less than 0.5 ng/mL in this study. Overall survival: events in the analysis of overall survival (OS) included deaths of any cause. Tumour‐free survival (TFS) events were defined by the occurrence of 1 of the following: local recurrence, distant metastases, contralateral or ipsilateral breast tumour, or death of breast cancer. Only adverse events related to hormonal effects and serious adverse events that occurred during chemotherapy with or without treatment with goserelin were routinely assessed, with assessment according to the Common Terminology Criteria for Adverse Events, version 4.03. Subgroups measured and reported: hormone‐receptor‐positive and hormone‐receptor‐negative participants  Age 35 years old
Identification	Country: China  Setting: two hospitals: Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital in Shanghai and Zhejiang Cancer Hospital in Hangzhou  Author's name: Xiangyun Zong  Institution: Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital (Shanghai) and Zhejiang Cancer Hospital in (Hangzhou)  Email: tigerzong@msn.com  Address: Shanghai Jiao Tong University Shanghai Affiliated Sixth People’s Hospital, Shanghai 200233, China  Aim of study: to determine whether administering GnRHa during chemotherapy in premenopausal women with breast cancer can reduce ovarian impairment Possible conflicts of interest: Dr Zong reported grants from the Science and Technology Commission of Shanghai Municipality during the conduct of the study. No other disclosures were reported.  Start and end date: September 2015 to August 2017
Notes	Author confirmed risk of bias via email. No extra raw data available Ethical approval needed/obtained for study: the trial protocol was approved by the ethics committee at each site.  Informed consent obtained: written informed consent was obtained from all participants.  Sponsorship source: The Science and Technology Commission of Shanghai Municipality medical program grant 15411966500 and Zhejiang Medical Association cancer research program grant 2015ZYC‐A07.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The randomization procedure was prepared by an independent statistician." Comment: not described
Allocation concealment (selection bias)	Low risk	Quote: "The assignments remained concealed in opaque, sealed envelopes"
Blinding of participants and personnel (performance bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	High risk	Comment: no blinding; this outcome is likely to be influenced.
Blinding of participants and personnel (performance bias) Other adverse events	Low risk	Quote: "All the patients, as well as all investigators who administered treatment and assessed outcomes, were unaware of the trial group assignments until the randomisation had been completed. The allocation was masked from the data analysts." Comment: these outcomes are unlikely to be influenced.
Blinding of outcome assessment (detection bias) Ovarian failure, live birth, overall survival, clinical pregnancy, disease‐free survival, time‐to‐pregnancy, pregnancy‐related adverse events	Low risk	Comment: no blinding, but this outcome is unlikely to be influenced.
Blinding of outcome assessment (detection bias) Other adverse events	High risk	Comment: no blinding, this outcome is likely to be influenced.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: per‐protocol analysis performed
Selective reporting (reporting bias)	Low risk	Comment: all predefined outcomes were reported. Addition by study author: "All the data analysis was done according to the study plan, except for the fertility data. We pointed out in the discussion that the reason is that we believe that pregnancy and childbirth within three years after primary breast cancer treatment is a serious negative factor for breast cancer prognosis."
Other bias	Unclear risk	Comment: "The allocation was masked from the data analysts. Not clear if (part of it) was blinded now or not.  Baseline characteristics were comparable between groups."

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ABVD: adriamycin‐bleomycin‐vinblastine‐dacarbazine regimen; AMH: anti‐Müllerian hormone; CI: confidence interval; E2: oestradiol; ER: oestrogen receptor; FSH: follicle‐stimulating hormone; GnRH: gonadotropin‐releasing hormone; GnRHa: gonadotropin‐releasing hormone agonist; Gy: gray; HER‐2: human epidermal growth factor receptor 2; HR: hazard ratio; IHC: immunohistochemical; ITT: intention to treat; IU: international units; IV: intravenous; LH: luteinising‐hormone; LHRHa: luteinising hormone‐releasing hormone agonist; MCT: metronomic chemotherapy; n/N: number; N/A: not applicable; NCRI: National Institute for Cancer Research; OC: oral contraceptive; OPU: ovum pick up; OS: overall survival; P: probability; POI: premature ovarian insufficiency; PR: progesterone receptor; RCT: randomised controlled trial; rFSH: recombinant follicle‐stimulating hormone; RES: relapse‐free survival; SD: standard deviation; SEM: standard error of the mean; ULN: upper limit of normal; vs: versus; WHO: World Health Organization

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Badawy 2009	Unreliable author, fraudulent trial: the authenticity of several RCTs from Badawy are questioned; multiple journals published about this problem
Blumenfeld 2009	Commentary/letter
Stewart 2021	Commentary/letter
Wikander 2021	Wrong setting
Wildiers 2006	Commentary/letter

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Characteristics of studies awaiting classification [ordered by study ID]

EUCTR2006‐002600‐33‐BE.

Methods	Open RCT
Participants	Premenopausal women (aged minimum 18, maximum 50) with stage I, II or IIIa breast cancer, both oestrogen and progesterone receptor negative, candidate for adjuvant or neoadjuvant alkylating agent‐containing chemotherapy
Interventions	Goserelin acetate
Outcomes	Rate of ovarian failure at 2 years from initiation of chemotherapy Ovarian dysfunction at 1 year and 2 years following chemotherapy Ovarian reserve at 1 and 2 years Pregnancy and other fertility information after treatment and during the 5‐year follow‐up period
Notes	International Breast Cancer Study Group

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NCT00380406.

Methods	Design: RCT Setting: Ottawa Hospital Regional Cancer Institute (OHRCC) and the Cancer Center of South Eastern Ontario at Kingston General Hospital (CCSEO)
Participants	Inclusion criteria: women aged 18 to 38 years will be undergoing gonadotoxic curative/adjuvant chemotherapy for early stage disease have provided informed consent Exclusion criteria: women who have advanced stage disease and/or whose median survival is expected to be less than 6 months cancer of the ovaries, uterus, or fallopian tubes clinical or biochemical evidence of diminished ovarian reserve previously received chemotherapy or abdominal/pelvic radiation or have planned to receive abdominal/pelvic radiation pregnancy contraindications to intramuscular injections history of fractures secondary to/or documented osteoporosis
Interventions	Leuprolide acetate versus no treatment (only chemotherapy)
Outcomes	Protection against ovarian failure (12 months post chemotherapy) Sonographic (biophysical) and biochemical markers of ovarian reserve
Notes	Study completed, but no publications found and no contact with the author possible.

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NCT01035099.

Methods	Parallel, open label, randomised trial
Participants	Female breast cancer patient with breast cancer diagnosis after surgery and before undergoing chemotherapy, desiring fertility preservation with oocyte or embryo cryopreservation Healthy participants, according to documented medical history and physical examination, who have been diagnosed with breast cancer (oestrogen and progesterone receptor positive and/or negative) Below 45 years of age at time of informed consent Verbal or written clearance from medical or surgical oncologist to undergo controlled ovarian hyperstimulation‐IVF Delay to chemotherapy treatment will not jeopardise cancer treatment outcome Ovarian stimulation will not affect cancer treatment plan Transvaginal ultrasound scan within one month of starting stimulation with no clinically significant pelvic mass Serum FSH level (day 2 to 4) less than 25 Negative pregnancy test prior to beginning Letrozole or gonadotropin therapy Willing and able to comply with the protocol Voluntary provision of written informed consent, prior to any study‐related procedure that was not part of normal medical care, with the understanding that the subject can withdraw consent at any time without prejudice to her future medical care Willingness to provide follow‐up information on herself and babies born as part of this study
Interventions	Patients who are randomised to the titrated dose of letrozole will start gonadotropins in the evening of day 2 of their menstrual cycle with injectable FSH and human menopausal gonadotropin (HMG). Oral letrozole will be added to the stimulation in the following titrated regimen. Patients who are randomised to fixed dose letrozole will start letrozole 5 mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle.
Outcomes	Primary Mature oocyte yield Percent of mature oocyte yield calculated as number of mature oocytes divided by number of oocytes retrieved (per participant) Secondary Participant cycle cancellation rate Breast cancer recurrence rate Peak serum oestradiol level (pg/ml) FSH ng/ml (cycle day 2) AMH ng/ml (cycle day 2) Antral follicle count Total days stimulation medications Total medication dose Total number of oocytes retrieved Number of follicles on day of HCG Number of fertilised oocytes Number of good‐quality embryos Breast cancer recurrence at year 1 to 2 Breast cancer recurrence at year 2 to 3
Notes

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NCT01530607.

Methods	Open‐label RCT
Participants	Inclusion criteria: patients must be premenopausal women with a histologically confirmed diagnosis of operable stage I, II or IIIA invasive breast cancer patients must have tumours that are both oestrogen receptor negative and progesterone receptor negative aged 18 or greater and under age 50 years planned treatment must include 3 to 8 months or cycles of an alkylating agent containing postoperative or preoperative chemotherapy regimen that can be anthracycline‐based or non‐antrhacycline‐based for patients receiving chemotherapy in the preoperative setting, there must be no intention to give additional chemotherapy in the postoperative setting patients receiving postoperative chemotherapy must be registered within 84 days after the final surgical procedure required to adequately treat the primary tumour or axilla patients must not have received prior cytotoxic chemotherapy patients must not have received oestrogens, anti‐oestrogens, selective oestrogen receptor modulators, aromatase inhibitors, or hormonal forms of contraception within the preceding month no prior malignancy except for adequately treated basal cell skin cancer, in situ cancer or other cancer for which the patient has been disease‐free for five years after treatment with curative intent performance status of 0 to 2 by Zubrod criteria must agree to use an effective barrier contraceptive method must be informed of the investigational nature of this study and must sign and give written informed consent Exclusion criteria: pregnant or nursing women may not participate due to the possibility of foetal harm or of harm to nursing infants from this treatment regimen
Interventions	Goserelin versus no treatment (chemotherapy only)
Outcomes	Rate of premature ovarian insufficiency at two years
Notes	Study completed, but no publications found. No contact with the author was possible.

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NCT02661932.

Methods	Open‐‐label interventional trial
Participants	Inclusion criteria Breast cancer female patients of less than 41 years old Addressed to fertility preservation unit before starting chemotherapy Exclusion criteria Metastatic breast cancer Known premature ovarian failure Basal FSH > 20 IU Surgical contraindications
Interventions	Breast cancer patients undergo fertility preservation with letrozole‐associated controlled ovarian stimulation for oocyte collection. Letrozole is administered orally (5 mg/day) during the entire stimulation protocol until ovulation triggering.
Outcomes	Primary objective of the study is to evaluate efficiency of letrozole‐associated ovarian stimulation for fertility preservation in breast cancer patients in terms of oocyte maturation rate. Patients' results for primary endpoint are prospectively compared to infertile patients undergoing controlled ovarian stimulation without letrozole. Secondary objectives of the study aim to evaluate safety of the protocol. Oestradiol and progesterone levels at ovulation triggering, ovulation and during luteal phase after oocyte retrieval (days 3 and 8) The risk of disease relapse will be assessed by long‐term follow‐up of these patients (up to 5 years) as well as an evaluation of circulating tumoral DNA before and after ovarian stimulation. Obstetric outcomes will also be recorded.
Notes

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NCT02856048.

Methods	Prospective, multicentre, open RCT
Participants	Female aged 12 to 25 years Puberty Tanner 2 or more (staging of sexual development in which stage 2 marks the beginning of physical development) Diagnosis of cancer: sarcoma, Ewing, osteosarcoma, lymphoma Chemotherapy protocol with alkylating agents at an intermediate ovarian toxicity risk (cyclophosphamide 6 g/m2, ifosfamide 50 g/m², procarbazine 4 g/m², lomustine 350 mg/m² or melphalan 140 mg/m² or a combination of these drugs). All participants with an osteosarcoma, Ewing sarcoma except pelvic localisation, Hodgkin lymphoma treatment group III (stages II B, III B and IV), B cell lymphoma group C, rhabdomyosarcoma treated with at least 8 Ifosfamide Vincristin Actinomycin (IVA) courses, synoviosarcoma group II T > 5 cm and group III, adult type sarcoma group I and II T > 5 cm and group III Before starting any chemotherapy Covered by medical insurance
Interventions	Triptorelin (GnRHa) + chemotherapy versus chemotherapy alone
Outcomes	Variation in AMH serum levels between both groups Secondary outcome measures Number of patients with AMH serum levels < 5th percentile in each group Intra‐patient variation in AMH serum levels between groups up to 36 months Centralised hormonal dosages and study of potential factors associated with the efficacy of GnRHa co‐treatment in preventing ovarian reserve loss (if there is one) AFC on ultrasound between the 2 groups at month 24 Delay of resumption of menses between the 2 groups up to the end of the follow‐up; comparison of delay of resumption of menses between the 2 groups Levels of markers of ovarian reserve: AMH, FSH, oestradiol between groups at months 12, 24 and 36; centralised hormone dosage Pregnancy rate in the 2 groups up to the end of the follow‐up (an average of 3 years) Adverse events related to triptorelin co‐treatment up to the end of the follow‐up (an average of 3 years) Relative change in BMD of the lumbar spine, left femoral neck and whole body in the 2 groups at baseline and at month 12 and month 36
Notes

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Unknown 2015.

Methods	Prospective, parallel, randomised clinical trial
Participants	Premenopausal women (aged minimum 18, maximum 45 years) with stage I, II or III breast cancer, candidate for adjuvant or neoadjuvant chemotherapy
Interventions	Standard chemotherapy with or without goserelin
Outcomes	Ovarian failure DFS, OS, FSH, E2, AMH Ovarian dysfunction Pregnancy Time to resumption of menstrual activity
Notes	Peking Union Medical College Hospital

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AFC: antral follicular count; AMH: anti‐Müllerian hormone; BMD: bone mass density; DFS: disease‐free survival; E2: oestradiol; FSH: follicle‐stimulating hormone; GnRHa: gonadotrophin‐releasing hormone; HCG: human chorionic gonadotropin; IU: international unit; IVF: in vitro fertilisation; OS: overall survival; RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

NCT04536467.

Study name	Prevention of chemotherapy‐induced ovarian failure with goserelin in premenopausal lymphoma patients
Methods	Blinding: no Power: based on the results from the literature and to ensure a power of 80% and a type I error probability of 5%  Total number randomised: sample size: 80 Outcome definitions: evaluating ovarian function by: at the start of treatment and after 3 cycles of chemotherapy treatment and at the end of 6 cycles of chemotherapy through:  ‐ FSH level ‐ oestradiol level  ‐ AMH level. 1 year follow‐up after chemotherapy  Secondary outcome measures:  ‐ overall response determined by tumour assessments from radiological tests, including one of the following (computed tomography scan, magnetic resonance imaging positron‐emission tomography or physical examinations according RECIL 2017 criteria ‐ adverse events (sweating, hot flushes, vaginal bleeding, vaginal dryness, headaches)
Participants	Inclusion criteria:  ‐ confirmed lymphoma cancer radiological and pathological or by clinical evaluation receiving chemotherapy treatment  ‐ normal FSH‐level, oestradiol level (FSH levels less than 10IU/L at the time of random assignment)  ‐ female  ‐ age between 17 to 40 years  ‐ written informed consent Exclusion criteria:  ‐ known hypersensitivity reaction to investigational compounds or incorporated substances  ‐ primary ovarian dysfunction, previous history of amenorrhoea > 3 months  ‐ age > 40 years ‐ pregnant or lactating patients, prior use of hormonal contraceptives has to be discontinued before first goserelin injection  ‐ patients who are unlikely to comply with trial requirements (eg, confusion, psychological or mood disturbances, alcoholism, vaginitis, vaginal bleeding, cardiac arrhythmia)
Interventions	GnRHa  Description: goserelin will be given as a 3.6 mg subcutaneous injection in the abdominal wall every 4 weeks (28 ± 3 days) plus standard chemotherapy at start of regimen for 3 months.  Co‐interventions: participants will take only standard chemotherapy for 3 months. Description: no treatment  Co‐interventions: participants will take only standard chemotherapy for 3 months.
Outcomes	Premature ovarian failure
Starting date	1 March 2019
Contact information
Notes	RECIL: International Working Group consensus response evaluation criteria in lymphoma

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NCT05328258.

Study name	Use of GnRHa during chemotherapy for fertility protection (ProFertil)
Methods	Double‐blind
Participants	Inclusion criteria: ‐ signed informed consent  ‐ breast cancer or acute leukaemias, lymphomas (Hodgkin and non‐Hodgkin) or sarcomas (osteo, soft tissue and Ewing) confirmed by histology and assigned for disease‐specific chemotherapy  ‐ confirmed menarche  ‐ ECOG performance status 0 to 1 ‐ adequate bone marrow, renal, hepatic and cardiac functions, and absence of other uncontrolled medical or psychiatric disorders Exclusion criteria: ‐ demonstrated premature ovarian failure at time of randomisation according to clinical or biochemical data  ‐ previous or planned bilateral oophorectomy ‐ pregnancy or breastfeeding at time of start of chemotherapy  ‐ other malignancy diagnosed within the last five years  ‐ uncontrolled hypertension, heart, liver, kidney related or other uncontrolled medical or psychiatric disorders including previous or current diagnosis of anorexia  ‐ known osteoporosis  ‐ known low platelet count with increased bleeding risk or refractory thrombocytopenia in women with acute leukaemias ‐ known or suspected allergy against triptorelin ‐ direct radiation of the gonads previous or planned (TBI allowed) ‐ mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation
Interventions	GnRHa: triptorelin intramuscularly once every month or every third month during gonadotoxic chemotherapy treatment. Dose either 11.25 mg triptorelin for participants having at least 3 months gonadotoxic treatment, or 3.75 mg for participants during one month of gonadotoxic treatment  Placebo: 0.9% sodium chloride, intramuscularly once every month or every third month during gonadotoxic chemotherapy treatment The dose will be provided both as one injection compensating for 3 months' effect and one injection compensating for 1 month's effect to maintain the study blinding.
Outcomes	AMH levels in women with breast cancer 12 months after end of treatment AMH levels in women with acute leukaemias, lymphomas and sarcomas 12 months after end of treatment Changes in AFC in women with breast cancer and with acute leukaemia, lymphoma and sarcoma, respectively Changes in ovarian reserve with or without GnRHa by observation of AMH levels The difference in recovery of AMH levels between the GnRHa group and the placebo group The proportion of females with or without GnRHa that develop ovarian insufficiency by determination of FSH, inhibin and oestradiol at end of gonadotoxic chemotherapy Comparison of FSH, inhibin and oestradiol between the GnRHa group and the placebo group Impact of body mass index (kg/m2) on changes in ovarian reserve with or without GnRHa at baseline, during treatment, at end of gonadotoxic chemotherapy Longitudinal observation of AMH levels, FSH, inhibin and oestradiol. Impact of use of contraceptives (yes/no) in changes of ovarian reserve Longitudinal observation of AMH levels, FSH, inhibin and oestradiol Impact of endocrine adjuvant therapy (yes/no) in changes of ovarian reserve The effect of GnRHa with or without GnRHa on ovarian blood supply The proportion of females with or without GnRHa that develop amenorrhoea (no menstruation) at end of gonadotoxic chemotherapy Comparison of the proportion that develop amenorrhoea (no menstruation) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Pregnancy wish after cancer treatment in women with or without GnRHa Comparison of pregnancy wish (study‐specific questionnaire) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively. Fertility and childbirth after cancer treatment in women with or without GnRHa who attempt pregnancy during follow‐up at end of chemotherapy Comparison of pregnancy attempts (study‐specific questionnaire) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Fertility and childbirth after cancer treatment in women with or without GnRHa who attempt pregnancy during follow‐up at end of gonadotoxic chemotherapy Comparison of pregnancy outcome between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Health‐related quality of life at end of gonadotoxic chemotherapy Comparison of validated outcome on health‐related QoL between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively Health‐related quality of life (FSFI) at end of gonadotoxic chemotherapy (EoT) Comparison of validated outcome of sexuality and reproductive health (Female Sexual Function Index (FSFI)) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Health‐related quality of life (HAD) at end of gonadotoxic chemotherapy (EoT) Comparison of validated outcome on health‐related QoL (Hospital Anxiety and Depression Scale (HAD)) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively. Development of comorbidities during follow‐up and bone mineral density at baseline, at end of gonadotoxic chemotherapy (EoT) Comparison of bone mineral density between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Disease‐specific oncological outcomes: disease‐free survival at 12 months, 2 years, 3 years, 4 years and 5 years after EoT Investigation of disease‐free survival between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Disease‐specific oncological outcomes: recurrence rate at 12 months, 2 years, 3 years, 4 years and 5 years after EoT Investigation of recurrence rate between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively Disease‐specific oncological outcomes: overall survival at 12 months, 2 years, 3 years, 4 years and 5 years after EoT Investigation of overall survival between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukaemia, lymphoma and sarcoma, respectively.
Starting date	31 March 2023
Contact information	kenny.rodriguez‐wallberg@ki.se
Notes

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AFC: absolute lymphocyte count; AMH: anti‐Müllerian hormone; ECOG: Eastern Cooperative Oncology Group; EoT: end of treatment; FSH: follicle‐stimulating hormone; GnRHa: gonadotropin‐releasing hormone agonist; TBI: traumatic brain injury

Differences between protocol and review

In the process of writing this review, the review authors made some changes from the protocol.

We amended the definition of the primary outcome 'ovarian insufficiency' by agreement with the Cochrane Gynaecology and Fertility Group editorial base. The definition now is: "Ovarian insufficiency: assessed by the presence of irreversible amenorrhoea lasting for at least 12 months and FSH‐level, measured at least once, equal to or higher than 25 MIU/mL in the presence of a negative pregnancy test".
We added the subgroup 'ovarian insufficiency, any definition' because the definition stated in our protocol was very strict. We thought that adding the broader definition as a subgroup would give us a deeper insight into this outcome.
We added the number of oocytes retrieved after ovarian stimulation as a secondary outcome because this is one of the most important outcome measures in controlled ovarian hyperstimulation protocols.
We changed the definitions of the subgroups 'age at start of intervention' and 'age at the wish to conceive'. We used two age groups (under 35 years old and 35 years old and above) instead of the predefined three age groups (under 30 years old, 30 to 40 years old, over 40 years old).

Contributions of authors

Task	Author
Drafted the protocol	MAJW, EG, RvE, CF
Selected which trials to include	MAJW, EG
Extracted data from trials	MAJW, EG
Entered data into Review Manager software	MAJW
Carried out the analyses	MAJW
Interpreted the analyses	MAJW, EG, RE
Drafted the final review	MAJW, EG, RvE, CF

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Sources of support

Internal sources

No sources of support provided

External sources

No sources of support provided

Declarations of interest

The authors (MAJW, EG, RvE, CF) declare that none of them have any known competing financial interest or personal relationships that influences, could have appeared to influence, the work reported in this review and the results presented.

New

References

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References to studies excluded from this review

Badawy 2009 {published data only}

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References to studies awaiting assessment

EUCTR2006‐002600‐33‐BE {published data only}

EUCTR2006-002600-33-BE. Phase III trial of LHRH analog administration during chemotherapy to reduce ovarian failure following chemotherapy in early stage, hormone-receptor negative breast cancer. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2006-002600-33-BE (first registered 23 October 2006).

NCT00380406 {unpublished data only}

Kashyap S. Protecting ovaries and fertility during chemotherapy - the PROOF trial: a randomized controlled trial of gonadotropin releasing hormone agonist (GnRHa) for fertility preservation in oncology patients. https://clinicaltrials.gov/show/NCT00380406 (first posted 23 September 2006).

NCT01035099 {unpublished data only}

NCT01035099. RCT of fixed vs titrated letrozole in breast cancer patient undergoing IVF [A randomized open label clinical trial of fixed dose letrozole vs. titrated letrozole for in vitro fertilization with cryopreservation of oocytes and embryos in breast cancer patients]. https://clinicaltrials.gov/study/NCT01035099 (first posted 18 December 2009).

NCT01530607 {unpublished data only}

NCT01530607. Administration during chemotherapy to reduce ovarian failure following chemotherapy in early stage, hormone-receptor negative breast cancer. https://clinicaltrials.gov/show/NCT01530607 (first posted 23 January 2012).

NCT02661932 {published data only}

NCT02661932. Fertility preservation in breast cancer patients (Brovale) [Efficiency and safety study of ovarian stimulation with letrozole for fertility preservation in breast cancer patients]. https://www.clinicaltrials.gov/study/NCT02661932 (first posted 25 January 2016).

NCT02856048 {published and unpublished data}

NCT02856048. Co-treatment with GnRH analogs on the ovarian reserve in young women treated with alkylating agents for cancer (PRESOV) [Assessment of the effect of a co-treatment with GnRH analogs on the ovarian reserve in adolescents and young women treated with alkylating agents for cancer]. https://clinicaltrials.gov/search?cond=NCT02856048 (first posted 4 August 2016).

Unknown 2015 {published data only}

References to ongoing studies

NCT04536467 {unpublished data only}

NCT04536467. Prevention of chemotherapy-induced ovarian failure with goserelin in premenopausal lymphoma patients. https://clinicaltrials.gov/ct2/show/NCT04536467 (first posted 2 September 2020).

NCT05328258 {published data only}

NCT05328258. Use of GnRHa during chemotherapy for fertility protection (ProFertil) [A phase 3 randomised double-blinded placebo-controlled study of use of GnRHa during chemotherapy for fertility protection of young women and teenagers with cancer]. https://clinicaltrials.gov/ct2/show/NCT05328258 (first posted 14 April 2022). [DOI] [PMC free article] [PubMed]

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PERMALINK

Interventions for fertility preservation in women with cancer undergoing chemotherapy

Maria AJ Weterings

Elizabeth Glanville

Rik Eekelen

Cindy Farquhar

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Summary of findings table ‐ Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients.

Summary of findings 2. Summary of findings table ‐ Ovarian suppression using gonadotropin‐releasing hormone agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients.

Summary of findings 3. Summary of findings table ‐ Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus ovarian suppression using GnRH agonists in breast cancer patients.

Background

Description of the condition

Description of the intervention

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos

Ovarian suppression using GnRH agonists

Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos

Ovarian suppression using GnRH agonists

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Comparison 1: controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos

Comparison 2: ovarian suppression during chemotherapy using GnRH agonists

Comparison 3: controlled ovarian hyperstimulation with gonadotropins and a protective agent, followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

1.

2.

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

1. Summary of findings table ‐ Ovarian suppression using gonadotrophin‐releasing hormone agonists versus placebo, usual care, no treatment or another agent in the same group, for people with other cancers.

Results

Description of studies

Results of the search

3.

Comparisons

Study design and setting

Participants

Interventions

Outcomes

Excluded studies

Risk of bias in included studies

Sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessors

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

1. Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos versus placebo, usual care, no treatment or another agent from the same group

1.1 Women with breast cancer

1.1.1. Number of oocytes retrieved after ovarian stimulation