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. 2019 Apr 4;2019(4):CD009127. doi: 10.1002/14651858.CD009127.pub2

Chemotherapy‐related late adverse effects on ovarian function in female survivors of childhood cancer and cancer in the reproductive age

Annelies Overbeek 1,✉, Marleen H van den Berg 1, Flora E van Leeuwen 2, Gertjan JL Kaspers 3, Leontien CM Kremer 4, Cornelis B Lambalk 5, Eline van Dulmen‐den Broeder 6
PMCID: PMC6564077

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The first objective is to evaluate the prevalence of ovarian dysfunction after treatment with chemotherapy for childhood cancer or cancer in the reproductive age.

The second objective is to evaluate the relationship between ovarian function and a specific chemotherapy group (e.g. alkylating agents, anthracyclines etc.) or a specific chemotherapeutic agent (e.g. cyclophosphamide, daunorubicin etc.), dose of chemotherapy, age at time of treatment, and time since treatment.

Background

Over the last decades, more effective treatment regimens for childhood cancer have led to a significant rise in long‐term survival. However, survivors of childhood cancer, as well as survivors of cancer in the reproductive age are at risk of adverse late effects on the reproductive system which may not become apparent until many years later. Because the pool of primordial follicles in women is fixed, cancer treatment, through its associated cell kill, might (even in childhood) substantially deplete this oocyte pool, potentially leading to ovarian dysfunction, infertility and premature menopause.

It has been demonstrated that radiotherapy to the abdomen and pelvis has deleterious effects on ovarian function. The degree of harm is related to the localisation, total radiation dose, fractionation schedule and age at time of treatment (Wallace 2005). Cranial irradiation (>35–40 Gy) can impair the hypothalamic pituitary function, resulting in hypogonadism through GnRH or FSH/LH deficiency. Radiation to the pelvis may, in addition to causing severe damage to the ovarian follicle pool, induce uterine fibrosis, which may complicate future pregnancies.

In contrast to these adverse late effects of radiotherapy on ovarian function, the exact mechanism by which specific chemotherapeutics do harm in females remains unclear. Histopathology of the ovary has shown that chemotherapy destroys the primordial follicles and can lead to ovarian atrophy in animal models. Other mechanisms causing damage to the ovary include injury to blood vessels and focal ovarian cortical fibrosis (Meirow 2000). Recently, the 'burn‐out' hypothesis was postulated, explaining the loss of follicles after chemotherapy. This hypothesis is based on research with genetically modified mice that do not produce anti‐Mullerian hormone (AMH‐null). The mice show increased activation of primordial follicles, leading to increased atresia of large follicles, and consequently accelerating the depletion of the total follicle pool. Treatment with chemotherapy destroys growing follicles and these follicles are therefore prevented from producing AMH. AMH inhibits primordial follicle recruitment, so a drop in AMH levels might lead to an increase in large follicles and a decrease in primordial follicles (Meirow 2010). It is known that chemotherapy may induce damage to the ovary, and that this damage is drug, dose and age dependent. Small studies assessing clinical outcomes of gonadal function (Lantinga 2006; Lie Fong 2008; Bath 2003; Larsen 2003) and large cohort studies (Byrne 1987; Chemaitilly 2006; Chiarelli 1999; Reinmuth 2008; Sklar 2006; Green 2009) in which gonadotoxicity was assessed by questionnaire data have associated the following chemotherapeutic agents with gonadotoxicity: alkylating agents, antimetabolites, platinum agents, taxanes, procarbazine and possibly vinca‐alkaloids.

All women are endowed with their entire non‐replenishable pool of follicles from birth. Initially there are 6‐7 million primordial follicles present at the fourth month of fetal development, whereas only 400,000‐600,000 primordial follicles remain at menarche, and finally at the stage of menopause, the number of remaining follicles has dropped to below 1000. From the age of approximately 31 years fecundity decreases, leading to natural sterility, menstrual cycle irregularity and menopause (Lambalk 2009). Recently, a new model for the total population of non‐growing follicles was calculated from eight histological studies in which numbers of non‐growing follicles were assessed from conception to menopause. The rate of non‐growing follicle recruitment increases from birth to 14 years and then declines with age until menopause. The model showed that 95% of women aged 30, had only 12% of their total non‐growing follicle population left, and by the age of 40, only 3% remained. Furthermore, the model showed that 81% of the variance in total follicle pool was due to age (Wallace 2010). Age at natural menopause in the developed world ranges between 40 years and 58 years, with an approximate mean of 51.4 years. Ethnicity as well as lifestyle and reproductive factors (smoking, parity, age at menarche) are associated with age at menopause (Henderson 2008).

Premature menopause is diagnosed when amenorrhoea is present before the age of 40 years with hypersecretion of FSH. There are many terms used for this condition, including premature ovarian failure, primary ovarian failure and hypergonadotropic hypogonadism. Recently, Nelson introduced a more accurate term: primary ovarian insufficiency, defined as amenorrhoea for four months or more, with two serum FSH levels (obtained at least one month apart) in the menopausal range in a woman under 40 years of age (Nelson 2009).

There are many different ways to assess ovarian reserve and ovarian function. Ovarian reserve tests concentrate either on measurements of hormones in the blood, produced by the ovary (Anti‐Mullerian hormone, inhibin B) or the pituitary (FSH), or on ultrasonographic measurements of the ovaries (antral follicle count, ovarian volume). Of the endocrinological markers, AMH seems superior in that it changes gradually with age, as opposed to FSH and inhibin B that only change at the end of the reproductive life span. Furthermore, some studies (La Marca 2006; Tsepelidis 2007), but not all (Hadlow 2012; Overbeek 2012; Cook 2000; Streuli 2009; Wunder 2008), show that AMH sampling does not seem to require specific timing and its reproducibility between cycles is good. Antral follicle counts have been found to correspond well with histological analysis (which is the golden standard) of the follicle pool and show a gradual decline with age. This allows for predictions of ovarian reserve relatively early in life. Careful history taking, with special attention to family history, cycle shortening and occurrence of vasomotor symptoms, can also provide tools to aid in the prediction of age at menopause. Ovarian biopsy, inhibin A, LH, estradiol and progesterone are not considered reliable markers for assessing ovarian reserve (Lambalk 2009).

To our knowledge, no systematic review is available summarizing and comparing outcomes of ovarian function following chemotherapy only for childhood cancer or cancer in the reproductive age. To ensure good quality care and up‐to‐date information for female childhood cancer survivors and female survivors of cancer in the reproductive age, more insight is needed into the late effects of chemotherapy on ovarian function. With the current trend to postpone childbearing to the early thirties, evidence‐based insights are needed on the effect of various cancer treatments, doses of treatment and ages at which treatment occurred on ovarian reserve and the subsequent risk of premature menopause. If risk groups can be identified, tailored options for fertility preservation and solid advice can be offered for future patients. This will not only make it easier to prevent involuntary childlessness but also prevent menopause‐associated conditions such as symptoms of oestrogen deficiency, osteoporosis and cardiovascular disease. Moreover, protocols could be modified depending on their gonadotoxicity in order to preserve fertility in future patients.

Objectives

The first objective is to evaluate the prevalence of ovarian dysfunction after treatment with chemotherapy for childhood cancer or cancer in the reproductive age.

The second objective is to evaluate the relationship between ovarian function and a specific chemotherapy group (e.g. alkylating agents, anthracyclines etc.) or a specific chemotherapeutic agent (e.g. cyclophosphamide, daunorubicin etc.), dose of chemotherapy, age at time of treatment, and time since treatment.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised controlled trials, clinically controlled trials, cohort studies, case‐control studies and cross‐sectional or longitudinal studies examining the effect of chemotherapy on ovarian function outcomes in our search. We excluded case reports and case series.

We defined cohort studies as studies in which a group of consecutive patients treated for childhood cancer or cancer in the reproductive age was followed from a similar well‐defined point in the course of the disease (i.e. at least 2‐year survivors). The described study group could have been the entire original cohort of cancer survivors or a subgroup of the original cohort, based on well‐defined inclusion criteria. The patients in the original cohort represented the whole group of cancer survivors. The described study group encompassed the cancer survivors from the original cohort included in the study. The study groups of interest were the cancer survivors within the original cohort who received chemotherapy only.

Types of participants

Regarding the clinical outcomes (i.e. endocrinological and ultrasonographical measurements), we included female survivors of childhood cancer or adult cancer survivors under the age of 40 years at time of outcome assessment. This age cut‐off was chosen because the definition of primary ovarian insufficiency implies a reduced ovarian function before the age of 40 (Nelson 2009). Regarding the self‐reported outcomes (i.e. age at menopause), we included female survivors of childhood cancer and cancer in the reproductive age, and did not impose an age restriction at the time of outcome assessment. Minimal follow‐up had to be at least two years after diagnosis. We included all forms of cancer diagnosed in patients younger than 38 years (i.e. aged 40 minus two years of follow‐up).

Types of interventions

We included all studies that describe treatment with chemotherapy, either with or without surgery. We excluded patients that underwent surgery to the ovaries. Since the current review aimed to assess the effect of chemotherapy only on the ovary, we excluded all cases in which radiotherapy might have had a deleterious effect on ovarian function. As a consequence, we excluded all studies in which chemotherapy is unequivocally combined with subdiaphragmatic radiotherapy, total body irradiation or radiotherapy on the brain from the analyses.

Types of outcome measures

Primary outcomes

  • Age at menopause

  • Signs of primary ovarian insufficiency (elevated FSH, amenorrhoea before age 40)

Secondary outcomes

Other signs of reduced ovarian reserve:

  • Endocrinologically:

    • low anti‐Mullerian hormone

    • elevated inhibin B

  • Ultrasonographically:

    • low or absent antral follicle count

    • decreased ovarian volume

Because different cut‐off values for the mentioned outcomes were applied in the original studies, we used the cut‐off values as defined by the authors of these studies.

Search methods for identification of studies

See: Cochrane Childhood Cancer Group methods used in reviews (Module CCG)

The initial objective of the literature search was to identify all studies reporting on treatment‐related late effects on ovarian function in childhood cancer survivors and cancer survivors in the reproductive age. Afterwards we selected those studies in which the effect of chemotherapy has been described and analyzed as a separate treatment modality.

Electronic searches

We searched the following electronic databases:

MEDLINE/PubMed (from 1945 to present), EMBASE/Ovid (from 1980 to present) and The Cochrane Central Library of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue). The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are stated in the appendices (Appendix 1, Appendix 2, Appendix 3).

Searching other resources

To find information about trials not registered in CENTRAL , MEDLINE or EMBASE, either published or unpublished, we searched the reference lists of relevant articles and reviews. We scanned the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2005 to 2013) and European Society of Late Complications of Childhood Cancer (ESLCCC) (from 2007 to 2013) electronically or otherwise by hand.

We searched the ISRCTN register (www.isrctn.org/), the WHO International Clinical Trials Registry Platform (WHO ICTRP, www.who.int/ictrp/en/), and the register of the National Institute of Health (clinicaltrials.gov/) for ongoing trials. We did not impose language restrictions and will update the searches every two years.

Data collection and analysis

Selection of studies

After performing the search strategy described previously, two reviewers (AO, MvdB) independently selected studies meeting the inclusion criteria. We resolved discrepancies between reviewers by consensus. We obtained in full any study which seemed to meet the inclusion criteria on grounds of the title, or abstract, or both, for closer inspection. We clearly stated details of reasons for exclusion of any study considered for this review.

Data extraction and management

Two reviewers independently performed data extraction using standardised forms. We extracted data on the following items.

1. Study characteristics, including:

  • study design

  • number of patients in the study cohort

  • number of patients fulfilling the review's inclusion criteria (i.e. female, under the age of 40 at time of clinical outcome assessment, reported on subgroup treated with chemotherapy only, no ovarian surgery)

  • number of patients tested for late adverse effects

2. Participants, including:

  • age at time of study

  • age at diagnosis/start of treatment

  • diagnosis/original cancer

  • year of diagnosis

  • years of survival

  • land of origin/ethnicity

3. Exposure, including:

  • type of chemotherapy

  • treated according to specified protocol for malignancy

  • cumulative chemotheraputic dose per drug

  • surgery for primary cancer, excluding ovarian surgery

  • radiotherapy other than subdiaphragmatic and brain or total body irradiation

4. Outcome measures:

  • age at menopause (retrospectively assessed as the age at which menses naturally ceased to occur for at least 12 months, not due to other causes (such as pregnancy or breastfeeding)

  • signs of primary ovarian insufficiency, including:

    • elevated FSH (cut‐off value as defined by author of original study)

    • amenorrhoea (cessation of menses ≥ 6 months)

  • other signs of reduced ovarian reserve, including:

    • low anti‐Mullerian hormone (cut‐off value as defined by author of original study)

    • elevated inhibin B (cut‐off value as defined by author of original study)

    • low/absent antral follicle count (cut‐off value as defined by author of original study

    • decreased ovarian volume (cut‐off value as defined by author of original study)

5. Length of follow‐up

6. Risk factors:

  • chemotherapy group

  • chemotherapeutic agent

  • dose of chemotherapy

  • age at time of treatment

  • time since treatment

  • surgery to the hypothalamus or pituitary

7. Risk of bias assessment

In case of disagreement, we re‐examined the abstracts and articles and discussed discrepancies until we achieved consensus.

Assessment of risk of bias in included studies

We based the assessment of risk of bias on earlier described checklists for observational studies according to Evidence‐Based Medicine Criteria (Grimes 2002, Loke 2007). Two reviewers independently undertook the assessment of risk of bias of the included studies, concerning the formation of the study group, the follow‐up and outcome assessments, and the methods used for risk estimation in each study. The risk of bias assessment criteria for observational studies are described in Table 9. For the risk of bias assessment of case‐control studies, we adapted the criteria slightly with regard to the selection of cases and controls. Cases and controls had to be selected based on comparable patient characteristics (i.e. age and/or cancer treatment). For RCTs and CCTs we used the definitions as described in the CCG module (Module CCG). We scored risk of bias assessment according to the criteria mentioned in Table 9 or the CCG module (Module CCG) and reported descriptives for all studies.

Table 1.

Risk of bias assessment for observational studies

Internal validity External validity
Study group Selection bias (representative: yes/no)
if the described study group consisted of more than 90% of the original cohort of cancer survivors
or
if it was a random sample with respect to the cancer treatment		 Reporting bias (well‐defined: yes/no)
if the type of chemotherapy was mentioned
and
if the in‐ and exclusion criteria are described
Follow‐up Attrition bias (adequate: yes/no)                           if the outcome was assessed for more than 90% of the study group of interest (++)
or
if the outcome was assessed for 60‐90% of the study group of interest (+)		 Reporting bias (well‐defined: yes/no)
if the length of follow‐up was mentioned
Outcome Detection bias (blind: yes/no)
if the outcome assessors were blinded to the investigated determinant		 Reporting bias (well‐defined: yes/no)
if the outcome definition was objective and precise, and methods of outcome measurement are described
Risk Estimation Confounding (adjustment for other factors: yes/no)
if important prognostic factors (i.e. age, sex, co‐treatment) or follow‐up were taken adequately into account		 Analyses (well‐defined: yes/no)
if a relative risk, odds ratio, attributable risk, excess absolute risk, standardised incidence rate, linear or logistic regression model, mean difference, or Chi2 was calculated
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Measures of treatment effect

Prevalence, cumulative incidence, mean difference, relative risk, odds ratio, attributable risk, and other associated outcomes.

Dealing with missing data

If necessary, we contacted authors of individual studies to clarify or gather missing data with regard to study selection, risk of bias assessment and data extraction.

Assessment of heterogeneity

Heterogeneity was assessed both by visual inspection of the forest plots and by a formal statistical test for heterogeneity, i.e. the I² statistic. If there was significant heterogeneity, defined as I² > 50%, this was reported (Higgins 2008). Due to significant heterogeneity we used the random‐effects model. The data did not allow assessing potential sources of clinical heterogeneity.

Assessment of reporting biases

We planned to construct a funnel plot to graphically ascertain the potential presence of publication bias. However, because none of the included studies in the current analysis could be pooled, we could not construct funnel plots.

Data synthesis

Data were entered into RevMan and analysed according to the guidelines of the Cochrane Handbook. A random‐effects model was used. To construct plots for the prevalence of amenorrhoea and elevated FSH levels we used the generic inverse variance function of RevMan. As pooling was not possible, we summarised the studies descriptively.

Sensitivity analysis

We did not perform sensitivity analyses since pooling was not possible.

Acknowledgements

We would like to thank Edith Leclercq for developing the search strategies for the different databases. Furthermore, we would like to thank Elvira van Dalen for her contribution as the Coordinating Editor. The editorial base of the Cochrane Childhood Cancer Group is funded by Kinderen Kankervrij (KiKa, Children Cancer‐Free).

Appendices

Appendix 1. Search strategy for PubMed

1. For ovarian function the following MeSH headings and text words will be used:

follicle stimulating hormone OR follicle stimulating hormones OR follicle stimulating hormon* OR Follicle‐Stimulating Hormone OR Follitropin OR FSH OR human FSH OR human follicle stimulating hormone OR human follicle stimulating hormones OR human follicle stimulating hormon* OR follicle stimulating hormone, human OR 9002‐68‐0 OR Antimullerian hormone OR Antimullerian hormones OR Antimullerian hormon* OR Anti‐mullerian hormone OR Anti‐mullerian hormones OR Anti‐mullerian hormon* OR Mullerian Inhibiting Hormone OR Mullerian Inhibiting Substance OR Mullerian‐Inhibitory Substance OR Mullerian Inhibitory Substance OR Mullerian‐Inhibiting Factor OR Mullerian Inhibiting Factor OR Mullerian‐Inhibiting Hormone OR Anti‐Mullerian Factor OR Anti Mullerian Factor OR Mullerian Regression Factor OR Mullerian Duct OR Mullerian Ducts OR Mullerian Duct* OR 80497‐65‐0 OR antral follicle count OR AFC OR ovarian OR premature menopause OR early menopause OR ovarian failure OR premature ovarian failure OR premature ovarian failures OR Ovarian failure, premature OR Acute ovarian failure OR AOF OR Ovarian function OR ovarian damage OR menopausal status OR Gonadotropin‐Resistant Ovary Syndrome OR Gonadotropin Resistant Ovary Syndrome OR Gonadotropin‐Resistant Ovary Syndromes OR Ovary Syndrome, Gonadotropin‐Resistant OR Ovary Syndromes, Gonadotropin‐Resistant OR Resistant Ovary Syndrome OR Ovary Syndrome, Resistant OR Ovary Syndromes, Resistant OR Resistant Ovary Syndromes OR "Ovary/drug effects"[Mesh] OR "Ovary/radiation effects"[Mesh] OR "Ovary/radiotherapy"[Mesh] OR "Ovary/surgery"[Mesh] OR "Ovary/therapy"[Mesh] OR "Ovary/physiopathology"[Mesh] OR "Ovarian Diseases/chemically induced"[Mesh] OR Genital Diseases, Female OR Female infertility OR infertility/etiology OR primary ovarian insufficiency OR ovarian insufficiency OR gonadotoxicity OR gonado toxicity OR gonadotoxic OR gonadotoxic* OR gonadal damage OR hypergonadotropic amenorrhoea OR inhibin B OR inhibin OR inhibins OR gonad dysfunction OR gonadal function OR gonadal effects OR gonada* OR gonado* OR ovarian reserve OR gonadal hormone deficiency

2. For children and women of reproductive age the following MeSH headings and text words will be used:

infant OR infan* OR newborn OR newborn* OR new‐born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR schools, nursery OR infant, newborn OR young adult[mh] OR adult[mh] OR young adult OR young woman OR young women OR female[mh]

3. For cancer broad the following MeSH headings and text words will be used:

cancer OR cancers OR cancer* OR oncology OR oncolog* OR neoplasm OR neoplasms OR neoplasm* OR carcinoma OR carcinom* OR tumor OR tumour OR tumor* OR tumour* OR tumors OR tumours OR malignan* OR malignant OR hematooncological OR hemato oncological OR hemato‐oncological OR hematologic neoplasms OR hematolo*

4. For childhood cancer the following MeSH headings and text words will be used:

(((leukemia OR leukemi* OR leukaemi* OR (childhood ALL) OR AML OR lymphoma OR lymphom* OR hodgkin OR hodgkin* OR T‐cell OR B‐cell OR non‐hodgkin OR sarcoma OR sarcom* OR sarcoma, Ewing's OR Ewing* OR osteosarcoma OR osteosarcom* OR wilms tumor OR wilms* OR nephroblastom* OR neuroblastoma OR neuroblastom* OR rhabdomyosarcoma OR rhabdomyosarcom* OR teratoma OR teratom* OR hepatoma OR hepatom* OR hepatoblastoma OR hepatoblastom* OR PNET OR medulloblastoma OR medulloblastom* OR PNET* OR neuroectodermal tumors, primitive OR retinoblastoma OR retinoblastom* OR meningioma OR meningiom* OR glioma OR gliom*) OR (pediatric oncology OR paediatric oncology)) OR (childhood cancer OR childhood tumor OR childhood tumors)) OR (brain tumor* OR brain tumour* OR brain neoplasms OR central nervous system neoplasm OR central nervous system neoplasms OR central nervous system tumor* OR central nervous system tumour* OR brain cancer* OR brain neoplasm* OR intracranial neoplasm*) OR (leukemia lymphocytic acute) OR (leukemia, lymphocytic, acute[mh])

5. For survivors the following MeSH headings and text words will be used:

Survivor OR survivors OR Long‐Term Survivors OR Long Term Survivors OR Long‐Term Survivor OR Survivor, Long‐Term OR Survivors, Long‐Term OR survivo* OR surviving

Final search 1 AND 2 AND (3 OR 4) AND 5

[*=zero or more charaters]

Appendix 2. Search strategy for Embase

1. For ovarian function the following Emtree terms and text words will be used:

1. follicle stimulating hormone.mp. or exp follitropin/ 2. (follicle stimulating hormones or follicle stimulating hormon$ or follicle‐stimulating hormone).mp. 3. (follitropin or FSH or human FSH).mp. 4. (human follicle stimulating hormone or human follicle stimulating hormones or human follicle stimulating hormon$).mp. 5. 9002‐68‐0.rn. 6. (antimullerian hormone or AMH).mp. or exp Muellerian inhibiting factor/ 7. (antimullerian hormones or antimullerian hormon$ or anti‐mullerian hormone or anti‐mullerian hormones or anti‐mullerian hormon$).mp.8. (Mullerian Inhibiting Hormone or Mullerian Inhibiting Substance or Mullerian‐Inhibiting Substance).mp. 9. (Mullerian Inhibitory Substance or Mullerian‐Inhibiting Hormone or Mullerian Inhibiting Factor or Mullerian‐Inhibiting Factor or MIF).mp. 10. (Anti‐Mullerian Factor or Anti Mullerian Factor or Mullerian Regression Factor).mp. 11. Mullerian Duct.mp. or exp Muellerian duct/ 12. (Mullerian Ducts or Mullerian Duct$).mp. or 80497‐65‐0.rn. 13. (antral follicle count or AFC or ovarian).mp. 14. (early menopause or premature menopause).mp. or exp early menopause/ 15. ovarian failure.mp. or exp ovary insufficiency/ 16. (premature ovarian failure or premature ovarian failures or premature ovarian failure or POF).mp. 17. exp premature ovarian failure/ 18. (Acute ovarian failure or AOF or imminent ovarian failure or IOF).mp. 19. Ovarian function.mp. or exp ovary function/ 20. (ovarian damage or menopausal status).mp. 21. (Gonadotropin‐Resistant Ovary Syndrome or Gonadotropin Resistant Ovary Syndrome or Gonadotropin‐Resistant Ovary Syndromes or Gonadotropin Resistant Ovary Syndromes).mp. 22. exp resistant ovary syndrome/ or Resistant Ovary Syndrome.mp. 23. Resistant Ovary Syndromes.mp. 24. ovary/su [Surgery] 25. ovary disease/rt, si [Radiotherapy, Side Effect] 26. (Ovarian Disease or Ovarian Diseases).mp. 27. (female genital disease or female genital diseases).mp. 28. female infertility.mp. or exp female infertility/ 29. infertility/et [Etiology] 30. primary ovarian insufficiency.mp. 31. ovarian insufficiency.mp. or exp ovary insufficiency/ 32. (gonadotoxicity or gonado toxicity).mp. 33. (gonadotoxic or gonadotoxic$ or gonadal damage).mp. 34. hypergonadotropic amenorrhoea.mp. 35. (inhibin B or inhibins).mp. 36. inhibin.mp. or exp inhibin B/ 37. gonad dysfunction.mp. or exp gonad dysfunction/ 38. human menopausal gonadotropin.mp. or exp human menopausal gonadotropin/ 39. (gonadal function or gonad function).mp. or exp gonad function/ 40. ovarian reserve.mp. or exp ovarian reserve/ 41. (gonadal effects or gonada$ or gonado$).mp. 42. gonadal hormone deficiency.mp. 43. or/1‐42

2. For children and women of reproductive age the following Emtree terms and text words will be used: 1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/ 2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/ or female/ 3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/ 4. or/1‐3 5. (infant$ or newborn$ or (new adj born$) or baby or baby$ or babies or neonate$ or perinat$ or postnat$).mp. 6. (child$ or (school adj child$) or schoolchild$ or (school adj age$) or schoolage$ or (pre adj school$) or preschool$).mp. 7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp. 8. (minors$ or (under adj ag$) or underage$ or juvenil$ or youth$ or young adult).mp. 9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp. 10. (young woman or young women or young adult).mp. 11. (pediatric$ or paediatric$ or peadiatric$).mp. 12. (school or schools or (high adj school$) or highschool$ or (primary adj school$) or (nursery adj school$) or (elementary adj school) or (secondary adj school$) or kindergar$).mp. 13. or/5‐12 14. 4 or 13

3. For cancer broad the following Emtree terms and text words will be used:

1. (cancer or cancers or cancer$).mp. 2. (oncology or oncolog$).mp. or exp oncology/ 3. (neoplasm or neoplasms or neoplasm$).mp. or exp neoplasm/ 4. (carcinoma or carcinom$).mp. or exp carcinoma/ 5. (tumor or tumour or tumor$ or tumour$ or tumors or tumours).mp. or exp tumor/ 6. (malignan$ or malignant).mp. 7. (hematooncological or hemato oncological or hemato‐oncological or hematologic neoplasms or hematolo$).mp. or exp hematologic malignancy/ 8. or/1‐7

4. For childhood cancer the following Emtree terms and text words will be used:

1. (leukemia or leukemi$ or leukaemi$ or (childhood adj ALL) or acute lymphocytic leukemia).mp. 2. (AML or lymphoma or lymphom$ or hodgkin or hodgkin$ or T‐cell or B‐cell or non‐hodgkin).mp. 3. (sarcoma or sarcom$ or Ewing$ or osteosarcoma or osteosarcom$ or wilms tumor or wilms$).mp. 4. (nephroblastom$ or neuroblastoma or neuroblastom$ or rhabdomyosarcoma or rhabdomyosarcom$ or teratoma or teratom$ or hepatoma or hepatom$ or hepatoblastoma or hepatoblastom$).mp. 5. (PNET or medulloblastoma or medulloblastom$ or PNET$ or neuroectodermal tumors or primitive neuroectodermal tumor$ or retinoblastoma or retinoblastom$ or meningioma or meningiom$ or glioma or gliom$).mp. 6. (pediatric oncology or paediatric oncology).mp. 7. ((childhood adj cancer) or (childhood adj tumor) or (childhood adj tumors) or childhood malignancy or (childhood adj malignancies) or childhood neoplasm$).mp. 8. ((pediatric adj malignancy) or (pediatric adj malignancies) or (paediatric adj malignancy) or (paediatric adj malignancies)).mp. 9. ((brain adj tumor$) or (brain adj tumour$) or (brain adj neoplasms) or (brain adj cancer$) or brain neoplasm$).mp. 10. (central nervous system tumor$ or central nervous system neoplasm or central nervous system neoplasms or central nervous system tumour$).mp. 11. intracranial neoplasm$.mp. 12. LEUKEMIA/ or LYMPHOMA/ or brain tumor/ or central nervous system tumor/ or teratoma/ or sarcoma/ or osteosarcoma/ 13. nephroblastoma/ or neuroblastoma/ or rhabdomyosarcoma/ or hepatoblastoma/ or medulloblastoma/ or neuroectodermal tumor/ or retinoblastoma/ or meningioma/ or glioma/ or childhood cancer/ 14. or/1‐13

5. For survivors the following Emtree terms and text words will be used:

1. (survivor or survivors or (long adj term survivor) or (long adj term survivors) or survivo$).mp. 2. survivor/ or cancer survivor/ 3. surviving.mp. 4. 1 or 2 or 3

Final search 1 AND 2 AND (3 OR 4) AND 5

[mp= title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; $=zero or more characters; /= Emtree term; rn= registry number]

Appendix 3. Search strategy for Cochrane Central Register of Controlled Trials (CENTRAL)

1. For ovarian function the following text words will be used:

follicle stimulating hormone OR follicle stimulating hormones OR follicle stimulating hormon* OR Follicle‐Stimulating Hormone OR Follitropin OR FSH OR human FSH OR human follicle stimulating hormone OR human follicle stimulating hormones OR human follicle stimulating hormon* OR Antimullerian hormone OR Antimullerian hormones OR Antimullerian hormon* OR Anti‐mullerian hormone OR Anti‐mullerian hormones OR Anti‐mullerian hormon* OR Mullerian Inhibiting Hormone OR Mullerian Inhibiting Substance OR Mullerian‐Inhibitory Substance OR Mullerian Inhibitory Substance OR Mullerian‐Inhibiting Factor OR Mullerian Inhibiting Factor OR Mullerian‐Inhibiting Hormone OR Anti‐Mullerian Factor OR Anti Mullerian Factor OR Mullerian Regression Factor OR Mullerian Duct OR Mullerian Ducts OR Mullerian Duct* OR antral follicle count OR AFC OR ovarian OR premature menopause OR early menopause OR ovarian failure OR premature ovarian failure OR premature ovarian failures OR Ovarian failure, premature OR Acute ovarian failure OR AOF OR Ovarian function OR ovarian damage OR menopausal status OR Gonadotropin‐Resistant Ovary Syndrome OR Gonadotropin Resistant Ovary Syndrome OR Gonadotropin‐Resistant Ovary Syndromes OR Resistant Ovary Syndrome OR Resistant Ovary Syndromes OR Female Genital Diseases OR Female infertility OR “primary ovarian insufficiency” OR ovarian insufficiency OR gonadotoxicity OR gonado toxicity OR gonadotoxic OR gonadotoxic* OR gonadal damage OR hypergonadotropic amenorrhoea OR inhibin B OR inhibin OR inhibins OR gonad dysfunction OR gonadal function OR gonadal effects OR gonada* OR gonado* OR ovarian reserve OR gonadal hormone deficiency

2. For children and women of reproductive age the following text words will be used:

infant OR infan* OR newborn OR newborn* OR new‐born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR young adult OR adult OR young woman OR young women OR female

3. For cancer broad the following text words will be used:

cancer OR cancers OR cancer* OR oncology OR oncolog* OR neoplasm OR neoplasms OR neoplasm* OR carcinoma OR carcinom* OR tumor OR tumour OR tumor* OR tumour* OR tumors OR tumours OR malignan* OR malignant OR hematooncological OR hemato oncological OR hemato‐oncological OR hematologic neoplasms OR hematolo*

4. For childhood cancer the following text words will be used:

(leukemia OR leukemi* OR leukaemi* OR (childhood ALL) OR AML OR lymphoma OR lymphom* OR hodgkin* OR T‐cell OR B‐cell OR non‐hodgkin OR sarcoma OR sarcom* OR Ewing* OR osteosarcoma OR osteosarcom* OR wilms tumor OR wilms* OR nephroblastom* OR neuroblastoma OR neuroblastom* OR rhabdomyosarcoma OR rhabdomyosarcom* OR teratoma OR teratom* OR hepatoma OR hepatom* OR hepatoblastoma OR hepatoblastom* OR PNET OR medulloblastoma OR medulloblastom* OR PNET* OR neuroectodermal tumors, primitive OR retinoblastoma OR retinoblastom* OR meningioma OR meningiom* OR glioma OR gliom* OR pediatric oncology OR paediatric oncology OR childhood cancer OR childhood tumor OR childhood tumors OR cancer or neoplasms or tumor or cancers or neoplasm or tumors)

5. For survivors the following text words will be used:

Survivor OR survivors OR Long‐Term Survivors OR Long Term Survivors OR Long‐Term Survivor OR survivo* OR surviving

Final search 1 AND 2 AND (3 OR 4) AND 5

The search will be performed in Title, Abstract or Keywords

[* = zero or more characters]

What's new

Date Event Description
4 April 2019 Amended In consultation with the authors this protocol has been withdrawn
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Declarations of interest

None known.

Notes

In consultation with the authors this protocol has been withdrawn

Withdrawn from publication for reasons stated in the review

References

Additional references

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