Cancer Treatment-Related Ovarian Dysfunction in Women of Childbearing Potential: Management and Fertility Preservation Options

PURPOSE

To review the complex concerns of oncofertility created through increased cancer survivorship and the long-term effects of cancer treatment in young adults.

DESIGN

Review chemotherapy-induced ovarian dysfunction, outline how fertility may be addressed before treatment initiation, and discuss barriers to oncofertility treatment and guidelines for oncologists to provide this care to their patients.

CONCLUSION

In women of childbearing potential, ovarian dysfunction resulting from cancer therapy has profound short- and long-term implications. Ovarian dysfunction can manifest as menstrual abnormalities, hot flashes, night sweats, impaired fertility, and in the long term, increased cardiovascular risk, bone mineral density loss, and cognitive deficits. The risk of ovarian dysfunction varies between drug classes, number of received lines of therapy, chemotherapy dosage, patient age, and baseline fertility status. Currently, there is no standard clinical practice to evaluate patients for their risk of developing ovarian dysfunction with systemic therapy or means to address hormonal fluctuations during treatment. This review provides a clinical guide to obtain a baseline fertility assessment and facilitate fertility preservation discussions.

INTRODUCTION

The global cancer incidence in women of childbearing potential (WCBP; women age 15-39 years who experience menstruation, are capable of becoming pregnant, and are premenopausal) is 52.32 per 100,000 per year.¹ In the United States, more than 45,000 WCBP are diagnosed with cancer each year,² and although occurrence is substantial, treatment advancements have resulted in increased survivorship. The 5-year survival for cancer in WCBP is now >80% owing in part to novel targeted therapies.^3-6 As advancements continue, focus has increased on issues of survivorship, particularly in younger patients (including the effects on fertility and future childbearing).

CONTEXT

• Key Objective

• To provide an overview of the challenges faced by women of childbearing potential regarding oncofertility during cancer treatment and throughout survivorship.

• Knowledge Generated

• Increased awareness is needed around oncofertility and related fertility-preservation resources among health care practitioners and women undergoing cancer treatment. Patient treatment plans should be collaborative, review gonadotoxic potential of various treatments, offer options for fertility counseling, and consider the individual tumor type and health status of a patient, as well as their future fertility goals.

• Relevance (S. Bhatia)

• This review serves as a clinical guide for all available options and resources to preserve fertility among women with cancer.*

• *Relevance section written by JCO Associate Editor Smita Bhatia, MD, MPH, FASCO.

The demand for oncofertility care has been increasing.⁷ This care encompasses counseling for fertility preservation and providing these procedures, assessing the timing and modality of future childbearing, managing sexual dysfunction, addressing hormonal alterations, providing contraceptive counseling, and facilitating fertility-related psychosocial support. However, oncofertility-related care remains a challenge. Several systematic reviews report that oncologists lack knowledge of fertility evaluation, preservation, counseling, and referral resources.^8-10 Despite patients' desire for future fertility, few are offered or receive counseling and timely fertility preservation before starting oncologic treatment (15.8%-57.0%),^11-14 and utilization of fertility preservation remains low (15%-25%).^11,13 Patients report concerns regarding urgency in starting cancer treatment, relationship status, vertical transmission of cancer genes, mental and physical demands, and cost as reasons against pursuing fertility preservation.¹⁴ Here, we review ovarian dysfunction observed in patients undergoing treatment in the context of oncofertility. This review is intended to aid clinical oncologists in providing comprehensive care to WCBP throughout cancer treatment and survivorship.

DESIGN: OVARIAN DYSFUNCTION RESULTING FROM SYSTEMIC TREATMENTS

Definition

Ovarian dysfunction in WCBP secondary to gonadotoxic agents has been described as premature menopause, premature ovarian failure, chemotherapy-induced amenorrhea, and primary ovarian insufficiency (POI). Generally, POI is the preferred term, as ovarian follicular activity may intermittently recover, and the term premature implies a biologically arbitrary (but statistically significant) age cutoff of 40 years for cessation of menses. The term POI distinguishes an impairment that is intrinsic to the ovary (primary), as opposed to other nonovarian or endocrine dysfunctions (secondary), such as hypothalamic-pituitary disorders and adrenal disease. Clinically, it is defined by menstrual irregularity for at least 3 consecutive months and hypergonadotropic hypogonadism with sex steroid deficiency and follicle-stimulating hormone (FSH) >40 IU/L on two separate measurements spaced at least 1 month apart.^15-17

In this review, the term ovarian dysfunction will be used to discuss the complex ovarian impairments related to systemic oncologic treatment because there is no consensus on the clinical definition that captures the spectrum of ovarian impairments resulting from treatment. Ovarian dysfunction can manifest beyond POI and encompass additional factors that affect fertility. The degree of ovarian dysfunction and its reversibility can vary by patient age, individual predisposition, and current treatment and previous treatment.^18-21 This variability highlights the potential challenges in evaluating ovarian dysfunction, which is rarely assessed during drug development trials.¹⁹

Pathophysiology

Multiple mechanisms have been proposed regarding the underlying pathophysiology of chemotherapy-induced gonadotoxicity. Ovarian tissue ischemia may be caused by vasoconstriction or inhibition of angiogenesis.¹⁶ Follicular apoptosis directly results from DNA cross-linking/intercalation or inhibition of protein synthesis through DNA methylation inhibition. Follicular death may also arise from disruption to follicular cycling, as inhibition of microtubule assembly can arrest follicles in metaphase.²² Destruction of larger follicles results in a loss of anti-Müllerian hormone (AMH), which is responsible for the suppression of the primordial follicular pool. Primordial follicles are then activated and subsequently recruited in an effort to replace the loss of growing follicles.²³ The primordial follicular pool represents a finite, nongrowing population; therefore, once it is depleted, follicles are not replaced.

Risk of Ovarian Dysfunction

The various therapies used during treatment confer differing risks of ovarian dysfunction. An overview of the risk of amenorrhea associated with various agents throughout the literature is summarized in Figure 1. Chemotherapy administration may result in permanent amenorrhea, although recently, the results from the CANTO cohort indicate that chemotherapy-related amenorrhea (CRA) has variable persistence.³⁸ In 1,676 women, the incidence of CRA decreased across years of post-treatment follow-up (year 1, 83.1%; year 2, 72.8%; year 4, 66.7%), and persistence was age-dependent. At 4 years after treatment, the risk for patients age 44 years and younger ranged from 23% to 73% across age subgroups, whereas CRA risk was roughly 90% across all 4 years for patients age 45 years and older. Patient-related factors such as age and baseline fertility, cumulative dose, and cycle schedule affect this risk.³⁹ These factors can be compared at various dosages across patient populations with the cyclophosphamide equivalent dose (CED) calculator, specifically in the case of alkylating agents.⁴⁰ A CED ≥4,000 mg/m² is associated with a significant risk of infertility. Among traditional chemotherapies, alkylating agents pose the highest risk for deleterious effects on fertility secondary to direct primordial follicle toxicity by the induction of double-stranded DNA breaks in oocytes and germ cells.^22,24 By contrast, the antimetabolites and vinca alkaloids, such as vincristine and methotrexate, are classified as low risk for primordial follicle toxicity.^22,25 Platinum agents (cisplatin, carboplatin, and oxaliplatin) carry a risk for oocyte damage through accumulation of ABL and TAp-63-α, which activates proapoptotic promoters.⁴¹ Specific therapies also vary in their fertility impact. For example, the risk for doxorubicin ranges from low to high, depending on treatment regimen and patient age. Patients who are older than 40 years are at highest risk, whereas those younger than 30 years are at low risk. Taxanes are associated with moderate risk for amenorrhea.^26,27

FIG 1.

Risk of permanent amenorrhea associated with chemotherapeutic agents.^20,21,24-37 These are general guidelines only. Additional factors such as specific age at time of treatment, baseline ovarian reserve, and specific treatment regimen will determine the individual risk for ovarian toxicity. ^aDose is based on cyclophosphamide equivalent dose. ^bDegree of gonadotoxic potential debated. ^cOn the basis of traditional dosing regimen. Dose-dense administration may be more gonadotoxic. ^dSuspected moderate risk on the basis of limited data. ^eLimited data. Increased malformation risk in offspring noted with female exposure to tyrosine kinase inhibitors during conception/pregnancy. ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AC, doxorubicin and cyclophosphamide; AC-T, doxorubicin, cyclophosphamide, taxol regimen; CAF, cyclophosphamide, doxorubicin, and fluorouracil; CD20, cluster of differentiate 20; CEF, cyclophosphamide, epirubicin, and fluorouracil; CHOEP, CHOP plus etoposide; CHOP, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; CMF, cyclophosphamide, methotrexate, and fluorouracil; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; HER2, human epidermal growth factor receptor 2; TBI, total-body irradiation; VEGF, vascular endothelial growth factor.

The impact of radiation on fertility can be high,⁴² as oocytes are extremely sensitive to radiation, and radiation effects can lower chances for a successful pregnancy.⁴³ Direct, high doses of uterine radiation can lead to irreversible vascular and muscular damage, reducing a woman's ability to conceive and carry a child. Whole-body radiation is associated with increased risk for miscarriage, preterm labor, and low birth weight. However, below 4 Gy, radiation does not appear to affect fertility.

Surgical treatment could result in diminished ovarian reserve and premature ovarian dysfunction,^44,45 and if ovaries are removed, surgically induced menopause.⁴⁶ Some fertility-sparing surgeries can allow for conservation of the uterus and portions of a single ovary.⁴⁶ However, treatment options are highly dependent on tumor histology and a patient's age and reproductive plans.

Evidence of gonadotoxicity from immunotherapy and targeted agents, such as small-molecule inhibitors, is limited and mixed. Immunotherapies, particularly ipilimumab, are linked to risk of hypophysitis, which can lead to secondary hypogonadism.^47-49 Small-molecule inhibitors, such as tyrosine kinase inhibitors^50-52 and mammalian target of rapamycin (mTOR) inhibitors,^27,53,54 have demonstrated varied effects on ovarian reserve in animal studies, but human data (although limited) suggest associations with decreased ovarian reserve. Tyrosine kinase inhibitors have shown varied ovarian effects preclinically,^50-52,55-57 whereas most clinical case series show reversible POI.^58,59 In animal studies, mTOR inhibitors have demonstrated ovarian protection, as rapamycin attenuated cyclophosphamide-induced follicular apoptosis and maintained normal AMH levels.^27,53,54 Rapamycin also helped prevent primordial follicle loss after cryopreservation.⁵³ Primordial, secondary, and antral follicle counts were increased with the combination of everolimus and cisplatin.⁵⁴ Unfortunately, these preclinical models did not translate to improved outcomes in humans. Clinical observational studies show association with menstrual disorders and ovarian cysts during treatment with mTOR inhibitors, specifically sirolimus.^60-62 Reassuringly, normal menstrual cycles were restored a few months after treatment cessation.

Clinical Presentation

Systemic cancer treatments can lead to primary and secondary hypogonadism.^47-49 For women, the resultant hypoestrogenic state often presents as menstrual irregularities (oligomenorrhea and amenorrhea) and vasomotor symptoms, including hot flashes and night sweats. Ovarian dysfunction may present initially as biochemical abnormalities such as an increase in FSH or decrease in AMH before progressing into clinical symptoms of irregular or absent menses. However, FSH can be a delayed marker of ovarian dysfunction,⁶³ and abnormal results may appear after the ability for fertility preservation has passed. Currently, there is no standard clinical practice to monitor reproductive hormone status in patients at baseline or during systemic treatment.¹⁵ Consequently, these types of events may be under-reported if they are not associated with clinical symptoms. To appropriately assess for ovarian dysfunction, providers must maintain a high clinical suspicion and rely on patient history with regard to menstrual changes and abnormalities. Patients who note alterations in menstrual flow, regularity, cycle length and duration, or other characteristics should undergo further laboratory testing of ovarian function. In earlier stages of ovarian dysfunction, women may be able to conceive as a result of intermittent ovarian function. However, persistent hypoestrogenic state may lead to decreased sexual function and increased risk of cardiovascular disease, bone mineral density loss, and neurocognitive deficits.¹⁵ Cognitive function and memory decline have also been associated with ovarian insufficiency and can increase the risk for anxiety, depression, parkinsonism, or dementia in women experiencing hypogonadism.¹⁵

FERTILITY MANAGEMENT BEFORE INITIATION OF CHEMOTHERAPY

Fertility Preservation Counseling

Guidelines from both the American Society for Reproductive Medicine and American Society of Clinical Oncology state that health care providers should discuss infertility risks and fertility preservation options with all reproductive-aged patients before they undergo oncology treatment.^64,65 Such discussions typically address associated infertility risk, desire for future childbearing, complications of delaying or altering treatment for fertility preservation, life stage (eg, age and partner status), options for fertility preservation, costs, and potential long-term risks of treatment to future offspring.⁶⁴ Despite these recommendations, many women do not receive fertility counseling because oncologists often report discomfort in having these conversations with patients owing to their lack of knowledge and the perception that it may not be of benefit to the patient.^66-69 In a recent systematic review, providers' knowledge of fertility preservation options was found to be as low as 22%, depending on provider type and specific methods of preservation.¹⁰ Additional barriers to counseling include a lack of training and resources, time constraints, and the need for timely referral options to reproductive specialists. Time-sensitive fertility discussions can be overwhelming in the context of a new cancer diagnosis, but they are an important component of cancer-related care.^14,64,66

The reports from young adult female cancer survivors have shown that receiving fertility preservation counseling reduces long-term regret and dissatisfaction.^14,66,67 Improved quality of life was observed in patients who received external fertility preservation counseling and in patients who chose to preserve fertility, compared with patients counseled by an oncology team alone.^66,67 Optimally, patients should be informed about the effect of cancer treatment on their reproductive future, even when fertility preservation may not be feasible, because the counseling and an increased understanding of the treatment plan carries a demonstrated benefit.⁶⁶

Ovarian Reserve Testing

Baseline ovarian reserve testing is recommended for all WCBP who are receiving treatment for a cancer diagnosis to assess future fertility and track post-treatment ovarian function. Baseline testing may help identify those at risk for diminished ovarian reserve and can provide a benchmark for assessing changes through the course of treatment. Biochemical assessments include basal FSH and estradiol, AMH, and antral follicular count (AFC) via transvaginal ultrasonography (Table 1). Of these, AMH is considered to have the greatest clinical value for determining ovarian reserve because it is a more sensitive marker than FSH for diagnosing ovarian dysfunction⁶³ and a better correlate to primordial follicle pool and successful oocyte retrieval than AFC.^63,77-79 However, AFC should be implemented in addition to AMH, as AFC can provide additional data regarding baseline ovarian reserve.⁸⁰ It is important to note the limitations of these measures: FSH testing must be obtained early in the menstrual cycle (typically cycle days 2-5) in conjunction with an estradiol level to provide meaningful information.⁶³ Additionally, some assessments (FSH and estradiol in particular) can be altered by concomitant use of oral contraceptives.^63,64,76 Measurements of AMH and AFC should be interpreted carefully, as reference values of these markers change with increasing age.⁸¹ In addition, ovarian reserve markers have predictive value for response to ovarian stimulation but do not necessarily reflect the future ability to conceive or to attain a live birth.⁶³ Prognostic scoring systems have been proposed to predict the duration and likelihood of post-treatment ovarian function recovery. For example, in a model by Su et al,⁸² one point each is allocated on the basis of age younger than 40 years, pretreatment AMH >0.7 ng/mL, and BMI ≥25 kg/m². The highest score of three points indicates best prognosis, with 75% recovering ovarian function within 160 days after chemotherapy, compared with a score of one point, which has an estimated best prognosis of 75% recovery of ovarian function within 570 days of treatment cessation.⁸²

TABLE 1.

Ovarian Reserve Assessment

Fertility Preservation Options

Guidelines from American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend consideration of oocyte or embryo cryopreservation before initiation of any treatment.^64,83 Timing of cryopreservation no longer depends on the stage of the menstrual cycle, but patients and providers must consider whether cancer treatment can be delayed the requisite 2-3 weeks to facilitate a cycle of ovarian stimulation.^83,84 Ovarian tissue cryopreservation (OTC) is an option for prepubertal female patients or patients for whom treatment delay is unacceptable.^64,84 Although OTC is recommended for adult patients if treatment initiation is urgent, it is not recommended for patients age 36 years and older.²⁰ Additional considerations of OTC include the risk of reimplanting malignant tissue.⁸⁵ Ovarian cortex tissue can be screened by polymerase chain reaction testing to identify markers of malignant cells before reimplantation, but screening cannot determine the malignant potential of these cells once reimplanted. Histologic examination of cryopreserved tissue or in vitro maturation of oocytes can help avoid the risk of implanting tumor cells. Although OTC results in successful live births, it is not available at all centers and may not be suitable for all patients.⁸⁶

Menstrual suppression with a gonadotropin-releasing hormone agonist (GnRHa) is a proposed and controversial fertility protection method that can be used concurrently with cancer treatment.⁸⁷ The primary proposed mechanism of gonadoprotection by GnRHa suggests that by inducing a temporary and reversible prepubertal state, the ovaries are theoretically more resistant to chemotherapy-induced toxicity. This approach appears to have no adverse effect on disease-free survival. GnRHa is a standard option provided in several countries. Although the preponderance of literature suggests some degree of protection with GnRHa,^87-89 data regarding efficacy are mixed. A meta-analysis found GnRHa to be associated with a significant reduction (P = .013) in the risk of ovarian dysfunction.⁸⁸ However, the decreased risk provided by GnRHa was dependent on cancer type, with the highest risk reduction observed in patients with breast and ovarian cancers and no effect identified in studies of patients with lymphoma. GnRHa also significantly increased the number of pregnancies and the probability of becoming pregnant in patients receiving chemotherapy but had no effect on menstrual status or AMH and FSH levels after chemotherapy treatment was complete.⁸⁹ An additional meta-analysis of clinical trials reported similar findings of GnRHa benefit, citing a significant decrease in ovarian dysfunction rates in patients, decreased follicular decline, increased return of regular menses, return of cyclic ovarian function, and increased pregnancy rates.⁸⁷ Despite these findings, the utility and efficacy of GnRHa remains controversial, given conflicting results among publications assessing efficacy.^88,89

Utilization of different fertility preservation methods varies widely. In one retrospective study, Letourneau et al⁶⁷ surveyed 918 patients who underwent treatment that had the potential to affect their fertility. Of these patients, 61% (n = 560) received fertility counseling from their oncology team; 90% (n = 505) of those counseled did not continue to visit a specialist or take action to preserve fertility. Among women who did choose to preserve fertility (36 of 918 patients), half used ovarian suppression therapy, and most of the remainder (17 of 18) chose to preserve either their embryos or their eggs.⁶⁷ One patient pursued bilateral oophoropexy. Of the women surveyed in this study, those who were more likely to preserve their fertility included patients without children and those younger than 35 years at the time of cancer diagnosis.

Barriers to Oncofertility Care and Solutions

Despite the need, reports from cancer survivors show that the rate of fertility counseling is relatively low among women undergoing cancer treatment, with 16%-59% of female patients reporting that they did not have a conversation related to fertility concerns with treatment. Additionally, 4%-25% reported a lack of access to fertility preservation options,^13,67 and only 27% reported receiving sufficient fertility preservation information at the time of diagnosis.¹¹

A systematic review identified six key themes that hindered the ability of females with cancer to decide about fertility preservation.⁹⁰ Barriers included a lack of timely information, fear of the perceived risk of delaying treatment or exacerbating their cancer, lack of referral for fertility preservation from their oncology care team, emotional burden from cancer diagnosis, personal situation, and cost. Although barriers included both internal and external factors, oncology care teams can support patients through referral for counseling, assurance about timing of treatment, and discussion of fertility concerns when reviewing treatment plans. Improvements in patient awareness are needed, and providing information regarding oncofertility and fertility preservation via pamphlets or online decision aids can facilitate patient decision making.^7,91 Additionally, patients can be offered consults or referrals to discuss fertility preservation treatment options with a reproductive endocrinology and infertility physician or advanced practice provider who specializes in oncofertility. No outside referral is required before consultation with a fertility specialist, and many fertility clinics have expedited pathways to accommodate immediate referral in this patient population. General gynecologists can also discuss the basics of fertility preservation with patients newly diagnosed with cancer; however, treatment depends on the specialized field of reproductive endocrinology and infertility. Fertility navigators may be instituted within cancer treatment centers to help patients navigate fertility preservation counseling before the initiation of treatment.

Continuing medical education for the health care team regarding fertility preservation options, available resources, referral systems, and shared decision-making conversations will ensure that patients receive the most up-to-date information in the rapidly developing field of oncofertility.^8,91 Improved communication between care providers would benefit the patient, particularly when assessing the time constraints related to treatment initiation.

MANAGEMENT DURING SYSTEMIC TREATMENT

Management of Ovarian Dysfunction During Systemic Treatment

Patients should be assessed to identify concerns and symptoms related to ovarian dysfunction during treatment. For vasomotor symptoms such as hot flashes that are secondary to estrogen deficiency, behavioral and lifestyle changes to reduce temperature (eg, layered clothing) should be suggested as a first step.⁹² Pharmacologic interventions include nonhormonal options for those at risk of exacerbation or recurrence of cancer with hormonal therapy (eg, breast cancer). Second-line treatments after patient education and behavioral modification are venlafaxine, gabapentin, or clonidine, which are frequently used as nonhormonal interventions if lifestyle modifications fail. Fluoxetine and paroxetine should not be used with tamoxifen, as these and other selective serotonin reuptake inhibitors are potent inhibitors of CYP2D6 and can reduce efficacy of some treatments by impairing drug metabolism in certain patients. Oxybutynin showed preliminary efficacy in reducing vasomotor symptoms in a recent clinical trial.⁹³ For non–hormone-sensitive tumors, hormone replacement can provide substantial symptomatic relief. Hormone-replacement therapy options include oral contraceptive pills, estrogen pills or patches with oral progesterone, progesterone implants, or intrauterine devices for uterine protection.⁹⁴ The method of choice depends on patient history, preference, and risk factors. The decision to start hormonal replacement during systemic treatment should be discussed with both the oncologist and the gynecologist or reproductive endocrinologist managing the patient's care. There is no standard of care regarding the testing of hormone levels (FSH or AMH) in patients during treatment; however, if a patient presents with symptoms consistent with ovarian dysfunction, these tests could be considered. Specifically, AMH testing may be useful for assessing ovarian reserve and confirming ovarian dysfunction in patients already on treatment, as it shows little susceptibility to alteration with hormone replacement therapy.^73-75,95 Although AMH is not considered a reliable indicator of ovarian function in patients actively using GnRHa,⁷⁵ it can be informative as early as 3 months after treatment cessation.⁷⁵

Ovarian/Gonadal Protection During Systemic Treatment

Although GnRHa is most commonly used for gonadoprotection, medroxyprogesterone and oral contraceptives may be used for menstrual suppression.⁸³ GnRHa treatment should begin before initiation of chemotherapy,^83,96 is administered monthly or every 12 weeks via intramuscular injection (Table 2),⁹⁷ and is typically limited to duration of chemotherapy. If a patient has thrombocytopenia, GnRHa can be administered subcutaneously. GnRHa induces a hypoestrogenic state within 2 weeks of initiation. Vaginal bleeding is expected approximately 2 weeks after the first injection, followed by amenorrhea. The most common adverse effects are vasomotor symptoms and bone density loss with extended therapy.

TABLE 2.

Dosing of Menstrual Suppression Therapies⁹⁷

SURVEILLANCE OF SURVIVORS/POSTCHEMOTHERAPY

Guidelines for Management

After completion of gonadotoxic cancer treatment, an inquiry regarding signs of hypoestrogenism, including menstrual irregularities (amenorrhea and oligomenorrhea), vasomotor symptoms, vaginal dryness, and dyspareunia is warranted. Assessment of ovarian function should be considered by testing FSH and estradiol or AMH regularly for at least 12-18 months after completion of chemotherapy.⁹⁸ Serial assessment of AMH and FSH after treatment is important, as altered levels have been observed for up to 2 years after treatment cessation.⁹⁹ Although AMH levels may not return to pretreatment baseline, they are considered a useful predictor of ovarian reserve 2 years after treatment. Referral to a reproductive endocrinologist, medical endocrinologist, or gynecologist is recommended for consideration of sex steroid–replacement therapy if patients exhibit signs of ovarian dysfunction, as extended periods of hypoestrogenism are associated with increased risk of dementia, osteoporosis, and cardiovascular disease.

Pregnancy is generally not recommended within 2 years after completion of therapy, when risk of relapse is highest.¹⁰⁰ Across cancer types, the risks of preterm birth, low birth weight, and infants who are small for their gestational age are lowest between 2 and 5 years after treatment. These risks increase in pregnancies conceived ≥5 years after treatment cessation. Additionally, initiating pregnancy too soon after treatment may impose adverse outcomes secondary to post-therapy implications such as poor wound healing, inflammation, insufficient weight gain, immunosuppression, and cardiovascular effects. Complications associated with longer intervals may be attributed to poor cancer prognosis and fertility challenges related to treatment or other individual predispositions. The decision to initiate pregnancy after treatment is complex, and special consideration should be given to the types of prior treatments on pregnancy, delivery, and obstetric complications, as well as congenital abnormalities, hereditary conditions, the need for additional treatments, risk for recurrence (particularly in hormone-driven tumors), and patient age.^20,100 Patients should consult with the oncology care team, fertility specialists, and/or maternal fetal medicine specialists to evaluate the risks to personal and fetal health.

Role of Oncologists in Post-Treatment Surveillance

Oncologists are uniquely positioned as first-line providers to assess ovarian dysfunction. However, adverse effects of chemotherapy are known to be under-reported during clinical trials and post-treatment oncologic follow-up,^101-103 as the FDA does not require investigation or reporting of adverse events related to ovarian dysfunction for approval of treatments.^19,104 In early phases, ovarian dysfunction may be missed because clinical manifestations (eg, menstrual irregularities) are not easily observable to the clinician and patients may not report them. The incidence may also be underappreciated, given the under-representation of women across oncology clinical trials.¹⁰⁵ Assessment of patient-reported symptoms allows for optimization of long-term outcomes, including a survival benefit and quality of life for the patient.¹⁰²

DISCUSSION

In conclusion, the detrimental effect of cancer treatment regimens on reproductive health has been well established.^{21,47-49,57,60,61} Chemotherapy-induced ovarian dysfunction has significant health consequences, and potential risks should be recognized in this patient population. Short-term effects include vasomotor symptoms and sexual dysfunction, and longer-term effects include low bone mass, osteoporosis, and increased cardiovascular risks. Patients should be counseled regarding the potential negative reproductive consequences.^{7,21,24,47-49,64,83,91}

An assessment of baseline ovarian function and counseling regarding fertility preservation are recommended before initiation of systemic therapy for all reproductive-aged patients who desire future fertility.^63,98 Counseling about fertility preservation options has been shown to reduce long-term regret and dissatisfaction among cancer survivors and may be associated with improvements in physical and psychologic quality of life.^63,65-67 Physicians should be proactive in discussing ovarian dysfunction risk and related health sequelae when reviewing treatment plans with patients. Oncologists should also be vigilant in assessing patients for symptoms and signs of ovarian dysfunction during and after treatment. By offering fertility counseling and proactive surveillance for ovarian dysfunction, oncologists can provide the best opportunity for patients to improve quality of life in survivorship, including future reproductive success.

AUTHOR CONTRIBUTIONS

Conception and design: Laurie J. McKenzie

Collection and assembly of data: All authors

Data analysis and interpretation: Laurie J. McKenzie

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Cancer Treatment-Related Ovarian Dysfunction in Women of Childbearing Potential: Management and Fertility Preservation Options

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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No other potential conflicts of interest were reported.