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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 3-8

Role of ovarian reserve testing in cancer survivors


Department of Reproductive Medicine, Sushrut Assisted Conception Clinic, Shreyas Hospital, Kolhapur, Maharashtra, India

Date of Web Publication25-Jun-2019

Correspondence Address:
Dr. Padma Rekha Jirge
Sushrut Assisted Conception Clinic, Shreyas Hospital, 2013E, 6th Lane, Rajarampuri, Kolhapur - 416 008, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tofj.tofj_1_19

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  Abstract 


Improved survival in children and young women affected with malignancies bring forth the impact of gonadotoxic chemotherapy and radiotherapy on future fertility. This review looks at the understanding of mechanisms of damage to ovarian follicular pool and the evolution of assessment of ovarian reserve. The search for articles was done through PubMed. The review summarizes the current evidence on the value of ovarian reserve testing in young cancer survivors.

Keywords: Anti-Mullerian hormone, cancer survivors, gonadotoxicity, ovarian reserve tests


How to cite this article:
Jirge PR. Role of ovarian reserve testing in cancer survivors. Onco Fertil J 2019;2:3-8

How to cite this URL:
Jirge PR. Role of ovarian reserve testing in cancer survivors. Onco Fertil J [serial online] 2019 [cited 2019 Nov 13];2:3-8. Available from: http://www.tofjonline.org/text.asp?2019/2/1/3/261249




  Introduction Top


Survival in those affected with childhood cancer has seen a consistent improvement in the past three decades due to a very effective treatment combination of surgery, chemotherapy and radiotherapy. Childhood hematological malignancies and breast cancer constitute majority of the malignancies in children and young women. The cure rate has reached as high as 70% for hematological malignancies.[1] They may experience certain late side effects of treatment, in particular with chemotherapy and radiotherapy.[2] One such important effect is an adverse impact on the ovarian reserve during the reproductive years.[3] As 1 in every 1000 young adults in their third decade of life is a childhood cancer survivor, a negative impact on fertility potential understandably has very important implications for the quality of life.[1] There is an ongoing pursuit to develop new treatment strategies to minimize the long-term side effects without compromising the efficacy of treatment.[4] Current evidence suggests that diagnosed with malignancies at 14 years of age is 50% less likely to achieve pregnancy than those before the age of 5.[5] In addition, there remains a group of young adults receiving gonadotoxic chemotherapy to achieve disease cure who may experience important consequences to future fertility.

Fertility preservation (FP) has an invaluable role in extending the reproductive lifespan for young women affected with malignancies. Advances in clinical and laboratory aspects of FP encompassing a multidisciplinary approach, evolution of novel clinical protocols and vitrification of ovarian tissue, eggs and embryos have all made FP a reality. However, there still remains a percentage of the affected population who has not been offered or availed of this opportunity. In addition, FP may not be considered necessary while managing some of the malignancies with chemotherapeutic agents of low gonadotoxicity. Alternatively, there may not be an effective method of FP available in very young children.[6] Hence, a comprehensive understanding of the impact of cancer therapy on ovarian reserve, and the currently available methods for evaluating the residual ovarian reserve following such treatment are both important.


  Materials and Methods Top


Literature search was made using the key words “ovarian reserve,” “ovarian reserve tests,” and “cancer survivors and fertility” using PubMed (1966–2019). A total of 1695 articles were found. Further searches were made for individual ovarian reserve tests (ORTs) in cancer survivors using their titles as key words. Appropriate cross-references were manually searched.

Mechanism of damage to ovarian reserve

It is widely known that ovaries have finite number of primordial follicles established during the fetal life, which undergoes a progressive reduction throughout the reproductive lifespan until menopause when it is exhausted.[7] Surgical excision of one of the ovaries (oophorectomy) is an accepted modality of management for very early ovarian malignancy or borderline ovarian tumors in those who wish to conserve fertility. It is understandable that such procedures reduce the quantity of primordial follicles considerably. The current evidence suggests that oophorectomy for any indication will lead to a reduction in the ovarian reserve.[8] It is unclear at present whether any compensatory mechanisms exist in the remaining ovary to prevent the consequent early reproductive aging. Preliminary evidence from a study in mice does not reveal any reduction in apoptosis or consequent slowing of follicular exhaustion in the remaining ovary.[9]

The damage due to chemotherapy is complex to evaluate and may be insidious.[10] Chemotherapy regimens, including alkylating agents, are known to be the most deleterious for ovarian reserve. Taxanes, in combination with alkylating agents, have an additive toxic effect on the ovarian reserve.[11],[12] Histological assessment of ovaries in women subjected to chemotherapy has shown reduction in the primordial follicular pool.[13],[14]In vivo studies in rodents and in vitro studies in human ovarian xenografts have shown that primary damage to ovarian reserve happens through primordial follicular death (apoptosis).[15],[16] The mechanism involves damage to oocyte DNA, the most detrimental type being double-stranded DNA breaks. The oocyte initially attempts to repair the DNA damage through the ataxia telangiectasia mutated-mediated DNA damage repair pathway. For cells in which the DNA damage cannot be repaired, elimination occurs through apoptosis, and unless the cell is arrested in growth (cell senescence).[17],[18] A transient amenorrhea and decline in Anti-Mullerian hormone (AMH) can be experienced with any form of chemotherapy including those known to have low toxicity due to damage to the growing follicular pool.[6],[17] However, the extent of damage to the primordial pool determines the magnitude of longitudinal decline in ovarian reserve.

In addition to damage to the follicles, stromal alteration due to vascular injury is another important mechanism, which adversely impacts the ovarian reserve. It is known that stromal vascular injury and primordial follicle density are inversely related.[19] Another recent theory on the mechanism of ovarian toxicity is through increased follicle activation, which causes an increase in follicular recruitment, leading to a depletion of ovarian reserve, and consequently an ovarian failure.[20] However, this concept awaits confirmation.

Target area, dose, and type of radiotherapy are the factors that determine the extent of ovarian toxicity.[3],[21],[22] All women and children receiving total body irradiation before bone marrow-derived stem cell transplant (SCT) develop ovarian failure.[23] Cranial irradiation of 18–24 Gy in children with acute lymphoblastic leukemia may adversely affect hypothalamo–pituitary axis. Alternatively, radiation to the pelvis in doses <2 Gy or radiation to lumbosacral spine, are known to have direct ovarian toxic effect. In addition, pelvic radiation has a damaging effect on the uterus.[2],[4],[24]

However, damage due to chemotherapy and radiotherapy can be insidious and not become apparent immediately.

Impact of cancer therapy on ovarian reserve – clinical aspects

The clinical implications of injury to ovarian follicular mechanism can range from no detectable clinical impact to complete ovarian failure. This is influenced by the type of chemotherapeutic agent and/or radiotherapy used, age of the patient, and preexisting ovarian reserve. As women experience an age-related decline in ovarian reserve, the negative impact of cancer therapy is more profound in women in advanced reproductive age group.[3] Even though initial studies used the occurrence of amenorrhea as a criteria to diagnose reduced ovarian reserve, it is now understood that loss of fertility occurs much earlier to the onset of amenorrhea.[25],[26] Restoration of menstrual cycles following amenorrhea is variable and is noted in 39%–55% of women younger than 40 years of age, while the incidence drops of 0%–11% in those older than 40.[27] It must be noted that regular menstrual cycles or documentation of ovulation do not indicate a good ovarian reserve.[26]

Identifying women with declining but with residual functional ovarian reserve is very important for future fertility in young cancer survivors. Past two decades have seen the evolution of various ovarian reserve markers to predict ovarian response to controlled ovarian stimulation (COS) in in vitro fertilization (IVF) and also to some extent predict the ovarian reserve over a period of time. Use of these markers to assess ovarian reserve in young cancer survivors has provided important insights to the ovarian reserve and reproductive lifespan in young women wishing fertility. The following section details the role of various ovarian reserve markers in this scenario [Table 1].
Table 1: Ovarian reserve tests used in evaluation of ovarian reserve in young cancer survivors

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Ovarian reserve tests

Follicle-stimulating hormone

Baseline serum follicle-stimulating hormone (FSH) concentration on day 2–3 of the cycle has been used to assess ovarian reserve in young women following chemotherapy/radiotherapy for many years. Elevated levels of FSH and amenorrhea are the diagnostic of ovarian failure.[28],[29] However, it is now understood that normal FSH levels do not necessarily imply normal ovarian reserve and more sensitive markers are necessary for the evaluation of ovarian reserve.[30] FSH is one of the late markers to indicate perimenopausal transition as highlighted in some of the earliest studies in cancer survivors, and hence, relying on basal FSH alone may lead to lost opportunities to achieve spontaneous or treatment-related pregnancies in young cancer survivors.[26],[31]

Estradiol

With declining ovarian reserve, there is advanced recruitment of follicles, and hence, an elevation in basal estradiol (E2) levels on cycle day 2 or day 3 due to an early selection of dominant follicle. However, the clinical evidence does not support its routine use in IVF patients as an ORT.[7],[30] The available evidence in young cancer survivors also suggests that basal E2 alone does not identify a declining ovarian reserve reliably.[26]

Anti-Mullerian hormone

AMH is produced by the granulosa cells within the ovarian follicles of preantral and early antral stages and is considered to be the most sensitive marker of ovarian reserve.[32],[33] Comparison of multiple markers shows that serum AMH is the earliest marker to show a decline in ovarian reserve in young cancer survivors.[11],[34] AMH is generally undetectable in those who have undergone SCT due to the occurrence of premature ovarian failure (POF). It is reduced in those with regular menstrual cycles following chemotherapy in particular with alkylating agents, indicating a higher risk of POF or reduced reproductive lifespan. This phenomenon is noted even in those who conceive.[23] Further evidence suggests that pretreatment AMH has a positive correlation to posttreatment occurrence of menses.[23] The assessment of ovarian reserve with AMH levels following chemotherapy in adolescents and young adults suggests that the ovarian age is advanced by approximately 10–12 years.[35],[36]

Antral follicle count and ovarian volume

Antral follicle count (AFC) and ovarian volume measured with transvaginal ultrasonography (TVS) are reduced in young cancer survivors with regular menstruation and ovulation in comparison to age-matched controls despite similar number of ovulatory cycles.[23],[26] Ovarian volume appears to identify treatment-related decline in ovarian reserve earlier than AFC.[26] However, the decline in AMH precedes any decline in ultrasound parameters of ovarian reserve.[34],[36] In addition, measurement of AFC and ovarian volume requires a TVS on day 2–3 of the menstrual cycle. Unlike women undergoing evaluation or treatment for infertility, its acceptance may be low in young cancer survivors.

Inhibin B

Similar to AMH, inhibin B is a direct product of granulosa cells. However, unlike AMH, it is produced by the large antral follicles. Inhibin B is not routinely used due to lack of reliable assays and availability of more robust ovarian reserve markers such as AMH.[7],[30] This view is supported by the current evidence in young cancer survivors (CS).[3]

Studies evaluating the ovarian reserve in cancer survivors have consistently shown a discrepancy in the rate and magnitude of the decline in AMH and AFC or inhibin B.[11],[37],[38],[39] Studies utilizing multiple ORT reveal that AMH shows a rapid decline during chemotherapy, whereas AFC and inhibin B show only a modest decline, thus indicating primordial and preantral follicles being the primary target of toxicity, with relative sparing of larger follicles. Thus, while AMH, AFC, and inhibin B have similar ability to predict ovarian response to COS, the latter two are less effective in reflecting the ovarian reserve following gonadotoxic therapy.[37],[39]

AMH with its low inter and intracycle variability is preferred to AFC, which requires TVS to be performed in the early follicular phase. The tests should be used to identify those with reduced ovarian reserve to improve awareness toward prioritizing natural or treatment-related conceptions and appropriate treatment strategies, while the reasonable chance of success exists in those with reduced ovarian reserve. However, the current evidence does not support their use to predict fertility potential.


  Discussion Top


Children and young adult cancer survivors are likely to experience a reduction in ovarian reserve. This may be related to the disease process; or surgery, chemotherapy, and radiotherapy used as curative measures. Age, pretreatment ovarian reserve, type of malignancy, and treatment protocol all influence the risk of POF.[40],[41] Even though persistent amenorrhea beyond 1 year of treatment was considered as the indicator of poor ovarian reserve, it soon became apparent that large majority of young cancer survivors with regular menstrual cycles and normal FSH may have lower than the expected ovarian reserve.[3],[39]

ORT is primarily developed to predict ovarian response to COS during the ovarian reserve. Availability of very sensitive markers for the assessment of ovarian reserve such as AMH and AFC has contributed to improve our understanding of ovarian reserve. In the general population, it is well documented that there is an age related, progressive decline in ovarian reserve.[42] Studies involving one or more of ORTs have consistently shown a decline in ovarian reserve following chemotherapy or radiotherapy.[43],[44],[45],[46] Further, it is known that gonadotoxic therapy advances the ovarian age by 10–12 years.[35],[36],[43] Following an initial drop in AMH after chemotherapy, the rate of decline subsequently appears to be similar to that in the controls suggesting that the decline is related to the loss of primordial follicles rather than increased rate of follicle loss.[47],[48] There is some evidence that pretreatment AMH values >2 ng/ml are associated with a better acute posttreatment recovery of ovarian function compared to lower pretreatment levels.[41] Whether the oogonial stem cells present in the ovaries can lead to ovarian follicle and oocyte production are unknown at this time.[49]

The existing evidence from longitudinal studies suggests that young cancer survivors have a reduced reproductive lifespan.[47],[48] Those with well-conserved ovarian reserve in their mid-twenties appear to continue to do so till mid-thirties with a good chance of successful conception.[38] Importantly, proportion of abnormal ORTs increases significantly in women >35 years of age indicating a reduced reproductive lifespan.[50] The detrimental effect of gonadotoxic therapy on fertility could be less severe if young survivors seek for pregnancy early.[51] This highlights the need for a fertility awareness consultation in their early adult life including assessment of ovarian reserve and appropriate counseling about early recourse to pregnancy or to FP, if the same has not been performed before gonadotoxic therapy.[38] There are some women who are genetically predisposed to early menopause. Occurrence of a malignancy necessitating chemotherapy and/or radiotherapy may accelerate the onset of premature menopause. Effective strategies to identify such women pretreatment and appropriate counseling for FP will be of importance.[52] Evidence from a recent study suggests that cancer survivors with PCOS have better ovarian reserve compared to those without PCOS following chemotherapy but are less likely to achieve their reproductive goals.[53] The underlying mechanisms contributing to infertility in PCOS may explain such a paradox. Another area of concern is the late effect on ovarian reserve with chemotherapeutic agents considered to have low gonadotoxicity.[54] This may lead to a reduced reproductive potential in such women, particularly if they wish to delay conception; thus indicating a need for FP-oriented counseling in them. Some women who have cryopreserved ovarian tissue before gonadotoxic treatment may at a later date undergo orthoptic transplantation of ovarian tissue. The preliminary data available from such women suggests that ORTs, including AMH may not be reliable in predicting the ovarian function or the fertility potential.[55]

Children's Oncology Group, International Late Effects of Childhood Cancer Guideline Harmonization Group, and PanCareSurFup, an European Union-funded organization have the following recommendations for monitoring ovarian function in young cancer survivors:[56],[57],[58]

  • For prepubertal cancer survivors-Annual monitoring of growth and Tanner stage are important to identify signs of POF. Baseline FSH, luteinizing hormone (LH), and E2 should be assessed at the age of 13. Those who do not show signs of puberty by the age of 13 or those who do not attain menarche by the age of 16 should be referred to pediatric endocrinologist, and a consultation with reproductive medicine specialist should be sought for those at a high risk of POF
  • For postpubertal cancer survivors-A baseline FSH and LH should be checked a year after therapy. With the emerging evidence, the addition of AMH is recommended for baseline assessment. Patients exposed to alkylating chemotherapy or pelvic radiation should be referred to a reproductive medicine specialist in view of a high risk of POF. The same consideration should be given to those who wish to delay childbearing or already showing signs of poor ovarian reserve.


Ovarian reserve testing not only helps guide young cancer survivors to optimize their decisions on childbearing but also to address the contraceptive need and long-term health matters optimally.


  Conclusion Top


ORTs play an important role in assessing the ovarian reserve in young cancer survivors and to offer informative counseling in diverse areas such as contraception, long-term health concerns following POF, on prioritizing fertility or to consider FP. A combination of pretreatment assessment of AMH followed by posttreatment monitoring appears to provide a better understanding of magnitude of reduction in ovarian reserve. The current evidence suggests that fertility potential remains good till mid-thirties but declines rapidly thereafter even in those with previously well-preserved ovarian reserve, thus highlighting the reduced reproductive lifespan in young cancer survivors exposed to gonadotoxic therapies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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