Outcomes of Fertility Preservation Consults for Women at Risk for Primary Ovarian Insufficiency Due to History of Cancer Treatment or Mosaic Turner Syndrome

Introduction

Adolescents and young adult (AYA) patients at increased risk of primary ovarian insufficiency (POI) due to either history of cancer treatment or genetic factors pose a unique challenge for fertility preservation. Advancements in diagnosis and management of cancer have increased life expectancy for thousands of girls and young women. Unfortunately, the gonadotoxic effects of chemoradiation can have long-term consequences, increasing risk of infertility and POI.^1–4 Similarly, individuals with mosaic Turner syndrome (TS) are also faced with an elevated risk of POI at a young age due to premature depletion of oocytes related to chromosomal aneuploidy.^5,6

Both groups often present similarly, with an adolescent or young woman who is several years away from beginning her family, but already faced with significantly diminished ovarian reserve. Fertility preservation efforts are often of critical importance to these patients, many of whom are at risk of oocyte depletion before they are ready to become pregnant. Despite this urgency, there is a paucity of data regarding the results of attempts at fertility preservation in these populations. Furthermore, no reliable guidelines have been established for appropriate patient selection, triggers for intervention, or choice of stimulation protocols for this population.

The objective of this study was to investigate outcomes of adolescents and young women referred for fertility preservation consultation after a diagnosis of mosaic TS or with a history of gonadotoxic chemotherapy and/or radiation therapy.

Methods

This was a retrospective chart review of patients at risk of POI due to prior cancer treatment or mosaic TS seen for fertility preservation consultation in a single academic fertility practice from January 2017 to August 2019. The project was deemed exempt from full review by the University of Michigan Institutional Review Board.

Demographic information, cancer diagnosis and therapy, ovarian reserve testing, discussion of fertility preservation options, and outcomes of fertility preservation efforts up to March 31, 2020 were recorded. Ovarian reserve testing included antral follicle count (AFC), serum anti-Müllerian hormone (AMH), and/or early follicular serum follicle-stimulating hormone (FSH) and estradiol. Based on both history and ovarian reserve, patients were counseled on fertility preservation options and feasibility. A diagnosis of POI was based on amenorrhea (absence of menses >12 consecutive months) and two elevated FSH values >40 mIU/mL. In cases of TS mosaicism, the karyotype result was reviewed when available. For patients with a history of cancer treatment, the diagnosis and treatment course were reviewed. The cyclophosphamide equivalent dosing (CED) was calculated using the standard formula. ⁷

Ovarian stimulation was performed with a Gonadotropin Releasing Hormone antagonist protocol. Starting dose of gonadotropin was selected based on age and baseline AFC. Results of ovarian stimulation were collected, including total gonadotropin dose, days of stimulation, peak estradiol level, total oocytes retrieved, and total mature oocytes retrieved. In cancelled cycles, the reason for cancellation was recorded. A descriptive analysis of the data is presented.

Results

Twenty-four AYAs at risk of POI from either prior cancer treatment (n = 21) or mosaic TS (n = 3) were seen for fertility preservation over the designated time period. The mean time from completion of cancer treatment to consultation was 6.46 years. The mean age at time of consult was 21.6 years. Table 1 includes available demographic information, and Table 2 summarizes individual treatment courses.

Of 24 AYA patients evaluated, 3 were diagnosed with POI, and counseled that they were not candidates for ovarian stimulation—one was previously treated for Ewing sarcoma with chemotherapy (CED 10449.6 mg/m²) and radiation (55.8 Gy left ischium, 15 Gy whole lung); the second underwent bone marrow transplant for sickle cell disease (CED 5121 mg/m²); and the third had mosaic TS.

A fourth patient was suspected of POI at initial consult due to infrequent menses and initial FSH 39.1 mIU/mL and estradiol 52 pg/mL (drawn 2 years postchemotherapy). Random FSH repeated 1 month later was 9.7 mIU/mL, with estradiol 177 pg/mL. FSH repeated 4 days later was 6.3 mIU/mL; estradiol value was not obtained due to laboratory error. She was counseled that her FSH levels seemed to be fluctuating, and there was a chance of spontaneous conception. She began attempts to conceive later that year and reported spontaneous pregnancy after ∼4 months.

Ten patients (mean age 24.5) proceeded with oocyte cryopreservation (Table 2). Nine patients were cancer survivors and one had mosaic TS. Of these patients, four cycles were cancelled due to poor response, after an average of 10.8 days of stimulation (range 7–13 days). Of those who cancelled, only 1 patient pursued subsequent cycles, resulting in 11 cryopreserved mature oocytes over 3 cycles. Her diagnosis was mosaic TS.

The in vitro fertilization (IVF) cycle information and outcomes are summarized in Table 3. The six patients who completed their first attempted cycle had a mean AMH of 0.653 ng/mL, mean FSH of 10.3 mIU/mL, and mean AFC of 8.8 follicles. Four of these patients had reliable chemotherapy exposure information. The mean CED of treatment was 7541.5 mg/m². Among the four with cancelled cycles, three had undetectable AMH and the fourth had AMH of 0.36 ng/mL. Mean AFC was 7. One patient could not have AFC performed before cycle start. The patient with mosaic TS had an AFC of 14 and later successfully cryopreserved oocytes as mentioned above. The total number of mature oocytes retrieved ranged from 1 to 10 per retrieval, with an overall mean of 3.8 per retrieval. When all completed cycles were included, there was an average of 6.3 oocytes cryopreserved per patient. Mean peak estradiol was 985.7 pg/mL in completed cycles and 361 pg/mL in cancelled cycles. The mean amount of gonadotropin used was 5487.5 international units (IUs) in completed cycles and 4218.8 IUs in cancelled cycles.

Additional information on ovarian reserve testing, prior treatment, and IVF cycle outcomes is presented in the tables.

Conclusion

POI is a relatively rare condition in the general population, with gonadotoxic treatment and genetic causes as two well-recognized etiologies.^6,8,9 Monosomy X or TS is the most established genetic cause and will result in POI in virtually all affected women, though there is some variation in onset—often as a result of mosaicism.^6,8 Among survivors of childhood cancer, ∼6.0% will experience acute ovarian failure within 5 years of cancer treatment, and an additional 9%–11% will have POI by age 40.^3,4 Despite differences in etiology of ovarian failure, many parallels can be drawn between young women in both groups, as they may be pressed to consider fertility preservation consultation several years before they are ready to begin their family due to awareness of diminishing ovarian reserve. In this cohort of 24 AYAs seen for fertility preservation consultation, 10 ultimately attempted oocyte cryopreservation. Despite ovarian reserve testing predicting poor stimulation outcomes, six of these young women were ultimately successful in cryopreservation of oocytes or embryos for later use.

As childhood cancer survival has improved, there is increased emphasis on improving quality of life for survivors, including renewed focus on reproductive health, fertility, and family building.^1,9–14 Both radiotherapy and chemotherapy treatment, particularly those regimens including alkylating agents, increase the risk of infertility.^2,11 There is also evidence that cancer survivors are more likely to seek assisted reproductive technology services at a younger age, but less likely to achieve pregnancy and livebirth than their counterparts without cancer treatment. ¹² In a comparison of women with cancer who underwent ovarian stimulation pre- versus postcancer treatment, there were no differences in oocyte yield for those who made it to retrieval. However, there were more cancellations in the postchemotherapy group; cancellation was more likely with an AFC ≤6; and chance of cancellation increased as the AFC decreased with a dose–response relationship. ¹ This relationship appears to hold true in our cohort, as the average AFC was lower among patients whose cycles were cancelled.

While it is generally accepted that pretreatment consultation with a specialist to discuss reproductive implications of cancer treatment is essential, many authors suggest that a more comprehensive approach is needed, and recommend extending counseling and treatment into survivorship.^3,4,13,15 Survey-based studies of cancer survivors have evaluated both experiences with pretreatment consultation with a fertility specialist and post-treatment fertility concerns; findings showed that those who had a consultation were more concerned about their fertility after their treatment, and that the level of concern was not correlated with the actual risk of gonadotoxicity based on the treatment received.^13,15 Moreover, childhood cancer survivors are at risk of POI, which has health implications beyond infertility.^3,4 Models designed to help assess risk of POI after exposure to both alkylating agents and radiotherapy are being developed, and evaluated to allow providers to more accurately predict risk and provide more individualized counseling for patients before treatment and in follow-up after treatment is completed. ⁹

A parallel concern for comprehensive, longitudinal care exists concerning patients with TS, as ovarian function declines early and quickly in girls with TS, even in those with mosaic karyotypes.^5,8 Several publications call for fertility preservation consultations for these girls by at least age 13 or 14 or at menarche, regardless of age, to allow ovarian reserve evaluation and counseling on the available options for future fertility.^5,8,16 If ovarian reserve assessment is initially reassuring, serial monitoring of AMH can be considered to allow more time for psychosocial development. ¹⁶ However, AMH may not be a reliable indicator of ovarian reserve in adolescence or in TS patients specifically, though there is work to validate its use in this group. ¹⁷ A case series of seven adolescent and young women with TS attempting IVF cycles to cryopreserve oocytes reported no correlation between AMH or AFC levels and number of oocytes retrieved. ¹⁸ Interestingly, the first oocyte cryopreservation cycle our patient with mosaic TS attempted was cancelled due to poor response. However, given her AFC of 14, higher than expected with AMH <0.1 ng/mL, she was allowed to attempt a second stimulation cycle. She ultimately completed 3 ovarian stimulation cycles that resulted in cryopreservation of 11 mature oocytes.

While AMH is a valuable tool, a complete evaluation of ovarian reserve can help guide appropriate recommendations and fully informed decision making. Assessing AFC in particular is often challenging in TS patients, as evaluation with vaginal ultrasound is the most accurate, but is often not feasible for girls in early adolescence. ⁸ Abdominal ultrasound assessment of AFC may be more challenging, but can be used successfully, as in the case presented here. Several case reports have been published documenting attempts at fertility preservation through oocyte cryopreservation in adolescents and young women with TS, with varying degrees of success.^16,18–21 While ovarian tissue cryopreservation is a theoretical option, there have been no reports thus far of successful pregnancy using this method in a patient with TS.^5,18

Our study is similarly limited by its retrospective nature and relatively small sample size as are previous reports. The rapidly advancing field of fertility preservation has only recently provided the opportunity to attempt stimulation in the group of patients we present. We anticipate that larger, prospective studies will help address many of the questions surrounding stimulation in this population.

Although the etiology of their diminished ovarian reserve may differ, patients with a diagnosis of TS and patients with a history of cancer treatment at a young age present similar challenges for fertility preservation. Given the severely diminished ovarian reserve as a result of either TS or history of cancer treatment, these two groups have a very similar “social” presentation of young women who must often address fertility preservation decisions very early in their reproductive years. Navigating the decision-making process can become even more complicated as oocyte/embryo cryopreservation is often not covered by insurance and may be costly (>USD $5000 in most cases). If the young patients in our cohort had waited until they were ready to attempt conception to seek care, their ovarian reserve may have diminished to a point that oocyte retrieval was not feasible. It is important to consider the possibility of appropriately timed ovarian stimulation in select young TS patients and patients with a history of cancer treatment. While ovarian stimulation cycles can result in cryopreserved oocytes, even when there is already evidence of significantly diminished ovarian reserve, further study is needed to establish reliable guidelines for appropriate patient selection, time to initiate treatment, and stimulation protocols when attempting ovarian stimulation in this population. In addition, we must work to ensure accessibility of fertility preservation services for these young women, and continue to address their fertility concerns early and often to allow them to make well-informed decisions about their reproductive health.