Gonadal failure is a health and quality-of-life concern in hematopoietic cell transplant (HCT) survivors. While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, the risk is unclear after reduced-intensity conditioning (RIC). Gonadotropin-releasing hormone agonists decrease ovarian failure rates following conventional chemotherapy, but little is known about its effectiveness with HCT. We investigated the impact of leuprolide on ovarian function after MA conditioning and monitored ovarian function after RIC in this descriptive pilot study. Post-menarchal females <50 years undergoing HCT with adequate baseline ovarian function (follicle-stimulating hormone (FSH) level <40 mIU/mL and normal menstruation) were eligible. Prior to MA conditioning, leuprolide was administered. Those undergoing RIC were observed. FSH was measured at various time points. Seventeen women aged 12–45 years were evaluated (7 in the intervention group and 10 in the observation group). Compared to the historical high rate of ovarian failure after MA conditioning, 3 of 7 evaluable Lupron recipients had ovarian failure at a median of 703 days post transplant. Ovarian failure occurred in 1 of 10 recipients of RIC at a median follow-up of 901 days. In conclusion, leuprolide may protect ovarian function after MA conditioning. Additionally, RIC with cyclophosphamide, fludarabine and low-dose TBI has a low risk of ovarian failure.
Over the past two decades there has been a significant increase in survival following hematopoietic cell transplantation (HCT) due to improved therapeutic modalities and supportive-care measures. With increasing numbers of long-term survivors comes a new focus on prevention of late treatment-related complications, including gonadal failure.
Cytotoxic therapy for malignancy is associated with a high risk of ovarian dysfunction, occurring in as many as 40% of women.1 This rate increases to nearly 100% following myeloablative (MA) HCT.2, 3 Less is known about the incidence of ovarian dysfunction after reduced-intensity conditioning (RIC); studies addressing this are few in number and are based on retrospective data and isolated patient reports.4, 5 As well, comparing the ovarian function of prepubertal to pubertal females who are treated for malignancy shows that prepubertal patients are more likely to retain or recover normal ovarian function following conventional (non-HCT, anti-neoplastic) cytotoxic therapy.3 These findings suggest a role for ovarian follicle suppression during chemotherapy, and hence during HCT, to preserve ovarian function.
Gonadotropin-releasing hormone agonists (GnRHa), such as leuprolide, have paradoxical effects on the pituitary, with initial stimulation of the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), followed by the inhibition of the release of these hormones through negative feedback. This creates, in essence, a temporary pre-pubertal milieu.6, 7 GnRHa may protect undifferentiated follicles from chemotherapy via direct tissue effects, decreasing ovarian blood flow (and, therefore, chemotherapy exposure), upregulating intragonadal antiapoptotic molecules and protecting ovarian germline stem cells.8 Indeed, GnRHa have been shown to decrease the rate of ovarian failure in those receiving conventional chemotherapy.9, 10, 11, 12 However, little is known about their efficacy in the HCT population. Prior studies researching ovarian dysfunction following chemotherapy and HCT have primarily targeted fertility preservation.8, 12 While infertility is an important manifestation of ovarian failure, there are others too, including loss of menstruation, reduced bone density, sexual dysfunction and the need for hormone replacement. These factors significantly impact the quality of life of affected women.
The primary aims of this descriptive pilot study were to determine the safety profile and effectiveness of leuprolide in ovarian function in recipients of MA HCT, and to evaluate the incidence of ovarian failure in recipients of a RIC regimen over time.
Materials and methods
Study cohort selection
The study protocol was reviewed and approved by the Institutional Review Board at the University of Minnesota, and all patients or guardians provided informed consent (ClinicalTrials.gov Identifier: NCT01343368). All post-menarchal females <50 years of age who were scheduled to undergo HCT at the University of Minnesota between December 2012 and July 2014 were approached for participation. Eligible patients had adequate ovarian function prior to HCT, defined by a baseline FSH level less than 40 units per liter (U/L) and normal menstrual cycles. Patients were excluded if they had a history of ovarian cancer, surgical resection of one or both ovaries, or use of GnRHa in the last 12 months if lab results were unable to demonstrate adequate ovarian function prior to administration of the GnRHa.
Study design and procedures
Females undergoing MA conditioning were assigned to the intervention group and treated with leuprolide (long-acting 11.25 mg IM once+short-acting 0.2 mg (SC) daily for 14 days) within 30 days prior to initiation of the HCT conditioning regimen based on a study by Pereyra Pacheco et al.12 Those undergoing RIC were assigned to the observation group. While this latter group was allowed to receive routine hormonal therapy for the suppression of menses during the peri-transplant period, which is typically characterized by prolonged, severe thrombocytopenia, none were treated with leuprolide and these patients were observed with no additional intervention. See Figure 1.
Ovarian function and related symptoms were followed in all study patients with serial laboratory assessments and menses questionnaires. FSH was measured at baseline, at days 100 and 180, and at 1 and 2 years following transplant. Ovarian failure was defined as an FSH level greater than 40 mIU/mL. As GnRHa carry a known risk of hypoestrogenism-associated decreased bone mineral density, dual-energy X-ray absorptiometry (DXA) scans (GE Healthcare Lunar Prodigy scanner; Madison WI) using Encore software version 9.3 were performed in the intervention group at baseline, 1 and 2 years following transplant. DXA Z-scores for the lumbar spine and the bilateral femoral necks were calculated. DXA scans were not performed as part of the study for the observational group as leuprolide was not used. Free thyroxine (T4) and thyroid-stimulating hormone were measured in the intervention group only at baseline, and at 1 and 2 years following transplant to rule out hypothyroidism as a potential confounding variable in the interpretation of menstrual history. Questionnaires were completed by all subjects at baseline, days 30, 60, 100, 180, and at 1 and 2 years following transplant. The questionnaires included information about the age at menarche, resumption of menses after HCT, regularity of menstrual cycles both prior to and after HCT, pregnancy history, sexual history, current or past history of hormonal contraceptive use, current symptoms that could be related to ovarian failure (including hot flashes, night sweats, vaginal dryness), and any potential side effects potentially attributable to GnRHa therapy.
Patients were screened for eligibility between December 2012 and July 2014. During this time, 107 women were screened as potential participants based on the criterion age <50 years. Of those, 51 were deemed ineligible, mainly due to young age making them likely to be premenarchal or due to prior exposure to leuprolide. Fifty-six patients in total were presented for the study, of which 9 were enrolled in the intervention group and 10 in the observation group.
Nine women undergoing MA transplant were enrolled in the intervention group (Table 1). Two of these patients were not evaluable (one patient died 34 days following HCT and the other was lost to follow-up prior to day 100). The remaining seven patients had a median age of 23 years at the time of HCT (range, 17–45 years). Six of the seven evaluable patients were transplanted for malignancies and one underwent HCT for an inherited bone marrow failure syndrome. Five out of the seven patients in the intervention group received a minimum of seven cycles of conventional chemotherapy or had previous exposure to alkylating agents. MA donor sources and conditioning regimens were variable. Out of the seven patients, three had an autologous HCT, two had matched sibling donor HCT, one had matched unrelated donor HCT and one had an umbilical cord blood transplant. Three out of the seven patients received 1320 cGy TBI. The patients in the intervention group were followed for a median of 2 years (range, 100 days to 2 years).
Safety profile and effectiveness of leuprolide
Women in the intervention group had a rate of ovarian failure of 43% (3 out of 7 subjects) at a median of 703 days post transplant (range, 206–754 days) (Figure 2). Two of the three patients with ovarian failure received TBI as part of their conditioning regimen. The underlying diagnoses for those with ovarian failure were multiple myeloma, chronic myeloid leukemia and anaplastic large-cell lymphoma. The patient with chronic myeloid leukemia had not received any prior gonadotoxic chemotherapy, but did receive TBI as part of her conditioning regimen.
Questionnaires administered at regular time intervals following transplant revealed no serious adverse events related to leuprolide therapy. Two patients reported intermittent hot flushes. Four patients experienced menstrual bleeding during the first 30 days after transplant. The bleeding was described as minimal and was treated with either platelet transfusion or estrogen. It was not discernable whether the bleeding was related to withdrawal bleeding related to leuprolide administration, thrombocytopenia or a combination of both. Two patients with normalized FSH had recovery of regular menstruation within a year following HCT. One patient with a normalized FSH did not have resumption of normal menses, but did have an intrauterine device in place. The three patients with an FSH >40 mIU/mL described continued hot flashes and occasional mood lability following HCT. None of the three patients with ovarian failure reported resumption of menstruation.
DXA scans were obtained at baseline for five out of the seven patients. All patients who had initial screening scans had Z-scores of the lumbar spine and bilateral femoral necks that were within normal limits. Of the five patients with baseline DXA data, three patients had follow-up evaluations at 1-year post transplant (Table 2). All three patients who had 1-year follow-up DXA scans had a decrease in Z-score in their lumbar spine (mean of 1.23±0.76) and femoral neck (mean of 0.97±0.91).
Baseline thyroid functioning in all seven patients was within normal limits. Three out of the seven patients had thyroid function screening results available at 1-year post transplant; all remained within normal limits.
Ten women underwent allogeneic RIC (Table 3). The median age at transplant was 16.5 years (range of 13 to 23 years). Six patients were transplanted for aplastic anemia, one for sickle cell anemia, one for a Maroteaux-Lamy syndrome (MPS VI), one for sideroblastic anemia and one for Hodgkin’s lymphoma. Only two patients had exposure to alkylating agents prior to HCT. RIC regimens generally included cyclophosphamide (50 mg/kg), fludarabine (150–200 mg/m2, TBI (200-300 cGy) +/− anti-thymocyte globulin or alemtuzumab. One patient received alemtuzumab, clofarabine and melphalan. Five out of the 10 patients received matched unrelated donor HCT. Three patients received matched sibling donor bone marrow HCT. The remaining two patients received umbilical cord blood transplant HCT. The patients in the observation group were followed for a median of 2 years (range of 15 months to 2 years).
Ovarian function following RIC
The incidence of ovarian failure for women after RIC was 10% (1 out of 10 subjects) (Figure 3). The single patient with ovarian failure had received a second transplant due to graft failure; therefore, she had received two separate RIC conditioning regimens, both containing alkylating agents. Of the nine patients whose FSH remained <40 U/L, four reported resumption of normal and regular menstruation following HCT. Two of the nine patients had resumption of menses, but it remained irregular at the most recent evaluation. One patient experienced only occasional spotting. The status of resumption of menses for the remaining two patients is unknown.
Despite the known risk of ovarian dysfunction following HCT, there has been little research in the area of ovarian functional preservation. Most research has focused on follicle, embryo and ovarian tissue cryopreservation, which address fertility issues associated with ovarian failure. In patients who must undergo transplantation in an expedited manner or who do not have the financial resources to undergo the procedure, tissue preservation is not a feasible option. It is also important to note that infertility is only one of the consequences of ovarian dysfunction. Premature ovarian failure can have a significant impact on quality of life, including hot flushes, risk of osteoporosis and mood lability. As a result of these concerns, it is important to investigate alternative, non-invasive methods to preserve ovarian function, such as the use of GnRHa as highlighted in this trial.
This descriptive pilot study has two main findings that are of interest and should be investigated with further studies. First, the use of GnRHa appeared safe and may preserve ovarian function in women undergoing MA HCT. The incidence of ovarian failure in this pilot study was lower (43%) than has been historically reported after MA HCT (80–90%).13, 14, 15, 16 Importantly, these results were present despite the majority of women having received significant gonadotoxic chemotherapy prior to HCT. The second finding is that RIC with cyclophosphamide, fludarabine and low-dose TBI, and minimal prior therapy exposures is associated with a low risk of ovarian failure.
GnRHa have been shown to preserve ovarian function in chemotherapy-treated patients outside of the HCT setting. For instance, a meta-analysis published in 2009 looked at nine studies including a total of 366 women who had undergone HTC between 1987 and 2007. A 68% increase in the preservation of ovarian function was demonstrated with the use of GnRHa during chemotherapy. Twenty-two percent of the women treated with GnRHa went on to have successful pregnancies, compared with 14% who did not receive GnRHa.17 A more recent review from 2015 by Blumenfeld and Evron similarly noted that the majority of previous studies in the prior 10 years (20 out of 28 studies) reported positive effects on ovarian function with the use of GnRHa.18 Another prospective randomized study between GnRHa and chemotherapy or chemotherapy alone in 80 patients with breast cancer also demonstrated improved ovarian function with the use of GnRHa, and at a follow-up of 8 months those patients who received GnRHa had lower FSH levels (8.3 vs 15.2 IU/mL, P<0.009) and were more likely to resume menstruation (89.6 vs 33.3%, P<0.001). Spontaneous ovulation resumed in 69.2% of GnRHa-treated patients vs 25.6% of those without treatment (P<0.001).9
Although these results seem promising, a paucity of data exists on similar use of GnRHa in the HCT population. Cheng et al.19 also evaluated ovarian function after HCT following GnRHa therapy in a prospective study consisting of 44 evaluable women with a median age of 25 years and median follow-up of 355 days. Out of the 44 women enrolled, 41 were receiving HCT for malignancy. Patients underwent both allogeneic and autologous HCT and all patients received GnRHa, including both those undergoing MA and non-MA preparatory regimens. Women were given a higher dose of leuprolide in the form of a one-time, 3-month depot IM injection of leuprolide (22.5 mg) within 2 months prior to HCT. This was then followed by a second 22.5 mg IM injection 3 months after the first injection. The authors defined preserved ovarian function as an FSH level ⩽20 IU/L, an LH level ⩽20 IU/L, an estradiol level ⩾30 pmol/L and resumption of menstruation for ⩾3 months. These investigators failed to demonstrate any substantial impact on ovarian function with the use of GnRHa prior to HCT. Only 7 out of the 44 patients (16%) met the criteria for preserved ovarian function. Interestingly, of those undergoing non-MA HCT (10 out of the 44 evaluable patients) only one patient had preserved ovarian function.19 These results differ significantly from our study. This may be partly due to their more rigorous definition for ovarian failure as well as the longer duration of follow-up in our study, which allows more time for ovarian function to recover. Importantly, the dosing and timing of leuprolide administration also differed. By using a combination of long-acting and short-acting leuprolide in this study it was thought that the delay in inhibiting pituitary gonadotropin secretion could be minimized during the administration of conditioning chemotherapy. This may have resulted in improved ovarian function preservation in this study by avoiding chemotherapy exposure during this delay. However, this mechanism of action cannot be confirmed in our study since daily gonadotropin levels were not drawn during this time period.
A more optimistic conclusion regarding the effectiveness of GnRHa use in the HCT population was found in another prospective, non-randomized study by Blumenfeld et al.20 Eighty-three women were evaluated following HCT for malignant conditions. Fifty-six percent of women enrolled in the study chose to receive the GnRHa Decapeptyl CR as a measure to preserve ovarian function. In contrast to our study and the above mentioned study, the GnRHa was given within 10–14 days and in a smaller dose (3.75 mg). Premature ovarian failure was defined as amenorrhea associated with an FSH level 40 mIU/mL, and they also defined cyclic ovarian function as resumption of menses for at least 6 months following HCT, ultrasonographic evidence of ovarian follicles or corpus luteum, and normal FSH and LH levels or pregnancy. Cyclic ovarian function returned in 38.3% of those who received the GnRHa and 11.1% of those who did not. The effect was most pronounced for those undergoing treatment for lymphomas (66.7% COF after leuprolide). The authors concluded that the use of GnRHa may in fact be quite protective of ovarian function, especially in those undergoing HCT for lymphoma.20
Further delineation of specific risk factors for ovarian failure following HCT is needed, in order to guide patient expectations for ovarian function after treatment. In our study, it appears that the women most at risk for gonadatoxicity despite GnRHa use are those who were exposed to MA doses of TBI as part of their conditioning regimen. The correlation between TBI use and high rates of ovarian failure is well known and has been reported in prior studies.13, 14, 15, 16 As a result of this correlation, ovarian shielding has been attempted. While there have been a number of case reports documenting successful use of ovarian shielding during TBI, such methods have not been standardized or frequently adopted. There is also an additional concern that the ovaries may contain malignant cells that are then protected against the effects of TBI.21, 22, 23, 24 Additionally, while high doses of alkylating agents have been reported to increase the risk of ovarian failure16, most of the patients in the intervention group who received alkylating agents only for HCT conditioning retained their ovarian function even with heavy exposure prior to the HCT preparative regimen. This may indicate that GnRHa may be most beneficial in the setting of MA chemotherapy-only approaches.
Prevention of ovarian failure is an important endpoint when evaluating the use of GnRHa; however, breakthrough bleeding after transplant is another complication that could potentially be prevented by the use of GnRHa prior to HCT. Two small studies in HCT patients showed that long-acting GnRHa were successful at suppressing menses in 73–96.5% of patients.6
Importantly, timing of treatment was vital, as suppression was most effective if the first dose was given at least 2 weeks prior to the onset of thrombocytopenia (6% if more than 2 weeks prior versus 33% if later).6 Our study demonstrated adequate menstrual suppression during the first 30 days following HCT in three of the seven patients who received GnRHa. The four patients who did have breakthrough bleeding during this time period were controlled with either the administration of estrogen or platelet transfusion.
Decreased bone density is a potential side effect from GnRHa use, and our limited number of patients with 1-year follow-up evaluations did have a decrease in bone density. However, these findings are potentially multifactorial given the risk associated with HCT alone. Of note, pamidronate has been shown to be effective in preventing or reducing bone loss during HCT, and bisphophonate treatment could be considered in future clinical trials involving leuprolide to determine if bone density loss can be minimized.25, 26, 27
In regard to those patients in the observation group who underwent RIC, there are very limited studies looking at ovarian preservation. Notably, the definition of RIC and what is used is also extremely variable. It is a strength of this study that the RIC regimen was almost uniform (9/10 patients). A separate study by Assouline et al.28 also sought to describe the effect of RIC on ovarian function and fertility. The 22 patients underwent RIC HCT for a number of underlying conditions, with the vast majority being for malignancy (19/22). Of those patients, the conditioning regimens were extremely variable. Unlike our study, which showed optimistic findings for those undergoing RIC HCT, this study demonstrated impaired ovarian function in 86.3% of patients. All patients transplanted for a non-malignant condition had regular menses and pregnancies following HCT. This likely demonstrates the importance of chemotherapy exposures for underlying malignancy even prior to HCT.
Although the results of our study are promising, there are some limitations, including heterogeneous diagnoses and varying gonadotoxic exposures prior to HCT. The age of the patients was also variable. It is known that younger patients, especially those who are prepubertal, have a larger pool of functioning oocytes, making their risk of premature ovarian failure lower than that for older adults. Age has been shown to be a factor in the ability to preserve ovarian function in studies of survivors of breast cancer and other malignancies.29, 30, 31 Notably, the patients who received leuprolide were followed for a median of 703 days, but many of the studies that cite ovarian failure rates of >90% had follow-up times that were longer and it is possible that some of the women in our study with preserved ovarian function may go on to develop ovarian failure over time. With regard to the RIC patients only, most were being treated for non-malignant conditions and thus they were not exposed to significant amounts of chemotherapy prior to their conditioning. This may not be the case for all patients undergoing RIC HCT, which limits the generalizability of these findings. The precise doses of gonadotoxic chemotherapy also could not be calculated due to our institution serving as a large referral center, thus making these records difficult to obtain. The most notable limitation was the small sample size for both the MA and RIC groups, restricting firm conclusions from this study.
In conclusion, this pilot study indicates that the use of GnRHa therapy given prior to MA conditioning may preserve ovarian function in a significant proportion of patients. The study highlights the importance of consideration of GnRHa therapy for those women undergoing MA HCT, regardless of their prior chemotherapy or radiation exposures. Additionally, while low rates of ovarian failure were seen in women undergoing RIC HCT, care should be taken to counsel patients about their risks individually. Further studies with a larger sample size and longer duration of follow-up are needed to confirm these findings.
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This work was supported by grants from the University of Minnesota Grant-in-Aid program and the Minnesota Medical Foundation.
The authors declare no conflict of interest.
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Phelan, R., Mann, E., Napurski, C. et al. Ovarian function after hematopoietic cell transplantation: a descriptive study following the use of GnRH agonists for myeloablative conditioning and observation only for reduced-intensity conditioning. Bone Marrow Transplant 51, 1369–1375 (2016) doi:10.1038/bmt.2016.150