Perspectives on the co-treatment with GnRHa in female patients undergoing hematopoietic stem cell transplantation

in Endocrine Connections

Outcomes after hematopoietic stem cell transplantation (HSCT) for patients with both malignant and nonmalignant diseases have improved significantly in recent years. However, the endocrine system is highly susceptible to damage by the high-dose chemotherapy and/or irradiation used in the conditioning regimen before HSCT. Ovarian failure and subsequent infertility are frequent complications that long-term HSCT survivors and their partners face with a negative impact on their QoL. Several meta-analyses of randomized clinical trials showed that gonadotropin-releasing hormone agonist (GnRHa) administration in advance of starting standard chemotherapy decreases the risk of gonadal dysfunction and infertility in cancer patients, but GnRHa use for ovarian protection in HSCT patients is not fully determined. In this review, we are discussing the potential preservation of ovarian function and fertility in pubertal girls/premenopausal women who undergo HSCT using GnRHa in parallel with conditioning chemotherapy, focusing on the current data available and making some special remarks regarding the use of GnRHa.

Abstract

Outcomes after hematopoietic stem cell transplantation (HSCT) for patients with both malignant and nonmalignant diseases have improved significantly in recent years. However, the endocrine system is highly susceptible to damage by the high-dose chemotherapy and/or irradiation used in the conditioning regimen before HSCT. Ovarian failure and subsequent infertility are frequent complications that long-term HSCT survivors and their partners face with a negative impact on their QoL. Several meta-analyses of randomized clinical trials showed that gonadotropin-releasing hormone agonist (GnRHa) administration in advance of starting standard chemotherapy decreases the risk of gonadal dysfunction and infertility in cancer patients, but GnRHa use for ovarian protection in HSCT patients is not fully determined. In this review, we are discussing the potential preservation of ovarian function and fertility in pubertal girls/premenopausal women who undergo HSCT using GnRHa in parallel with conditioning chemotherapy, focusing on the current data available and making some special remarks regarding the use of GnRHa.

Introduction

Hematopoietic stem cell transplantation (HSCT) is increasingly used for the treatment of both malignant and nonmalignant diseases. Survival after autologous/allogeneic HSCT is no longer the highest concern, as many patients survive the acute complications of the procedure and remain free of their original disease. Instead, long-term side effects are important to recognize and treat (1, 2, 3) to maintain a good quality of life (QoL) for HSCT recipients (4, 5). Gonadal insufficiency and subsequent infertility are frequent problems that long-term HSCT survivors and their partners face with a negative impact on their QoL (4, 5). Beside infertility, premature ovarian failure (POF) can have a significant impact on QoL (6), including hot flashes, risk for osteoporosis and mood lability (7).

Total body irradiation, even low-dose regimen, as well as the chemotherapeutic agents used in the conditioning regimen for HSCT, and the deleterious effects of chronic graft vs host disease implies a risk of consequent gonadotoxicity (8, 9, 10). A review of the literature on gonadal toxicity of HSCT clearly stated that the risk of ovarian damage and POF is very high in HSCT recipients (11). Gonadal damage following HSCT results in a spectrum of gonadal function with varied clinical outcomes (5). Ovarian failure after HSCT has been observed in 65–84% of transplant recipients (5, 12, 13, 14). In patients performing HSCT for hematological malignancies, the incidence of POF is even higher than 90% (15). More than 80% of HSCT recipients present permanent amenorrhea following conditioning regimen with cyclophosphamide/total body irradiation (TBI) or cyclophosphamide/busulfan (8, 16). While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, the risk is unclear after reduced-intensity conditioning (RIC) (7, 17). However, analysis of the contribution of conditioning regimens to gonadotoxicity may be confounded by the disease itself or prior exposure to cytotoxic agents. In addition, there is a considerable difference between prepubertal/postpubertal girls undergoing HSCT (7, 18). When HSCT is performed in prepubertal girls, the risk for future gonadal insufficiency is approximately 50% (19). A half of the prepubertal girls treated with chemotherapy and hyper-fractionated TBI retain adequate ovarian function to enter puberty and menstruate regularly after transplantation (20). Therefore, creating a ‘prepubertal milieu’ using GnRHa can be regarded as an option for preserving normal gonadal function in young women performing HSCT (8, 21). Although human primordial follicles are not directly under gonadotrophin influence it seems that GnRH co-treatment offers a degree of protection to follicle reserves by decreasing ovarian perfusion and thus minimizing penetration of gonadotoxic agents to the primordial follicles, which leads to the protection of undifferentiated germ-line stem cells and the upregulation of antiapoptotic molecules (21, 22).

It has been demonstrated by several meta-analyses of clinical randomized studies that the use of GnRHa before/during starting standard chemotherapy decreases the risk of gonadal dysfunction and infertility in patients with different types of cancer (23, 24). Still, the possible utility of this technique of preserving normal ovarian function and fertility in HSCT recipients has not yet been established (25).

Methods

This is a literature review from reliable electronic databases conducted between October 2016 and April 2017 using the following key words related to the topic: ‘gonadotropin-releasing hormone analogues’, ‘GnRHa’, ‘luteinizing hormone-releasing hormone agonist’, ‘LHRHa’, ‘gonadal function’, ‘ovarian failure’, ‘fertility’, ‘fertility preservation’, ‘pregnancy’, ‘hematopoietic’, ‘transplantation’, ‘chemotherapy’, ‘cancer’. Only articles published in the last five years and several articles of great scientific importance were selected and commented in this review.

The first part of the present review aims at describing the effectiveness of GnRHa co-administration during standard chemotherapy for preservation of normal gonadal function and fertility in young patients with cancer. In the second part, which represents the aim of the present paper, we are discussing the potential preservation of ovarian function and fertility in pubertal girls/premenopausal women who undergo HSCT using GnRHa in parallel with conditioning chemotherapy. In the last part of the review, we make some special remarks regarding the use of GnRHa.

Critical analysis of selected studies

The efficacy of GnRHa co-treatment before/during standard chemotherapy in young cancer patients

GnRHa co-treatment in terms of ovarian protection in cancer patients

The role of temporary ovarian suppression with GnRHa before/during chemotherapy in preserving ovarian function and fertility is not unequivocally accepted. Several systematic reviews and meta-analyses of randomized clinical trials (RCT) assessing the efficacy of GnRHa co-treatment (Table 1) showed that GnRHa co-treatment reduces POF and increases the pregnancy rate (PR) in survivors (Table 2) (23, 24, 26, 27, 28, 29, 30, 31). However, other meta-analyses have found that GnRHa given with chemotherapy was associated with increased rates of recovery of regular menses, but the evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility pointing to the fact that further investigations are needed (32, 33).

Table 1

Summary of the meta-analyses of RCT assessing the efficacy of GnRHa given before and during chemotherapy in cancer patients.

ReferenceNo. of patients includedPatient populationEndpoint
Pro
 Lambertini, 20151231BCPOF, PR
 Shen, 20151062BCPOF, PR
 Del Mastro, 2014765BC, HL, ovarian cancerPOF
 Sun, 2014621BC, HL, ovarian cancerPOF
 Yang, 2013528BCResumption of menses, spontaneous ovulation, PR
 Wang, 2013677BCResumption of menses
 Bedaiwy, 2011340BC, HL, ovarian cancerResumption of menses, spontaneous ovulation
 Chen, 2011VariousResumption of menses, spontaneous ovulation, PR
 Munhoz, 2016856BCResumption of regular menses, PR
Contra
 Elgindy, 2015907VariousResumption of menstruation, ovarian reserve, PR

BC, breast cancer; HL, Hodgkin lymphoma; POF, premature ovarian failure; PR, pregnancy rate; RCT, randomized clinical trials.

Table 2

The results of the meta-analyses of RCT assessing the efficacy of GnRHa given before/during chemotherapy.

ReferenceEndpointNo. of patientsResults GnRHa vs controlP value
Pro
 Lambertini, 2015POF123118.5% vs 33.5%, OR = 0.36<0.001
1-year Amenorrhea88231% vs 42.9%, OR = 0.55<0.001
PR70633 vs 9, OR = 1.830.041
DFS62619.5% vs 18.8%, HR = 1.000.939
 Shen, 2015POF1064OR 2.57, 95% CI 1.65–4.010.0001
PROR 0.177; 95% CI = 0.92, 1.400.09
 Del Mastro, 2014POF765OR = 0.43; 95% CI: 0.22–0.840.013
 Sun, 2014POF6219.66% vs 26.67%, RR of 0.45, 95% CI 0.22–0.920.02
 Yang, 2013POF528RR of 0.40, 95% CI 0.21–0.75
RMRR = 1.31, 95% CI 0.93–1.85
PRRR = 0.96, 95% CI 0.20–4.56
 Wang, 2013RM677OR 2.681; 95% CI, 1.169–6.146
 Chen, 2011RMRR 1.90, 95% CI 1.30–2.79
AmenorrheaRR 0.08, 95% CI 0.01–0.58
OvulationRR 2.70, 95% CI 1.52–4.79
PRRR 0.21, 95% CI 0.01–4.09
 Bedaiwy, 2011RM34057.22% vs 35.22%0.03
OR 3.46; 95% CI, 1.13–10.57
Spontaneous9860.41% vs 22%0.0002
OvulationOR 5.70; 95% CI, 2.29–14.20
 Munhoz, 2016RM 6 months856OR = 2.41; 95% CI 1.40–4.150.002
RM 12 months778OR 1.85; 95% CI 1.33–2.590.0003
PR218OR 1.85; 95% CI 1.02–3.360.04
Contra
 Elgindy, 2015RM90768.4% vs 59.9%, RR 1.12, 95% CI 0.99–1.270.7
PRRR 1.63, 95% CI 0.94–2.82

CI, confidence interval; DFS, disease-free survival; OR, odds ratio; POF, premature ovarian failure; PR, pregnancy rate; RCT, randomized clinical trials; RM, resumption of menses; RR, relative risk.

The largest meta-analysis that provides convincing evidence of the protective role of GnRHa in young cancer patients is the one performed by Lambertini and coworkers in breast cancer patients (23), which showed a significant reduced risk of POF and increased number of patients achieving pregnancy in patients receiving GnRHa co-treatment (Table 2). Additionally, the study of Moore and coworkers demonstrated a more favorable disease-free survival (P = 0.04) and overall survival rates (P = 0.05) alongside with preserving the ovarian function (POF rate at 2 years was 8% in the GnRH arm vs 22% in the standard chemotherapy arm, OR: 0.30, P = 0.04) and improved fertility in the GnRHa arm (21% in the GnRHa arm vs 11% in the chemotherapy-alone group, P = 0.03) (34).

In 2014, Blumenfeld and coworkers summarized in a meta-analysis that included 1837 patients (1059 in the RCT), the pros and cons of using GnRHa to minimize the gonadotoxic effect of chemotherapy and preserve fertility in patients with different types of oncological/autoimmune disorders. The concept underlined was that preventing POF is preferable to treating it, following the dictum ‘an ounce of prevention is worth a pound of cure’ (35).

Summary of the studies assessing the efficacy of GnRHa in cancer patients in terms of fertility preservation

Temporary ovarian suppression with GnRHa during chemotherapy has been studied as a strategy to preserve ovarian function rather than as an option for fertility preservation (36) considering that the recovery of cyclic ovarian function after chemotherapy does not always imply fertility restoration (36). A prospective observational study performed by Huser and coworkers involving 108 females newly diagnosed with HL who were treated with different types of chemotherapy while receiving GnRHa to preserve ovarian function demonstrated significantly better fertility outcomes among HL patients receiving less gonadotoxic chemotherapy (34.1% in HL patients receiving less gonadotoxic chemotherapy vs 3.1% in the most gonadotoxic chemotherapy group) (37). However, the limitation of the study is that all patients in the trial received GnRHa in addition to different regimens of chemotherapy. Therefore, the protection of GnRHa on ovarian function and fertility preservation could not be appropriately assessed in the lack of a control group not receiving GnRHa. The results of a prospective RCT performed by Demesteere and coworkers also point to the fact that GnRHa co-treatment might have a protective role on fertility outcome (38). The long-term follow-up of patients included in this study (67 of the initial 129 patients) revealed that 53.1% (17/32 patients) and 42.8% (15/35) patients achieved pregnancy in the GnRHa and control groups, respectively (P = 0.467). Furthermore, five pregnancies (two in the GnRHa group and three in the control group) occurred in patients with protocol-defined POF (38). However, the authors concluded that triptorelin was not effective in improving fertility considering the high PR observed in both groups (38). The issue of fertility preservation by GnRHa co-treatment was also addressed by Blumenfeld and coworkers in a large retrospective study, which demonstrated a high PR in the GnRHa group (69.7% vs 42.4% in the control group, P = 0.0003) (21). Spontaneous pregnancies occurred in 80 women (65.6%) in the GnRHa group in comparison to 25 (37.9%) in the control group (OR = 3.12; P = 0.0004) (21). In addition, the age for those who spontaneously conceived was 14–38 years in the GnRHa arm compared to 14–30 years in control group suggesting a possible prolongation of the fertile window by almost 10 years (21). After publishing the results of his study, Del Mastro & Lambertini concluded that the data presented are very encouraging, supporting the idea of administering GnRHa before and during gonadotoxic therapy not only for recovery of cyclic ovarian function after chemotherapy, but also for fertility restoration (36). Del Mastro pointed out to the fact that the studies evaluating the efficacy of GnRHa therapy report a very high PR: 61% by Blumenfeld and coworkers (21), 71% by Wong and coworkers (39), 88% by Moore and coworkers (34), suggesting that the temporary suppression with GnRHa during chemotherapy may not be a strategy only for fertility preservation, but also to increase the likelihood of achieving a pregnancy (36).

The potential protective role of GnRHa co-treatment during chemotherapy in young female patients undergoing HSCT

As recommended by major international guidelines, it is of critical importance to discuss with all patients at diagnosis regarding late side effects of therapy and the options for preservation of normal gonadal function and the possibility for future fertility (5, 40, 41). In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are accepted methods for fertility (5). Other options such as temporary ovarian suppression with gonadotropin-releasing hormone analogues (GnRHa) during chemotherapy are still considered experimental (5, 42).

Summary of the studies assessing the efficacy of GnRHa in HSCT recipients in terms of ovarian protection

To date, only a few studies have addressed the issue of GnRHa efficacy in terms of ovarian protection in HSCT patients (Tables 3 and 4). Blumenfeld and coworkers compared in a prospective, non-randomized study the rate of POF after HSCT in young women receiving GnRHa in conjunction with gonadotoxic chemotherapy vs chemotherapy alone (21). Eighty-three women undergoing HSCT for malignant diseases were enrolled in the study and fifty women chose to receive GnRHa within 10–14 days to chemotherapy. POF was defined as amenorrhea associated with a FSH level above 40 IU/mL (25). The study found that GnRHa co-treatment in parallel with conditioning chemotherapy before HSCT may significantly decrease the POF rate from 82% to 33% in lymphoma patients. Furthermore, cyclic ovarian function (COF) defined as resumption of menses for at least 6 months following HSCT, ultrasonographic evidence of ovarian follicles or corpus luteum and normal FSH and LH levels or pregnancy, was present in 38.3% women who received the GnRHa in comparison with 11.1% in the chemotherapy-alone group. In lymphoma patients, the COF returned in 66.7% women in the GnRH arm vs 18.2% for control. The authors concluded that GnRHa use may be beneficial in women undergoing HSCT, especially for lymphoma (25).

Table 3

Summary of the studies assessing the efficacy of GnRHa given before and during chemotherapy in HSCT recipients in terms of ovarian function and fertility preservation.

ReferenceType of studyNo of patientsEndpoint
Blumenfeld, 2012Prospective, nonrandomized study83COF
Cheng, 2012Prospective, phase II study44COF
Pup, 2014Retrospective study17PR
Phelan, 2016Prospective study17POF
Demesteere, 2016Prospective randomized study10POF
COF, ovarian reserve (AMH level), DFS

AMH, anti-Mullerian hormone; COF, cyclic ovarian function; DFS, disease-free survival; POF, premature ovarian failure.

Table 4

Results of the studies assessing the efficacy of GnRHa given before and during chemotherapy in HSCT recipients in terms of ovarian function and fertility preservation.

ReferenceNo of patientsPrevious CxtType of HSCTType of diseaseResults
Blumenfeld, 201283Allo/autoVarious18/47 in GnRHa group vs 4/36 in control group
33AutoLymphoma14/21 in GnRHa group vs 2/11 in control group
Cheng, 201244Yes (42/44)Allo/autoVarious7/44
29AlloAllo HSCT2/29, P = 0.04
15Auto HSCT5/15
Pup, 201417AutoLymphoma5/17
Phelan, 201617 (7 received GnRHa)YesAuto/alloVarious3/7
Demesteere, 201610 (3 received GnRHa)NoAutoLymphoma2/3 in GnRHa group vs 4/7 in control group

HSCT, hematopoietic stem cell transplantation.

Also, Cheng and coworkers analyzed in a phase II prospective study the effectiveness of GnRHa use in HSCT recipients (43). Among the 44 patients evaluated in the study who performed HSCT, 33 women received MA regimens and 11 non-MA regimens. The median age of the patients was 25 years with a median follow-up period of 355 days. The study found that a total of 16% (7/44) women restored normal ovarian function, 18% (6/33) in the MA group and 9% (1/11) in the non-MA, respectively (P = 0.66). A third of the patients who performed autologous transplantation (33%) resumed COF compared with 7% of patients who underwent allogeneic transplantation (P = 0.04). Five of the seven patients that restored COF had HL. The authors concluded that leuprolide was not able to preserve the ovarian function in patients who underwent HSCT using either MA or non-MA regimens (43). Their work was criticized by colleagues in the medical field for several reasons. First, GnRH-a was administered before the conditioning chemotherapy preceding HSCT, not before patient’s first exposure to chemotherapeutic agents (almost all patients received at least one prior chemotherapy regimen and 12 patients also received prior local radiation) (44). Secondly, the dosage of GnRHa was twice the dose of triptorelin/leuprolide used in previous studies, which led to 9 patients dropout because of the high rate of side effects (44).

In another study, Phelan and coworkers investigated the impact of leuprolide on ovarian function after MA conditioning (intervention group) and monitored ovarian function after RIC in a descriptive pilot study (observational group) that included 7 evaluable patients in the interventional arm (that received GnRHa) and 10 patients in the observational group (7). The patients in the first group underwent both autologous and allogeneic HSCT, while the women in the observational arm received allogeneic RIC. The authors used a combination of long-acting and short-acting leuprolide. FSH was measured at baseline, days 100 and 180, and at 1 and 2 years following HSCT, and the POF was defined as an FSH level over 40 IU/mL. The incidence of POF in the intervention group was 43% (3 out of 7 subjects) at a median of 703 days post-transplant (range, 206–754 days), lower than the incidence reported in the literature (5, 12, 13, 14), suggesting a protective role of GnRH co-administration (7). However, as the author commented, the period of follow-up was rather short (median of 703 days post transplant), and it is possible that some of the women in the interventional group with preserved ovarian function may develop POF over time (7). In the observational group that received RIC, the incidence of POF was 10% (the single patient in this group with POF received a second transplant). Still, most of the patients in the observational group were treated for nonmalignant conditions and only two of them were exposed to significant amounts of gonadotoxic chemotherapy (alkylating agents) prior to their conditioning regimen for the HSCT (7).

Fertility impairment after HSCT

Prevention of ovarian failure is an important endpoint when evaluating the use of GnRHa (7). However, even where gonadal recovery and pregnancy occur, it is important that the patient be aware that their ovarian reserve may be reduced by conditioning or pre-HCT chemoradiotherapy and that POF remains probable (5). In recent years, because of improvement in the prognosis of HSCT survivors, fertility issues have received increased attention. Studies have shown that most survivors of pediatric HSCT express the desire to have children in the future (8). Although both the patients and their parents are focused on survival at the time of diagnosis, for the majority, fertility becomes a secondary issue. Because of these concerns, fertility preservation options should be discussed with all patients having to undergo HSCT (8, 45).

Fertility rate is severely affected following HSCT with a conception rate <1% (8, 46, 47). Only 0.6% of patients (232 patients) conceived after one autologous or allogeneic BMT, according to an extensive survey, involving 19,412 allogeneic and 17,950 autologous transplanted patients (46). Similarly, in another study, only 3% female patients conceived after HSCT (12). The same results came from the study of Sanders and coworkers performed on 708 pre- and postpubertal survivors of HSCT, which reported a PR of 4.5% (32 patients) (13). However, it is important to recognize that these studies assessing fertility after HCT are limited by the fact that they have not accounted for whether patients were actually trying to conceive (5). A recent publication by Dyer and coworkers that investigated the impact of allogeneic HSCT on fertility reported that 22% survivors tried to conceive, with 10.3% PR (48). Although RIC with exposure to no or reduced dose TBI appear to be less deleterious to reproductive function (5, 7), more research is needed to determine whether these regimens result in better pregnancy outcomes.

Hormonal therapies such as the use of or GnRHa to suppress ovarian function during cancer treatment are one of the simplest means of preserving fertility. However, its efficacy is not well studied in HSCT recipients (5). There is one report in the literature of a postpubertal lymphoma patient that had two spontaneous pregnancies and successful deliveries after repeated autologous transplantation and GnRHa co-treatment (49). The author suggested that the prepubertal milieu induced by the GnRHa might have contributed to the preserved fertility, despite repeated HSCT (49). Also, during the long-term follow-up of 67 HL patients in a RCT, one pregnancy was reported after egg donation in a patient from the GnRHa group, who was treated with the HSCT conditioning regimen (38).

In addition, a retrospective study performed by Pup and coworkers including 17 consecutive women of child-bearing age affected by lymphoma who underwent HSCT described a high rate of parenthood (29%). Five patients became pregnant and 1 out of 5 had two pregnancies and all women who conceived had received GnRHa co-treatment, suggesting a protective role of this therapy for fertility preservation (50).

Rational perspectives regarding the use of GnRHa

The mechanisms that are currently proposed to explain the protective role of GnRHa is that it simulates the prepubertal hormonal milieu (8, 21) and furthermore, decreases the ovarian perfusion and thus the exposure of the primordial follicles to the cytotoxic agents (21, 22). Another important advantage of GnRHa co-treatment is that it decreases the thrombocytopenia-associated menorrhagia leading to an improved survival (21, 37, 39, 51). Cytopenia achieved during transplantation includes thrombocytopenia, which can be problematic during menses. GnRHa provide menses suppression by inducing a hypogonadotropic, hypogonadal state that mimics prepubertal amenorrhea (52).

The GnRH-a administration should be timed as early as possible, usually within 10–14 days before starting first chemotherapy cycle (21, 25). In cases of urgency in initiating the chemotherapy, the interval may be shorter (1–7 days). Different agents have been used in the studies assessing GnRHa efficiency in preserving normal gonadal function and fertility in cancer patients and HSCT recipients (Table 5). Most studies used a monthly injection of 3.75 mg triptorelin or leuprolide depot (11.25 mg every 3 months) or 3.6 mg goserelin (7, 21, 38, 51). However, Cheng and coworkers used a very high dosage of the GnRHa, twice the commonly used dosage in previous studies (43).

Table 5

Different GnRHa protocols used in the studies that assessed its potential benefit before/during high-dose chemotherapy in preserving normal gonadal function and fertility in HSCT female recipients.

StudyGnRHaDoseTiming
Blumenfeld, 2008, 2012TriptorelinA monthly depot injection of 3.75 mg10–14 days before any gonadotoxic therapy and monthly during chemotherapy
Cheng, 2011Leuprolide22.5 mg in a 3-month depot i.m. injection2 months prior to HSCT
Phelan, 2016LeuprolideLong-acting 11.25 mg i.m. once + short-acting 0.2 mg s.c. daily for 14 days30 days prior to initiation of the HSCT conditioning regimen
Demeestere, 2013, 2016Triptorelin11.25 mg every 12 weeks in addition to norethisterone acetate at 5 mg once per day10 days before the start of chemotherapy if possible

The most common side effects of GnRHa are the signs and symptoms associated with hypoestrogenism including hot flashes, headaches and osteoporosis. Initially, there is an increase of FSH and LH secretion (so-called ‘flare effect’) that lasts for 2–3 weeks, followed by the hypogonadotropic state. GnRHa carries a known risk of hypoestrogenism-associated decreased bone mineral density (5). Therefore, its use should be limited to a short period of time, especially in patients with hematological malignancies that are exposed to high doses of glucocorticoids (44). It has been suggested that administration of the GnRHa 10–14 days before chemotherapy is sufficient to overcome the flare-up effect of the agonist and to establish the hypogonadotropic milieu (44).

GnRHa co-treatment may be beneficial in patients who receive high-dose chemotherapy before HSCT, but is not useful in conditioning regimens that include TBI. In these circumstances, ovarian shielding may be more appropriate (53, 54, 55, 56). Still, the pilot study performed by Phelan and coworkers highlighted the importance of considering temporary sex steroid blockade with GnRHa for young women undergoing MA regimens for HSCT, regardless of their prior chemotherapy or radiation exposures (7).

Conclusion

Based on the available studies, GnRHa co-treatment appears to improve ovarian function and the ability to achieve pregnancy following standard chemotherapy. There are some promising preliminary results in terms of ovarian function preservation with the concomitant use of GnRHa and conditioning chemotherapy. Still, more data are needed to define the role of GnRHa in ovarian function and fertility preservation in young women/pubertal girls undergoing HSCT.

Until further data are available, premenopausal women and pubertal girls facing chemotherapy for HSCT should be counseled about ovarian preservation option, including the use of GnRHa therapy, keeping in mind that it is inexpensive, noninvasive and has minimal side effects.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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  • 19

    VatanenAWilhelmssonMBorgströmBGustafssonBTaskinenMSaarinen-PihkalaUMWiniarskiJJahnukainenK. Ovarian function after allogeneic hematopoietic stem cell transplantation in childhood and adolescence. European Journal of Endocrinology 2014 170 211218. (doi:10.1530/EJE-13-0694)

  • 20

    SarafoglouK.BouladF.GillioA.SklarC. Gonadal function after bone marrow transplantation for acute leukemia during childhood. Journal of Pediatrics 1997 130 210216. (doi:10.1016/S0022-3476(97)70345-7)

  • 21

    BlumenfeldZZurHDannEJ. Gonadotropin releasing hormone agonist cotreatment during chemotherapy may increase pregnancy rate in survivors. Oncologist 2015 20 12831289. (doi:10.1634/theoncologist.2015-0223)

  • 22

    BlumenfeldZ. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. Oncologist 2007 12 10441054. (doi:10.1634/theoncologist.12-9-1044)

  • 23

    LambertiniMCeppiMPoggioFPeccatoriFAAzimHAJrUgoliniDPronzatoPLoiblSMooreHCPartridgeAH Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies. Annals of Oncology 2015 26 24082419. (doi:10.1093/annonc/mdv374)

  • 24

    Del MastroLCeppiMPoggioFBighinCPeccatoriFDemeestereILevaggiAGiraudiSLambertiniMD’AlonzoA Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treatment Reviews 2014 40 675683. (doi:10.1016/j.ctrv.2013.12.001)

  • 25

    BlumenfeldZPatelBLeibaRZuckermanT. Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation. Fertility and Sterility 2012 98 12661270. (doi:10.1016/j.fertnstert.2012.07.1144)

  • 26

    ShenYWZhangXMLvMChenLQinTJWangFYangJLiuPJYangJ. Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis. OncoTargets and Therapy 2015 8 33493359. (doi:10.2147/OTT.S95936)

  • 27

    SunXDongolSJiangJKongB. Protection of ovarian function by GnRH agonists during chemotherapy: a meta-analysis. International Journal of Oncology 2014 44 13351340. (doi:10.3892/ijo.2014.2296)

  • 28

    YangBShiWYangJLiuHZhaoHLiXJiaoS. Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials. Breast 2013 22 150157. (doi:10.1016/j.breast.2012.12.008)

  • 29

    WangCChenMFuFHuangM. Gonadotropin-releasing hormone analog cotreatment for the preservation of ovarian function during gonadotoxic chemotherapy for breast cancer: a meta-analysis. PLoS ONE 2013 8 e66360. (doi:10.1371/journal.pone.0066360)

  • 30

    ChenHLiJCuiTHuL. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy induced premature ovarian failure in premenopausal women. Cochrane Database of Systematic Reviews 2011 9 CD008018. (doi:10.1002/14651858.CD008018.pub2)

  • 31

    BedaiwyMAAbou-SettaAMDesaiNHurdWStarksDEl-NasharSAAl-InanyHGFalconeT. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis. Fertility and Sterility 2011 95 906914. (doi:10.1016/j.fertnstert.2010.11.017)

  • 32

    MunhozRRPereiraAASasseADHoffPMTrainaTAHudisCAMarquesRJ. Gonadotropin-releasing hormone agonists for ovarian function preservation in premenopausal women undergoing chemotherapy for early-stage breast cancer: a systematic review and meta-analysis. JAMA Oncology 2016 2 6573. (doi:10.1001/jamaoncol.2015.3251)

  • 33

    ElgindyESibaiHAbdelghaniAMostafaM. Protecting ovaries during chemotherapy through gonad suppression: a systematic review and meta-analysis. Obstetrics and Gynecology 2015 126 187195. (doi:10.1097/AOG.0000000000000905)

  • 34

    MooreHCUngerJMPhillipsKABoyleFHitreEPorterDFrancisPAGoldsteinLJGomezHLVallejosCS Goserelin for ovarian protection during breast cancer adjuvant chemotherapy. New England Journal of Medicine 2015 372 923932. (doi:10.1056/NEJMoa1413204)

  • 35

    BlumenfeldZKatzGEvronA. ‘An ounce of prevention is worth a pound of cure’: the case for and against GnRH-agonist for fertility preservation. Annals of Oncology 2014 25 17191728. (doi:10.1093/annonc/mdu036)

  • 36

    Del MastroLLambertiniM. Temporary ovarian suppression with gonadotropin-releasing hormone agonist during chemotherapy for fertility preservation: toward the end of the debate? Oncologist 2015 20 12331235. (doi:10.1634/theoncologist.2015-0373)

  • 37

    HuserMSmardovaLJankuPCrhaIZakovaJStouracPJarkovskyJMayerJVentrubaP. Fertility status of Hodgkin lymphoma patients treated with chemotherapy and adjuvant gonadotropin-releasing hormone analogues. Journal of Assisted Reproduction and Genetics 2015 32 11871193. (doi:10.1007/s10815-015-0452-z)

  • 38

    DemeestereIBricePPeccatoriFAKentosADupuisJZacheePCasasnovasOVan Den NesteEDecheneJDe MaertelaerV No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial. Journal of Clinical Oncology 2016 34 25682574. (doi:10.1200/JCO.2015.65.8864)

  • 39

    WongMO’NeillSWalshGSmithIE. Goserelin with chemotherapy to preserve ovarian function in pre-menopausal women with early breast cancer: menstruation and pregnancy outcomes. Annals of Oncology 2013 24 133138. (doi:10.1093/annonc/mds250)

  • 40

    LorenAWManguPBBeckLNBrennanLMagdalinskiAJPartridgeAHQuinnGWallaceWHOktayK & American Society of Clinical Oncology. Fertility preservation for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology. 2013 31 25002510. (doi:10.1200/JCO.2013.49.2678)

  • 41

    BastingsLWestphalJRBeerendonkCCBraatDDPeekR. Fertility preservation in young patients before allogeneic haematopoietic SCT. Bone Marrow Transplantation 2012 47 313314. (doi:10.1038/bmt.2011.235)

  • 42

    ChatterjeeRKottaridisPD. Treatment of gonadal damage in recipients of allogeneic or autologous transplantation for haematological malignancies. Bone Marrow Transplantation 2002 30 629635 (doi:10.1038/sj.bmt.1703721)

  • 43

    ChengYCTakagiMMilbourneAChamplinREUenoNT. Phase II study of gonadotropin-releasing hormone analog for ovarian function preservation in hematopoietic stem cell transplantation patients. Oncologist 2012 17 233238. (doi:10.1634/theoncologist.2011-0205)

  • 44

    BlumenfeldZ. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function. Oncologist 2012 17 162163. (doi:10.1634/theoncologist.2011-0351)

  • 45

    LorenAWBrazauskasRChowEJGilleeceMHalterJJacobsohnDAJoshiSPidalaJQuinnGPWangZ Physician perceptions and practice patterns regarding fertility preservation in hematopoietic cell transplant recipients. Bone Marrow Transplantation 2013 48 10911097. (doi:10.1038/bmt.2013.13)

  • 46

    SaloojaNSzydloRMSocieGRioBChatterjeeRLjungmanPVan LintMTPowlesRJacksonGHinterberger-FischerM Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 2001 358 271276. (doi:10.1016/S0140-6736(01)05482-4)

  • 47

    Frey TirriBHäusermannPBertzHGreinixHLawitschkaASchwarzeCPWolffDHalterJPDörflerDMoffatR. Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD. Bone Marrow Transplantation 2015 50 39. (doi:10.1038/bmt.2014.242)

  • 48

    DyerGGilroyNBradfordJBriceLKabirMGreenwoodMLarsenSRMooreJHertzbergMKwanJ A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia. British Journal of Haematology 2016 172 592601. (doi:10.1111/bjh.13872)

  • 49

    BlumenfeldZZuckermanT. Repeated spontaneous pregnancies and successful deliveries after repeated autologous stem cell transplantation and GnRH-agonist treatment. Oncologist 2010 15 5960. (doi:10.1634/theoncologist.2009-0269)

  • 50

    PupLDZanetERupoloMTalaminiRTirelliUMazzucatoMSteffanAZanussiSDorettoPMichieliM. Which tools may help physicians in female fertility prediction after autologous bone marrow transplantation for lymphoma? A pilot study. Journal of Chemotherapy 2014 26 293299. (doi:10.1179/1973947813Y.0000000162)

  • 51

    PoorvuPDBartonSEDuncanCNLondonWBLauferMRLehmannLEMarcusKJ. Use and effectiveness of gonadotropin-releasing hormone agonists for prophylactic menstrual suppression in postmenarchal women who undergo hematopoietic cell transplantation. Journal of Pediatric and Adolescent Gynecology 2016 29 265268. (doi:10.1016/j.jpag.2015.10.013)

  • 52

    ChangKMeridethMAStrattonP. Hormone use for therapeutic amenorrhea and contraception during hematopoietic cell transplantation. Obstetrics and Gynecology 2015 126 779784. (doi:10.1097/AOG.0000000000001031)

  • 53

    NakagawaKKandaYYamashitaHHosoiYOshimaKOhtomoKBanNYamakawaSNakagawaSChibaS. Preservation of ovarian function by ovarian shielding when undergoing total body irradiation for hematopoietic stem cell transplantation: a report of two successful cases. Bone Marrow Transplantation 2006 37 583587. (doi:10.1038/sj.bmt.1705279)

  • 54

    NakagawaKKandaYYamashitaHNakagawaSSasanoNOhtomoKOshimaKKumanoKBanNNannyaY Ovarian shielding allows ovarian recovery and normal birth in female hematopoietic SCT recipients undergoing TBI. Bone Marrow Transplantation 2008 42 697699.

  • 55

    KandaYWadaHYamasakiRKawamuraKIshiharaYSakamotoKAshizawaMSatoMMachishimaTTerasako-SaitoK Protection of ovarian function by two distinct methods of ovarian shielding for young female patients who receive total body irradiation. Annals of Hematology 2014 93 287292. (doi:10.1007/s00277-013-1852-8)

  • 56

    IshibashiNMaebayashiTAizawaTSakaguchiMAbeOSaitoTTanakaYChinMMugishimaH. Successful pregnancy and delivery after radiation with ovarian shielding for acute lymphocytic leukemia before menarche. Journal of Pediatric Hematology/Oncology 2015 37 e292e294. (doi:10.1097/MPH.0000000000000309)

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References

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DvorakCCGraciaCRSandersJEChengEYBakerKSPulsipherMAPetrykA. NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, and reproductive risks. Biology of Blood and Marrow Transplantation 2011 17 17251738. (doi:10.1016/j.bbmt.2011.10.006)

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LetourneauJMEbbelEEKatzPPKatzAAiWZChienAJMeliskoMECedarsMIRosenMP. Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer. Cancer 2012 118 17101717. (doi:10.1002/cncr.26459)

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JoshiSSavaniBNChowEJGilleeceMHHalterJJacobsohnDAPidalaJQuinnGPCahnJYJakubowskiAA Clinical guide to fertility preservation in hematopoietic cell transplant recipients. Bone Marrow Transplantation 2014 49 477484. (doi:10.1038/bmt.2013.211)

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ChiodiSSpinelliSRaveraGPettiARVan LintMTLamparelliTGualandiFOcchiniDMordiniNBerissoG Quality of life in 244 recipients of allogeneic bone marrow transplantation. British Journal of Haematology 2000 110 614619. (doi:10.1046/j.1365-2141.2000.02053.x)

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PhelanRMannENapurskiCDeForTEPetrykAMillerWPWagnerJEVernerisMRSmithAR. 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 Transplantation 2016 51 13691375. (doi:10.1038/bmt.2016.150)

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OrioFMuscogiuriGPalombaSSerioBSessaMGiudiceVFerraraITauchmanovàLColaoASelleriC. Endocrinopathies after allogeneic and autologous transplantation of hematopoietic stem cells. Scientific World Journal 2014 2014 282147. (doi:10.1155/2014/282147)

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MohtyBMohtyM. Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update. Blood Cancer Journal 2011 1 14. (doi:10.1038/bcj.2011.14)

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JadoulPDonnezJ. How does bone marrow transplantation affect ovarian function and fertility? Current Opinion in Obstetrics and Gynecology 2012 24 164171. (doi:10.1097/GCO.0b013e328353bb57)

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CarterARobisonLLFranciscoLSmithDGrantMBakerKSGurneyJGMcGlavePBWeisdorfDJFormanSJ Prevalence of conception and pregnancy outcomes after hematopoietic cell transplantation: report from the Bone Marrow Transplant Survivor Study. Bone Marrow Transplantation 2006 37 10231029. (doi:10.1038/sj.bmt.1705364)

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SandersJEHawleyJLevyWGooleyTBucknerCDDeegHJDoneyKStorbRSullivanKWitherspoonR Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996 87 30453052.

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LorenAWChowEJacobsohnDAGilleeceMHalterJJoshiSWangZSobocinskiKAGuptaVHaleGA Pregnancy after hematopoietic cell transplantation: a report from the late effects working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biology of Blood and Marrow Transplantation 2011 17 157166. (doi:10.1016/j.bbmt.2010.07.009)

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TauchmanovàLSelleriCDe RosaGEspositoMOrioFJrPalombaSBifulcoGNappiCLombardiGRotoliB Gonadal status in reproductive age women after haematopoietic stem cell transplantation for haematological malignancies. Human Reproduction 2003 18 14101416. (doi:10.1093/humrep/deg295)

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LambertiniMDel MastroLPescioMCAndersenCYAzimHAJrPeccatoriFACostaMRevelliASalvagnoFGennariA Cancer and fertility preservation: international recommendations from an expert meeting. BMC Medicine 2016 14 1. (doi:10.1186/s12916-015-0545-7)

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ShimizuMSawadaAYamadaKKondoWKoyama-SatoMShimizuSKomuraHYasuiMInoueMKawaK. Encouraging results of preserving ovarian function after allo-HSCT with RIC. Bone Marrow Transplantation 2012 47 141142. (doi:10.1038/bmt.2011.14)

18

MertensACRamsayNKKourisSNegliaJP. Patterns of gonadal dysfunction following bone marrow transplantation. Bone Marrow Transplantation 1998 22 345350. (doi:10.1038/sj.bmt.1701342)

19

VatanenAWilhelmssonMBorgströmBGustafssonBTaskinenMSaarinen-PihkalaUMWiniarskiJJahnukainenK. Ovarian function after allogeneic hematopoietic stem cell transplantation in childhood and adolescence. European Journal of Endocrinology 2014 170 211218. (doi:10.1530/EJE-13-0694)

20

SarafoglouK.BouladF.GillioA.SklarC. Gonadal function after bone marrow transplantation for acute leukemia during childhood. Journal of Pediatrics 1997 130 210216. (doi:10.1016/S0022-3476(97)70345-7)

21

BlumenfeldZZurHDannEJ. Gonadotropin releasing hormone agonist cotreatment during chemotherapy may increase pregnancy rate in survivors. Oncologist 2015 20 12831289. (doi:10.1634/theoncologist.2015-0223)

22

BlumenfeldZ. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. Oncologist 2007 12 10441054. (doi:10.1634/theoncologist.12-9-1044)

23

LambertiniMCeppiMPoggioFPeccatoriFAAzimHAJrUgoliniDPronzatoPLoiblSMooreHCPartridgeAH Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies. Annals of Oncology 2015 26 24082419. (doi:10.1093/annonc/mdv374)

24

Del MastroLCeppiMPoggioFBighinCPeccatoriFDemeestereILevaggiAGiraudiSLambertiniMD’AlonzoA Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treatment Reviews 2014 40 675683. (doi:10.1016/j.ctrv.2013.12.001)

25

BlumenfeldZPatelBLeibaRZuckermanT. Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation. Fertility and Sterility 2012 98 12661270. (doi:10.1016/j.fertnstert.2012.07.1144)

26

ShenYWZhangXMLvMChenLQinTJWangFYangJLiuPJYangJ. Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis. OncoTargets and Therapy 2015 8 33493359. (doi:10.2147/OTT.S95936)

27

SunXDongolSJiangJKongB. Protection of ovarian function by GnRH agonists during chemotherapy: a meta-analysis. International Journal of Oncology 2014 44 13351340. (doi:10.3892/ijo.2014.2296)

28

YangBShiWYangJLiuHZhaoHLiXJiaoS. Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials. Breast 2013 22 150157. (doi:10.1016/j.breast.2012.12.008)

29

WangCChenMFuFHuangM. Gonadotropin-releasing hormone analog cotreatment for the preservation of ovarian function during gonadotoxic chemotherapy for breast cancer: a meta-analysis. PLoS ONE 2013 8 e66360. (doi:10.1371/journal.pone.0066360)

30

ChenHLiJCuiTHuL. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy induced premature ovarian failure in premenopausal women. Cochrane Database of Systematic Reviews 2011 9 CD008018. (doi:10.1002/14651858.CD008018.pub2)

31

BedaiwyMAAbou-SettaAMDesaiNHurdWStarksDEl-NasharSAAl-InanyHGFalconeT. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis. Fertility and Sterility 2011 95 906914. (doi:10.1016/j.fertnstert.2010.11.017)

32

MunhozRRPereiraAASasseADHoffPMTrainaTAHudisCAMarquesRJ. Gonadotropin-releasing hormone agonists for ovarian function preservation in premenopausal women undergoing chemotherapy for early-stage breast cancer: a systematic review and meta-analysis. JAMA Oncology 2016 2 6573. (doi:10.1001/jamaoncol.2015.3251)

33

ElgindyESibaiHAbdelghaniAMostafaM. Protecting ovaries during chemotherapy through gonad suppression: a systematic review and meta-analysis. Obstetrics and Gynecology 2015 126 187195. (doi:10.1097/AOG.0000000000000905)

34

MooreHCUngerJMPhillipsKABoyleFHitreEPorterDFrancisPAGoldsteinLJGomezHLVallejosCS Goserelin for ovarian protection during breast cancer adjuvant chemotherapy. New England Journal of Medicine 2015 372 923932. (doi:10.1056/NEJMoa1413204)

35

BlumenfeldZKatzGEvronA. ‘An ounce of prevention is worth a pound of cure’: the case for and against GnRH-agonist for fertility preservation. Annals of Oncology 2014 25 17191728. (doi:10.1093/annonc/mdu036)

36

Del MastroLLambertiniM. Temporary ovarian suppression with gonadotropin-releasing hormone agonist during chemotherapy for fertility preservation: toward the end of the debate? Oncologist 2015 20 12331235. (doi:10.1634/theoncologist.2015-0373)

37

HuserMSmardovaLJankuPCrhaIZakovaJStouracPJarkovskyJMayerJVentrubaP. Fertility status of Hodgkin lymphoma patients treated with chemotherapy and adjuvant gonadotropin-releasing hormone analogues. Journal of Assisted Reproduction and Genetics 2015 32 11871193. (doi:10.1007/s10815-015-0452-z)

38

DemeestereIBricePPeccatoriFAKentosADupuisJZacheePCasasnovasOVan Den NesteEDecheneJDe MaertelaerV No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial. Journal of Clinical Oncology 2016 34 25682574. (doi:10.1200/JCO.2015.65.8864)

39

WongMO’NeillSWalshGSmithIE. Goserelin with chemotherapy to preserve ovarian function in pre-menopausal women with early breast cancer: menstruation and pregnancy outcomes. Annals of Oncology 2013 24 133138. (doi:10.1093/annonc/mds250)

40

LorenAWManguPBBeckLNBrennanLMagdalinskiAJPartridgeAHQuinnGWallaceWHOktayK & American Society of Clinical Oncology. Fertility preservation for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology. 2013 31 25002510. (doi:10.1200/JCO.2013.49.2678)

41

BastingsLWestphalJRBeerendonkCCBraatDDPeekR. Fertility preservation in young patients before allogeneic haematopoietic SCT. Bone Marrow Transplantation 2012 47 313314. (doi:10.1038/bmt.2011.235)

42

ChatterjeeRKottaridisPD. Treatment of gonadal damage in recipients of allogeneic or autologous transplantation for haematological malignancies. Bone Marrow Transplantation 2002 30 629635 (doi:10.1038/sj.bmt.1703721)

43

ChengYCTakagiMMilbourneAChamplinREUenoNT. Phase II study of gonadotropin-releasing hormone analog for ovarian function preservation in hematopoietic stem cell transplantation patients. Oncologist 2012 17 233238. (doi:10.1634/theoncologist.2011-0205)

44

BlumenfeldZ. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function. Oncologist 2012 17 162163. (doi:10.1634/theoncologist.2011-0351)

45

LorenAWBrazauskasRChowEJGilleeceMHalterJJacobsohnDAJoshiSPidalaJQuinnGPWangZ Physician perceptions and practice patterns regarding fertility preservation in hematopoietic cell transplant recipients. Bone Marrow Transplantation 2013 48 10911097. (doi:10.1038/bmt.2013.13)

46

SaloojaNSzydloRMSocieGRioBChatterjeeRLjungmanPVan LintMTPowlesRJacksonGHinterberger-FischerM Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 2001 358 271276. (doi:10.1016/S0140-6736(01)05482-4)

47

Frey TirriBHäusermannPBertzHGreinixHLawitschkaASchwarzeCPWolffDHalterJPDörflerDMoffatR. Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD. Bone Marrow Transplantation 2015 50 39. (doi:10.1038/bmt.2014.242)

48

DyerGGilroyNBradfordJBriceLKabirMGreenwoodMLarsenSRMooreJHertzbergMKwanJ A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia. British Journal of Haematology 2016 172 592601. (doi:10.1111/bjh.13872)

49

BlumenfeldZZuckermanT. Repeated spontaneous pregnancies and successful deliveries after repeated autologous stem cell transplantation and GnRH-agonist treatment. Oncologist 2010 15 5960. (doi:10.1634/theoncologist.2009-0269)

50

PupLDZanetERupoloMTalaminiRTirelliUMazzucatoMSteffanAZanussiSDorettoPMichieliM. Which tools may help physicians in female fertility prediction after autologous bone marrow transplantation for lymphoma? A pilot study. Journal of Chemotherapy 2014 26 293299. (doi:10.1179/1973947813Y.0000000162)

51

PoorvuPDBartonSEDuncanCNLondonWBLauferMRLehmannLEMarcusKJ. Use and effectiveness of gonadotropin-releasing hormone agonists for prophylactic menstrual suppression in postmenarchal women who undergo hematopoietic cell transplantation. Journal of Pediatric and Adolescent Gynecology 2016 29 265268. (doi:10.1016/j.jpag.2015.10.013)

52

ChangKMeridethMAStrattonP. Hormone use for therapeutic amenorrhea and contraception during hematopoietic cell transplantation. Obstetrics and Gynecology 2015 126 779784. (doi:10.1097/AOG.0000000000001031)

53

NakagawaKKandaYYamashitaHHosoiYOshimaKOhtomoKBanNYamakawaSNakagawaSChibaS. Preservation of ovarian function by ovarian shielding when undergoing total body irradiation for hematopoietic stem cell transplantation: a report of two successful cases. Bone Marrow Transplantation 2006 37 583587. (doi:10.1038/sj.bmt.1705279)

54

NakagawaKKandaYYamashitaHNakagawaSSasanoNOhtomoKOshimaKKumanoKBanNNannyaY Ovarian shielding allows ovarian recovery and normal birth in female hematopoietic SCT recipients undergoing TBI. Bone Marrow Transplantation 2008 42 697699.

55

KandaYWadaHYamasakiRKawamuraKIshiharaYSakamotoKAshizawaMSatoMMachishimaTTerasako-SaitoK Protection of ovarian function by two distinct methods of ovarian shielding for young female patients who receive total body irradiation. Annals of Hematology 2014 93 287292. (doi:10.1007/s00277-013-1852-8)

56

IshibashiNMaebayashiTAizawaTSakaguchiMAbeOSaitoTTanakaYChinMMugishimaH. Successful pregnancy and delivery after radiation with ovarian shielding for acute lymphocytic leukemia before menarche. Journal of Pediatric Hematology/Oncology 2015 37 e292e294. (doi:10.1097/MPH.0000000000000309)

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