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Utility of gonadotropin-releasing hormone agonists for fertility preservation in women receiving chemotherapy: pros and cons

2020; Elsevier BV; Volume: 114; Issue: 4 Linguagem: Inglês

10.1016/j.fertnstert.2020.08.011

1556-5653

Marie‐Madeleine Dolmans, Hugh S. Taylor, Kenny A. Rodriguez‐Wallberg, Zeev Blumenfeld, Matteo Lambertini, Michael von Wolff, Jacques Donnez,

Ovarian cancer diagnosis and treatment

The term "ovarian reserve" is typically used to refer to the population of primordial follicles (PMFs) (1Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5e8772Crossref PubMed Scopus (354) Google Scholar). This population is very sensitive to cytotoxic drugs, especially alkylating agents (cyclophosphamide, busulfan, ifosfamide). Among them, cyclophosphamide (CPA) is the alkylating agent that causes the most damage to oocytes and granulosa cells (2Meirow D. Nugent D. The effects of radiotherapy and chemotherapy on female reproduction.Hum Reprod Update. 2001; 7: 535-543Crossref PubMed Scopus (596) Google Scholar). Alkylating-like platinum complexes (such as cisplatin, anthracyclanes [including doxorubicin]) should also be considered as ovo-toxic drugs. Alkylating agents and platinum complexes work similarly, creating DNA cross-links in replicating cells, which finally cause DNA breaks and ultimately trigger apoptosis. Granulosa cells of growing follicles are highly sensitive to toxic drugs, resulting in their apoptosis, as a major mechanism of many chemotherapy agents. The loss of larger growing follicles is responsible for the significant decrease in antimüllerian hormone (AMH) levels during chemotherapy. AMH produced by growing follicles is thought to have an important inhibitory effect on the rate of PMF activation (3Durlinger A.L. Kramer P. Karels B. de Jong F.H. Uilenbroek J.T. Grootegoed J.A. Themmen A.P. Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary.Endocrinology. 1999; 140: 5789-5796Crossref PubMed Scopus (573) Google Scholar). Inhibitory interactions between neighboring PMFs slowing down the rate of activation were also proposed (4Da Silva-Buttkus P. Marcelli G. Franks S. Stark J. Hardy K. Inferring biological mechanisms from spatial analysis: prediction of a local inhibitor in the ovary.Proc Natl Acad Sci U S A. 2009; 106: 456-461Crossref PubMed Scopus (62) Google Scholar). Gaytan et al. (5Gaytan F. Morales C. Leon S. Garcia-Galiano D. Roa J. Tena-Sempere M. Crowding and follicular fate: spatial determinants of follicular reserve and activation of follicular growth in the mammalian ovary.PLoS One. 2015; 10e0144099Crossref Scopus (0) Google Scholar) suggested that loss of some PMFs would reduce the inhibitory influence on other PMFs within the cluster. Chemotherapy drugs can also damage the ovary by inducing PMF activation, leading to the "burn-out" of the PMF (6Roness H. Kashi O. Meirow D. Prevention of chemotherapy-induced ovarian damage.Fertil Steril. 2016; 105: 20-29Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 7Kalich-Philosoph L. Roness H. Carmely A. Fishel-Bartal M. Ligumsky H. Paglin S. et al.Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility.Sci Transl Med. 2013; 5185ra62Crossref PubMed Scopus (205) Google Scholar). Roness et al. (6Roness H. Kashi O. Meirow D. Prevention of chemotherapy-induced ovarian damage.Fertil Steril. 2016; 105: 20-29Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) suggested that there is an AMH level drop within 12 hours of CPA treatment, then subsequently an increase to twice baseline. This increase is maintained for 14 days post-CPA treatment and it was proposed that this AMH increase was due to an increase of growing follicles due to overactivation of quiescent PMFs (6Roness H. Kashi O. Meirow D. Prevention of chemotherapy-induced ovarian damage.Fertil Steril. 2016; 105: 20-29Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 7Kalich-Philosoph L. Roness H. Carmely A. Fishel-Bartal M. Ligumsky H. Paglin S. et al.Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility.Sci Transl Med. 2013; 5185ra62Crossref PubMed Scopus (205) Google Scholar). The biochemical pathways that regulate the activation of PMF include growth factors acting through various pathways, such as the PI3K/PTEN/AKT pathway and the Hippo pathway (8Kawamura K. Cheng Y. Suzuki N. Deguchi M. Sato Y. Takae S. et al.Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment.Proc Natl Acad Sci U S A. 2013; 110: 17474-17479Crossref PubMed Scopus (328) Google Scholar, 9Grosbois J. Demeestere I. Dynamics of PI3K and Hippo signaling pathways during in vitro human follicle activation.Hum Reprod. 2018; 33: 1705-1714Crossref PubMed Scopus (20) Google Scholar, 10Masciangelo R. Hossay C. Donnez J. Dolmans M.M. Does the Akt pathway play a role in follicle activation after grafting of human ovarian tissue?.Reprod Biomed Online. 2019; 39: 196-198Abstract Full Text Full Text PDF PubMed Google Scholar, 11Masciangelo R. Hossay C. Chiti M.C. Manavella D.D. Amorim C.A. Donnez J. et al.Role of the PI3K and Hippo pathways in follicle activation after grafting of human ovarian tissue.J Assist Reprod Genet. 2020; 37: 101-108Crossref Scopus (2) Google Scholar). These same pathways are also involved in the process of follicle activation observed early after transplantation of ovarian tissue (the post transplantation "burn-out" effect) (11Masciangelo R. Hossay C. Chiti M.C. Manavella D.D. Amorim C.A. Donnez J. et al.Role of the PI3K and Hippo pathways in follicle activation after grafting of human ovarian tissue.J Assist Reprod Genet. 2020; 37: 101-108Crossref Scopus (2) Google Scholar) and are responsible for the loss of PMFs (12Dolmans M.M. Martinez-Madrid B. Gadisseux E. Guiot Y. Yuan W.Y. Torre A. et al.Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice.Reproduction. 2007; 134: 253-262Crossref PubMed Scopus (130) Google Scholar). According to Spears et al., the AKT pathway (acting via FOXO3a) is modulated by both chemotherapy drugs and protectants (14Spears N. Lopes F. Stefansdottir A. Rossi V. De Felici M. Anderson R.A. et al.Ovarian damage from chemotherapy and current approaches to its protection.Hum Reprod Update. 2019; 25: 673-693Crossref PubMed Scopus (20) Google Scholar). However, a very recent work reported by Luan et al. (15Luan Y. Edmonds M.E. Woodruff T.K. Kim S.Y. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide.J Endocrinol. 2019; 240: 243-256Crossref PubMed Scopus (11) Google Scholar) contrasts with the Roness et al. (6Roness H. Kashi O. Meirow D. Prevention of chemotherapy-induced ovarian damage.Fertil Steril. 2016; 105: 20-29Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) and Kalich-Philosoph et al. (7Kalich-Philosoph L. Roness H. Carmely A. Fishel-Bartal M. Ligumsky H. Paglin S. et al.Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility.Sci Transl Med. 2013; 5185ra62Crossref PubMed Scopus (205) Google Scholar) reports. Indeed, Luan et al. (15Luan Y. Edmonds M.E. Woodruff T.K. Kim S.Y. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide.J Endocrinol. 2019; 240: 243-256Crossref PubMed Scopus (11) Google Scholar) showed that the numbers of Ki67 positive cells were comparable in PBS and CPA injected 8-week-old mice implying that CPA does not activate PMFs into the growing pool of follicles. They demonstrate in an experimental model that CPA induces the loss of primordial oocytes through apoptosis, leading to oocyte death and depletion of the ovarian reserve and that inhibitors of apoptotic pathway components protect follicles from CPA-induced damage (15Luan Y. Edmonds M.E. Woodruff T.K. Kim S.Y. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide.J Endocrinol. 2019; 240: 243-256Crossref PubMed Scopus (11) Google Scholar). We should bear in mind that chemotherapy drugs can also damage the ovarian stroma and vasculature (16Oktem O. Oktay K. A novel ovarian xenografting model to characterize the impact of chemotherapy agents on human primordial follicle reserve.Cancer Res. 2007; 67: 10159-10162Crossref PubMed Scopus (122) Google Scholar, 17Meirow D. Dor J. Kaufman B. Shrim A. Rabinovici J. Schiff E. et al.Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury.Hum Reprod. 2007; 22: 1626-1633Crossref PubMed Scopus (166) Google Scholar), negatively impacting the ovarian reserve as well as the normal follicle development. In conclusion, for growing follicles, there is large evidence linking CPA exposure to growing follicle and granulosa cells apoptosis. Concerning the PMF, its pool is clearly negatively affected by CPA exposure; however, from the last studies in human ovaries it is not always clear whether the loss of PMF is due to apoptosis (direct damage) and/or is a result of indirect loss due to accelerated activation (14Spears N. Lopes F. Stefansdottir A. Rossi V. De Felici M. Anderson R.A. et al.Ovarian damage from chemotherapy and current approaches to its protection.Hum Reprod Update. 2019; 25: 673-693Crossref PubMed Scopus (20) Google Scholar). The concept of a simple medical treatment that preserves fertility by suppressing ovarian function is appealing; it allows the avoidance of ovarian stimulation/retrieval or surgical intervention to remove oocytes from the adverse effects of gonadotoxic chemotherapy. Unfortunately, suppressing oocyte maturation does not ensure protection of PMFs from toxic exposure. The PMFs consist of an oocyte surrounded by a single layer of flattened granulosa cells and constitute the ovarian reserve. A great majority of these follicles remain dormant throughout most of a woman's life, arrested at prophase I of meiosis. Numerous PMFs resume development each menstrual cycle, independent of gonadotropin stimulation. This follicle activation is irreversible and tightly controlled by not yet fully defined intraovarian signals, not gonadotropins, producing waves of follicular development until menopause. As PMFs are not recruited by gonadotropins, it is not biologically plausible that use of an agent to suppress gonadotropin production would have an impact on the PMF pool. Histological studies in human ovaries have shown that chemotherapy treatments cause loss of PMFs (18Familiari G. Caggiati A. Nottola S.A. Ermini M. Di Benedetto M.R. Motta P.M. Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin's disease.Hum Reprod. 1993; 8: 2080-2087Crossref PubMed Scopus (158) Google Scholar, 19Himelstein-Braw R. Peters H. Faber M. Morphological study of the ovaries of leukaemic children.Br J Cancer. 1978; 38: 82-87Crossref PubMed Google Scholar). Oktem and Oktay and others have shown that gonadotoxic chemotherapy destroys ovarian germ cells by inducing severe DNA damage both in women and in murine models (20Oktem O. Oktay K. Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function.Cancer. 2007; 110: 2222-2229Crossref PubMed Scopus (162) Google Scholar, 21Soleimani R. Heytens E. Darzynkiewicz Z. Oktay K. Mechanisms of chemotherapy-induced human ovarian aging: double-strand DNA breaks and microvascular compromise.Aging. 2011; 3: 782-793Crossref PubMed Google Scholar, 22Zymanska K.J. Tan X. Oktay K. Unraveling the mechanisms of chemotherapy-induced damage to human primordial follicle reserve: road to developing therapeutics for fertility preservation and reversing ovarian aging.Mol Hum Reprod. 2020; 26: 553-566Crossref Scopus (0) Google Scholar). Women treated with alkylating regimens have significantly lower counts of PMFs when compared with those receiving nonalkylating agents or no chemotherapy (23Oktay K. Taylan E. Sugishita Y. Failure of goserelin to prevent chemotherapy- induced damage to ovarian reserve.Cancer Res. 2018; 78 (PD7-07)Google Scholar). Chemotherapy regimens, especially those containing alkylating agents, result in significant loss of ovarian reserve by destroying PMFs. Oktay et al. (24Oktay K. Harvey B.E. Partridge A.H. Quinn G.P. Reinecke J. Taylor H.S. et al.Fertility preservation in patients with cancer: ASCO clinical practice guideline update.J Clin Oncol. 2018; 36: 1994-2001Crossref PubMed Scopus (258) Google Scholar) also showed that gonadotropin-releasing hormone agonists (GnRH-a) coadministration did not prevent chemotherapy-induced PMF DNA damage and cell death in a murine model. GnRH-a desensitize and decrease the numbers of pituitary GnRH receptors resulting in greatly diminished follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the pituitary. Because PMFs do not express FSH, LH, or GnRH receptors, GnRH-a cannot directly affect these follicles or ovarian reserve (Fig. 1) (25Oktay K. Briggs D. Gosden R.G. Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles.J Clin Endocrinol Metab. 1997; 82: 3748-3751Crossref PubMed Google Scholar). Loss of the small numbers of maturing primary, preantral, or antral follicles would not have a long-term impact on ovarian reserve. However, it has been hypothesized that GnRH-a may still antagonize the cytotoxicity of chemotherapeutics through unknown mechanisms. If true, this effect would not be confined to the ovary and would likely also inhibit the activity of chemotherapy on cancers. Fortunately, GnRH-a does not appear to reduce the effectiveness of chemotherapy. There is no evidence that GnRH antagonists have a direct effect on PMFs. AMH is perhaps the most widely used marker of ovarian reserve. AMH is produced by the preantral and small antral follicles. AMH inhibits recruitment of follicles from the resting pool during the process of folliculogenesis and selection of the dominant follicle. As a product of active granulosa cells, and not the PMF, AMH can serve only as an indirect marker of ovarian reserve. Although AMH may give some reassurance of folliculogenesis, it cannot directly evaluate the number of PMFs in the ovarian reserve or accurately predict pregnancy. Furthermore, it does not account for the detrimental effects of DNA damage on the oocyte itself that may further limit fertility. AMH is diminished after chemotherapy but may underestimate the full extent of damage to ovarian reserve after chemotherapy. In summary, there is no biologically plausible theory that would justify administration of GnRH antagonists for the protection of the hormone-insensitive PMF. The best way to protect the PMF from damage is to remove it from the exposure using assisted reproductive technology and oocyte retrieval or by surgical tissue removal for future transplantation (26Donnez J. Dolmans M. Fertility preservation in women.N Engl J Med. 2017; 377: 1657-1665Crossref PubMed Scopus (223) Google Scholar, 27Donnez J. Dolmans M.M. Diaz C. Pellicer A. Ovarian cortex transplantation: time to move on from experimental studies to open clinical application.Fertil Steril. 2015; 104: 1097-1098Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). This point of view is reflected in the most recent American Society for Clinical Oncology Clinical Practice Guidelines (24Oktay K. Harvey B.E. Partridge A.H. Quinn G.P. Reinecke J. Taylor H.S. et al.Fertility preservation in patients with cancer: ASCO clinical practice guideline update.J Clin Oncol. 2018; 36: 1994-2001Crossref PubMed Scopus (258) Google Scholar). GnRH-a should not be used in place of proven fertility preservation methods. When meta-analyses collide, a final answer is unlikely to be found. There are several reasons for such collisions, including the obvious methodological pitfalls; but in general, it is well understood that the overall conclusions derived from a meta-analysis will depend on the quality of the studies included (28De Vrieze J. The metawars: meta-analyses were supposed to end scientific debates–often, they only cause more controversy.Science. 2018; 361: 1184-1188Crossref Scopus (13) Google Scholar). To date, data of a substantial number of women receiving GnRH-a during treatment for cancer or autoimmune diseases in clinical trials have been meta-analyzed. However, results have sometimes collided. What are the possible reasons for this discrepancy? First, it is important to highlight that sound investigations of efficacious fertility preservation methods in women treated for cancer or autoimmune diseases are complicated. As the proportion of women from the cohort who will wish to become pregnant or who will attempt pregnancy is unknown, the a priori population needed for such a study, using the most relevant fertility outcomes for the women in this setting, the livebirth rate, is likely not feasible. A possible illustration for this is the summary of two recent well-powered clinical trials regarding assisted reproductive technology (ART) treatment in cohorts of women in which every individual in the study would attempt pregnancy (29Groenewoud E.R. Cohlen B.J. Al-Oraiby A. Brinkhuis E.A. Broekmans F.J. de Bruin J.P. et al.A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer.Hum Reprod. 2016; 31: 1483-1492Crossref PubMed Scopus (84) Google Scholar, 30Lensen S. Osavlyuk D. Armstrong S. Stadelmann C. Hennes A. Nappier E. et al.A randomized trial of endometrial scratching before in vitro fertilization.N Engl J Med. 2019; 380: 325-334Crossref PubMed Scopus (43) Google Scholar). In the first study, a predefined expected livebirth rate of 35%, based on previous data, indicated the need to randomize 1,150 women. The number was not achieved, and, additionally troublesome, the actual livebirth rate obtained in the study was lower than the rate anticipated in the sample size calculation (29Groenewoud E.R. Cohlen B.J. Al-Oraiby A. Brinkhuis E.A. Broekmans F.J. de Bruin J.P. et al.A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer.Hum Reprod. 2016; 31: 1483-1492Crossref PubMed Scopus (84) Google Scholar). The second trial found no beneficial effect of endometrial scratching in ART treatments (30Lensen S. Osavlyuk D. Armstrong S. Stadelmann C. Hennes A. Nappier E. et al.A randomized trial of endometrial scratching before in vitro fertilization.N Engl J Med. 2019; 380: 325-334Crossref PubMed Scopus (43) Google Scholar). In that study, the needed number of women was achieved, with an actual successful randomization of 1,364 women and well-powered results supporting the inefficacity of the intervention investigated (30Lensen S. Osavlyuk D. Armstrong S. Stadelmann C. Hennes A. Nappier E. et al.A randomized trial of endometrial scratching before in vitro fertilization.N Engl J Med. 2019; 380: 325-334Crossref PubMed Scopus (43) Google Scholar). Many investigators have considered recovery of menses after chemotherapy treatment—or the opposite, treatment-induced amenorrhea—as sufficient clinical surrogates for fertility. Unfortunately, the surrogates chosen have not been uniformly predefined and have differed across studies, affecting the power calculations and resulting in heterogeneous outcomes. Investigators have reported pregnancies at variable follow-up, sometimes as short as 12 months (Table 2), raising questions concerning how long we should wait for pregnancies to occur, as it is not expected that women would attempt a pregnancy soon after the completion of cancer treatment.Table 2Data on biochemical markers of ovarian reserve from randomized controlled trials investigating GnRH-a co-treatment during chemotherapy in women treated for cancerCancer typeAuthor(s), year (reference)Ovarian marker studiedProtective effect in ovarian markers Yes/NoStudy size, follow-up duration, and results with regard to markers of ovarian reserve and pregnancies reportedHodgkin lymphomaBehringer et al., 2010 (36Behringer K. Wildt L. Mueller H. Mattle V. Ganitis P. van den Hoonaard B. et al.No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group.Ann Oncol. 2010; 21: 2052-2060Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar)AMH, FSH, estradiol, InhibinNoClinical trial. A priori assumption of 70% protection rate for GnRH-a. 23 Women enrolled. Study follow-up 6, 12, and 18 mo. Ovarian reserve preservation rate was found to be 0%, and study was prematurely closed. No pregnancies occurred during follow-up.Breast cancerMunster et al., 2012 (37Munster P.N. Moore A.P. Ismail-Khan R. Cox C.E. Lacevic M. Gross-King M. et al.Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer.J Clin Oncol. 2012; 30: 533-538Crossref PubMed Scopus (166) Google Scholar)Inhibin A and B, FSHNoClinical trial. Planned for 124 patients using an expected amenorrhea rate of 10% in GnRH-a group, compared to 30% in control group and 5-y follow-up. Study stopped for futility after 49 enrolled subjects. At 18-mo follow-up, two women had conceived naturally in the control group, compared to none in GnRH-a group.Breast cancer, ER negGerber et al., 2011 (38Gerber B. von Minckwitz G. Stehle H. Reiner T. Felderbaum R. Maass N. et al.Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study.J Clin Oncol. 2011; 29: 2334-2341Crossref PubMed Scopus (201) Google Scholar)AMH, Inhibin B, estradiol, FSH, AFCNoClinical trial. Multicenter. 60 Women randomized, 56 completed the study. Follow-up at 4 years for AMH and Inhibin. Marked reduction of AMH and suggested decrease in ovarian function in almost all patients at 2-y follow-up, despite restoration of menstruation. Two pregnancies reported, one in each arm.Breast cancer,ER negElgindy et al., 2011 (39Elgindy E.A. El-Haieg D.O. Khorshid O.M. Ismail E.I. Abdelgawad M. Sallam H.N. et al.Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial.Obstet Gynecol. 2013; 121: 78-86Crossref PubMed Scopus (95) Google Scholar)AMH, FSH, LH, estradiol, AFCNoClinical trial. Multicenter. 100 Patients randomized. Follow-up at 6, 12, and 18 mo. Ovarian markers reduced similarly in both arms.Breast cancerDel Mastro et al., 2011 (40Del Mastro L. Boni L. Michelotti A. Gamucci T. Olmeo N. Gori S. et al.Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.JAMA. 2011; 306: 269-276Crossref PubMed Scopus (265) Google Scholar)No sensitive ovarian markers were investigated, but estradiol and FSH were randomly assessed and reportedFSH and E2 levels were not available in about 30% of patientsClinical trial. Multicenter. Estimated 280 women needed after assumption of a 60% rate of early menopause in the control group and power to detect a 20% absolute reduction in early menopause in GnRH-a co-treatment group. 282 Women enrolled and 260 evaluated at 12-mo follow-up. Four pregnancies reported, three in GnRH-a and one in control group.Breast cancerMoore et al., 2015 (41Moore H.C. Unger J.M. Phillips K.A. Boyle F. Hitre E. Porter D. et al.Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.N Engl J Med. 2015; 372: 923-932Crossref PubMed Scopus (290) Google Scholar)FSH, estradiol, and Inhibin at year 1 and 2 were included as endpoints, but not reportedInhibin, E2 and FSH were not reportedClinical trial. Multicenter. Study originally powered for 416 patients by year 2. Reported on 218. More women attempted pregnancy in the GnRH-a group vs controls. At 5-year follow-up, 18 children had been born in the GnRH-a group and 12 in the control group. No data as to whether pregnancies were achieved through ART.LymphomaDemeestere et al., 2016 (31Demeestere I. Brice P. Peccatori F.A. Kentos A. Dupuis J. Zachee P. et al.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.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (120) Google Scholar)AMH, FSHNoClinical trial. Multicenter. Estimated 157 women needed on the basis of an assumed 40% difference of chemotherapy-induced ovarian failure between arms. Enrollment was stopped after 129 randomized women, due to similar ovarian failure rates between groups. AMH at 2–4 y and 5–7 y decreased similarly in both arms. During the 7-y follow-up, 17/32 and 15/35 women conceived in the GnRH-a and control groups, respectively, without significant statistical differences between groups.Breast cancerLeonard et al., 2017 (42Leonard R.C.F. Adamson D.J.A. Bertelli G. Mansi J. Yellowlees A. Dunlop J. et al.GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial.Ann Oncol. 2017; 28: 1811-1816Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar)AMH, FSH, LH, randomly assessedNoClinical trial. Multicenter. Study powered for 250 patients on basis of an expected 20% reduction of rate of premature menopause in GnRH-a group. Analysis reported on 202 patients. No significant differences in AMH found at 3, 12, or 24 mo.Note: A few studies have reported on pregnancies achieved during follow-up. All studies were unblinded. Follow-up has been variable among studies, with the longest follow-up reported in the study by Demeestere et al. (31Demeestere I. Brice P. Peccatori F.A. Kentos A. Dupuis J. Zachee P. et al.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.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (120) Google Scholar). Antimüllerian hormone has been used systematically as a marker of ovarian reserve across the studies. None of the randomized studies investigating changes in ovarian markers associated with chemotherapy found a beneficial effect of GnRH-a co-treatment. AMH = antimüllerian hormone; ART = assisted reproductive technology; ER = estrogen receptor; FSH = follicle-stimulating hormone; GnRH-a = gonadotropin-releasing hormone agonist; LH = luteinizing hormone; neg = negative. Open table in a new tab Note: A few studies have reported on pregnancies achieved during follow-up. All studies were unblinded. Follow-up has been variable among studies, with the longest follow-up reported in the study by Demeestere et al. (31Demeestere I. Brice P. Peccatori F.A. Kentos A. Dupuis J. Zachee P. et al.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.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (120) Google Scholar). Antimüllerian hormone has been used systematically as a marker of ovarian reserve across the studies. None of the randomized studies investigating changes in ovarian markers associated with chemotherapy found a beneficial effect of GnRH-a co-treatment. AMH = antimüllerian hormone; ART = assisted reproductive technology; ER = estrogen receptor; FSH = follicle-stimulating hormone; GnRH-a = gonadotropin-releasing hormone agonist; LH = luteinizing hormone; neg = negative. Why is this important? A favor for higher PR in women who have received GnRH-a has not been confirmed in the only well-powered randomized controlled study with sufficient long-term follow-up (31Demeestere I. Brice P. Peccatori F.A. Kentos A. Dupuis J. Zachee P. et al.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.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (120) Google Scholar). Even considering that a long follow-up period could improve the quality of studies designed to capture clinical outcomes, current data indicate that only a minority, between 10% and 20% of women accessing fertility preservation, seek care after the completion of cancer treatment to attempt pregnancy (32Cobo A. Garcia-Velasco J. Domingo J. Pellicer A. Remohi J. Elective and onco-fertility preservation: factors related to IVF outcomes.Hum Reprod. 2018; 33: 2222-2231Crossref PubMed Scopus (39) Google Scholar, 33Moravek M.B. Confino R. Smith K.N. Kazer R.R. Klock S.C. Lawson A.K. et al.Long-term outcomes in cancer patients who did or did not pursue fertility preservation.Fertil Steril. 2018; 109: 349-355Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 34Marklund A. Eloranta S. Wikander I. Kitlinski M.L. Lood M. Nedstrand E. et al.Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer–a prospective nationwide Swedish multicenter study.Hum Reprod. 2020; 35: 929-938Crossref Scopus (1) Google Scholar). Hence, most women might not attempt pregnancy in the future. For this reason, there is a need to find further appropriate surrogate outcomes for female fertility potential and to make these studies feasible. What about using AMH as biochemical marker of ovarian reserve? The idea has been around for several years. However, the biomarker has been included as a surrogate endpoint in only a minority of studies (Table 2). Some of these studies have also been included in a meta-analysis, which did not find any protective effects of GnRH-a in AMH levels (35Elgindy E. Sibai H. Abde