“It ain't necessarily so…”

Abstract

To the Editor:I have read with interest the case report by Azem et al. (1Azem F. Hasson J. Cohen T. Shwartz T. Mey-Raz N. Almog B. et al.Retrieval of immature oocytes after chemotherapy for Hodgkin's disease and prolonged ovarian down-regulation with gonadotropin-releasing hormone agonist.Fertil Steril. 2009; 92 (e1–e2): 828Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar), and congratulate them. However, several points need clarification.1.The authors conclude from the presence of germinal vesicle–stage oocytes in the medium on the presence of antral follicles. Antral follicles can be clearly visualized by ultrasound and seen in the extirpated ovary. The authors failed to mention the visualization of antral follicles either in vivo by ultrasound, or in vitro in the excised ovary. In the same issue of Fertility & Sterility, Revel et al. (2Revel A. Revel-Vilk S. Aizenman E. Porat-Katz A. Safran A. Ben-Meir A. et al.At what age can human oocytes be obtained?.Fertil Steril. 2009; 92: 458-463Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), have aspirated 179 oocytes in all observed follicles before ovarian cryopreservation in patients aged 5–20 years. The finding of immature ova in the medium is not a proof of antral follicles. It could have been mechanically dispersed from preantral follicles.2.The authors refer to the Human Reproduction Update editorial (3Hughes E.G. Neal M.S. Ovarian suppression to protect against chemotherapy-induced ovarian toxicity: helpful or just hopeful.Hum Reprod Update. 2008; 14: 541-542Crossref PubMed Scopus (5) Google Scholar) in response to our (4Blumenfeld Z. von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy.Hum Reprod Update. 2008; 14: 543-552Crossref PubMed Scopus (173) Google Scholar) and our colleagues' (5Beck-Fruchter R. Weiss A. Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data.Hum Reprod Update. 2008; 14: 553-561Crossref PubMed Scopus (86) Google Scholar) reviews. The editorial mentioned a prospective randomized study that has been presented as a poster, claiming that if published, after peer review, it may settle the debate. Indeed, the referred study has been published in Fertility & Sterility (6Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar), showing 11.4% premature ovarian failure (POF) in the GnRH-agonist group versus 66% POF in controls (P<.001). In the past decade 16 publications had similar positive results (4Blumenfeld Z. von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy.Hum Reprod Update. 2008; 14: 543-552Crossref PubMed Scopus (173) Google Scholar, 5Beck-Fruchter R. Weiss A. Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data.Hum Reprod Update. 2008; 14: 553-561Crossref PubMed Scopus (86) Google Scholar, 6Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 7Blumenfeld Z. Avivi I. Eckman A. Epelbaum R. Rowe J.M. Dann E.J. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma.Fertil Steril. 2008; 89: 166-173Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 8Blumenfeld Z. 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 ([Review]): 1044-1054Crossref PubMed Scopus (218) Google Scholar, 9Moore H.C. Ovarian failure after chemotherapy for breast cancer and the role of gonadotropin-releasing hormone analogs in protection of ovarian function.in: American Society of Clinical Oncology 2008 educational book. American Society of Clinical Oncology, Alexandria (VA)2008: 39-42Google Scholar, 10Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.Google Scholar, 11Ataya K. Rao L.V. Laurence E. Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys.Biol Reprod. 1995; 52: 365-372Crossref PubMed Scopus (264) Google Scholar). A recent American Society of Clinical Oncology publication (9Moore H.C. Ovarian failure after chemotherapy for breast cancer and the role of gonadotropin-releasing hormone analogs in protection of ovarian function.in: American Society of Clinical Oncology 2008 educational book. American Society of Clinical Oncology, Alexandria (VA)2008: 39-42Google Scholar), similarly found the rates of POF to be 0–6% with GnRH-a versus 32%–47% without it. Recently, another prospective randomized study (10Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.Google Scholar) had similar results. Thus, there are three prospective peer-reviewed studies (6Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 10Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.Google Scholar, 11Ataya K. Rao L.V. Laurence E. Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys.Biol Reprod. 1995; 52: 365-372Crossref PubMed Scopus (264) Google Scholar) with positive results. A recent meta-analysis (12Clowse M.E. Behera M.A. Anders C.K. Copland S. Coffman C.J. Leppert P.C. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens' Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (168) Google Scholar) has found a significant beneficial role for the agonists on both preservation of ovarian function and conception: 68% increase in the rate of preserved ovarian function (relative risk [RR]=1.68, 95% confidence interval [CI]=1.34–2.1). Among the GnRH-a treated women, 22% achieved pregnancy compared with 14% without GnRH-a (RR=1.65, 95% CI=1.03–2.6) (12Clowse M.E. Behera M.A. Anders C.K. Copland S. Coffman C.J. Leppert P.C. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens' Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (168) Google Scholar). This meta-analysis (12Clowse M.E. Behera M.A. Anders C.K. Copland S. Coffman C.J. Leppert P.C. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens' Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (168) Google Scholar) concluded that women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRH-a.3.There are many unknown and equivocal matters in this important issue. Similarly, the group who has published the first delivery after transplantation of ovarian tissue has recently published their disappointing results: “IVF in women with orthotopically grafted frozen-thawed ovarian tissue involves a higher risk of empty follicles, abnormal or immature oocytes, and low embryo transfer rates” (13Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van Langendonckt A, et al. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. Published online August 11, 2009.Google Scholar). Therefore, we should all admit we are still far from having an ubiquitous solution for all these young patients.4.Azem et al. (1Azem F. Hasson J. Cohen T. Shwartz T. Mey-Raz N. Almog B. et al.Retrieval of immature oocytes after chemotherapy for Hodgkin's disease and prolonged ovarian down-regulation with gonadotropin-releasing hormone agonist.Fertil Steril. 2009; 92 (e1–e2): 828Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar) have matured in vitro the ova retrieved from the medium and cryopreserved for future IVF. However, it has been shown that ova exposed to chemotherapy exhibit a high rate of chromosomal aberrations, miscarriages, and possibly fetal malformations (14Meirow D. Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data.J Natl Cancer Inst Monogr. 2005; 34: 21-25Crossref PubMed Scopus (64) Google Scholar). Chemotherapy is mutagenic to germ cells at various stages of maturation (14Meirow D. Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data.J Natl Cancer Inst Monogr. 2005; 34: 21-25Crossref PubMed Scopus (64) Google Scholar).5.Ovarian cryopreservation, GnRH-a administration, and follicular aspiration should be offered to all such patients. Furthermore, GnRH-a can effectively prevent the thrombocytopenia-associated menorrhagia in these patients (15Meirow D. Rabinovici J. Katz D. Or R. Shufaro Y. Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone–releasing hormone agonist and depo-medroxyprogesterone acetate.Cancer. 2006; 107: 1634-1641Crossref PubMed Scopus (68) Google Scholar). To the Editor: I have read with interest the case report by Azem et al. (1Azem F. Hasson J. Cohen T. Shwartz T. Mey-Raz N. Almog B. et al.Retrieval of immature oocytes after chemotherapy for Hodgkin's disease and prolonged ovarian down-regulation with gonadotropin-releasing hormone agonist.Fertil Steril. 2009; 92 (e1–e2): 828Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar), and congratulate them. However, several points need clarification.1.The authors conclude from the presence of germinal vesicle–stage oocytes in the medium on the presence of antral follicles. Antral follicles can be clearly visualized by ultrasound and seen in the extirpated ovary. The authors failed to mention the visualization of antral follicles either in vivo by ultrasound, or in vitro in the excised ovary. In the same issue of Fertility & Sterility, Revel et al. (2Revel A. Revel-Vilk S. Aizenman E. Porat-Katz A. Safran A. Ben-Meir A. et al.At what age can human oocytes be obtained?.Fertil Steril. 2009; 92: 458-463Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), have aspirated 179 oocytes in all observed follicles before ovarian cryopreservation in patients aged 5–20 years. The finding of immature ova in the medium is not a proof of antral follicles. It could have been mechanically dispersed from preantral follicles.2.The authors refer to the Human Reproduction Update editorial (3Hughes E.G. Neal M.S. Ovarian suppression to protect against chemotherapy-induced ovarian toxicity: helpful or just hopeful.Hum Reprod Update. 2008; 14: 541-542Crossref PubMed Scopus (5) Google Scholar) in response to our (4Blumenfeld Z. von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy.Hum Reprod Update. 2008; 14: 543-552Crossref PubMed Scopus (173) Google Scholar) and our colleagues' (5Beck-Fruchter R. Weiss A. Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data.Hum Reprod Update. 2008; 14: 553-561Crossref PubMed Scopus (86) Google Scholar) reviews. The editorial mentioned a prospective randomized study that has been presented as a poster, claiming that if published, after peer review, it may settle the debate. Indeed, the referred study has been published in Fertility & Sterility (6Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar), showing 11.4% premature ovarian failure (POF) in the GnRH-agonist group versus 66% POF in controls (P<.001). In the past decade 16 publications had similar positive results (4Blumenfeld Z. von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy.Hum Reprod Update. 2008; 14: 543-552Crossref PubMed Scopus (173) Google Scholar, 5Beck-Fruchter R. Weiss A. Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data.Hum Reprod Update. 2008; 14: 553-561Crossref PubMed Scopus (86) Google Scholar, 6Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 7Blumenfeld Z. Avivi I. Eckman A. Epelbaum R. Rowe J.M. Dann E.J. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma.Fertil Steril. 2008; 89: 166-173Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 8Blumenfeld Z. 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 ([Review]): 1044-1054Crossref PubMed Scopus (218) Google Scholar, 9Moore H.C. Ovarian failure after chemotherapy for breast cancer and the role of gonadotropin-releasing hormone analogs in protection of ovarian function.in: American Society of Clinical Oncology 2008 educational book. American Society of Clinical Oncology, Alexandria (VA)2008: 39-42Google Scholar, 10Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.Google Scholar, 11Ataya K. Rao L.V. Laurence E. Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys.Biol Reprod. 1995; 52: 365-372Crossref PubMed Scopus (264) Google Scholar). A recent American Society of Clinical Oncology publication (9Moore H.C. Ovarian failure after chemotherapy for breast cancer and the role of gonadotropin-releasing hormone analogs in protection of ovarian function.in: American Society of Clinical Oncology 2008 educational book. American Society of Clinical Oncology, Alexandria (VA)2008: 39-42Google Scholar), similarly found the rates of POF to be 0–6% with GnRH-a versus 32%–47% without it. Recently, another prospective randomized study (10Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.Google Scholar) had similar results. Thus, there are three prospective peer-reviewed studies (6Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 10Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.Google Scholar, 11Ataya K. Rao L.V. Laurence E. Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys.Biol Reprod. 1995; 52: 365-372Crossref PubMed Scopus (264) Google Scholar) with positive results. A recent meta-analysis (12Clowse M.E. Behera M.A. Anders C.K. Copland S. Coffman C.J. Leppert P.C. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens' Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (168) Google Scholar) has found a significant beneficial role for the agonists on both preservation of ovarian function and conception: 68% increase in the rate of preserved ovarian function (relative risk [RR]=1.68, 95% confidence interval [CI]=1.34–2.1). Among the GnRH-a treated women, 22% achieved pregnancy compared with 14% without GnRH-a (RR=1.65, 95% CI=1.03–2.6) (12Clowse M.E. Behera M.A. Anders C.K. Copland S. Coffman C.J. Leppert P.C. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens' Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (168) Google Scholar). This meta-analysis (12Clowse M.E. Behera M.A. Anders C.K. Copland S. Coffman C.J. Leppert P.C. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens' Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (168) Google Scholar) concluded that women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRH-a.3.There are many unknown and equivocal matters in this important issue. Similarly, the group who has published the first delivery after transplantation of ovarian tissue has recently published their disappointing results: “IVF in women with orthotopically grafted frozen-thawed ovarian tissue involves a higher risk of empty follicles, abnormal or immature oocytes, and low embryo transfer rates” (13Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van Langendonckt A, et al. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. Published online August 11, 2009.Google Scholar). Therefore, we should all admit we are still far from having an ubiquitous solution for all these young patients.4.Azem et al. (1Azem F. Hasson J. Cohen T. Shwartz T. Mey-Raz N. Almog B. et al.Retrieval of immature oocytes after chemotherapy for Hodgkin's disease and prolonged ovarian down-regulation with gonadotropin-releasing hormone agonist.Fertil Steril. 2009; 92 (e1–e2): 828Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar) have matured in vitro the ova retrieved from the medium and cryopreserved for future IVF. However, it has been shown that ova exposed to chemotherapy exhibit a high rate of chromosomal aberrations, miscarriages, and possibly fetal malformations (14Meirow D. Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data.J Natl Cancer Inst Monogr. 2005; 34: 21-25Crossref PubMed Scopus (64) Google Scholar). Chemotherapy is mutagenic to germ cells at various stages of maturation (14Meirow D. Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data.J Natl Cancer Inst Monogr. 2005; 34: 21-25Crossref PubMed Scopus (64) Google Scholar).5.Ovarian cryopreservation, GnRH-a administration, and follicular aspiration should be offered to all such patients. Furthermore, GnRH-a can effectively prevent the thrombocytopenia-associated menorrhagia in these patients (15Meirow D. Rabinovici J. Katz D. Or R. Shufaro Y. Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone–releasing hormone agonist and depo-medroxyprogesterone acetate.Cancer. 2006; 107: 1634-1641Crossref PubMed Scopus (68) Google Scholar). Retrieval of immature oocytes after chemotherapy for Hodgkin's disease and prolonged ovarian down-regulation with gonadotropin-releasing hormone agonistFertility and SterilityVol. 92Issue 2PreviewTo describe isolation and in vitro maturation of primary oocytes from the ovarian cortex in the presence of hypothalamic pituitary down-regulation. Full-Text PDF Uncertainty regarding the biological plausibility of GnRH agonist for gonadal protectionFertility and SterilityVol. 92Issue 6PreviewReply of the Authors: Full-Text PDF