It ain’t necessarily so…

17 09 2009

To the Editor:

I have read with interest the case report by Azem et al. (1), 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 in vivo, by ultrasound, or in vitro in the excised ovary. Indeed, in the same issue of Fertility and Sterility, Revel et al. (2), report aspirating 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 (3) in response to our (4) and our colleagues’ (5)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 and Sterility (6), showing 11.4% premature ovarian failure (POF) in the GnRH-a group vs. 66% POF in controls (P<.001). In the last decade, 16 publications had similar positive results (4–11). A recent ASCO publication (9), similarly found the rates of POF to be 0 – 6% with GnRH-a vs. 32% – 47% without it. Recently, another prospective randomized study (10) had similar results. Thus, there are three prospective peer reviewed studies (6,10,11) with positive results. A recent meta-analysis (12) has found a significant beneficial role for the agonists in both preservation of ovarian function and conception: 68% increase in the rate of preserved ovarian function (RR = 1.68, CI=1.34-2.1). Among the GnRH-a treated women, 22% achieved pregnancy compared with 14% without GnRH-a (RR = 1.65, CI=1.03-2.6) (12). This meta-analysis (12) concluded that women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRH-a.

3. Indeed there are many unknown and equivocal matters in this important issue. Similarly, the group that 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." (13). Therefore, we should all admit we are still far from having a ubiquitous solution for all these young patients.

4. Azem et al. (1) 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 (14). Chemotherapy is mutagenic to germ cells at various stages of maturation (14).

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 (15).

Zeev Blumenfeld, M.D.
Reproductive Endocrinology
Department of Obstetrics and Gynecology
Rambam Medical Center
Technion-Faculty of Medicine
Haifa, Israel

References
1. Azem 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: 828.e1–e2.

2. Revel 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: 458-63.

3. Hughes EG, Neal MS. Ovarian suppression to protect against chemotherapy- induced ovarian toxicity: helpful or just hopeful. Hum Reprod Update 2008;14:541–2.

4. Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 2008;14:543–52.

5. Beck-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;14:553–61.

6. Badawy 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: 694-7.

7. Blumenfeld Z, Avivi I, Eckman A, Epelbaum R, Rowe JM, Dann EJ. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril 2008; 89: 166-73.

8. Blumenfeld 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: 1044-54. Review.

9. Moore HC. 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. Alexandria (VA): American Society of Clinical Oncology, 2008: 39–42.

10. Sverrisdottir 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.

11. Ataya K, Rao LV, Laurence E, Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys. Biol Reprod 1995; 52:365–72.

12. Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens’ Health (Larchmt). 2009; 18: 311-9.

13. Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van Langendonckt A, Pirard C. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. 2009 Aug 11. [Epub ahead of print].

14. Meirow D, Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data. J Natl Cancer Inst Monogr. 2005;34:21-5.

15. Meirow 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: 1634–41.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.09.037

The Authors Respond:

The biological plausibility of using GnRH agonists for fertility preservation is a matter of controversy (1). Several possible explanations for the beneficial effect of GnRH agonists to minimize chemotherapy-associated gonadotoxicity have been suggested (1, 2). One of them proposes that the hypogonadotropic milieu decreases the number of primordial follicles that enter the differentiation stage, which are more vulnerable to chemotherapy than arrested follicles. If this were the case, even preantral follicles (as suggested by Dr. Blumenfeld) would not be expected to be found in the medium.

There is no argument about the importance of the prospective randomized study by Badawy et al., but it had not been given approval by an ethical committee (3). At any rate, it was not our intention to join in the debate between the different studies mentioned by Dr. Blumenfeld: we believe that these issues have already been dealt with comprehensively in the paper by Oktay et al. (1)

We respect the works that Dr. Blumenfeld cited in support of his stance but, at the same time, wish to point out that he did not refer to the letter to the editor written by his own colleagues, which refuted his findings (4).

We are aware of the mutagenic potential of chemotherapy. In the reported case, however, our patient was treated by ABVD, which is well known for its low mutagenic effect. Additionally, if Dr. Blumenfeld’s assumption is correct, the follicles should be initially quiescent and so would not be affected by chemotherapy which mainly affects cleaving cells.

Foad Azem, M.D.
Dalit Ben-Yosef, Ph.D.
Beni Almog, MD
Joseph B. Lessing, M.D.
Ami Amit, M.D.

The Sara Racine IVF Unit
Lis Maternity Hospital

Tel Aviv Sourasky Medical Center
Tel Aviv, Israel

References
1. Oktay K, Sönmezer M, Oktem O, Fox K, Emons G, Bang H. Absence of conclusive evidence for the safety and efficacy of gonadotropin-releasing hormone analogue treatment in protecting against chemotherapy-induced gonadal injury. Oncologist 2007; 12:1055-66.

2. Muller U, Stahel A. Gonadal function after MA COP-B or VACOP-B with or without dose intensification and ABMT in young patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 1993;4:399–402.

3. Badawy 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; 91:694-7.

4. Kol S, Leithman A, Itskovitz-Eldor J. Evidence-based medicine or just a theory? Fertil Steril 2009; 92:e9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.09.038

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