Ovarian cryopreservation versus ovarian suppression by GnRH analogues: primum non nocere.

Sir, I have read with great interest the recent Human Reproduction Debate article on ovarian tissue banking by Oktay and Sonmezer (2004). Whereas I congratulate Dr Oktay and his associates for the successful embryo development retrieved from heterotrophic transplanted cryopreserved ovarian tissue (Oktay et al., 2004), I believe the article manuscript falls short of an objective and balanced presentation of the perspectives that should be presented to the confused and intimidated patient facing the uncertainty regarding the best way to maximize her future chances for parenthood after surviving the malignant disease and its treatment. More specifically, whereas I agree that a large, prospective, randomized study is needed to substantiate the role of GnRH agonist as a possible effective adjunct to minimize chemotherapy-associated gonadotoxicity, their article failed to present a balanced overview. For instance, Oktay and Sonmezer (2004) cite Teinturier et al.’s study (1998) as a clinical example that prepubertal children who have been treated with heavy chemotherapy suffer premature ovarian failure (POF). However, in the cited study, only 12 of the 21 girls (57%) had clinical and hormonal evidence of ovarian failure, and the remaining nine had completed normal puberty (Teinturier et al., 1998). Similarly to our results (Blumenfeld et al., 1996, 2002; Blumenfeld, 2003), Pereyra-Pacheco et al. (2001) have reported their experience regarding the protecting effect of GnRH agonist in parallel to chemotherapy in adolescent females. Whereas all their GnRH agonist-treated patients resumed cyclic ovarian function, all the patients in the chemotherapyalone (without GnRH agonist) group experienced hypergonadotrophic amenorrhoea in spite of their young age (PereyraPacheco et al., 2001). Furthermore, Ataya et al. (1995), in the only prospective randomized study in which ovarian histology has been assessed, showed that GnRH agonist in female Rhesus monkeys did protect the ovary from cyclophosphamide-induced gonadal damage. Administration of GnRH agonist in parallel with cyclophosphamide significantly decreased the daily rate of follicular decline and the total number of primordial follicles lost during the chemotherapeutic insult, as compared to cyclophosphamide alone (without GnRH agonist). Whereas Oktay and Sonmezer (2004) claim that ‘no study showed the presence of these receptors on human primordial follicles or oocytes’, according to another recent Human Reproduction review (Revel and Schenker, 2003) more recent data show that GnRH receptors expressed by human ovarian cancer cell lines mediate the anti-proliferative effects of GnRH agonist (Volker et al., 2002; Grundker and Emons, 2003). Oktay and Sonmezer (2004) do not recommend GnRH agonist as an effective way of fertility preservation since ‘. 90% of all ovarian follicles are at the resting stage and they do not express FSH receptors’. However, Patsoula et al. (2003) have identified messenger RNA for the FSH and LH receptors in oocytes at different stages, indicating a physiological role in the oocyte maturation process in the human. Moreover, Zheng et al. (1996) have identified FSH receptor mRNA expression in both primary and primordial follicles, and Flaws et al. (1997) have found that the ovaries of transgenic mice with high LH levels had normal primordial follicle pool at birth, decreasing to about 68% fewer primordial follicles and 53% fewer primary follicles than controls, within 3 months of age. Flaws et al.’s (1997) results suggest that, in addition to having profound effects on growing follicles, chronically elevated LH levels deplete the primordial follicle pool and thus may hasten the onset of reproductive senescence. As recently shawn by the revolutionary work of Tilly’s group (Johnson et al., 2004), freedom from old dogmas may significantly sustain progress of science and medicine. Regardless of the possible mechanism(s) through which GnRH agonist may possibly decrease chemotherapy-associated gonadotoxicity (GnRH agonist receptor effect, decreasing gonadotrophin concentrations, decreasing ovarian perfusion due to hypoestrogenic milieu, or possibly through a sphingosine-1-phosphatemediated event or through germline stem cell preservation) we need to offer to our patients all the possible avenues for rescue of fertility and preservation of ovarian function. Until ovarian cryopreservation or metaphase II cryopreservation prove themselves as clinically effective methods, comparable to IVF and embryo cryopreservation, we should support our patients with all the available information and offer them all available treatment options. Anything less than that may violate the ancient rule ‘primum non nocere’ (Blumenfeld et al., 2002).