Reply of the Authors

Abstract

We thank Drs. Baird and Steiner for showing interest in an intriguing finding in our paper which suggested increasing serum antimullerian hormone (AMH) levels over repetitive oocyte donation cycles (1Bukulmez O. Li Q. Carr B.R. Leader B. Doody K.M. Doody K.J. Repetitive oocyte donation does not decrease serum anti-mullerian hormone levels.Fertil Steril. 2010; 94: 905-912Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Eleven patients who underwent six cycles presented with both higher baseline AMH levels and a significantly increasing trend of AMH levels over their repetitive oocyte donation cycles. When controlled for other confounders, this significant trend could not be demonstrated for other donors who underwent three, four, and five repetitive oocyte donation cycles (Fig. 1 in our paper), although the raw data (Fig. 2 in our paper) suggested otherwise. It should also be noted that in general, oocyte yield as demonstrated by FSH dose–oocyte ratio stayed stable over time. As we also mentioned (1Bukulmez O. Li Q. Carr B.R. Leader B. Doody K.M. Doody K.J. Repetitive oocyte donation does not decrease serum anti-mullerian hormone levels.Fertil Steril. 2010; 94: 905-912Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), studies in mouse and rat have implied that FSH may be instrumental in premature depletion of ovarian follicles and that the oocyte and embryo quality may decrease with gonadotropin stimulation of ovaries (2Dursun P. Gultekin M. Yuce K. Ayhan A. What is the underlying cause of aneuploidy associated with increasing maternal age? Is it associated with elevated levels of gonadotropins?.Med Hypotheses. 2006; 66: 143-147Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). However, there is no proof that FSH treatment itself is associated with further ovarian aging in humans. For example, it has been speculated that monotropic rise of FSH in women with diminished ovarian reserve may have further deleterious effects on follicle and oocyte quality (3Broekmans F.J. Soules M.R. Fauser B.C. Ovarian aging: mechanisms and clinical consequences.Endocr Rev. 2009; 30: 465-493Crossref PubMed Scopus (664) Google Scholar). It has also been suggested that supraphysiologic doses of gonadotropins used in assisted reproduction may induce meiotic errors (2Dursun P. Gultekin M. Yuce K. Ayhan A. What is the underlying cause of aneuploidy associated with increasing maternal age? Is it associated with elevated levels of gonadotropins?.Med Hypotheses. 2006; 66: 143-147Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar), although it is not known if gonadotropin treatment itself is associated with long-lasting effects on remaining ovarian follicular pool. It is also not clear if FSH treatment leads to exhaustion of follicles which would not otherwise be stimulated or it simply salvages the follicles which would otherwise end up with apoptosis.It also remains to be elucidated if increased AMH levels can be associated with increased follicular exhaustion in humans. In patients with polycystic ovary syndrome (PCOS), AMH levels may be very high and may stay high for chronologic age over years (4Piltonen T. Morin-Papunen L. Koivunen R. Perheentupa A. Ruokonen A. Tapanainen J.S. Serum anti-Mullerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome.Hum Reprod. 2005; 20: 1820-1826Crossref PubMed Scopus (213) Google Scholar). Rather than showing clues of earlier follicle exhaustion, it appears that reproductive age may even be extended in women with PCOS and high AMH levels (5Tehrani F.R. Solaymani-Dodaran M. Hedayati M. Azizi F. Is polycystic ovary syndrome an exception for reproductive aging?.Hum Reprod. 2010; 25: 1775-1781Crossref PubMed Scopus (77) Google Scholar). In antral follicles, the overall effect of AMH seems to be reduced follicle sensitivity to FSH. A number of in vitro studies have shown that FSH-stimulated follicle growth was inhibited by the addition of AMH (6Pellatt L. Rice S. Mason H.D. Anti-mullerian hormone and polycystic ovary syndrome: a mountain too high?.Reproduction. 2010; 139: 825-833Crossref PubMed Scopus (151) Google Scholar). In our study, increasing AMH levels were associated with both increased FSH dose and increased oocyte yield, keeping the FSH dose–oocyte ratio stable. Owing to the retrospective properties of our report, we could not speculate what the oocyte yield would be if the FSH dose was kept constant. Similarly, we could not comment on pregnancy rates, because the recipient and male factors were not the focus of our study.We think that our findings need confirmation with large prospective cohort studies. As Drs. Baird and Steiner suggested, it would have been beneficial to monitor AMH levels from anonymous donors remote from their last oocyte retrieval. We are pleased that our results generated another hypothesis which may require further epidemiologic and translational studies to prove any biologic plausibility. We thank Drs. Baird and Steiner for showing interest in an intriguing finding in our paper which suggested increasing serum antimullerian hormone (AMH) levels over repetitive oocyte donation cycles (1Bukulmez O. Li Q. Carr B.R. Leader B. Doody K.M. Doody K.J. Repetitive oocyte donation does not decrease serum anti-mullerian hormone levels.Fertil Steril. 2010; 94: 905-912Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Eleven patients who underwent six cycles presented with both higher baseline AMH levels and a significantly increasing trend of AMH levels over their repetitive oocyte donation cycles. When controlled for other confounders, this significant trend could not be demonstrated for other donors who underwent three, four, and five repetitive oocyte donation cycles (Fig. 1 in our paper), although the raw data (Fig. 2 in our paper) suggested otherwise. It should also be noted that in general, oocyte yield as demonstrated by FSH dose–oocyte ratio stayed stable over time. As we also mentioned (1Bukulmez O. Li Q. Carr B.R. Leader B. Doody K.M. Doody K.J. Repetitive oocyte donation does not decrease serum anti-mullerian hormone levels.Fertil Steril. 2010; 94: 905-912Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), studies in mouse and rat have implied that FSH may be instrumental in premature depletion of ovarian follicles and that the oocyte and embryo quality may decrease with gonadotropin stimulation of ovaries (2Dursun P. Gultekin M. Yuce K. Ayhan A. What is the underlying cause of aneuploidy associated with increasing maternal age? Is it associated with elevated levels of gonadotropins?.Med Hypotheses. 2006; 66: 143-147Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). However, there is no proof that FSH treatment itself is associated with further ovarian aging in humans. For example, it has been speculated that monotropic rise of FSH in women with diminished ovarian reserve may have further deleterious effects on follicle and oocyte quality (3Broekmans F.J. Soules M.R. Fauser B.C. Ovarian aging: mechanisms and clinical consequences.Endocr Rev. 2009; 30: 465-493Crossref PubMed Scopus (664) Google Scholar). It has also been suggested that supraphysiologic doses of gonadotropins used in assisted reproduction may induce meiotic errors (2Dursun P. Gultekin M. Yuce K. Ayhan A. What is the underlying cause of aneuploidy associated with increasing maternal age? Is it associated with elevated levels of gonadotropins?.Med Hypotheses. 2006; 66: 143-147Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar), although it is not known if gonadotropin treatment itself is associated with long-lasting effects on remaining ovarian follicular pool. It is also not clear if FSH treatment leads to exhaustion of follicles which would not otherwise be stimulated or it simply salvages the follicles which would otherwise end up with apoptosis. It also remains to be elucidated if increased AMH levels can be associated with increased follicular exhaustion in humans. In patients with polycystic ovary syndrome (PCOS), AMH levels may be very high and may stay high for chronologic age over years (4Piltonen T. Morin-Papunen L. Koivunen R. Perheentupa A. Ruokonen A. Tapanainen J.S. Serum anti-Mullerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome.Hum Reprod. 2005; 20: 1820-1826Crossref PubMed Scopus (213) Google Scholar). Rather than showing clues of earlier follicle exhaustion, it appears that reproductive age may even be extended in women with PCOS and high AMH levels (5Tehrani F.R. Solaymani-Dodaran M. Hedayati M. Azizi F. Is polycystic ovary syndrome an exception for reproductive aging?.Hum Reprod. 2010; 25: 1775-1781Crossref PubMed Scopus (77) Google Scholar). In antral follicles, the overall effect of AMH seems to be reduced follicle sensitivity to FSH. A number of in vitro studies have shown that FSH-stimulated follicle growth was inhibited by the addition of AMH (6Pellatt L. Rice S. Mason H.D. Anti-mullerian hormone and polycystic ovary syndrome: a mountain too high?.Reproduction. 2010; 139: 825-833Crossref PubMed Scopus (151) Google Scholar). In our study, increasing AMH levels were associated with both increased FSH dose and increased oocyte yield, keeping the FSH dose–oocyte ratio stable. Owing to the retrospective properties of our report, we could not speculate what the oocyte yield would be if the FSH dose was kept constant. Similarly, we could not comment on pregnancy rates, because the recipient and male factors were not the focus of our study. We think that our findings need confirmation with large prospective cohort studies. As Drs. Baird and Steiner suggested, it would have been beneficial to monitor AMH levels from anonymous donors remote from their last oocyte retrieval. We are pleased that our results generated another hypothesis which may require further epidemiologic and translational studies to prove any biologic plausibility. Anti-müllerian hormone (AMH) and repetitive oocyte donationFertility and SterilityVol. 95Issue 1PreviewTo the Editor: Full-Text PDF