AMH and Repetitive Oocyte Donation

27 09 2010

To the Editor:

The data that Bukulmez et al. present on increases in AMH with each oocyte donation cycle (Figure 2) is unexpected and provocative (1). The increase appeared to be most pronounced when donation cycles occurred in rapid succession, as demonstrated most convincingly in Group 6. The increase could be due to FSH stimulation of preantral and early antral follicles, the follicular stages that produce the most AMH (2). Though FSH is not thought to drive follicular development at these stages, these follicles have a vascular supply and FSH is thought to synergize their growth (2). However, if stimulation of preantral and early antral follicles was the only effect of FSH treatment, one would expect the AMH to increase for only one or two donation cycles (the combined time-span that follicles spend in these stages) and then level off. Given that AMH continues to increase across six donation cycles over a period of nearly 18 months, suggests that follicles from earlier stages are also affected, possibly even accelerating the rate at which resting follicles are activated. If the activation persisted, ovarian reserve might be negatively impacted.

Regulation of resting follicle activation is not understood, and human data on primary, preantral, and early antral follicle development is limited. Data from egg donors might give hints about these processes and the role of FSH. Monitoring the degree of increase in AMH in relation to the time interval between donation cycles could be informative. In addition, since a donor’s AMH levels would be expected to eventually decline to baseline after the final FSH treatment, monitoring AMH changes after treatment ends would be of interest.

The tendency for the pregnancy rate to decline from 61% to 45% between donation cycles 1 and 7 (Table 1), though not statistically significant, may be a concern. Could possible stimulatory effects of FSH treatment on early follicle growth have adverse effects on the oocytes within?

Donna Day Baird, Ph.D.
Epidemiology Branch
National Institute of Environmental Health Sciences
National Institutes of Health
Research Triangle Park, North Carolina

Anne Z. Steiner, M.D., M.P.H.
Department of Obstetrics and Gynecology
University of North Carolina
Chapel Hill, North Carolina

References
1. Bukulmez O, Li Q, Carr BR, Leader B, Doody KM, Doody KJ. Repetitive oocyte donation does not decrease serum anti-Müllerian hormone levels. Fertil Steril 2010;94:905-12.

2. Gougeon A. Human ovarian follicular development: From activation of resting follicles to preovulatory maturation. Ann Endocrinol 2010;71:132-43.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.09.051

The Authors Respond:

We thank Drs. Baird and Steiner for showing interest in an intriguing finding in our paper which suggested increasing serum AMH levels over repetitive oocyte donation cycles (1). Eleven patients who underwent 6 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 3, 4 and 5 repetitive oocyte donation cycles (Figure 1 panels), although the raw data (Figure 2) 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 (1), studies in mouse and rat have implied that FSH may be instrumental in premature depletion of ovarian follicles and the oocyte and embryo quality may decrease with gonadotropin stimulation of ovaries (2). However, there is no proof that FSH treatment itself is associated with further ovarian aging in humans. For instance, 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 (3).

It has also been suggested that supraphysiologic doses of gonadotropins used in assisted reproduction may induce meiotic errors (2), 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 also 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 the chronologic age over the years (4). Rather than showing clues of earlier follicle exhaustion, it seems that reproductive age may even be extended in women with PCOS and high AMH levels (5). In antral follicles, the overall effect of AMH seems to be reducing follicle sensitivity to FSH. A number of in vitro studies have shown that FSH-stimulated follicle growth was inhibited by the addition of AMH (6).

In our study increasing AMH levels were associated with both increased FSH dose and oocyte yield keeping FSH dose/oocyte ratio stable. Due to retrospective properties of this report we cannot speculate what the oocyte yield would be if the FSH dose was kept constant. With the same token, we may not comment on pregnancy rates since the recipient and male factors were not the focus of our study.

We believe our findings need confirmation with large prospective cohort studies. As Drs. Baird and Steiner have 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 biological plausibility.

Orhan Bukulmez, M.D.
Division of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
University of Florida College of Medicine
Gainesville, Florida

Bruce R. Carr, M.D.
Kevin J. Doody, M.D.
Division of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas

References
1. Bukulmez O, Li Q, Carr BR, Leader B, Doody KM, Doody KJ. Repetitive oocyte donation does not decrease serum anti-Mullerian hormone levels. Fertil Steril 2010;94:905-12.

2. Dursun 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;66:143-7.

3. Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009;30:465-93.

4. Piltonen T, Morin-Papunen L, Koivunen R, Perheentupa A, Ruokonen A, Tapanainen JS. 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;20:1820-6.

5. Tehrani FR, Solaymani-Dodaran M, Hedayati M, Azizi F. Is polycystic ovary syndrome an exception for reproductive aging? Hum Reprod 2010;25:1775-81.

6. Pellatt L, Rice S, Mason HD. Anti-Mullerian hormone and polycystic ovary syndrome: a mountain too high? Reproduction 2010;139:825-33.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.09.052

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