To the Editor:
We have read with great interest the study by Singer et al. (1) and we would like to comment on the relationship between anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in polycystic ovary syndrome (PCOS).
Singer et al., in women undergoing IVF, reported a negative association between FSH and AMH serum levels, concluding that AMH levels are highly predictive of FSH levels and can be used as independent indicators of ovarian reserve (1).
Recently, Dumesic et al. also reported that intrafollicular AMH levels negatively correlated with FSH in follicles of normoandrogenic ovulatory women undergoing IVF, concluding that intrafollicular AMH reflects follicle sensitivity to FSH (2).
In an earlier study (3), we have noted increased serum AMH levels in PCOS women. Moreover, AMH levels were negatively correlated to body mass index (BMI) and were independently predicted by LH, testosterone and BMI. We concluded that increased LH levels might be an independent link between PCOS-associated disorders of ovulation and the increased serum AMH concentrations.
In order to assess whether the findings of Singer et al. and Dumesic et al. from a cohort of older women undergoing IVF, could be applied to younger women with PCOS, we selected a population of 50 ovulatory women as controls and 200 PCOS women with biochemical hyperandrogenemia, oligo- and/or anovulation (ANOV), and/or polycystic ovaries on ultrasound (PCO).
Serum AMH levels were not correlated with serum FSH levels in PCOS and ovulatory women. On the contrary, serum AMH levels were correlated to LH levels in PCOS women (r=0.414, p<0.001). Serum AMH levels were also negatively correlated to BMI for both PCOS (r=-0.222, p=0.007) and ovulatory women (r=-0.696, p<0.001). Indeed, by dividing all women according to BMI (limit 25 Kg/m2), serum AMH levels were significantly higher in normal weight PCOS (6.88±3.60 ng/mL vs. 4.99±2.16 ng/mL, p<0.001) and normal weight ovulatory women (4.11±1.29 ng/mL vs. 2.41±0.25 ng/mL, p<0.001).
We can therefore raise the hypothesis that serum AMH levels are differently modulated in conditions of pure ovarian reserve, like women undergoing IVF, compared to young women with hyperandrogenemia. The latter is particularly true for normal-weight hyperandrogenic PCOS women, which actually represent the more “pure” form of PCOS.
In conditions of increased LH and normal-to-low FSH, such as PCOS, AMH serum levels are increased and tend to be associated to serum LH, while in conditions of increased FSH such as premature ovarian failure, AMH serum levels are decreased and tend to be associated to serum FSH.
Neoklis A. Georgopoulos, Ph.D.a
Athanasia Piouka, M.Sc.b
Ilias Katsikis, Ph.D.b
Alexandros D. Saltamavros, Ph.D.a
George Decavalas Ph.D.a
Dimitrios Panidis, Ph.D.b
aDepartment of Obstetrics and Gynecology
Division of Reproductive Endocrinology
University of Patras Medical School
bDivision of Endocrinology and Human Reproduction
Second Department of Obstetrics and Gynecology
Aristotle University of Thessaloniki
1. Singer T, Barad DH, Weghofer A, Gleicher N. Correlation of antimüllerian hormone and baseline follicle-stimulating hormone levels. Fertil Steril 2009;91:2616-9.
2. Dumesic DA, Lesnick TG, Stassart JP, Ball GD, Wong A, Abbott DH. Intrafollicular antimullerian hormone levels predict follicle responsiveness to follicle-stimulating hormone (FSH) in normoandrogenic ovulatory women undergoing gonadotropin releasing-hormone analog/recombinant human FSH therapy for in vitro fertilization and embryo transfer. Fertil Steril 2009;92:217-21.
3. Piouka A, Farmakiotis D, Katsikis I, Macut D, Gerou S, Panidis D. Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab 2009;296:E238-43.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.006
The Authors Respond:
We appreciate the interest of Dr. Georgopoulos and colleagues in our study. In response to our observation of an inverse relationship between FSH and AMH among women undergoing in vitro fertilization, they have offered their own observation that among women with polycystic ovarian syndrome the FSH/AMH relationship is not present. They further offer evidence that AMH concentration is directly related to luteinizing hormone (LH) among women with PCOS.
While a relationship between serum AMH and LH concentration among women with PCO is plausible, we fail to see the utility of such an observation. AMH is produced by antral and pre-antral follicles. Antral follicles decrease with reproductive aging, and as a consequence, serum concentration of AMH falls (1). Fewer antral follicles result in a fall in both inhibin and sex steroids, leading to a consequent rise in FSH.(2) Thus, while serum AMH is directly linked to ovarian reserve, serum FSH is a few steps removed from this process.
Our study related the serum FSH to serum AMH.(3) Such a relationship may be used to help clinical interpretation of AMH concentration with regard to prediction for ovarian reserve. We did not imply a direct physiologic relationship between AMH and FSH secretion, other than the common link as a reflection of follicular dynamics.
The observation of increased AMH among women with PCO-like ovaries is a further example of the direct relationship of serum AMH to antral follicles, which are abundantly present in the ovaries of women with PCOS. It is well known, and was at one time part of the diagnostic criteria for PCOS, that women with this condition often have increased serum concentration of LH. Thus a direct relationship of LH and AMH demonstrated in a population of women with PCOS is not a surprise. Indeed, elevated serum concentration of AMH may have utility in the diagnosis of PCOS(4), not as a surrogate for serum LH measurement, but as a direct reflection of the increased antral follicle pool.
We did not propose that AMH levels are modulated by FSH and do not believe that our correspondents have offered credible evidence to support their hypothesis that BMI and LH directly modulate AMH among women with PCO. Instead we interpret both our study and the data provided by Georgopoulos et al. as further support of the well established relationship between antral follicle numbers and serum AMH.
David H Barad, M.D., M.S.
Norbert Gleicher, M.D.
Tomer Singer, M.D.
The Center for Human Reproduction
New York, New York
1. Fanchin R, Schonauer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18:323-7.
2. Scheffer GJ, Broekmans FJ, Dorland M, Habbema JD, Looman CW, te Velde ER. Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil Steril 1999;72:845-51.
3. Singer T, Barad DH, Weghofer A, Gleicher N. Correlation of antimullerian hormone and baseline follicle-stimulating hormone levels. Fertil Steril 2009;91:2616-9.
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.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.007