The Role of Anti-Müllerian Hormone in Ovarian Function, Dysfunction and Aging

The ovary is of major importance for both reproduction and the endocrine status of women. Follicle development in the ovary is regulated by gonadotropins but also by intra-ovarian factors, such as anti-Müllerian hormone (AMH). In mice, AMH inhibits primordial follicle recruitment, thereby influencing ovarian aging, and suppresses FSH sensitivity of growing follicles. The aim of this thesis was to investigate the role of the AMH signaling pathway in the mouse and human ovary. Our studies in mice showed that serum AMH levels reflect the size of the primordial follicle pool, and therefore, AMH is a useful marker for the ovarian reserve. The role of the AMH signaling pathway in human ovarian physiology was studied using a genetic approach. Frequent polymorphisms in several genes of the AMH signaling pathway (AMH, AMHR2, and ACVR1) were identified, and associated with various endpoints of ovarian function using large population-based and case- control cohorts of women. We observed that the AMHR2 polymorphism was associated with age at menopause in interaction with the number of offspring. Association studies in normo-ovulatory women revealed that AMH and AMHR2 polymorphisms were associated with estradiol levels, suggesting a role for AMH in the regulation of FSH sensitivity in the human ovary. In addition, the role of AMH signaling in the pathophysiology of polycystic ovary syndrome (PCOS) was studied. Our results suggest that AMH signaling contribute! s to the severity of the PCOS phenotype. The studies described in this thesis show that AMH will contribute to a better understanding of ovarian function, dysfunction and aging. Eventually, this may lead to improved treatment of infertility and of health problems related to ovarian aging in women.

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