Anti-Müllerian Hormone: Function and Molecular Mechanism of Action in the Ovary

Menopause, the end of menstrual cycling, is a major milestone in the aging process in women. The cessation of ovarian function is accompanied by the almost complete absence of female sex steroid hormone secretion by the ovaries in postmenopausal life. Consequently, before and after the menopausal transition very different physiological hormonal regimens prevail, which have a major impact on healthy aging of women and their quality of life. After menopause, due to the loss of exposure to protective female sex steroid hormones, women have an increased risk for different health problems (such as osteoporosis, cardiovascular diseases and a decreased cognitive function). In addition, the age at menopause is associated with the age at which infertility starts. Approximately, 20 years before menopause female fertility starts to decrease, culminating through sub-fertility into complete infertility 10 years before menopause. Since the age at menopause affects the length of the postmenopausal period and the age of infertility, it is of utmost importance to understand the process leading to menopause. Menopause is caused by the exhaustion of the follicle stock in the ovaries. The limited supply of primordial follicles is formed during fetal life and cannot be replenished afterwards. The number of primordial follicles decreases by outgrowth of follicles or by atresia. Studies on the anti-Müllerian hormone (AMH) null mice showed that AMH inhibits the outgrowth of primordial follicles and thereby inhibits the exhaustion of follicles in the ovary. This thesis focuses on the role of AMH in the ovary and investigates through which molecular mechanisms these effects are achieved. In the General Introduction (Chapter 1), the process of follicle development from primordial to pre-ovulatory follicle is described. This process is regulated by follicle-stimulating hormone (FSH) and luteinizing hormone (LH), produced by the pituitary, but also by several intra-ovarian factors. One important family of growth- and differentiation factors which plays a role in follicle development is the transforming growth factor b (TGFb) superfamily, to which also AMH belongs. The involvement of several TGFb family members in follicle development is described and the emphasis is on the known effects of AMH on follicle development and the clinical relevance of these findings. AMH is a member of the TGFb superfamily and family members signal through a receptor complex consisting of a type II and a type I transmembrane serine/threonine kinase receptor.