Grant: Project Grant

Reproduction is controlled by hormones from the brain, pituitary gland, and gonads (ovaries and testicles). The pituitary sits at the base of the brain and secretes follicle-stimulating hormone (FSH) in response to hormones from the brain and gonads. In women, FSH stimulates the growth of ovarian follicles. These are structures that contain oocytes (eggs). FSH stimulated follicle growth is a prerequisite for subsequent ovulation. FSH is used clinically to treat women that do not ovulate normally or have otherwise unexplained infertility. In response to FSH, the ovaries produce hormones called inhibins. Inhibins act in the pituitary to suppress FSH secretion. This feedback system is essential for controlling FSH levels such that only one follicle will ovulate in a typical menstrual cycle. Inhibins mediate their effects by binding to proteins (receptors) on the surface of FSH-producing gonadotrope cells in the pituitary called betaglycan and TGFBR3L. There are two forms of inhibin, A and B. Betaglycan acts as receptor for both inhibins. In contrast, TGFBR3L is a specific inhibin B receptor. We discovered that mice lacking either of these receptors have increased FSH levels or activity, leading to enhanced follicle growth, ovulation, and fertility. In contrast, mice lacking both receptors have very high FSH, greatly enlarged ovaries, and ovulate four times as many eggs as normal but are nevertheless infertile. The goals of this project grant are to determine: 1) the cause of infertility in mice lacking inhibin action in their gonadotropes, 2) how inhibins bind to betaglycan and TGFBR3L to mediate their actions, and 3) how TGFBR3L expression is restricted to gonadotrope cells. The results will provide novel insights into inhibin control of FSH and reproduction. They will also provide the necessary foundation for our efforts to develop inhibin directed therapies to regulate FSH levels to treat human infertility.