Grant: Project Grant

Reproduction is controlled by a hormonal feedback system called the hypothalamic-pituitary-gonadal axis. The hypothalamus of the brain produces and secretes gonadotropin-releasing hormone (GnRH), which reaches the pituitary gland. The pituitary sits at the base of the brain and, in response to GnRH, produces two additional hormones called luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH travel via the bloodstream to the ovaries in women and testicles in men where they stimulate fundamental aspects of reproductive physiology. In women, the two hormones stimulate growth and ovulation of egg-containing structures called follicles. They also stimulate production of hormones such estrogen and inhibin. In men, LH stimulates testosterone production. Together with FSH, this testosterone controls sperm production. FSH also stimulates inhibin production. Steroid hormones, like estrogen and testosterone, travel back to the brain, where they suppress GnRH secretion. This leads to decreases in LH and FSH secretion. In contrast, inhibins travel to the pituitary where they suppress FSH without affecting LH. Inhibins are thought to produce their actions by blocking the activity of yet another hormone called activin. Activins are thought to be made by the pituitary and stimulate FSH production. In contrast, research from our lab suggests that hormones like activins, but not activins themselves, stimulate FSH and are blocked by inhibins. Moreover, our work shows that our current conceptions of how inhibins suppress FSH are either incorrect or incomplete. In this application, we propose to identify the activin-like hormone that stimulates FSH as well as the mechanisms through which inhibins block this hormone. The result of this work will redefine our understanding of basic mechanisms of reproductive hormone control. Moreover, we may identify a new approach to treat human infertility.