Grant: Operating Grant

Fertility is dependent upon the coordinated activities of the brain, the pituitary gland (which sits at the base of the brain), and the gonads (ovaries and testicles). These organs communicate with one another via chemical messengers called hormones, which are produced in one organ and then travel to another via the bloodstream. For successful reproduction, the brain sends a signal called gonadotropin-releasing hormone (GnRH) to the pituitary. In response, the pituitary produces and secretes the gonadotropin hormones, which travel to the gonads to: 1) instruct them to make steroid hormones, such as estrogen and testosterone, and 2) stimulate the growth of eggs and sperm. Estrogen and testosterone travel back through the circulation to the brain and pituitary to inhibit further release of GnRH and gonadotropins. In this way, an equilibrium in the system is established. This balance is critical for fertility; perturbations at the brain, pituitary, or gonadal level cause infertility. For example, people with deficiencies in GnRH production or action fail to go through puberty and/or are infertile. Drugs that act like GnRH and others that block its actions are used clinically to treat diverse conditions, including delayed puberty, infertility, and hormone-dependent diseases (for example, breast and prostate cancers). Nevertheless, our understanding of how GnRH produces its actions is incomplete and roughly 70% of GnRH-deficiencies remain unexplained. The goals of this proposal are therefore to understand how GnRH stimulates gonadotropin hormone production and secretion. We will use powerful genetic mouse models to understand these processes in living animals. The results of these studies may provide an understanding of currently unexplained causes of GnRH-deficiency and, in so doing, identify novel therapeutic targets in the treatment of human infertility and hormone-dependent disease.