Grant: Operating Grant

Human fertility depends on the coordinated activities of many organs in the body. These organs communicate with each other via chemical messengers called hormones. In general, hormones produced by one organ travel via the bloodstream to control the function of other organs. In the case of the reproductive system, the brain synthesizes and secretes gonadotropin-releasing hormone (GnRH), which controls production and release of two other hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), by the pituitary gland. The pituitary sits at the base of the brain and secretes FSH and LH into the bloodstream following GnRH binding to its receptor on specific pituitary cells. If we think of GnRH as a key, then its receptor serves as the lock in to which this key uniquely fits. Once secreted, FSH and LH act on the ovaries in women and the testicles in men to control the production of eggs and sperm as well as the synthesis of steroid hormones like estrogen and testosterone. These steroids then feedback to the brain to control their own production by inhibiting GnRH secretion. Though we have a general understanding of where and how each of these hormones acts, fundamental questions remain unanswered. In this application, we address three general questions about how GnRH functions. First, does GnRH activate common or distinct pathways in pituitary cells to stimulate the synthesis and secretion of FSH and LH? Second, do pituitary cells make a protein that helps GnRH preferentially stimulate LH? Finally, does the GnRH receptor have unique features that enables it to preferentially control LH versus FSH synthesis? The answers to these questions will not only advance our knowledge of the hormonal control of reproduction, but will also identify novel causes and treatments for human infertility and other disorders of the reproductive system, including polycystic ovarian syndrome.