Stephanie Beth Seminara, MD
Dr. Seminara’s research focuses upon the genes which modulate GnRH secretion from the hypothalamus. GnRH controls pulsatile gonadotropin secretion, modulates gonadal steroid feedback, and brings about full fertility in the adult. However, the genetic modulators that turn on GnRH secretion at the time of puberty and sustain the physiological amplitude and frequency so essential for normal reproductive function remain unclear. Dr. Seminara and her team have utilized genetic tools in patients with GnRH deficiency (i.e., idiopathic hypogonadotropic hypogonadism [IHH]), and discovered that, in both the human and the mouse, mutations in the G protein-coupled receptor GPR54 cause hypogonadotropic hypogonadism and failure to enter puberty. Kisspeptin, the ligand for GPR54, is now appreciated to be a critical gatekeeper that integrates several central and peripheral signals necessary for normal GnRH release. Dr. Seminara has developed a translational research program to study the physiology of the kisspeptin/GPR54 pathway as well as continuing her efforts in novel gene discovery. She has elaborated genotype-phenotype correlations for patients with mutations in GPR54, and worked to demonstrate that gain of function mutations in GPR54 can be a cause of central precocious puberty. She has created mice with targeted deletions of both Gpr54 and its ligand, Kiss1, to explore the physiology of this pathway in the rodent. She has collaborated with primate investigators to demonstrate that continuous kisspeptin administration down regulates the reproductive cascade, thereby making it a therapeutic target for reproductive disorders. She is now poised to bring her investigations back to the human model, completing the translational research cycle.