The goal of the Center for Reproductive Science and Medicine at UC San Diego is to develop understanding of the fundamental mechanisms that cause disordered function of the hypothalamic-pituitary-ovarian axis in Polycystic Ovary Syndrome (PCOS). Polycystic ovary syndrome (PCOS) is the most common cause of female infertility, occurring in about 1 in 10 women of childbearing age. PCOS is currently the most common endocrine disorder of reproductive-aged women, affecting between five and 10 percent of women aged 15-44 or more than four million women in the U.S. It is estimated that the total annualized cost of evaluating and providing care to PCOS women is $4.6 billion dollars. Hallmarks are disordered neuroendocrine function, metabolic abnormalities, obesity, androgen excess, and anovulation, but the etiology remains unknown. Our Center is an integrated program of three projects that address the fundamental mechanisms of PCOS utilizing clinical studies in women with PCOS, genetic approaches, cultured cell models, and mouse models of PCOS.
Our research program in Reproductive Endocrinology was initiated at the inception of the Department of Reproductive Medicine at UC San Diego in 1970 under the direction of Drs. Kenneth Ryan and Samuel S. C. Yen and included Drs. Fred Naftolin, Howard Judd, John Davies, and Kurt Benirschke with support by the Rockefeller Foundation. P50 NICHD Specialized Population Research Center Grant was awarded in 1979 and Dr. Yen directed the Center for 19 years. Under his leadership, the center made important discoveries that had major impact on basic and clinical reproductive endocrinology. Investigators associated with the Center during this period were: Gregory Erickson, Aaron Hsueh, Eli Adashi, James Schreiber, Jim Liu, Jim Schaffer, Allen Lein, Robert Rebar, Bruce Kessell, Robert Caspar, Robert Reid, Ralph Kazer, Ken Muse, Sarah Berga, Joseph Mortola, and Ana Murphy. In 1992, Dr. Pamela Mellon joined as Co-Director with Dr. Yen, and Mellon, and included Drs. Erickson, and Jerrold Olefsky. In 1997, Pamela became Director with the addition of Jeffrey Chang as co-Director, Shunichi Shimasaki, and Nicholas Webster and Mark Lawson. The transition afforded a unique opportunity to fulfill our goal to bring the most advanced approaches to bear on fundamental questions of hypothalamic-pituitary-ovarian axis regulation in health and disease.
The flagship theme of our Center has always been the translation of basic research to clinical medicine. Among the historic achievements were the rigorous examination of gonadotropin secretory dynamics and characterization of LH and FSH responses to GnRH through the menstrual cycle, seminal contributions upon which mechanisms of ovarian steroid feedback were based. Subsequently, the specific relationships between estrogen and progesterone to gonadotropin release were identified which clearly established the precise temporal endocrine signals that regulate menstrual cyclicity. Notably, most of these collective efforts were performed in vivo in normal women and women with a variety of ovulatory disorders. The spectrum of study included the transitional intervals of puberty and menopause, and pathologic anovulatory conditions, including polycystic ovary syndrome.
The Center pioneered the development of the serum-free cell culture models for granulosa and theca cells, now used by investigators worldwide who study interaction of oocytes, theca, and granulosa cells in follicle development. This research done by Drs. Hsueh, Erickson, and Shimasaki, stands as an example of how major breakthroughs in basic research have been translated to humans. The novel concepts that IGF-I, IGF-BPs, and their proteases play critical roles in regulating FSH- and LH-dependent follicle differentiation have proven clinically relevant in normal women and patients with PCOS.
The Center also established the key neuroendocrine model systems for investigation of hypothalamic and pituitary control of reproduction in the GT1-7, αT3-1, and LβT2 cell lines for investigation of GnRH and the gonadotropin hormones. These cell lines are utilized by numerous investigators in the SCCPIR/NCTRI program and world-wide to advance understanding of fundamental mechanisms of hypothalamic pulsatile secretion of GnRH, neuropeptide and neurotransmitter control of GnRH, developmental origins of GnRH neurons and pituitary gonadotropes, hormonal regulation in gonadotropes, and the molecular basis of gonadotropin gene regulation. These are examples of the types of translational research that led, in part, to the distinguished reputation of the Center at UC San Diego in linking basic and clinical reproductive research.
In years 25-33, the UC San Diego Center focused on three highly integrated and collaborative projects led by Drs. Mellon, Olefsky, and Chang, with Drs. Webster, Lawson, Kauffman, Thackray, Breen, Duleba, and Shimasaki as Co-Investigators. This multidisciplinary team placed special emphasis on hormonal regulation of hypothalamic-pituitary-ovarian axis in humans and animal models. Our current renewal for years 34-38 focuses three projects under the leadership of Drs. Chang, Lawson and Mellon, and studies free fatty acids and androgens in PCOS to continue our ground-breaking translational discoveries within the UC San Diego Center for Reproductive Science and Medicine. We have been funded through 2021 and look forward to a successful future.