Marshall, John C.
Andrew D. Hart Professor of Internal Medicine; Director, Center for Research in Reproduction, Medicine: Endocrinology and Metabolism
- BS, Human Neuroanatomy, Victoria University of Manchester (UK)
- MB ChB, Medicine, Victoria University of Manchester (UK)
- MRCP, Internal Medicine, Royal College of Physicians (London, UK)
- MD, Endocrinology, Victoria University of Manchester (UK)
Mechanisms of GnRH Regulation of Gonadotropin and Steriod Synthesis; the Etiology of PCOS in Adolescence
Dr. Marshall's laboratory has studied the intracellular mechanisms by which Gonadotropin Releasing Hormone (GnRH) stimulates the synthesis of gonadotropin subunits and secretion of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). These basic studies indicated that the frequency of the GnRH signal differentially regulated gene expression. Recent studies have taken this observation to the clinical level in investigating the disorder of polycystic ovarian syndrome-a common disorder which affects some 7-8% of reproductive-age women and is associated with excess production of male hormone, infertility, obesity, and a tendency in later life to develop diabetes. The disorder is the commonest cause of infertility and abnormal ovulation and appears to develop from the effects of exposure to excess male hormone before and during the pubertal maturational process. This in turn leads to impaired regulation of the frequency of GnRH pulse secretion by steroid hormones. Specifically excess testosterone blocks progesterone inhibition and slowing of GnRH pulse secretion. As a consequence, rapid GnRH pulse signals favor LH synthesis by the pituitary which in turns drives the ovary to maintain the androgen excess. The disorder develops before or during pubertal maturation and in animal models may reflect intrauterine exposure to excess androgen. Our present work focuses on the origins of excess testosterone in pre- and peripubertal girls and has shown that the present epidemic of obesity is associated with increased male hormone levels in 65-70% of obese girls. We believe this triggers abnormal maturation of the steroid-GnRH feedback mechanisms in the hypothalamus with persistence of rapid GnRH secretion and maintenance of the syndrome in adulthood. Present studies are assessing the effects of obesity on adrenal androgen production, the timing of ovarian androgen excess and the duration and degrees of excess androgen required to modify regulation of GnRH secretion. The long-term goals are to inhibit or block excess androgen production prior to any permanent modification of the ovarian steroid-GnRH axis.