John C. Marshall, MD, PhD
Degree(s): MD, PhD
Graduate School: Victoria University of Manchester, UK
Primary Appointment: Andrew D. Hart Professor of Internal Medicine;
Director, Center for Research in Reproduction
Mechanisms of GnRH regulation of gonadotropin and steriod synthesis; the etiology of PCOS in adolescence.
Email Address: email@example.com
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.
Burt-Solorzano CM, McCartney CR, Blank SK, Knudsen KL, Marshall JC. Hyperandrogenemia in adolescent girls: origins of abnormal GnRH secretion. Brit J Obstet Gynec 117:143-149, 2010. PMCID 2994606.
Knudsen KL, Blank SK, Burt-Solorzano C, Patne JS, Chang RJ, Caprio S, Marshall JC, McCartney CR. Hyperandrogenemia in obese peripubertal girls: Correlates and potential etiological determinants. Obesity18,2118-2124, 2010 (E pub March 2010 as doi:10.1038/oby.2010.58), PMCID 2932780.
Burger LL, Haisenleder DJ, Marshall JC. GnRH pulse frequency differentially regulates SF-1, DAX1, and serum response factor --potential mechanism for GnRH pulse frequency regulation of LH transcription in the rat. Endocrine 39: 212-219, 2011. (PMID21409515)
Jane JA, Starke RM, Elzoghby MA, Reames DL, Payne SC, Vance ML, Thorner MO, Marshall JC, Laws ER. Endoscopic transphenoidal surgery for acromegaly: Remission using modern criteria, complications and predictors of outcome. J Clin Endrocinol Metab 96:2732-2740, 2011. (PMID21715544)
Haisenleder DJ, Schoenfelder AH, Marcinko ES, Geddis LM, Marshall JC. Estimation of estradiol in mouse serum samples:--evaluation of commercial estradiol immunoassays. Endocrinology 152:4443-4447, 2011. (doi:10.1210/en-2011-1501,152:2011. (PMCID 3198998)
Abshire MY, Blank SK, Chhabra S, McCartney CR, Eagleson CA, Marshall JC. Role of androgen recepter CAG repeat polymorphism length in hypothalamic progesterone sensitivity in hyperandrogenemic adolescent girls. Endocrine 41: 156-158, 2012. (doi:10.1007/s 12020-011-9563-1, 2011) PMCID 3253981.
McGee W, Bishop C, Bahar A, Pohl C, Chang RJ, Marshall JC, Pau F, Stouffer R, Cameron J. Elevated androgens during puberty in female rhesus monkeys lead to increased neuronal drive to the reproductive axis: a possible component of polycystic ovary syndrome. Human Reproduction, 27:531-540, 2012 (doi: 10.1093/humrep/der393). PMCID 3258033
Marshall JC, Dunaif A. Should all women with PCOS be treated for insulin resistance. Fertility and Sterility, 97:18-22, 2012. (doi:10.1016/j.fertnstert.2011.11.036). PMCID 3277302
Burt-Solorzano CM, Beller JP, Abshire MY, Collins JS, McCartney CR, Marshall JC. Neuroendocrinedysfunction in polycystic ovary syndrome. Steroids, 77:332-337, 2012 (doi:10.1016/j.steroids.2011.12.007) (PMCID3453528)
Collins JS, Marshall JC, McCartney CR. Differential sleep-wake
sensitivity of GnRH secretion to progesterone inhibition in early
pubertal girls. Neuroendocrinology, 2012 Mar 1 (doi:10.1159/000336395).
(PMC Journal in Progress)