Temporally regulated secretion of the pituitary gonadotropins luteinizing hormone (LH) and folliclestimulating hormone (FSH) is critical for steroidogenesis and fertility. LH and FSH are tightly controlled by hypothalamic gonadotropin-releasing hormone (GnRH) pulses, and directly and indirectly by ovarian steroids. GnRH pulse amplitude and frequency are regulated physiologically by estrogen (E), progesterone (P) and testosterone (T). High-frequency GnRH pulses occur with E stimulation and favor LH secretion and LH subunit gene transcription, whereas low-frequency pulses occur with P plus E and preferentially stimulate FSH secretion and the FSHbeta gene. Polycystic ovarian syndrome (PCOS) conservatively affects between 6-8% of women of reproductive age, and is characterized by hyper-androgenism, erratic menstrual cycles, and infertility. Many women also have insulin resistance and hyper-insulinemia, with or without obesity. Between 30-90% of PCOS patients have increased LH/FSH ratios, and P is less effective in reducing GnRH pulse frequency and altering gonadotropin secretion in these women. P sensitivity can be partially restored by antiandrogens in some women. Treatment with the insulin sensitizing drug, metformin, can also restore fertility in some subjects, but sites and mechanism of action of insulin or this drug on the reproductive axis are unclear. Understanding mechanisms underlying GnRH gonadotrope regulation is critical to develop treatments for PCOS. Proposed studies will use the prenatal androgenized (PNA) mouse model that mimics many symptoms of PCOS, including elevated LH and T, erratic reproductive cycles and glucose intolerance. We will examine regulated gonadotropin expression, and responses to GnRH and P feedback in PNA and control gonadotropes. Treatment of mice with antiandrogen and metformin will test potential contributions of elevated T or insulin insensitivity to PNA responses. The role of androgen receptor CAG repeat length in influencing T responses will be evaluated in vitro and in transgenic mice. We will also examine the pulsatile GnRH stimulation of gonadotropin gene transcription requirement for proteasome activity, and if insulin or T modulate this process and may thus contribute to dysregulated LH/FSH ratios seen in PCOS.

Public Health Relevance

Understanding mechanisms underlying GnRH regulation of the gonadotrope, and how steroids and insulin modulate gonadotrope function and the reproductive axis, is critical to developing treatments for PCOS. These studies will use the PNA mouse model that mimics many symptoms of PCOS to examine alterations in gonadotrope function and if and how treatment with antiandrogen and insulin sensitizing drugs restore nnnarintrnnfi rfisnonsfts and fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD028934-20
Application #
8446144
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
20
Fiscal Year
2013
Total Cost
$239,771
Indirect Cost
$73,390
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Huizhen; Larson, Melissa; Jablonka-Shariff, Albina et al. (2014) Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice. Proc Natl Acad Sci U S A 111:5735-40
Torchen, Laura C; Fogel, Naomi R; Brickman, Wendy J et al. (2014) Persistent apparent pancreatic ?-cell defects in premenarchal PCOS relatives. J Clin Endocrinol Metab 99:3855-62
Liu, D M; Torchen, L C; Sung, Y et al. (2014) Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. Hum Reprod 29:2764-72
Collins, Jessicah S; Beller, Jennifer P; Burt Solorzano, Christine et al. (2014) Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia. J Clin Endocrinol Metab 99:2887-96
Roland, Alison V; Moenter, Suzanne M (2014) Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: insight from animal models. Front Neuroendocrinol 35:494-511
McGee, W K; Bishop, C V; Pohl, C R et al. (2014) Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys. Am J Physiol Endocrinol Metab 306:E1292-304
Pike, Jack W; McDowell, Erin; McCahan, Suzanne M et al. (2014) Identification of gene expression changes in postnatal rat foreskin after in utero anti-androgen exposure. Reprod Toxicol 47:42-50
Garcia, Thomas X; Costa, Guilherme M J; Fran├ža, Luiz R et al. (2014) Sub-acute intravenous administration of silver nanoparticles in male mice alters Leydig cell function and testosterone levels. Reprod Toxicol 45:59-70
Lu, Guanyi; Su, Gang; Zhao, Yunge et al. (2014) Dietary phytoestrogens inhibit experimental aneurysm formation in male mice. J Surg Res 188:326-38
Anderson, Amy D; Solorzano, Christine M Burt; McCartney, Christopher R (2014) Childhood obesity and its impact on the development of adolescent PCOS. Semin Reprod Med 32:202-13

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