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
Bu, Pengli; Yagi, Shintaro; Shiota, Kunio et al. (2017) Origin of a rapidly evolving homeostatic control system programming testis function. J Endocrinol 234:217-232
Gorsic, Lidija K; Kosova, Gulum; Werstein, Brian et al. (2017) Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:2862-2872
Prins, Gail S; Ye, Shu-Hua; Birch, Lynn et al. (2017) Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose-Response Analysis. Environ Health Perspect 125:077007
Sam, Susan; Vellanki, Priyathama; Yalamanchi, Sudha K et al. (2017) Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome. Metabolism 71:125-131
Clark, Nicole C; Pru, Cindy A; Yee, Siu-Pok et al. (2017) Conditional Ablation of Progesterone Receptor Membrane Component 2 Causes Female Premature Reproductive Senescence. Endocrinology 158:640-651
Jonak, Carrie R; Lainez, Nancy M; Roybal, Lacey L et al. (2017) c-JUN Dimerization Protein 2 (JDP2) Is a Transcriptional Repressor of Follicle-stimulating Hormone ? (FSH?) and Is Required for Preventing Premature Reproductive Senescence in Female Mice. J Biol Chem 292:2646-2659
Deckard, Charles; Walker, Azida; Hill, Brent J F (2017) Using three-point bending to evaluate tibia bone strength in ovariectomized young mice. J Biol Phys 43:139-148
Levasseur, Adrien; St-Jean, Guillaume; Paquet, Marilène et al. (2017) Targeted Disruption of YAP and TAZ Impairs the Maintenance of the Adrenal Cortex. Endocrinology 158:3738-3753
Scalici, Jennifer M; Arapovic, Sanja; Saks, Erin J et al. (2017) Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC). Cancer 123:977-984
Reid, Sara Pittenger; Kao, Chia-Ning; Pasch, Lauri et al. (2017) Ovarian morphology is associated with insulin resistance in women with polycystic ovary syndrome: a cross sectional study. Fertil Res Pract 3:8

Showing the most recent 10 out of 446 publications