Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway by which the brain controls fertility. In the common reproductive disorder polycystic ovary syndrome (PCOS), GnRH neurons are hyperactive, leading to increased frequency of luteinizing hormone (LH) release from the pituitary, driving increased levels of testosterone production. Androgens have a stimulatory role centrally, forming a positive feedback loop to increase GnRH neuron activity. Androgens also interfer with the normal negative feedback actions of progesterone, which typically reduce activity of this system. In addition to infertility, PCOS predisposes women to many metabolic disorders, including insulin resistance, central adiposity and dyslipidemia. Elevated insulin can also act to increase testosterone production, further stimulating the above positive feedback loop. In this proposal, we will examine neurobiological mechanisms underlying the effects of androgens, progesterone and metabolic cues in regulating GnRH neurons, as well as how these factors interact at the central level using state-of-the-art electrophysiological approaches combined with careful animal model development. This main thrust will be complemented by electrophysiological and limited metabolic studies of a mouse model that has many of the phenotypic characteristics of women with PCOS.
In Aim 1, the effects of steroids and metabolic cues on the intrinsic properties of GnRH neurons will be studied, including how these factors interact to alter ion channel function.
Aim 2 will examine the changes in GABAergic fast synaptic transmission to GnRH neurons that are brought about by steroids and metabolic cues.
In Aim 3, we will continue characterization of prenatally androgenized mice as a preclinical model for PCOS. Mice treated prenatally with dihydrotestosterone exhibit disrupted estrous cycles, and elevated levels of testosterone and LH similar to women with PCOS. Preliminary data indicate these mice are glucose intolerant independent of altered adiposity. We will further characterize the metabolic phenotype and examine the causal relationships between reproductive and metabolic aspects of this disorder. Together these studies will provide novel information about the basic biology of GnRH neurons and the pathological state of PCOS that will lead to preclinical and clinical trials of new therapies

Public Health Relevance

Polycystic ovary syndrome (PCOS) affects 6-8% of women and is the leading cause of infertility. By studying how the brain, ovaries and metabolic tissues interact in this disorder, we can identify new targets for therapeutic intervention.

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 #
8446137
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
$239,770
Indirect Cost
$73,391
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Xiyin; Khatri, Shikha; Broaddus, Russell et al. (2016) Deletion of Arid1a in Reproductive Tract Mesenchymal Cells Reduces Fertility in Female Mice. Biol Reprod 94:93
York, J Philippe; Ren, Yi Athena; Zeng, Jie et al. (2016) Growth Arrest Specific 2 (GAS2) is a Critical Mediator of Germ Cell Cyst Breakdown and Folliculogenesis in Mice. Sci Rep 6:34956
Adams, Jaye; Liu, Zhilin; Ren, Yi Athena et al. (2016) Enhanced Inflammatory Transcriptome in the Granulosa Cells of Women With Polycystic Ovarian Syndrome. J Clin Endocrinol Metab 101:3459-68
Torchen, Laura C; Kumar, Ajay; Kalra, Bhanu et al. (2016) Increased antimüllerian hormone levels and other reproductive endocrine changes in adult male relatives of women with polycystic ovary syndrome. Fertil Steril 106:50-5
Saatcioglu, Hatice Duygu; Cuevas, Ileana; Castrillon, Diego H (2016) Control of Oocyte Reawakening by Kit. PLoS Genet 12:e1006215
Lefèvre, Pavine L C; Berger, Robert G; Ernest, Sheila R et al. (2016) Exposure of Female Rats to an Environmentally Relevant Mixture of Brominated Flame Retardants Targets the Ovary, Affecting Folliculogenesis and Steroidogenesis. Biol Reprod 94:9
Abedini, Atefeh; Zamberlam, Gustavo; Lapointe, Evelyne et al. (2016) WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling. FASEB J 30:1534-47
Mittelman-Smith, Melinda A; Krajewski-Hall, Sally J; McMullen, Nathaniel T et al. (2016) Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats. Endocrinology 157:2015-27
Rubel, Cory A; Wu, San-Pin; Lin, Lin et al. (2016) A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function. Cell Rep 17:1414-1425
Stephens, Shannon B Z; Chahal, Navdeep; Munaganuru, Nagambika et al. (2016) Estrogen Stimulation of Kiss1 Expression in the Medial Amygdala Involves Estrogen Receptor-α But Not Estrogen Receptor-β. Endocrinology 157:4021-4031

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