Polycystic ovary syndrome (PCOS) is a common disorder of women marked by hyperandrogenemia (HA) and ovulatory dysfunction. Additionally, PCOS is associated with obesity and other metabolic abnormalities (e.g., insulin resistance). A number of pathophysiological mechanisms underlie PCOS. Neuroendocrine abnormalities play a significant role in most women with PCOS. PCOS is associated with relative resistance of the gonadotropin releasing hormone pulse generator to negative feedback by progesterone and estradiol: this defect appears to be a result of HA, and can also occur in adolescents with HA. We have hypothesized that peripubertal HA can promote the development of PCOS in part via induction of hypothalamic resistance to negative feedback. However, the cause of peripubertal HA remains unknown. Obesity is a well-recognized pathophysiological factor in the HA of adult PCOS;and recent data demonstrate that peripubertal obesity is associated with HA. However, the mechanisms underlying the relationship between peripubertal obesity and HA?and the marked variability of androgens observed among obese girls?are unknown. Preliminary data suggests that obese pre- and early pubertal girls with high androgen levels also exhibit greater degrees of insulin resistance compared to obese girls with lower androgens.
Aim 1 of this pilot project involves detailed assessments of insulin resistance and LH pulsatility in obese peripubertal girls, and its primary goal is to define the importance of insulin resistance in causing HA in obese peripubertal girls. Secondarily, the contributions of elevated LH in obesity-associated HA across puberty will be assessed. Characterization of the factors underlying peripubertal HA may permit prediction of which pre- and early pubertal girls will subsequently go on to develop symptoms of PCOS. The goal of Aim 2 is to investigate other factors that may plausibly contribute directly to HA in peripubertal girls, including insulin-like growth factor-l [IGF-I], cytokines, and adipokines. In this setting, potential confounding factors (e.g., insulin, LH) will be carefully assessed. Data generated by this project will prompt novel future U54 studies to investigate the complex interactions among metabolic and classical endocrine pathways that lead to PCOS.
The polycystic ovary syndrome (PCOS) is a highly-prevalent disorder of women that is marked by reproductive and metabolic abnormalities. PCOS is associated with obesity and often begins in adolescence. However, the cause of adolescent PCOS remains unknown. Through this project, the role of peripubertal obesity in the development of hyperandrogenemia and PCOS will be investigated.
|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 antimÃ¼llerian 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|
|LefÃ¨vre, 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-Î± But Not Estrogen Receptor-Î². Endocrinology 157:4021-4031|
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