Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous syndrome of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Most PCOS women also have insulin resistance (IR) beyond that predicted by body mass index (BMI), increasing the risk for diabetes. Although many PCOS women are overweight, in nonobese PCOS women, breakdown of lipids (lipolysis) is decreased in subcutaneous (SC) abdominal fat cells (adipocytes), causing enlarged SC abdominal adipocytes that correlate in size with IR. This finding may be due to androgen excess, since androgen decreases lipolysis and inhibits SC abdominal adipogenesis, whereby adipose stem cells become preadipocytes and differentiate to adipocytes. Thus, androgen excess in PCOS may decrease numbers of adipocytes in SC abdominal adipose and reduce capacity of this adipose to safely store fat. When energy intake exceeds this capacity, SC abdominal adipocytes may overfill with lipid, mobilizing free fatty acids to ectopic locations (lipotoxicity), promoting IR and ovarian dysfunction. We hypothesize that androgen excess in lean PCOS women decreases adipogenic differentiation and increases adipocyte lipid content in a constrained SC abdominal adipose store, inducing lipotoxicity, IR and ovarian dysfunction. If so, antiandrogen therapy with flutamide for 6 months to lean PCOS women should improve SC abdominal adipogenesis, insulin sensitivity and ovarian function and morphology. We will 1) compare differences in SC abdominal adipogenesis in lean PCOS women vs. age- and BMI matched controls;2) examine the effect of 6-month fiutamide therapy in lean PCOS women on SC abdominal adipogenesis, body fat distribution, metabolic function and ovarian folliculogenesis;and 3) determine the underlying mechanisms whereby androgen inhibits adipogenesis. Understanding if androgen excess in lean PCOS women disrupts SC abdominal adipogenesis to impair ovarian function will establish a crucial link between adipogenic and ovarian dysfunction, allowing development of new clinical strategies that improve reproduction in PCOS women and enhance safety of ovulation-inducing agents during infertility therapy.

Public Health Relevance

Women with polycystic ovary syndrome (PCOS) have androgen excess, ovarian dysfunction and abnormal glucose metabolism. Their elevated androgen levels may impair subcutaneous (SC) abdominal fat storage, mobilizing fatty acids and substances from fat to other tissues, disrupting ovarian function and glucose metabolism. Blocking excess androgen action with the antiandrogen flutamide in lean PCOS women may restore SC abdominal fat storage, ovulation and metabolism, improving reproduction in PCOS women and enhancing safety of ovulation-inducing agents in those individuals who need them.

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 #
1U54HD071836-01A1
Application #
8510090
Study Section
Special Emphasis Panel (ZHD1-DSR-L (55))
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$214,492
Indirect Cost
$13,500
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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