Polycystic Ovary Syndrome (PCOS) is an endocrinopathy of unknown etiology that affects as many as 8% of the female population and is the most common cause of female infertility. The chronic anovulation and hyperandrogenism characteristic of PCOS is promulgated by insulin resistance and the resultant hyperinsulinemia in the majority of affected individuals. The insulin resistance predisposes those with the disorder to type 2 diabetes and is a known risk factor for early onset of cardiovascular disease. Tumor necrosis factor alpha (TNF-alpha), an inflammatory cytokine produced by adipose tissue and activated mononuclear cells (MNC) has been implicated as a mediator of insulin resistance in PCOS. The proposed research will involve the perspective study of 40 reproductive age women (18-40 years). Twenty of the women will have PCOS (10 normal weight and 10 obese) and 20 will be weight-matched ovulatory controls. The central hypothesis is that a physiologic carbohydrate challenge triggers excessive TNF-alpha release from MNC of women with PCOS.
The specific aims are: 1) to examine TNF-alpha release from MNC of women with PCOS in response to glucose stimulation; 2) to examine the inflammation pathway in MNC of women with PCOS in response to glucose stimulation. The approach involves the quantification of TNF-alpha release from MNC culture supernatants of women with PCOS before and after in vivo glucose exposure during a standard oral glucose challenge test and under euglycemic and hyperglycemic conditions in vitro using cultured MNC isolated from fasting blood samples. The inflammatory response of MNC in women with PCOS will also be evaluated before and after in vivo glucose challenge by measuring [reactive oxygen species] ROS generation, expression of protein markers of the inflammation pathway and activated nuclear factor kappa B (NFkB). It is our expectation that the approach used in this study will demonstrate excessive MNC-derived TNF-alpha release and a pronounced inflammatory response following glucose stimulation. These results will be significant in that they will identify the MNC as an additional source of excess TNF-alpha in PCOS aside from adipose tissue, and the inflammatory mechanism responsible for excessive TNF-alpha release from MNC. This will lead to important advances in the therapy of PCOS designed to ameliorate insulin resistance by reducing inflammation. It will also provide precedence for future studies to determine the molecular mechanism responsible for the sensitivity of MNC to postprandial hyperglycemia in women with PCOS that places these individuals in a proinflammatory state. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD048535-03
Application #
7188972
Study Section
Special Emphasis Panel (ZHD1-DRG-D (FG))
Program Officer
Parrott, Estella C
Project Start
2006-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2010-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$71,854
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Malin, Steven K; Kirwan, John P; Sia, Chang Ling et al. (2015) Pancreatic ?-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-?B activation and systemic inflammation. Am J Physiol Endocrinol Metab 308:E770-7
González, Frank (2015) Nutrient-Induced Inflammation in Polycystic Ovary Syndrome: Role in the Development of Metabolic Aberration and Ovarian Dysfunction. Semin Reprod Med 33:276-86
González, Frank; Sia, Chang Ling; Shepard, Marguerite K et al. (2014) The altered mononuclear cell-derived cytokine response to glucose ingestion is not regulated by excess adiposity in polycystic ovary syndrome. J Clin Endocrinol Metab 99:E2244-51
González, Frank; Kirwan, John P; Rote, Neal S et al. (2014) Evidence of mononuclear cell preactivation in the fasting state in polycystic ovary syndrome. Am J Obstet Gynecol 211:635.e1-7
González, Frank; Sia, Chang Ling; Bearson, Dawn M et al. (2014) Hyperandrogenism induces a proinflammatory TNF? response to glucose ingestion in a receptor-dependent fashion. J Clin Endocrinol Metab 99:E848-54
González, Frank; Kirwan, John P; Rote, Neal S et al. (2014) Glucose and lipopolysaccharide regulate proatherogenic cytokine release from mononuclear cells in polycystic ovary syndrome. J Reprod Immunol 103:38-44
Gonzalez, Frank; Kirwan, John P; Rote, Neal S et al. (2013) Glucose ingestion stimulates atherothrombotic inflammation in polycystic ovary syndrome. Am J Physiol Endocrinol Metab 304:E375-83
González, Frank; Kirwan, John P; Rote, Neal S et al. (2013) Elevated circulating levels of tissue factor in polycystic ovary syndrome. Clin Appl Thromb Hemost 19:66-72
González, Frank; Sia, Chang Ling; Stanczyk, Frank Z et al. (2012) Hyperandrogenism exerts an anti-inflammatory effect in obese women with polycystic ovary syndrome. Endocrine 42:726-35
González, Frank (2012) Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 77:300-5

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