Premature Aging of Cardiovascular/Platelet Function in Polycystic Ovarian Syndrome



      The objective of this study was to compare the impact of aging on nitric oxide (NO) modulation of platelet and vascular function in healthy women and women with polycystic ovary syndrome.

      Methods and Results

      A case-control study of women ages 18 to 60 years, comparing women with polycystic ovarian syndrome against age-matched healthy controls, was performed. A total of 242 women, of whom 109 had polycystic ovarian syndrome (based on Rotterdam criteria), participated in the study. Women who were pregnant or on clopidogrel were excluded from the study. Inhibition of platelet aggregation by nitric oxide (primary outcome measure), vascular endothelial function, plasma concentrations of NG, NG-dimethyl-L-arginine (ADMA), endothelial progenitor cell count, and high-sensitivity C-reactive protein (markers of endothelial dysfunction and inflammation) were assessed. With increasing age in control women, there was progressive attenuation of platelet responses to NO, impairment of endothelial function, and elevation of ADMA levels (P ≤.001). Irrespective of age, women with polycystic ovarian syndrome exhibited greater impairment of all these parameters (all P <.05, 2-way analysis of variance) and demonstrated these anomalies earlier in life.


      Normal aging in women is associated with attenuation of NO-based signaling in platelets and blood vessels. In women with polycystic ovarian syndrome, these changes are present from early adult life and may contribute to premature atherogenesis.


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        • Ehrmann D.A.
        Polycystic ovary syndrome.
        N Engl J Med. 2005; 352: 1223-1236
        • Wang J.X.
        • Davies M.J.
        • Norman R.J.
        Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment.
        Hum Reprod. 2001; 16: 2606-2609
        • Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group
        Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).
        Hum Reprod. 2004; 19: 41-47
        • Norman R.J.
        • Masters S.
        • Hague W.
        Hyperinsulinemia is common in family members of women with polycystic ovary syndrome.
        Fertil Steril. 1996; 66: 942-947
        • Dunaif A.
        • Hoffman A.R.
        • Scully R.E.
        • et al.
        Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization.
        Obstet Gynecol. 1985; 66: 545-552
        • Apridonidze T.
        • Essah P.A.
        • Iuorno M.J.
        • Nestler J.E.
        Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 2005; 90: 1929-1935
        • Legro R.S.
        • Kunselman A.R.
        • Dodson W.C.
        • Dunaif A.
        Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.
        J Clin Endocrinol Metab. 1999; 84: 165-169
        • Norman R.J.
        Obesity, polycystic ovary syndrome and anovulation—how are they interrelated?.
        Curr Opin Obstet Gynecol. 2001; 13: 323-327
        • Orio Jr., F.
        • Palomba S.
        • Cascella T.
        • et al.
        Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 2004; 89: 4588-4593
        • Paradisi G.
        • Steinberg H.O.
        • Hempfling A.
        • et al.
        Polycystic ovary syndrome is associated with endothelial dysfunction.
        Circulation. 2001; 103: 1410-1415
        • Tarkun I.
        • Arslan B.C.
        • Canturk Z.
        • Turemen E.
        • Sahin T.
        • Duman C.
        Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation.
        J Clin Endocrinol Metab. 2004; 89: 5592-5596
        • Dereli D.
        • Ozgen G.
        • Buyukkececi F.
        • Guney E.
        • Yilmaz C.
        Platelet dysfunction in lean women with polycystic ovary syndrome and association with insulin sensitivity.
        J Clin Endocrinol Metab. 2003; 88: 2263-2268
        • Rajendran S.
        • Willoughby S.R.
        • Chan W.P.
        • et al.
        Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects.
        Atherosclerosis. 2009; 204: 509-514
        • Willoughby S.R.
        • Stewart S.
        • Holmes A.S.
        • Chirkov Y.Y.
        • Horowitz J.D.
        Platelet nitric oxide responsiveness: a novel prognostic marker in acute coronary syndromes.
        Arterioscler Thromb Vasc Biol. 2005; 25: 2661-2666
        • Wild R.A.
        • Grubb B.
        • Hartz A.
        • Van Nort J.J.
        • Bachman W.
        • Bartholomew M.
        Clinical signs of androgen excess as risk factors for coronary artery disease.
        Fertil Steril. 1990; 54: 255-259
        • Krentz A.J.
        • von Muhlen D.
        • Barrett-Connor E.
        Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease.
        Menopause. 2007; 14: 284-292
        • Azevedo G.D.
        • Duarte J.M.
        • Souza M.O.
        • Costa E.S.T.D.
        • Soares E.M.
        • Maranhao T.M.
        Menstrual cycle irregularity as a marker of cardiovascular risk factors at postmenopausal years.
        Arq Bras Endocrinol Metabol. 2006; 50 ([Portuguese]): 876-883
        • Goubareva I.
        • Gkaliagkousi E.
        • Shah A.
        • Queen L.
        • Ritter J.
        • Ferro A.
        Age decreases nitric oxide synthesis and responsiveness in human platelets and increases formation of monocyte-platelet aggregates.
        Cardiovasc Res. 2007; 75: 793-802
        • Celermajer D.S.
        • Sorensen K.E.
        • Spiegelhalter D.J.
        • Georgakopoulos D.
        • Robinson J.
        • Deanfield J.E.
        Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women.
        J Am Coll Cardiol. 1994; 24: 471-476
        • Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group
        Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.
        Fertil Steril. 2004; 81: 19-25
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • Naylor B.A.
        • Treacher D.F.
        • Turner R.C.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • de Resende M.M.
        • Huw L.Y.
        • Qian H.S.
        • Kauser K.
        Role of endothelial nitric oxide in bone marrow-derived progenitor cell mobilization.
        Handb Exp Pharmacol. 2007; : 37-44
        • Goldstein L.J.
        • Gallagher K.A.
        • Bauer S.M.
        • et al.
        Endothelial progenitor cell release into circulation is triggered by hyperoxia-induced increases in bone marrow nitric oxide.
        Stem Cells. 2006; 24: 2309-2318
        • Boger R.H.
        • Bode-Boger S.M.
        • Szuba A.
        • et al.
        Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.
        Circulation. 1998; 98: 1842-1847
        • Chirkov Y.Y.
        • Chirkova L.P.
        • Horowitz J.D.
        Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris.
        Naunyn Schmiedebergs Arch Pharmacol. 1996; 354: 520-525
        • Wilkinson I.B.
        • Cockcroft J.R.
        • Webb D.J.
        Pulse wave analysis and arterial stiffness.
        J Cardiovasc Pharmacol. 1998; 32: S33-S37
        • Heresztyn T.
        • Worthley M.I.
        • Horowitz J.D.
        Determination of l-arginine and NG, NG - and NG, NG' -dimethyl-L-arginine in plasma by liquid chromatography as AccQ-Fluor fluorescent derivatives.
        J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 805: 325-329
        • Vasa M.
        • Fichtlscherer S.
        • Aicher A.
        • et al.
        Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.
        Circ Res. 2001; 89: E1-E7
        • Diamanti-Kandarakis E.
        • Alexandraki K.
        • Piperi C.
        • et al.
        Inflammatory and endothelial markers in women with polycystic ovary syndrome.
        Eur J Clin Invest. 2006; 36: 691-697
        • Chirkov Y.Y.
        • Holmes A.S.
        • Chirkova L.P.
        • Horowitz J.D.
        Nitrate resistance in platelets from patients with stable angina pectoris.
        Circulation. 1999; 100: 129-134
        • Willoughby S.R.
        • Rajendran S.
        • Chan W.P.
        • et al.
        Ramipril sensitizes platelets to nitric oxide: implications for therapy in high-risk patients.
        J Am Coll Cardiol. 2012; 60: 887-894
        • Castelli W.P.
        Epidemiology of coronary heart disease: the Framingham study.
        Am J Med. 1984; 76: 4-12
        • Heutling D.
        • Schulz H.
        • Nickel I.
        • et al.
        Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment.
        J Clin Endocrinol Metab. 2008; 93: 82-90