Adipocytokines, Sex Hormones, and Cardiovascular Risk Factors in Postmenopausal Women: Factor Analysis of the Rancho Bernardo Study

Abstract

Steroid sex hormones modulate the expression of adipocytokines implicated in the pathogenesis of athero-thrombotic cardiovascular disease. We used exploratory factor analysis to search for latent associations between circulating sex steroid hormones, adipocytokines, and cardiovascular risk factors in a well-characterized cohort of postmenopausal women. Among participants in the Rancho Bernardo community study we identified 515 Caucasian women with a mean age of 74±8 years and mean body mass index of 24.2±3.7 kg/m². All had intact ovaries and none was using estrogen therapy. We constructed models aiming for structural clarity and high loading of variables on individual factors. Total adiponectin loaded with major lipid subfractions (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and fasting triglycerides) and with sex hormone-binding globulin. Leptin loaded with central obesity (waist circumference) and fasting insulin levels. Neither adipocytokine loaded with total or bioavailable testosterone or with estradiol or dehydroepiandrosterone sulfate. Sex hormones consistently loaded together on a separate factor; this co-segregation was not influenced by body mass index. Exclusion of women with diabetes did not alter these observations. In conclusion, we identified evidence of latent associations between adipocytokines and a range of cardiovascular risk factors in postmenopausal women. Our results suggest that cardiovascular risk in older women may be modulated through a hitherto unrecognized association between adiponectin, lipid subfractions, and sex hormone bioavailability.

Key words

adiponectin - leptin - menopause - androgens - insulin - cardiovascular disease

References

• 1 Ren J. Leptin and hyperleptinemia – from friend to foe for cardiovascular function.  J Endocrinol. 2004;  181 1-10
• 2 Jacobs HS, Conway GS. Leptin, polycystic ovaries and polycystic ovary syndrome.  Hum Reprod Update. 1999;  5 166-171
• 3 Orio Jr F, Palomba S, Cascella T, Milan G, Mioni R, Pagano C, Zullo F, Colao A, Lombardi G, Vettor R. Adiponectin levels in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2003;  88 2619-2623
• 4 Rathmann W, Herder C. Adiponectin and cardiovascular mortality: evidence for “reverse epidemiology”.  Horm Metab Res. 2007;  39 1-2
• 5 Dekker JM, Funahashi T, Nijpels G, Pilz S, Stehouwer DC, Snijder MB, Bouter LM, Matsuzawa Y, Shimomura I, Heine RJ. Prognostic value of adiponectin for cardiovascular disease and mortality.  J Clin Endocrinol Metab. 2008;  93 1489-1496
• 6 Kizer JR, Barzilay JI, Kuller LH, Gottdiener JS. Adiponectin and risk of coronary heart disease in older men and women.  J Clin Endocrinol Metab. 2008;  93 3357-3364
• 7 Spranger J, Möhlig M, Wegewitz U, Ristow M, Pfeiffer AF, Schill T, Schlösser HW, Brabant G, Schöfl C. Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome.  Clin Endocrinol (Oxf). 2004;  61 738-746
• 8 Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome.  Clin Endocrinol (Oxf). 2004;  60 1-17
• 9 Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association?.  Endocr Rev. 2003;  24 302-312
• 10 Wu FC, von Eckardstein A. Androgens and coronary artery disease.  Endocr Rev. 2003;  24 183-217
• 11 Arnal JF, Bayard F. Vasculoprotective effects of oestrogens.  Clin Exp Pharmacol Physiol. 2001;  28 1032-1034
• 12 Krentz AJ, 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
• 13 Rosner W. A simplified method for the quantitative determination of testosterone-estradiol-binding globulin activity in human plasma.  J Clin Endocrinol Metab. 1972;  34 983-988
• 14 Tremblay RR, Dube JY. Plasma concentrations of free and non-TeBG bound testosterone in women on oral contraceptives.  Contraception. 1974;  10 599-605
• 15 Goodman-Gruen D, Barrett-Connor E. Sex differences in the association of endogenous sex hormone levels and glucose tolerance status in older men and women.  Diabetes Care. 2000;  23 912-918
• 16 Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, Monauni T, Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.  Diabetes Care. 2000;  23 57-63
• 17 Lipid Research Clinics Program (US) . Laboratory Methods Committee. Bethesda, Md.: National Heart and Lung Institute, National Institutes of Health (DHEW Publication No 75-628) 1974
• 18 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.  Clin Chem. 1972;  18 499-502
• 19 Lawlor DA, Ebrahim S, May M, Davey Smith G. (Mis)use of factor analysis in the study of insulin resistance syndrome.  Am J Epidemiol. 2004;  159 1013-1018
• 20 Hajamor S, Despres JP, Couillard C, Lemieux S, Tremblay A, Prud’homme D, Tchernof A. Relationship between sex hormone-binding globulin levels and features of the metabolic syndrome.  Metabolism. 2003;  52 724-730
• 21 Tworoger SS, Mantzoros C, Hankinson SE. Relationship of plasma adiponectin with sex hormone and insulin-like growth factor levels.  Obesity (Silver Spring). 2007;  15 2217-2224
• 22 Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue – an update.  Horm Metab Res. 2007;  39 314-321
• 23 Lara-Castro C, Fu Y, Chung BH, Garvey WT. Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease.  Curr Opin Lipidol. 2007;  18 263-270
• 24 Verges B, Petit JM, Duvillard L, Dautin G, Florentin E, Galland F, Gambert P. Adiponectin is an important determinant of apoA-I catabolism.  Arterioscler Thromb Vasc Biol. 2006;  26 1364-1369
• 25 Sowers JR. Obesity as a cardiovascular risk factor.  Am J Med. 2003;  115 ((Suppl 8A)) 37S-41S
• 26 Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, Matsuda M, Kondo H, Furuyama N, Kihara S, Nakamura T, Tochino Y, Funahashi T, Matsuzawa Y. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein.  Diabetes. 2002;  51 2734-2741
• 27 Casabiell X, Pineiro V, Vega F, De La Cruz LF, Dieguez C, Casanueva FF. Leptin, reproduction and sex steroids.  Pituitary. 2001;  4 93-99
• 28 Leyva F, Godsland IF, Ghatei M, Proudler AJ, Aldis S, Walton C, Bloom S, Stevenson JC. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk.  Arterioscler Thromb Vasc Biol. 1998;  18 928-933
• 29 Ford ES. Factor analysis and defining the metabolic syndrome.  Ethn Dis. 2003;  13 429-437
• 30 Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity.  J Biol Chem. 2003;  278 9073-9085
• 31 Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.  J Biol Chem. 2004;  279 12152-12162

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