Research Article| Volume 60, ISSUE 2, P180-185, February 2011

Serum concentrations of high–molecular weight adiponectin and their association with sex steroids in premenopausal women

Published:January 25, 2010DOI:


      At present, the association between adiponectin and sex hormones in women is controversial. Recent studies suggest that it is high–molecular weight (HMW) adiponectin and the HMW to total adiponectin ratio rather than total adiponectin that are associated with antiatherogenic activities, insulin sensitivity, metabolic syndrome, and prediction of cardiovascular events. The present study aimed to investigate whether measuring HMW adiponectin and the HMW to total adiponectin ratio rather than total adiponectin might be more useful to detect an association between circulating female sex steroids and adipocytokines. In a clinical trial, we investigated the associations of total adiponectin, HMW adiponectin, and the HMW to adiponectin ratio with several androgens and estradiol in 36 healthy premenopausal women with regular cycles. No association between the investigated sex hormones and adiponectin was observed. The HMW adiponectin was negatively correlated with estradiol after adjustment for age and body mass index. The HMW to total adiponectin ratio was significantly negatively associated with testosterone, free testosterone, and androstenedione. The testosterone to estradiol ratio, as a parameter for the estrogen-androgen balance, was not associated with adiponectin or the HMW isoform. In conclusion, there is a negative association between estradiol and HMW adiponectin, and between testosterone, free testosterone, and androstenedione and the HMW to adiponectin ratio. Thus, one mechanism whereby female sex steroids may influence the cardiovascular risk of women could be alteration of the relationship between HMW and total adiponectin concentrations in plasma.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Nishida M.
        • Funahashi T.
        • Shimomura I.
        Pathophysiological significance of adiponectin.
        Med Mol Morphol. 2007; 40: 55-67
        • Scherer P.E.
        • Williams S.
        • Fogliano M.
        • et al.
        A novel serum protein similar to C1q, produced exclusively in adipocytes.
        J Biol Chem. 1995; 270: 26746-26749
        • Motoshima H.
        • Wu X.
        • Mahadev K.
        • et al.
        Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL.
        Biochem Biophys Res Commun. 2004; 315: 264-271
        • Berg A.H.
        • Combs T.P.
        • Du X.
        • et al.
        The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
        Nat Med. 2001; 7: 947-953
        • Hotta K.
        • Funahashi T.
        • Arita Y.
        • et al.
        Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1595-1599
        • Weyer C.
        • Funahashi T.
        • Tanaka S.
        • et al.
        Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.
        J Clin Endocrinol Metab. 2001; 86: 1930-1935
        • Arita Y.
        • Kihara S.
        • Ouchi N.
        • et al.
        Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
        Biochem Biophys Res Commun. 1999; 257: 79-83
        • Shimabukuro M.
        • Higa N.
        • Asahi T.
        • et al.
        Hypoadiponectinemia is closely linked to endothelial dysfunction in man.
        J Clin Endocrinol Metab. 2003; 88: 3236-3240
        • Kumada M.
        • Kihara S.
        • Sumitsuji S.
        • et al.
        Association of hypoadiponectinemia with coronary artery disease in men.
        Arterioscler Thromb Vasc Biol. 2003; 23: 85-89
        • Cnop M.
        • Havel P.J.
        • Utzschneider K.M.
        • et al.
        Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.
        Diabetologia. 2003; 46: 459-469
        • Pajvani U.B.
        • Du X.
        • Combs T.P.
        • et al.
        Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity.
        J Biol Chem. 2003; 278: 9073-9085
        • Pajvani U.B.
        • Hawkins M.
        • Combs T.P.
        • et al.
        Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.
        J Biol Chem. 2004; 279: 12152-12162
        • Nakano Y.
        • Tajima S.
        • Yoshimi A.
        • et al.
        A novel enzyme-linked immunosorbent assay specific for high–molecular-weight adiponectin.
        J Lipid Res. 2006; 47: 1572-1582
        • Kobayashi H.
        • Ouchi N.
        • Kihara S.
        • et al.
        Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.
        Circ Res. 2004; 94: e27-e31
        • Bobbert T.
        • Rochlitz H.
        • Wegewitz U.
        • et al.
        Changes of adiponectin oligomer composition by moderate weight reduction.
        Diabetes. 2005; 54: 2712-2719
        • Aso Y.
        • Yamamoto R.
        • Wakabayashi S.
        • et al.
        Comparison of serum high–molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin.
        Diabetes. 2006; 55: 1954-1960
        • Hara K.
        • Horikoshi M.
        • Yamauchi T.
        • et al.
        Measurement of the high–molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome.
        Diabetes Care. 2006; 29: 1357-1362
        • von Eynatten M.
        • Humpert P.M.
        • Bluemm A.
        • et al.
        High–molecular weight adiponectin is independently associated with the extent of coronary artery disease in men.
        Atherosclerosis. 2008; 199: 123-128
        • Degawa-Yamauchi M.
        • Moss K.A.
        • Bovenkerk J.E.
        • et al.
        Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor alpha.
        Obes Res. 2005; 13: 662-669
        • Bottner A.
        • Kratzsch J.
        • Muller G.
        • et al.
        Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels.
        J Clin Endocrinol Metab. 2004; 89: 4053-4061
        • Martos-Moreno G.A.
        • Barrios V.
        • Argente J.
        Normative data for adiponectin, resistin, interleukin 6, and leptin/receptor ratio in a healthy Spanish pediatric population: relationship with sex steroids.
        Eur J Endocrinol. 2006; 155: 429-434
        • Tabara Y.
        • Osawa H.
        • Kawamoto R.
        • et al.
        Reduced high–molecular-weight adiponectin and elevated high-sensitivity C-reactive protein are synergistic risk factors for metabolic syndrome in a large-scale middle-aged to elderly population: the Shimanami Health Promoting Program Study.
        J Clin Endocrinol Metab. 2008; 93: 715-722
        • Tamakoshi K.
        • Yatsuya H.
        • Wada K.
        • et al.
        The transition to menopause reinforces adiponectin production and its contribution to improvement of insulin-resistant state.
        Clin Endocrinol (Oxf). 2007; 66: 65-71
        • Laughlin G.A.
        • Barrett-Connor E.
        • May S.
        Sex-specific association of the androgen to oestrogen ratio with adipocytokine levels in older adults: the Rancho Bernardo Study.
        Clin Endocrinol (Oxf). 2006; 65: 506-513
        • Leung K.C.
        • Xu A.
        • Craig M.E.
        • et al.
        Adiponectin isoform distribution in women–relationship to female sex steroids and insulin sensitivity.
        Metabolism. 2009; 58: 239-245
        • Gavrila A.
        • Chan J.L.
        • Yiannakouris N.
        • et al.
        Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies.
        J Clin Endocrinol Metab. 2003; 88: 4823-4831
        • Kunnari A.
        • Santaniemi M.
        • Jokela M.
        • et al.
        Estrogen replacement therapy decreases plasma adiponectin but not resistin in postmenopausal women.
        Metabolism. 2008; 57: 1509-1515
        • Chalvatzas N.
        • Dafopoulos K.
        • Kosmas G.
        • et al.
        Effect of ovarian hormones on serum adiponectin and resistin concentrations.
        Fertil Steril. 2009; 91: 1189-1194
        • Dafopoulos K.
        • Sourlas D.
        • Kallitsaris A.
        • et al.
        Blood ghrelin, resistin, and adiponectin concentrations during the normal menstrual cycle.
        Fertil Steril. 2008; 92: 1389-1394
        • Kleiblova P.
        • Springer D.
        • Haluzik M.
        The influence of hormonal changes during menstrual cycle on serum adiponectin concentrations in healthy women.
        Physiol Res. 2006; 55: 661-666
        • Nishizawa H.
        • Shimomura I.
        • Kishida K.
        • et al.
        Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein.
        Diabetes. 2002; 51: 2734-2741
        • Hong S.C.
        • Yoo S.W.
        • Cho G.J.
        • et al.
        Correlation between estrogens and serum adipocytokines in premenopausal and postmenopausal women.
        Menopause. 2007; 14: 835-840
        • Waki H.
        • Yamauchi T.
        • Kamon J.
        • et al.
        Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.
        J Biol Chem. 2003; 278: 40352-40363
        • Chu M.C.
        • Cosper P.
        • Nakhuda G.S.
        • et al.
        A comparison of oral and transdermal short-term estrogen therapy in postmenopausal women with metabolic syndrome.
        Fertil Steril. 2006; 86: 1669-1675
        • Tworoger S.S.
        • Mantzoros C.
        • Hankinson S.E.
        Relationship of plasma adiponectin with sex hormone and insulin-like growth factor levels.
        Obesity (Silver Spring). 2007; 15: 2217-2224
        • Escobar-Morreale H.F.
        • Villuendas G.
        • Botella-Carretero J.I.
        • et al.
        Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study.
        Hum Reprod. 2006; 21: 2257-2265
        • Nishida M.
        • Moriyama T.
        • Ishii K.
        • et al.
        Effects of IL-6, adiponectin, CRP and metabolic syndrome on subclinical atherosclerosis.
        Clin Chim Acta. 2007; 384: 99-104
        • Kern P.A.
        • Di Gregorio G.B.
        • Lu T.
        • et al.
        Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor–alpha expression.
        Diabetes. 2003; 52: 1779-1785
        • Zhang Y.
        • Nadeau M.
        • Faucher F.
        • et al.
        Progesterone metabolism in adipose cells.
        Mol Cell Endocrinol. 2009; 298: 76-83
        • Lanfranco F.
        • Zitzmann M.
        • Simoni M.
        • et al.
        Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy.
        Clin Endocrinol (Oxf). 2004; 60: 500-507
        • Page S.T.
        • Herbst K.L.
        • Amory J.K.
        • et al.
        Testosterone administration suppresses adiponectin levels in men.
        J Androl. 2005; 26: 85-92
        • Kapoor D.
        • Clarke S.
        • Stanworth R.
        • et al.
        The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.
        Eur J Endocrinol. 2007; 156: 595-602
        • Luque-Ramirez M.
        • Alvarez-Blasco F.
        • Escobar-Morreale H.F.
        Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients.
        Obesity (Silver Spring). 2009; 17: 3-9
        • Dieudonne M.N.
        • Pecquery R.
        • Boumediene A.
        • et al.
        Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids.
        Am J Physiol. 1998; 274: C1645-1652
        • Horenburg S.
        • Fischer-Posovszky P.
        • Debatin K.M.
        • et al.
        Influence of sex hormones on adiponectin expression in human adipocytes.
        Horm Metab Res. 2008; 40: 779-786
        • Gui Y.
        • Silha J.V.
        • Murphy L.J.
        Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse.
        Obes Res. 2004; 12: 1481-1491
        • Xu A.
        • Chan K.W.
        • Hoo R.L.
        • et al.
        Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes.
        J Biol Chem. 2005; 280: 18073-18080
        • Pinhas-Hamiel O.
        • Singer S.
        • Pilpel N.
        • et al.
        Adiponectin levels in adolescent girls with polycystic ovary syndrome.
        Clin Endocrinol (Oxf). 2009; 71: 823-827
        • Hernandez-Morante J.J.
        • Milagro F.
        • Gabaldon J.A.
        • et al.
        Effect of DHEA-sulfate on adiponectin gene expression in adipose tissue from different fat depots in morbidly obese humans.
        Eur J Endocrinol. 2006; 155: 593-600
        • Perez-de-Heredia F.
        • Sanchez J.
        • Priego T.
        • et al.
        Adiponectin is involved in the protective effect of DHEA against metabolic risk in aged rats.
        Steroids. 2008; 73: 1128-1136
        • Poretsky L.
        • Song L.
        • Brillon D.J.
        • et al.
        Metabolic and hormonal effects of oral DHEA in premenopausal women with HIV infection: a randomized, prospective, placebo-controlled pilot study.
        Horm Metab Res. 2009; 41: 244-249
        • Stanczyk F.Z.
        Measurement of androgens in women.
        Semin Reprod Med. 2006; 24: 78-85