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Sex Hormone-Binding Globulin and the Metabolic Syndrome

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Male Hypogonadism

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Sex steroids are implicated in the etiology of the metabolic syndrome (MetS) with different effects in men and women that likely reflect the sex dimorphic balance between circulating testosterone and estradiol levels. In men, low testosterone levels are a major risk factor for the MetS, and testosterone replacement therapy has been proposed as treatment option for associated conditions, i.e., type 2 diabetes and cardiovascular disease. The plasma levels and tissue availability of androgens and estrogens are regulated by sex hormone-binding globulin (SHBG), reduced plasma levels of which are a risk factor for the development of MetS. This chapter reviews the biochemical and molecular properties of SHBG and its role in the regulation of androgen and estrogen action; the molecular mechanisms that control the hepatic production of plasma SHBG, and how these are dysregulated in MetS patients. New information linking genetic mutations that may influence SHBG production or function with the etiology of MS-associated diseases are discussed. The utility of plasma SHBG and free testosterone measurements as biomarkers of MetS risk is also reviewed.

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References

  1. Anderson JL, May HT, Lappe DL, et al. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system. Am J Cardiol. 2016;117(5):794–9.

    Article  CAS  PubMed  Google Scholar 

  2. Corona GG, Rastrelli G, Maseroli E, Sforza A, Maggi M. Testosterone replacement therapy and cardiovascular risk: A review. World J Mens Health. 2015;33(3):130–42.

    Article  Google Scholar 

  3. Dimopoulou C, Ceausu I, Depypere H, et al. EMAS position statement: Testosterone replacement therapy in the aging male. Maturitas. 2016;84:94–9.

    Article  CAS  PubMed  Google Scholar 

  4. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91(3):843–50.

    Article  CAS  PubMed  Google Scholar 

  5. Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol. 2013;9(8):479–93.

    Article  CAS  PubMed  Google Scholar 

  6. Kim C, Halter JB. Endogenous sex hormones, metabolic syndrome, and diabetes in men and women. Curr Cardiol Rep. 2014;16(4):467-014-0467-6.

    Google Scholar 

  7. Antonio L, Wu FC, O’Neill TW, et al. Associations between sex steroids and the development of metabolic syndrome: a longitudinal study in European men. J Clin Endocrinol Metab. 2015;100(4):1396–404.

    Article  CAS  PubMed  Google Scholar 

  8. Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab. 2005;90(5):2618–23.

    Article  CAS  PubMed  Google Scholar 

  9. Faulds MH, Zhao C, Dahlman-Wright K, Gustafsson JA. The diversity of sex steroid action: regulation of metabolism by estrogen signaling. J Endocrinol. 2012;212(1):3–12.

    Article  CAS  PubMed  Google Scholar 

  10. Ohlsson C, Wallaschofski H, Lunetta KL, et al. Genetic determinants of serum testosterone concentrations in men. PLoS Genet. 2011;7(10):e1002313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hammond GL, Wu TS, Simard M. Evolving utility of sex hormone-binding globulin measurements in clinical medicine. Curr Opin Endocrinol Diabetes Obes. 2012;19(3):183–9.

    Article  CAS  PubMed  Google Scholar 

  12. Hammond GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011;85(3):431–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):1036–41.

    Article  CAS  PubMed  Google Scholar 

  14. Bhasin S, Jasjua GK, Pencina M, et al. Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: The Framingham heart study. Diabetes Care. 2011;34(11):2464–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Haffner SM, Valdez RA, Morales PA, Hazuda HP, Stern MP. Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men. J Clin Endocrinol Metab. 1993;77(1):56–60.

    CAS  PubMed  Google Scholar 

  16. Lindstedt G, Lundberg PA, Lapidus L, Lundgren H, Bengtsson C, Bjorntorp P. Low sex-hormone-binding globulin concentration as independent risk factor for development of NIDDM. 12-yr follow-up of population study of women in Gothenburg, Sweden. Diabetes. 1991;40(1):123–8.

    Article  CAS  PubMed  Google Scholar 

  17. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37(6):667–87.

    Article  CAS  PubMed  Google Scholar 

  18. Vikan T, Schirmer H, Njolstad I, Svartberg J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur J Endocrinol. 2010;162(4):747–54.

    Article  CAS  PubMed  Google Scholar 

  19. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295(11):1288–99.

    Article  CAS  PubMed  Google Scholar 

  20. Mather KJ, Kim C, Christophi CA, et al. Steroid sex hormones, sex hormone-binding globulin, and diabetes incidence in the diabetes prevention program. J Clin Endocrinol Metab. 2015;100(10):3778–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu B, Xu Y, Liang JM, et al. Intrauterine insulin resistance in fetuses of overweight mothers. J Obstet Gynaecol Res. 2013;39(1):132–8.

    Article  CAS  PubMed  Google Scholar 

  22. de Oya I, Schoppen S, Lasuncion MA, et al. Sex hormone-binding globulin levels and metabolic syndrome and its features in adolescents. Pediatr Diabetes. 2010;11(3):188–94.

    Article  PubMed  CAS  Google Scholar 

  23. Krishnasamy SS, Chang C, Wang C, Chandiramani R, Winters SJ. Sex hormone-binding globulin and the risk for metabolic syndrome in children of South Asian Indian origin. Endocr Pract. 2012;18(5):668–75.

    Article  PubMed  Google Scholar 

  24. Wang Q, Kangas AJ, Soininen P, et al. Sex hormone-binding globulin associations with circulating lipids and metabolites and the risk for type 2 diabetes: Observational and causal effect estimates. Int J Epidemiol. 2015;44(2):623–37.

    Article  CAS  PubMed  Google Scholar 

  25. Roberts CK, Croymans DM, Aziz N, Butch AW, Lee CC. Resistance training increases SHBG in overweight/obese, young men. Metabolism. 2013;62(5):725–33.

    Article  CAS  PubMed  Google Scholar 

  26. Facchiano E, Scaringi S, Veltri M, et al. Age as a predictive factor of testosterone improvement in male patients after bariatric surgery: Preliminary results of a monocentric prospective study. Obes Surg. 2013;23(2):167–72.

    Article  PubMed  Google Scholar 

  27. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril. 1994;61(4):598–604.

    Article  CAS  PubMed  Google Scholar 

  28. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):58–68.

    Article  CAS  PubMed  Google Scholar 

  29. Anderson DC. Sex-hormone-binding globulin. Clin Endocrinol (Oxf). 1974;3(1):69–96.

    Article  CAS  Google Scholar 

  30. Dewis P, Petsos P, Newman M, Anderson DC. The treatment of hirsutism with a combination of desogestrel and ethinyl oestradiol. Clin Endocrinol (Oxf). 1985;22(1):29–36.

    Article  CAS  Google Scholar 

  31. Nisker JA, Hammond GL, Davidson BJ, et al. Serum sex hormone-binding globulin capacity and the percentage of free estradiol in postmenopausal women with and without endometrial carcinoma. A new biochemical basis for the association between obesity and endometrial carcinoma. Am J Obstet Gynecol. 1980;138(6):637–42.

    Article  CAS  PubMed  Google Scholar 

  32. Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest. 2002;109(7):973–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bartha JL, Comino-Delgado R, Romero-Carmona R, Gomez-Jaen MC. Sex hormone-binding globulin in gestational diabetes. Acta Obstet Gynecol Scand. 2000;79(10):839–45.

    CAS  PubMed  Google Scholar 

  34. Hedderson MM, Ferrara A. Response to comment on Hedderson et al. Prepregnancy SHBG concentrations and risk for subsequently developing gestational diabetes mellitus. Diabetes Care. 2014;37:1296–1303. Diabetes Care. 2014;37(12):e280–1845.

    Google Scholar 

  35. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666–72.

    Article  CAS  PubMed  Google Scholar 

  36. Wu TS, Hammond GL. Naturally occurring mutants inform SHBG structure and function. Mol Endocrinol. 2014;28(7):1026–38.

    Article  PubMed  CAS  Google Scholar 

  37. Baker ME, French FS, Joseph DR. Vitamin K-dependent protein S is similar to rat androgen-binding protein. Biochem J. 1987;243(1):293–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gershagen S, Fernlund P, Edenbrandt CM. The genes for SHBG/ABP and the SHBG-like region of vitamin K-dependent protein S have evolved from a common ancestral gene. J Steroid Biochem Mol Biol. 1991;40(4–6):763–9.

    Article  CAS  PubMed  Google Scholar 

  39. Joseph DR, Baker ME. Sex hormone-binding globulin, androgen-binding protein, and vitamin K-dependent protein S are homologous to laminin A, merosin, and Drosophila crumbs protein. FASEB J. 1992;6(7):2477–81.

    CAS  PubMed  Google Scholar 

  40. Evenas P, Dahlback B, Garcia de Frutos P. The first laminin G-type domain in the SHBG-like region of protein S contains residues essential for activation of the receptor tyrosine kinase sky. Biol Chem. 2000;381(3):199–209.

    Article  CAS  PubMed  Google Scholar 

  41. Miguel-Queralt S, Knowlton M, Avvakumov GV, Al-Nouno R, Kelly GM, Hammond GL. Molecular and functional characterization of sex hormone binding globulin in zebrafish. Endocrinology. 2004;145(11):5221–30.

    Article  CAS  PubMed  Google Scholar 

  42. Miguel-Queralt S, Avvakumov GV, Blazquez M, Piferrer F, Hammond GL. Sea bass (Dicentrarchus labrax) sex hormone binding globulin: molecular and biochemical properties and phylogenetic comparison of its orthologues in multiple fish species. Mol Cell Endocrinol. 2005;229(1–2):21–9.

    Article  CAS  PubMed  Google Scholar 

  43. Beck K, Gruber TM, Ridgway CC, Hughes W, Sui L, Petra PH. Secondary structure and shape of plasma sex steroid-binding protein–comparison with domain G of laminin results in a structural model of plasma sex steroid-binding protein. Eur J Biochem. 1997;247(1):339–47.

    Article  CAS  PubMed  Google Scholar 

  44. Avvakumov GV, Grishkovskaya I, Muller YA, Hammond GL. Crystal structure of human sex hormone-binding globulin in complex with 2-methoxyestradiol reveals the molecular basis for high affinity interactions with C-2 derivatives of estradiol. J Biol Chem. 2002;277:45219–25.

    Article  CAS  PubMed  Google Scholar 

  45. Grishkovskaya I, Avvakumov GV, Sklenar G, Dales D, Hammond GL, Muller YA. Crystal structure of human sex hormone-binding globulin: Steroid transport by a laminin G-like domain. EMBO J. 2000;19(4):504–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YA. Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation. J Biol Chem. 2002;277:32086–93.

    Article  CAS  PubMed  Google Scholar 

  47. Grishkovskaya I, Avvakumov GV, Hammond GL, Muller YA. Resolution of a disordered region at the entrance of the human sex hormone-binding globulin steroid-binding site. J Mol Biol. 2002;318:621–6.

    Article  CAS  PubMed  Google Scholar 

  48. Avvakumov GV, Grishkovskaya I, Muller YA, Hammond GL. Resolution of the human sex hormone-binding globulin dimer interface and evidence for two steroid-binding sites per homodimer. J Biol Chem. 2001;276:34453–7.

    Article  CAS  PubMed  Google Scholar 

  49. Rosner W, Toppel S, Smith RN. Testosterone-estradiol-binding globulin of human plasma: denaturation and protection. Biochim Biophys Acta. 1974;351(1):92–8.

    Article  CAS  PubMed  Google Scholar 

  50. Avvakumov GV, Muller YA, Hammond GL. Steroid-binding specificity of human sex hormone-binding globulin is influenced by occupancy of a zinc-binding site. J Biol Chem. 2000;275:25920–5.

    Article  CAS  PubMed  Google Scholar 

  51. Bocchinfuso WP, Warmels-Rodenhiser S, Hammond GL. Expression and differential glycosylation of human sex hormone-binding globulin by mammalian cell lines. Mol Endocrinol. 1991;5:1723–9.

    Article  CAS  PubMed  Google Scholar 

  52. Power SG, Bocchinfuso WP, Pallesen M, Warmels-Rodenhiser S, Van Baelen H, Hammond GL. Molecular analyses of a human sex hormone-binding globulin variant: evidence for an additional carbohydrate chain. J Clin Endocrinol Metab. 1992;75(4):1066–70.

    CAS  PubMed  Google Scholar 

  53. Strel’chyonok OA, Avvakumov GV, Survilo LI. A recognition system for sex-hormone-binding protein-estradiol complex in human decidual endometrium plasma membranes. Biochim Biophys Acta. 1984;802(3):459–66.

    Article  PubMed  Google Scholar 

  54. Khan MS, Hryb DJ, Hashim GA, Romas NA, Rosner W. Delineation and synthesis of the membrane receptor-binding domain of sex hormone-binding globulin. J Biol Chem. 1990;265(30):18362–5.

    CAS  PubMed  Google Scholar 

  55. Rosner W. The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev. 1990;11(1):80–91.

    Article  CAS  PubMed  Google Scholar 

  56. Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA. Interactions of sex hormone-binding globulin with target cells. Mol Cell Endocrinol. 2010;316(1):79–85.

    Article  CAS  PubMed  Google Scholar 

  57. Porto CS, Gunsalus GL, Bardin CW, Phillips DM, Musto NA. Receptor-mediated endocytosis of an extracellular steroid-binding protein (TeBG) in MCF-7 human breast cancer cells. Endocrinology. 1991;129(1):436–45.

    Article  CAS  PubMed  Google Scholar 

  58. Hammes A, Andreassen TK, Spoelgen R, et al. Role of endocytosis in cellular uptake of sex steroids. Cell. 2005;122:751–62.

    Article  CAS  PubMed  Google Scholar 

  59. Ng KM, Catalano MG, Pinos T, et al. Evidence that fibulin family members contribute to the steroid-dependent extravascular sequestration of sex hormone-binding globulin. J Biol Chem. 2006;281(23):15853–61.

    Article  CAS  PubMed  Google Scholar 

  60. Berube D, Seralini GE, Gagne R, Hammond GL. Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12—p13). Cytogenet Cell Genet. 1990;54(1–2):65–7.

    CAS  PubMed  Google Scholar 

  61. Hammond GL, Underhill DA, Rykse HM, Smith CL. The human sex hormone-binding globulin gene contains exons for androgen-binding protein and two other testicular messenger RNAs. Mol Endocrinol. 1989;3:1869–76.

    Article  CAS  PubMed  Google Scholar 

  62. Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM. Human sex hormone-binding globulin gene expression—multiple promoters and complex alternative splicing. BMC Mol Biol. 2009;10:37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Pinos T, Barbosa-Desongles A, Hurtado A, et al. Identification, characterization and expression of novel sex hormone binding globulin alternative first exons in the human prostate. BMC Mol Biol. 2009;10:59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Selva DM, Hogeveen KN, Hammond GL. Repression of the human sex hormone-binding globulin gene in Sertoli cells by upstream stimulatory transcription factors. J Biol Chem. 2005;280(6):4462–8.

    Article  CAS  PubMed  Google Scholar 

  65. Selva DM, Bassas L, Munell F, et al. Human sperm sex hormone-binding globulin isoform: characterization and measurement by time-resolved fluorescence immunoassay. J Clin Endocrinol Metab. 2005;90(11):6275–82.

    Article  CAS  PubMed  Google Scholar 

  66. Joseph DR. Structure, function, and regulation of androgen-binding protein/sex hormone-binding globulin. Vitam Horm. 1994;49:197–280.

    Article  CAS  PubMed  Google Scholar 

  67. Hammond GL, Langley MS, Robinson PA. A liquid-phase immunoradiometric assay (IRMA) for human sex hormone binding globulin (SHBG). J Steroid Biochem. 1985;23(4):451–60.

    Article  CAS  PubMed  Google Scholar 

  68. Jänne M, Deol HK, Power SG, Yee SP, Hammond GL. Human sex hormone-binding globulin gene expression in transgenic mice. Mol Endocrinol. 1998;12(1):123–36.

    Article  PubMed  Google Scholar 

  69. Hong EJ, Sahu B, Janne OA, Hammond GL. Cytoplasmic accumulation of incompletely glycosylated SHBG enhances androgen action in proximal tubule epithelial cells. Mol Endocrinol. 2011;25(2):269–81.

    Article  CAS  PubMed  Google Scholar 

  70. Leinonen P, Hammond GL, Lukkarinen O, Vihko R. Serum sex hormone binding globulin and testosterone binding after estradiol administration, castration, and their combination in men with prostatic carcinoma. Invest Urol. 1979;17(1):24–7.

    CAS  PubMed  Google Scholar 

  71. Cunningham SK, Loughlin T, Culliton M, McKenna TJ. The relationship between sex steroids and sex-hormone-binding globulin in plasma in physiological and pathological conditions. Ann Clin Biochem. 1985;22 (Pt 5)(Pt 5):489–97.

    Google Scholar 

  72. Belgorosky A, Rivarola MA. Progressive decrease in serum sex hormone-binding globulin from infancy to late prepuberty in boys. J Clin Endocrinol Metab. 1986;63(2):510–2.

    Article  CAS  PubMed  Google Scholar 

  73. Belgorosky A, Rivarola MA. Changes in serum sex hormone-binding globulin and in serum non-sex hormone-binding globulin-bound testosterone during prepuberty in boys. J Steroid Biochem. 1987;27(1–3):291–5.

    Article  CAS  PubMed  Google Scholar 

  74. Ibanez L, Potau N, Dunger D, de Zegher F. Precocious pubarche in girls and the development of androgen excess. J Pediatr Endocrinol Metab. 2000;13(Suppl 5):1261–3.

    PubMed  Google Scholar 

  75. Pugeat M, Cousin P, Baret C, Lejeune H, Forest MG. Sex hormone-binding globulin during puberty in normal and hyperandrogenic girls. J Pediatr Endocrinol Metab. 2000;13(Suppl 5):1277–9.

    PubMed  Google Scholar 

  76. Aydin B, Winters SJ. Sex Hormone Binding Globulin in Children and Adolescents. J Clin Res Pediatr Endocrinol. 2015;8(1):1–12.

    Google Scholar 

  77. Vermeulen A, Kaufman JM, Giagulli VA. Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab. 1996;81(5):1821–6.

    CAS  PubMed  Google Scholar 

  78. Stomati M, Hartmann B, Spinetti A, et al. Effects of hormonal replacement therapy on plasma sex hormone-binding globulin, androgen and insulin-like growth factor-1 levels in postmenopausal women. J Endocrinol Invest. 1996;19(8):535–41.

    Article  CAS  PubMed  Google Scholar 

  79. Goto A, Chen BH, Song Y, et al. Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women. Clin Chem. 2014;60(1):174–85.

    Article  CAS  PubMed  Google Scholar 

  80. Karim R, Stanczyk FZ, Brinton RD, Rettberg J, Hodis HN, Mack WJ. Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab. 2015;100(2):508–15.

    Article  CAS  PubMed  Google Scholar 

  81. Brenta G, Schnitman M, Gurfinkiel M, et al. Variations of sex hormone-binding globulin in thyroid dysfunction. Thyroid. 1999;9(3):273–7.

    Article  CAS  PubMed  Google Scholar 

  82. Wang N, Zhai H, Zhu C, et al. Combined association of vitamin D and sex hormone binding globulin with nonalcoholic fatty liver disease in men and postmenopausal women: A cross-sectional study. Medicine (Baltimore). 2016;95(4):e2621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Glass AR, Swerdloff RS, Bray GA, Dahms WT, Atkinson RL. Low serum testosterone and sex-hormone-binding-globulin in massively obese men. J Clin Endocrinol Metab. 1977;45(6):1211–9.

    Article  CAS  PubMed  Google Scholar 

  84. Estour B, Pugeat M, Lang F, Dechaud H, Pellet J, Rousset H. Sex hormone binding globulin in women with anorexia nervosa. Clin Endocrinol (Oxf). 1986;24(5):571–6.

    Article  CAS  PubMed  Google Scholar 

  85. Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab. 1988;67(3):460–4.

    Article  CAS  PubMed  Google Scholar 

  86. Holly JM, Dunger DB, Al-Othman SA, Savage MO, Wass JA. Sex hormone binding globulin levels in adolescent subjects with diabetes mellitus. Diabet Med. 1992;9(4):371–4.

    Google Scholar 

  87. Daka B, Rosen T, Jansson PA, Rastam L, Larsson CA, Lindblad U. Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden. Endocr Connect. 2012;2(1):18–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest. 2007;117(12):3979–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Weinberg ME, Manson JE, Buring JE, et al. Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women. Metabolism. 2006;55(11):1473–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Janne M, Hammond GL. Hepatocyte nuclear factor-4 controls transcription from a TATA-less human sex hormone-binding globulin gene promoter. J Biol Chem. 1998;273(51):34105–14.

    Article  CAS  PubMed  Google Scholar 

  91. Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384(6608):458–60.

    Article  CAS  PubMed  Google Scholar 

  92. Fang B, Mane-Padros D, Bolotin E, Jiang T, Sladek FM. Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors. Nucleic Acids Res. 2012;40(12):5343–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Winters SJ, Gogineni J, Karegar M, et al. Sex hormone-binding globulin gene expression and insulin resistance. J Clin Endocrinol Metab. 2014;99(12):E2780–8.

    Article  CAS  PubMed  Google Scholar 

  94. Hertz R, Magenheim J, Berman I, Bar-Tana J. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature. 1998;392(6675):512–6.

    Article  CAS  PubMed  Google Scholar 

  95. Dhe-Paganon S, Duda K, Iwamoto M, Chi YI, Shoelson SE. Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand. J Biol Chem. 2002;277(41):37973–6.

    Article  CAS  PubMed  Google Scholar 

  96. Wisely GB, Miller AB, Davis RG, et al. Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. Structure. 2002;10(9):1225–34.

    Article  CAS  PubMed  Google Scholar 

  97. Petrescu AD, Hertz R, Bar-Tana J, Schroeder F, Kier AB. Ligand specificity and conformational dependence of the hepatic nuclear factor-4alpha (HNF-4alpha). J Biol Chem. 2002;277(27):23988–99.

    Article  CAS  PubMed  Google Scholar 

  98. Sladek FM. What are nuclear receptor ligands? Mol Cell Endocrinol. 2011;334(1–2):3–13.

    Article  CAS  PubMed  Google Scholar 

  99. Nayeem F, Nagamani M, Anderson KE, Huang Y, Grady JJ, Lu LJ. Dietary beta-tocopherol and linoleic acid, serum insulin, and waist circumference predict circulating sex hormone-binding globulin in premenopausal women. J Nutr. 2009;139(6):1135–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Delarue J, Magnan C. Free fatty acids and insulin resistance. Curr Opin Clin Nutr Metab Care. 2007;10(2):142–8.

    Article  CAS  PubMed  Google Scholar 

  101. Selva DM, Hammond GL. Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha. J Mol Endocrinol. 2009;43(1):19–27.

    Article  CAS  PubMed  Google Scholar 

  102. Peter A, Kantartzis K, Machann J, et al. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes. 2010;59(12):3167–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shin JY, Kim SK, Lee MY, et al. Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes. Diabetes Res Clin Pract. 2011;94(1):156–62.

    Article  CAS  PubMed  Google Scholar 

  104. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Simo R, Barbosa-Desongles A, Lecube A, Hernandez C, Selva DM. Potential role of tumor necrosis factor-alpha in downregulating sex hormone-binding globulin. Diabetes. 2012;61(2):372–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Simo R, Barbosa-Desongles A, Hernandez C, Selva DM. IL1beta down-regulation of sex hormone-binding globulin production by decreasing HNF-4alpha via MEK-1/2 and JNK MAPK pathways. Mol Endocrinol. 2012;26(11):1917–27.

    Article  CAS  PubMed  Google Scholar 

  108. Simo R, Saez-Lopez C, Lecube A, Hernandez C, Fort JM, Selva DM. Adiponectin upregulates SHBG production: molecular mechanisms and potential implications. Endocrinology. 2014;155(8):2820–30.

    Article  PubMed  CAS  Google Scholar 

  109. Selva DM, Hammond GL. Peroxisome-proliferator receptor gamma represses hepatic sex hormone-binding globulin expression. Endocrinology. 2009;150(5):2183–9.

    Article  CAS  PubMed  Google Scholar 

  110. Mousavinasab F, Tahtinen T, Jokelainen J, et al. The Pro12Ala polymorphism of the PPAR gamma 2 gene influences sex hormone-binding globulin level and its relationship to the development of the metabolic syndrome in young Finnish men. Endocrine. 2006;30(2):185–90.

    Article  CAS  PubMed  Google Scholar 

  111. Regieli JJ, Jukema JW, Doevendans PA, et al. PPAR gamma variant influences angiographic outcome and 10-year cardiovascular risk in male symptomatic coronary artery disease patients. Diabetes Care. 2009;32(5):839–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sridhar S, Walia R, Sachdeva N, Bhansali A. Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: A randomized double-blind placebo-controlled study. Clin Endocrinol (Oxf). 2013;78(3):454–9.

    Article  CAS  Google Scholar 

  113. Meikle AW, Stanish WM, Taylor N, Edwards CQ, Bishop CT. Familial effects on plasma sex-steroid content in man: Testosterone, estradiol and sex-hormone-binding globulin. Metabolism. 1982;31(1):6–9.

    Article  CAS  PubMed  Google Scholar 

  114. Gershagen S, Lundwall A, Fernlund P. Characterization of the human sex hormone binding globulin (SHBG) gene and demonstration of two transcripts in both liver and testis. Nucleic Acids Res. 1989;17:9245–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gershagen S, Henningsson K, Fernlund P. Subunits of human sex hormone binding globulin. Interindividual variation in size. J Biol Chem. 1987;262:8430–7.

    CAS  PubMed  Google Scholar 

  116. Cousin P, Dechaud H, Grenot C, Lejeune H, Pugeat M. Human variant sex hormone-binding globulin (SHBG) with an additional carbohydrate chain has a reduced clearance rate in rabbit. J Clin Endocrinol Metab. 1998;83(1):235–40.

    CAS  PubMed  Google Scholar 

  117. Ding EL, Song Y, Manson JE, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361:1152–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Pang XN, Yuan Y, Sun Y, Shen JP, Zha XY, Hu Y. The relationship of sex hormone-binding globulin (SHBG) gene polymorphisms with serum SHBG level and metabolic syndrome in Chinese Han males. Aging Clin Exp Res. 2014;26(6):583–9.

    Article  PubMed  Google Scholar 

  119. Hogeveen KN, Talikka M, Hammond GL. Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA) n repeat element within an Alu sequence. J Biol Chem. 2001;276(39):36383–90.

    Article  CAS  PubMed  Google Scholar 

  120. Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences. Mol Cell Endocrinol. 2010;316(1):60–5.

    Article  CAS  PubMed  Google Scholar 

  121. Xita N, Milionis HJ, Galidi A, et al. The (TAAAA) n polymorphism of the SHBG gene in men with the metabolic syndrome. Exp Clin Endocrinol Diabetes. 2011;119(2):126–8.

    Article  CAS  PubMed  Google Scholar 

  122. Xita N, Tsatsoulis A, Chatzikyriakidou A, Georgiou I. Association of the (TAAAA) n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels. J Clin Endocrinol Metab. 2003;88(12):5976–80.

    Article  CAS  PubMed  Google Scholar 

  123. Perry JR, Weedon MN, Langenberg C, et al. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet. 2010;19(3):535–44.

    Article  CAS  PubMed  Google Scholar 

  124. Riancho JA, Valero C, Zarrabeitia MT, Garcia-Unzueta MT, Amado JA, Gonzalez-Macias J. Genetic polymorphisms are associated with serum levels of sex hormone binding globulin in postmenopausal women. BMC Med Genet. 2008;9:112-2350-9-112.

    Google Scholar 

  125. Wickham EP,3rd, Ewens KG, Legro RS, Dunaif A, Nestler JE, Strauss JF,3rd. Polymorphisms in the SHBG gene influence serum SHBG levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2011;96(4):E719–27.

    Google Scholar 

  126. White MJ, Eren F, Agirbasli D, Williams SM, Agirbasli M. SHBG gene polymorphism (rs1799941) associates with metabolic syndrome in children and adolescents. PLoS ONE. 2015;10(2):e0116915.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Eriksson AL, Lorentzon M, Mellstrom D, et al. SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density. J Clin Endocrinol Metab. 2006;91:5029–37.

    Article  CAS  PubMed  Google Scholar 

  128. Jin G, Sun J, Kim ST, et al. Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men. Hum Mol Genet. 2012;21(23):5222–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Thompson DJ, Healey CS, Baynes C, et al. Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3490–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Vos MJ, Mijnhout GS, Rondeel JM, Baron W, Groeneveld PH. Sex hormone binding globulin deficiency due to a homozygous missense mutation. J Clin Endocrinol Metab. 2014;99(9):E1798–802.

    Article  CAS  PubMed  Google Scholar 

  131. Chen C, Smothers J, Lange A, Nestler JE, Strauss Iii JF, Wickham Iii EP. Sex hormone-binding globulin genetic variation: associations with type 2 diabetes mellitus and polycystic ovary syndrome. Minerva Endocrinol. 2010;35(4):271–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sarne DH, Refetoff S, Rosenfield RL, Farriaux JP. Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration. J Clin Endocrinol Metab. 1988;66(4):740–6.

    Article  CAS  PubMed  Google Scholar 

  133. Legrand E, Hedde C, Gallois Y, et al. Osteoporosis in men: a potential role for the sex hormone binding globulin. Bone. 2001;29(1):90–5.

    Article  CAS  PubMed  Google Scholar 

  134. Varsavsky M, Reyes-Garcia R, Garcia-Martin A, Gonzalez-Ramirez AR, Aviles-Perez MD, Munoz-Torres M. SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporos Int. 2013;24(2):713–9.

    Article  CAS  PubMed  Google Scholar 

  135. Vanderschueren D, Laurent MR, Claessens F, et al. Sex steroid actions in male bone. Endocr Rev. 2014;35(6):906–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zha XY, Hu Y, Pang XN, Zhu JH, Chang GL, Li L. The association between sex hormone-binding globulin gene polymorphism with bone mineral density. Steroids. 2016;106:9–18.

    Article  CAS  PubMed  Google Scholar 

  137. Rodriguez A, Muller DC, Metter EJ, et al. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab. 2007;92(9):3568–72.

    Article  CAS  PubMed  Google Scholar 

  138. Li C, Ford ES, Li B, Giles WH, Liu S. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care. 2010;33(7):1618–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Andersson B, Marin P, Lissner L, Vermeulen A, Bjorntorp P. Testosterone concentrations in women and men with NIDDM. Diabetes Care. 1994;17(5):405–11.

    Article  CAS  PubMed  Google Scholar 

  140. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000;23(4):490–4.

    Article  CAS  PubMed  Google Scholar 

  141. Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2011;40(1):189–207.

    Article  PubMed  Google Scholar 

  142. Haring R, Volzke H, Felix SB, et al. Prediction of metabolic syndrome by low serum testosterone levels in men: Results from the study of health in Pomerania. Diabetes. 2009;58(9):2027–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wallace IR, McKinley MC, Bell PM, Hunter SJ. Sex hormone binding globulin and insulin resistance. Clin Endocrinol (Oxf). 2013;78(3):321–9.

    Article  CAS  Google Scholar 

  144. Niskanen L, Laaksonen DE, Punnonen K, Mustajoki P, Kaukua J, Rissanen A. Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome. Diabetes Obes Metab. 2004;6(3):208–15.

    Article  CAS  PubMed  Google Scholar 

  145. Muraleedharan V, Jones TH. Testosterone and the metabolic syndrome. Ther Adv Endocrinol Metab. 2010;1(5):207–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Antonio L, Wu FC, O’Neill TW, et al. Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone. J Clin Endocrinol Metab. 2016:jc20154106.

    Google Scholar 

  147. Hammond GL, Nisker JA, Jones LA, Siiteri PK. Estimation of the percentage of free steroid in undiluted serum by centrifugal ultrafiltration-dialysis. J Biol Chem. 1980;255(11):5023–6.

    CAS  PubMed  Google Scholar 

  148. Hammoud A, Gibson M, Hunt SC, et al. Effect of Roux-en-Y gastric bypass surgery on the sex steroids and quality of life in obese men. J Clin Endocrinol Metab. 2009;94(4):1329–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22(12):1835–42.

    Article  PubMed  Google Scholar 

  150. Mora M, Aranda GB, de Hollanda A, Flores L, Puig-Domingo M, Vidal J. Weight loss is a major contributor to improved sexual function after bariatric surgery. Surg Endosc. 2013;27(9):3197–204.

    Article  PubMed  Google Scholar 

  151. Calderon B, Galdon A, Calanas A, et al. Effects of bariatric surgery on male obesity-associated secondary hypogonadism: comparison of laparoscopic gastric bypass with restrictive procedures. Obes Surg. 2014;24(10):1686–92.

    Article  PubMed  Google Scholar 

  152. Mihalca R, Copaescu C, Sirbu A, et al. Laparoscopic sleeve gastrectomy improves reproductive hormone levels in morbidly obese males—a series of 28 cases. Chirurgia (Bucur). 2014;109(2):198–203.

    CAS  PubMed  Google Scholar 

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  1. Cellular & Physiological Sciences, Life Sciences Center, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

    Geoffrey L. Hammond PhD

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  1. Department of Medicine, Endocrinology, D, University of Louisville Health Sciences, Louisville, USA

    Stephen J. Winters

  2. Department of Surgery and Cancer, Imperial College London, London, United Kingdom

    Ilpo T. Huhtaniemi

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Hammond, G.L. (2017). Sex Hormone-Binding Globulin and the Metabolic Syndrome. In: Winters, S., Huhtaniemi, I. (eds) Male Hypogonadism. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-53298-1_15

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