Estrogens and Body Weight Regulation in Men

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)

Abstract

Our understanding of the metabolic roles of sex steroids in men has evolved substantially over recent decades. Whereas testosterone once was believed to contribute to metabolic risk in men, the importance of adequate androgen exposure for the maintenance of metabolic health has been demonstrated unequivocally. A growing body of evidence now also supports a critical role for estrogens in metabolic regulation in men. Recent data from clinical intervention studies indicate that estradiol may be a stronger determinant of adiposity than testosterone in men, and even short-term estradiol deprivation contributes to fat mass accrual. The following chapter will outline findings to date regarding the mechanisms, whereby estrogens contribute to the regulation of body weight and adiposity in men. It will present emergent clinical data as well as preclinical findings that reveal mechanistic insights into estrogen-mediated regulation of body composition. Findings in both males and females will be reviewed, to draw comparisons and to highlight knowledge gaps regarding estrogen action specifically in males. Finally, the clinical relevance of estrogen exposure in men will be discussed, particularly in the context of a rising global prevalence of obesity and expanding clinical use of sex steroid-based therapies in men.

References

  1. Abdelgadir, S. E., Resko, J. A., Ojeda, S. R., Lephart, E. D., McPhaul, M. J., & Roselli, C. E. (1994). Androgens regulate aromatase cytochrome P450 messenger ribonucleic acid in rat brain. Endocrinology, 135, 395–401.CrossRefPubMedGoogle Scholar
  2. Ahima, R. S., Stanley, T. L., Khor, V. K., Zanni, M. V., & Grinspoon, S. K. (2011). Estrogen sulfotransferase is expressed in subcutaneous adipose tissue of obese humans in association with TNF-alpha and SOCS3. The Journal of Clinical Endocrinology and Metabolism, 96, E1153–E1158.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Anderson, L. A., McTernan, P. G., Barnett, A. H., & Kumar, S. (2001). The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: Influence of gender and site. The Journal of Clinical Endocrinology and Metabolism, 86, 5045–5051.CrossRefPubMedGoogle Scholar
  4. Archer, Z. A., Findlay, P. A., McMillen, S. R., Rhind, S. M., & Adam, C. L. (2004). Effects of nutritional status and gonadal steroids on expression of appetite-regulatory genes in the hypothalamic arcuate nucleus of sheep. The Journal of Endocrinology, 182, 409–419.CrossRefPubMedGoogle Scholar
  5. Armamento-Villareal, R., Aguirre, L. E., Qualls, C., & Villareal, D. T. (2016). Effect of lifestyle intervention on the hormonal profile of frail, obese older men. The Journal of Nutrition, Health & Aging, 20, 334–340.CrossRefGoogle Scholar
  6. Ayoub, R., Page, S. T., Swerdloff, R. S., Liu, P. Y., Amory, J. K., Leung, A., Hull, L., Blithe, D., Christy, A., Chao, J. H., Bremner, W. J., & Wang, C. (2016). Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): A potential oral, male contraceptive. Andrology, 5(2), 278–285.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Barros, R. P., Machado, U. F., Warner, M., & Gustafsson, J. A. (2006). Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proceedings of the National Academy of Sciences of the United States of America, 103, 1605–1608.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Barros, R. P., Gabbi, C., Morani, A., Warner, M., & Gustafsson, J. A. (2009). Participation of ERalpha and ERbeta in glucose homeostasis in skeletal muscle and white adipose tissue. American Journal of Physiology Endocrinology and Metabolism, 297, E124–E133.CrossRefPubMedGoogle Scholar
  9. Bélanger, C., Hould, F. S., Lebel, S., Biron, S., Brochu, G., & Tchernof, A. (2006). Omental and subcutaneous adipose tissue steroid levels in obese men. Steroids, 71, 674–682.CrossRefPubMedGoogle Scholar
  10. Bhasin, S., Woodhouse, L., & Storer, T. W. (2003). Androgen effects on body composition. Growth Hormone & IGF Research, 13(Suppl A), S63–S71.CrossRefGoogle Scholar
  11. Bhasin, S., Cunningham, G. R., Hayes, F. J., Matsumoto, A. M., Snyder, P. J., Swerdloff, R. S., Montori, V. M., & Task Force, E. S. (2010). Testosterone therapy in men with androgen deficiency syndromes: An endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism, 95, 2536–2559.CrossRefPubMedGoogle Scholar
  12. Bhattacharya, I., Tarabar, S., Liang, Y., Pradhan, V., Owens, J., & Oemar, B. (2016). Safety, pharmacokinetic, and pharmacodynamic evaluation after single and multiple ascending doses of a novel selective androgen receptor modulator in healthy subjects. Clinical Therapeutics, 38, 1401–1416.CrossRefPubMedGoogle Scholar
  13. Blankenstein, M. A., Szymczak, J., Daroszewski, J., Milewicz, A., & Thijssen, J. H. (1992). Estrogens in plasma and fatty tissue from breast cancer patients and women undergoing surgery for non-oncological reasons. Gynecological Endocrinology, 6, 13–17.CrossRefPubMedGoogle Scholar
  14. Blasko, E., Haskell, C. A., Leung, S., Gualtieri, G., Halks-Miller, M., Mahmoudi, M., Dennis, M. K., Prossnitz, E. R., Karpus, W. J., & Horuk, R. (2009). Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. Journal of Neuroimmunology, 214, 67–77.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Brind, J., Strain, G., Miller, L., Zumoff, B., Vogelman, J., & Orentreich, N. (1990). Obese men have elevated plasma levels of estrone sulfate. International Journal of Obesity, 14, 483–486.PubMedGoogle Scholar
  16. Brown, L. M., & Clegg, D. J. (2010). Central effects of estradiol in the regulation of food intake, body weight, and adiposity. The Journal of Steroid Biochemistry and Molecular Biology, 122, 65–73.CrossRefPubMedGoogle Scholar
  17. Brown, T. J., Naftolin, F., & Maclusky, N. J. (1992). Sex differences in estrogen receptor binding in the rat hypothalamus: Effects of subsaturating pulses of estradiol. Brain Research, 578, 129–134.CrossRefPubMedGoogle Scholar
  18. Burnett-Bowie, S. A., Roupenian, K. C., Dere, M. E., Lee, H., & Leder, B. Z. (2009). Effects of aromatase inhibition in hypogonadal older men: A randomized, double-blind, placebo-controlled trial. Clinical Endocrinology (Oxf), 70, 116–123.CrossRefGoogle Scholar
  19. Cannata, D. H., Kirschenbaum, A., & Levine, A. C. (2012). Androgen deprivation therapy as primary treatment for prostate cancer. The Journal of Clinical Endocrinology and Metabolism, 97, 360–365.CrossRefPubMedGoogle Scholar
  20. Carani, C., Qin, K., Simoni, M., Faustini-Fustini, M., Serpente, S., Boyd, J., Korach, K. S., & Simpson, E. R. (1997). Effect of testosterone and estradiol in a man with aromatase deficiency. The New England Journal of Medicine, 337, 91–95.CrossRefPubMedGoogle Scholar
  21. Carrier, N., Saland, S. K., Duclot, F., He, H., Mercer, R., & Kabbaj, M. (2015). The anxiolytic and antidepressant-like effects of testosterone and estrogen in gonadectomized male rats. Biological Psychiatry, 78, 259–269.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Castanho, T. C., Moreira, P. S., Portugal-Nunes, C., Novais, A., Costa, P. S., Palha, J. A., Sousa, N., & Santos, N. C. (2014). The role of sex and sex-related hormones in cognition, mood and well-being in older men and women. Biological Psychology, 103, 158–166.CrossRefPubMedGoogle Scholar
  23. Cederroth, C. R., Vinciguerra, M., Kühne, F., Madani, R., Doerge, D. R., Visser, T. J., Foti, M., Rohner-Jeanrenaud, F., Vassalli, J. D., & Nef, S. (2007). A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice. Environmental Health Perspectives, 115, 1467–1473.PubMedPubMedCentralGoogle Scholar
  24. Cederroth, C. R., Vinciguerra, M., Gjinovci, A., Kühne, F., Klein, M., Cederroth, M., Caille, D., Suter, M., Neumann, D., James, R. W., Doerge, D. R., Wallimann, T., Meda, P., Foti, M., Rohner-Jeanrenaud, F., Vassalli, J. D., & Nef, S. (2008). Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism. Diabetes, 57, 1176–1185.CrossRefPubMedGoogle Scholar
  25. Chakraborty, S., Sachdev, A., Salton, S. R., & Chakraborty, T. R. (2008). Stereological analysis of estrogen receptor expression in the hypothalamic arcuate nucleus of ob/ob and agouti mice. Brain Research, 1217, 86–95.CrossRefPubMedGoogle Scholar
  26. Chao, J., Rubinow, K. B., Kratz, M., Amory, J. K., Matsumoto, A. M., & Page, S. T. (2016). Short-term estrogen withdrawal increases adiposity in healthy men. The Journal of Clinical Endocrinology and Metabolism, 101, 3724–3731.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Clegg, D. J., Brown, L. M., Woods, S. C., & Benoit, S. C. (2006). Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes, 55, 978–987.CrossRefPubMedGoogle Scholar
  28. Clegg, D. J., Brown, L. M., Zigman, J. M., Kemp, C. J., Strader, A. D., Benoit, S. C., Woods, S. C., Mangiaracina, M., & Geary, N. (2007). Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats. Diabetes, 56, 1051–1058.CrossRefPubMedGoogle Scholar
  29. Cooke, P. S., Heine, P. A., Taylor, J. A., & Lubahn, D. B. (2001). The role of estrogen and estrogen receptor-alpha in male adipose tissue. Molecular and Cellular Endocrinology, 178, 147–154.CrossRefPubMedGoogle Scholar
  30. Corona, G., Rastrelli, G., Morelli, A., Vignozzi, L., Mannucci, E., & Maggi, M. (2011). Hypogonadism and metabolic syndrome. Journal of Endocrinological Investigation, 34, 557–567.CrossRefPubMedGoogle Scholar
  31. Corona, G., Rastrelli, G., Monami, M., Saad, F., Luconi, M., Lucchese, M., Facchiano, E., Sforza, A., Forti, G., Mannucci, E., & Maggi, M. (2013). Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: A systematic review and meta-analysis. European Journal of Endocrinology, 168, 829–843.CrossRefPubMedGoogle Scholar
  32. Cunningham, M., & Gilkeson, G. (2011). Estrogen receptors in immunity and autoimmunity. Clinical Reviews in Allergy & Immunology, 40, 66–73.CrossRefGoogle Scholar
  33. D’Eon, T. M., Souza, S. C., Aronovitz, M., Obin, M. S., Fried, S. K., & Greenberg, A. S. (2005). Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. The Journal of Biological Chemistry, 280, 35983–35991.CrossRefPubMedGoogle Scholar
  34. Dakin, R. S., Walker, B. R., Seckl, J. R., Hadoke, P. W., & Drake, A. J. (2015). Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. International Journal of Obesity (Lond), 39, 1539–1547.CrossRefGoogle Scholar
  35. Davis, K. E., Carstens, E. J., Irani, B. G., Gent, L. M., Hahner, L. M., & Clegg, D. J. (2014). Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Hormones and Behavior, 66(1), 196–207.CrossRefPubMedPubMedCentralGoogle Scholar
  36. de Boer, H., Verschoor, L., Ruinemans-Koerts, J., & Jansen, M. (2005). Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism. Diabetes, Obesity & Metabolism, 7, 211–215.CrossRefGoogle Scholar
  37. Deslypere, J. P., Verdonck, L., & Vermeulen, A. (1985). Fat tissue: A steroid reservoir and site of steroid metabolism. The Journal of Clinical Endocrinology and Metabolism, 61, 564–570.CrossRefPubMedGoogle Scholar
  38. Dieudonne, M. N., Pecquery, R., Leneveu, M. C., & Giudicelli, Y. (2000). Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: Evidence for sex and site-related specificities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor gamma2. Endocrinology, 141, 649–656.CrossRefPubMedGoogle Scholar
  39. Dieudonné, M. N., Leneveu, M. C., Giudicelli, Y., & Pecquery, R. (2004). Evidence for functional estrogen receptors alpha and beta in human adipose cells: Regional specificities and regulation by estrogens. American Journal of Physiology Cell Physiology, 286, C655–C661.CrossRefPubMedGoogle Scholar
  40. Dieudonné, M. N., Sammari, A., Dos Santos, E., Leneveu, M. C., Giudicelli, Y., & Pecquery, R. (2006). Sex steroids and leptin regulate 11beta-hydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: Sex specificities. The Journal of Steroid Biochemistry and Molecular Biology, 99, 189–196.CrossRefPubMedGoogle Scholar
  41. Ding, E. L., Song, Y., Malik, V. S., & Liu, S. (2006). Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis. JAMA, 295, 1288–1299.CrossRefPubMedGoogle Scholar
  42. Fan, W., Yanase, T., Nomura, M., Okabe, T., Goto, K., Sato, T., Kawano, H., Kato, S., & Nawata, H. (2005). Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes, 54, 1000–1008.CrossRefPubMedGoogle Scholar
  43. Finan, B., Yang, B., Ottaway, N., Stemmer, K., Müller, T. D., Yi, C. X., Habegger, K., et al. (2012). Targeted estrogen delivery reverses the metabolic syndrome. Nature Medicine, 18, 1847–1856.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Finkelstein, J. S., Lee, H., Burnett-Bowie, S. A., Pallais, J. C., Yu, E. W., Borges, L. F., Jones, B. F., Barry, C. V., Wulczyn, K. E., Thomas, B. J., & Leder, B. Z. (2013). Gonadal steroids and body composition, strength, and sexual function in men. The New England Journal of Medicine, 369, 1011–1022.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Flores, R., Shi, J., Fuhrman, B., Xu, X., Veenstra, T. D., Gail, M. H., Gajer, P., Ravel, J., & Goedert, J. J. (2012). Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: A cross-sectional study. Journal of Translational Medicine, 10, 253.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Foryst-Ludwig, A., & Kintscher, U. (2010). Metabolic impact of estrogen signalling through ERalpha and ERbeta. The Journal of Steroid Biochemistry and Molecular Biology, 122, 74–81.CrossRefPubMedGoogle Scholar
  47. Foryst-Ludwig, A., Clemenz, M., Hohmann, S., Hartge, M., Sprang, C., Frost, N., Krikov, M., Bhanot, S., Barros, R., Morani, A., Gustafsson, J. A., Unger, T., & Kintscher, U. (2008). Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genetics, 4, e1000108.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Frank, A., Brown, L. M., & Clegg, D. J. (2014). The role of hypothalamic estrogen receptors in metabolic regulation. Frontiers in Neuroendocrinology, 35, 550–557.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Gao, Q., Mezei, G., Nie, Y., Rao, Y., Choi, C. S., Bechmann, I., Leranth, C., Toran-Allerand, D., Priest, C. A., Roberts, J. L., Gao, X. B., Mobbs, C., Shulman, G. I., Diano, S., & Horvath, T. L. (2007). Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nature Medicine, 13, 89–94.CrossRefPubMedGoogle Scholar
  50. Gerriets, V. A., & MacIver, N. J. (2014). Role of T cells in malnutrition and obesity. Frontiers in Immunology, 5, 379.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Gillies, G. E., & McArthur, S. (2010). Estrogen actions in the brain and the basis for differential action in men and women: A case for sex-specific medicines. Pharmacological Reviews, 62, 155–198.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Giudicelli, Y., Dieudonne, M. N., Lacasa, D., Pasquier, Y. N., & Pecquery, R. (1993). Modulation by sex hormones of the membranous transducing system regulating fatty acid mobilization in adipose tissue. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 48, 91–100.CrossRefPubMedGoogle Scholar
  53. Grasa, M. M., Esteve, M., Masanés, R. M., Yubero, P., Blay, M., López-Martí, J., Cabot, C., Vilà, R., Fernández-López, J. A., Remesar, X., & Alemany, M. (2001). Oral gavage of oleoyl-oestrone has a stronger effect on body weight in male Zucker obese rats than in female. Diabetes, Obesity & Metabolism, 3, 203–208.CrossRefGoogle Scholar
  54. Hamilton, E. J., Gianatti, E., Strauss, B. J., Wentworth, J., Lim-Joon, D., Bolton, D., Zajac, J. D., & Grossmann, M. (2011). Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clinical Endocrinology, 74, 377–383.CrossRefPubMedGoogle Scholar
  55. Hammoud, A., Carrell, D. T., Meikle, A. W., Xin, Y., Hunt, S. C., Adams, T. D., & Gibson, M. (2010). An aromatase polymorphism modulates the relationship between weight and estradiol levels in obese men. Fertility and Sterility, 94, 1734–1738.CrossRefPubMedGoogle Scholar
  56. Harada, N., Hanaoka, R., Horiuchi, H., Kitakaze, T., Mitani, T., Inui, H., & Yamaji, R. (2016). Castration influences intestinal microflora and induces abdominal obesity in high-fat diet-fed mice. Scientific Reports, 6, 23001.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Heine, P. A., Taylor, J. A., Iwamoto, G. A., Lubahn, D. B., & Cooke, P. S. (2000). Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 97, 12729–12734.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Hemsell, D. L., Grodin, J. M., Brenner, P. F., Siiteri, P. K., & MacDonald, P. C. (1974). Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. The Journal of Clinical Endocrinology and Metabolism, 38, 476–479.CrossRefPubMedGoogle Scholar
  59. Holland, A. M., Roberts, M. D., Mumford, P. W., Mobley, C. B., Kephart, W. C., Conover, C. F., Beggs, L. A., Balaez, A., Otzel, D. M., Yarrow, J. F., Borst, S. E., & Beck, D. T. (2016). Testosterone inhibits expression of lipogenic genes in visceral fat by an estrogen-dependent mechanism. Journal of Applied Physiology. (1985, 121, 792–805.CrossRefPubMedGoogle Scholar
  60. Homma, H., Kurachi, H., Nishio, Y., Takeda, T., Yamamoto, T., Adachi, K., Morishige, K., Ohmichi, M., Matsuzawa, Y., & Murata, Y. (2000). Estrogen suppresses transcription of lipoprotein lipase gene. Existence of a unique estrogen response element on the lipoprotein lipase promoter. The Journal of Biological Chemistry, 275, 11404–11411.CrossRefPubMedGoogle Scholar
  61. Ihunnah, C. A., Wada, T., Philips, B. J., Ravuri, S. K., Gibbs, R. B., Kirisci, L., Rubin, J. P., Marra, K. G., & Xie, W. (2014). Estrogen Sulfotransferase/SULT1E1 promotes human adipogenesis. Molecular and Cellular Biology, 34, 1682–1694.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Isidori, A. M., Giannetta, E., Greco, E. A., Gianfrilli, D., Bonifacio, V., Isidori, A., Lenzi, A., & Fabbri, A. (2005). Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: A meta-analysis. Clinical Endocrinology (Oxf), 63, 280–293.CrossRefGoogle Scholar
  63. Jasuja, G. K., Travison, T. G., Davda, M., Murabito, J. M., Basaria, S., Zhang, A., Kushnir, M. M., Rockwood, A. L., Meikle, W., Pencina, M. J., Coviello, A., Rose, A. J., D'Agostino, R., Vasan, R. S., & Bhasin, S. (2013a). Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham heart study. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences, 68, 733–740.CrossRefPubMedGoogle Scholar
  64. Jasuja, G. K., Travison, T. G., Davda, M., Rose, A. J., Zhang, A., Kushnir, M. M., Rockwood, A. L., Meikle, W., Coviello, A. D., D'Agostino, R., Vasan, R. S., & Bhasin, S. (2013b). Circulating estrone levels are associated prospectively with diabetes risk in men of the Framingham Heart Study. Diabetes Care, 36, 2591–2596.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Wreford, N. G., Proietto, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2000). Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proceedings of the National Academy of Sciences of the United States of America, 97, 12735–12740.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Misso, M. L., Wreford, N. G., Proietto, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2001). Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. The Journal of Steroid Biochemistry and Molecular Biology, 79, 3–9.CrossRefPubMedGoogle Scholar
  67. Jones, M. E., Boon, W. C., Proietto, J., & Simpson, E. R. (2006). Of mice and men: The evolving phenotype of aromatase deficiency. Trends in Endocrinology and Metabolism, 17, 55–64.CrossRefPubMedGoogle Scholar
  68. Jones, T. H., Arver, S., Behre, H. M., Buvat, J., Meuleman, E., Moncada, I., Morales, A. M., Volterrani, M., Yellowlees, A., Howell, J. D., Channer, K. S., & Investigators, T. (2011). Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care, 34, 828–837.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Juang, P. S., Peng, S., Allehmazedeh, K., Shah, A., Coviello, A. D., & Herbst, K. L. (2014). Testosterone with dutasteride, but not anastrozole, improves insulin sensitivity in young obese men: A randomized controlled trial. The Journal of Sexual Medicine, 11, 563–573.CrossRefPubMedGoogle Scholar
  70. Kahles, F., Meyer, C., Möllmann, J., Diebold, S., Findeisen, H. M., Lebherz, C., Trautwein, C., Koch, A., Tacke, F., Marx, N., & Lehrke, M. (2014). GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes, 63, 3221–3229.CrossRefPubMedGoogle Scholar
  71. Kaminetsky, J., Werner, M., Fontenot, G., & Wiehle, R. D. (2013). Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. The Journal of Sexual Medicine, 10, 1628–1635.CrossRefPubMedGoogle Scholar
  72. Kautzky-Willer, A., & Handisurya, A. (2009). Metabolic diseases and associated complications: Sex and gender matter! European Journal of Clinical Investigation, 39, 631–648.CrossRefPubMedGoogle Scholar
  73. Keating, N. L., O’Malley, A. J., & Smith, M. R. (2006). Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. Journal of Clinical Oncology, 24, 4448–4456.CrossRefPubMedGoogle Scholar
  74. Keating, N. L., O’Malley, A., Freedland, S. J., & Smith, M. R. (2012). Diabetes and cardiovascular disease during androgen deprivation therapy: Observational study of veterans with prostate cancer. Journal of the National Cancer Institute, 104, 1518–1523.CrossRefPubMedGoogle Scholar
  75. Kellert, B. A., Nguyen, M. C., Nguyen, C., Nguyen, Q. H., & Wagner, E. J. (2009). Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis. European Journal of Pharmacology, 622, 15–24.CrossRefPubMedPubMedCentralGoogle Scholar
  76. Khan, M. J., Gerasimidis, K., Edwards, C. A., & Shaikh, M. G. (2016). Role of gut microbiota in the aetiology of obesity: Proposed mechanisms and review of the literature. Journal of Obesity, 2016, 7353642.PubMedPubMedCentralGoogle Scholar
  77. Khor, V. K., Tong, M. H., Qian, Y., & Song, W. C. (2008). Gender-specific expression and mechanism of regulation of estrogen sulfotransferase in adipose tissues of the mouse. Endocrinology, 149, 5440–5448.CrossRefPubMedPubMedCentralGoogle Scholar
  78. Kim, E. D., McCullough, A., & Kaminetsky, J. (2016). Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: Restoration instead of replacement. BJU International, 117, 677–685.CrossRefPubMedGoogle Scholar
  79. Kley, H. K., Deselaers, T., Peerenboom, H., & Krüskemper, H. L. (1980a). Enhanced conversion of androstenedione to estrogens in obese males. The Journal of Clinical Endocrinology and Metabolism, 51, 1128–1132.CrossRefPubMedGoogle Scholar
  80. Kley, H. K., Edelmann, P., & Krüskemper, H. L. (1980b). Relationship of plasma sex hormones to different parameters of obesity in male subjects. Metabolism, 29, 1041–1045.CrossRefPubMedGoogle Scholar
  81. Kovats, S. (2012). Estrogen receptors regulate an inflammatory pathway of dendritic cell differentiation: Mechanisms and implications for immunity. Hormones and Behavior, 62, 254–262.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Kovats, S. (2015). Estrogen receptors regulate innate immune cells and signaling pathways. Cellular Immunology, 294, 63–69.CrossRefPubMedPubMedCentralGoogle Scholar
  83. Lacasa, D., Taleb, S., Keophiphath, M., Miranville, A., & Clement, K. (2007). Macrophage-secreted factors impair human adipogenesis: Involvement of proinflammatory state in preadipocytes. Endocrinology, 148, 868–877.CrossRefPubMedGoogle Scholar
  84. Lebherz, C., Kahles, F., Piotrowski, K., Vogeser, M., Foldenauer, A. C., Nassau, K., Kilger, E., Marx, N., Parhofer, K. G., & Lehrke, M. (2016). Interleukin-6 predicts inflammation-induced increase of Glucagon-like peptide-1 in humans in response to cardiac surgery with association to parameters of glucose metabolism. Cardiovascular Diabetology, 15, 21.CrossRefPubMedPubMedCentralGoogle Scholar
  85. Loves, S., Ruinemans-Koerts, J., & de Boer, H. (2008). Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. European Journal of Endocrinology, 158, 741–747.CrossRefPubMedGoogle Scholar
  86. Loves, S., de Jong, J., van Sorge, A., Telting, D., Tack, C. J., Hermus, A., Westerterp, K., & de Boer, H. (2013). Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia. European Journal of Endocrinology, 169, 705–714.CrossRefPubMedGoogle Scholar
  87. Lu, C., Kumar, P. A., Fan, Y., Sperling, M. A., & Menon, R. K. (2010). A novel effect of growth hormone on macrophage modulates macrophage-dependent adipocyte differentiation. Endocrinology, 151, 2189–2199.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Lumeng, C. N., DelProposto, J. B., Westcott, D. J., & Saltiel, A. R. (2008). Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes, 57, 3239–3246.CrossRefPubMedPubMedCentralGoogle Scholar
  89. MacDonald, A. A., Herbison, G. P., Showell, M., & Farquhar, C. M. (2010). The impact of body mass index on semen parameters and reproductive hormones in human males: A systematic review with meta-analysis. Human Reproduction Update, 16, 293–311.CrossRefPubMedGoogle Scholar
  90. Maffei, L., Rochira, V., Zirilli, L., Antunez, P., Aranda, C., Fabre, B., Simone, M. L., Pignatti, E., Simpson, E. R., Houssami, S., Clyne, C. D., & Carani, C. (2007). A novel compound heterozygous mutation of the aromatase gene in an adult man: Reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome. Clinical Endocrinology, 67, 218–224.CrossRefPubMedGoogle Scholar
  91. Mah, P. M., & Wittert, G. A. (2010). Obesity and testicular function. Molecular and Cellular Endocrinology, 316, 180–186.CrossRefPubMedGoogle Scholar
  92. Mather, K. J., Kim, C., Christophi, C. A., Aroda, V. R., Knowler, W. C., Edelstein, S. E., Florez, J. C., Labrie, F., Kahn, S. E., Goldberg, R. B., Barrett-Connor, E., & Program, D. P. (2015). Steroid sex hormones, sex hormone-binding globulin, and diabetes incidence in the diabetes prevention program. The Journal of Clinical Endocrinology and Metabolism, 100, 3778–3786.CrossRefPubMedPubMedCentralGoogle Scholar
  93. Mathis, D. (2013). Immunological goings-on in visceral adipose tissue. Cell Metabolism, 17, 851–859.CrossRefPubMedPubMedCentralGoogle Scholar
  94. Matsumine, H., Hirato, K., Yanaihara, T., Tamada, T., & Yoshida, M. (1986). Aromatization by skeletal muscle. The Journal of Clinical Endocrinology and Metabolism, 63, 717–720.CrossRefPubMedGoogle Scholar
  95. Mauvais-Jarvis, F., Clegg, D. J., & Hevener, A. L. (2013). The role of estrogens in control of energy balance and glucose homeostasis. Endocrine Reviews, 34, 309–338.CrossRefPubMedPubMedCentralGoogle Scholar
  96. Meng, M. V., Grossfeld, G. D., Sadetsky, N., Mehta, S. S., Lubeck, D. P., & Carroll, P. R. (2002). Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. Urology, 60, 7–11. discussion 11–12.CrossRefPubMedGoogle Scholar
  97. Merchenthaler, I., Lane, M. V., Numan, S., & Dellovade, T. L. (2004). Distribution of estrogen receptor alpha and beta in the mouse central nervous system: In vivo autoradiographic and immunocytochemical analyses. The Journal of Comparative Neurology, 473, 270–291.CrossRefPubMedGoogle Scholar
  98. Mihalca, R., & Fica, S. (2014). The impact of obesity on the male reproductive axis. Journal of Medicine and Life, 7, 296–300.PubMedPubMedCentralGoogle Scholar
  99. Misso, M. L., Murata, Y., Boon, W. C., Jones, M. E., Britt, K. L., & Simpson, E. R. (2003). Cellular and molecular characterization of the adipose phenotype of the aromatase-deficient mouse. Endocrinology, 144, 1474–1480.CrossRefPubMedGoogle Scholar
  100. Monteagudo, P. T., Falcão, A. A., Verreschi, I. T., & Zanella, M. T. (2016). The imbalance of sex-hormones related to depressive symptoms in obese men. The Aging Male, 19, 20–26.CrossRefPubMedGoogle Scholar
  101. Monteiro, R., Teixeira, D., & Calhau, C. (2014). Estrogen signaling in metabolic inflammation. Mediators of Inflammation, 2014, 615917.CrossRefPubMedPubMedCentralGoogle Scholar
  102. Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C., & Qin, K. (1995). Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. The Journal of Clinical Endocrinology and Metabolism, 80, 3689–3698.PubMedGoogle Scholar
  103. Morton, G. J., & Schwartz, M. W. (2011). Leptin and the central nervous system control of glucose metabolism. Physiological Reviews, 91, 389–411.CrossRefPubMedPubMedCentralGoogle Scholar
  104. Muschamp, J. W., & Hull, E. M. (2007). Melanin concentrating hormone and estrogen receptor-alpha are coexstensive but not coexpressed in cells of male rat hypothalamus. Neuroscience Letters, 427, 123–126.CrossRefPubMedPubMedCentralGoogle Scholar
  105. Mystkowski, P., Seeley, R. J., Hahn, T. M., Baskin, D. G., Havel, P. J., Matsumoto, A. M., Wilkinson, C. W., Peacock-Kinzig, K., Blake, K. A., & Schwartz, M. W. (2000). Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss. The Journal of Neuroscience, 20, 8637–8642.PubMedGoogle Scholar
  106. Ogawa, S., Chan, J., Gustafsson, J. A., Korach, K. S., & Pfaff, D. W. (2003). Estrogen increases locomotor activity in mice through estrogen receptor alpha: Specificity for the type of activity. Endocrinology, 144, 230–239.CrossRefPubMedGoogle Scholar
  107. Ohlsson, C., Hellberg, N., Parini, P., Vidal, O., Bohlooly-Y, M., Bohlooly, M., Rudling, M., Lindberg, M. K., Warner, M., Angelin, B., & Gustafsson, J. A. (2000). Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochemical and Biophysical Research Communications, 278, 640–645.CrossRefPubMedGoogle Scholar
  108. Olefsky, J. M., & Glass, C. K. (2010). Macrophages, inflammation, and insulin resistance. Annual Review of Physiology, 72, 219–246.CrossRefPubMedGoogle Scholar
  109. Palin, S. L., McTernan, P. G., Anderson, L. A., Sturdee, D. W., Barnett, A. H., & Kumar, S. (2003). 17Beta-estradiol and anti-estrogen ICI: Compound 182,780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdominal adipocytes. Metabolism, 52, 383–388.CrossRefPubMedGoogle Scholar
  110. Pedersen, S. B., Bruun, J. M., Hube, F., Kristensen, K., Hauner, H., & Richelsen, B. (2001). Demonstration of estrogen receptor subtypes alpha and beta in human adipose tissue: Influences of adipose cell differentiation and fat depot localization. Molecular and Cellular Endocrinology, 182, 27–37.CrossRefPubMedGoogle Scholar
  111. Pedersen, S. B., Kristensen, K., Hermann, P. A., Katzenellenbogen, J. A., & Richelsen, B. (2004). Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. The Journal of Clinical Endocrinology and Metabolism, 89, 1869–1878.CrossRefPubMedGoogle Scholar
  112. Pellitero, S., Olaizola, I., Alastrue, A., Martínez, E., Granada, M. L., Balibrea, J. M., Moreno, P., Serra, A., Navarro-Díaz, M., Romero, R., & Puig-Domingo, M. (2012). Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obesity Surgery, 22, 1835–1842.CrossRefPubMedGoogle Scholar
  113. Petersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005). Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes, 54, 603–608.CrossRefPubMedPubMedCentralGoogle Scholar
  114. Phillips, I., Shah, S. I., Duong, T., Abel, P., & Langley, R. E. (2014). Androgen deprivation therapy and the re-emergence of parenteral estrogen in prostate cancer. Oncol Hematol Rev, 10, 42–47.PubMedPubMedCentralGoogle Scholar
  115. Popkin, B. M., Adair, L. S., & Ng, S. W. (2012). Global nutrition transition and the pandemic of obesity in developing countries. Nutrition Reviews, 70, 3–21.CrossRefPubMedPubMedCentralGoogle Scholar
  116. Price, T. M., O’Brien, S. N., Welter, B. H., George, R., Anandjiwala, J., & Kilgore, M. (1998). Estrogen regulation of adipose tissue lipoprotein lipase – possible mechanism of body fat distribution. American Journal of Obstetrics and Gynecology, 178, 101–107.CrossRefPubMedGoogle Scholar
  117. Qiu, Y., Nguyen, K. D., Odegaard, J. I., Cui, X., Tian, X., Locksley, R. M., Palmiter, R. D., & Chawla, A. (2014). Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell, 157, 1292–1308.CrossRefPubMedPubMedCentralGoogle Scholar
  118. Remesar, X., Tang, V., Ferrer, E., Torregrosa, C., Virgili, J., Masanés, R. M., Fernández-López, J. A., & Alemany, M. (1999). Estrone in food: A factor influencing the development of obesity? European Journal of Nutrition, 38, 247–253.CrossRefPubMedGoogle Scholar
  119. Ribas, V., Drew, B. G., Le, J. A., Soleymani, T., Daraei, P., Sitz, D., Mohammad, L., Henstridge, D. C., Febbraio, M. A., Hewitt, S. C., Korach, K. S., Bensinger, S. J., & Hevener, A. L. (2011). Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proceedings of the National Academy of Sciences of the United States of America, 108, 16457–16462.CrossRefPubMedPubMedCentralGoogle Scholar
  120. Ribas, V., Drew, B. G., Zhou, Z., Phun, J., Kalajian, N. Y., Soleymani, T., Daraei, P., et al. (2016). Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Science Translational Medicine, 8, 334ra354.CrossRefGoogle Scholar
  121. Riebe, C. J., Hill, M. N., Lee, T. T., Hillard, C. J., & Gorzalka, B. B. (2010). Estrogenic regulation of limbic cannabinoid receptor binding. Psychoneuroendocrinology, 35, 1265–1269.CrossRefPubMedPubMedCentralGoogle Scholar
  122. Rogers, N. H., Perfield, J. W., Strissel, K. J., Obin, M. S., & Greenberg, A. S. (2009). Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology, 150, 2161–2168.CrossRefPubMedPubMedCentralGoogle Scholar
  123. Roselli, C. E., Liu, M., & Hurn, P. D. (2009). Brain aromatization: Classic roles and new perspectives. Seminars in Reproductive Medicine, 27, 207–217.CrossRefPubMedPubMedCentralGoogle Scholar
  124. Ruan, H., Hacohen, N., Golub, T. R., Van Parijs, L., & Lodish, H. F. (2002). Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: Nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes, 51, 1319–1336.CrossRefPubMedGoogle Scholar
  125. Sanchis, D., Balada, F., del Mar, G. M., Virgili, J., Peinado, J., Monserrat, C., Fernández-López, J. A., Remesar, X., & Alemany, M. (1996). Oleoyl-estrone induces the loss of body fat in rats. International Journal of Obesity and Related Metabolic Disorders, 20, 588–594.PubMedGoogle Scholar
  126. Sanchis, D., Balada, F., Picó, C., Grasa, M. M., Virgili, J., Farrerons, C., Palou, A., Fernández-López, J. A., Remesar, X., & Alemany, M. (1997). Rats receiving the slimming agent oleoyl-estrone in liposomes (Merlin-2) decrease food intake but maintain thermogenesis. Archives of Physiology and Biochemistry, 105, 663–672.CrossRefPubMedGoogle Scholar
  127. Schneider, G., Kirschner, M. A., Berkowitz, R., & Ertel, N. H. (1979). Increased estrogen production in obese men. The Journal of Clinical Endocrinology and Metabolism, 48, 633–638.CrossRefPubMedGoogle Scholar
  128. Serrano, M., Grasa, M. M., Janer, G., Fernández-López, J. A., & Alemany, M. (2009). Oleoyl-estrone affects lipid metabolism in adrenalectomized rats treated with corticosterone through modulation of SREBP1c expression. The Journal of Steroid Biochemistry and Molecular Biology, 117, 15–22.CrossRefPubMedGoogle Scholar
  129. Shahani, S., Braga-Basaria, M., & Basaria, S. (2008). Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. The Journal of Clinical Endocrinology and Metabolism, 93, 2042–2049.CrossRefPubMedGoogle Scholar
  130. Simerly, R. B., Chang, C., Muramatsu, M., & Swanson, L. W. (1990). Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. The Journal of Comparative Neurology, 294, 76–95.CrossRefPubMedGoogle Scholar
  131. Simpson, E. R. (1998). Genetic mutations resulting in estrogen insufficiency in the male. Molecular and Cellular Endocrinology, 145, 55–59.CrossRefPubMedGoogle Scholar
  132. Simpson, E. R. (2003). Sources of estrogen and their importance. The Journal of Steroid Biochemistry and Molecular Biology, 86, 225–230.CrossRefPubMedGoogle Scholar
  133. Simpson, E. R. (2004). Aromatase: Biologic relevance of tissue-specific expression. Seminars in Reproductive Medicine, 22, 11–23.CrossRefPubMedGoogle Scholar
  134. Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R. M., Specker, B., Williams, T. C., Lubahn, D. B., & Korach, K. S. (1994). Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. The New England Journal of Medicine, 331, 1056–1061.CrossRefPubMedGoogle Scholar
  135. Spencer, M., Yao-Borengasser, A., Unal, R., Rasouli, N., Gurley, C. M., Zhu, B., Peterson, C. A., & Kern, P. A. (2010). Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. American Journal of Physiology Endocrinology and Metabolism, 299, E1016–E1027.CrossRefPubMedPubMedCentralGoogle Scholar
  136. Stephens, J. M., Lee, J., & Pilch, P. F. (1997). Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. The Journal of Biological Chemistry, 272, 971–976.CrossRefPubMedGoogle Scholar
  137. Stoffel-Wagner, B., Watzka, M., Schramm, J., Bidlingmaier, F., & Klingmüller, D. (1999). Expression of CYP19 (aromatase) mRNA in different areas of the human brain. The Journal of Steroid Biochemistry and Molecular Biology, 70, 237–241.CrossRefPubMedGoogle Scholar
  138. Stout, M. B., Steyn, F. J., Jurczak, M. J., Camporez, J. G., Zhu, Y., Hawse, J. R., Jurk, D., Palmer, A. K., Xu, M., Pirtskhalava, T., Evans, G. L., de Souza, S. R., Frank, A. P., White, T. A., Monroe, D. G., Singh, R. J., Casaclang-Verzosa, G., Miller, J. D., Clegg, D. J., LeBrasseur, N. K., von Zglinicki, T., Shulman, G. I., Tchkonia, T., & Kirkland, J. L. (2017). 17α-Estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences, 72(1), 3–15.Google Scholar
  139. Straub, R. H. (2007). The complex role of estrogens in inflammation. Endocrine Reviews, 28, 521–574.CrossRefPubMedGoogle Scholar
  140. Suganami, T., & Ogawa, Y. (2010). Adipose tissue macrophages: Their role in adipose tissue remodeling. Journal of Leukocyte Biology, 88, 33–39.CrossRefPubMedGoogle Scholar
  141. Tagawa, N., Yuda, R., Kubota, S., Wakabayashi, M., Yamaguchi, Y., Kiyonaga, D., Mori, N., Minamitani, E., Masuzaki, H., & Kobayashi, Y. (2009). 17Beta-estradiol inhibits 11beta-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes. The Journal of Endocrinology, 202, 131–139.CrossRefPubMedGoogle Scholar
  142. Takeda, K., Toda, K., Saibara, T., Nakagawa, M., Saika, K., Onishi, T., Sugiura, T., & Shizuta, Y. (2003). Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. The Journal of Endocrinology, 176, 237–246.CrossRefPubMedGoogle Scholar
  143. Tan, R. B., Guay, A. T., & Hellstrom, W. J. (2014). Clinical use of aromatase inhibitors in adult males. Sex Medicine Review, 2, 79–90.CrossRefGoogle Scholar
  144. Thirumalai, A., Berkseth, K. E., & Amory, J. K. (2017). Treatment of hypogonadism: Current and future therapies. F1000Research, 6, 68.CrossRefPubMedPubMedCentralGoogle Scholar
  145. Titolo, D., Cai, F., & Belsham, D. D. (2006). Coordinate regulation of neuropeptide Y and agouti-related peptide gene expression by estrogen depends on the ratio of estrogen receptor (ER) alpha to ERbeta in clonal hypothalamic neurons. Molecular Endocrinology, 20, 2080–2092.CrossRefPubMedGoogle Scholar
  146. Toda, K., Hayashi, Y., & Saibara, T. (2010). Deletion of tumor necrosis factor-alpha receptor type 1 exacerbates insulin resistance and hepatic steatosis in aromatase knockout mice. Biochimica et Biophysica Acta, 1801, 655–664.CrossRefPubMedGoogle Scholar
  147. Toran-Allerand, C. D., Tinnikov, A. A., Singh, R. J., & Nethrapalli, I. S. (2005). 17alpha-estradiol: A brain-active estrogen? Endocrinology, 146, 3843–3850.CrossRefPubMedGoogle Scholar
  148. Tritos, N. A., Segal-Lieberman, G., Vezeridis, P. S., & Maratos-Flier, E. (2004). Estradiol-induced anorexia is independent of leptin and melanin-concentrating hormone. Obesity Research, 12, 716–724.CrossRefPubMedGoogle Scholar
  149. Van Sinderen, M. L., Steinberg, G. R., Jørgensen, S. B., To SQ, Knower, K. C., Clyne, C. D., Honeyman, J., Chow, J. D., Herridge, K. A., Jones, M. E., Simpson, E. R., & Boon, W. C. (2014). Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO) mouse. PLoS One, 9, e87230.CrossRefPubMedPubMedCentralGoogle Scholar
  150. Vilà, R., Adán, C., Grasa, M. M., Masanés, R. M., Esteve, M., Cabot, C., Fernández-López, J. A., Remesar, X., & Alemany, M. (1999). Effect of food deprivation on rat plasma estrone fatty acid esters. Diabetes, Obesity & Metabolism, 1, 353–356.CrossRefGoogle Scholar
  151. Viljanen, A. P., Iozzo, P., Borra, R., Kankaanpää, M., Karmi, A., Lautamäki, R., Järvisalo, M., Parkkola, R., Rönnemaa, T., Guiducci, L., Lehtimäki, T., Raitakari, O. T., Mari, A., & Nuutila, P. (2009). Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. The Journal of Clinical Endocrinology and Metabolism, 94, 50–55.CrossRefPubMedGoogle Scholar
  152. Wada, T., Ihunnah, C. A., Gao, J., Chai, X., Zeng, S., Philips, B. J., Rubin, J. P., Marra, K. G., & Xie, W. (2011). Estrogen sulfotransferase inhibits adipocyte differentiation. Molecular Endocrinology, 25, 1612–1623.CrossRefPubMedPubMedCentralGoogle Scholar
  153. Wang, H., & Ye, J. (2015). Regulation of energy balance by inflammation: Common theme in physiology and pathology. Reviews in Endocrine & Metabolic Disorders, 16, 47–54.CrossRefGoogle Scholar
  154. Wang, F., Vihma, V., Soronen, J., Turpeinen, U., Hämäläinen, E., Savolainen-Peltonen, H., Mikkola, T. S., Naukkarinen, J., Pietiläinen, K. H., Jauhiainen, M., Yki-Järvinen, H., & Tikkanen, M. J. (2013). 17β-Estradiol and estradiol fatty acyl esters and estrogen-converting enzyme expression in adipose tissue in obese men and women. The Journal of Clinical Endocrinology and Metabolism, 98, 4923–4931.CrossRefPubMedGoogle Scholar
  155. Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003). Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation, 112, 1796–1808.CrossRefPubMedPubMedCentralGoogle Scholar
  156. Wiehle, R., Cunningham, G. R., Pitteloud, N., Wike, J., Hsu, K., Fontenot, G. K., Rosner, M., Dwyer, A., & Podolski, J. (2013). Testosterone restoration by enclomiphene citrate in men with secondary hypogonadism: Pharmacodynamics and pharmacokinetics. BJU international, 112(8), 11881200.CrossRefPubMedCentralGoogle Scholar
  157. Wiehle, R. D., Fontenot, G. K., Wike, J., Hsu, K., Nydell, J., Lipshultz, L., & Group Z-CS. (2014). Enclomiphene citrate stimulates testosterone production while preventing oligospermia: A randomized phase II clinical trial comparing topical testosterone. Fertility and Sterility, 102, 720–727.CrossRefPubMedGoogle Scholar
  158. Wing, R. R., & Group LAR. (2010). Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the Look AHEAD trial. Archives of Internal Medicine, 170, 1566–1575.PubMedGoogle Scholar
  159. Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., & Chen, H. (2003). Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of Clinical Investigation, 112, 1821–1830.CrossRefPubMedPubMedCentralGoogle Scholar
  160. Xu, Y., Nedungadi, T. P., Zhu, L., Sobhani, N., Irani, B. G., Davis, K. E., Zhang, X., Zou, F., Gent, L. M., Hahner, L. D., Khan, S. A., Elias, C. F., Elmquist, J. K., & Clegg, D. J. (2011). Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metabolism, 14, 453–465.CrossRefPubMedPubMedCentralGoogle Scholar
  161. Ye, J., & McGuinness, O. P. (2013). Inflammation during obesity is not all bad: Evidence from animal and human studies. American Journal of Physiology Endocrinology and Metabolism, 304(5), E466–E477.Google Scholar
  162. Zitzmann, M., Rohayem, J., Raidt, J., Kliesch, S., Kumar, N., Sitruk-Ware, R., & Nieschlag, E. (2017). Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: A randomized clinical trial. Andrology, 5(3), 516–526.CrossRefPubMedGoogle Scholar
  163. Zumoff, B., Miller, L. K., & Strain, G. W. (2003). Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone. Metabolism, 52, 1126–1128.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Metabolism, Endocrinology, and Nutrition Department of MedicineUniversity of WashingtonSeattleUSA

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