Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies

References

• Ellis L. Evolutionary Neuroandrogenic Theory and Universal Gender Differences in Cognition and Behavior. Sex Roles. 2011;64(9–10):707–722.
   Web of Science ®Google Scholar
• Clarkson J, Herbison AE. Hypothalamic control of the male neonatal testosterone surge. Philos Trans R Soc Lond B Biol Sci. 2016;371(1688):20150115.
   PubMed Web of Science ®Google Scholar
• Zambrano E, Guzmán C, Rodríguez-González GL, et al. Fetal programming of sexual development and reproductive function. Mol Cell Endocrinol. 2014;382(1):538–549.
   PubMed Web of Science ®Google Scholar
• Tapanainen J, Kellokumpu-Lehtinen P, Pelliniemi L, et al. Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metab. 1981;52(1):98–102.
   PubMed Web of Science ®Google Scholar
• Siiteri PK, Wilson JD. Testosterone formation and metabolism during male sexual differentiation in the human embryo. J Clin Endocrionol Metab. 1974;38(1):113–125.
   PubMed Web of Science ®Google Scholar
• Christine Knickmeyer R, Baron-Cohen S. Fetal testosterone and sex differences. Early Hum Dev. 2006;82(12):755–760.
   PubMed Web of Science ®Google Scholar
• Forest MG, De Peretti E, Bertrand J. Hypothalamic-pituitary-gonadal relationships in man from birth to puberty. Clin Endocrinol. 1976;5(5):551–569.
   PubMed Web of Science ®Google Scholar
• Ward IL, Ward OB, Affuso JD, et al. Fetal testosterone surge: specific modulations induced in male rats by maternal stress and/or alcohol consumption. Horm Behav. 2003;43(5):531.
   PubMed Web of Science ®Google Scholar
• Habert R, Picon R. Testosterone, dihydrotestosterone and estradiol-17 beta levels in maternal and fetal plasma and in fetal testes in the rat. J Steroid Biochem. 1984;21(2):193–198.
   PubMedGoogle Scholar
• O’Shaughnessy PJ, Baker PJ, Johnston H. The foetal Leydig cell– differentiation, function and regulation. Int J Androl. 2006;29(1):90–95. discussion 105-108.
   PubMedGoogle Scholar
• Welsh M, Saunders PT, Fisken M, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008;118(4):1479–1490.
   PubMed Web of Science ®Google Scholar
• Suzuki K, Ogino Y, Murakami R, et al. Embryonic development of mouse external genitalia: insights into a unique mode of organogenesis. Evol Dev. 2002;4(2):133–141.
   PubMed Web of Science ®Google Scholar
• Corbier P, Edwards DA, Roffi J. The neonatal testosterone surge: a comparative study. Arch Int Physiol Biochim Biophys. 1992;100(2):127–131.
   PubMed Web of Science ®Google Scholar
• Ward OB, Ward IL, Denning JH, et al. Postparturitional testosterone surge in male offspring of rats stressed and/or fed ethanol during late pregnancy. Horm Behav. 2002;41(2):229–235.
   PubMed Web of Science ®Google Scholar
• Starka L, Pospisilova H, Hill M. Free testosterone and free dihydrotestosterone throughout the life span of men. J Steroid Biochem Mol Biol. 2009;116(1–2):118–120.
   PubMed Web of Science ®Google Scholar
• Silva MA, Villasenor RMV, Marquez SR, et al. Testosterone Levels and Development of the Penile Spines and Testicular Tissue during the Postnatal Growth in Wistar Rats. Adv Sex Med. 2013;3:1–9.
   Google Scholar
• Reckelhoff JF, Zhang H, Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension. 1998;31(1 Pt 2):435–439.
   PubMed Web of Science ®Google Scholar
• Wu X, Arumugam R, Zhang N, et al. Androgen profiles during pubertal Leydig cell development in mice. Reproduction. 2010;140(1):113–121.
   PubMed Web of Science ®Google Scholar
• Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26(6):833–876.
   PubMed Web of Science ®Google Scholar
• Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. New Engl J Med. 2010;363(2):123–135.
   PubMed Web of Science ®Google Scholar
• Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev. 2003;24:313–340.
   PubMed Web of Science ®Google Scholar
• The coronary drug project. Design, methods, and baseline results. Circulation. 1973;47(3Suppl):I1–50.
   Google Scholar
• Laughlin GA, Barrett Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–75.
   PubMed Web of Science ®Google Scholar
• Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: european prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007;116:2694–2701.
   PubMed Web of Science ®Google Scholar
• Araujo AB, Dixon JM, Suarez EA, et al. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):3007–3019.
   PubMed Web of Science ®Google Scholar
• Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011;165(5):687–701.
   PubMed Web of Science ®Google Scholar
• Ruige JB, Mahmoud AM, De Bacquer D, et al. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011;97(11):870–875.
   PubMed Web of Science ®Google Scholar
• Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–2559.
   PubMed Web of Science ®Google Scholar
• Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol. 2005;63(3):280–293.
   PubMed Web of Science ®Google Scholar
• Elliott J, Kelly SE, Millar AC, et al. Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis. BMJ Open. 2017;7(11):e015284.
   PubMed Web of Science ®Google Scholar
• Shoskes DA, Hakim LS. Testosterone replacement therapy. Transl Androl Urol. 2016;5(6):812–813.
   PubMed Web of Science ®Google Scholar
• Comhaire F. Hormone replacement therapy and longevity. Andrologia. 2016;48(1):65–68.
   PubMed Web of Science ®Google Scholar
• Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050–2058.
   PubMed Web of Science ®Google Scholar
• Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13(10):1327–1351.
   PubMed Web of Science ®Google Scholar
• Corona GG, Rastrelli G, Maseroli E, et al. Testosterone Replacement Therapy and Cardiovascular Risk: a Review. World J Mens Health. 2015;33(3):130–142.
   PubMedGoogle Scholar
• Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(6):2560–2575.
   PubMed Web of Science ®Google Scholar
• Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451–1457.
   PubMed Web of Science ®Google Scholar
• Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82(1):29–39.
   PubMed Web of Science ®Google Scholar
• Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108.
   PubMed Web of Science ®Google Scholar
• Borst SE, Shuster JJ, Zou B, et al. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med. 2014;12:211.
   PubMed Web of Science ®Google Scholar
• FDA. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. 2014 Available from: https://wwwfdagov/Drugs/DrugSafety/ucm436259htm.
   Google Scholar
• Health Canada. Information Update - Possible cardiovascular problems associated with testosterone products. Available from: 2014. http://healthycanadiansgcca/recall-alert-rappel-avis/hc-sc/2014/40587a-engphp.
   Google Scholar
• Goodman N, Guay A, Dandona P, et al. American Association Of Clinical Endocrinologists And American College Of Endocrinology Position Statement On The Association Of Testosterone And Cardiovascular Risk. Endocr Pract. 2015;21(9):1066–1073.
   PubMed Web of Science ®Google Scholar
• European Medicine Agency. PRAC review does not confirm increase in heart problems with testosterone medicines. 2014 Available from: http://wwwemaeuropaeu/ema/indexjsp?curl=pages/news_and_events/news/2014/10/news_detail_002187jsp&mid=WC0b01ac058004d5c1.
   Google Scholar
• Corona G, Giagulli VA, Maseroli E, et al. Therapy Of Endocrine Disease: testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol. 2016;174(3):R99–R116.
   PubMed Web of Science ®Google Scholar
• Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706–2715.
   PubMed Web of Science ®Google Scholar
• Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–1645.
   PubMed Web of Science ®Google Scholar
• Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359–404.
   PubMed Web of Science ®Google Scholar
• Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881–887.
   PubMed Web of Science ®Google Scholar
• Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011;8(1):272–283.
   PubMed Web of Science ®Google Scholar
• Brand JS, Rovers MM, Yeap BB, et al. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies. PloS One. 2014;9(7):e100409.
   PubMed Web of Science ®Google Scholar
• Brand JS, van der Tweel I, Grobbee DE, et al. 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.
   PubMed Web of Science ®Google Scholar
• Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Pract Res Clinical Endocrinol Metab. 2013;27(4):557–579.
   PubMed Web of Science ®Google Scholar
• Ding EL, Song Y, Malik VS, et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295(11):1288–1299.
   PubMed Web of Science ®Google Scholar
• Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl. 2011;34(6 Pt 1):528–540.
   PubMed Web of Science ®Google Scholar
• Kelly DM, Jones TH. Testosterone and obesity. Obes Rev. 2015;16(7):581–606.
   PubMed Web of Science ®Google Scholar
• Whitsel EA, Boyko EJ, Matsumoto AM, et al. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med. 2001;111(4):261–269.
   PubMed Web of Science ®Google Scholar
• Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian J Androl. 2014;16(1):146–152.
   PubMed Web of Science ®Google Scholar
• Grossmann M, Hoermann R, Wittert G, et al. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin Endocrinol. 2015;83(3):344–351.
   PubMed Web of Science ®Google Scholar
• Corona G, Giagulli VA, Maseroli E, et al. Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J Endocrinol Invest. 2016;39(9):967–981.
   PubMed Web of Science ®Google Scholar
• Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2018;68(1):7–30.
   PubMed Web of Science ®Google Scholar
• Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448–4456.
   PubMed Web of Science ®Google Scholar
• Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306(21):2359–2366.
   PubMed Web of Science ®Google Scholar
• Zhao J, Zhu S, Sun L, et al. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of population-based observational studies. PloS One. 2014;9(9):e107516.
   PubMed Web of Science ®Google Scholar
• Bosco C, Bosnyak Z, Malmberg A, et al. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur Urology. 2015;68(3):386–396.
   PubMed Web of Science ®Google Scholar
• Meng F, Zhu S, Zhao J, et al. Stroke related to androgen deprivation therapy for prostate cancer: a meta-analysis and systematic review. BMC Cancer. 2016;16:180.
   PubMed Web of Science ®Google Scholar
• Haseen F, Murray LJ, Cardwell CR, et al. The effect of androgen deprivation therapy on body composition in men with prostate cancer: systematic review and meta-analysis. J Cancer Surviv. 2010;4(2):128–139.
   PubMed Web of Science ®Google Scholar
• Wang H, Sun X, Zhao L, et al. Androgen deprivation therapy is associated with diabetes: evidence from meta-analysis. J Diabetes Investig. 2016;7(4):629–636.
   PubMed Web of Science ®Google Scholar
• Bosco C, Crawley D, Adolfsson J, et al. Quantifying the evidence for the risk of metabolic syndrome and its components following androgen deprivation therapy for prostate cancer: a meta-analysis. PloS One. 2015;10(3):e0117344.
   PubMed Web of Science ®Google Scholar
• Diver MJ, Imtiaz KE, Ahmad AM, et al. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol. 2003;58(6):710–717.
   PubMed Web of Science ®Google Scholar
• Wehr E, Pilz S, Boehm BO, et al. Association of vitamin D status with serum androgen levels in men. Clin Endocrinol. 2010;73(2):243–248.
   PubMed Web of Science ®Google Scholar
• Blouin K, Boivin A, Tchernof A. Androgens and body fat distribution. J Steroid Biochem Mol Biol. 2008;108(3–5):272–280.
   PubMed Web of Science ®Google Scholar
• Shores MM, Biggs ML, Arnold AM, et al. Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. J Clin Endocrinol Metab. 2014;99(6):2061–2068.
   PubMed Web of Science ®Google Scholar
• Shores MM, Arnold AM, Biggs ML, et al. Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study. Clin Endocrinol. 2014;81(5):746–753.
   PubMed Web of Science ®Google Scholar
• Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. New Engl J Med. 2010;363(2):109–122.
   PubMed Web of Science ®Google Scholar
• Iwamoto T, Yanase T, Horie H, et al. Late-onset hypogonadism (LOH) and androgens: validity of the measurement of free testosterone levels in the diagnostic criteria in Japan. Int J Urol. 2009;16(2):168–174.
   PubMed Web of Science ®Google Scholar
• Kodama K, Tojjar D, Yamada S, et al. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36(6):1789–1796.
   PubMed Web of Science ®Google Scholar
• Min KJ, Lee CK, Park HN. The lifespan of Korean eunuchs. Curr Biol. 2012;22(18):R792–R793.
   PubMed Web of Science ®Google Scholar
• Nieschlag E, Nieschlag S, Behre HM. Lifespan and testosterone. Nature. 1993;366(6452):215.
   PubMed Web of Science ®Google Scholar
• Zirkin BR, Tenover JL. Aging and declining testosterone: past, present, and hopes for the future. J Androl. 2012;33(6):1111–1118.
   PubMedGoogle Scholar
• Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95(4):1810–1818.
   PubMed Web of Science ®Google Scholar
• Kraemer WJ, Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med. 2005;35(4):339–361.
   PubMed Web of Science ®Google Scholar
• Corona G, Rastrelli G, Monami M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 2013;168(6):829–843.
   PubMed Web of Science ®Google Scholar
• Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988;240:889–895.
   PubMed Web of Science ®Google Scholar
• Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007;28:778–808.
   PubMed Web of Science ®Google Scholar
• Harada N, Yasunaga R, Higashimura Y, et al. Glyceraldehyde-3-phosphate dehydrogenase enhances transcriptional activity of androgen receptor in prostate cancer cells. J Biol Chem. 2007;282(31):22651–22661.
   PubMed Web of Science ®Google Scholar
• Harada N, Ohmori Y, Yamaji R, et al. ARA24/Ran enhances the androgen-dependent NH2- and COOH-terminal interaction of the androgen receptor. Biochem Biophys Res Commun. 2008;373(3):373–377.
   PubMed Web of Science ®Google Scholar
• Harada N, Yokoyama T, Yamaji R, et al. RanBP10 acts as a novel coactivator for the androgen receptor. Biochem Biophys Res Commun. 2008;368(1):121–125.
   PubMed Web of Science ®Google Scholar
• Harada N, Takagi T, Nakano Y, et al. Protein arginine methyltransferase 10 is required for androgen-dependent proliferation of LNCaP prostate cancer cells. Biosci Biotechnol Biochem. 2015;79(9):1430–1437.
   PubMed Web of Science ®Google Scholar
• Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23:175–200.
   PubMed Web of Science ®Google Scholar
• Wang L, Hsu CL, Chang C. Androgen receptor corepressors: an overview. Prostate. 2005;63:117–130.
   PubMed Web of Science ®Google Scholar
• Palazzolo I, Gliozzi A, Rusmini P, et al. The role of the polyglutamine tract in androgen receptor. J Steroid Biochem Mol Biol. 2008;108(3–5):245–253.
   PubMed Web of Science ®Google Scholar
• Harada N, Mitani T, Higashimura Y, et al. Involvement of three glutamine tracts in human androgen receptor transactivation. J Steroid Biochem Mol Biol. 2010;118(1–2):77–84.
   PubMed Web of Science ®Google Scholar
• Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.
   PubMed Web of Science ®Google Scholar
• Lin HY, Yu IC, Wang RS, et al. Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology. 2008;47(6):1924–1935.
   PubMed Web of Science ®Google Scholar
• Yu IC, Lin HY, Liu NC, et al. Hyperleptinemia without obesity in male mice lacking androgen receptor in adipose tissue. Endocrinology. 2008;149(5):2361–2368.
   PubMed Web of Science ®Google Scholar
• McInnes KJ, Smith LB, Hunger NI, et al. Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis. Diabetes. 2012;61(5):1072–1081.
   PubMed Web of Science ®Google Scholar
• Ophoff J, Van Proeyen K, Callewaert F, et al. Androgen signaling in myocytes contributes to the maintenance of muscle mass and fiber type regulation but not to muscle strength or fatigue. Endocrinology. 2009;150(8):3558–3566.
   PubMed Web of Science ®Google Scholar
• Zeier M, Schonherr R, Amann K, et al. Effects of testosterone on glomerular growth after uninephrectomy. Nephrol Dial Transplant. 1998;13(9):2234–2240.
   PubMed Web of Science ®Google Scholar
• Ikeda Y, Aihara K, Sato T, et al. Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. J Biol Chem. 2005;280(33):29661–29666.
   PubMed Web of Science ®Google Scholar
• Kochakian CD, Tillotson C, Endahl GL. Castration and the growth of muscles in the rat. Endocrinology. 1956;58(2):226–231.
   PubMed Web of Science ®Google Scholar
• Navarro G, Xu W, Jacobson DA, et al. Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male. Cell Metabolism. 2016;23(5):837–851.
   PubMed Web of Science ®Google Scholar
• Harada N, Yoda Y, Yotsumoto Y, et al. Androgen signaling expands beta-cell mass in male rats and beta-cell androgen receptor is degraded under high-glucose conditions. Am J Physiol Endocrinol Metab. 2017;314:E274–E286.
   PubMed Web of Science ®Google Scholar
• De Gendt K, Verhoeven G. Tissue- and cell-specific functions of the androgen receptor revealed through conditional knockout models in mice. Mol Cell Endocrinol. 2012;352(1–2):13–25.
   PubMed Web of Science ®Google Scholar
• Yu IC, Lin HY, Sparks JD, et al. Androgen receptor roles in insulin resistance and obesity in males: the linkage of androgen-deprivation therapy to metabolic syndrome. Diabetes. 2014;63(10):3180–3188.
   PubMed Web of Science ®Google Scholar
• Chang C, Yeh S, Lee SO, et al. Androgen Receptor (AR) Pathophysiological Roles in Androgen Related Diseases in Skin, Bone/Muscle,Metabolic Syndrome and Neuron/Immune Systems: lessons Learned from Mice Lacking AR in Specific Cells. Nucl Recept Signal. 2013;11:e001.
   PubMedGoogle Scholar
• Kerkhofs S, Denayer S, Haelens A, et al. Androgen receptor knockout and knock-in mouse models. J Mol Endocrinol. 2009;42(1):11–17.
   PubMed Web of Science ®Google Scholar
• Rana K, Davey RA, Zajac JD. Human androgen deficiency: insights gained from androgen receptor knockout mouse models. Asian J Androl. 2014;16(2):169–177.
   PubMed Web of Science ®Google Scholar
• Chang C, Lee SO, Wang RS, et al. Androgen receptor (AR) physiological roles in male and female reproductive systems: lessons learned from AR-knockout mice lacking AR in selective cells. Biol Reprod. 2013;89(1):21.
   PubMed Web of Science ®Google Scholar
• Verhoeven G, Willems A, Denolet E, et al. Androgens and spermatogenesis: lessons from transgenic mouse models. Philos Trans R Soc Lond B Biol Sci. 2010;365(1546):1537–1556.
   PubMed Web of Science ®Google Scholar
• Harada N, Hanaoka R, Horiuchi H, et al. Castration influences intestinal microflora and induces abdominal obesity in high-fat diet-fed mice. Sci Rep. 2016;6:23001.
   PubMed Web of Science ®Google Scholar
• Bourghardt J, Wilhelmson AS, Alexanderson C, et al. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology. 2010;151(11):5428–5437.
   PubMed Web of Science ®Google Scholar
• Huang CK, Pang H, Wang L, et al. New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis. Hypertension. 2014;63(6):1345–1353.
   PubMed Web of Science ®Google Scholar
• Takov K, Wu J, Denvir MA, et al. The role of androgen receptors in atherosclerosis. Mol Cell Endocrinol. 2017. DOI:10.1016/j.mce.2017.10.006
   PubMed Web of Science ®Google Scholar
• Field RA. Effect of castration on meat quality and quantity. J Anim Sci. 1971;32(5):849–858.
   PubMed Web of Science ®Google Scholar
• Balaji N, Sivaraman T, Sivakumar T, et al. Influence of castration on growth rate and body measurements in large white yorkshire pigs. Indian J Anim Res. 2006;40(2):123–126.
   Google Scholar
• Qing Z, Xian Z, Hua Z. The effect of early castration on weight gain in male rabbits. In: Cahiers Options Mediterraneennes. 1994;8:401–405.
   Google Scholar
• Payne AP. A comparison of the effects of androstenedione, dihydrotestosterone and testosterone propionate on aggression in the castrated male golden hamster. Physiol Behav. 1974;13(1):21–26.
   PubMed Web of Science ®Google Scholar
• Swanson HH. Effects of pre- and post-pubertal gonadectomy on sex differences in growth, adrenal and pituitary weights of hamsters. J Endocrinol. 1967;39(4):555–564.
   PubMed Web of Science ®Google Scholar
• Gentry RT, Wade GN. Androgenic control of food intake and body weight in male rats. J Comp Physiol Psychol. 1976;90(1):18–25.
   PubMed Web of Science ®Google Scholar
• Krotkiewski M, Kral JG, Karlsson J. Effects of castration and testosterone substitution on body composition and muscle metabolism in rats. Acta Physiol Scand. 1980;109(3):233–237.
   PubMedGoogle Scholar
• Inoue T, Zakikhani M, David S, et al. Effects of castration on insulin levels and glucose tolerance in the mouse differ from those in man. Prostate. 2010;70(15):1628–1635.
   PubMed Web of Science ®Google Scholar
• Wade GN, Gray JM. Gonadal effects on food intake and adiposity: a metabolic hypothesis. Physiol Behav. 1979;22(3):583–593.
   PubMed Web of Science ®Google Scholar
• Sato T, Matsumoto T, Yamada T, et al. Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochem Biophys Res Commun. 2003;300:167–171.
   PubMed Web of Science ®Google Scholar
• Lin HY, Xu Q, Yeh S, et al. Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes. 2005;54(6):1717–1725.
   PubMed Web of Science ®Google Scholar
• Fan W, Yanase T, Nomura M, et al. 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. 2005;54:1000–1008.
   PubMed Web of Science ®Google Scholar
• Rana K, Fam BC, Clarke MV, et al. Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance. Am J Physiol Endocrinol Metab. 2011;301(5):E767–E778.
   PubMed Web of Science ®Google Scholar
• Dubois V, Laurent MR, Jardi F, et al. Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice. Endocrinology. 2016;157(2):648–665.
   PubMed Web of Science ®Google Scholar
• Ophoff J, Callewaert F, Venken K, et al. Physical activity in the androgen receptor knockout mouse: evidence for reversal of androgen deficiency on cancellous bone. Biochem Biophys Res Commun. 2009;378(1):139–144.
   PubMed Web of Science ®Google Scholar
• Notini AJ, Davey RA, McManus JF, et al. Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. J Mol Endocrinol. 2005;35(3):547–555.
   PubMed Web of Science ®Google Scholar
• MacLean HE, Chiu WS, Notini AJ, et al. Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice. FASEB J. 2008;22(8):2676–2689.
   PubMed Web of Science ®Google Scholar
• Adthapanyawanich K, Kumchantuek T, Nakata H, et al. Morphology and gene expression profile of the submandibular gland of androgen-receptor-deficient mice. Arch Oral Biol. 2015;60(2):320–332.
   PubMed Web of Science ®Google Scholar
• Ihemelandu EC, Ibebunjo C. Comparison of the effect of castration on the development of postural and non-postural muscles of mice. Acta Anat. 1992;143(4):283–288.
   PubMedGoogle Scholar
• Nikolaenko L, Jia Y, Wang C, et al. Testosterone replacement ameliorates nonalcoholic fatty liver disease in castrated male rats. Endocrinology. 2014;155(2):417–428.
   PubMed Web of Science ®Google Scholar
• Rothwell NJ, Stock MJ. Energy balance and brown fat activity in adrenalectomized male, female, and castrated male rats. Metabolism. 1986;35(7):657–660.
   PubMed Web of Science ®Google Scholar
• Christoffersen B, Raun K, Svendsen O, et al. Evalution of the castrated male Sprague-Dawley rat as a model of the metabolic syndrome and type 2 diabetes. Int J Obes. 2006;30(8):1288–1297.
   Web of Science ®Google Scholar
• Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology. 2004;63(4):742–745.
   PubMed Web of Science ®Google Scholar
• Harada N, Hanaoka R, Hanada K, et al. Hypogonadism alters cecal and fecal microbiota in male mice. Gut Microbes. 2016;7(6):533–539.
   PubMed Web of Science ®Google Scholar
• Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010;11(1):11–18.
   PubMed Web of Science ®Google Scholar
• Yu IC, Lin HY, Liu NC, et al. Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-kappaB-mediated PTP1B expression. Diabetes. 2013;62(2):411–423.
   PubMed Web of Science ®Google Scholar
• Raskin K, De Gendt K, Duittoz A, et al. Conditional inactivation of androgen receptor gene in the nervous system: effects on male behavioral and neuroendocrine responses. J Neurosci. 2009;29(14):4461–4470.
   PubMed Web of Science ®Google Scholar
• Juntti SA, Tollkuhn J, Wu MV, et al. The androgen receptor governs the execution, but not programming, of male sexual and territorial behaviors. Neuron. 2010;66(2):260–272.
   PubMed Web of Science ®Google Scholar
• Senmaru T, Fukui M, Okada H, et al. Testosterone deficiency induces markedly decreased serum triglycerides, increased small dense LDL, and hepatic steatosis mediated by dysregulation of lipid assembly and secretion in mice fed a high-fat diet. Metabolism. 2013;62(6):851–860.
   PubMed Web of Science ®Google Scholar
• Delzenne NM, Cani PD. Interaction between obesity and the gut microbiota: relevance in nutrition. Annu Rev Nutr. 2011;31:15–31.
   PubMed Web of Science ®Google Scholar
• Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–1031.
   PubMed Web of Science ®Google Scholar
• Lam YY, Mitchell AJ, Holmes AJ, et al. Role of the gut in visceral fat inflammation and metabolic disorders. Obesity. 2011;19(11):2113–2120.
   PubMed Web of Science ®Google Scholar
• Ley RE, Turnbaugh PJ, Klein S, et al. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–1023.
   PubMed Web of Science ®Google Scholar
• Yurkovetskiy L, Burrows M, Khan AA, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2):400–412.
   PubMed Web of Science ®Google Scholar
• Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–1088.
   PubMed Web of Science ®Google Scholar
• Org E, Mehrabian M, Parks BW, et al. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016;7(4):313–322.
   PubMed Web of Science ®Google Scholar
• Moreno-Indias I, Sanchez-Alcoholado L, Sanchez-Garrido MA, et al. Neonatal androgen exposure causes persistent gut microbiota dysbiosis related to metabolic disease in adult female rats. Endocrinology. 2016;157(12):4888–4898.
   PubMed Web of Science ®Google Scholar
• Heitmann BL, Frederiksen P. Thigh circumference and risk of heart disease and premature death: prospective cohort study. BMJ. 2009;339:b3292.
   PubMed Web of Science ®Google Scholar
• Chambon C, Duteil D, Vignaud A, et al Myocytic androgen receptor controls the strength but not the mass of limb muscles. Proc Natl Acad Sci U S A. 2010;107(32):14327–14332.
   PubMed Web of Science ®Google Scholar
• Callewaert F, Venken K, Ophoff J, et al. Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha. FASEB J. 2009;23(1):232–240.
   PubMed Web of Science ®Google Scholar
• Dubois V, Laurent MR, Sinnesael M, et al. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle. FASEB J. 2014;28(7):2979–2994.
   PubMed Web of Science ®Google Scholar
• Bindels LB, Delzenne NM. Muscle wasting: the gut microbiota as a new therapeutic target?. Int J Biochem Cell Biol. 2013;45(10):2186–2190.
   PubMed Web of Science ®Google Scholar
• Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26(3):439–451.
   PubMed Web of Science ®Google Scholar
• Nishizawa H, Shimomura I, Kishida K, et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes. 2002;51(9):2734–2741.
   PubMed Web of Science ®Google Scholar
• Laughlin GA, 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. 2006;65(4):506–513.
   PubMed Web of Science ®Google Scholar
• Laughlin GA, Barrett-Connor E, May S. Sex-specific determinants of serum adiponectin in older adults: the role of endogenous sex hormones. Int J Obes. 2007;31(3):457–465.
   Web of Science ®Google Scholar
• Lanfranco F, Zitzmann M, Simoni M, et al. Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy. Clin Endocrinol. 2004;60(4):500–507.
   PubMed Web of Science ®Google Scholar
• Xia F, Xu X, Zhai H, et al. Castration-induced testosterone deficiency increases fasting glucose associated with hepatic and extra-hepatic insulin resistance in adult male rats. Reprod Biol Endocrinol. 2013;11:106.
   PubMed Web of Science ®Google Scholar
• Rhodes CJ. Type 2 diabetes-a matter of beta-cell life and death?. Science. 2005;307(5708):380–384.
   PubMed Web of Science ®Google Scholar
• Cho JH, Kim JW, Shin JA, et al. beta-cell mass in people with type 2 diabetes. J Diabetes Investig. 2011;2(1):6–17.
   PubMed Web of Science ®Google Scholar
• Ra D. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–795.
   PubMed Web of Science ®Google Scholar
• Ferrannini E, Mari A. beta-Cell function in type 2 diabetes. Metabolism. 2014;63(10):1217–1227.
   PubMed Web of Science ®Google Scholar
• Morimoto S, Morales A, Zambrano E, et al. Sex steroids effects on the endocrine pancreas. J Steroid Biochem Mol Biol. 2010;122(4):107–113.
   PubMed Web of Science ®Google Scholar
• Harada N, Katsuki T, Takahashi Y, et al. Androgen receptor silences thioredoxin-interacting protein and competitively inhibits glucocorticoid receptor-mediated apoptosis in pancreatic β-cells. J Cell Biochem. 2015;116(6):998–1006.
   PubMed Web of Science ®Google Scholar
• Morimoto S, Fernandez-Mejia C, Romero-Navarro G, et al. Testosterone effect on insulin content, messenger ribonucleic acid levels, promoter activity, and secretion in the rat. Endocrinology. 2001;142(4):1442–1447.
   PubMed Web of Science ®Google Scholar
• Morimoto S, Mendoza-Rodriguez CA, Hiriart M, et al. Protective effect of testosterone on early apoptotic damage induced by streptozotocin in rat pancreas. J Endocrinol. 2005;187(2):217–224.
   PubMed Web of Science ®Google Scholar
• Palomar-Morales M, Morimoto S, Mendoza-Rodriguez CA, et al. The protective effect of testosterone on streptozotocin-induced apoptosis in beta cells is sex specific. Pancreas. 2010;39(2):193–200.
   PubMed Web of Science ®Google Scholar
• Rossini AA, Williams RM, Appel MC, et al. Sex differences in the multiple-dose streptozotocin model of diabetes. Endocrinology. 1978;103(4):1518–1520.
   PubMed Web of Science ®Google Scholar
• Li RJ, Qiu SD, Wang HX, et al. Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus. Apoptosis. 2008;13(8):959–971.
   PubMed Web of Science ®Google Scholar
• Xu G, Kaneto H, Laybutt DR, et al. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007;56(6):1551–1558.
   PubMed Web of Science ®Google Scholar
• Otani K, Kulkarni RN, Baldwin AC, et al. Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice. Am J Physiol Endocrinol Metab. 2004;286(1):E41–E49.
   PubMed Web of Science ®Google Scholar
• Hribal ML, Perego L, Lovari S, et al. Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans. FASEB J. 2003;17(10):1340–1342.
   PubMed Web of Science ®Google Scholar
• Vanderford NL. Regulation of beta-cell-specific and glucose-dependent MafA expression. Islets. 2011;3(1):35–37.
   PubMed Web of Science ®Google Scholar
• Chen F, Sha M, Wang Y, et al. Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models. Diabetologia. 2016;59(2):316–324.
   PubMed Web of Science ®Google Scholar
• Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28(2):187–218.
   PubMed Web of Science ®Google Scholar
• Brown LM, Clegg DJ. Central effects of estradiol in the regulation of food intake, body weight, and adiposity. J Steroid Biochem Mol Biol. 2010;122(1–3):65–73.
   PubMed Web of Science ®Google Scholar
• Harada N, Inui H, Yamaji R. Competitive and compensatory effects of androgen signaling and glucocorticoid signaling. Receptors Clin Investig. 2015;2(3):e785.
   Google Scholar