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Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans

André Tchernof, Dannick Brochu, Ina Maltais‐Payette, Mohamed Fouad Mansour, Geneviève B. Marchand, Anne‐Marie Carreau, Jordanna Kapeluto

10.1002/cphy.c170009

Source: Volume 8, Issue 4, October 2018

Published online: September 2018

Full Article on Wiley Online Library



ABSTRACT

The sexual dimorphism in human body fat distribution suggests a causal role for sex hormones. This is of particular importance when considering the role of excess visceral adipose tissue accumulation as a critical determinant of obesity‐related cardiometabolic alterations. Scientific literature on the modulation of body fat distribution by androgens in humans is abundant, remarkably inconsistent and difficult to summarize. We reviewed relevant literature on this topic, with a particular emphasis on androgen replacement, androgen effects on selected parameters of adipose tissue function and adipose tissue steroid‐converting enzymes. In men, low androgenic status mostly reflected by reduced total testosterone is a frequent feature of visceral obesity and the metabolic syndrome. Regarding testosterone therapy, however, studies must be appreciated in the context of current controversies on their cardiovascular effects. Analyses of available studies suggest that decreases in waist circumference in response to testosterone are more likely observed in men with low levels of testosterone and high BMI at study onset. In women with androgen excess, higher testosterone and free testosterone levels are fairly consistent predictors of increased abdominal and/or visceral adipose tissue accumulation, which is not the case in nonhyperandrogenic women. Regarding mechanisms, androgens decrease adipogenesis and markers of lipid storage in vitro in men and women. Evidence also suggest that local steroid transformations by adipose tissue steroid‐converting enzymes expressed in a depot‐specific fashion may play a role in androgen‐mediated modulation of body fat distribution. Accumulating evidence shows that androgens are critical modulators of body fat distribution in both men and women. © 2018 American Physiological Society. Compr Physiol 8:1253‐1290, 2018.

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Figure 1. Figure 1. Illustration of the interindividual variability in visceral fat accumulation for a given total body fat mass in women. Computed tomography axial images were obtained at the L4‐L5 vertebrae level in four women examined in the supine position. The visceral cavity was delineated and adipose tissue was highlighted and quantified as described in (73). Visceral adipose tissue (VAT) is shown in grey on the bottom scan of each panel. Total body fat mass was measured by dual‐energy x‐ray absorptiometry. For consistency, waist circumference (WC) values were obtained by measuring the perimeter of each scan by image analysis. Other anthropometric measurements were obtained in a standardized manner. The image in Panel A shows a cross‐section of the abdomen of a woman with low VAT accumulation and a propensity for subcutaneous adipose tissue (SAT) storage. She is characterized by the highest BMI value and also has the highest SAT area (367 cm2). Images in Panels B and C show abdominal cross‐sections from women with intermediary amounts of VAT. Their SAT areas are 260 and 327 cm2, respectively. The image in Panel D shows a cross‐section of the abdomen of a woman with a high propensity for VAT storage. SAT area is 281 cm2. These substantial differences in VAT accumulation are noted in four women with similar heights (±5 cm) and rigorously similar body fat mass values (±100 g, 0.4% difference).
Figure 2. Figure 2. Contrasting effects of available randomized control trials (RCTs) and observational studies describing the effect of testosterone replacement therapy (TRT) on the body mass index (BMI). Studies included in this figure were identified as described in the text. Most RCTs reported a nonsignificant effect of TRT on BMI whereas a higher proportion of observational studies reported a significant decrease in BMI following TRT. Numerical values on the charts indicate the number of study treatment groups in each category.
Figure 3. Figure 3. Contrasting effects of available randomized control trials (RCTs) and observational studies describing the effect of testosterone replacement therapy (TRT) on waist circumference (WC). Studies included in this figure were identified as described in the text. Most RCTs reported a nonsignificant effect of TRT on WC whereas a much higher proportion of observational studies reported a significant decrease in WC following TRT. Numerical values on the charts indicate the number of study treatment groups in each category.
Figure 4. Figure 4. Correlation between average baseline total testosterone concentration and initial BMI in trials on testosterone replacement therapy (TRT) that observed either a decrease in waist circumference (WC) (grey squares), or no change in WC (black circles). Data were extracted from randomized control trials and observational studies as described in the text. Statistical significance of the change in WC was used as described in each publication. The correlation was significant (Spearman rank correlation coefficient ‐0.41, P < 0.01). None of the studies reporting a significant effect of TRT on WC had average baseline total testosterone values above 11 nmol/L.
Figure 5. Figure 5. Correlation between average baseline total testosterone concentration and initial waist circumference (WC) in trials on testosterone replacement therapy (TRT) that observed either a decrease in WC (gray squares), or no change in WC (black circles). Data were extracted from randomized control trials and observational studies as described in the text. Statistical significance of the change in WC was used as described in each publication. The correlation was close to significance (Spearman rank correlation coefficient −0.30, P < 0.06). None of the studies reporting a significant effect of TRT on WC had average baseline total testosterone values above 11 nmol/L.
Figure 6. Figure 6. Schematic representation of the pathways of androgen synthesis and inactivation in adipose tissue. This is a partial version of the figure in our review article (265). HSD, hydroxysteroid dehydrogenase; P450 arom, P450 aromatase; E1, estrone; E2, estradiol; 5α‐red, 5α‐reductase; UGT2B15, UDP‐glucuronosyltransferase 2B15; G, glucuronide (two isomers of the glucuronide derivative are formed, 3α and 17β).
Figure 7. Figure 7. Tridimensional confocal imaging of 17β‐HSD type 2 in human adipose tissues. (A) CD31 labelling (endothelial cell marker); (B) 17β‐HSD type 2 labelling; (C) merging of the labelings; and (D) isotype controls. The experiment shows a clear colocalization of CD31 and 17β‐HSD type 2 in the blood vessels of the tissue (97). Reprinted with permission.
Figure 8. Figure 8. Activity, expression, and localization of 17β‐HSD type 2 in human adipose microvascular endothelial cells. (A) Androstenedione formation rate after 24 h incubation with 0.03 µmol/L 14C‐testosterone and inhibition with EM‐919 (EM); (B) mRNA expression level of CD31 and 17β‐HSD type 2 expressed as number of copies/µg total RNA; (C and D) immunohistochemical localization of 17β‐HSD type 2; and (E and F) rabbit antiserum. Scale bar 20 µm. Mean ± SEM are shown. *P < 0.05 (97). Reprinted with permission.
Figure 9. Figure 9. Activity of 5α‐reductases type 1, 2, or 3 and inhibitory effects of 4‐MA or finasteride in HEK‐293 stably overexpressing each isoenzyme. (A) Untransfected cells; (B) 5α‐reductase type 1‐expressing cells; (C) 5α‐reductase type 2‐expressing cells; and (D) 5α‐reductase type 3‐expressing cells. Thin‐layer chromatography images and corresponding densitometric analyses are shown for each cell line. A‐dione, androstanedione; 4‐dione, androstenedione; FINA, finasteride. Mean ± SEM (98). 4‐MA corresponds to 17β‐N,N‐diethylcarbamoyl‐4‐methyl‐4‐aza‐5α‐androstan‐3‐one. Reprinted with permission.
Figure 10. Figure 10. Effect of 5α‐reductase inhibitors on preadipocyte differentiation. G3PDH activity in differentiating subcutaneous preadipocytes treated with (A) androstenedione (4‐dione, n = 7) and (B) 500 nmol/L of 4‐MA or (C) finasteride (FINA) over 14 days. G3PDH activity in differentiating subcutaneous preadipocytes treated with (D) testosterone (Testo, n = 5) and (E) 500 nmol/L of 4‐MA or (F) finasteride (FINA) over 14 days. G3PDH activity expressed as % of control (CTL). Mean ± SEM. *P < 0.05 (98). Reprinted with permission.


Figure 1. Illustration of the interindividual variability in visceral fat accumulation for a given total body fat mass in women. Computed tomography axial images were obtained at the L4‐L5 vertebrae level in four women examined in the supine position. The visceral cavity was delineated and adipose tissue was highlighted and quantified as described in (73). Visceral adipose tissue (VAT) is shown in grey on the bottom scan of each panel. Total body fat mass was measured by dual‐energy x‐ray absorptiometry. For consistency, waist circumference (WC) values were obtained by measuring the perimeter of each scan by image analysis. Other anthropometric measurements were obtained in a standardized manner. The image in Panel A shows a cross‐section of the abdomen of a woman with low VAT accumulation and a propensity for subcutaneous adipose tissue (SAT) storage. She is characterized by the highest BMI value and also has the highest SAT area (367 cm2). Images in Panels B and C show abdominal cross‐sections from women with intermediary amounts of VAT. Their SAT areas are 260 and 327 cm2, respectively. The image in Panel D shows a cross‐section of the abdomen of a woman with a high propensity for VAT storage. SAT area is 281 cm2. These substantial differences in VAT accumulation are noted in four women with similar heights (±5 cm) and rigorously similar body fat mass values (±100 g, 0.4% difference).


Figure 2. Contrasting effects of available randomized control trials (RCTs) and observational studies describing the effect of testosterone replacement therapy (TRT) on the body mass index (BMI). Studies included in this figure were identified as described in the text. Most RCTs reported a nonsignificant effect of TRT on BMI whereas a higher proportion of observational studies reported a significant decrease in BMI following TRT. Numerical values on the charts indicate the number of study treatment groups in each category.


Figure 3. Contrasting effects of available randomized control trials (RCTs) and observational studies describing the effect of testosterone replacement therapy (TRT) on waist circumference (WC). Studies included in this figure were identified as described in the text. Most RCTs reported a nonsignificant effect of TRT on WC whereas a much higher proportion of observational studies reported a significant decrease in WC following TRT. Numerical values on the charts indicate the number of study treatment groups in each category.


Figure 4. Correlation between average baseline total testosterone concentration and initial BMI in trials on testosterone replacement therapy (TRT) that observed either a decrease in waist circumference (WC) (grey squares), or no change in WC (black circles). Data were extracted from randomized control trials and observational studies as described in the text. Statistical significance of the change in WC was used as described in each publication. The correlation was significant (Spearman rank correlation coefficient ‐0.41, P < 0.01). None of the studies reporting a significant effect of TRT on WC had average baseline total testosterone values above 11 nmol/L.


Figure 5. Correlation between average baseline total testosterone concentration and initial waist circumference (WC) in trials on testosterone replacement therapy (TRT) that observed either a decrease in WC (gray squares), or no change in WC (black circles). Data were extracted from randomized control trials and observational studies as described in the text. Statistical significance of the change in WC was used as described in each publication. The correlation was close to significance (Spearman rank correlation coefficient −0.30, P < 0.06). None of the studies reporting a significant effect of TRT on WC had average baseline total testosterone values above 11 nmol/L.


Figure 6. Schematic representation of the pathways of androgen synthesis and inactivation in adipose tissue. This is a partial version of the figure in our review article (265). HSD, hydroxysteroid dehydrogenase; P450 arom, P450 aromatase; E1, estrone; E2, estradiol; 5α‐red, 5α‐reductase; UGT2B15, UDP‐glucuronosyltransferase 2B15; G, glucuronide (two isomers of the glucuronide derivative are formed, 3α and 17β).


Figure 7. Tridimensional confocal imaging of 17β‐HSD type 2 in human adipose tissues. (A) CD31 labelling (endothelial cell marker); (B) 17β‐HSD type 2 labelling; (C) merging of the labelings; and (D) isotype controls. The experiment shows a clear colocalization of CD31 and 17β‐HSD type 2 in the blood vessels of the tissue (97). Reprinted with permission.


Figure 8. Activity, expression, and localization of 17β‐HSD type 2 in human adipose microvascular endothelial cells. (A) Androstenedione formation rate after 24 h incubation with 0.03 µmol/L 14C‐testosterone and inhibition with EM‐919 (EM); (B) mRNA expression level of CD31 and 17β‐HSD type 2 expressed as number of copies/µg total RNA; (C and D) immunohistochemical localization of 17β‐HSD type 2; and (E and F) rabbit antiserum. Scale bar 20 µm. Mean ± SEM are shown. *P < 0.05 (97). Reprinted with permission.


Figure 9. Activity of 5α‐reductases type 1, 2, or 3 and inhibitory effects of 4‐MA or finasteride in HEK‐293 stably overexpressing each isoenzyme. (A) Untransfected cells; (B) 5α‐reductase type 1‐expressing cells; (C) 5α‐reductase type 2‐expressing cells; and (D) 5α‐reductase type 3‐expressing cells. Thin‐layer chromatography images and corresponding densitometric analyses are shown for each cell line. A‐dione, androstanedione; 4‐dione, androstenedione; FINA, finasteride. Mean ± SEM (98). 4‐MA corresponds to 17β‐N,N‐diethylcarbamoyl‐4‐methyl‐4‐aza‐5α‐androstan‐3‐one. Reprinted with permission.


Figure 10. Effect of 5α‐reductase inhibitors on preadipocyte differentiation. G3PDH activity in differentiating subcutaneous preadipocytes treated with (A) androstenedione (4‐dione, n = 7) and (B) 500 nmol/L of 4‐MA or (C) finasteride (FINA) over 14 days. G3PDH activity in differentiating subcutaneous preadipocytes treated with (D) testosterone (Testo, n = 5) and (E) 500 nmol/L of 4‐MA or (F) finasteride (FINA) over 14 days. G3PDH activity expressed as % of control (CTL). Mean ± SEM. *P < 0.05 (98). Reprinted with permission.
References
 1.Agledahl I, Hansen JB, Svartberg J. Impact of testosterone treatment on postprandial triglyceride metabolism in elderly men with subnormal testosterone levels. Scand J Clin Lab Invest 68: 641‐648, 2008.
 2.Allan CA, Strauss BJ, Burger HG, Forbes EA, McLachlan RI. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab 93: 139‐146, 2008.
 3.Anderson LA, McTernan PG, Harte AL, Barnett AH, Kumar S. The regulation of HSL and LPL expression by DHT and flutamide in human subcutaneous adipose tissue. Diabetes Obes Metab 4: 209‐213, 2002.
 4.Andersson S, Russell DW. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha‐reductases. Proc Natl Acad Sci U S A 87: 3640‐3644, 1990.
 5.Arafa M, Zohdy W, Aboulsoud S, Shamloul R. Prevalence of late‐onset hypogonadism in men with type 2 diabetes mellitus. Andrologia 44(Suppl 1): 756‐763, 2012.
 6.Armellini F, Zamboni M, Castelli S, Robbi R, Mino A, Todesco T, Bergamo‐Andreis IA, Bosello O. Interrelationships between intraabdominal fat and total serum testosterone levels in obese women. Metabolism 43: 390‐395, 1994.
 7.Arnlov J, Pencina MJ, Amin S, Nam BH, Benjamin EJ, Murabito JM, Wang TJ, Knapp PE, D'Agostino RB, Sr., Bhasin S, Vasan RS. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 145: 176‐184, 2006.
 8.Ates S, Yesil G, Sevket O, Molla T, Yildiz S. Comparison of metabolic profile and abdominal fat distribution between karyotypically normal women with premature ovarian insufficiency and age matched controls. Maturitas 79: 306‐310, 2014.
 9.Aversa A, Bruzziches R, Francomano D, Greco EA, Fornari R, Di Luigi L, Lenzi A, Migliaccio S. Effects of long‐acting testosterone undecanoate on bone mineral density in middle‐aged men with late‐onset hypogonadism and metabolic syndrome: Results from a 36 months controlled study. Aging Male 15: 96‐102, 2012.
 10.Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, Spera G. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle‐aged men with late‐onset hypogonadism and metabolic syndrome: Results from a 24‐month, randomized, double‐blind, placebo‐controlled study. J Sex Med 7: 3495‐3503, 2010.
 11.Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest 33: 776‐783, 2010.
 12.Aydin K, Cinar N, Aksoy DY, Bozdag G, Yildiz BO. Body composition in lean women with polycystic ovary syndrome: Effect of ethinyl estradiol and drospirenone combination. Contraception 87: 358‐362, 2013.
 13.Azzouni F, Mohler J. Role of 5alpha‐reductase inhibitors in benign prostatic diseases. Prostate Cancer Prostatic Dis 15: 222‐230, 2012.
 14.Barber TM, Golding SJ, Alvey C, Wass JA, Karpe F, Franks S, McCarthy MI. Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome. J Clin Endocrinol Metab 93: 999‐1004, 2008.
 15.Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede‐Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S. Adverse events associated with testosterone administration. N Engl J Med 363: 109‐122, 2010.
 16.Battaglia C, Battaglia B, Mancini F, Paradisi R, Fabbri R, Venturoli S. Ultrasonographic extended‐view technique for evaluation of abdominal fat distribution in lean women with polycystic ovary syndrome. Acta Obstet Gynecol Scand 90: 600‐608, 2011.
 17.Behre HM, Tammela TL, Arver S, Tolra JR, Bonifacio V, Lamche M, Kelly J, Hiemeyer F, Giltay EJ, Gooren LJ. A randomized, double‐blind, placebo‐controlled trial of testosterone gel on body composition and health‐related quality‐of‐life in men with hypogonadal to low‐normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open‐label follow‐up. Aging Male 15: 198‐207, 2012.
 18.Bélanger C, Hould FS, Lebel S, Biron S, Brochu G, Tchernof A. Omental and subcutaneous adipose tissue steroid levels in obese men. Steroids 71: 674‐682, 2006.
 19.Bélanger C, Luu‐The V, Dupont P, Tchernof A. Adipose tissue intracrinology: Potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Horm Metab Res 34: 737‐745, 2002.
 20.Bellemare V, Laberge P, Noel S, Tchernof A, Luu‐The V. Differential estrogenic 17beta‐hydroxysteroid dehydrogenase activity and type 12 17beta‐hydroxysteroid dehydrogenase expression levels in preadipocytes and differentiated adipocytes. J Steroid Biochem Mol Biol 114: 129‐134, 2009.
 21.Beltran‐Sanchez H, Harhay MO, Harhay MM, McElligott S. Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999‐2010. J Am Coll Cardiol 62: 697‐703, 2013.
 22.Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM, Task Force ES. Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95: 2536‐2559, 2010.
 23.Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R. Testosterone replacement increases fat‐free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 82: 407‐413, 1997.
 24.Bhattacharya RK, Khera M, Blick G, Kushner H, Nguyen D, Miner MM. Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: Data from the Testim Registry in the US (TRiUS). BMC Endocr Disord 11: 18, 2011.
 25.Blouin K, Blanchette S, Richard C, Dupont P, Luu‐The V, Tchernof A. Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women. Am J Physiol Endocrinol Metab 288: E398‐404, 2005.
 26.Blouin K, Boivin A, Tchernof A. Androgens and body fat distribution. J Steroid Biochem Mol Biol 108: 272‐280, 2008.
 27.Blouin K, Despres JP, Couillard C, Tremblay A, Prud'homme D, Bouchard C, Tchernof A. Contribution of age and declining androgen levels to features of the metabolic syndrome in men. Metabolism 54: 1034‐1040, 2005.
 28.Blouin K, Nadeau M, Mailloux J, Daris M, Lebel S, Luu‐The V, Tchernof A. Pathways of adipose tissue androgen metabolism in women: Depot differences and modulation by adipogenesis. Am J Physiol Endocrinol Metab 296: E244‐255, 2009.
 29.Blouin K, Nadeau M, Perreault M, Veilleux A, Drolet R, Marceau P, Mailloux J, Luu‐The V, Tchernof A. Effects of androgens on adipocyte differentiation and adipose tissue explant metabolism in men and women. Clin Endocrinol (Oxf) 72: 176‐188, 2010.
 30.Blouin K, Richard C, Belanger C, Dupont P, Daris M, Laberge P, Luu‐The V, Tchernof A. Local androgen inactivation in abdominal visceral adipose tissue. J Clin Endocrinol Metab 88: 5944‐5950, 2003.
 31.Blouin K, Richard C, Brochu G, Hould FS, Lebel S, Marceau S, Biron S, Luu‐The V, Tchernof A. Androgen inactivation and steroid‐converting enzyme expression in abdominal adipose tissue in men. J Endocrinol 191: 637‐649, 2006.
 32.Blouin K, Veilleux A, Luu‐The V, Tchernof A. Androgen metabolism in adipose tissue: Recent advances. Mol Cell Endocrinol 301: 97‐103, 2009.
 33.Borg W, Shackelton CHL, Pahuja SL, Hochberg RB. Long‐lived testosterone esters in the rat. Proc Natl Acad Sci U S A 92 1545‐1549, 1995.
 34.Borruel S, Fernandez‐Duran E, Alpanes M, Marti D, Alvarez‐Blasco F, Luque‐Ramirez M, Escobar‐Morreale HF. Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 98: 1254‐1263, 2013.
 35.Borst SE, Yarrow JF, Conover CF, Nseyo U, Meuleman JR, Lipinska JA, Braith RW, Beck DT, Martin JS, Morrow M, Roessner S, Beggs LA, McCoy SC, Cannady DF, II, Shuster JJ. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: A randomized, controlled trial. Am J Physiol Endocrinol Metab 306: E433‐442, 2014.
 36.Bouchard C, Tchernof A, Tremblay A. Predictors of body composition and body energy changes in response to chronic overfeeding. Int J Obes (Lond) 38: 236‐242, 2014.
 37.Bouloux PM, Legros JJ, Elbers JM, Geurts TB, Kaspers MJ, Meehan AG, Meuleman EJ. Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: A 1‐year, randomized, placebo‐controlled, dose‐ranging study. Aging Male 16: 38‐47, 2013.
 38.Boulton KL, Hudson DU, Coppack SW, Frayn KN. Steroid hormone interconversions in human adipose tissue in vivo. Metabolism 41: 556‐559, 1992.
 39.Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 6: 1‐7, 2003.
 40.Boyapati SM, Shu XO, Gao YT, Dai Q, Yu H, Cheng JR, Jin F, Zheng W. Correlation of blood sex steroid hormones with body size, body fat distribution, and other known risk factors for breast cancer in post‐menopausal Chinese women. Cancer Causes Control 15: 305‐311, 2004.
 41.Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men–a clinical research center study. J Clin Endocrinol Metab 81: 3469‐3475, 1996.
 42.Bujalska IJ, Walker EA, Tomlinson JW, Hewison M, Stewart PM. 11Beta‐hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: From de‐activation to generation of cortisol. Endocr Res 28: 449‐461, 2002.
 43.Buttler RM, Martens F, Fanelli F, Pham HT, Kushnir MM, Janssen MJ, Owen L, Taylor AE, Soeborg T, Blankenstein MA, Heijboer AC. Comparison of 7 published LC‐MS/MS methods for the simultaneous measurement of testosterone, androstenedione, and dehydroepiandrosterone in serum. Clin Chem 61: 1475‐1483, 2015.
 44.Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. 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 16: 146‐152, 2014.
 45.Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM. Effect of long‐acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double‐blind, placebo‐controlled, randomized study. J Am Coll Cardiol 54: 919‐927, 2009.
 46.Canadian obesity clinical practice guidelines expert panel. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children. CMAJ 176: 1‐117, 2007.
 47.Cao Y, Zhang S, Zou S, Xia X. The relationship between endogenous androgens and body fat distribution in early and late postmenopausal women. PLoS One 8: e58448, 2013.
 48.Carranza‐Lira S, Velasco Diaz G, Olivares A, Chan Verdugo R, Herrera J. Correlation of Kupperman's index with estrogen and androgen levels, according to weight and body fat distribution in postmenopausal women from Mexico City. Int J Fertil Womens Med 51: 83‐88, 2006.
 49.Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, Fournier M, Storer TW. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170: 870‐878, 2004.
 50.Casey ML, MacDonald PC, Andersson S. 17 beta‐Hydroxysteroid dehydrogenase type 2: Chromosomal assignment and progestin regulation of gene expression in human endometrium. J Clin Invest 94: 2135‐2141, 1994.
 51.Casson PR, Toth MJ, Johnson JV, Stanczyk FZ, Casey CL, Dixon ME. Correlation of serum androgens with anthropometric and metabolic indices in healthy, nonobese postmenopausal women. J Clin Endocrinol Metab 95: 4276‐4282, 2010.
 52.Chaves VE, Frasson D, Kawashita NH. Several agents and pathways regulate lipolysis in adipocytes. Biochimie 93: 1631‐1640, 2011.
 53.Chazenbalk G, Singh P, Irge D, Shah A, Abbott DH, Dumesic DA. Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78: 920‐926, 2013.
 54.Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M, Filippi F, Muggeo M, De Sandre G. Moderate alcohol consumption and its relation to visceral fat and plasma androgens in healthy women. Int J Obes Relat Metab Disord 20: 206‐212, 1996.
 55.Corbould AM, Bawden MJ, Lavranos TC, Rodgers RJ, Judd SJ. The effect of obesity on the ratio of type 3 17beta‐hydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra‐abdominal adipose tissue of women. Int J Obes Relat Metab Disord 26: 165‐175, 2002.
 56.Corbould AM, Judd SJ, Rodgers RJ. Expression of types 1, 2, and 3 17 beta‐hydroxysteroid dehydrogenase in subcutaneous abdominal and intra‐abdominal adipose tissue of women. J Clin Endocrinol Metab 83: 187‐194, 1998.
 57.Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, Maggi M. Testosterone supplementation and body composition: Results from a meta‐analysis of observational studies. J Endocrinol Invest 39: 967‐981, 2016.
 58.Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, Maggi M. Therapy of endocrine disease: Testosterone supplementation and body composition: Results from a meta‐analysis study. Eur J Endocrinol 174: R99‐R116, 2016.
 59.Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, Maggi M. Testosterone and metabolic syndrome: A meta‐analysis study. J Sex Med 8: 272‐283, 2011.
 60.Cosar E, Ucok K, Akgun L, Koken G, Sahin FK, Arioz DT, Bas O. Body fat composition and distribution in women with polycystic ovary syndrome. Gynecol Endocrinol 24: 428‐432, 2008.
 61.Cote JA, Lessard J, Mailloux J, Laberge P, Rheaume C, Tchernof A. Circulating 5alpha‐dihydrotestosterone, abdominal obesity and adipocyte characteristics in women. Horm Mol Biol Clin Investig 12: 391‐400, 2012.
 62.Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC, Skinner JS, Wilmore JH, Despr JP, Bouchard C. Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: The HERITAGE family study. J Clin Endocrinol Metab 85: 1026‐1031, 2000.
 63.Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab 93: 914‐919, 2008.
 64.Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo‐controlled trial of androgen effects on muscle and bone in men requiring long‐term systemic glucocorticoid treatment. J Clin Endocrinol Metab 88: 3167‐3176, 2003.
 65.Cristancho AG, Lazar MA. Forming functional fat: A growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 12: 722‐734, 2011.
 66.Davis SR, Castelo‐Branco C, Chedraui P, Lumsden MA, Nappi RE, Shah D, Villaseca P. Understanding weight gain at menopause. Climacteric 15: 419‐429, 2012.
 67.De Pergola G, Triggiani V, Giorgino F, Cospite MR, Garruti G, Cignarelli M, Guastamacchia E, Giorgino R. The free testosterone to dehydroepiandrosterone sulphate molar ratio as a marker of visceral fat accumulation in premenopausal obese women. Int J Obes Relat Metab Disord 18: 659‐664, 1994.
 68.de Pergola G, Xu X, Yang S, Giorgino R, Björntorp P. Up‐regulation of androgen receptor binding in male rat fat pad adipose precursor cells exposed to testosterone: Study in a whole cell assay system. J Steroid Biochem Molec Biol 4: 553‐558, 1990.
 69.De Pergola G, Zamboni M, Sciaraffia M, Turcato E, Pannacciulli N, Armellini F, Giorgino F, Perrini S, Bosello O, Giorgino R. Body fat accumulation is possibly responsible for lower dehydroepiandrosterone circulating levels in premenopausal obese women. Int J Obes Relat Metab Disord 20: 1105‐1110, 1996.
 70.De Simone M, Verrotti A, Iughetti L, Palumbo M, Farello G, Di Cesare E, Bernabei R, Rosato T, Lozzi S, Criscione S. Increased visceral adipose tissue is associated with increased circulating insulin and decreased sex hormone binding globulin levels in massively obese adolescent girls. J Endocrinol Invest 24: 438‐444, 2001.
 71.Dean JD, Carnegie C, Rodzvilla J, Smith T. Long‐term effects of testim(r) 1% testosterone gel in hypogonadal men. Rev Urol 7: 87‐94, 2005.
 72.Demers LM. Androgen deficiency in women; role of accurate testosterone measurements. Maturitas 67: 39‐45, 2010.
 73.Deschenes D, Couture P, Dupont P, Tchernof A. Subdivision of the subcutaneous adipose tissue compartment and lipid‐lipoprotein levels in women. Obes Res 11: 469‐476, 2003.
 74.Deslypere JP, Verdonck L, Vermeulen A. Fat tissue: A steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab 61: 564‐570, 1985.
 75.Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 444: 881‐887, 2006.
 76.Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Sandhu S, Green K, Makdissi A, Hejna J, Chaudhuri A, Punyanitya M, Dandona P. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 39: 82‐91, 2016.
 77.Dicker A, Ryden M, Naslund E, Muehlen IE, Wiren M, Lafontan M, Arner P. Effect of testosterone on lipolysis in human pre‐adipocytes from different fat depots. Diabetologia 47: 420‐428, 2004.
 78.Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. 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, 2000.
 79.Dixon JB, O'Brien PE. Neck circumference a good predictor of raised insulin and free androgen index in obese premenopausal women: Changes with weight loss. Clin Endocrinol (Oxf) 57: 769‐778, 2002.
 80.Dolfing JG, Stassen CM, van Haard PM, Wolffenbuttel BH, Schweitzer DH. Comparison of MRI‐assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: Less visceral fat with PCOS. Hum Reprod 26: 1495‐1500, 2011.
 81.Dong Z, Chen X, Li L, Huang J, Yin Q, Yang D. Free testosterone level correlated with the metabolic abnormalities dependent on central obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 120: 355‐360, 2012.
 82.Douchi T, Ijuin H, Nakamura S, Oki T, Yamamoto S, Nagata Y. Body fat distribution in women with polycystic ovary syndrome. Obstet Gynecol 86: 516‐519, 1995.
 83.Douchi T, Yoshimitsu N, Nagata Y. Relationships among serum testosterone levels, body fat and muscle mass distribution in women with polycystic ovary syndrome. Endocr J 48: 685‐689, 2001.
 84.Drolet R, Simard M, Plante J, Laberge P, Tremblay Y. Human type 2 17 beta‐hydroxysteroid dehydrogenase mRNA and protein distribution in placental villi at mid and term pregnancy. Reprod Biol Endocrinol 5: 30, 2007.
 85.Emmelot‐Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: A randomized controlled trial. JAMA 299: 39‐52, 2008.
 86.Etminan M, Skeldon SC, Goldenberg SL, Carleton B, Brophy JM. Testosterone therapy and risk of myocardial infarction: A pharmacoepidemiologic study. Pharmacotherapy 35: 72‐78, 2015.
 87.Evans DJ, Barth JH, Burke CW. Body fat topography in women with androgen excess. Int J Obes 12: 157‐162, 1988.
 88.Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 57: 304‐310, 1983.
 89.Fader AN, Arriba LN, Frasure HE, von Gruenigen VE. Endometrial cancer and obesity: Epidemiology, biomarkers, prevention and survivorship. Gynecol Oncol 114: 121‐127, 2009.
 90.Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, Carmina E, Chang J, Yildiz BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne CN, Norman RJ, Dunaif A, Franks S, Wild RA, Dumesic D, Barnhart K. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM‐Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 97: 28‐38.e25, 2012.
 91.Feher T, Bodrogi L. A comparative study of steroid concentrations in human adipose tissue and the peripheral circulation. Clin Chim Acta 126: 135‐141, 1982.
 92.Feher T, Halmy L, Bodrogi L, Kazik MH. Dehydroepiandrosterone concentration in adipose tissue of normal and overweight subjects. Horm Metab Res 8: 372‐374, 1976.
 93.Fernandez‐Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos‐Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM. Clinical review 1: Adverse effects of testosterone therapy in adult men: A systematic review and meta‐analysis. J Clin Endocrinol Metab 95: 2560‐2575, 2010.
 94.Ferrando AA, Sheffield‐Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ. Testosterone administration to older men improves muscle function: Molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 282: E601‐607, 2002.
 95.Field AE, Colditz GA, Willett WC, Longcope C, McKinlay JB. The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone‐binding globulin in middle‐aged men. J Clin Endocrinol Metab 79: 1310‐1316, 1994.
 96.Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF, Jr., Hoover RN. Increased risk of non‐fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9: e85805, 2014.
 97.Fouad Mansour M, Pelletier M, Boulet MM, Mayrand D, Brochu G, Lebel S, Poirier D, Fradette J, Cianflone K, Luu‐The V, Tchernof A. Oxidative activity of 17beta‐hydroxysteroid dehydrogenase on testosterone in male abdominal adipose tissues and cellular localization of 17beta‐HSD type 2. Mol Cell Endocrinol 414: 168‐176, 2015.
 98.Fouad Mansour M, Pelletier M, Tchernof A. Characterization of 5alpha‐reductase activity and isoenzymes in human abdominal adipose tissues. J Steroid Biochem Mol Biol 161: 45‐53, 2016.
 99.Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Effects of testosterone undecanoate replacement and withdrawal on cardio‐metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: A pilot study. J Endocrinol Invest 37: 401‐411, 2014.
 100.Francomano D, Lenzi A, Aversa A. Effects of five‐year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol 2014: 527470, 2014.
 101.Frederiksen L, Glintborg D, Hojlund K, Hougaard DM, Brixen K, Rasmussen LM, Andersen M. Osteoprotegerin levels decrease during testosterone therapy in aging men and are associated with changed distribution of regional fat. Horm Metab Res 45: 308‐313, 2013.
 102.Frederiksen L, Hojlund K, Hougaard DM, Brixen K, Andersen M. Testosterone therapy increased muscle mass and lipid oxidation in aging men. Age (Dordr) 34: 145‐156, 2012.
 103.Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: Mechanisms, morbidity and management. Asian J Androl 16: 223‐231, 2014.
 104.Fujioka K, Kajita K, Wu Z, Hanamoto T, Ikeda T, Mori I, Okada H, Yamauchi M, Uno Y, Morita H, Nagano I, Takahashi Y, Ishizuka T. Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor. Am J Physiol Endocrinol Metab 302: E694‐704, 2012.
 105.Gapstur SM, Gann PH, Kopp P, Colangelo L, Longcope C, Liu K. Serum androgen concentrations in young men: A longitudinal analysis of associations with age, obesity, and race. The CARDIA male hormone study. Cancer Epidemiol Biomarkers Prev 11: 1041‐1047, 2002.
 106.Garaulet M, Perex‐Llamas F, Fuente T, Zamora S, Tebar FJ. Anthropometric, computed tomography and fat cell data in an obese population: Relationship with insulin, leptin, tumor necrosis factor‐alpha, sex hormone‐binding globulin and sex hormones. Eur J Endocrinol 143: 657‐666, 2000.
 107.Gargano EM, Allegretta G, Perspicace E, Carotti A, Van Koppen C, Frotscher M, Marchais‐Oberwinkler S, Hartmann RW. 17beta‐Hydroxysteroid dehydrogenase Type 2 inhibition: Discovery of selective and metabolically stable compounds inhibiting both the human enzyme and its murine ortholog. PLoS One 10: e0134754, 2015.
 108.Gianatti EJ, Dupuis P, Hoermann R, Strauss BJ, Wentworth JM, Zajac JD, Grossmann M. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: A randomized controlled trial. Diabetes Care 37: 2098‐2107, 2014.
 109.Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, Whyte M, McMillan CV, Bradley C, Martin FC. The effects of growth hormone and/or testosterone in healthy elderly men: A randomized controlled trial. J Clin Endocrinol Metab 91: 477‐484, 2006.
 110.Glintborg D, Andersen M, Hagen C, Frystyk J, Hulstrom V, Flyvbjerg A, Hermann AP. Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls. Eur J Endocrinol 155: 337‐345, 2006.
 111.Glintborg D, Christensen LL, Kvorning T, Larsen R, Brixen K, Hougaard DM, Richelsen B, Bruun JM, Andersen M. Strength training and testosterone treatment have opposing effects on migration inhibitor factor levels in ageing men. Mediators Inflamm 2013: 539156, 2013.
 112.Godoy‐Matos AF, Vaisman F, Pedrosa AP, Farias ML, Mendonca LM, Pinheiro MF. Central‐to‐peripheral fat ratio, but not peripheral body fat, is related to insulin resistance and androgen markers in polycystic ovary syndrome. Gynecol Endocrinol 25: 793‐798, 2009.
 113.Gopal RA, Bothra N, Acharya SV, Ganesh HK, Bandgar TR, Menon PS, Shah NS. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocr Pract 16: 570‐576, 2010.
 114.Goss AM, Darnell BE, Brown MA, Oster RA, Gower BA. Longitudinal associations of the endocrine environment on fat partitioning in postmenopausal women. Obesity (Silver Spring) 20: 939‐944, 2012.
 115.Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev 78: 783‐809, 1998.
 116.Grossmann M, Hoermann R, Wittert G, Yeap BB. 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 (Oxf) 83: 344‐351, 2015.
 117.Guo Y, Qi Y, Yang X, Zhao L, Wen S, Liu Y, Tang L. Association between polycystic ovary syndrome and gut microbiota. PLoS One 11: e0153196, 2016.
 118.Gupta V, Bhasin S, Guo W, Singh R, Miki R, Choong K, Tchkonia T, Lebrasseur NK, Flanagan JN, Hamilton JA, Viereck JC, Narula NS, Kirkland JL, Jasuja R. Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes. Mol Cell Endocrinol 296: 32‐40, 2008.
 119.Guthrie JR, Dennerstein L, Taffe JR, Ebeling PR, Randolph JF, Burger HG, Wark JD. Central abdominal fat and endogenous hormones during the menopausal transition. Fertil Steril 79: 1335‐1340, 2003.
 120.Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study. J Sex Med 11: 840‐856, 2014.
 121.Haffner SM, Katz MS, Dunn JF. Increased upper body and overall adiposity is associated with decreased sex hormone binding globulin in postmenopausal women. Int J Obes 15: 471‐478, 1991.
 122.Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract 8: e339‐349, 2014.
 123.Haider A, Yassin A, Doros G, Saad F. Effects of long‐term testosterone therapy on patients with “diabesity”: Results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol 2014: 683515, 2014.
 124.Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long‐term testosterone therapy: Observational, real‐life data from a registry study. Vasc Health Risk Manag 12: 251‐261, 2016.
 125.Hammond GL. Plasma steroid‐binding proteins: Primary gatekeepers of steroid hormone action. J Endocrinol 230: R13‐25, 2016.
 126.Harada N, Hanaoka R, Hanada K, Izawa T, Inui H, Yamaji R. Hypogonadism alters cecal and fecal microbiota in male mice. Gut Microbes 7: 533‐539, 2016.
 127.Harada N, Hanaoka R, Horiuchi H, Kitakaze T, Mitani T, Inui H, Yamaji R. Castration influences intestinal microflora and induces abdominal obesity in high‐fat diet‐fed mice. Sci Rep 6: 23001, 2016.
 128.Hartig SM, He B, Newberg JY, Ochsner SA, Loose DS, Lanz RB, McKenna NJ, Buehrer BM, McGuire SE, Marcelli M, Mancini MA. Feed‐forward inhibition of androgen receptor activity by glucocorticoid action in human adipocytes. Chem Biol 19: 1126‐1141, 2012.
 129.Hauner H, Ditschuneit HH, Pal SB, Moncayo R, Pfeiffer EF. Fat distribution, endocrine and metabolic profile in obese women with and without hirsutism. Metabolism 37: 281‐286, 1988.
 130.Hernandez‐Morante JJ, Perez‐de‐Heredia F, Lujan JA, Zamora S, Garaulet M. Role of DHEA‐S on body fat distribution: Gender‐ and depot‐specific stimulation of adipose tissue lipolysis. Steroids 73: 209‐215, 2008.
 131.Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty‐two‐week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 30: 726‐733, 2009.
 132.Hildreth KL, Barry DW, Moreau KL, Vande Griend J, Meacham RB, Nakamura T, Wolfe P, Kohrt WM, Ruscin JM, Kittelson J, Cress ME, Ballard R, Schwartz RS. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low‐normal testosterone levels. J Clin Endocrinol Metab 98: 1891‐1900, 2013.
 133.Holte J, Bergh T, Gennarelli G, Wide L. The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women. Clin Endocrinol (Oxf) 41: 473‐481, 1994.
 134.Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901‐911, 2007.
 135.Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: A randomised placebo‐controlled trial. Eur J Endocrinol 167: 531‐541, 2012.
 136.Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev 11: 11‐18, 2010.
 137.Imperlini E, Mancini A, Alfieri A, Martone D, Caterino M, Orru S, Buono P. Molecular effects of supraphysiological doses of doping agents on health. Mol BioSyst 11: 1494‐1506, 2015.
 138.Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle‐aged men: A meta‐analysis. Clin Endocrinol (Oxf) 63: 280‐293, 2005.
 139.Ivandic A, Prpic‐Krizevac I, Bozic D, Barbir A, Peljhan V, Balog Z, Glasnovic M. Insulin resistance and androgens in healthy women with different body fat distributions. Wien Klin Wochenschr 114: 321‐326, 2002.
 140.Ivandic A, Prpic‐Krizevac I, Sucic M, Juric M. Hyperinsulinemia and sex hormones in healthy premenopausal women: Relative contribution of obesity, obesity type, and duration of obesity. Metabolism 47: 13‐19, 1998.
 141.Janssen I, Powell LH, Kazlauskaite R, Dugan SA. Testosterone and visceral fat in midlife women: The Study of Women's Health Across the Nation (SWAN) fat patterning study. Obesity (Silver Spring) 18: 604‐610, 2010.
 142.Jin CH, Yuk JS, Choi KM, Yi KW, Kim T, Hur JY, Shin JH. Body fat distribution and its associated factors in Korean women with polycystic ovary syndrome. J Obstet Gynaecol Res 41: 1577‐1583, 2015.
 143.Jo DG, Lee HS, Joo YM, Seo JT. Effect of testosterone replacement therapy on bone mineral density in patients with Klinefelter syndrome. Yonsei Med J 54: 1331‐1335, 2013.
 144.Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34: 828‐837, 2011.
 145.Joyner J, Hutley L, Cameron D. Intrinsic regional differences in androgen receptors and dihydrotestosterone metabolism in human preadipocytes. Horm Metab Res 34: 223‐228, 2002.
 146.Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: The double‐blinded placebo‐controlled Moscow study. Clin Endocrinol (Oxf) 73: 602‐612, 2010.
 147.Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH. The effect of testosterone replacement therapy on adipocytokines and C‐reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol 156: 595‐602, 2007.
 148.Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 154: 899‐906, 2006.
 149.Karabulut A, Yaylali GF, Demirlenk S, Sevket O, Acun A. Evaluation of body fat distribution in PCOS and its association with carotid atherosclerosis and insulin resistance. Gynecol Endocrinol 28: 111‐114, 2012.
 150.Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 81: 4358‐4365, 1996.
 151.Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26: 833‐876, 2005.
 152.Kaye SA, Folsom AR, Soler JT, Prineas RJ, Potter JD. Associations of body mass and fat distribution with sex hormone concentrations in postmenopausal women. Int J Epidemiol 20: 151‐156, 1991.
 153.Keller JL, Casson PR, Toth MJ. Relationship of androgens to body composition, energy and substrate metabolism and aerobic capacity in healthy, young women. Steroids 76: 1247‐1251, 2011.
 154.Kelley ST, Skarra DV, Rivera AJ, Thackray VG. The gut microbiome is altered in a letrozole‐induced mouse model of polycystic ovary syndrome. PLoS One 11: e0146509, 2016.
 155.Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 56: M266‐272, 2001.
 156.Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL. Indices of relative weight and obesity. Int J Epidemiol 43: 655‐665, 2014.
 157.Killinger DW, Perel E, Danilescu D, Kharlip L, Lindsay WR. Influence of adipose tissue distribution on the biological activity of androgens. Ann N Y Acad Sci 595: 199‐211, 1990.
 158.Kirchengast S, Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod 16: 1255‐1260, 2001.
 159.Ko YH, Moon du G, Moon KH. Testosterone replacement alone for testosterone deficiency syndrome improves moderate lower urinary tract symptoms: One year follow‐up. World J Mens Health 31: 47‐52, 2013.
 160.Kolditz CI, Langin D. Adipose tissue lipolysis. Curr Opin Clin Nutr Metab Care 13: 377‐381, 2010.
 161.Korhonen S, Hippelainen M, Vanhala M, Heinonen S, Niskanen L. The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: A controlled community‐based study. Fertil Steril 79: 1327‐1334, 2003.
 162.Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT. Testosterone and sex hormone‐binding globulin predict the metabolic syndrome and diabetes in middle‐aged men. Diabetes Care 27: 1036‐1041, 2004.
 163.Legro RS, Schlaff WD, Diamond MP, Coutifaris C, Casson PR, Brzyski RG, Christman GM, Trussell JC, Krawetz SA, Snyder PJ, Ohl D, Carson SA, Steinkampf MP, Carr BR, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Myers ER, Santoro N, Eisenberg E, Zhang M, Zhang H, Reproductive Medicine N. Total testosterone assays in women with polycystic ovary syndrome: Precision and correlation with hirsutism. J Clin Endocrinol Metab 95: 5305‐5313, 2010.
 164.Lemieux S, Prud'homme D, Bouchard C, Tremblay A, Després JP. Sex differences in the relation of visceral adipose tissue accumulation to total body fatness. Am J Clin Nutr 58: 463‐467, 1993.
 165.Lessard J, Tchernof A. Interaction of the glucocorticoid and androgen receptors in adipogenesis. Chem Biol 19: 1079‐1080, 2012.
 166.Li J, Ding Z, Wang Z, Lu JF, Maity SN, Navone NM, Logothetis CJ, Mills GB, Kim J. Androgen regulation of 5alpha‐reductase isoenzymes in prostate cancer: Implications for prostate cancer prevention. PLoS One 6: e28840, 2011.
 167.Li M, Björntorp P. Effects of testosterone on triglyceride uptake and mobilization in different adipose tissues in male rats in vivo. Obesity Res 3: 113‐119, 1995.
 168.Liedtke S, Schmidt ME, Vrieling A, Lukanova A, Becker S, Kaaks R, Zaineddin AK, Buck K, Benner A, Chang‐Claude J, Steindorf K. Postmenopausal sex hormones in relation to body fat distribution. Obesity (Silver Spring) 20: 1088‐1095, 2012.
 169.Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR, Handelsman DJ. The short‐term effects of high‐dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab 88: 3605‐3613, 2003.
 170.Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome. Bjog 113: 1203‐1209, 2006.
 171.Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes 32: 949‐958, 2008.
 172.Lowe CE, O'Rahilly S, Rochford JJ. Adipogenesis at a glance. J Cell Sci 124: 2681‐2686, 2011.
 173.Luu‐The V. Analysis and characteristics of multiple types of human 17beta‐hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol 76: 143‐151, 2001.
 174.MacKenzie SM, Huda SS, Sattar N, Fraser R, Connell JM, Davies E. Depot‐specific steroidogenic gene transcription in human adipose tissue. Clin Endocrinol (Oxf) 69: 848‐854, 2008.
 175.Magnussen LV, Glintborg D, Hermann P, Hougaard DM, Hojlund K, Andersen M. Effect of testosterone on insulin sensitivity, oxidative metabolism and body composition in aging men with type 2 diabetes on metformin monotherapy. Diabetes Obes Metab 18: 980‐989, 2016.
 176.Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail 9: 44‐50, 2007.
 177.Manneras‐Holm L, Leonhardt H, Kullberg J, Jennische E, Oden A, Holm G, Hellstrom M, Lonn L, Olivecrona G, Stener‐Victorin E, Lonn M. Adipose tissue has aberrant morphology and function in PCOS: Enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab 96: E304‐311, 2011.
 178.Marchais‐Oberwinkler S, Xu K, Wetzel M, Perspicace E, Negri M, Meyer A, Odermatt A, Moller G, Adamski J, Hartmann RW. Structural optimization of 2,5‐thiophene amides as highly potent and selective 17beta‐hydroxysteroid dehydrogenase type 2 inhibitors for the treatment of osteoporosis. J Med Chem 56: 167‐181, 2013.
 179.Marin P, Holmang S, Gustafsson C, Jonsson L, Kvist H, Elander A, Eldh J, Sjostrom L, Holm G, Bjorntorp P. Androgen treatment of abdominally obese men. Obes Res 1: 245‐251, 1993.
 180.Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle‐aged obese men. Int J Obes Relat Metab Disord 16: 991‐997, 1992.
 181.Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A transgenic model of visceral obesity and the metabolic syndrome. Science (New York, NY) 294: 2166‐2170, 2001.
 182.Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long‐term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol 161: 443‐449, 2009.
 183.Michaud A, Lacroix‐Pepin N, Pelletier M, Veilleux A, Noel S, Bouchard C, Marceau P, Fortier MA, Tchernof A. Prostaglandin (PG) F2 alpha synthesis in human subcutaneous and omental adipose tissue: Modulation by inflammatory cytokines and role of the human aldose reductase AKR1B1. PLoS One 9: e90861, 2014.
 184.Minnemann T, Schubert M, Freude S, Hubler D, Gouni‐Berthold I, Schumann C, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhovel F. Comparison of a new long‐acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism. J Endocrinol Invest 31: 718‐723, 2008.
 185.Mongraw‐Chaffin ML, Anderson CA, Allison MA, Ouyang P, Szklo M, Vaidya D, Woodward M, Golden SH. Association between sex hormones and adiposity: Qualitative differences in women and men in the multi‐ethnic study of atherosclerosis. J Clin Endocrinol Metab 100: E596‐600, 2015.
 186.Moon du G, Park MG, Lee SW, Park K, Park JK, Kim SW, Park NC, Ahn TY, Paick JS, Seo JT, Yang DY, Lee JY, Kim JJ. The efficacy and safety of testosterone undecanoate (Nebido((R))) in testosterone deficiency syndrome in Korean: A multicenter prospective study. J Sex Med 7: 2253‐2260, 2010.
 187.Morley JE, Perry HM, III, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM, Jr. Effects of testosterone replacement therapy in old hypogonadal males: A preliminary study. J Am Geriatr Soc 41: 149‐152, 1993.
 188.Munzer T, Harman SM, Hees P, Shapiro E, Christmas C, Bellantoni MF, Stevens TE, O'Connor KG, Pabst KM, St Clair C, Sorkin JD, Blackman MR. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J Clin Endocrinol Metab 86: 3604‐3610, 2001.
 189.Naharci MI, Pinar M, Bolu E, Olgun A. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocr Pract 13: 629‐635, 2007.
 190.Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ, III, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 355: 1647‐1659, 2006.
 191.Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes 56: 1517‐1526, 2007.
 192.O'Reilly MW, House PJ, Tomlinson JW. Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol 143c: 277‐284, 2014.
 193.Occhiato EG, Guarna A, Danza G, Serio M. Selective non‐steroidal inhibitors of 5 alpha‐reductase type 1. J Steroid Biochem Mol Biol 88: 1‐16, 2004.
 194.Oh JY, Lee JA, Lee H, Oh JY, Sung YA, Chung H. Serum C‐reactive protein levels in normal‐weight polycystic ovary syndrome. Korean J Intern Med 24: 350‐355, 2009.
 195.Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 90: 1502‐1510, 2005.
 196.Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol 402: 113‐119, 2015.
 197.Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR. Reduced adipose tissue oxygenation in human obesity: Evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58: 718‐725, 2009.
 198.Pasquali R, Antenucci D, Melchionda N, Fabbri R, Venturoli S, Patrono D, Capelli M. Sex hormones in obese premenopausal women and their relationships to body fat mass and distribution, B cell function and diet composition. J Endocrinol Invest 10: 345‐350, 1987.
 199.Pasquali R, Casimirri F, Cantobelli S, Labate AM, Venturoli S, Paradisi R, Zannarini L. Insulin and androgen relationships with abdominal body fat distribution in women with and without hyperandrogenism. Horm Res 39: 179‐187, 1993.
 200.Pasquali R, Casimirri F, Cantobelli S, Melchionda N, Morselli Labate AM, Fabbri R, Capelli M, Bortoluzzi L. Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism 40: 101‐104, 1991.
 201.Pecquery R, Dieudonne MN, Cloix JF, Leneveu MC, Dausse JP, Giudicelli Y. Enhancement of the expression of the a2‐adrenoreceptor protein and mRNA by a direct effect of androgens in white adipocytes. Biochem Biophys Res Commun 206: 112‐118, 1995.
 202.Pecquery R, Leneveu MC, Giudicelli Y. Influence of androgenic status on the alpha 2/beta‐adrenergic control of lipolysis in white fat cells: Predominant alpha 2‐antilipolytic response in testosterone‐treated‐castrated hamsters. Endocrinology 122: 2590‐2596, 1988.
 203.Pedersen SB, Borglum JD, Brixen K, Richelsen B. Relationship between sex hormones, body composition and metabolic risk parameters in premenopausal women. Eur J Endocrinol 133: 200‐206, 1995.
 204.Penaforte FR, Japur CC, Diez‐Garcia RW, Chiarello PG. Upper trunk fat assessment and its relationship with metabolic and biochemical variables and body fat in polycystic ovary syndrome. J Hum Nutr Diet 24: 39‐46, 2011.
 205.Perel E, Daniilescu D, Kindler S, Kharlip L, Killinger DW. The formation of 5 alpha‐reduced androgens in stromal cells from human breast adipose tissue. J Clin Endocrinol Metab 62: 314‐318, 1986.
 206.Permpongkosol S, Tantirangsee N, Ratana‐olarn K. Treatment of 161 men with symptomatic late onset hypogonadism with long‐acting parenteral testosterone undecanoate: Effects on body composition, lipids, and psychosexual complaints. J Sex Med 7: 3765‐3774, 2010.
 207.Pexman‐Fieth C, Behre HM, Morales A, Kan‐Dobrosky N, Miller MG. A 6‐month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel. Aging Male 17: 1‐11, 2014.
 208.Phillips GB, Jing T, Heymsfield SB. Does insulin resistance, visceral adiposity, or a sex hormone alteration underlie the metabolic syndrome? Studies in women. Metabolism 57: 838‐844, 2008.
 209.Poirier D, Bydal P, Tremblay MR, Sam KM, Luu‐The V. Inhibitors of type II 17beta‐hydroxysteroid dehydrogenase. Mol Cell Endocrinol 171: 119‐128, 2001.
 210.Pope HG, Jr., Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S. Adverse health consequences of performance‐enhancing drugs: An Endocrine Society scientific statement. Endocr Rev 35: 341‐375, 2014.
 211.Pouliot MC, Despres JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, Nadeau A, Lupien PJ. Waist circumference and abdominal sagittal diameter: Best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol 73: 460‐468, 1994.
 212.Pritchard J, Despres JP, Gagnon J, Tchernof A, Nadeau A, Tremblay A, Bouchard C. Plasma adrenal, gonadal, and conjugated steroids before and after long‐term overfeeding in identical twins. J Clin Endocrinol Metab 83: 3277‐3284, 1998.
 213.Pritchard J, Despres JP, Gagnon J, Tchernof A, Nadeau A, Tremblay A, Bouchard C. Plasma adrenal, gonadal, and conjugated steroids following long‐term exercise‐induced negative energy balance in identical twins. Metabolism 48: 1120‐1127, 1999.
 214.Puder JJ, Varga S, Kraenzlin M, De Geyter C, Keller U, Muller B. Central fat excess in polycystic ovary syndrome: Relation to low‐grade inflammation and insulin resistance. J Clin Endocrinol Metab 90: 6014‐6021, 2005.
 215.Quinkler M, Bujalska IJ, Tomlinson JW, Smith DM, Stewart PM. Depot‐specific prostaglandin synthesis in human adipose tissue: A novel possible mechanism of adipogenesis. Gene 380: 137‐143, 2006.
 216.Quinkler M, Sinha B, Tomlinson JW, Bujalska IJ, Stewart PM, Arlt W. Androgen generation in adipose tissue in women with simple obesity‐–a site‐specific role for 17beta‐hydroxysteroid dehydrogenase type 5. J Endocrinol 183: 331‐342, 2004.
 217.Rajapaksha M, Thomas JL, Streeter M, Prasad M, Whittal RM, Bell JD, Bose HS. Lipid‐mediated unfolding of 3beta‐hydroxysteroid dehydrogenase 2 is essential for steroidogenic activity. Biochemistry 50: 11015‐11024, 2011.
 218.Rasmussen JJ, Schou M, Selmer C, Johansen ML, Gustafsson F, Frystyk J, Dela F, Faber J, Kistorp C. Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids. Clin Endocrinol (Oxf) 87: 249‐256, 2017.
 219.Ravaglia G, Forti P, Maioli F, Boschi F, Bernardi M, Pratelli L, Pizzoferrato A, Gasbarrini G. The relationship of dehydroepiandrosterone sulfate (DHEAS) to endocrine‐metabolic parameters and functional status in the oldest‐old. Results from an Italian study on healthy free‐living over‐ninety‐year‐olds. J Clin Endocrinol Metab 81: 1173‐1178, 1996.
 220.Rebuffé‐Scrive M, Mårin P, Björntorp P. Effect of testosterone on abdominal adipose tissue in men. Int J Obes 15: 791‐795, 1991.
 221.Rodriguez‐Tolra J, Torremade Barreda J, del Rio L, di Gregorio S, Franco Miranda E. Effects of testosterone treatment on body composition in males with testosterone deficiency syndrome. Aging Male 16: 184‐190, 2013.
 222.Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes & development 14: 1293‐1307, 2000.
 223.Rosner W. Plasma steroid‐binding proteins. Endocrinol Metab Clin North Am 20: 697‐720, 1991.
 224.Rosner W. Free estradiol and sex hormone‐binding globulin. Steroids 99: 113‐116, 2015.
 225.Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement. J Clin Endocrinol Metab 92: 405‐413, 2007.
 226.Rosner W, Vesper H, Endocrine S, American Association for Clinical C, American Association of Clinical E, Androgen Excess PS, American Society for B, Mineral R, American Society for Reproductive M, American Urological A, Association of Public Health L, Endocrine S, Laboratory Corporation of A, North American Menopause S, and Pediatric Endocrine S. Toward excellence in testosterone testing: A consensus statement. J Clin Endocrinol Metab 95: 4542‐4548, 2010.
 227.Saad F, Gooren LJ, Haider A, Yassin A. A dose‐response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl 29: 102‐105, 2008.
 228.Saad F, Haider A, Doros G, Traish A. Long‐term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring) 21: 1975‐1981, 2013.
 229.Saad F, Yassin A, Doros G, Haider A. Effects of long‐term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I‐III: Observational data from two registry studies. Int J Obes (Lond) 40: 162‐170, 2016.
 230.Saad F, Yassin A, Haider A, Doros G, Gooren L. Elderly men over 65 years of age with late‐onset hypogonadism benefit as much from testosterone treatment as do younger men. Korean J Urol 56: 310‐317, 2015.
 231.Samson M, Labrie F, Zouboulis CC, Luu‐The V. Biosynthesis of dihydrotestosterone by a pathway that does not require testosterone as an intermediate in the SZ95 sebaceous gland cell line. J Invest Dermatol 130: 602‐604, 2010.
 232.Schwarz ER, Willix RD, Jr. Impact of a physician‐supervised exercise‐nutrition program with testosterone substitution in partial androgen‐deficient middle‐aged obese men. J Geriatr Cardiol 8: 201‐206, 2011.
 233.Seftel A. Male hypogonadism. Part II: Etiology, pathophysiology, and diagnosis. Int J Impot Res 18: 223‐228, 2006.
 234.Seidell JC, Cigolini M, Charzewska J, Ellsinger BM, Di Biase G, Bjorntorp P, Hautvast JG, Contaldo F, Szostak V, Scuro LA. Androgenicity in relation to body fat distribution and metabolism in 38‐year‐old women‐‐‐the European Fat Distribution Study. J Clin Epidemiol 43: 21‐34, 1990.
 235.Setayeshgar S, Whiting SJ, Vatanparast H. Metabolic syndrome in Canadian adults and adolescents: Prevalence and associated dietary intake. ISRN Obes 2012: 816846, 2012.
 236.Severinsen MT, Kristensen SR, Johnsen SP, Dethlefsen C, Tjonneland A, Overvad K. Anthropometry, body fat, and venous thromboembolism: A Danish follow‐up study. Circulation 120: 1850‐1857, 2009.
 237.Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, Sharma R, Parashara D, Savin VJ, Ambrose JA, Barua RS. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 36: 2706‐2715, 2015.
 238.Sheffield‐Moore M, Dillon EL, Casperson SL, Gilkison CR, Paddon‐Jones D, Durham WJ, Grady JJ, Urban RJ. A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. J Clin Endocrinol Metab 96: E1831‐E1837, 2011.
 239.Siervogel RM, Demerath EW, Schubert C, Remsberg KE, Chumlea WC, Sun S, Czerwinski SA, Towne B. Puberty and body composition. Horm Res 60: 36‐45, 2003.
 240.Sih R, Morley JE, Kaiser FE, Perry HM, III, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: A 12‐month randomized controlled trial. J Clin Endocrinol Metab 82: 1661‐1667, 1997.
 241.Simard M, Drolet R, Blomquist CH, Tremblay Y. Human type 2 17beta‐hydroxysteroid dehydrogenase in umbilical vein and artery endothelial cells: Differential inactivation of sex steroids according to the vessel type. Endocrine 40: 203‐211, 2011.
 242.Simon D, Charles MA, Lahlou N, Nahoul K, Oppert JM, Gouault‐Heilmann M, Lemort N, Thibult N, Joubert E, Balkau B, Eschwege E. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: A 3‐month randomized placebo‐controlled trial. Diabetes Care 24: 2149‐2151, 2001.
 243.Singh R, Artaza JN, Taylor WE, Braga M, Yuan X, Gonzalez‐Cadavid NF, Bhasin S. Testosterone inhibits adipogenic differentiation in 3T3‐L1 cells: Nuclear translocation of androgen receptor complex with beta‐catenin and T‐cell factor 4 may bypass canonical Wnt signaling to down‐regulate adipogenic transcription factors. Endocrinology 147: 141‐154, 2006.
 244.Singh R, Artaza JN, Taylor WE, Gonzalez‐Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor‐mediated pathway. Endocrinology 144: 5081‐5088, 2003.
 245.Skogastierna C, Hotzen M, Rane A, Ekstrom L. A supraphysiological dose of testosterone induces nitric oxide production and oxidative stress. Eur J Prev Cardiol 21: 1049‐1054, 2014.
 246.Smith JD, Borel AL, Nazare JA, Haffner SM, Balkau B, Ross R, Massien C, Almeras N, Després JP. Visceral adipose tissue indicates the severity of cardiometabolic risk in patients with and without type 2 diabetes: Results from the INSPIRE ME IAA study. JCEM 97: 1517‐1525, 2012.
 247.Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 85: 2670‐2677, 2000.
 248.Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 84: 2647‐2653, 1999.
 249.Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 88: 2673‐2681, 2003.
 250.Sugimoto Y, Lopez‐Solache I, Labrie F, Luu‐The V. Cations inhibit specifically type I 5 alpha‐reductase found in human skin. J Invest Dermatol 104: 775‐778, 1995.
 251.Suzuki T, Sasano H, Andersson S, Mason JI. 3beta‐Hydroxysteroid dehydrogenase/delta5→4‐isomerase activity associated with the human 17beta‐hydroxysteroid dehydrogenase type 2 isoform. J Clin Endocrinol Metab 85: 3669‐3672, 2000.
 252.Svartberg J, Aasebo U, Hjalmarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6‐month randomized controlled trial. Respir Med 98: 906‐913, 2004.
 253.Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res 20: 378‐387, 2008.
 254.Svendsen PF, Nilas L, Norgaard K, Jensen JE, Madsbad S. Obesity, body composition and metabolic disturbances in polycystic ovary syndrome. Hum Reprod 23: 2113‐2121, 2008.
 255.Svensson PA, Gabrielsson BG, Jernas M, Gummesson A, Sjoholm K. Regulation of human aldoketoreductase 1C3 (AKR1C3) gene expression in the adipose tissue. Cell Mol Biol Lett 13: 599‐613, 2008.
 256.Sze MA, Schloss PD. Looking for a signal in the noise: Revisiting obesity and the microbiome. mBio 7, 2016.
 257.Szymczak J, Milewicz A, Thijssen JH, Blankenstein MA, Daroszewski J. Concentration of sex steroids in adipose tissue after menopause. Steroids 63: 319‐321, 1998.
 258.Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N, Lacroix I, Somma‐Delpero C, Boudou P. Testosterone measured by 10 immunoassays and by isotope‐dilution gas chromatography‐mass spectrometry in sera from 116 men, women, and children. Clin Chem 49: 1381‐1395, 2003.
 259.Takeyama J, Suzuki T, Hirasawa G, Muramatsu Y, Nagura H, Iinuma K, Nakamura J, Kimura KI, Yoshihama M, Harada N, Andersson S, Sasano H. 17beta‐Hydroxysteroid dehydrogenase type 1 and 2 expression in the human fetus. J Clin Endocrinol Metab 85: 410‐416, 2000.
 260.Tan WS, Low WY, Ng CJ, Tan WK, Tong SF, Ho C, Khoo EM, Lee G, Lee BC, Lee V, Tan HM. Efficacy and safety of long‐acting intramuscular testosterone undecanoate in aging men: A randomised controlled study. BJU Int 111: 1130‐1140, 2013.
 261.Taylor AE, Keevil B, Huhtaniemi IT. Mass spectrometry and immunoassay: How to measure steroid hormones today and tomorrow. Eur J Endocrinol 173: D1‐12, 2015.
 262.Tchernof A. Sex differences in energy balance, body composition and body fat distribution. In: Brown FM, Wyckoff J, Tsatsoulis A, editors. Diabetes in Women: Pathophysiology and Therapy, New York: Humana Press, 2009.
 263.Tchernof A, Beaulieu M, Lévesque E, Couture P, Poncelet P, Hum DW, Bélanger A. Expression of androgen metabolizing enzymes UDP‐glucuronosyltransferases 2B15 and 2B17 in human subcutaneous and omental adipose tissue. Obes Res 5(suppl. 1): 66S, 1997.
 264.Tchernof A, Bélanger C, Morisset AS, Richard C, Mailloux J, Laberge P, Dupont P. Regional differences in adipose tissue metabolism in women: Minor effect of obesity and body fat distribution. Diabetes 55: 1353‐1360, 2006.
 265.Tchernof A, Boulet MM, Nadeau M, Luu‐The V. Updated survey of the steroid‐converting enzymes in human adipose tissues. J Steroid Biochm Mol Biol 147: 56‐69, 2015.
 266.Tchernof A, Despres JP. Sex steroid hormones, sex hormone‐binding globulin, and obesity in men and women. Horm Metab Res 32: 526‐536, 2000.
 267.Tchernof A, Despres JP. Pathophysiology of human visceral obesity: An update. Physiol Rev 93: 359‐404, 2013.
 268.Tchernof A, Despres JP, Belanger A, Dupont A, Prud'homme D, Moorjani S, Lupien PJ, Labrie F. Reduced testosterone and adrenal C19 steroid levels in obese men. Metabolism 44: 513‐519, 1995.
 269.Tchernof A, Despres JP, Dupont A, Belanger A, Nadeau A, Prud'homme D, Moorjani S, Lupien PJ, Labrie F. Relation of steroid hormones to glucose tolerance and plasma insulin levels in men. Importance of visceral adipose tissue. Diabetes Care 18: 292‐299, 1995.
 270.Tchernof A, Labrie F. Dehydroepiandrosterone, obesity and cardiovascular disease risk: A review of human studies. Eur J Endocrinol 151: 1‐14, 2004.
 271.Tchernof A, Labrie F, Belanger A, Prud'homme D, Bouchard C, Tremblay A, Nadeau A, Despres JP. Androstane‐3alpha,17beta‐diol glucuronide as a steroid correlate of visceral obesity in men. J Clin Endocrinol Metab 82: 1528‐1534, 1997.
 272.Tchernof A, Labrie F, Belanger A, Prud'homme D, Bouchard C, Tremblay A, Nadeau A, Despres JP. Relationships between endogenous steroid hormone, sex hormone‐binding globulin and lipoprotein levels in men: Contribution of visceral obesity, insulin levels and other metabolic variables. Atherosclerosis 133: 235‐244, 1997.
 273.Tchernof A, Mansour MF, Pelletier M, Boulet MM, Nadeau M, Luu‐The V. Updated survey of the steroid‐converting enzymes in human adipose tissues. J Steroid Biochem Mol Biol 147: 56‐69, 2015.
 274.Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 75: 1092‐1098, 1992.
 275.Tirabassi G, Delli Muti N, Corona G, Maggi M, Balercia G. Androgen receptor gene CAG repeat polymorphism regulates the metabolic effects of testosterone replacement therapy in male postsurgical hypogonadotropic hypogonadism. Int J Endocrinol 2013: 816740, 2013.
 276.Titus MA, Li Y, Kozyreva OG, Maher V, Godoy A, Smith GJ, Mohler JL. 5alpha‐Reductase type 3 enzyme in benign and malignant prostate. Prostate 74: 235‐249, 2014.
 277.Tomlinson JW, Finney J, Hughes BA, Hughes SV, Stewart PM. Reduced glucocorticoid production rate, decreased 5alpha‐reductase activity, and adipose tissue insulin sensitization after weight loss. Diabetes 57: 1536‐1543, 2008.
 278.Tosi F, Di Sarra D, Kaufman JM, Bonin C, Moretta R, Bonora E, Zanolin E, Moghetti P. Total body fat and central fat mass independently predict insulin resistance but not hyperandrogenemia in women with polycystic ovary syndrome. J Clin Endocrinol Metab 100: 661‐669, 2015.
 279.Tran BX, Nair AV, Kuhle S, Ohinmaa A, Veugelers PJ. Cost analyses of obesity in Canada: Scope, quality, and implications. Cost Eff Resour Alloc 11: 3, 2013.
 280.Tsilchorozidou T, Honour JW, Conway GS. Altered cortisol metabolism in polycystic ovary syndrome: Insulin enhances 5alpha‐reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab 88: 5907‐5913, 2003.
 281.Turcato E, Zamboni M, De Pergola G, Armellini F, Zivelonghi A, Bergamo‐Andreis IA, Giorgino R, Bosello O. Interrelationships between weight loss, body fat distribution and sex hormones in pre‐ and postmenopausal obese women. J Intern Med 241: 363‐372, 1997.
 282.Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y, Nakagawa H. Novel 5 alpha‐steroid reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer. Cancer Sci 99: 81‐86, 2008.
 283.Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Macfarlane DP, Marshall I, Stewart LH, Walker BR, Andrew R. 5alpha‐reductase type 1 modulates insulin sensitivity in men. J Clin Endocrinol Metab 99: E1397‐E1406, 2014.
 284.Vaidya D, Dobs A, Gapstur SM, Golden SH, Cushman M, Liu K, Ouyang P. Association of baseline sex hormone levels with baseline and longitudinal changes in waist‐to‐hip ratio: Multi‐Ethnic Study of Atherosclerosis. Int J Obes (Lond) 36: 1578‐1584, 2012.
 285.Van Loan MD. Total body composition: Birth to old age. In: Roche AF, Heymsfield SB, Lohman TG, editors. Human Body Composition. Champaign, IL: Human Kinetics, 1996, pp. 205‐215.
 286.Van Schothorst EM, Franssen‐van Hal N, Schaap MM, Pennings J, Hoebee B, Keijer J. Adipose gene expression patterns of weight gain suggest counteracting steroid hormone synthesis. Obes Res 13: 1031‐1041, 2005.
 287.Vandenput L, Mellstrom D, Lorentzon M, Swanson C, Karlsson MK, Brandberg J, Lonn L, Orwoll E, Smith U, Labrie F, Ljunggren O, Tivesten A, Ohlsson C. Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men. J Clin Endocrinol Metab 92: 4130‐4137, 2007.
 288.Varlamov O, Chu MP, McGee WK, Cameron JL, O'Rourke RW, Meyer KA, Bishop CV, Stouffer RL, Roberts CT, Jr. Ovarian cycle‐specific regulation of adipose tissue lipid storage by testosterone in female nonhuman primates. Endocrinology 154: 4126‐4135, 2013.
 289.Varlamov O, White AE, Carroll JM, Bethea CL, Reddy A, Slayden O, O'Rourke RW, Roberts CT, Jr. Androgen effects on adipose tissue architecture and function in nonhuman primates. Endocrinology 153: 3100‐3110, 2012.
 290.Veilleux A, Blouin K, Tchernof A. Mechanisms of androgenic action in adipose tissue. Clin Lipidol 4: 367‐378, 2009.
 291.Veilleux A, Cote JA, Blouin K, Nadeau M, Pelletier M, Marceau P, Laberge PY, Luu‐The V, Tchernof A. Glucocorticoid‐induced androgen inactivation by aldo‐keto reductase 1C2 promotes adipogenesis in human preadipocytes. Am J Physiol Endocrinol Metab 302: E941‐E949, 2012.
 292.Veilleux A, Tchernof A. Sex differences in body fat distribution. In: Symonds ME, editor. Adipose Tissue Biology (1st ed.). Nottingham: Springer, 2012, pp. 123‐166.
 293.Vigen R, O'Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310: 1829‐1836, 2013.
 294.Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, Andrew R, Yki‐Jarvinen H, Olsson T, Walker BR. Intra‐adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol (Oxf) 66: 440‐446, 2007.
 295.Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: Comparison of current laboratory methods versus liquid chromatography‐tandem mass spectrometry. J Clin Endocrinol Metab 89: 534‐543, 2004.
 296.Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. Long‐term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 89: 2085‐2098, 2004.
 297.Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley RE, Berman N, Davidson T, Barstow TJ, Sinow R, Alexander G, Swerdloff RS. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men–‐a clinical research center study. J Clin Endocrinol Metab 81: 3654‐3662, 1996.
 298.Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 85: 2839‐2853, 2000.
 299.Wang L, Li S, Zhao A, Tao T, Mao X, Zhang P, Liu W. The expression of sex steroid synthesis and inactivation enzymes in subcutaneous adipose tissue of PCOS patients. J Steroid Biochem Mol Biol 132: 120‐126, 2012.
 300.Wells JC. Sexual dimorphism of body composition. Best Pract Res Clin Endocrinol Metab 21: 415‐430, 2007.
 301.Wetzel M, Marchais‐Oberwinkler S, Hartmann RW. 17beta‐HSD2 inhibitors for the treatment of osteoporosis: Identification of a promising scaffold. Bioorg Med Chem 19: 807‐815, 2011.
 302.Wierman ME, Basson R, Davis SR, Khosla S, Miller KK, Rosner W, Santoro N. Androgen therapy in women: An Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab 91: 3697‐3710, 2006.
 303.Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low‐normal gonadal status. J Gerontol A Biol Sci Med Sci 58: 618‐625, 2003.
 304.Wu L, Einstein M, Geissler WM, Chan HK, Elliston KO, Andersson S. Expression cloning and characterization of human 17 beta‐hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha‐hydroxysteroid dehydrogenase activity. J Biol Chem 268: 12964‐12969, 1993.
 305.Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: A systematic review and meta‐analysis of placebo‐controlled randomized trials. BMC Med 11: 108, 2013.
 306.Xu X, de Pergola G, Björntorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells. Endocrinology 126: 1229‐1234, 1990.
 307.Xu XF, de Pergola G, Björntorp P. Testosterone increases lipolysis and the number of beta‐adrenoceptors in male rat adipocytes. Endocrinology 128: 379‐382, 1991.
 308.Yang Z, Zhang N. The burden of overweight and obesity on long‐term care and Medicaid financing. Med Care 52: 658‐663, 2014.
 309.Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long‐term testosterone replacement therapy on body weight and metabolic parameters in hypogonadal in middle‐aged and elderly men. Clin Endocrinol (Oxf) 84: 107‐114, 2016.
 310.Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes 3: 73‐83, 2013.
 311.Yildirim B, Sabir N, Kaleli B. Relation of intra‐abdominal fat distribution to metabolic disorders in nonobese patients with polycystic ovary syndrome. Fertil Steril 79: 1358‐1364, 2003.
 312.Young NR, Baker HW, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 77: 1028‐1032, 1993.
 313.Yucel A, Noyan V, Sagsoz N. The association of serum androgens and insulin resistance with fat distribution in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 126: 81‐86, 2006.
 314.Zamboni M, Armellini F, Turcato E, de Pergola G, Todesco T, Bissoli L, Bergamo Andreis IA, Bosello O. Relationship between visceral fat, steroid hormones and insulin sensitivity in premenopausal obese women. J Intern Med 236: 521‐527, 1994.
 315.Zerradi M, Dereumetz J, Boulet MM, Tchernof A. Androgens, body fat distribution and adipogenesis. Curr Obes Rep 3: 396‐403, 2014.
 316.Zgliczynski S, Ossowski M, Slowinska‐Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 121: 35‐43, 1996.
 317.Zhang Y, Nadeau M, Faucher F, Lescelleur O, Biron S, Daris M, Rheaume C, Luu‐The V, Tchernof A. Progesterone metabolism in adipose cells. Mol Cell Endocrinol 298: 76‐83, 2009.
 318.Zierath JR, Livingston JN, Thorne A, Bolinder J, Reynisdottir S, Lonnqvist F, Arner P. Regional difference in insulin inhibition of non‐esterified fatty acid release from human adipocytes: Relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate‐1 pathway. Diabetologia 41: 1343‐1354, 1998.
 319.Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: A study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med 10: 579‐588, 2013.

 

 

 

 

Teaching Material

 

 

A. Tchernof, D. Brochu, I. Maltais-Payette, M. F. Mansour, G. B. Marchand, A. -M. Carreau, J. Kapeluto. Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans. Compr Physiol 8: 2018, 1253-1290.

Didactic Synopsis

Major Teaching Points:

  • Reduced total testosterone is observed frequently in men with abdominal and/or visceral obesity and the metabolic syndrome.
  • Reports on testosterone replacement therapy in men show that:
  • Observational studies have reported decreases in waist circumference in response to testosterone more frequently than randomized controlled trials.
  • This may be explained in part by the lower average waist circumference or BMI values and higher testosterone levels at baseline in randomized controlled trials compared to observational studies.
  • Independent of study design, decreases in waist circumference in response to testosterone are observed more frequently in men with low levels of testosterone and high BMI at study onset.
  • In women with androgen excess, higher testosterone and free testosterone levels are frequent correlates of increased abdominal and/or visceral fat accumulation; this may not necessarily be the case in nonhyperandrogenic women.
  • Steroid-converting enzymes expressed in adipose tissues may be involved in androgen-meditated modulation of body fat distribution.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: A large interindividual variability can be observed in visceral fat accumulation assessed by computed tomography. Computed tomography scans (top panels labeled A-D) were obtained at the L4-L5 vertebrae level in four women and visceral adipose tissue areas were measured (bottom panels). Despite the fact that all women have a very similar total body fat mass assessed by dual-energy x-ray absorptiometry (± 100 g difference) and a very similar height (≤ 5 cm differences), the area of visceral adipose tissue varies from 48 to 130 cm2. These differences are not perfectly reflected by the body mass index (BMI) or body weight. Although visceral fat accumulation is on average higher in men compared to women for a given level of adiposity, similar interindividual variability in visceral fat accumulation can be observed in men.

Figure 2 Teaching points: There is a major difference between available randomized control trials (RCTs) and observational studies, which examined the effects of testosterone replacement therapy (TRT) on the body mass index (BMI) in men. Most RCTs reported a non-significant effect of TRT on the body mass index (BMI) whereas a higher proportion of observational studies reported a significant decrease in BMI following TRT. Numerical values on the charts indicate the number of study treatment groups in each category. This may be explained in part by the lower average BMI values and higher testosterone values at baseline in RCTs compared to observational studies.

Figure 3 Teaching points: There is a major difference between available randomized control trials (RCTs) and observational studies, which examined the effects of testosterone replacement therapy (TRT) on waist circumference (WC) in men. Most RCTs reported a non-significant effect of TRT on WC whereas a much higher proportion of observational studies reported a significant decrease in WC following TRT. Numerical values on the charts indicate the number of study treatment groups in each category. This may be explained in part by the lower average WC values and higher testosterone values at baseline in RCTs compared to observational studies.

Figure 4 Teaching points: This is a logical follow-up to Figure 2. When using baseline body mass index (BMI) and total testosterone values at baseline from available RCTs and observational studies on testosterone replacement therapy (TRT) in men, a negative correlation is observed between BMI and total testosterone levels. Interestingly, the studies that reported a significant loss of WC in response to TRT generally segregated to the left of the regression, suggesting that independent of trial design, studies enrolling obese men with low baseline total testosterone are more likely to report a decrease in WC in response to TRT.

Figure 5 Teaching points: This is a logical follow-up to Figure 3. When using baseline waist circumference (WC) and total testosterone values at baseline from available RCTs and observational studies on testosterone replacement therapy (TRT) in men, a negative correlation is observed between WC and total testosterone levels. Interestingly, the studies that reported a significant loss of WC in response to TRT generally segregated to the left of the regression, suggesting that independent of trial design, studies enrolling men with low baseline total testosterone and a high WC are more likely to report a decrease in WC in response to TRT.

Figure 6 Teaching points: This is a representation of the steroid conversions, which can take place in adipose tissue under the action of steroidogenic enzymes targeting androgens. Steroid precursors such as DHEA or androstenedione may be locally transformed to active testosterone and/or DHT, which then bind to the androgen receptor. Inactivation of testosterone to androstenedione may also be detected (see other figures). Additional reactions that were identified in adipose tissue include the inactivation of DHT by 3α-reduction and glucuronide conjugation as well as aromatization of androstenedione or testosterone to 5α-reduced steroids. Abbreviations are the following: HSD, hydroxysteroid dehydrogenase; P450 arom, P450 aromatase; E1, estrone; E2, estradiol; 5α-red, 5α-reductase; UGT2B15, UDP-glucuronosyltransferase 2B15; G, glucuronide (two isomers of the glucuronide derivative are formed, 3α and 17β).

Figure 7 Teaching points: We have reported that the conversion of testosterone to androstenedione could be detected in adipose tissue homogenates and adipose tissue explants. We have shown that 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD-2) was likely responsible for this activity. However, when examining isolated primary cultures of preadipocytes or mature adipocytes, this activity was generally low. Using tridimensional confoncal imaging of 17β-HSD type 2 in human adipose tissue samples, we demonstrated that the enzyme clearly co-localized with CD31, an endothelial cell marker, in the blood vessels of adipose tissue.

Figure 8 Teaching points: This is a logical follow-up to Figure 7. We further confirmed the cellular localization of the 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD-2) isoenzyme in human adipose tissue-derived microvascular endothelial cells. Panel A shows androstenedione (4-dione) formation in these cells using testosterone as a substrate. The activity is blocked by 17β-HSD-2 inhibitor EM-919 (EM). Panel B shows expression of the endothelial cell marker CD31 and the HSD2B mRNA coding for 17β-HSD-2. Histological analysis in Panels E and F show strong expression of the enzyme in this cell type. Panels C and D are the negative controls.

Figure 9 Teaching points: We tested the effects of two 5α-reductase inhibitors on each 5α-reductase isoenzyme using three HEK-293 cell lines each overexpressing one of the 5α-reductase isoenzymes (5α-reductase type 1, type 2, or type 3). The inhibitors were finasteride (FINA) and 4-MA. Thin-layer chromatography images and corresponding densitometry analyses are shown for each cell line. CTL, control; A-dione, androstanedione; 4-dione, androstenedione. Cells overexpressing 5α-reductase type 1 showed very strong androstenedione-to-androstanedione activity that was slightly blunted by 4-MA, but not by finasteride. Strong activity was detected also in the 5α-reductase type 2 cell line, but was inhibited by both inhibitors. Cells overexpressing 5α-reductase type 3 had lower activity, which was blocked completely by both 4-MA and finasteride. With the exception of the type 2 enzyme, which is not expressed in adipose tissue, inhibitors were effective against the type 3 isoenzyme, but not against type 1. Taken together with other evidence, this experiment provides indirect support for a role of 5α-reductase type 3 in adipose tissue.

Figure 10 Teaching points: This is a logical follow-up to Figure 9. We tested the effect of 5α-reductase inhibitors on human primary preadipocyte differentiation. Cells were incubated with either testosterone or androstenedione, and with or without 5α-reductase inhibitors 4-MA or finasteride (FINA). The extent of preadipocyte differentiation was assessed by glyceraldehyde-3-phosphate dehydrogenase activity (G3PDH). The 5α-reductase inhibitors completely reversed the inhibitory effect of androstenedione and testosterone on preadipocyte differentiation. We had shown that testosterone and DHT both inhibit preadipocyte differentiation in visceral and subcutaneous primary preadipocyte cultures of both sexes. These findings support the notion that DHT generated through 5α-reductase action may be responsible for an important portion of the effect of both androstenedione and testosterone on preadipocyte differentiation. G3PDH activity expressed as % of control (CTL). *P < 0.05.

 

 

 

 


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Article Title: Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans
 

How to Cite

André Tchernof, Dannick Brochu, Ina Maltais‐Payette, Mohamed Fouad Mansour, Geneviève B. Marchand, Anne‐Marie Carreau, Jordanna Kapeluto. Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans. Compr Physiol 2018, 8: 1253-1290. doi: 10.1002/cphy.c170009