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

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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.

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 (). 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 (). 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 (). 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 (). 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 (). 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 (). 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 (). 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 (). 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 (). 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 (). 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 (). 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 (). Reprinted with permission.
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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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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