Metabolism of sex steroids is influenced by acquired adiposity-A study of young adult male monozygotic twin pairs

- Serum DHT is lower and free E2 higher in the heavier compared to the leaner co-twins.
- General adiposity inversely correlates with serum androgens and SHBG within pairs.
- Serum total testosterone is best explained by serum SHBG in multivariate analysis.
- AKR1C2 is overexpressed in subcutaneous adipose tissue from the heavier co-twins.
- AKR1C2 and CYP19A1 mRNA expressions positively correlate with adiposity within pairs.

Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n = 18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22-36 kg/m2] included 9 male MZ twin pairs discordant for BMI [intra-pair difference (Δ) in BMI ≥3 kg/m2]. Sex steroid concentrations were determined by liquid chromatography-tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean ΔBMI = 5.9 kg/m2), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P = 0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P = 0.021) and cortisol-producing HSD11B1 (P = 0.008) higher in the heavier compared to the leaner co-twins. Serum free 17β-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P = 0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P = 0.006; and 123 (43) vs. 105 (27) pmol/l, P = 0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone-binding globulin (SHBG) concentrations (P < 0.01 for all), 2) intra-abdominal fat with total testosterone and SHBG (P < 0.05), and 3) liver fat with SHBG (P = 0.006). Also, 4) general and intra-abdominal adiposity correlated positively with mRNA expressions of AKR1C2, HSD11B1, and aromatase in adipose tissue (P < 0.05). In conclusion, acquired adiposity was associated with decreased serum DHT and increased estrogen concentrations, independent of genetic factors and age. The reduction of DHT could be linked to its increased degradation (by AKR1C2 and HSD11B1) and increased estrogen levels to increased adiposity-related expression of aromatase in adipose tissue.