Structure, Function, and Regulation of Androgen-Binding Protein/Sex Hormone-Binding Globulin

Over the past decade, there have been important breakthroughs in our understanding of the regulation and function of sex hormone–binding globulin (SHBG). A recent genome-wide association and Mendelian randomization study has provided new insights at the population level. Thorough study of genetic variants affecting serum SHBG has identified de novo lipogenesis as one of the mechanistic links between the metabolic syndrome and reduced serum SHBG levels in humans. Furthermore, careful deduction of the Mendelian randomization results suggests a direct, causal role for SHBG in the pathogenesis of type 2 diabetes, as a hepatokine, in women. These findings prompt the development of SHBG-raising therapies as a means to prevent or treat disorders such as type 2 diabetes and polycystic ovary syndrome.

Obese subjects of all ages and sex have reduced plasma SHBG levels. Whether these low plasma SHBG levels play a role in obesity development is unknown. In the present work we wanted to explore if SHBG overexpression could prevent obesity development induced by high fat diet (HFD). To do so, we fed humanized SHBG transgenic male mice and their wild-type littermates with control diet (CD) or HFD over the course of 8 weeks. The results showed that SHBG overexpression protected against body weight gain and fat accumulation induced by HFD. In addition, SHBG overexpression also abrogated the increase in insulin, leptin and resistin levels, as well as the reduction in adiponectin, induced by HFD. Mechanistically, the SHBG protection against HFD-induced obesity was achieved by stimulating lipolysis in white adipose tissue. Furthermore, we have demonstrated the SHBG cell-autonomous effect using human primary visceral adipocytes. Taking together, our results demonstrate that SHBG overexpression protects against diet-induced obesity and improves the metabolic profile of male mice fed a HFD diet.

Previous studies have reported that glycated albumin (GA) is affected by body fat distribution. Sex hormones are reported to play an important role in fat metabolism.

This study aimed to explore the influence of sex hormones on the relationship between body fat and GA in a community population.

We recruited 763 middle-aged and elderly subjects with normal glucose tolerance from communities. GA was determined using the enzyme method, and serum estradiol (E₂), total testosterone, and sex hormone–binding globulin (SHBG) were detected using chemiluminescent microparticle immunoassays.

There was a statistically significant association between SHBG and GA remained after adjusting for body fat in both men and women.

The average serum GA levels were 13.40 ± 1.10% in the 298 men and 465 postmenopausal women included in this study. GA presented a significant downward trend with increasing quartiles of total fat mass (FM), limb FM, and trunk FM in both men and women (all P for trend < .01). In men, total testosterone, free testosterone, and SHBG were positively correlated with GA (both P < .01), and the correlation between SHBG and GA remained after adjusting for body fat (P < .01). In women, E2, free testosterone, bioactive testosterone, and SHBG were correlated with GA (all P < .01); furthermore, the positive correlation between SHBG and GA and the inverse correlation between E2 and GA remained after adjusting for body fat (both P < .05). Multivariate linear regression analyses showed that in addition to trunk FM, SHBG was positively correlated with GA in both men and women (standardized β = 0.136, P = .035; standardized β = 0.101, P = .033); however, E2 was not independently correlated with GA in women.

SHBG may contribute to the influence of body fat, especially trunk fat on GA levels.

This study used an automated bioelectrical impedance analyzer to measure segmental body composition including limb FM and trunk FM and further investigated the role of segmental body fat in the correlation between SHBG and GA. Sex hormones may explain in part why body fat content and distribution can alter GA levels.

SHBG is positively correlated with serum GA levels, and this correlation is independent of total or segmental body fat.

Xu Y, Ma X, Shen Y, et al. Influence of Sex Hormones on the Relationship Between Body Fat and Glycated Albumin Levels. J Sex Med 2020;17:903–910.

In this study, bioaccumulation and transfer characteristics of dechlorane plus (DP) were examined between human adipose tissue and matched maternal serum, and the possible transfer mechanism between tissues was further discussed. The median level of total DP was 971 pg g⁻¹ wet weight (ww) and 1.22 ng g⁻¹ lipid weight (lw) in adipose tissue, respectively, and was 34.7 pg g⁻¹ ww and 3.98 ng g⁻¹ lw for serum, respectively. DP wet levels’ positive association with fat contents of five types of human tissues indicated that DP distribution might be related to lipid-driven mechanism. However, the lipid-adjusted adipose-serum partitioning ratios were estimated to be 0.35 for syn-DP and 0.35 for anti-DP, accordingly, which implied that the DP distribution between serum and adipose tissues, was not only regulated by the tissue lipid contents. Both the internal mono-dechlorination of anti-DP, and stereo-selective behavior of DP isomers were not found in DP transfer from blood to adipose tissue. The marginal positive relationship was observed between serum levels and apolipoprotein A concentrations (p = 0.095 for total DP and 0.045 for syn-DP), and neither association was found between serum levels and thyroid hormone concentrations (THs). To our best knowledge, this is the first report about the accumulation relationship of DP between human adipose tissue and blood stream with the corresponding distribution-related mechanism.

Steroid hormones play important roles in normal physiological functions and diseases. Sex steroids hormones are important in the biology and treatment of sex hormone-related cancer such as prostate cancer and breast cancer. Cells may take up steroids using multiple mechanisms. The conventionally accepted hypothesis that steroids cross cell membrane through passive diffusion has not been tested rigorously. Experimental data suggested that cells may take up sex steroid using an active uptake mechanism. ³H-testosterone uptake by prostate cancer cells showed typical transporter-mediated uptake kinetic. Cells retained testosterone taken up from the medium. The uptake of testosterone was selective for certain steroid hormones but not others. Data also indicated that the active and selective uptake mechanism resided in cholesterol-rich membrane domains, and may involve ATP and membrane transporters. In summary, the present study provided strong evidence to support the existence of an active and selective molecular mechanism for sex steroid uptake.

Sex hormone binding globulin (Shbg) is a plasma glycoprotein that binds and transports steroids in the blood of all vertebrate classes apart from birds. In the present study we characterized shbg from pejerrey, a fish species with a well characterized temperature-dependent sex determination. The pejerrey shbg mRNA comprises 1185 bp encoding for a 395 amino acid Shbg precursor protein that includes a leader sequence for secretion. Relative quantification of shbg transcript abundance revealed expression early in development coinciding with the sex-determining period and probably in association with temperature leading to male determination. The hepatopancreas was the main site of shbg expression, which varied according to the sex cycle in females. It was also expressed in gills, gonads, gut and taste buds during both larval stages and in adult fish. The presence of Shbg in organs in close contact with the environment such as gills, pseudobranchs, gut and taste buds suggests that these are potential sources of uptake or release of steroids/xenosteroids to and from the aquatic environment.