Sex Hormone Binding Globulin [SHBG]

[Michael Scally MD]

The Potential Effect of Aberrant Testosterone Levels on Common Diseases

Testosterone has historically been linked to sexual dysfunction; however, it has recently been shown to affect other physical and mental attributes. We attempted to determine whether changes in serum testosterone could play a role in chronic or degenerative diseases.

We used two separate genetic instruments comprising of variants from JMJD1C and SHBG regions and conducted a two-sample Mendelian randomization for type II diabetes (T2D), gout, rheumatoid arthritis (RA), schizophrenia, bipolar disorder, Alzheimer’s disease and depression.

For the JMJD1C locus, one unit increase in log transformed testosterone was significantly associated with RA (OR = 1.69, p = 0.02), gout (OR = 0.469, p = 0.001) and T2D (OR = 0.769, p = 0.048). Similarly, one unit increase in log transformed testosterone using variants from the SHBG locus was associated with depression (OR = 1.02, p < 0.0001), RA (OR = 1.254, p < 0.0001) and T2D (OR = 0.88, p < 0.0001).

Our results show that low levels of serum testosterone levels may cause gout and T2D, while higher than normal levels of testosterone may result in RA and depression. Our findings suggest that fluctuations in testosterone levels may have severe consequences that warrant further investigation.

Syed AAS, He L, Shi Y. The Potential Effect of Aberrant Testosterone Levels on Common Diseases: A Mendelian Randomization Study. Genes. 2020;11(7):721. https://www.mdpi.com/2073-4425/11/7/721

 

[Michael Scally MD]

Serum Testosterone is Inversely, and Sex Hormone-Binding Globulin Directly, Associated with All-Cause Mortality

Context - Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase.

Objective - To analyse associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men.

Design, setting and participants - The UK Biobank prospective cohort study of community-dwelling men 40-69 years-old, followed for 11 years.

Main outcome measures - All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions and other covariates. Models for testosterone included SHBG, and vice versa.

Results - In complete case analysis of 149,436 men with 10,053 deaths (1,925 CVD and 4,927 cancer-related), men with lower testosterone had higher mortality from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio

---

=1.14, 95% confidence interval [CI]=1.06-1.22, overall trend P<0.001), and cancer (HR=1.20, CI=1.09-1.33, P<0.001), with no association for CVD deaths. Similar results were seen for cFT.

Men with lower SHBG had lower mortality from any cause (Q1 vs Q5, HR=0.68, CI=0.63-0.73, P<0.001), CVD (HR=0.70, CI=0.59-0.83, P<0.001), and cancer (HR=0.80, CI=0.72-0.89, P<0.001). A multiply-imputed dataset (N=208,425, 15,914 deaths, 3,128 CVD and 7,468 cancer-related) and analysis excluding deaths within first two years (9,261, 1,734 and 4,534 events) yielded similar results.

Conclusions - Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

Yeap BB, Marriott RJ, Antonio L, et al. Serum testosterone is inversely, and sex hormone-binding globulin directly, associated with all-cause mortality in men. The Journal of Clinical Endocrinology & Metabolism 2020. Serum testosterone is inversely, and sex hormone-binding globulin directly, associated with all-cause mortality in men

 

[Michael Scally MD]

Research Progress on The Relationship Between Sex Hormone-Binding Globulin and Male Reproductive System Diseases

Sex hormone-binding globulin, also known as testosterone-estradiol-binding globulin, is a multifunctional protein synthesised by hepatocytes. Sex hormone-binding globulin specifically binds and transports sex hormones to regulate plasma bioactive sex hormone levels and affects their bioavailability.

As male sex hormone expression is dominated by testosterone, the binding of sex hormone-binding globulin with testosterone leads to the reduction in bioavailable testosterone, which cannot fulfil its physiological roles, thereby resulting in male infertility, erectile and gonadal dysfunction, prostate cancer and other male reproductive system diseases.

Sex hormone-binding globulin may be involved in the pathogenesis of male reproductive system diseases, seriously affecting the quality of life of men. In this article, we review the association between sex hormone-binding globulin and male reproductive system diseases.

Wan Q, Xie Y, Zhou Y, Shen X. Research progress on the relationship between sex hormone-binding globulin and male reproductive system diseases. Andrologia. 2020 Oct 28:e13893. doi: 10.1111/and.13893. Epub ahead of print. PMID: 33112478. https://onlinelibrary.wiley.com/doi/10.1111/and.13893

 

[Michael Scally MD]

Allosterically Coupled Multi-Site Binding of Testosterone to Human Serum Albumin

Human serum albumin (HSA) acts as a carrier for testosterone, other sex hormones, fatty acids, and drugs. However, the dynamics of testosterone's binding to HSA and the structure of its binding sites remain incompletely understood.

Here, we characterized the dynamics of testosterone's binding to HSA and the stoichiometry and structural location of the binding sites using two-dimensional nuclear magnetic resonance (2D NMR), fluorescence spectroscopy, bis-ANS partitioning, and equilibrium dialysis, complemented by molecular modeling.

2D NMR studies showed that testosterone competitively displaced 18-[ 13C]-oleic acid from at least three known fatty acid binding sites on HSA that also bind many drugs. Binding isotherms of testosterone's binding to HSA generated using fluorescence spectroscopy and equilibrium dialysis were nonlinear and the apparent Kd varied with different concentrations of testosterone and HSA.

The binding isotherms neither conformed to a linear binding model with 1:1 stoichiometry nor to two independent binding sites; the binding isotherms were most consistent with two or more allosterically coupled binding sites. Molecular dynamics studies revealed that testosterone's binding to fatty acid binding site 3 on HSA was associated with conformational changes at site 6, indicating that residues in in these two distinct binding sites are allosterically coupled.

Conclusions: There are multiple, allosterically coupled binding sites for testosterone on HSA. Testosterone shares these binding sites on HSA with free fatty acids, which could displace testosterone from HSA under various physiological states or disease conditions, affecting its bioavailability.

Jayaraj A, Schwanz HA, Spencer DJ, et al. Allosterically coupled multi-site binding of testosterone to human serum albumin. Endocrinology. 2020 Oct 30:bqaa199. doi: 10.1210/endocr/bqaa199. Epub ahead of print. PMID: 33125473. Allosterically coupled multi-site binding of testosterone to human serum albumin

 

[Michael Scally MD]

Association of Gonadal Hormones and Sex Hormone Binding Globulin with Risk of Diabetes

Aim: Late-onset hypogonadism in men is related to the development of diabetes. The association of gonadal hormones, sex hormone binding globulin with diabetes has been studied in various studies. However, there is no cohort study on the relationship between gonadal hormone, sex hormone binding globulin and diabetes in Chinese. We aimed to provide an insight into the possible association in middle-aged and elderly Chinese males.

Methods: We included a population sample of 673 subjects aged 40 years or older. Total testosterone (TT), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH) was detected. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to estimate insulin sensitivity. Diabetes was diagnosed according to the 2010 American Diabetes Association criteria.

Results: With an average follow-up time of 3.2 ± 0.5 years, 9.8% of participants had developed diabetes. The prevalence of diabetes was decreased according to increasing SHBG quartiles (Q1:13.1%, Q2: 12.0%, Q3: 11.2%, Q4: 3.0%, P for trend<0.0001) and TT (Q1:16.0%, Q2: 7.9%, Q3: 9.0%, Q4: 6.4%, P for trend<0.0001). The ORs of diabetes for increasing SHBG quartiles were 4.52 (95% CI 1.40 - 14.57), 4.32 (95% CI 1.33 - 14.06), 3.89 (95% CI 1.21 - 12.50) and 1.00 (reference), respectively.

But the odds of prevalent diabetes were not increased in different quartiles of TT, FSH and LH. In subgroup analyses, the relationship between SHBG and risk of incident diabetes was significantly increased in the population aged over 60, without insulin resistance and with eGFR<90ml/min per 1.73m2 .

Conclusion: Compared with gonadal hormones, lower level of SHBG is independently associated with risk of diabetes in middle-aged and elderly Chinese males.

Li N, Huang C, Lan B, Lin D, Wang C, You L, Li L, Li F, Xiao H, Yan L, Lao G, Sun K. Association of gonadal hormones and sex hormone binding globulin with risk of diabetes: a cohort study in middle-aged and elderly males. Int J Clin Pract. 2021 Jan 5:e14008. doi: 10.1111/ijcp.14008. Epub ahead of print. PMID: 33400357. https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14008