Sex Hormone Binding Globulin [SHBG]

[Michael Scally MD]

Rastrelli G, Corona G, Cipriani S, Mannucci E, Maggi M. Sex hormone binding globulin is associated with androgen deficiency features independently of total testosterone. Clinical Endocrinology. http://dx.doi.org/10.1111/cen.13530

Objective: It is recognized that total testosterone (TT) does not sufficiently describe androgen status when sex hormone binding globulin (SHBG) is altered. However, in humans, evidence supporting the existence of a hypogonadism due to low T bioactivity is scanty. The aim of the study was to assess whether changes in SHBG levels, independently of TT, are associated with subjective and objective androgen dependent parameters.

Design: Cross-sectional observation.

Patients: 2622 men (aged 51.1±13.5 years) attending a Sexual Medicine and Andrology Outpatient Clinic for sexual dysfunctions.

Measurements: All patients underwent a standardized diagnostic protocol before starting any treatment. Clinical and biochemical parameters have been collected. Higher ANDROTEST score has been used as a comprehensive marker of more severe hypogonadal symptoms. Prostate specific antigen (PSA) and hematocrit have been used as objective surrogate markers of T bioactivity.

Results: After adjusting for TT and lifestyle, SHBG showed a significant positive association with ANDROTEST score (B=0.79 [0.61;0.96], p<0.0001). Conversely, higher SHBG, independently of TT, was negatively related to PSA (B=-0.86 [-0.83;-0.89]; p<0.0001) and hematocrit (B=-0.64 [-0.88;-0.40]; p<0.0001), after adjustment for the aforementioned confounders along with age and body mass index. Furthermore, a relationship between SHBG and lipids or blood pressure was found, with lower SHBG levels associated with a worse metabolic profile, independently of TT.

Conclusions: Higher SHBG, independently of TT, is associated with either subjective or objective androgen deficiency features. This indicates that besides a hypogonadism due to an impaired T production, a hypogonadism due to a lower biological activity of T does exist.

 

[Michael Scally MD]

Serum Sex Hormone Binding Globulin (SHBG) Relation with Different Components of Metabolic Syndrome in Men with Type 2 Diabetes

Sex hormone binding globulin (SHBG) is demonstrated to be decreased in subjects with metabolic syndrome (MetS). The aim of the present study was to investigate the association of SHBG in relation to MetS components among men with type 2 diabetes (T2D).

This cross-sectional study was carried out among 429 Saudi T2D male patients aged >30 years. Metabolic syndrome was defined using International Diabetes Federation (IDF) criteria. Fasting blood glucose (FBG), HbA1c, albumin, and lipid parameter were measured. Gonadal hormones, namely total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and SHBG were determined using ELISA.

The SHBG levels of the MetS group was significantly lower than non-MetS group 47.25+/-31.03 nmol/l vs. 56.55+/-37.84 nmol/l; p=0.013. As the MetS score increases, SHBG and HDL levels decrease while weight, BMI, waist circumference, SBP, DBP, FBG, HbA1c, TC, and TG levels increase. SHBG correlated with age, BMI, TG, HDL, TT, free testosterone, and bio-available testosterone.

This is the first study that provides detailed analyses of SHBG with MetS components in male diabetic subjects. The mean serum SHBG levels gradually declined with the addition of MetS components in T2D men. TT, free testosterone, and bio-available testosterone remained independently associated with SHBG by multivariable regression analysis.

Siddiqui K, Al-Rubeaan K, Nawaz SS, Aburisheh KH, Alaabdin AMZ, Tolba IA. Serum Sex Hormone Binding Globulin (SHBG) Relation with Different Components of Metabolic Syndrome in Men with Type 2 Diabetes. Horm Metab Res 2017. Serum Sex Hormone Binding Globulin (SHBG) Relation with Different Components of Metabolic Syndrome in Men with Type 2 Diabetes. - PubMed - NCBI

 

[tenpoundsleft]

This is an interesting topic BUT the miles of studies copy-pasted with no summary/takeaway don't help. And I'm interested in details, but this is too much.

To me, since I'm always on at least TRT and since I also supplement well in regards to SHBG (vitamin D, magnesium and others) do I really need to worry about SHBG getting too high? Just looking for a bottom line here.

If someone can put the undisputed factors - if they exist - in a brief list, that'd be great.

 

[James23]

This is an interesting topic BUT the miles of studies copy-pasted with no summary/takeaway don't help. And I'm interested in details, but this is too much.

To me, since I'm always on at least TRT and since I also supplement well in regards to SHBG (vitamin D, magnesium and others) do I really need to worry about SHBG getting too high? Just looking for a bottom line here.

If someone can put the undisputed factors - if they exist - in a brief list, that'd be great.

This study points to low SHBG being a result of metabolic syndrome. Vitamin D and magnesium lower SHBG.

The risk related to this study is of SHBG getting too low, not too high. Too low invites metabolic dysfunction and hypogonadism through HPTA feedback on free testosterone elevation (homeostasis), and too high invites hypogonadal symptoms through reduced free testosterone levels.

If your HPTA is healthy, increases in SHBG will be met with further increases in testosterone. Studies show a positive correlation between SHBG level and testosterone level in healthy men.

 

[tenpoundsleft]

This study points to low SHBG being a result of metabolic syndrome. Vitamin D and magnesium lower SHBG.

The risk related to this study is of SHBG getting too low, not too high. Too low invites metabolic dysfunction and hypogonadism through HPTA feedback on free testosterone elevation (homeostasis), and too high invites hypogonadal symptoms through reduced free testosterone levels.

If your HPTA is healthy, increases in SHBG will be met with further increases in testosterone. Studies show a positive correlation between SHBG level and testosterone level in healthy men.

I wasn't referencing any single study, just the thread in general. Too many quotes from studies done on old people, sedentary people, natty people, or all of the above.

What's the bottom line for the Meso crowd?

And I take my supps to help keep SHGB down, isn't that what we want?

 

[James23]

I wasn't referencing any single study, just the thread in general. Too many quotes from studies done on old people, sedentary people, natty people, or all of the above.

What's the bottom line for the Meso crowd?

And I take my supps to help keep SHGB down, isn't that what we want?

Not quite. SHBG isn't something that should ever creep upward in the first place without disease. Mine is 13 nmol/L (range 20-60 nmol/L) no matter what I do, for example.

The lower your SHBG, the lower your total testosterone will be. You can't create a higher FT:T ratio by lowering SHBG. That was an age old myth. Find a person who lowered SHBG and saw FT shoot up without TT shooting down. The HPTA isn't that stupid and will just adapt to what you did. The lower TT will result in the same total FT as you had in the first place.

 

[tenpoundsleft]

Not quite. SHBG isn't something that should ever creep upward in the first place without disease. Mine is 13 nmol/L (range 20-60 nmol/L) no matter what I do, for example.

The lower your SHBG, the lower your total testosterone will be. You can't create a higher FT:T ratio by lowering SHBG. That was an age old myth. Find a person who lowered SHBG and saw FT shoot up without TT shooting down. The HPTA isn't that stupid and will just adapt to what you did. The lower TT will result in the same total FT as you had in the first place.

We're working with the same premise? I.e. a physically active individual that is always on some level of exogenous test?

I'm not at all concerned with my TT/FT as I'm on at least 150mg of test year round.

 

[Michael Scally MD]

[OA] Cross-Sectional and Longitudinal Determinants of Serum Sex Hormone Binding Globulin (SHBG)

Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men.

Study participants comprised randomly selected 35–80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up.

The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships.

At baseline there were positive cross-sectional associations between age (β = 0.409, p<0.001), TT (β = 0.560, p<0.001), fT4 (β = 0.067, p = 0.019) and SHBG, and negative associations between triglycerides (β = -0.112, p<0.001), abdominal fat mass (β = -0.068, p = 0.032) and E2 (β = -0.058, p = 0.050) and SHBG. In longitudinal analysis the positive determinants of SHBG at 4.9 years were age (β = 0.406, p = <0.001), TT (β = 0.461, p = <0.001), and fT4 (β = 0.040, p = 0.034) and negative determinants were triglycerides (β = -0.065, p = 0.027) and abdominal fat mass (β = -0.078, p = 0.032).

Taken together these data suggest low SHBG is a marker of abdominal obesity and increased serum triglycerides, conditions which are known to have been associated with low testosterone and low T4.

Gyawali P, Martin SA, Heilbronn LK, et al. Cross-sectional and longitudinal determinants of serum sex hormone binding globulin (SHBG) in a cohort of community-dwelling men. PloS one 2018;13:e0200078. https://doi.org/10.1371/journal.pone.0200078

 

[Michael Scally MD]

Ramachandran S, Strange RC, Fryer AA, Saad F, Hackett GI. The association of sex hormone-binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes. Andrology 2018. https://doi.org/10.1111/andr.12520

Background Serum sex hormone-binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM).

Objectives To confirm the association of serum sex hormone-binding globulin with mortality and then determine whether this association is mediated by age and total testosterone concentration.

Materials and Methods We studied 364 men (median age: 66 years) with T2DM over a median follow-up of 4.3 years using the Cox regression to study associations between sex hormone-binding globulin, age, total testosterone, and mortality.

Results Mortality was significantly and independently associated with sex hormone-binding globulin, age, and total testosterone. In pairwise combinations of age and sex hormone-binding globulin dichotomized by median values, the association of sex hormone-binding globulin with mortality was age-dependent. Relative to the combination of age >66 years/SHBG >35 nmol/L (mortality 22.5%), the other combinations were associated with significantly less mortality (mortality in men ≤66 years/SHBG ≤ 35 nmol/L was 3.23%).

In men >66 years, SHBG ≤ 35 nmol/L was associated with decreased mortality (HR: 0.41, p = 0.037) compared with SHBG > 35 nmol/L. In men ≤66 years, there was no significant difference between those with sex hormone-binding globulin above or below the median (HR: 1.73, p = 0.56, reference: SHBG ≤ 35 nmol/L). TT < 12 nmol/L was associated with increased mortality in both age categories.

Men >66 years with the reference combination of SHBG > 35 nmol/L and TT < 12 nmol/L (36.84%) nmol/L had significantly higher mortality than those with SHBG > 35 nmol/L and TT ≥ 12 (18.06%) and those with SHBG ≤ 35 nmol/L and TT < 12 nmol/L (13.79%).

Discussion Our data suggest sex hormone-binding globulin and total testosterone have particular impact on mortality in men aged over 66 years. Further, in older men, the combination of high sex hormone-binding globulin levels and low total testosterone is associated with greater risk than either high sex hormone-binding globulin or low total testosterone individually. Conclusions Our findings are compatible with data suggesting the importance of sex hormone-binding globulin lies in mediating free testosterone levels.

 

[Michael Scally MD]

Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome: In Vitro Evidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages

Sex hormone-binding globulin (SHBG) is a serum protein released mainly by the liver, and a low serum level correlates with a risk for metabolic syndrome including diabetes, obesity, and cardiovascular events. However, the underlying molecular mechanism(s) linking SHBG and metabolic syndrome remains unknown.

In this study, using adipocytes and macrophages, we focused on the in vitro effects of SHBG on inflammation as well as lipid metabolism. Incubation with 20 nM SHBG markedly suppressed lipopolysaccharide- (LPS-) induced inflammatory cytokines, such as MCP-1, TNFα, and IL-6 in adipocytes and macrophages, along with phosphorylations of JNK and ERK. Anti-inflammatory effects were also observed in 3T3-L1 adipocytes cocultured with LPS-stimulated macrophages.

In addition, SHBG treatment for 18 hrs or longer significantly induced the lipid degradation of differentiated 3T3-L1 cells, with alterations in its corresponding gene and protein levels. Notably, these effects of SHBG were not altered by coaddition of large amounts of testosterone or estradiol.

In conclusion, SHBG suppresses inflammation and lipid accumulation in macrophages and adipocytes, which might be among the mechanisms underlying the protective effect of SHBG, that is, its actions which reduce the incidence of metabolic syndrome.

Yamazaki H, Kushiyama A, Sakoda H, et al. Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome: In Vitro Evidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages. Mediators of Inflammation 2018;2018:12. https://doi.org/10.1155/2018/3062319

 

[Michael Scally MD]

[OA] Basal Endogenous Steroid Hormones, Sex Hormone-Binding Globulin, Physical Fitness, and Health Risk Factors

Purpose: Few large-scale population-based studies have adequately examined the relationships between steroid hormones, health status and physical fitness. The purpose of the study was to describe the relationship of serum basal endogenous steroid hormones (testosterone, TES; empirical free testosterone, EFT; cortisol, COR) and sex hormone-binding globulin (SHBG) to body composition, cardiovascular risk factors, and physical fitness in young healthy men.

Methods: Male reservists (25 +/- 4 years, N = 846) participated in the study. Basal TES, EFT, COR, and SHBG were measured in morning fasted blood. Stepwise regression analyses were used to examine associations between individual hormones to four separate categories: (1) body composition; (2) cardiovascular risk factors; (3) relative, and (4) absolute physical fitness.

Results: Higher TES, EFT, and SHBG were associated with lower waist circumference (TES: beta = -0.239, p < 0.001; EFT: beta = -0.385, p < 0.001), % body fat (TES: beta = -0.163, p = 0.003), and body mass index (SHBG: beta = -0.435, p < 0.001).

Lower cardiovascular risk factors were associated with higher TES, EFT and SHBG concentrations, especially between SHBG and triglycerides (beta = -0.277, p < 0.001) and HDL (beta = 0.154, p < 0.001). Greater maximal relative aerobic capacity was concurrent with higher TES, EFT, and SHBG (beta = 0.171, 0.113, 0.263, p < 0.001, =0.005, <0.001, respectively).

Conclusion: Higher basal concentrations of TES, EFT, and SHBG were weakly associated with healthier body composition, fewer cardiovascular risk factors and greater relative aerobic capacity in healthy young men.

It would be interesting to investigate whether these relationships are still evident after a few decades, and how different training modes (endurance, strength or their combination) positively affect physical fitness, body composition and their regulatory mechanisms over the decades.

Gagnon SS, Nindl BC, Vaara JP, Santtila M, Hakkinen K, Kyrolainen H. Basal Endogenous Steroid Hormones, Sex Hormone-Binding Globulin, Physical Fitness, and Health Risk Factors in Young Adult Men. Front Physiol 2018;9:1005. Basal Endogenous Steroid Hormones, Sex Hormone-Binding Globulin, Physical Fitness, and Health Risk Factors in Young Adult Men

 

[Michael Scally MD]

[OA] Chaudhury CS, Mee T, Chairez C, et al. Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral Clearance. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2019. Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral Clearance

Background: Hepatitis C virus (HCV) and hepatic dysfunction are associated with low total and free testosterone (TT and FT) and high sex hormone-binding globulin (SHBG). However, little is known about changes in testosterone following successful HCV treatment.

Methods: We evaluated testosterone levels and the prevalence of low testosterone in a cohort of 327 men with chronic HCV infection (human immunodeficiency virus [HIV] coinfection = 150) and in a subset of 85 men with testosterone levels obtained pre-HCV treatment and after sustained virologic response (SVR). Median follow-up was 36 months.

Results: Participants with active HCV at baseline had higher TT (P < .0001) and SHBG (P < .0001) compared with participants who had achieved SVR, whereas FT did not differ. Low TT (<10.4 nmol/L) was more prevalent in participants with SVR compared with active HCV (P = .002); however, low FT (<0.1735 nmol/L) was common (50% active HCV, 43% SVR) and did not different between groups. For participants with longitudinal determinations, TT and SHBG decreased significantly (P < .0001) while FT remained unchanged post-SVR. Low FT persisted after SVR (pre-treatment 58%, post-SVR 54%, P = .72). HIV status and change in aspartate aminotrasferase-to-platelet ratio were significant independent predictors of change in FT following SVR.

Conclusions: During active HCV infection, testosterone deficiency may be masked due to elevated SHBG. Despite improvements in SHBG following SVR, low FT was common and persisted after HCV clearance, indicating the need for enhanced awareness and screening using estimates of FT following successful treatment of chronic HCV.

 

[Michael Scally MD]

Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes

Introduction The age-related fall in male testosterone levels can have clinical consequences. The concentration of serum-free testosterone, the putative bioactive moiety, is mediated by carrier proteins, especially SHBG. Aim The aim of this study was to consider the nature of hormone binding to carriers with new insights into determining calculated free testosterone levels and review how SHBG and testosterone influence age-related mortality.

Methods Where possible, we focused on recent literature describing binding of testosterone to carrier proteins or, associations among age, SHBG, testosterone, and mortality. We then used logistic regression to study the impact of SHBG and total testosterone on age-related mortality in men with type 2 diabetes mellitus (T2DM).

Main Outcome Measures The association between mortality and age and SHBG and/or total testosterone was determined in a cohort of 364 men with T2DM leading to a graphical display of the impact of SHBG/testosterone levels on age-related mortality.

Results Low total testosterone and high SHBG are independently associated with increased all-cause mortality. Our analyses support these findings showing that men with T2DM and a combination of total testosterone <12 nmol/L and SHBG >35nmol/L (odds ratio [OR]: 3.05; 95% CI: 1.43−6.53; P = .004) demonstrated an increased risk of mortality, independent of age (OR: 1.08; 95% CI: 1.06−1.11; P < .001). We graphically demonstrated that the risk combination altered the relationship between age and mortality.

Conclusion Until free testosterone is precisely, accurately, and conveniently measured, calculated values may provide useful even if somewhat inaccurate estimates. We also suggest that SHBG and testosterone assays are standardized to allow establishment of diagnostic and treatment thresholds. Although it is possible that the association in men with T2DM, among the combination of SHBG and total testosterone and age-related mortality is driven by free hormone levels, it is so far, unproven.

Ramachandran S, Hackett GI, Strange RC. Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes. Sexual Medicine Reviews 2019. https://www.sciencedirect.com/science/article/pii/S205005211930071X

 

[Michael Scally MD]

[OA] Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogonadism In Metabolic Syndrome?

Introduction: In men suffering from metabolic syndrome, accompanying insulin resistance may result in a lowering of sex hormone–binding globulin (SHBG) plasma levels and cause changes in their androgenic status.

Aim: The objective of the research was to assess selected androgens and SHBG plasma levels in males meeting diagnostic criteria for MS compared to healthy males.

Patients and methods: The group consisted of 65 men aged between 40 and 70 years old fitting IDF metabolic syndrome criteria and 84 controls. Dehydroepiandrosterone (DHEA) and its sulphate (DHEA–S), total and free testosterone and SHBG serum levels were evaluated. Calculated free and bioavailable testosterone were estimated using an algorithm proposed by the International Society for the Study of the Aging Male.

Results: Men diagnosed with MS showed a statistically significant decrease in plasma levels of DHEA in comparison to healthy ones: 11.579 (8.39–15.56) vs 14.014 (9.611–17.125) ng/mL; p = 0.0350, SHBG: 47.46 (35.78–62.83) vs 71.965 (54.45–91.56) nM/L; p<0.0001 and total testosterone: 5.2 (3.8–6.5) vs 6.3 (5.4–8.25) ng/mL; p = 0.0001 (values presented as a median with Q1–Q3).

Conclusion: The results suggest that SHBG is a good early marker for metabolic dysregulation in MS, considering its strength of association and significance is comparable to, or better than, those of MS criteria.

Jarecki P, Herman WA, Pawliczak E, Lacka K. Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogonadism In Metabolic Syndrome? Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019;12:2181-91. Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogo | DMSO

 

[Michael Scally MD]

Can Low SHBG Serum Concentration Be A Good Early Marker of Male Hypogonadism in Metabolic Syndrome?

Introduction: In men suffering from metabolic syndrome, accompanying insulin resistance may result in a lowering of sex hormone-binding globulin (SHBG) plasma levels and cause changes in their androgenic status.

Aim: The objective of the research was to assess selected androgens and SHBG plasma levels in males meeting diagnostic criteria for MS compared to healthy males.

Patients and methods: The group consisted of 65 men aged between 40 and 70 years old fitting IDF metabolic syndrome criteria and 84 controls. Dehydroepiandrosterone (DHEA) and its sulphate (DHEA-S), total and free testosterone and SHBG serum levels were evaluated. Calculated free and bioavailable testosterone were estimated using an algorithm proposed by the International Society for the Study of the Aging Male.

Results: Men diagnosed with MS showed a statistically significant decrease in plasma levels of DHEA in comparison to healthy ones: 11.579 (8.39-15.56) vs 14.014 (9.611-17.125) ng/mL; p = 0.0350, SHBG: 47.46 (35.78-62.83) vs 71.965 (54.45-91.56) nM/L; p<0.0001 and total testosterone: 5.2 (3.8-6.5) vs 6.3 (5.4-8.25) ng/mL; p = 0.0001 (values presented as a median with Q1-Q3).

Conclusion: The results suggest that SHBG is a good early marker for metabolic dysregulation in MS, considering its strength of association and significance is comparable to, or better than, those of MS criteria.

Jarecki P, Herman WA, Pawliczak E, Lacka K. Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogonadism In Metabolic Syndrome? Diabetes, metabolic syndrome and obesity : targets and therapy 2019;12:2181-91. Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogo | DMSO

 

[Michael Scally MD]

[OA] Sex Hormone-Binding Globulin, Androgens and Mortality

Objective: Sex hormone-binding globulin (SBHG) and androgen have been associated with mortality in women and men, but controversy still exists. Our objective was to investigate associations of SHBG and androgen with all-cause and cause-specific mortality in men and women.

Design: 1006 men and 709 peri- and postmenopausal women (age range: 45-82 years) from the German population-based KORA F4 cohort study were followed up for a median of 8.7 years.

Methods: SHBG was measured with an immunoassay, total testosterone (TT) and dihydrotestosterone (DHT) with mass-spectrometry in serum samples and we calculated free testosterone (cFT). To assess associations between SHBG and androgen levels and mortality, we calculated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox proportional-hazards models.

Results: 128 men (12.7%) and 70 women (9.9%) died.

In women, we observed positive associations of SHBG with all-cause (HR: 1.54, 95% CI: 1.16-2.04) and with other-cause mortality (HR: 1.86, 95% CI: 1.08-3.20) and for DHT with all-cause mortality (HR: 1.32, 95% CI: 1.00-1.73).

In men, we found a positive association of SHBG (HR: 1.24 95% CI: 1.00-1.54) and inverse associations of TT (HR: 0.87, 95% CI: 0.77-0.97) and cFT (HR: 0.84, 95% CI: 0.73-0.97) with all-cause mortality. No other associations were found for cause-specific mortality.

Conclusions: Higher SHBG levels were associated with increased risk of all-cause mortality in men and women. Lower TT and cFT levels in men and higher DHT levels in women were associated with increased risk of all-cause mortality. Future, well-powered population-based studies should further investigate cause-specific mortality risk.

Schederecker F, Cecil A, Prehn C, et al. Sex hormone-binding globulin, androgens and mortality: the KORA-F4 cohort study [published online ahead of print, 2020 Mar 1]. Endocr Connect. 2020;EC-20-0080. doi:10.1530/EC-20-0080 Sex hormone-binding globulin, androgens and mortality: the KORA-F4 cohort study in: Endocrine Connections - Ahead of print

 

[Michael Scally MD]

Testosterone Replacement Therapy: Pre-Treatment Sex Hormone Binding Globulin Levels and Age May Identify Clinical Subgroups

Background: Testosterone replacement therapy (TRT) improves health in some but not all men with type 2 diabetes (T2DM) and adult onset testosterone deficiency (TD). Such heterogeneity is compatible with the concept of patient subgroups that respond differently to therapy.

Objectives: Use baseline SHBG and age to identify putative subgroups that demonstrate different responses in variables such as waist circumference and HbA1c following TRT.

Materials and methods: A randomised double-blind trial approach was used to recruit and randomise men with T2DM and adult onset TD into placebo and TRT treated groups. Multiple regression was used to study differences between groups.

Results: Baseline SHBG and change in SHBG (∆SHBG) were inversely related in the TRT group. Both median values of SHBG and age mediated the effect of TRT on ∆SHBG depending on whether baseline values were ≤ or >median (28.1nmol/l, 63 years respectively). In men with both SHBG≤28.1 nmol/l and age≤63 years (subgroup 1), TRT was positively associated with ∆SHBG (c = 4.67, 95%CI 1.17 - 8.16, p=0.010) while in those with SHBG>28.1 nmol/l and age>63.1 years (subgroup 4) the association was inverse (c = -7.07, 95%CI -11.64 - -2.49, p=0.003). The association between TRT and change (∆) in waist circumference, HbA1c and International Index of Erectile Function (IIEF) score differed between subgroups; in subgroup 4 but not subgroup 1, the therapy was significantly, associated with ∆waist circumference, ∆HbA1c and ∆IIEF.

Discussion: Though the mechanism remains unclear, our finding of different responses to TRT in terms of change in waist circumference, HbA1c and IIEF score supports the concept of subgroups in men with T2DM and adult onset TD.

Conclusion: Our approach may provide a basis for identifying men who will or will not derive benefit from TRT though a larger study is required.

Ramachandran S, Hackett GI, Strange RC. Testosterone replacement therapy: Pre-treatment sex hormone binding globulin levels and age may identify clinical subgroups [published online ahead of print, 2020 May 8]. Andrology. 2020;10.1111/andr.12813. doi:10.1111/andr.12813 Error - Cookies Turned Off

 

[James23]

Just so I’m not misreading this, which group (above average SHBG or below average SHBG) was considered the non-responder group?

 

[Michael Scally MD]

Testosterone Replacement Therapy: Pre‐Treatment Sex Hormone‐Binding Globulin Levels and Age May Identify Clinical Subgroups

Background - Testosterone replacement therapy (TRT) improves health in some but not all men with type 2 diabetes (T2DM) and adult‐onset testosterone deficiency (TD). Such heterogeneity is compatible with the concept of patient subgroups that respond differently to therapy.

Objectives - Use baseline SHBG and age to identify putative subgroups that demonstrate different responses in variables such as waist circumference and HbA1c following TRT.

Materials and methods - A randomized double‐blind trial approach was used to recruit and randomize men with T2DM and adult‐onset TD into placebo and TRT‐treated groups. Multiple regression was used to study differences between groups.

Results - Baseline SHBG and change in SHBG (∆SHBG) were inversely related in the TRT group. Both median values of SHBG and age mediated the effect of TRT on ∆SHBG depending on whether baseline values were ≤ or>median (28.1 nmol/L, 63 years, respectively).

In men with both SHBG ≤ 28.1 nmol/L and age ≤ 63 years (subgroup 1), TRT was positively associated with ∆SHBG (c = 4.67, 95%CI 1.17‐8.16, P = .010) while in those with SHBG > 28.1 nmol/L and age > 63.1 years (subgroup 4) the association was inverse (c = −7.07, 95%CI −11.64 to −2.49, P = .003).

The association between TRT and change (∆) in waist circumference, HbA1c and International Index of Erectile Function (IIEF) score differed between subgroups; in subgroup 4 but not subgroup 1, the therapy was significantly associated with ∆waist circumference, ∆HbA1c and ∆IIEF.

Discussion - Though the mechanism remains unclear, our finding of different responses to TRT in terms of change in waist circumference, HbA1c and IIEF score supports the concept of subgroups in men with T2DM and adult‐onset TD.

Conclusion - Our approach may provide a basis for identifying men who will or will not derive benefit from TRT though a larger study is required.

Ramachandran, S, Hackett, GI, Strange, RC. Testosterone replacement therapy: Pre‐treatment sex hormone‐binding globulin levels and age may identify clinical subgroups. Andrology. 2020; 00: 1– 11. Error - Cookies Turned Off

 

[Michael Scally MD]

Lewis JG, Elder PA. Glycosylation may influence sex hormone-binding globulin measurements. Clinica chimica acta; international journal of clinical chemistry 2020. Glycosylation may influence sex hormone-binding globulin measurements - ScienceDirect

Highlights
· Discordant SHBG measurement was investigated by multiple ELISAs.
· Discordance not due to heterophile antibodies.
· SHBG affected by glycan removal and modification.
· Glycosylation may influence SHBG immunoassays.

A discordance between sex hormone-binding globulin (SHBG) measurements by 2-site ELISAs was investigated using pairings of various "in house" SHBG antibodies together with a concordant control. The 2-site monoclonal ELISAs used the same base coat (11F11) and discordance was observed with one top coat monoclonal antibody (7H9) and also when a polyclonal SHBG antibody was paired with the basecoat antibody (11F11).

Sialidase treatment of the discordant sample and purified SHBG revealed increased levels using 7H9 whereas there was no change in SHBG in the concordant sample. Conversely, following sialidase treatment, the discordant sample showed no change in SHBG measured using the other monoclonal antibody pairings whereas the SHBG levels in the concordant sample declined following sialidase using the same monoclonal antibody pairings.

This implicated glycosylation as a factor in antibody recognition and synthetic peptides spanning the two N-linked and one O-linked glycosylation regions showed that SHBG recognition by monoclonal antibody 7H9 could be disrupted by a peptide spanning the O-linked glycosylation site.

Hence rather than immunoassay discordance being attributed to heterophile antibodies or other circulating antibodies here it can be likely attributed to glycosylation affecting antibody recognition and hence the measurement of SHBG.