Testosterone replacement therapy: Pre‐treatment sex hormone‐binding globulin levels and age may identify clinical subgroups

Abstract

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.

Testosterone therapy reduces insulin resistance in men with adult‐onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open‐label phase

“…This was mirrored in the confirmatory cohort, apart from at Week 66, although significance ( p = 0.013) was again demonstrated at 102 weeks. This observation has been previously reported, although the mechanism is not clear 33,34 . E2 significantly increased ( p = 0.0040) at 18 weeks in men in the RCT of the study cohort but was not replicated at subsequent time points or in the confirmatory cohort.…”

“…This observation has been previously reported, although the mechanism is not clear. 33,34 E2 significantly increased ( p = 0.0040) at 18 weeks in men in the RCT of the study cohort but was not replicated at subsequent time points or in the confirmatory cohort. Tan et al 35 evaluated E2 levels post TTh in 34 016 men and found that 20.2% of these men demonstrated elevated E2 levels ≥156 pmol/L (42.6 pg/mL), with the increase being age-dependent.…”

“…Unfortunately, as HbA1c was not measured we could not compare our results with those of the T4DM Study, 23 which showed reduction in T2DM progression without significant HbA1c decrease. As TTh appears to be associated with a reduction in SHBG levels, 34 it would have been useful also to have measured free testosterone as opposed to cFT using the method by Vermeulen et al 46 Furthermore, access to data on changes in body composition in the two groups would have been interesting as ΔE2 could possibly be due to associations with both testosterone levels and adiposity 47 . We would also have wished for data on changes in diet and exercise as these could have been included as potential confounding variables.…”

Association Between Low Serum Testosterone and the Development of Metabolic Syndrome in Elderly Taiwanese Men

“…36 Furthermore, T replacement therapy was found to have a better therapeutic effect on decreasing waistline, HbA1c, and improving sexual function in patients with higher SHBG and older age in a randomized control trial. 37 However, in 2015, the US Food and Drug Administration still recommended the use T therapy only for classic hypogonadism but not for aged-related decline due to the lack of established efficacy and weak evidence on cardiovascular risk. 38 Though no definitive conclusions had been established, one double-blind, placebo-controlled study found similar adverse events, including an increase in prostate-specific antigen level, prostate cancer, cardiovascular events, and erythrocytosis, during the first year of the trial in the treatment and placebo groups.…”

Testosterone and type 2 diabetes prevention: translational lessons from the T4DM study

“…In the T4DM study, the benefits of injectable testosterone undecanoate (TU) for glycaemia were shown in the 2-h GTT but were not accompanied by any change in HbA1C (Wittert et al 2021). Previous small studies had previously reported little or no consistent benefit of TU treatment for HbA1C in studies of men without (Svartberg et al 2008) or with T2D (Gianatti et al 2014, Hackett et al 2014, Ramachandran et al 2020.…”