Baseline Testosterone Predicts Body Composition and Metabolic Response to Testosterone Therapy

Abstract

ContextMale hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy.ObjectiveThe aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl.MethodsThis is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40–74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA).ResultsMen with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (−3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (−4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (−6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (−40.2 ± 35.1 vs. −27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed.ConclusionT therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.

The complex pathophysiology of bone fragility in obesity and type 2 diabetes mellitus: therapeutic targets to promote osteogenesis

“…Apart from the myogenic machinery, Gao et al., further reported that osteoblast differentiation was activated by T therapy in MC3T3-E1 cells through ERK-1/2, activated Runx2 pathway ( 156 ). Changes in body composition and bone density with T therapy from our lab and other investigators support the above findings from in-vitro and animal studies ( 146 , 157 , 158 ). Hence, we hypothesize that the reciprocal effect of T therapy on fat mass, lean mass and bone mass is due to the shift in lineage differentiation from adipogenesis to both myogenesis and osteogenesis.…”

“…Pgc1a on the adipogenic/myogenic cascade need to be explored. We hypothesize that T therapy activates the trio cascade PPARγ-Prdm16-Pgc1a leading to initiation of the switch from adipogenesis to myogenesis along with promotion of osteogenesis ( Figure 2 ) responsible for the observed positive effect on fat mass, lean mass and bone mass in hypogonadal men ( 146 , 157 , 158 ). The Endocrine Society has suggested the use of T to maintain or prevent loss of lean mass in men with HIV ( 159 ).…”

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…Nitric oxide is necessary for maintaining and sustaining physiological oxygenation during the critical windows of cellular regeneration–rejuvenation and the timing hypothesis of hormone therapy. Physiological concentrations of testosterone significantly increased nitric oxide production ( Campelo et al, 2012 ), and baseline testosterone levels predict body composition and metabolic response to TRT ( Deepika et al, 2022 ) and support the prostate safety of TRT in newly diagnosed men with hypogonadism ( Debruyne et al, 2017 ).…”

Pharmacotherapy of male hypogonadism

“…In all the meta-analyses, TRT exerts a similar, positive effect in reducing fat mass and in increasing muscle mass, without changing body mass index (BMI) or weight [37,43,44]. A positive effect on fasting glycemia was also apparent, whereas a reduction in total cholesterol and triglycerides were evident in some, but not all, the meta-analyses [37].…”