Testosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment.

Epidemiological studies consistently demonstrate that lowered serum testosterone is not only common in men with established Type 2 diabetes, but also predicts future diabetic risks and increased mortality. Preclinical studies report plausible mechanisms by which low testosterone could mediate dysglycaemia. Exogenous testosterone treatment consistently reduces fat mass, increases muscle mass and improves insulin resistance in some studies, but the majority of currently available randomized controlled trials (RCTs) do not report a consistent glycaemic benefit. In men with diabetes, testosterone treatment effects on androgen deficiency-like clinical features are inconsistent, and effects on sexual dysfunction may be attenuated compared with men without diabetes. The long-term risks of testosterone treatment in older men without medical disease of the hypothalamic-pituitary-testicular axis are not known. Current RCTs are not definitive, owing to their small size, short duration and enrolment of men with mostly relatively good baseline glycaemic control not specifically selected for the presence of androgen deficiency symptoms. Although large, well-designed clinical trials are needed, given the benefit-risk ratio of testosterone treatment is not well understood, routine serum testosterone testing or testosterone treatment of asymptomatic men with Type 2 diabetes is currently not recommended. Carefully selected, symptomatic men with low testosterone who are informed of the lack of high-level evidence regarding the long-term benefits and risks of this approach may be offered a trial of testosterone treatment in combination with lifestyle measures, weight loss and optimization of comorbidities.

Correlation of visceral adipose tissue measured by Lunar Prodigy dual X-ray absorptiometry with MRI and CT in older men.

Quantification of abdominal visceral adipose tissue (VAT) is important to understand obesity-related comorbidities. We hypothesized that dual X-ray absorptiometry (DXA) measurements of VAT would correlate with traditional gold standards of magnetic resonance imaging (MRI) and computed tomography (CT) in older men. Deming regression and Bland-Altman plots were used to assess the agreement between VAT measured simultaneously by DXA and MRI (n=95) in a cohort of older males participating in a randomized trial of testosterone replacement for diabetes. We also correlated DXA with single-slice CT (n=102) in a cohort of older males undergoing testosterone deprivation for prostate cancer. Lunar Prodigy DXA scanners using enCORE software was used to measure VAT. DXA VAT volume strongly correlated with MRI VAT volume (r=0.90, P<0.0001) and CT VAT area (r=0.83, P<0.0001). As DXA assesses VAT volume in a smaller compartment than MRI, Bland-Altman analysis demonstrated DXA systematically underestimated VAT by an approximately 30% proportional bias. DXA VAT volume measured by Lunar Prodigy DXA scanners correlate well with gold standard MRI and CT quantification methods, and provides a low radiation, efficient, cost-effective option. Future clinical studies examining the effects of interventions on body composition and regional fat distribution may find DXA an appropriate volumetric method to quantify VAT.

Testosterone levels increase in association with recovery from acute fracture in men.

UNLABELLED: In this longitudinal case-control study, acute fracture was associated with low serum testosterone, which was transient in 43% of men. While assessment of gonadal status is part of the assessment of bone fragility, measurement of testosterone in the early period after fracture may overestimate the prevalence of androgen deficiency. INTRODUCTION: Measurement of circulating testosterone is recommended in the evaluation of bone fragility in men. Since acute illness can transiently decrease circulating testosterone, we quantified the association of acute fracture and serum testosterone levels. METHODS: A case-control study was conducted involving 240 men with a radiologically confirmed minimal trauma fracture presenting to a tertiary referral hospital and 89 age-matched men without a history of minimal trauma fracture serving as controls. Follow-up testosterone levels 6 months after baseline were available for 98 cases and 27 controls. Results were expressed as the median and interquartile (IQR) range. RESULTS: Compared to controls, cases had lower total testosterone [TT, 7.2 (3.5, 10.8) vs 13.6 (10.9, 17.1) nmol/L, p < 0.001]. The 143 cases treated as inpatients had lower testosterone levels than the 97 cases treated as outpatients [TT 4.7 (2.3, 8.1) vs 10.3 (7.5, 12.7) nmol/L, p < 0.001]. Group differences in calculated free testosterone (cFT) were comparable to the group differences in TT. At follow-up, in 98 cases, median TT increased from 6.5 nmol/L (3.2, 8.5) to 9.6 nmol/L (6.9, 12.0) p < 0.0001, and SHBG remained unchanged. Of cases with low testosterone, 43% with TT <10 nmol/L and/or cFT <230 pmol/L at presentation were reclassified as androgen sufficient at follow-up. TT was unchanged in the controls. CONCLUSIONS: Low testosterone levels in men presenting with an acute fracture may, at least in part, be due to an acute, fracture-associated, stress response. To avoid over diagnosis, evaluation for testosterone deficiency should be deferred until recovery from the acute event.

Obesity and age as dominant correlates of low testosterone in men irrespective of diabetes status.

Although men with type 2 diabetes (T2D) frequently have lowered testosterone levels, it is not well established whether this is ascribable to the diabetic state per se, or because of other factors, such as obesity. Our objective was to determine the prevalence and correlates of low testosterone in middle-aged men with diabetes. We conducted a cross-sectional study in 240 men including 80 men with type 1 diabetes (T1D), 80 men with T2D and 80 men without diabetes. Prevalence of a total testosterone ≤8 nmol/L was low, occurring in none of the men with T1D, 6.2% of men with T2D and 2.5% of men without diabetes. Men with T1D had higher testosterone levels compared with men without diabetes (p < 0.001), even after adjustment for body mass index (BMI) and age (p < 0.02). While men with T2D had lower testosterone compared with controls (p = 0.03), this was no longer significant when BMI and age were taken into account (p = 0.16). In the entire cohort, TT remained inversely associated with BMI independent of age, sex hormone-binding globulin and diabetic status (p = 0.01), whereas calculated free testosterone (cFT) was independently and inversely associated with age (p < 0.001), but not with BMI (p = 0.47). These results suggest that marked reductions in circulating testosterone are uncommon in middle-aged men with diabetes. Increasing BMI and age are dominant drivers of lowered total and cFT, respectively, independent of the presence or absence of diabetes.

Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy.

OBJECTIVE: Androgen deprivation therapy (ADT) for prostate cancer is associated with increases in fat mass and risk of type 2 diabetes; however, the relationship between sex steroid deficiency and abdominal fat distribution remains controversial. DESIGN: We conducted a 12-month prospective observational study at a tertiary referral centre. PATIENTS AND MEASUREMENTS: We investigated changes in abdominal fat distribution and insulin resistance in 26 men (70.6±6.8 years) with nonmetastatic prostate cancer during the first year of ADT. RESULTS: Twelve months of ADT increased visceral abdominal fat area by 22% (from 160.8±61.7 to 195.9±69.7 cm(2) ; P<0.01) and subcutaneous abdominal fat area by 13% (from 240.7±107.5 to 271.3±92.8 cm(2) ; P<0.01). Fat mass increased by 14% (+3.4 kg; P<0.001) and lean tissue mass decreased by 3.6% (-1·9 kg; P<0.001). Insulin resistance (HOMA-IR) increased by 12% (2.50±1.12 to 2.79±1.31, P<0.05). There was no change in fasting glucose or glycated haemoglobin levels. Total testosterone (TT) was inversely associated with visceral fat area independent of oestradiol (E2), but E2 was not associated with visceral fat area independent of TT. Visceral fat area, not TT or E2, was independently associated with insulin resistance. CONCLUSIONS: ADT for prostate cancer results in accumulation of both visceral and subcutaneous abdominal fat. Increased visceral fat area appears more closely linked to testosterone than oestradiol deficiency. Increased insulin resistance may arise secondary to visceral fat accumulation, rather than as a direct result of sex steroid deficiency.

Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy.

CONTEXT: Androgen deprivation therapy (ADT) used in the treatment of prostate cancer reduces bone mineral density (BMD) and predisposes to fractures. The structural basis of the BMD deficit and bone fragility is uncertain. OBJECTIVE AND PATIENTS: We investigated changes in bone microarchitecture in 26 men (70.6±6.8 yr) with nonmetastatic prostate cancer during the first year of ADT using the new technique of high-resolution peripheral quantitative computed tomography. DESIGN AND SETTING: We conducted a 12-month prospective observational study in the setting of a tertiary referral center. RESULTS: After 12 months of ADT, total volumetric density decreased by 5.2±5.4% at the distal radius and 4.2±2.7% at the distal tibia (both P<0.001). This was due to a decrease in cortical volumetric BMD (by 11.3±8.6% for radius and 6.0±4.2% for tibia, all P<0.001) and trabecular density (by 3.5±6.0% for radius and 1.5±2.3% for tibia, all P<0.01), after correcting for trabecularization of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (P<0.05). Total testosterone, but not estradiol, levels were independently associated with total and corrected cortical volumetric BMD at the tibia. CONCLUSIONS: Sex steroid deficiency induced by ADT for prostate cancer results in microarchitectural decay. Bone fragility in these men may be more closely linked to testosterone than estradiol deficiency.