Late‐onset hypogonadism: metabolic impact

Abstract

Background Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency. Objective To review the metabolic impact of late‐onset hypogonadism. Methods Comprehensive literature search with emphasis on recent publications. Results Obesity is one of the strongest modifiable risk factors for late‐onset hypogonadism, and coexisting diabetes leads to further hypothalamic‐pituitary‐testicular axis suppression. The hypothalamic‐pituitary‐testicular axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that hypothalamic‐pituitary‐testicular axis suppression is mediated by dysregulation of pro‐inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the paradigm that estradiol excess is a major contributor to hypothalamic‐pituitary‐testicular axis suppression. Instead, relative estradiol signaling deficiency may contribute to metabolic dysregulation in men with diabesity. While weight loss and optimization of comorbidities can reverse functional hypothalamic‐pituitary‐testicular axis suppression, testosterone treatment leads to metabolically favorable changes in body composition and to improvements in insulin resistance. Discussion The relationship between diabesity and late‐onset hypogonadism is bidirectional. Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects. Conclusions While recent research has provided new insights into mechanistic and clinical aspects of diabesity‐associated late‐onset hypogonadism, more evidence from well‐designed large trials is needed to guide the optimal clinical approach to such men.

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males

“…The mechanisms underlying such functional alterations in the HPT axis have not been completely clarified. However, it is plausible that metabolic disturbances and inflammatory states associated with obesity can directly interfere with T/gonadotrophin secretion at multiple levels …”

“…We place a lower value on the inconsistent, modest short‐term improvement in insulin resistance (HOMA‐IR) despite the consistent effect of T on body composition. However, TRT is indicated in men with MetS or T2DM who also have diagnosed hypogonadism for the management of traditional hypogonadal symptoms without the promise (or expectation) of improvements in metabolic status …”

The prevalence and demographic determinants of blood donors receiving testosterone replacement therapy at a large USA blood service organization

“…The demographic determinants of TRT blood donors in the tested blood centers revealed that these donors are likely to be middle‐aged white and Hispanic males, with average BMI over 30 kg/m 2 (defined as obese) and MAP that was significantly higher than that of their matched controls. As noted, obesity is a risk factor for late‐onset hypogonadism or testosterone deficiency, which may explain the observed differences in BMI values between TRT donors and controls. A previous study, which determined the rates of obesity and BMI in over 1 million blood donors between 2007‐2008, has suggested that about 29% of male donors were obese .…”

The Effects of Androgens on Cardiometabolic Syndrome: Current Therapeutic Concepts

“…80 In some men, the clinical signs of obesity and dysglycemia that include IR, MetS, and T2DM are consistent with androgen deficiency. 81 Men with obesity commonly show low serum T levels that were usually below 10.5 nM of total T, comparing with the normal T levels which are around 20 nM in healthy men (Figure 3). 82 Interestingly, the first signs of IR only can be observed when circulating T falls below 6 to 8 nM; however, patients with serum total T in the range 8 to 12 nM often have symptom of obesity-associated hypogonadism.…”