Testosterone deficiency, insulin resistance and the metabolic syndrome

Abstract

Changing lifestyles and an excess of food supply in developed countries have resulted in an increasing prevalence of overweight and obesity. As a consequence, a disorder of complex pathophysiology involving visceral adipose tissue as an endocrine organ, dyslipidemia, insulin resistance and hypertension has emerged—the so-called metabolic syndrome. This disorder can lead to the manifestation of type 2 diabetes mellitus and cardiovascular disease. In men, testosterone deficiency may contribute to the development of the metabolic syndrome. In turn, states of hyperinsulinemia and obesity lead to a reduction of testicular testosterone production. Testosterone has reciprocal effects on the generation of muscle and visceral adipose tissue by influencing the commitment of pluripotent stem cells and by inhibiting the development of preadipocytes. Insulin sensitivity of muscle cells is increased by augmenting mitochondrial capacity and fostering expression of oxidative phosphorylation genes. Testosterone has a protective effect on pancreatic β cells, which is possibly exerted by androgen-receptor-mediated mechanisms and influence of inflammatory cytokines. As some, but not all, epidemiological and interventional studies indicate, testosterone substitution might be helpful in preventing or attenuating the metabolic syndrome in aging men with late-onset hypogonadism and in hypogonadal patients with type 2 diabetes mellitus, but larger controlled trials are needed to confirm such hypotheses.

Key Points

  • Testosterone exerts fundamental effects on various elements of body composition and metabolism

  • Testosterone deficiency is associated with an increased prevalence of components of the metabolic syndrome, especially accumulation of visceral adipose tissue and insulin resistance

  • The adverse metabolic state and factors or hormones secreted by visceral adipose tissue contribute to the generation of hypogonadism

  • Studies suggest that testosterone substitution weakens the close relation between testosterone deficiency and insulin resistance and the metabolic syndrome, but more clinical evidence is needed to confirm these findings

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Figure 1: Self-perpetuating pathogenic circle between adverse metabolic parameters, with visceral adipose tissue as a pivotal component.
Figure 2: Link between metabolic disorders where the visceral adipose tissue is a key component and the testosterone deficiency syndrome.

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Zitzmann, M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol 5, 673–681 (2009). https://doi.org/10.1038/nrendo.2009.212

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