The dark side of testosterone deficiency: Basic science for non−scientists


Testosterone is a unique hormone because it impacts the development and function of many tissues and organs, including genitalia, adipocytes, skeletal muscle cells, smooth muscle cells, cardiac muscle cells, vascular endothelium, osteoblasts and hematoblasts. Therefore, it is not surprising that hypogonadism has wide ranging consequences for men’s health. Low testosterone is associated with several cardiovascular risk factors; insulin resistance, obesity, metabolic syndrome, diabetes, dyslipidemia, atherosclerosis, vascular stiffness, hypertension and sexual dysfunction.1

Testosterone is a powerful “metabolic hormone” that acts as a key regulator of energy metabolism; it regulates both lipid, protein and carbohydrate metabolism. Testosterone treatment increases muscle mass primarily by inducing muscle fiber hypertrophy. The prevalent view is that testosterone improves net muscle protein balance by stimulating muscle protein synthesis, decreasing muscle protein degradation, and improving reutilization of amino acids. In addition, testosterone increases myonuclear number and satellite cell number, while reducing body fat mass. The mechanisms underlying this is that testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage.2,3 The hypothesis that the primary site of androgen action is the pluripotent stem cell provides a unifying explanation for the observed reciprocal effects of testosterone on muscle and fat mass. This translates into a reduction in fat mass and increase in fat-free mass in men who are treated with testosterone therapy.4

Androgens also inhibit the differentiation of pre-adipocytes into adipocytes, which explains why low testosterone leads to accumulation of more adipocytes.3 Inactivation of the androgen receptor results in obesity caused by decreased energy expenditure and lipolytic activity.5 Experimental data also show that the testosterone-induced increase in energy expenditure and reduction in fat mass and glucose levels is derived from elevated mitochondrial biogenesis in skeletal muscle.6

Hypogonadism has negative effects on skeletal muscle, adipose tissue and the liver. In muscle tissue, low testosterone reduces myogenesis and muscle mass, as well as glycogen synthetase, mitochondrial function, GLUT-4 and IRS-1. In adipose tissue, low testosterone increases fat subcutaneous mass and visceral fat mass, as well as IL-β, IL-6, TNF-α and CRP. In the liver, low testosterone reduces lipid oxidation and beta-receptor activity. All these effects culminate in insulin resistance, which can progress to the metabolic syndrome and/or type 2 diabetes.

In summary, hypogonadism alters cellular, biochemical and physiological mechanisms in a way that induces a state of metabolic dysfunction, which contributes to:

  • Reduced muscle mass (by decreasing cellular differentiation and growth).
  • Reduced energy expenditure.
  • Increased lipid accumulation and increased fat mass.
  • Mitochondrial dysfunction.
  • Impaired glucose utilization.
  • insulin resistance, reduced insulin secretion and altered receptor down-stream mechanisms.
  • Erectile dysfunction.



Prof. Dr. med. Marija Pfeifer

Abdulmaged Traish, PhD
Boston University
School of Medicine


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