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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.
Impaired glucose utilization.
insulin resistance, reduced insulin secretion and altered receptor down-stream mechanisms.
Abdulmaged Traish, PhD Boston University School of Medicine
Maggio M, Basaria S. Welcoming low testosterone as a cardiovascular risk factor. Int J Impot Res. 2009 Jul-Aug;21(4):261-4.Return to content
Bhasin S, Taylor WE, Singh R, Artaza J, Sinha-Hikim I, Jasuja R, Choi H, Gonzalez-Cadavid NF. The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci. 2003 Dec;58(12):M1103-10. Review.Return to content
Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003 Nov;144(11):5081-8.Return to content
Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res. 2008 Jul-Aug;20(4):378-87Return to content
Fan W, Yanase T, Nomura M, Okabe T, Goto K, Sato T, Kawano H, Kato S, Nawata H. Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes. 2005 Apr;54(4):1000-8.Return to content
Usui T, Kajita K, Kajita T, Mori I, Hanamoto T, Ikeda T, Okada H, Taguchi K, Kitada Y, Morita H, Sasaki T, Kitamura T, Sato T, Kojima I, Ishizuka T. Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice. FEBS Lett. 2014 May 21;588(10):1935-41.Return to content