Examining the role of testosterone in the etiology and treatment of obesity, the metabolic syndrome and diabetes in hypogonadal men

Image: overweighted man

The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. Saad F, Gooren LJ. J Obes 2011:pii:471584.

This Research News article reviews an open-access article available in full from http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC2931403/.

The review looks beyond the role of testosterone in the male reproductive system and sexual functioning to consider its significance in the development and treatment of obesity, a condition that is acknowledged to be reaching global epidemic proportions.1 The role of testosterone in glucose homeostasis, lipid metabolism and cardiovascular (CV) pathology is examined, and the implications of low testosterone levels on morbidity and mortality are discussed. The article outlines evidence for the effects of normalizing testosterone levels on insulin sensitivity, visceral adiposity and lipid profiles, and addresses the safety of testosterone, particularly in elderly men.

Key Points

Testosterone plays a significant role in obesity, glucose homeostasis, and lipid metabolism:

  • Although androgens appear to be involved in the deposition of excess abdominal/visceral fat in males, continued androgen stimulation is no longer required once fat is stored, and low testosterone adversely affects processes related to fat storage and metabolism1
  • There is a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels increase the risk of type 2 diabetes mellitus1
  • Lower total testosterone and sex hormone-binding globulin (SHBG) predict a higher incidence of the metabolic syndrome (MetS)1
  • Testosterone replacement therapy (TRT) reverses part of the unfavourable risk profile for the development of diabetes and atherosclerosis in hypogonadal men1

There is a consensus that the administration of TRT to elderly hypogonadal men is a responsible strategy provided that accepted treatment guidelines2,3 are followed:

  • Rigorous scientific study does not support an adverse effect for testosterone on CV morbidity and mortality1
  • Evidence for a major role of testosterone in the development of prostate cancer in elderly men is lacking1
  • Exacerbation of voiding problems does not appear to be an issue in men with benign prostatic hyperplasia receiving testosterone treatment1

There is growing evidence and acceptance that testosterone is a pivotal hormone for many aspects of men’s health.1

What is known

The consequences of the rapid increase in the incidence of obesity in both the developed and the developing world are grave. Approximately 80% of obese adults also have type 2 diabetes, hypertension, CV disease, cancer, gallbladder disease or joint disorders, and 40% have two or more obesity-related diseases. Although there is evidence that testosterone has a significant role in the etiology and treatment of obesity, awareness of this in clinical practice may be limited.

Testosterone and Fat Distribution

The regional localization of body fat, predominantly in the abdominal regions in men and in peripheral areas, such as breasts, hips and thighs, in premenopausal women, suggests a role for sex steroids in the deposition of fat, although obese adults of either sex also store fat in the fat depots associated with the opposite sex. However, although androgens induce visceral fat accumulation in men, men who acquire hypogonadism later in life do not have less, and may indeed have a greater amount of visceral fat than eugonadal men. This suggests that continued androgen stimulation is not needed to maintain stored fat, in contrast to bone and muscle mass, which diminish in hypogonadal men. Induction of androgen deficiency in men with prostate cancer receiving androgen deprivation therapy increases fat mass, reduces insulin sensitivity, impairs lipid profiles and increases CV risk, as well as worsening metabolic control in men with diabetes mellitus. Furthermore, lower endogenous androgens predict central obesity in older men, and low testosterone adversely affects blood pressure (BP), fasting plasma glucose, lipids, and body mass index.

The Metabolic Syndrome

There is an established relationship between obesity and the MetS, the clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis, and CV morbidity and mortality. Visceral obesity is a central component of the MetS, together with insulin resistance, glucose intolerance, raised BP and dyslipidaemia. There is evidence across all age levels for a strong inverse relationship between the severity of features of the MetS, including visceral obesity, and plasma testosterone levels. A similar relationship is present between type 2 diabetes and testosterone, and low testosterone is an independent risk factor for the development of both the MetS and diabetes and their clinical sequels. Adiposity and associated insulin resistance has been shown to lower circulating levels of testosterone, even in younger men, and there is evidence for subtle disturbances in sex hormones in MetS that may contribute to its pathogenesis.

Addressing the Age-related Decline of Testosterone

There is increasing evidence that the decline of testosterone with age is not solely age-related, but significantly contributed to by disease. Studies have shown that TRT reduces total body fat and increases fat-free mass, without change in body weight, in middle-aged and ageing hypogonadal men while lowering total cholesterol levels. TRT also has a beneficial effect on visceral fat and other components of the MetS, including insulin resistance. There is also increasing evidence that normalization of testosterone levels may improve glycaemic control and reduce the metabolic complications of diabetes mellitus.

Measuring Testosterone

Although there is no universally accepted cutoff value of plasma testosterone that defines androgen deficiency, the normal range of total testosterone and free (bioavailable) testosterone levels in young males is generally considered valid for elderly men. Lower limits of 350 ng/dL (12 nmol/L) for total testosterone and 72 pg/mL (0.25 nmol/L) for free testosterone are clinically workable and widely accepted criteria, preferably measured in early morning samples for better reflection of androgen status. Full details of the diagnosis of hypogonadism can be found in current treatment guidelines.2,3

Safety

Despite existing concerns, a causal link between prostate cancer and testosterone therapy has not been established, and numerous well-designed studies have reported that TRT is not associated with an increased risk of prostate cancer in ageing men. Provided that guidelines for monitoring are followed,2,3 testosterone administration appears to be acceptably safe in ageing men without a prior history of prostate cancer or without evidence of harboring a prostate carcinoma. Nor does a concern that testosterone therapy may exacerbate voiding symptoms in men with benign prostatic hyperplasia appear to have foundation.

What this study adds

The role of TRT in the restoration of libido and potency in men with hypogonadism has long been accepted. However, this review draws together evidence for the key role played by testosterone in glucose homeostasis, lipid metabolism and the etiology of the MetS and associated diseases in ageing men. It challenges traditional assumptions held about testosterone regarding CV disease, voiding issues and prostate cancer. Further, it supports the emerging perspective which proposes a role for TRT in the treatment of the MetS and its sequels in men with hypogonadism, such as type 2 diabetes and CV disease. Epidemiological evidence that low testosterone is a predictor of mortality in elderly men is further indication that testosterone is a vital hormone for men’s health throughout the lifespan. Testosterone deficiency has serious health consequences, including the MetS and its sequels, type 2 diabetes, atherosclerotic disease, osteoporosis and loss of skeletal muscle mass and strength.

There is a growing consensus that the administration of testosterone replacement therapy to elderly hypogonadal men is a responsible strategy if accepted treatment guidelines are followed.

References

1. Saad F, Gooren LJ. The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. J Obes 2011:pii:471584.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91(6):1995-2010.
3. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130.

Related Links


Last updated: 2018
G.MKT.GM.MH.01.2018.0500