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Super Moderator
Obesity, type 2 diabetes, and testosterone in ageing men (2022)
Gary Wittert · Mathis Grossmann
Abstract
In the absence of obesity, adverse lifestyle behaviours, and use of medication such as opioids serum testosterone concentrations decrease by only a minimal amount at least until very advanced age in most men. Obesity is heterogeneous in its phenotype, and it is the accumulation of excess adipose tissue viscerally associated with insulin resistance, dyslipidaemia, inflammation, hypothalamic leptin resistance and gliosis that underpins the functional hypogonadism of obesity. Both central (hypothalamic) and peripheral mechanisms are involved resulting in a low serum total testosterone concentration, while LH and FSH are typically in the normal range. Peripherally a decrease in serum sex hormone binding globulin (SHBG) concentration only partially explains the decrease in testosterone and there is increasing evidence for direct effects in the testis. Men with obesity-associated functional hypogonadism and serum testosterone concentrations below 16 nmol/L are at increased risk of incident type 2 diabetes (T2D); high testosterone concentrations are protective. The magnitude of weight loss is linearly associated with an increase in serum testosterone concentration and with the likelihood of preventing T2D or reverting newly diagnosed disease; treatment with testosterone for 2 years increases the probability of a positive outcome from a lifestyle intervention alone by approximately 40%. Whether the additional favourable benefits of testosterone treatment on muscle mass and strength and bone density and quality in the long-term remains to be determined.
1 Ageing and the hypothalamic-pituitary-testicular (HPT) axis
2 Obesity and obesity-related chronic disorders and the HPT axis
2.1 Obesity
2.2 Obesity-related chronic disorders
2.3 Health-related behaviours
2.4 Medications
2.5 Macronutrient intake
2.6 Mechanisms of obesity-related HPT axis dysregulation
2.6.1 Central mechanisms
2.6.2 Peripheral mechanisms
3 Clinical implications
3.1 Serum testosterone and type 2 diabetes risk
3.2 Effect of weight loss on obesity-associated functional hypogonadism
3.3 Is there a role for treatment with testosterone?
3.4 Mechanism of the effect of testosterone on glucose metabolism
3.5 Implications for practice
● Low serum testosterone concentrations with increasing age are predominantly the consequence of obesity-associated chronic disease, opioid use, and modifiable health-related behaviours.
● The aim of clinical assessment must be to exclude the presence of pathological hypogonadism, identify and effectively manage co-morbid physical and psychological chronic conditions and provide education and support to optimise health-related behaviours. Such measures have been shown to treat or prevent chronic disease, increase serum testosterone concentration, and improve sexual function.
● Treatment with testosterone in combination with a lifestyle program in centrally obese men with impaired glucose tolerance or newly diagnosed T2D can decrease fat mass, improve glucose tolerance, and prevent or reverse recently diagnosed type 2 diabetes.
● The durability of benefit and longer-term safety of testosterone used as a pharmacological approach for T2D prevention in men with obesity-associated functional hypogonadism, and whether there are subgroups of men who will benefit, remain to be determined.
● It is not known whether the testosterone-induced increase in bone and skeletal muscle mass and grip strength will reduce the risks of subsequent fracture or frailty.
Gary Wittert · Mathis Grossmann
Abstract
In the absence of obesity, adverse lifestyle behaviours, and use of medication such as opioids serum testosterone concentrations decrease by only a minimal amount at least until very advanced age in most men. Obesity is heterogeneous in its phenotype, and it is the accumulation of excess adipose tissue viscerally associated with insulin resistance, dyslipidaemia, inflammation, hypothalamic leptin resistance and gliosis that underpins the functional hypogonadism of obesity. Both central (hypothalamic) and peripheral mechanisms are involved resulting in a low serum total testosterone concentration, while LH and FSH are typically in the normal range. Peripherally a decrease in serum sex hormone binding globulin (SHBG) concentration only partially explains the decrease in testosterone and there is increasing evidence for direct effects in the testis. Men with obesity-associated functional hypogonadism and serum testosterone concentrations below 16 nmol/L are at increased risk of incident type 2 diabetes (T2D); high testosterone concentrations are protective. The magnitude of weight loss is linearly associated with an increase in serum testosterone concentration and with the likelihood of preventing T2D or reverting newly diagnosed disease; treatment with testosterone for 2 years increases the probability of a positive outcome from a lifestyle intervention alone by approximately 40%. Whether the additional favourable benefits of testosterone treatment on muscle mass and strength and bone density and quality in the long-term remains to be determined.
1 Ageing and the hypothalamic-pituitary-testicular (HPT) axis
2 Obesity and obesity-related chronic disorders and the HPT axis
2.1 Obesity
2.2 Obesity-related chronic disorders
2.3 Health-related behaviours
2.4 Medications
2.5 Macronutrient intake
2.6 Mechanisms of obesity-related HPT axis dysregulation
2.6.1 Central mechanisms
2.6.2 Peripheral mechanisms
3 Clinical implications
3.1 Serum testosterone and type 2 diabetes risk
3.2 Effect of weight loss on obesity-associated functional hypogonadism
3.3 Is there a role for treatment with testosterone?
3.4 Mechanism of the effect of testosterone on glucose metabolism
3.5 Implications for practice
● Low serum testosterone concentrations with increasing age are predominantly the consequence of obesity-associated chronic disease, opioid use, and modifiable health-related behaviours.
● The aim of clinical assessment must be to exclude the presence of pathological hypogonadism, identify and effectively manage co-morbid physical and psychological chronic conditions and provide education and support to optimise health-related behaviours. Such measures have been shown to treat or prevent chronic disease, increase serum testosterone concentration, and improve sexual function.
● Treatment with testosterone in combination with a lifestyle program in centrally obese men with impaired glucose tolerance or newly diagnosed T2D can decrease fat mass, improve glucose tolerance, and prevent or reverse recently diagnosed type 2 diabetes.
● The durability of benefit and longer-term safety of testosterone used as a pharmacological approach for T2D prevention in men with obesity-associated functional hypogonadism, and whether there are subgroups of men who will benefit, remain to be determined.
● It is not known whether the testosterone-induced increase in bone and skeletal muscle mass and grip strength will reduce the risks of subsequent fracture or frailty.
