Hypogonadism and male obesity: Focus on unresolved questions

Abstract

Obesity, increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men and presents as one of the strongest predictors of receiving testosterone treatment. While low circulating total testosterone concentrations in modest obesity primarily reflect reduced concentrations of sex hormone binding globulin, more marked obesity can lead to genuine hypothalamic-pituitary-testicular axis (HPT) suppression. HPT axis suppression is likely mediated via pro-inflammatory cytokine and dysregulated leptin signalling and aggravated by associated comorbidities. Whether oestradiol-mediated negative hypothalamic-pituitary feedback plays a pathogenic role requires further study. Although the obesity-hypogonadism relationship is bidirectional, the effects of obesity on testosterone concentrations are more substantial than the effects of testosterone on adiposity. In markedly obese men submitted to bariatric surgery, substantial weight loss is very effective in reactivating the HPT axis. In contrast, lifestyle measures are less effective in reducing weight and generally only associated with modest increases in circulating testosterone. In randomized controlled clinical trials (RCTs), testosterone treatment does not reduce body weight, but modestly reduces fat mass and increases muscle mass. Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone. However, longer term, larger RCTs designed for patient-important outcomes and potential risks are required. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity-associated nonclassical hypogonadism. Lifestyle measures or where indicated bariatric surgery to achieve weight loss, and optimization of comorbidities remain first line.

Obesity and male hypogonadism: Tales of a vicious cycle

“…Dhindsa et al reported that total and free estradiol in hypogonadal diabetic men are even lower than in eugonadal diabetic men. This result led some authors to hypothesize that as circulating testosterone is the main substrate for aromatase, low testosterone concentration should be reflected in low estradiol concentration in hypogonadal men . In fact, a recent study by Ghanim et al reported that hypogonadal diabetic men's adipocytes expressed less aromatase and oestrogen receptor alpha when compared with eugonadal diabetic men.…”

“…Male hypogonadism is defined as a syndrome characterized by androgen deficiency, which can be classified as primary or secondary according to the aetiology of testosterone deficiency. Primary hypogonadism is caused by a testicular inability to secrete testosterone in normal amounts in order to sustain the physiological circulating concentrations, while secondary hypogonadism is due to reduced or inappropriately normal gonadotropin release and consequent disruption of the hypothalamic‐pituitary‐testicular (HPT) axis normal functioning . In brief, the HPT axis is regulated by kisspeptins, a family of peptides coexpressed in the hypothalamus, which are responsible to regulate the secretion and release of hypothalamic gonadotropin‐releasing hormone (GnRH).…”

“…Primary hypogonadism is caused by a testicular inability to secrete testosterone in normal amounts in order to sustain the physiological circulating concentrations, while secondary hypogonadism is due to reduced or inappropriately normal gonadotropin release and consequent disruption of the hypothalamic-pituitary-testicular (HPT) axis normal functioning. 17 In brief, the HPT axis is regulated by kisspeptins, a family of peptides coexpressed in the hypothalamus, which are responsible to regulate the secretion and release of hypothalamic gonadotropin-releasing hormone (GnRH). GnRH is ultimately released in pulses into the hypothalamic-pituitary portal vessels to stimulate the secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary.…”

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care

“…In middle-aged and older men, obesity is consistently associated with lower circulating testosterone without elevation of LH and FSH, 18,19 and loss of excess weight in obese men is associated with recovery of endogenous testosterone production. [20][21][22] In men with class 1 and 2 obesity, this may be attributable to lower SHBG and hence lower testosterone concentrations.…”

“…2 Managing the obesity, may also have additional health benefits. 18 Obesity is a risk factor for insulin resistance and for type 2 diabetes, and men with lower testosterone concentrations are more likely to have or to develop metabolic syndrome or diabetes. Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone.…”