Approach to the Patient: Low Testosterone Concentrations in Men With Obesity.

Pathologic hypogonadism requires irreversible organic disorders of the hypothalamic pituitary testicular axis and necessitates lifelong testosterone replacement.

• Pathologic hypogonadism occurs when serum testosterone is 'significantly and persistently reduced by irreversible organic (structural, genetic) disorders of the hypothalamic pituitary testicular axis'
• Men with pathologic hypogonadism require lifelong testosterone replacement
• This is distinguished from obesity-related testosterone reductions, which are reversible

Obesity causes reductions in serum testosterone that are primarily driven by reduced SHBG rather than true gonadal failure.

• Obesity-related reductions in SHBG, 'testosterone's principal circulating carrier protein, are primarily responsible for measured reductions in testosterone'
• Proportionately reduced testosterone and SHBG concentrations are accompanied by normal serum LH and FSH concentrations
• Normal LH and FSH confirm a eugonadal state in obese men with low testosterone
• The authors describe this condition as 'the pseudo-hypogonadism of obesity'

Obesity is not a cause of pathological hypogonadism and should be classified as a nongonadal illness syndrome.

• Mild or moderate reductions in serum testosterone in obesity 'are best considered nongonadal illness syndromes'
• Testosterone reduction in nongonadal illness is 'usually reversible upon amelioration of the underlying nongonadal illness'
• Obesity can result in nonspecific symptoms in conjunction with reduced serum testosterone and serum SHBG
• These nonspecific symptoms resemble but are not due to androgen deficiency

Clinically significant weight loss substantially reverses obesity-related reductions in serum testosterone and ameliorates nonspecific symptoms.

• Weight loss 'substantially reverses obesity-related reductions in serum testosterone'
• Weight loss 'ameliorates nonspecific symptoms resembling, but not due to, androgen deficiency'
• Reversible steps include weight reduction and optimizing management of type 2 diabetes mellitus, obstructive sleep apnea, depression, and other obesity-related comorbidities
• Rationalizing concomitant drug regimens is also identified as an important reversible step

Testosterone treatment is less effective than diet and lifestyle intervention for managing obesity-related low testosterone and associated symptoms.

• 'In the absence of pathological hypogonadism, testosterone treatment is less effective than a diet and lifestyle intervention to rectify the reversible conditions responsible for the nonspecific symptoms and associated reduced serum testosterone concentrations observed in men with obesity'
• Testosterone treatment is described as 'not indicated' in obese men without pathological hypogonadism
• Unwarranted off-label testosterone treatment can lead to adverse effects

Unwarranted off-label testosterone treatment in obese men without pathological hypogonadism carries multiple adverse effects.

• Adverse effects of unwarranted testosterone treatment include infertility
• Additional adverse effects include elevated hematocrit requiring venesection
• A prothrombotic state is identified as an adverse effect
• Testosterone dependence is identified as an adverse effect of unwarranted treatment