Obesity and Aging in Late-Onset Hypogonadism

Testosterone (T) declines with increasing age due to depletion of Leydig cells and an impaired testicular response to LH, and changes in hypothalamic–pituitary function which are aggravated by changes due to aging-related chronic illnesses. Obesity, independent of age, is also associated with low T from low SHBG and down-regulation of hypothalamic–pituitary gonadotropin secretion, the mechanisms for which may involve adipokines, pro-inflammatory cytokines and central insulin resistance. In contrast to classical pathological male hypogonadism, the T decline with aging/obesity (so-called late-onset hypogonadism or LOH) is relatively modest, often in the borderline rather than pathological range, and its clinical consequences remain uncertain. According to current practice guidelines, LOH can be recognized when low T is accompanied by cognate symptoms of androgen deficiency. However, the threshold(s) for subnormal T (total or free) and the nature or severity of symptoms are not well defined. Among the common symptoms in aging men that potentially may arise from low T, sexual dysfunction is considered the most specific for hypogonadism. There is also mounting evidence from recent randomized placebo controlled trials that T replacement in older men with LOH can improve sexual function. Although LOH is often associated with higher central fat mass and insulin resistance, particularly in type 2 diabetics, there is so far insufficient evidence that T treatment results in clinically significant improvement in glucose homeostasis or glycemic control. Low T, independent of obesity, is a predictor of increased overall and cardiovascular mortality. It is likely that low T represents a marker of poor health and obesity, rather than an actual path variable leading to adverse clinical outcomes. This is an important caveat when rationalizing T replacement as symptomatic treatment in older men, in whom the underlying cause of low T should always be sought and managed.