A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management

Abstract

Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible.

Evidence acquisition: Literature review from 1970 to October 2016.

Evidence synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling.

Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

Figure 1.

Causes of hypogonadism. (a) Causes of secondary hypogonadism. (b) Causes of primary hypogonadism. In middle-aged and older men, functional (late-onset, age-related onset, or adult onset) hypogonadism is usually associated with low or normal gonadotropin levels. In contrast to organic secondary hypogonadism due to structural, destructive, or congenital pathology, functional hypogonadism is due to functional HPT axis suppression. Whereas organic hypogonadism typically presents with clinically and biochemically severe androgen deficiency and is not usually reversible, functional hypogonadism often presents with less severe androgen deficiency, is potentially reversible, and is more common than organic hypogonadism. IHH, idiopathic hypogondadotropic hypogonadism; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; T, testosterone; T2DM, type 2 diabetes mellitus. Adapted from Matsumoto (12).

Figure 2.

Effect of weight loss on testosterone levels. Each datum point refers to an individual study, and the size of the datum point is proportional to the size of the study, ranging from 10 to 293 men. Open circles represent studies where weight loss was achieved by diet and exercise, and filled circles by bariatric surgery. Updated from Grossmann (20). For individual studies, refer to Supplemental Table 1.