Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)

After the age of 40, testosterone (T) production in men gradually decreases at a rate of 1.6% per year for total and to 2-3% per year for bioavailable T. Because of the age-related increase in sex hormone binding globulin, the magnitude of the decrease in bioavailable T in men is even greater than the decline in total T levels. This reduction in T production in men parallels the age-associated loss of muscle mass that leads to sarcopenia and impairment of function and the age-associated loss of bone mass that leads to osteopenia and fracture risk. Hypogonadism is a condition associated with multiple symptom complex including fatigue, depressed mood, osteoporosis, increased fat mass, loss of libido and reduced muscle strength, all of which deeply affect patient's quality of life. The prevalence of hypogonadismamong obese men ranges between 29.3% to 78.8%, with levels of androgens decreasing proportionately to the degree of obesity. This decline in T levels is exacerbated among obese patients due the suppression of the hypothalamic-pituitary-gonadal axis by hyperestrogenemia. The high expression of aromatase enzyme in the adipose tissue enhances the conversion of androgens into estrogens (E) which in turn exerts a negative feedback on hypothalamus and pituitary, inhibiting the production of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) and, as a consequence, of T by the testis resulting in hypogonadotropic hypogonadism (HH). Considering the high aromatase expression in the adipose tissue, the administration of T among obese men with HH could increase the conversion of the substrate T to estradiol (E2) and fuels the negative feedback on the hypothalamus and pituitary, producing a greater suppression of GnRH and gonadotropins.

Thus, men with obesity induced HH may benefit from other treatment strategies that target the pathophysiology of the disease. Weight loss intervention which improves hormonal and metabolic abnormalities related to obesity may also be considered a logical approach to improve obesity-induced HH.

One possible approach consists of the use of aromatase inhibitors (AI) to stop the conversion of T to E2 thereby interrupting the vicious cycle of E2 inhibition of the hypothalamic-pituitary-gonadal axis and restoring T production to normal levels. Increased T and reduced E2 levels have been reported in men with low levels of T after AI administration, even though very few studies investigated clinical outcomes.

We believe that AI use could promote positive changes on hypogonadal symptoms and body composition in HH severely obese patients, acting at the physiopathology of the disease without necessarily causing bone loss.