Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Abstract

Objective: Isolated hypogonadotropic hypogonadism (IHH) is frequently observed in severely obese men, probably as a result of increased estradiol (E 2 ) production and E 2 -mediated negative feedback on pituitary LH secretion. Aromatase inhibitors can reverse this process. This study evaluates whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect. Design: Open, uncontrolled 6-month pilot study in 12 severely obese men (body mass indexO 35.0 kg/m 2 ) with obesity-related IHH and free testosterone levels !225 pmol/l, treated with 2.5 mg letrozole once a week for 6 months. Results: Six weeks of treatment reduced total E 2 from 123G11 to 58G7 pmol/l (P!0.001, meanG S.E.M.), and increased serum LH from 4.4G0.6 to 11.1G1.5 U/l (P!0.001). Total testosterone rose from 5.9G0.5 to 19.6G1.4 nmol/l (P!0.001), and free testosterone from 163G13 to 604G 50 pmol/l (P!0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E 2 levels were stable throughout the week and during the 6-month treatment period. Conclusion: Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose !2.5 mg once a week is recommended.European Journal of Endocrinology 158 741-747

Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis

“…The increased amount of estrogen levels might, in turn, play a negative feedback on both the hypothalamus and the pituitary, leading to decreased LH secretion (22,55). Accordingly, it has been reported that a weekly low dose (2.5 mg) of the aromatase inhibitor letrozole can restore testosterone levels and increase LH levels in severely obese hypogonadal men (57). In line with this view, we now show that body weight loss, obtained either by a lifestyle or bariatric intervention, is associated with a decline in estrogen levels and a rise in gonadotropins and testosterone.…”

Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia

“…Testosterone replacement raises both serum testosterone and E 2 , whereas aromatase inhibitors induce a rise in testosterone but a decrease in E 2 (15). It appears that the expected beneficial effects of a rise in testosterone are offset by the decrease in estrogens.…”

“…Partial inhibition of aromatase activity is a more attractive approach, at least in theory. So far, two open-label, uncontrolled pilot studies have shown that the aromatase inhibitor letrozole can normalize serum testosterone and E 2 levels in OrHH (15). However, the clinical impact of this intervention is currently not known.…”

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

“…IHH is frequent in obese men, possibly as a consequence of enhanced aromatization of testosterone by aromatase, which is present in adipocytes in human (50). Treating obese men with an aromatase inhibitor restores normal testosterone levels (51). Some nonobese men also have excessive aromatase activity, possibly for genetic reasons, which results in nonobstructive azoospermia and low testosterone.…”