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

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 index>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 123 +/- 1.1 to 58 +/- 7 pmol/l (P<0.001, mean +/- S.E.M.), and increased serum LH from 4.4 +/- 0.6 to 11.1 +/- 1.5 U/l (P<0.001). Total testosterone rose from 5.9 +/- 0.5 to 19.6 +/- 1.4 nmol/l (P<0.00.1), and free testosterone from 1.63 +/- 13 to 604 +/- 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 E2 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.