Leflutrozole in male obesity-associated hypogonadotropic hypogonadism: Ph 2b double-blind randomised controlled trial.
Level 2 - randomized trial
Individual multi-center randomized controlled trial
PubMed 37579053 · doi:10.1093/ejendo/lvad099
What was done
A phase 2b double-blind, randomized controlled trial across 70 sites in Europe and the USA evaluated the aromatase inhibitor leflutrozole in 271 men with obesity-associated hypogonadotropic hypogonadism (BMI 30–50 kg/m², baseline mean 38.1 kg/m²; morning total testosterone < 10.41 nmol/L, baseline mean 7.97 nmol/L; and at least two androgen deficiency symptoms). Patients were randomized to weekly leflutrozole (0.1 mg, 0.3 mg, or 1.0 mg) or placebo for 24 weeks. The primary endpoint was normalization of total testosterone in at least 75% of patients at 24 weeks. Secondary endpoints included gonadotropins (LH/FSH), semen parameters, body composition, sexual dysfunction, and adverse events including bone mineral density.
What was found
The primary endpoint was achieved in all leflutrozole groups, with dose-tiered 24-week mean total testosterone levels: 15.89 nmol/L (0.1 mg), 17.78 nmol/L (0.3 mg), and 20.35 nmol/L (1.0 mg) versus 8.04 nmol/L for placebo. LH, FSH, semen volume, and total motile sperm count increased significantly with leflutrozole versus placebo. No improvements were observed in sexual dysfunction or body composition. Treatment-emergent adverse events more common in leflutrozole groups included raised hematocrit, hypertension, increased PSA, headache, and lumbar bone mineral density reductions (mean -1.24%, -1.30%, and -2.09% for 0.1 mg, 0.3 mg, and 1.0 mg, respectively, vs +0.66% for placebo), with no change at the hip.
Why it matters
Leflutrozole raises endogenous testosterone and preserves or improves semen parameters in obese hypogonadal men, avoiding the suppressive reproductive effects of exogenous testosterone. However, normalizing testosterone levels did not lead to symptomatic relief in sexual dysfunction or changes in body composition over 24 weeks.
Limits
There was a high dropout rate, with 81 of 271 randomized patients (29.9%) discontinuing the study. Leflutrozole treatment caused adverse metabolic and structural effects, notably dose-dependent reductions in lumbar spine bone mineral density, elevated hematocrit, and hypertension.
Cited by
- supports Obesity elevates the aromatization of testosterone to estrogen in adipose tissue, which causes heightened negative feedback on the hypothalamic-pituitary-gonadal axis and suppresses testosterone production.