Effects of estradiol on fat in men undergoing androgen deprivation therapy: a randomized trial.

OBJECTIVE: Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatisation to estradiol. However, no controlled study has assessed the effects of estradiol in the absence of testosterone. DESIGN: 6-month randomised, placebo-controlled trial with the hypothesis that men randomised to estradiol would reduce their fat mass. METHODS: 78 participants receiving androgen deprivation therapy for prostate cancer were randomised to 0.9 mg of 0.1% estradiol gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3 and month 6. The primary outcome was total fat mass. RESULTS: Serum estradiol increased in the estradiol group over 6 months compared to placebo, mean adjusted difference (MAD) 207 pmol/L (95% CI 123 - 292), p<0.001. Estradiol treatment changed total fat mass, MAD 1007g (95% CI 124-1891), but not significantly so, p=0.09. There were other consistent non-significant trends towards increased proportional fat mass, MAD 0.8% (95% CI 0.0-1.6), p=0.15; gynoid fat, MAD 147g (95% CI 2-293), p=0.08; visceral fat, 53g (95% CI 1-105) p=0.13; and subcutaneous fat, MAD 65g (95% CI 5-125), p=0.11. Android fat increased, MAD 164 g (95% CI 41-286), p=0.04. CONCLUSION: Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of T, may increase total and regional fat mass in men. Given the premature closure of trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether estradiol promotes fat expansion in the absence of T.