A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations

Abstract

Studies using exogenous high-dosage testosterone (T) or a combination regimen of physiologic T plus high-dosage levonorgestrel (LNG) administration in normal men have shown that oligoazoospermia (<3 million/mL) or azoospermia can be achieved in the majority of the men. However, these hormonal regimens have been associated with significant weight gain and suppression of serum high-density lipoprotein (HDL) cholesterol levels. We hypothesized that a combination of physiologic exogenous testosterone and lower dosage LNG would result in uniform severe oligoazoospermia or azoospermia in normal men but would cause fewer adverse metabolic side effects. We conducted a randomized, placebo-controlled, single-blind trial comparing 6 months of T enanthate (100 mg IM, weekly) plus LNG, 125 microg by mouth, daily (LNG 125; n = 18) or LNG, 250 microg by mouth, daily (LNG 250; n = 18) and compared these regimens with our previous study of the same dosage of T enanthate combined with placebo LNG (LNG 0; n = 18) or with 500 mg of LNG (LNG= 500; n = 18). All three combination regimens of T enanthate and LNG suppressed spermatogenesis more rapidly and resulted in significantly more uniform severe oligoazoospermia (<1 million/mL) than the T-alone regimen. Severe oligoazoospermia was achieved in 89% of the LNG 125, 89% of the LNG 250, and 78% of the LNG 500 groups, respectively, versus 56% of the men in LNG 0 (P < 0.05 for the combination groups vs. LNG 0), but there were no significant differences between the combination regimens (P = NS). All four groups gained significant weight compared with their baselines, although the gain tended to be greater as the dosage of LNG increased (2.0+/-0.9, 2.9+/-1.1, 3.6+/-1.0, and 5.4+/-1.0 kg gained, compared with baseline in the LNG 0, 125, 250, and 500 groups respectively; P < 0.05 compared with baseline). Serum levels of HDL cholesterol decreased in all of the groups, but the effect was larger as the dosage of LNG increased (4+/-4% vs. 13+/-4%, 20+/-3%, and 22+/-4% decrease in HDL levels from baseline in the LNG 0, LNG 125, LNG 250, and LNG 500 groups respectively; P = 0.06 for LNG 125 compared with LNG 0, and P < 0.05 for LNG 250 and LNG 500 compared with LNG 0). We conclude that 1) the combination of physiologic exogenous T enanthate and LNG suppresses spermatogenesis more effectively than T enanthate alone and that 2) the combination regimen of T enanthate plus lower dosage LNG suppresses sperm production comparably to T enanthate plus higher dosage LNG, while causing less weight gain and HDL cholesterol suppression. A combination regimen of physiologic testosterone plus a low dosage of levonorgestrel offers great promise as a safe and effective male contraceptive regimen.