No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. In addition, assessment of azoospermia can vary by sensitivity of the method used. Future trials need more attention to the methodological requirements for RCTs. More trials with adequate power would also be helpful.
A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations.
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.