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 regim en 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 regime ns have been associated with significant weight gain and suppression of ser um high-density lipoprotein (HDL) cholesterol levels. We hypothesized that a combination of physiologic exogenous testosterone and lower dosage LNG wo uld result in uniform severe oligoazoospermia or azoospermia in normal men but would cause fewer adverse metabolic side effects. We conducted a random ized, placebo-controlled, single-blind trial comparing 6 months of T enanth ate (100 mg IM, weekly) plus LNG, 125 mu g by mouth, daily (LNG 125; n = 18 ) or LNG, 250 mu g by mouth, daily (LNG 250; n = 18) and compared these reg imens with our previous study of the same dosage of T enanthate combined wi th placebo LNG (LNG 0; n = 18) or with 500 mg of LNG (LNG = 500; n = 18). A ll three combination regimens of T enanthate and LNG suppressed spermatogen esis more rapidly and resulted in significantly more uniform severe oligoaz oospermia (<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 b etween the combination regimens (P = NS). All four groups gained significan t weight compared with their baselines, although the gain tended to be grea ter 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, a nd 500 groups respectively; P < 0.05 compared with baseline). Serum levels of HDL cholesterol decreased in all of the groups, but the effect was large r 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 th at 1) the combination of physiologic exogenous T enanthate and LNG suppress es spermatogenesis more effectively than T enanthate alone and that 2) the combination regimen of T enanthate plus lower dosage LNG suppresses sperm p roduction comparably to T enanthate plus higher dosage LNG, while causing l ess weight gain and HDL cholesterol suppression. A combination regimen of p hysiologic testosterone plus a low dosage of levonorgestrel offers great pr omise as a safe and effective male contraceptive regimen.