Combined Transdermal Testosterone Gel and the Progestin Nestorone Suppresses Serum Gonadotropins in Men

Abstract

Previous studies have shown that administration of testosterone (T) alone or combined with a progestin has considerable contraceptive efficacy in men. Retrospective data from most hormonal male contraceptive studies have shown that addition of a progestin to testosterone (T) increased the rate and extent of the suppression of spermatogenesis. Nestorone (NES), a progesterone derivative without androgenic or estrogenic activity, has been investigated in women as a potential contraceptive but has not been studied in men. This prospective, randomized, open-label, 2-center trial investigated the effectiveness of transdermal NES gel alone, or in combination with T in suppressing gonadotropin, a surrogate marker for suppression of spermatogenesis. The study subjects were 100 healthy male volunteers who were randomized to 20 days of daily application with 1 of 5 groups (20 per group): either 2 or 4 mg NES (groups 1 and 2); 10 gm of T gel (group 3); or 10 gm of T gel plus either 2 or 4 mg NES (groups 4 and 5). Because there was suboptimal suppression of serum gonadotropins (0.5 IU/L or less) in about half of the study subjects in group 5 (daily 10 gm of T gel plus 4 mg NES), 2 additional groups were randomized to apply a higher dose of NES: daily 10 gm T gel plus either 6 or 8 mg NES gel (groups 6 and 7). The primary study outcome was the percentage of study subjects who had serum luteinizing hormone and follicle-stimulating hormone suppressed to 0.5 IU/L or less after 20 days of treatment. Of the original 140 volunteers, 16 were not efficacy evaluable because of noncompliance with the gel application and 5 withdrew primarily due to adverse reactions. The remaining 119 study subjects were compliant and had few serious adverse events. Both the NES alone and the T gel alone suppressed gonadotropins significantly but the reduction was greater with the T gel alone. The use of the higher doses of the NES gel (6 or 8 mg/d) in combination with the 10 gm T gel suppressed serum gonadotropin levels to less than 0.5 or 1 IU/L in significantly more men than either gel alone (P < 0.05). These findings demonstrate that the use of higher doses of NES (6 mg/d or higher) in combination with T gel has a substantial additive effect on the suppression of gonadotropins and is well tolerated.