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.
Combination of subcutaneous levonorgestrel implants and transdermal dihydrotestosterone gel for male hormonal contraception.
The primary aim of the present study was to determine the therapeutic dose of subcutaneous levonorgestrel (LNG) to induce azoospermia or severe oligozoospermia (<3 x 10(6)/mL) in normal men requiring contraception. Transdermal 5 alpha-dihydrotestosterone (DHT) was combined to the treatments to maintain peripheral androgen level. Forty-three 21-45-year-old healthy men were enrolled in this phase II randomised and comparative clinical performance study. The subjects were allocated to five groups to receive: (1) transdermal DHT (Andractim(R), Besins Iscovesco, Paris, France) and one subdermal LNG implant (Jadelle, Leiras, Turku, Finland); (2) transdermal DHT and two subdermal LNG implants; (3) transdermal DHT and four subdermal LNG implants; (4) transdermal DHT and oral LNG (Microluton, Schering, Germany); or (5) transdermal DHT only. A total of 27 men completed the suppression phase. None of them reached azoospermia. One subject with oral LNG and transdermal DHT reached <3 million/mL at 5 months of suppression, but not repeatedly. Together 2/27 (7%) subjects, one with oral LNG and DHT and the other with four subdermal LNG implants and DHT reached <5 million/mL temporarily. Altogether 9/27 (33%) subjects reached <20 million/mL. Serum testosterone concentrations (S-T) decreased significantly during the first 3 months of treatment with one, two and four LNG implants and DHT and during the next 3 months S-T remained significantly lower with two or four implants. Serum oestradiol concentrations (S-E(2)) decreased significantly during the first 3 months only with four implants, but at 6 months S-E(2) was lower also in the group with two implants. Serum luteinizing hormone (LH) decreased significantly only with two LNG implants and DHT gel at 5 and 6 months. Serum FSH did not decrease in any of the groups. None of the subjects filled the criteria to continue to the efficacy phase. A total of 16 men discontinued for various reasons. Of the 27 men completing the suppression phase, all have recovered to sperm levels >20 million/mL. There were no changes in blood count, lipid profile, liver function tests, prostate-specific antigen (PSA), sex hormone binding globulin (SHBG), prolactin or cortisol. The mixed antiglobulin reaction (MAR)-IgG, MAR-IgA or tray agglutination test (TAT) did not change during any of the treatments. The present study shows that the LNG implants themselves are well-tolerated by men and safe, and might be suitable for replacing part of the testosterone used as injections to reduce the androgen dose during male hormonal contraception. The DHT gel was considered as quite or very uncomfortable by 66% of the men because of feeling cold during the time it was on the skin, but noncompliance in using the gel was not reported by the men.