Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men.

CONTEXT: The development of a safe and effective reversible method of male contraception is still an unmet need. OBJECTIVE: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. DESIGN: Prospective multicentre study. SETTING: Ten study centers. PARTICIPANTS: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems. INTERVENTION: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. MAIN OUTCOMES MEASURES: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. RESULTS: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. CONCLUSIONS: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.

Male hormonal contraception: a double-blind, placebo-controlled study.

BACKGROUND: This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception. DESIGN AND STUDY SUBJECTS: In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk. RESULTS: Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16-18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups. CONCLUSIONS: The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.

Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis.

CONTEXT: Male hormonal contraceptive methods require effective suppression of sperm output. OBJECTIVE: The objective of the study was to define the covariables that influence the rate and extent of suppression of spermatogenesis to a level shown in previous World Health Organization-sponsored studies to be sufficient for contraceptive purposes (< or =1 million/ml). DESIGN: This was an integrated analysis of all published male hormonal contraceptive studies of at least 3 months' treatment duration. SETTING: Deidentified individual subject data were provided by investigators of 30 studies published between 1990 and 2006. PARTICIPANTS: A total of 1756 healthy men (by physical, blood, and semen exam) aged 18-51 yr of predominantly Caucasian (two thirds) or Asian (one third) descent were studied. This represents about 85% of all the published data. INTERVENTION(S): Men were treated with different preparations of testosterone, with or without various progestins. MAIN OUTCOME MEASURE: Semen analysis was the main measure. RESULTS: Progestin coadministration increased both the rate and extent of suppression. Caucasian men suppressed sperm output faster initially but ultimately to a less complete extent than did non-Caucasians. Younger age and lower initial blood testosterone or sperm concentration were also associated with faster suppression, but the independent effect sizes for age and baseline testicular function were relatively small. CONCLUSION: Male hormonal contraceptives can be practically applied to a wide range of men but require coadministration of an androgen with a second agent (i.e. progestin) for earlier and more complete suppression of sperm output. Whereas considerable progress has been made toward defining clinically effective combinations, further optimization of androgen-progestin treatment regimens is still required.

Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men.

BACKGROUND: We assessed attitudes towards and acceptability of male hormonal contraception among volunteers participating in a clinical trial of a prototype regimen, consisting of progestin and testosterone injections. METHODS: After completing screening, eligible men were randomly assigned to the no-treatment group (n = 40) or to receive injections of norethisterone enanthate and testosterone undecanoate or placebo at different intervals (n = 50) according to a blocked randomization list. They underwent self-administered questionnaires. RESULTS: The average age of the participants was approximately 28 years; most were involved in a stable relationship and had no children. Ninety-two percentage of the respondents thought that men and women should share responsibility for contraception and 75% said they would try a hormonal contraceptive if available. At the end of the treatment phase, 66% of the participants said that they would use such a method, and most rated its acceptability very highly; none reported it to be unacceptable. The injections themselves were indicated as the biggest disadvantage. No significant changes in sexual function or mood states were detected among the men who underwent hormone injections. CONCLUSIONS: The contraceptive tested in this study was well accepted by the participants over the course of 1 year.

Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen.

In this study we compared the effects of high-dose and low-dose testosterone enanthate (TE) administered with the same dose of cyproterone acetate (CPA). Eighteen men aged 21-45 were treated with CPA 5 mg/day and with TE 100 mg/week (n = 9; CPA-5-100) or TE 200 mg/week (n = 9; CPA-5-200) for 16 weeks. Semen analyses were performed every 2 weeks; physical examination and chemistry, hematology, gonadotropin, and testosterone measurements were performed every 4 weeks. At week 16 of treatment, sperm counts were significantly more suppressed in the CPA-5-100 group than in the CPA-5-200 group. Sperm counts returned to baseline in all subjects after hormone administration ceased. No difference in gonadotropin levels was found at any time between the 2 groups. During the treatment phase, testosterone levels were significantly higher in the CPA-5-200 group than in the CPA-5-100 group. The present study confirms that CPA/TE administration induces profound sperm suppression. An increase in the dose of androgen resulted in less profound sperm suppression despite no difference in gonadotropin suppression. These data suggest that high testosterone levels can maintain sperm production in men.

Twenty-one day administration of dienogest reversibly suppresses gonadotropins and testosterone in normal men.

Androgen-progestin combinations are promising male contraceptive regimens. Optimization of these regimens includes the development of new progestins with more favorable biological properties. In this context we tested the effects of the progestin dienogest (DNG) on reproductive hormones and metabolic parameters in men. After a 3-wk control period, 25 men were randomly assigned to receive daily doses of 2, 5, or 10 mg DNG or placebo and 10 mg cyproterone acetate for 21 d (n = 5 subjects/group). Subjects were followed for 2 wk after cessation of hormone administration. Weekly blood samples, physical examinations, hormone and chemistry measurements, semen analysis, and sexual/behavioral assessments were performed. These parameters were compared among study groups and within each group at different time points throughout the study periods. DNG and cyproterone acetate administration resulted in profound suppression of gonadotropins and T with no change in SHBG levels. No adverse effects were detected in any subject. Hormone levels returned to baseline after stopping hormone intake. DNG is a potent suppressor of gonadotropins and T in men and does not induce adverse effects over a 21-d administration. DNG is a promising progestin to be used in clinical trials for male contraception.