Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial.

OBJECTIVE: Fifty percent of pregnancies in the United States are unintended despite numerous contraceptive methods available to women. The only male contraceptive methods, vasectomy and condoms, are used by 10% and 16% of couples, respectively. Prior studies have shown efficacy of male hormonal contraceptives in development, but few have evaluated patient acceptability and potential use if commercially available. The objective of this study is to determine if a transdermal gel-based male hormonal contraceptive regimen, containing testosterone and Nestorone® gels, would be acceptable to study participants as a primary contraceptive method. STUDY DESIGN: As part of a three-arm, 6-month, double-blind, randomized controlled trial of testosterone and nestorone gels at two academic medical centers, subjects completed a questionnaire to assess the acceptability of the regimen. Of the 99 men randomized, 79 provided data for analysis. RESULTS: Overall, 56% (44/79) of men were satisfied or extremely satisfied with this gel-based method of contraception, and 51% (40/79) reported that they would recommend this method to others. One third of subjects (26/79) reported that they would use this as their primary method of contraception if it were commercially available today. However, men with concerns about sexually transmitted disease were significantly less satisfied than men without such concerns (p=0.03). CONCLUSIONS: A majority of the men who volunteered to participate in this trial of an experimental male hormonal contraceptive were satisfied with this transdermal male hormonal contraceptive. If commercially available, a combination of topical nesterone and testosterone gels could provide a reversible, effective method of contraception that is appealing to men. IMPLICATIONS: A substantial portion of men report they would use this transdermal male contraceptive regimen if commercially available. This method would provide a novel, reversible method of contraception for men, whose current choices are limited to condoms and vasectomy.

Integrity of the blood-testis barrier in healthy men after suppression of spermatogenesis with testosterone and levonorgestrel.

STUDY QUESTION: Do exogenous male hormonal contraceptives that suppress intratesticular testosterone and spermatogenesis interfere with the blood-testis barrier integrity in men? SUMMARY ANSWER: When spermatogenesis was suppressed by testosterone alone or combined with levonorgestrel (LNG) treatment in men, the structural appearance of Sertoli cell tight junctions remained intact in the human testis. WHAT IS ALREADY KNOWN: Testosterone promotes the integrity of the blood-testis barrier. Intratesticular androgen deprivation induced by exogenous testosterone plus a progestin to suppress spermatogenesis in a contraceptive regimen may disturb the structural and functional integrity of the blood-testis barrier. STUDY DESIGN, SIZE AND DURATION: Testicular biopsies were obtained from a sub-study of a randomized clinical trial of 36 healthy Chinese men who were treated for 18 weeks and followed for at least a 12-week recovery period. PARTICIPANTS/MATERIAL, SETTING, METHODS: Healthy Chinese male volunteers (27-48 years) were randomized to two treatment groups (n = 18/group) for 18 weeks: (1) testosterone undecanoate (TU) 1000 mg i.m. injection followed by a 500 mg injection every 6 weeks and (2) TU + LNG 250 µg orally daily. Blood samples were obtained from all participants before and during treatment and at the end of the recovery phase. Open testicular biopsies for this study were obtained from four men before treatment and from four men in each of the TU and TU + LNG groups at 2 and 9 weeks of treatment. The presence of antisperm antibodies was checked in the archived serum samples of the subjects at baseline, during treatment and at the end of the recovery period. Stored testicular biopsy samples from cynomolgus monkeys treated with either sub-cutaneous testosterone or placebo for 12 weeks were used for additional protein expression studies. MAIN RESULTS AND ROLE OF THE CHANCE: Expression of blood-testis barrier associated proteins quantified by immunohistochemistry (claudin 3, claudin 11, junctional adhesion molecule-A, zonula occludens-1) remained unchanged despite a significant decrease in the numbers of pachytene spermatocytes and round spermatids in the seminiferous tubules at 9 weeks in the TU + LNG group. This was confirmed by immunoblots showing a lack of quantitative change in these tight junction proteins in monkeys after testosterone treatment. There were no increases in serum antisperm antibodies in the volunteers during the study. LIMITATIONS/REASONS FOR CAUTION: The duration of the study was short and the long-term effects of male hormonal contraceptive treatments on the integrity of the blood-testis barrier remain to be determined. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the safety of male hormonal contraceptive treatment and does not corroborate the previous findings of disturbed immunological integrity of the blood-testis barrier from animal studies such as androgen receptor knockout mice and exogenous hormonal treatment in rats. STUDY FUNDING/COMPETING INTEREST: The study was supported by grants from the Contraceptive Research and Development Program and the Mellon Foundation (MFG-02-64, MFG-03-67), Endocrine, Metabolism and Nutrition Training Grant (T32 DK007571), the Clinical and Translational Science Institute at Los Angeles Biomedical and Harbor-UCLA Medical Center (UL1RR033176 and UL1TR000124) and the Los Angeles Biomedical Research Institute Summer High School Student Program.

A new combination of testosterone and nestorone transdermal gels for male hormonal contraception.

CONTEXT: Combinations of testosterone (T) and nestorone (NES; a nonandrogenic progestin) transdermal gels may suppress spermatogenesis and prove appealing to men for contraception. OBJECTIVE: The objective of the study was to determine the effectiveness of T gel alone or combined with NES gel in suppressing spermatogenesis. DESIGN AND SETTING: This was a randomized, double-blind, comparator clinical trial conducted at two academic medical centers. PARTICIPANTS: Ninety-nine healthy male volunteers participated in the study. INTERVENTIONS: Volunteers were randomized to one of three treatment groups applying daily transdermal gels (group 1: T gel 10 g+NES 0 mg/placebo gel; group 2: T gel 10 g+NES gel 8 mg; group 3: T gel 10 g+NES gel 12 mg). MAIN OUTCOME VARIABLE: The main outcome variable of the study was the percentage of men whose sperm concentration was suppressed to 1 million/ml or less by 20-24 wk of treatment. RESULTS: Efficacy data analyses were performed on 56 subjects who adhered to the protocol and completed at least 20 wk of treatment. The percentage of men whose sperm concentration was 1 million/ml or less was significantly higher for T+NES 8 mg (89%, P<0.0001) and T+NES 12 mg (88%, P=0.0002) compared with T+NES 0 mg group (23%). The median serum total and free T concentrations in all groups were maintained within the adult male range throughout the treatment period. Adverse effects were minimal in all groups. CONCLUSION: A combination of daily NES+T gels suppressed sperm concentration to 1 million/ml or less in 88.5% of men, with minimal adverse effects, and may be further studied as a male transdermal hormonal contraceptive.

Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen-deficient men.

OBJECTIVES: Testosterone replacement therapy in hypogonadal men relieves symptoms and restores serum testosterone levels to the physiological range. In this study, we assessed the safety, pharmacokinetics, and efficacy of the 2% formulation of testosterone topical solution applied daily to the axillae. DESIGN AND PATIENTS: An open-label trial was conducted in testosterone-deficient men who started on a daily dose of 60 mg of testosterone. Dose was adjusted on Days 45 and 90 when necessary to maintain serum testosterone levels within the physiological range (10·41-36·44 nmol/l) based on average serum testosterone levels on Days 15 and 60, respectively. Sexual function and mood changes were assessed by the Psychosexual Daily Questionnaire (PDQ) for the 7 days preceding visits at Days 1, 15, 60, and 120; and quality of life by SF-36 questionnaire on Days 1, 60, and 120. Safety parameters, laboratory tests, and adverse events were collected at each visit. RESULTS: Among the Completer Set (135 study completers and 3 patients who discontinued due to adverse events), 76·1% (Days 15/16), 84·8% (Days 60/61), and 84·1% (Days 120/121) had an average total testosterone level between 10·41-36·44 nmol/l. PDQ scores increased significantly from baseline to 120 days of treatment (p < 0·0001). Significant improvement was observed in the physical (p < 0·05) and mental (p < 0·0001) components of the SF-36 after 120 days of treatment. Adverse events reported in >2% of the 155 subjects who received ≥ 1 dose were application site irritation (7·1%), application site erythema (5·2%), headache (5·2%), increased hematocrit (3.9%), nasopharyngitis (3·9%), diarrhea (2·6%), and vomiting (2·6%). CONCLUSIONS: These results indicate that once-daily application of the testosterone topical solution 2% to the axillae is a safe and effective treatment for androgen replacement in hypogonadal men.

Male hormonal contraception: potential risks and benefits.

An effective, safe, reversible, and acceptable method of contraception is an important component of reproductive health and provides the opportunity of shared responsibility for family planning for both partners. Female hormonal contraceptives have been proven to be safe, reversible, available and widely acceptable by different populations. In contrast, male hormonal contraception, despite significant progress showing contraceptive efficacy comparable to female hormonal methods during last three decades, has not yet led to an approved product. Safety of a pharmaceutical product is an appropriate concern but the majority of male hormonal contraceptive clinical trials have not reported significant short term safety concerns. While the absence of serious adverse effects is encouraging, the studies have been designed for efficacy endpoints not long term safety. In this review we summarize potential risks and benefits of putative male hormonal contraceptives on reproductive and non-reproductive organs. While the review covers what we believe will be the likely class of drugs used for male hormonal contraception a true assessment of long term risks and benefits cannot be achieved without an available product.

Does ethnicity matter in male hormonal contraceptive efficacy?

The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.