Investigation of hormonal male contraception in African men: suppression of spermatogenesis by oral desogestrel with depot testosterone. A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. Male hormonal contraception: suppression of spermatogenesis by injectable testosterone undecanoate alone or with levonorgestrel implants in chinese men. Comparison of a gonadotropin releasing-hormone antagonist plus testosterone (T) versus T alone as potential male contraceptive regimens. Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in chinese men. An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations. Novel male hormonal contraceptive combinations: the hormonal and spermatogenic effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist. Depot gonadotropin-releasing hormone agonist blunts the androgen-induced suppression of spermatogenesis in a clinical trial of male contraception. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach.
Suppression of spermatogenesis to azoospermia is required for effective hormonal male contraception, but the degree of suppression varies between ethnic groups. We here report the first study of hormonal suppression of spermatogenesis in two African centres using a regimen of oral progestogen with depot testosterone. METHODS A total of 31 healthy men (21 black) were recruited in Cape Town and 21 men in Sagamu, Nigeria. Subjects were randomized to take either 150 or 300 micro g desogestrel daily p.o. with testosterone pellets. In Cape Town, desogestrel was administered for 24 weeks with 400 mg testosterone re-administered 12 weekly. In Sagamu, desogestrel was administered for 52 weeks with 200 mg testosterone (later increased to 400 mg) re-administered 12-weekly.
                In Cape Town, 22 men completed at least 20 weeks treatment. Azoospermia was achieved in 8/10 and 8/12 men in the 150 micro g and 300 micro g desogestrel groups. Four men in Sagamu withdrew. Azoospermia was achieved in all 17 men in the two groups. There were no significant changes in lipoprotein or haemoglobin concentrations in any group.
                These data demonstrate that the combination of oral desogestrel with depot testosterone is an effective regimen for suppression of spermatogenesis in African as in Caucasian and Chinese men, with azoospermia achieved in a total of 83/98 (85%) men. Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive. Monthly injections of testosterone undecanoate (TU) act as a male contraceptive by reversibly suppressing spermatogenesis to azoospermia or severe oligoazoospermia in 95% of Chinese men. In 5% of Chinese men, however, monthly TU administered alone fails to suppress spermatogenesis into contraceptive ranges, or sperm "rebound," leading to occurrences of pregnancy during treatment. Since combinations of progestins and androgens are associated with greater degrees of sperm suppression in white men, we hypothesized that the combination of TU and the progestin levonorgestrel (LNG) would result in improved spermatogenic suppression in Chinese men. Sixty-two healthy Chinese men were randomly assigned to one of the following 3 regimens: group I (n = 21) received 4 LNG rods (75 mg each), which were followed 4 weeks later by 500 mg of TU by intra-muscular (IM) injection every 8 weeks for 24 weeks; group II (n = 20) received 4 LNG implants, which were followed 4 weeks later by 1000 mg of TU by IM injection every 8 weeks for 24 weeks; and group III (n = 21) received TU 1000 mg by IM injection every 8 weeks for 24 weeks. Sperm counts, serum testosterone (T), luteinizing hormone, follicle-stimulating hormone, and LNG were measured every 2 weeks before, during, and after treatment. During treatment, group II demonstrated a trend toward a greater attainment of azoospermia than groups I and III (90% vs 62% [group I] vs 67% [group III]; P =.09). Attainments of either azoospermia or oligozoospermia (sperm density, <3 x 10(6)/mL) were 95%, 100%, and 86% for groups I, II, and III, respectively (P >.05 for comparisons between groups). Spermatogenesis in all subjects returned to the normal range after the implants were removed. No serious adverse events and no significant changes in serum chemistry occurred during the study. These results demonstrate that the combination of IM injections of high-dose TU every 2 months and LNG implants is associated with marked suppression of spermatogenesis in Chinese men. The combination of high-dose TU every 2 months and LNG implants is a promising candidate for future large-scale efficacy studies of hormonal male contraception in Chinese men. Efforts to develop a hormonal contraceptive regimen for men have focused on administration of testosterone (T), alone or together with other agents. Previous regimens have successfully induced azoospermia in only 50-70% of subjects, however. GnRH antagonists, alone or in combination with T, have been shown to induce azoospermia in a very high percentage of nonhuman primates. We tested the hypothesis that the addition of a GnRH antagonist to a high-dose T regimen would lead to a higher percentage of men developing azoospermia than would T alone. We administered the GnRH antagonist, Nal-Glu (100 micrograms/kg.day sc), plus T enanthate, 200 mg im weekly or placebo sc injections daily plus T enanthate, 200 mg im weekly, to separate groups of healthy men for 16-20 weeks. Seven of 10 men who received Nal-Glu plus T and 6 of 9 men who received T alone became azoospermic; gonadotropin levels were suppressed and T levels were increased similarly in both groups. There was a trend toward higher pretreatment gonadotropin levels and lower sperm counts in men who became azoospermic. Weight gain, development of acne, and increases in hematocrit and hemoglobin were similar in the two groups. In the majority of the men, sperm counts returned to the baseline levels within 4-5 months after treatment ended. We conclude that with the dosages of Nal-Glu and T we used in this study, the addition of GnRH antagonist to a high-dose T regimen does not increase the ability of T to suppress spermatogenesis in healthy men. Use of a higher dose of Nal-Glu, a lower dose of T, delaying the start of T replacement until several weeks after Nal-Glu injections are initiated, or prolonged hormonal administration might lead to a combination regimen that will suppress spermatogenesis more fully than does T alone. Surveys indicate that one form of acceptable male hormonal contraception would consist of injections given at 2- to 3-month intervals. This report describes a study of depot medroxyprogesterone acetate (DMPA) and testosterone undecanoate (TU) injected at 8-wk intervals for suppression of spermatogenesis in healthy Chinese men. After screening, 30 healthy volunteers were enrolled and randomly assigned to one of three dose groups (n = 10/group): 1000 mg TU (group A); 1000 mg TU plus 150 mg DMPA (group B); 1000 mg TU plus 300 mg DMPA (group C). All doses were given as im injections at 8-wk intervals. The study consisted of an 8-wk control (baseline) period, a 24-wk treatment period, and a 24-wk recovery period. Consistent azoospermia or severe oligozoospermia was achieved and maintained in all volunteers during the treatment period, except for two men in the TU-alone group who experienced a rebound in sperm concentrations. An 8-wk regimen of TU plus DMPA at both tested combination doses effectively suppressed spermatogenesis to azoospermia in Chinese men. All volunteers tolerated the injections; no serious adverse effects were reported. The lower-dose combination is recommended for further testing in an expanded clinical trial or contraceptive efficacy study. Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials. We postulated that the addition of a combined types I and II, 5alpha-reductase inhibitor (dutasteride) or long-acting GnRH antagonist (acyline) to combination testosterone plus levonorgestrel treatment may be advantageous in the suppression of spermatogenesis for male contraception. This study aimed to examine effects of novel combination contraceptive regimens on serum gonadotropins and androgens and sperm concentration.This study was divided into three phases: screening (2 wk), treatment (8 wk), and recovery (4 wk). Twenty-two men (n = 5-6/group) received 8 wk of treatment with testosterone enanthate (TE, 100 mg im weekly) combined with one of the following: 1) levonorgestrel (LNG) 125 mug orally daily; 2) LNG 125 microg plus dutasteride 0.5 mg orally daily; 3) acyline 300 microg/kg sc every 2 wk (as a comparator for any additional progestin effects); or 4) LNG 125 microg orally daily plus acyline 300 microg/kg sc every 2 wk. Serum gonadotropin levels were similarly suppressed by all treatments, falling to a nadir between 1.2 and 3.4% and 0.5 and 0.8% baseline for FSH and LH, respectively (P < 0.05). Serum dihydrotestosterone levels were significantly (P < 0.05) decreased in the dutasteride group throughout the treatment period to a nadir of 31% baseline (wk 7). No significant differences in sperm concentrations among treatment groups were seen. Severe oligospermia (0.1-3 million/ml) or azoospermia was seen in none of five and four of five in TE + LNG; two of six and four of six in TE + LNG + dutasteride; two of six and four of six in TE + acyline; and one of five and three of five in TE + LNG + acyline groups, respectively. There was one nonresponder in each of the TE + LNG and TE + LNG + acyline groups.We conclude that the addition of a combined types I and II, 5alpha-reductase inhibitor or long-acting GnRH antagonist to a testosterone plus LNG regimen provides no additional suppression of gonadotropins or sperm concentration over an 8-wk treatment period. However, further evaluation of the effects of these regimens on the testis (including testicular steroid levels and germ cell maturation) and the treatment of larger numbers of men (and for longer periods) may provide data to support their place in contraceptive development. Thus far, when tested as male contraceptives, GnRH agonists in combination with androgens were not very effective in producing azoospermia. Since in previous studies androgens were always given simultaneously with the GnRH agonist or later, we tested whether GnRH agonist administration after an initial androgen suppression phase might yield better results. After a control period, 3 groups of young healthy men (n = 8/group) received an initial loading dose of 400 mg 19-nortestosterone hexyloxyphenylpropionate (19NT-HPP), followed by 200 mg of the ester every 3 weeks for 24 weeks. One week after the first 19NT-HPP injection, 2 groups were given a single sc implant injection of 3.3 or 6.6 mg of the GnRH agonist buserelin, respectively, whereas a placebo implant was given to the third group. In the group receiving only 19NT-HPP, serum LH and FSH were markedly suppressed and remained low during the treatment phase. In the 16 volunteers receiving the buserelin implant LH and FSH were also suppressed on day 7, followed by a marked increase in the gonadotropins up to 2 weeks after buserelin implant injection. While LH was consistently suppressed for the remaining treatment phase, FSH returned to almost normal values in weeks 9-15. In contrast to the group treated with 19NT-HPP alone, in which sperm concentrations were reduced to oligozoospermia after only 3 weeks of treatment, the first suppressive effect in the 19NT-HPP/buserelin-treated groups was not seen before week 9. After 30 weeks, when the maximal suppression of spermatogenesis was seen, 4 of 8 volunteers in the group treated with 19NT-HPP alone were azoospermic, and the remaining 4 volunteers were oligozoospermic. In the groups treated with 19NT-HPP/buserelin, no more than 4 of 16 volunteers were azoospermic, and no more than 8 of 16 volunteers were oligozoospermic at any time point. It is concluded that GnRH agonist depot preparations have a blunting effect on the suppression of pituitary and testicular function caused by androgens in men participating in contraceptive trials. Studies using high dose testosterone (T) administration in normal men as a male contraceptive have resulted in azoospermia rates of only 50-70%. Previous studies of T and progestogen combinations have shown comparable rates of azoospermia, but have been uncontrolled or used T in doses less than that associated with maximal suppression of sperm production. We conducted a randomized, placebo-controlled, single blind trial comparing 6 months of T enanthate administration (100 mg, im, weekly) with the same dose of T enanthate in conjunction with the progestogen levonorgestrel (LNG; 500 micrograms, orally, daily) in 36 normal men, aged 20-42 yr (n = 18 in each group). The primary end points were induction of azoospermia or severe oligospermia (< 3 million sperm/mL). The combination of T plus LNG was much more effective in suppressing sperm production than T alone. Sixty-seven percent of the T plus LNG group (12 of 18) and 33% of the T alone group (6 of 18) achieved azoospermia by 6 months (P = 0.06). Severe oligospermia or azoospermia developed in 94% of the T plus LNG (17 of 18) group compared to 61% of the T alone group (11 of 18; P < 0.05). T plus LNG also suppressed sperm production more rapidly than T alone. Time to azoospermia was 9.9 +/- 1.0 vs. 15.3 +/- 1.9 weeks in the T plus LNG and T alone groups, respectively (mean +/- SEM; P < 0.05). Serum high density lipoprotein cholesterol decreased 21.7 +/- 3.6% in men given T plus LNG (P < 0.05), compared to only a 1.8 +/- 3.8% decrease in men in the T alone group. Average weight gain was 5.3 +/- 0.8 kg in the T plus LNG group and 2.3 +/- 0.9 kg in the T alone group (P < 0.05). Acne and increase in hemoglobin were similar in the two groups. We conclude that combination hormonal therapy with T plus a progestogen might offer a reversible male contraceptive approach with a more rapid onset of action and more reliable induction of both azoospermia and severe oligospermia than T alone.
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.