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Department of Andrology, Concord Hospital, and ANZAC Research Institute (L.T., A.J.C., M.J., P.Y.L., D.J.H.), University of Sydney, Sydney, New South Wales 2139, Australia; and Prince Henry’s Institute of Medical Research (E.F., R.I.M.), Monash Medical Center, Monash, Clayton VIC 3168, Australia
Address all correspondence and requests for reprints to: Prof. D. J. Handelsman, ANZAC Research Institute, Sydney, New South Wales 2139, Australia. E-mail: djh{at}anzac.edu.au.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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A hormonal male contraceptive must reversibly suppress sperm output to levels that reliably prevent conception with minimal side-effects (1). Although reversible hormonal suppression of sperm output was known (3) soon after the first clinical use of testosterone (4), systematic regimen and dose-finding studies were undertaken only in the 1970s (5, 6). These feasibility studies culminated in the proof of rinciple demonstrated by landmark WHO male contraceptive efficacy studies in the early 1990s (7, 8) using a prototype androgen-alone regimen in 670 couples in 10 countries. Using weekly im injections of testosterone enanthate to suppress sperm output, consistent suppression of sperm output to less than 3 million/ml provided very effective and reversible contraception, superior to condoms (the only reversible male method) and comparable with female oral contraception (9, 10). These studies also established effective monitoring guidelines for safe conduct of male contraceptive efficacy studies. The contraceptive failure rate in the WHO studies was directly proportional to residual sperm output, reinforcing the desirability of azoospermia or near-azoospermia as an ideal objective (11).
Since the WHO studies using a prototype androgen-alone regimen, second generation hormonal regimens featuring a combination of an androgen with a second gonadotropin-suppressing agent have proved more effective than androgen alone regimens (1). However, although GnRH antagonists are expensive and locally irritating (12) and estradiol is not sufficiently effective at tolerable doses (13), numerous synthetic progestins are available, with several progestin/androgen combination regimens showing promise for spermatogenic suppression (14, 15, 16, 17, 18), although few used a depot hormonal approach (14, 19), and no efficacy studies of a hormonal depot or an androgen/progestin combination were reported. A desirable feature for a hormonal male contraceptive is freedom from high demands on medication compliance, so that a depot regimen both avoids the need to take tablets daily and well suits the noncyclical male reproductive system. In a series of studies introducing testosterone implants as a prototype long-acting testosterone depot, we established that steady state testosterone delivery produced more efficient and effective suppression of spermatogenesis than weekly testosterone enanthate injections (20), and that the addition of a single 300-mg dose of depot medroxyprogesterone acetate (DMPA) to a suboptimally suppressive single testosterone depot dose (800 mg) produced more effective suppression of spermatogenesis than even the maximal testosterone depot dose (1200 mg) (14). By contrast, the addition of depot estradiol was only marginally more effective than testosterone depot at doses that produced unacceptable estrogenic side-effects (13). Hence, the overall objective of this study was to estimate the contraceptive efficacy of repeated doses of the combination of a prototype androgen/progestin depot combination that had proved highly effective at suppressing sperm output in a single dose. If the depot combination approach afforded sufficient suppression of spermatogenesis (approaching the ideal of universal azoospermia) so as to achieve high contraceptive efficacy while allowing for prolonged intervals between treatments, this would provide proof of principle for both the depot approach and the androgen/progestin combinations for hormonal male contraception. The present study was therefore designed to estimate the contraceptive efficacy of a combination of DMPA with testosterone implants at regular intervals.
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Materials and Methods |
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Volunteers were recruited by advertising and referral from contraceptive providers. Men, aged 18–50 yr, living for 1 yr or more in a stable relationship with a female partner were eligible if the couple sought a change in contraceptive method for at least 12 months. Men had to be in good general health (normal clinical and biochemical evaluation of liver, kidney, and hematological function), have normal reproductive function (no history of infertility, two semen analyses within normal limits), and provide written informed consent. Men were excluded for a history of major medical or psychiatric disorders, infertility in either partner, regular prescribed medication, and contraindications to minor local surgery or testosterone. Female partners had to be aged 18–38 yr, have regular menstrual cycles, have no history of infertility, not be seeking another pregnancy for at least 12 months, have a negative pregnancy test before entry to study and efficacy phase, and provide written informed consent. No financial incentives were provided apart from reimbursement of travel receipts. The study was conducted within National Health and Medical Research Council (Australia) guidelines for human experimentation with approval from the relevant local ethics committees.
Hormone treatments
The hormone treatment comprised a progestin, 300-mg DMPA (Pharmacia & Upjohn, Piscataway, NJ) injected every 3 months together with depot testosterone (four 200-mg pellets, Organon, West Orange, NJ) of pure crystalline steroid implanted under the abdominal skin under local anesthetic, lateral to the umbilicus by an experienced operator (21, 22). No sutures or antibiotics were required, and the biodegradable implants do not require removal.
Design
Efficacy was defined by the contraceptive failure rate during 12 months of hormonally induced suppression of spermatogenesis (<1 million/ml). As the primary efficacy end point was contraceptive failures (pregnancy), a placebo control could not be used. This threshold was set at this more stringent level than that used in the WHO male contraceptive efficacy studies [<3 million/ml after lowering from the original <5 million/ml (8)] to minimize unwanted pregnancies, as the contraceptive failure rate in the WHO studies was proportional to residual sperm output (1). The secondary end points were the suppression of sperm output and gonadotropin and the maintenance of eugonadal blood testosterone concentrations. The safety end points were unexpected adverse effects, clinical (gynecomastia, weight, blood pressure, psychological reactions, and changes in mood, behavior, or sexual function) and biochemical markers of androgen effects [hemoglobin, SHBG, lipids, and prostate-specific antigen (PSA)].
The study termination criterion was based on experience from the second WHO study (8). The contraceptive failure rate for men with sperm concentrations matching those in the efficacy phase of this study (0–1 million/ml) was 0.74 [95% confidence interval (CI), 0.09–2.7%]/100 person-years of exposure. Hence, if the contraceptive failure rate of this study significantly exceeded that of the comparable stratum of the second WHO study (3%, rounded off), coincidentally also the best estimate of first year failure rate of an oral contraceptive (9), the study would be discontinued for unacceptable failure rate. As the study objective was primarily descriptive, the sample size was based on the need for sufficient power to exclude an unacceptable contraceptive failure rate, and 50 couples providing a mean 450 monthly cycles (
38 person-years) met these criteria.
Two protocol amendments concerning hormone dosage were required. After the unexpected observations of several men with escape from spermatogenic suppression and/or symptomatic androgen deficiency between 5 and 6 months after start of the study, an unscheduled interim review identified that the 6-month interval between testosterone doses failed to maintain eugonadal testosterone concentrations. A protocol amendment changed testosterone implantations (800 mg) from every 6 to every 4 months. Subsequently, there were no further episodes of either spermatogenic escape or androgen deficiency. A second protocol amendment deleted the last medroxyprogesterone acetate dosage due to the slower than expected rate of recovery of spermatogenesis.
Procedures
Eligible men entered the suppression phase, which began with the first hormone administration and ended with entry into the efficacy phase within 6 months. Those couples not already using a barrier contraceptive method switched to one during the suppression phase. Men entered the efficacy phase when they had two consecutive monthly semen samples with sperm density less than 1 million/ml, and their wives had a negative pregnancy test. The efficacy phase began with the second eligible sperm sample when couples discontinued other (barrier) contraception for 12 months. The recovery phase began at the date corresponding to the end of the last administered hormone cycle (3 months after last depot medroxyprogesterone dose or 4 months after testosterone implant). Men had physical examinations every 6 months and routine clinical chemistry every 3 months. Throughout the study, men provided monthly blood and semen samples, and changes in well-being or sexual function were recorded if reported. Escape from spermatogenic suppression was defined as a semen sample with volume more than 1.0 ml and sperm concentration more than 1 million sperm/ml. This triggered a repeat semen analysis within 1 wk. If the repeat semen analysis confirmed escape, the couple were discontinued from the study and advised to switch to other methods of contraception if they wished to avoid pregnancy.
Assays
Semen samples collected by masturbation at the clinic laboratory were analyzed by standard WHO methods (23). Men were asked to maintain an abstinence interval of at least 2 d before each semen sample. Plasma samples were stored frozen for measurement within a single assay using commercial DELFIA immunoassays for LH, FSH, total testosterone, SHBG, and PSA. Within-assay coefficients of variation were less than 10% for all assays, and detection limits for gonadotropin assays were 0.1–0.2 IU/liter. Clinical chemistry assays (liver function, renal function, and lipids) were undertaken by routine autoanalyzer methods.
Data analysis
Continuous variables were analyzed by ANOVA for factorial or repeated measures designs with appropriate post hoc testing. Non-Gaussian sperm output data were cube root-transformed before analysis (24). Achievement of sperm output thresholds was analyzed by survival methods. Categorical variables were analyzed by exact contingency table methods using StatXact (Cytel, Cambridge, MA) software. CIs for proportions were estimated from the binomial distribution using the Blyth-Still-Casella CI algorithm (25). Due to the variable length of the suppression and recovery phases, the safety variables were analyzed conservatively according to the last observation carried forward technique, which reflect maximal observed effects during treatment and recovery. Data are expressed as mean and SE of the mean for continuous variables and as proportions and percentages for categorical variables. P < 0.05 was considered statistically significant.
A quantitative systematic review was undertaken to determine the speed and extent of suppression of sperm output from all previously reported androgen-based steroidal regimens (26). Relevant papers were located using electronic databases (MEDLINE, PubMED) supplemented by manual searching and tracing from published major reviews (1, 2, 5, 6, 27, 28). These papers included regimens featuring testosterone, dihydrotestosterone, or nandrolone or their esters as the androgen with or without medroxyprogesterone, cyproterone, levonorgestrel, or desogestrel as the progestin. Any study with inadequate reporting to verify the relevant features for this analysis was excluded. As many studies compared treatments or doses within a study, the unit for this quantitative analysis was each separate treatment group with at least eight men and receiving a distinct treatment regimen rather than the study as a whole. The primary end point was the degree of suppression of sperm output at 1 month, expressed as a percentage of baseline sperm output. The degree of suppression at 1 month was calculated from tabulated data or interpolated from figures. Considering the degree of suppression as a fraction with an underlying binomial distribution, the inverse variance weighted mean suppression was estimated using the number of men per treatment group as the weight variable, given that the variance is inversely related to the number of trials for a binomial distribution (29).
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Results |
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Among 84 men who underwent screening for entry into the study, 14 were ineligible according to study entry criteria due to oligozoospermia (8), medical illness (2), female infertility (2), or pregnancy (2). Another 15 declined to proceed with entry for personal reasons, including medical illness, wife pregnant, relationship breakdown, moved residence, changed job, and move of study center to another hospital. Among 55 men who entered the study, 14 were treated under the original 6-month intervals between testosterone implants, with the remaining 41 treated at 4-month intervals following the protocol amendment. None switched between testosterone treatment intervals. Men were treated for a median of 12 months (range, 3–16 months; mean ± SEM, 12 ± 0.6 months) and participated in the study for a median of 19 months (range, 3–30 months; mean, 17.5 ± 1 months). Female partners of 33 men had prior fertility, 24 in that relationship and 9 in another.
Contraceptive efficacy
No pregnancies were reported in 426 person-months (35.5 person-years) of efficacy exposure among 51 men. The 95% confidence limits for contraceptive failure rate are 0–8%. The mean duration of time in efficacy phase per person did not differ between men in the 4- and 6-month treatment regimens. Most men (26 of 51, 51%) entered the efficacy phase azoospermic, with eventually all becoming azoospermic (n = 49) or near-azoospermic (n = 2; lowest sperm density, 0.1 million/ml). Most efficacy exposure (90%) occurred during azoospermia; the remainder occurred during severe oligozoospermic (<1 M/ml). After completion of study, four men in couples seeking further fertility successfully achieved paternity, with the pregnancies resulting in one set of twins, two singleton births, and a spontaneous miscarriage.
Sperm output
Sperm output was rapidly suppressed (Figs. 1
and 2), with mean sperm density falling by 88% at 1 month and 98% by 2 months and with nearly all men (94%) entering efficacy within 3 months. The speed and extent of suppression of sperm output, defined as the percent decrease in sperm output at 1 month compared with baseline, were compared with all available published studies of androgen-based steroidal male contraceptive regimens. In the quantitative systematic review, 35 published studies involving androgen alone regimens (15 studies, 20 treatment groups) produced a weighted mean decrease in sperm output of 42% (median, 38%; range, 0–80%) at 1 month, whereas the androgen/progestin combination (20 studies, 30 treatment groups) produced a weighted mean decrease in sperm output of 51% (median, 50%; range, 0–86%) at 1 month.
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). The rate of spermatogenic recovery was not influenced by whether the men had the fifth injection of DMPA (data not shown). One man with myotonic dystrophy diagnosed during the recovery phase failed to recover spermatogenesis.
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Mean plasma testosterone concentrations were maintained within eugonadal reference range levels until the fourth month (Fig. 1
). In the original 6-month implantation regimen, mean plasma testosterone concentrations fell below the lower limit of the eugonadal reference range at months 5 and 6. In the amended 4-month regimen, eugonadal plasma testosterone concentrations were maintained consistently. Plasma SHBG concentrations were suppressed about 15% during treatment with recovery after treatment. Mean plasma LH and FSH were fully suppressed at the first month with virtually all sample having undetectable concentrations (Fig. 1). Subsequently, the 6-month testosterone implantation failed to maintain plasma LH and FSH suppression with escape from suppression in months 5–6 and 11–12 (each 5–6 months after testosterone implantation) preceding sperm escape. No escape from suppression of plasma LH and FSH was observed in the amended 4-month protocol.
Safety
Two serious adverse events were considered unrelated to drug exposure. One was the diagnosis of myotonic dystrophy after the presentation of muscular symptoms during the recovery phase. The second was the diagnosis of multiple congenital abnormalities (Vater Anomalad) (30) in one of identical twins conceived during the recovery phase. Pediatric and medical genetics consultants believed that this embryonic midline malformation was due to effects during pregnancy rather than hormonal, genetic, or paternal effects.
There were 27 discontinuations of treatment for protocol-related reasons (n = 15) comprising failure to suppress (n = 2), escape from suppression (n = 4), and problems with pellets (n = 6; dislike implants, n = 3; extrusion, n = 2; pain, n = 1); for medical reasons (n = 3; androgen deficiency, n = 2; mood fluctuation, n = 1); or for change in personal circumstances (n = 12) due to relocation away from study center (n = 5), relationship breakdown (n = 3), desire to have a child (n = 2), and incidental female infertility (n = 2). Symptomatic androgen deficiency (lethargy, sexual dysfunction, and gynecomastia) was reported during months 5 and 6 of the original (6-month implantation) protocol, but not in the amended (4-month) protocol. Supplemental testosterone was administered by an im injection to eight men: four requiring a single dose, and others receiving 2, 4, 7, and 12 doses. The one man with mood change reported emotional lability and feeling tearful without relation to hormone doses, but recovered promptly and fully after discontinuation.
Both hemoglobin and body weight increased significantly by approximately 3% over baseline during treatment (Table 1). After cessation of treatment, hemoglobin concentration, but not body weight, returned to baseline by the end of study. There were no significant effects on systolic or diastolic blood pressure, plasma PSA, or lipids (total low density lipoprotein, high density lipoprotein cholesterol, and triglycerides) nor any significant abnormalities of liver function tests, episodes of polycythemia or sleep apnea reported during the study.
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Discussion |
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After the WHO male contraceptive efficacy studies (7, 8), recently a Chinese multicenter male contraceptive efficacy study, using monthly injections of testosterone undecanoate in 308 healthy fertile men, also reported high contraceptive efficacy of 94.8% (32). This impressive finding depends upon the higher susceptibility of Chinese men to testosterone-induced azoospermia (33) first reported from the WHO studies (7, 8), which highlighted striking variation within and between centers in susceptibility to testosterone-induced azoospermia (33). Although testosterone-induced azoospermia is associated with higher pretreatment FSH concentrations, there are no differences in blood testosterone concentrations before or during treatment (33); in the androgen receptor CAG or GGC triplet repeat polymorphisms, postulated markers of tissue androgen sensitivity (34); or in the hepatic androgen-metabolizing enzyme (cytochrome P450 3A4) polymorphism (35). Hence, within- and between-population variations in susceptibility to testosterone-induced azoospermia remain to be explained. The ethnic differences in susceptibility to testosterone-induced azoospermia provide an important clue to pathogenesis. These may be explained by environmental factors, as exemplified by migrant studies showing differences in testosterone production rate (36) and prostate zonal volumes (37) between Chinese-born men residing inside and outside China. Whether such variations are due to nutritional or nondietary factors remains to be further clarified. On the other hand, it has been proposed that genetic factors may contribute to the higher susceptibility of Chinese men to testosterone-induced azoospermia (38). This seems likely to be less important, as the small difference of one CAG triplet repeat length between Chinese and non-Chinese populations has been reported (39), but not confirmed (40). Nor could CAG repeat length polymorphism explain the striking differences in central and total prostate volumes and in blood dihydrotestosterone concentrations between Chinese and Australian non-Chinese men (41) or in susceptibility to prostate cancer (40). Although androgen-alone regimens are simplest, their practical limitation is their inability to achieve uniform azoospermia, especially among non-Chinese men. Hence, although such regimens are effective in China (32), they are inadequate for other populations (42). By contrast, the much more effective spermatogenic suppression of androgen-progestin combinations abolishes ethnic differences in susceptibility to hormonally induced azoospermia (43, 44). The lack of ethnic differences in susceptibility to combination hormonal regimens is hard to reconcile with the recent claim that CAG triplet repeat number predicts the likelihood of spermatogenic suppression (38). As the latter study involved pooling of selected small studies using six different suboptimal hormonal regimens, these observations, based on complex post hoc analyses, may reflect the heterogeneity between suboptimal regimens rather than within individuals. Resolution of this dichotomy will require replication in a prospective study using a single effective hormonal combination regimen.
The safety outcomes were reassuring. The major problem was the unexpected occurrence of androgen deficiency in a number of men between 5 and 6 months after testosterone implantation. This was surprising given extensive pharmacological characterization, and experience with these implants showed a consistent duration of action of about 6 months (21, 22, 45, 46). This shortening of duration of action was due to a previously unrecognized drug interaction with DMPA-induced lowering of SHBG (14) accelerating the metabolic clearance rate of testosterone (47). When this was recognized and rectified by a protocol amendment shortening the interval between implants from 6 to 4 months, no further episodes of androgen deficiency were observed in the remaining 75% of men who participated in the study. The relatively high discontinuation rate (27 of 55, 49%) is typical of male contraceptive efficacy studies of this duration, where young couples seek to obtain a novel contraceptive service but receive no financial inducements to participate. For example, a similar population in the WHO studies had 114 of 271 (42%) and 148 of 399 (29%) men discontinue for the same range of reasons. This is in sharp contrast to volunteers for spermatogenic suppression (nonefficacy) studies in which they are promised no contraceptive benefit, but are often paid for participation, which provides a strong incentive to complete the demanding protocols that usually have high completion rates. This experience highlights that future male contraceptive efficacy studies should plan for similar discontinuation rates. There were no serious adverse effects related to drug treatment. There were no significant adverse effects on conventional surrogate markers for cardiovascular (lipids and blood pressure) and prostate (PSA) disease. Potential adverse effects of androgens, such as abnormal liver function, polycythemia, or sleep apnea, were not observed, and the expected androgen effects on hemoglobin were modest and reversible. The persistent weight gain was unexpected, but of modest degree. Recently, other androgen/progestin studies have also reported persistent weight gain, which may be due to the progestin component or the combination, as it was not a consistent feature of androgen-alone regimens. Nevertheless, the long-term safety of such a regimen, particularly for cardiovascular and prostate disease, requires thorough evaluation of real, rather than surrogate, end points in clinical trials comparable to safety studies of female hormonal contraception. In concert, however, these findings suggest that custom-developed androgen/progestin combinations may provide an acceptable basis for a widely usable reversible, hormonal male contraceptive regimen.
Hormonal male contraception exploits the dependence of sperm production on pituitary gonadotropin secretion by reversibly eliminating LH and FSH effects on the testis. Analogous to female hormonal contraception, this exploits the natural and reversible modulation of the mammalian reproductive system by its trophic hormones during puberty, pregnancy, and seasonality. Fully effective spermatogenic suppression, however, requires complete elimination of gonadotropin action on Sertoli cells, which necessitates complete inhibition of pituitary LH and FSH secretion to eliminate both FSH action and fully deplete intratesticular testosterone. The present study reinforces the pivotal importance of reliable gonadotropin suppression for sufficiently effective and sustained suppression of sperm output for contraception. Where gonadotropin suppression is suboptimal, sperm escape follows predictably. This highlights the need for reliability in regular hormone administration, for which depot regimens are better adapted.
The strikingly rapid initial suppression of sperm output is a distinctive feature of this combination regimen, compared with other regimens (reviewed in Ref. 1). This was confirmed by the quantitative systematic review of speed and extent of suppression of sperm output at 1 month, showing that the prototype depot combination used in this study had the fastest reported fall in sperm output at 1 month. Interestingly, the next fastest regimens also involved DMPA injections (14, 48, 49, 50), suggesting that this progestin may have distinctive properties worth further characterization. Direct inhibition of Leydig cell testosterone biosynthesis by medroxyprogesterone or its metabolites (51) could accelerate depletion of intratesticular testosterone, leading to premature spermiation (50), and may explain this dramatic initial effectiveness. Recovery of sperm output was complete for all except one man with a previously undiagnosed testicular disorder. The duration of human spermatogenesis (2.5 months) and the time to clearance of sperm from the genital tract after vasectomy (3 months) dictate that male contraceptive methods based on eliminating sperm from the ejaculate will have a similar time course as vasectomy (52), albeit relatively slower in onset and offset, compared with other modern female contraceptive methods (1, 9).
The desirability of a depot approach for hormonal male contraception follows from its greater convenience (lesser demands on compliance), higher efficacy (more reliable and predictable delivery), and safety (nonoral route). Longer, more convenient intervals between dosages reduce the demands for compliance, whether coitally or calendar-related, making it likely to ensure higher contraceptive reliability in typical use. Depot implants are the most effective form of contraception in women, rivaling sterilization in efficacy, but are reversible (9, 10). All implants require minor surgery for insertion, but nonbiodegradable depots require removal, which can create difficulties (53). Most oral contraceptive failures are due to not taking the pill on schedule, with objective recordings showing that less than 33% of oral contraceptive pills are taken on schedule (54). This is consistent with the known influence of symptomatic reinforcement and infrequent dosing in improved adherence to medication schedules. The parenteral (nonoral) routes of administration for gonadal steroid depots are likely to have superior safety profiles, as they can be more accurately dose-titrated as well as avoid first pass hepatic effects, notably for hepatic proteins such as SHBG, T4-binding globulin, clotting factors, and apolipoproteins (55, 56). For these reasons, a depot regimen with a 3- to 4-month interval between doses for a nonremovable depot would be ideal for a hormonal male contraceptive aiming for wide usage.
Although this study provides proof of principle for a depot, combination hormonal male contraceptive, the prototype regimen comprising two preexisting depot hormonal preparations is suboptimal, although feasible in specialized clinics. More convenient, purpose-developed, depot commercial products are necessary to make this combined depot hormonal approach more widely available. Although DMPA has long been used in female contraception and was among the first progestins evaluated in feasibility studies for hormonal male contraception (6), its persistence may explain the relatively slow recovery from spermatogenic suppression observed. More modern depot progestins developed for female contraception have shown promise in early studies of suppression of human spermatogenesis. For example, levonorgestrel- (17, 57) and etonogestrel (18)-releasing subdermal implants as well as depot norethisterone injections (19) have suppressed sperm output in most men. However, optimal combinations are yet to be defined before contraceptive efficacy studies can be undertaken, and the long-term safety of the higher doses of synthetic progestins required in men will also need to be defined. Improved testosterone depot preparations, such as testosterone microspheres (58, 59), testosterone undecanoate (60, 61), and 7-methyl, 19-nortestosterone (62), promise longer acting injectable androgen depots suitable for male contraceptive regimens, assuming the large injection volume is overcome. The unexpectedly shorter duration of action of testosterone implants in this study (4 months) compared with extensive experience with androgen replacement therapy in hypogonadal men (6 months) of similar age and health (22) was probably due to the approximately 15% lowering of circulating SHBG (14), which accelerates the testosterone metabolic clearance rate (47). Whether an accelerated testosterone clearance rate will be a consistent feature of progestins when combined with testosterone in contraceptive regimens is not clear, but it is more likely for oral progestins with their inevitable first pass hepatic effects, including lowering SHBG.
This study still required the unattractive feature of monthly semen monitoring. With sufficiently demonstrated predictability, practical hormonal male contraceptive regimens would dispense with regular semen monitoring and require only the verification of azoospermia, similar to conventional clearance required after vasectomy. The present study confirms that with adequate hormonal delivery, reliable suppression of sperm output can be sustained for at least 12 months and should be maintainable indefinitely as long as treatment continues. Nevertheless, suboptimal hormone delivery (including noncompliance with regular doses) could allow escape from suppression and risk contraceptive failure. The tolerance margin for noncompliance with practical combination regimens will need clarification. This study also confirms that with adequate monitoring based on the modified WHO scheme, such escapes can be detected sufficiently early that unwanted pregnancies are avoided.
The need for new male contraceptives arises from the fact that existing reliable and reversible contraception methods do not work well for all couples during the varying needs through their reproductive lives. A depot hormonal male contraceptive is intended for couples in stable relationships, whereas for men without a regular relationship, barrier methods are preferable for their dual benefits in preventing sexually transmitted disease as well as unwanted pregnancy. Likely niches would include the postpartum period (when estrogen-containing contraceptives are contraindicated during lactation), delaying vasectomy (when the children remain young), as an alternative to less reliable male methods, or when female methods are not tolerated. Despite skeptics (63, 64), recent surveys suggest that substantial proportions of men in various communities welcome (65, 66), and their women support (67), the use of a novel male contraceptive method. Although based on forced choice surveys involving a hypothetical product (24), the findings indicate a priori acceptance of hormonal male contraception in the general community of reproductive age. Further commercial development of custom-developed, second generation male contraceptive products requires industrial research and development, which has, however, languished in recent decades (42). Based on the proof of principle provided by this study, further commercial development of hormonal male contraceptive products can now be considered medically and scientifically feasible, although progress depends primarily on other factors.
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Acknowledgments |
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Footnotes |
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Abbreviations: CI, Confidence interval; DMPA, depot medroxyprogesterone acetate; PSA, prostate-specific antigen.
Received January 22, 2003.
Accepted July 2, 2003.
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References |
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-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men. Hum Reprod 14:2200–2206This article has been cited by other articles:
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), in which 41 men received 800 mg testosterone at 4-month intervals. Note the inadequate maintenance of plasma testosterone with escape of plasma LH and FSH between the fifth and sixth month on the original protocol, but not on the amended protocol. Note also the nonlinear (cube root) scale of the y-axis for sperm output. Dotted lines represent the upper and lower limits of the eugonadal reference range for young men. For further details, see text.
), 1 million/ml (•), and 3 million/ml (
). Note the entry threshold for the efficacy phase was a sperm density of less than 1 million/ml at 2 consecutive months. The dotted line represents the median time to reach the threshold, with the numerical values listed. For further details, see text.