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Abstract

A credible, reversible male contraceptive with sufficient efficacy and convenience to rival established female methods has been eagerly awaited for some years. What are the issues surrounding its development and when is a launch likely? At present, many different approaches and targets have been identified for further development. These include spermatogenesis, unique testicular proteins, immunocontraception, the vas deferens and the potential method currently closest to fruition, hormonal contraception. This is now in Phase III studies in China and commercial studies are underway in Europe.

Keywords

contraceptive acceptability eppin immunocontraception male hormonal contraception progestogens reversible inhibition of sperm under guidance selective androgen receptor modulators spermatogenesis testosterone

Women have traditionally carried the responsibility for contraception, but increasingly in recent years this emphasis has changed [1]. Many men are keen to be viewed as equally trustworthy in this regard and to play a greater role, but their options currently remain extremely limited. Vasectomy has remained a popular choice of contraception for couples that have completed their family, and condom usage is prevalent in part due to its dual function of both contraception and prevention of sexually transmitted infection, particularly in the era of HIV/AIDS; but both of these methods have considerable drawbacks which limit their appeal to, and use by a large proportion of couples requiring contraception. To redress this balance, there are currently a number of different targets being explored as potential male contraceptives. This article will briefly review the current status of both hormonal and nonhormonal approaches.

Male hormonal contraception

Currently, male hormonal contraception (MHC) is the experimental method nearest to fruition. It is based on the suppression of gonadotrophin secretion, thus removing trophic support to the testis. This results in loss of spermatogenesis, but also of testosterone production. Testosterone administration is therefore an essential component of any regimen in order to prevent hypogonadal symptoms. Specific research into this area has been undertaken over the past 25 years, but the first study to report the inhibitory effect of exogenous testosterone on spermatogenesis was reported in 1939 [2]. Following a period of investigation of a range of preparations and doses, two landmark multicenter studies by the World Health Organization (WHO) carried out in the 1980s and early 1990s truly established the principle that testosterone administration could reliably suppress spermatogenesis for effective and reversible contraception [3]. In the initial trial, azoospermia (total absence of sperm in the ejaculate) was used as the entry criterion to a 12-month efficacy phase, which was achieved by 70% of subjects (137 men) [4]. In the second trial, 357 men took part and 268 of these became azoospermic [5]. In the azoospermic group, no pregnancies in 230 person-years of use were reported. In the oligospermic group (sperm count 0.1–3.0 × 10⁶/ml), four pregnancies in 49.4 person-years were reported, giving a combined pregnancy rate of 1.4/100 person-years (confidence interval [CI]: 0.4–3.7) In both of these studies the hormonal regimen was weekly intramuscular injection of 200 mg testosterone enanthate.

For a MHC regimen to cause effective spermatogenic suppression, three basic principles should be met:

Profound suppression of both luteinizing hormone and follicle-stimulating hormone

Lowering of intratesticular testosterone concentrations

Replacement of peripheral testosterone to physiologic levels

Despite the importance of the WHO studies discussed above, the administration of exogenous testosterone alone met with mixed success. In Caucasian men administration of exogenous testosterone alone did not result in universal spermatogenic suppression. For reasons that have yet to be explained, suppression of spermatogenesis varies by ethnicity. In other ethnic groups, such as Chinese men, suppression with exogenous testosterone alone is more successful. A recent large-scale efficacy study in China appears very promising, with 296 out of 308 men achieving azoospermia or severe oligozoospermia (less than 3 × 10 sperm/ml). In addition, no pregnancies were caused by these men [6]. The overall efficacy was 94.8% and a larger Phase III study is underway. One of the drawbacks of administering exogenous testosterone alone is that supraphysiologic concentrations of the hormone are required, resulting in effects which may be adverse in the longer term, such as raised hematocrit and reduced high-density lipoprotein cholesterol concentrations [7,8]. Additionally, while universal azoospermia is the ultimate objective, it is likely that very low sperm concentrations (<1 × 10 sperm/ml) will provide excellent contraception. This has been suggested to be an acceptable goal for trials aimed at regulatory approval in the medium term [9].

Following the initial investigations of exogenous testosterone alone, many subsequent studies have been undertaken to combine administration of exogenous testosterone with other hormones in order to:

Reduce the amount of exogenous testosterone given and thereby reduce the incidence of supraphysiologic circulating exogenous testosterone levels

To achieve a better rate of adequate spermatogenic suppression, especially among Caucasian men

The two approaches to this that have been explored are the addition of a progestogen or a gonadotrophin-releasing hormone (GnRH) analog, both of which have had some success. GnRH agonists already have established uses in the management of conditions in both men and women, including prostate and breast cancer and endometriosis. In male contraceptive trials; however, they do not result in sufficient gonadotrophin and subsequent spermatogenic suppression [10,11]. GnRH antagonists; however, are more promising but their usage has been impaired by their high cost and the need for frequent injections. In two early studies using the prototype antagonist Nal-Glu, 14 of 16 participants became azoospermic [12,13]. The newer product cetrorelix has also demonstrated highly effective spermatogenic suppression [14]. Novel preparations such as tevarelix, abarelix and acyline [15 –17], which have a longer duration of action, are now becoming available. The arrival of these novel preparations offers new promise for the use of GnRH antagonists as adjunctive agents.

Progestogens are potent inhibitors of gonadotrophin secretion in men, as in women, although the physiologic significance of progesterone receptors in men is unknown. In recent years there have been favorable results reported of the use of a range of progestogens with exogenous testosterone, including those of the authors' studies investigating desogestrel and its active metabolite etonogestrel [18,19]. One such study investigated the effectiveness of desogestrel (150 or 300 μg daily) in conjunction with testosterone pellets (400 mg/12-weekly) in both Chinese and Caucasian subjects. In the lower-dose group, 22 out of 31 subjects became azoospermic, as did all of those in the higher dosage group (n = 28) [18]. A recent efficacy study from Australia combined depot medroxyprogesterone acetate with testosterone pellets and the results were very encouraging, with 53 out of 55 subjects achieving spermatogenic suppression to under 1 × 10⁶ sperm/ml, in order to enter a 12-month efficacy phase. There were no reported pregnancies in 35.5 person-years of contraceptive exposure [20]. There have also been promising results observed with other progestogens including levonorgestrel, cyproterone acetate and norethisterone [21 –23]. Currently, it appears that the progestogens make more likely candidates than GnRH antagonists for inclusion in a first-line marketable product.

Both exogenous testosterone and its adjunctive agents, progestogens and GnRH analogs, are available in a variety of delivery methods. Exogenous testosterone is currently available as short- and long-acting injectables, slow-release subcutaneous pellets, transdermal patches, cutaneous gel, oral preparations and a buccal adhesive tablet [24]. Progestogens are available as oral preparations, long-acting injectables and slow-release implants. GnRH analogs are currently only available as injectables, although there is much interest in developing orally active small molecules. There is therefore a very wide range of potential combinations of steroids and delivery methods, which paradoxically may have had a negative impact on research in this field. Many studies have only a small number of participants and the different combinations of hormones and dosages make direct comparisons difficult. A recent Cochrane review concluded that large randomized, controlled trials are necessary before any conclusions can be drawn as to which combination of preparations has superior efficacy and that most studies to date have not been adequately powered to detect potentially important differences [25].

There are currently a few promising candidates for commercial production including testosterone undecanoate (intramuscularly) alone, now under investigation in Chinese men, and the combinations of either testosterone undecanoate (intramuscularly) or exogenous testosterone pellets (subcutaneous) in conjunction with long-acting progestogens such as etonogestrel, norethisterone or depot medroxyprogesterone acetate that have been investigated in Europe and elsewhere [26]. Currently, a practical oral exogenous testosterone preparation remains unlikely due to high first-pass liver metabolism and thus a need for frequent administration.

Much of the research into the field of MHCs has to date been carried out in the public sector. Recently there has been increasing interest from pharmaceutical companies in developing a marketable product and commercial studies are currently underway [27].

Safety issues are another prime concern for product development. We do not currently fully know the implications of long-term exogenous hormone administration in normal men. From data collected during clinical trials we have been able to monitor the effect of hormone administration on physiologic parameters such as hematocrit, hemoglobin concentration, cholesterol and other lipid concentrations and body composition. These surrogates are of some value but potential effects, for example, on cardiovascular and prostate cancer risk, will require long-term postmarketing surveillance. This can potentially be balanced by trying to design some health benefits into a product, analogous to the many benefits of combined oral contraception for women. One example of this is the use of the synthetic androgen 17α-methyl-19-nortestosterone (MENT, discussed below), which is not subject to 5α-reduction and is therefore relatively less potent at the prostate.

Is there a market for this type of product? In essence; yes, the authors believe that there is. One immediate group is those men whose partners have contraindications to some of the common forms of female contraception such as the combined oral contraceptive. The widespread use of the existing male methods, despite their limitations, also undermines any suggestions that men are not or will not become involved in contraception. From acceptability studies the authors and others have shown that there are men who are keen to try this method of contraception and that their partners would trust them to do so [28 –30].

17α-methyl-19-nortestosterone

Although synthetic androgens have a very checkered safety history [31], novel preparations may have some interesting and useful features, such as selective metabolism giving degrees of tissue selectivity. One such compound is MENT. This is a potent synthetic androgen, approximately ten-times more potent than testosterone at the androgen receptor, but it is resistant to 5α-reductase. This means it is relatively less stimulatory to the prostate. However, it is aromatized and thus should be active in supporting bone mass. It has been investigated as an agent for exogenous testosterone replacement in hypogonadal men to good effect [32 –34]. However, there are concerns regarding its ability to adequately support bone mass at doses which appear to support other androgen-dependent functions [33]. It has also been demonstrated to suppress spermatogenesis when administered alone [35] and further investigations of its contraceptive potential are currently underway.

Selective androgen receptor modulators

One future option for combating the difficulties of androgen delivery for physiological replacement in MHC is the use of selective androgen receptor modulators (SARMs). The term SARM was introduced in 1999 to describe molecules that target the androgen receptor in a distinct way with tissue-specific biologic effects [36]. There has recently been rising interest in the possibility of developing selective male hormones that only target the androgen receptor in certain tissues. For example, in elderly men it may one day be possible to administer a SARM that has trophic effects on bone and muscle mass but has no significant effect on reproductive tissues [36]. SARMs have been shown to confer tissue-selective anabolic and androgenic properties in vivo and appear to possess the advantages of oral bioavailability, androgenreceptor specificity, reduced activity in the prostate, absence of steroid related side effects and the potential for structural modification [37]. Conversely it may be possible to create SARMs that exert their effect only on the hypothalamo–pituitary–testis axis [38], which would be particularly promising as a male contraceptive. One SARM, C-6, was recently tested as an oral contraceptive in male rats. It showed good oral availability, a relatively long half-life (6.3 h) and marked suppression of spermatogenesis after 10 weeks of treatment [39].

Nonhormonal methods

There are a broad range of nonhormonal methods of contraception being developed for men but most have yet to reach the clinical trial stage. The basis for this approach is the identification of targets that are specific to the tissues involved in male fertility such as within the testis, epididymis and vas deferens, and the process of spermatogenesis. The main potential advantage of this approach is that testicular hormone production would be unaffected, avoiding many of the problems of MHC, and there may also be a more rapid onset of action. However, past experience with this approach in clinical trials has not been very successful, with one apparently promising lead, gossypol, resulting in irreversible azoospermia in some men and a high incidence of significant side effects [40]. Presently, there seem to be more potential targets than research groups able to investigate them. A brief introduction to some of the most promising recent results is presented below.

Alkylated imino sugars

Alkylated imino sugars are monosaccharide analogs that inhibit enzymes involved in glycoconjugate biosynthesis and catabolism. These compounds have been developed for the treatment of glycosphingolipid lysosomal storage diseases. One of these compounds, N-butyldeoxynojirimycin, is now in clinical use for Type 1 Gaucher disease. During preclinical studies it was noticed that male mice became reversibly infertile following 3 weeks of administration of this prototype drug, whereas female mice were unaffected [41]. The reproductive effects of N-butyldeoxynojirimycin and another agent, N-butyldeoxygalactonojirimycin, have been further investigated in male mice. Although sperm morphology and physiology are altered the sperm remain genetically intact [42], which is an important safety consideration.

Immunocontraception

There is a large variety of potential targets in the male for immunocontraception, including follicle-stimulating hormone and GnRH, sperm-specific antigens, and epididymal proteins. Immunization against follicle-stimulating hormone in monkeys has not proved to be very encouraging, demonstrating variable efficacy with some individuals becoming inconsistently azoospermic and others having a sperm concentration that remained in the normal range [43,44].

An example of using a testicular/epididymal approach is the use of immunization against the protease eppin as a nonhormonal contraceptive. Eppin is expressed only in the testis, epididymis and by sperm. A total of seven out of nine bonnet monkeys immunized against eppin demonstrated high antibody titers and all of these seven monkeys failed to impregnate known fertile females. Sperm production was not affected, the mechanism of action is believed to be a specific impairment of sperm motility. However, only five out of the seven monkeys regained their fertility following cessation of immunization [45], leading to concerns about the reversibility of this approach to contraceptive development.

Sperm targets

A family of ion channel proteins unique to mature sperm have been identified, known as cation channel of sperm (CatSper). CatSper 1 initiates calcium influx into the principal piece of the sperm tail, which is required for sperm motility [46]. Male mice with significant mutations in the CatSper 1 gene are infertile but appear to be otherwise normal [47]. Other family members have been identified and are under investigation [48].

Vas deferens targets

A variety of vas occlusives have been investigated with the hope of producing a readily reversible male contraceptive. Traditional vasectomy is a highly effective form of contraception but its reversibility is not intended or guaranteed, nor is that of the slightly less invasive no-scalpel vasectomy technique. No-scalpel vasectomy is a new adaptation that utilizes specially designed pointed forceps to effect skin puncture and hold the vas. A number of bio-medical devices have been developed in the hope that they can provide a reversible method of male contraception including wires, injectable and insertable plugs, a t-shaped control valve and other intraluminal devices [49]. One of the most promising of these agents is reversible inhibition of sperm under guidance (RISUG), a copolymer of styrene maleic anhydride in a solvent vehicle, which has undergone extensive testing in man. While not preventing sperm production, it appears to destroy sperm as they pass, causing ‘necrozoospermia’ rather than azoospermia. During a Phase II trial, 25 men in India had this agent injected into the vas lumen bilaterally and all showed the absence of viable sperm, in most within 2 months of administration [50]. Previous studies have confirmed nontoxicity and reversibility in monkeys [51,52]. A Phase III clinical trial in man is currently ongoing [49]. The intravas device formerly known as the Shug, (an insertable plug) has also entered clinical trials.

Conclusion

MHC is now making significant progress and the results of large-scale and commercially funded studies currently underway will provide further information vital to future development. In this brief article we have covered fully the large number of potential avenues for development of nonhormonal contraceptives, but many of those described show promise. There are distinct advantages to a nonhormonal method and it is expected that further advances in this field will allow clinical trials to be undertaken.

Future perspective

The development of contraceptive methods targeted at men has been very much the poor relation. While there are clear reasons why this has been so, there has been a steady increase in interest in male methods from the public and now the pharmaceutical industry. It is likely that in a few years, couples will be able to choose a hormonal male method. Nonhormonal methods are further off, but it is hoped that once MHC has become established, this will provide a significant spur to the development of a wide range of different methods that will appeal to more couples, more of the time.

Executive summary

Acceptability

It has been established by questionnaire studies in a range of countries that there is a market for a new male contraceptive agent.

Male hormonal contraception

Currently the most likely contender for commercial reality in the next few years.

A long-acting product (i.e., an implant or depot injection) will probably be available before an oral preparation, although there appears to be a market for both.

The most promising combination is of a progestogen with physiologic testosterone replacement.

The present involvement of the pharmaceutical industry greatly raises hopes for the rapid development of a product.

Nonhormonal contraception

Many promising targets have been identified.

Of these, reversible inhibition of sperm under guidance and the intravas device are in clinical trials and show promise. Very few of the other approaches have yet to reach the stage of clinical trials, therefore the commercial reality for any that survive the rigors of the drug development process is many years away.

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Contraceptive Choices: Is the Future with Men?

Abstract

Keywords

Male hormonal contraception

17α-methyl-19-nortestosterone

Selective androgen receptor modulators

Nonhormonal methods

Alkylated imino sugars

Immunocontraception

Sperm targets

Vas deferens targets

Conclusion

Future perspective

References