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Hormonal approaches to male contraception: Approaching reality
Molecular and Cellular Endocrinology 250 (2006) 2–7
Hormonal approaches to male contraception: Approaching reality Frederick C.W. Wu ∗ Department of Endocrinology, Manchester Royal Infirmary, University of Manchester, Oxford Rd, Manchester M13 9WL, United Kingdom
Abstract The ‘pre-testicular’ suppression of gonadotrophins is the most likely approach for reversible therapeutic male fertility control to reach imminent clinical application. Maintenance of spermatogenesis depends on adequate gonadotrophin and intratesticular testosterone concentrations. Hormonal contraception for men interrupts this physiological axis by various means of gonadotrophin suppression; this interferes with spermatogonial differentiation and meiosis entry resulting in reversible azoospermia or severe oligozoospermia in virtually all men. Clinical trials have confirmed that high contraceptive efficacy, similar to female hormonal contraceptives, can be reliably attained with few side effects. However, the simultaneous suppression of Leydig cell steroidogenesis mandates the requirement for testosterone replacement in hormonal male contraception. Combination regimens of new synthetic progestins and androgens at various stages of development are being investigated with the lead products poised to go into phase III trials. Heterogeneity in response to spermatogenesis suppression has been observed within and between population; the mechanisms are unclear. This new method of reversible and effective contraception has registered high acceptability in surveys of both men and women. The recent entry of pharmaceutical companies into this area of research and development has considerably enhanced the prospects of translating years of academic efforts into new products which provide added family planning choice for many couples. © 2006 Published by Elsevier Ireland Ltd. Keywords: Contraception; Androgens; Testosterone; Progestins; Hormonal contraception; Spermatogenesis
1. Introduction That one third of couples worldwide (and 41% in the UK in 2001) chooses a male contraceptive method is a testament to substantial male participation in family planning. Yet only two options are currently available to men: a reversible method (condom) that is not reliable and the only reliable method (vasectomy) that is generally not reversible. While younger men without a regular partner are best served by the dual protection against sexually transmitted infections and unintended pregnancy offered by condoms, there is a real and substantial unmet need for men in stable relationships eager to share the responsibility for family planning. In this respect, a new reversible male method as reliable as modern female products will significantly expand the currently limited choice and encourage increased contraceptive uptake and continuation in men. In principle, the series of unique cell types, biologically processes and gonad-specific genes that underlie the physiological functions of the testis (spermatogenesis, spermiogenesis, spermiation), epididymis (sperm volume regulation, surface membrane protein interaction and acquisition of motility), and the
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ejaculated spermatozoa in the female genital tract (acrosome reaction, egg recognition/binding/fusion) should provide numerous potential opportunities for contraceptive targeting. Indeed, in the last decade, an increasing range of key genes and molecules have been identified from knockout animal models of infertility which could provide theoretical candidates for potential contraceptive development (Matzuk and Lamb, 2002). However, the enormous economic investment required in developing preventative medications in the current drug regulatory climate, excessive liability risks and relative lack of public funding all conspire to make it unlikely that completely novel contraceptive products will emerge from basic science leads in the foreseeable future. In contrast, hormone contraception for men relies mainly on off the shelf (and often forgotten) compounds and formulations, some of which have good safety profiles from many years of clinical use in androgen replacement and in female contraception. This relatively ‘low-tech’ approach, bypassing or expediting some of the obstacles inherent to the development of completely new agents, offer realistic prospects of marketing a new reversible and effective contraceptive product within a reasonable time span. Such a method would instantly broaden the contraceptive options for men who seek alternatives to female methods used for many years by their partners, who may have developed side effects, medical contra-indications or simply wish a break; men
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whose partners are lactating in the post-partum period and for those who are undecided or wish to defer vasectomy (Anderson and Baird, 2002). 2. Mechanism of action The aim of male hormonal contraception is to suppress/arrest spermatogenesis reversibly and induce temporary infertility while preserving other androgen-dependent physiological functions without unwanted metabolic effects. Spermatogenesis is regulated by pituitary gonadotrophins (LH and FSH). FSH is required specifically for sertoli cells’ support of the mitotic and meiotic germ cells while testosterone (T) synthesis by the Leydig cells is stimulated by LH. Both FSH and high concentrations of intra-testicular T (as a proxy for LH action) are critical to the quantitative maintenance of spermatogenesis in the adult testis, the actions of both being to some extent interchangeable when either one of the two signals is abrogated. It follows that for the purpose of hormonal contraception, both FSH as well as LH have to be suppressed concurrently in order to turn off spermatogenesis through the intra-testicular testosterone deprivation and FSH deficiency. The sites of spermatogenesis disruption may include (1) a block in the differentiation of type Ap spermatogonia to type B spermatogonia, which diminishes the number of spermatocytes going into meiosis and spermiogenesis; (2) failure of spermiation and (3) increased apoptosis of spermatocytes and spermatids during meiosis (McLachlan et al., 2002; De Gendt et al., 2004). It is fortuitous and fortunate that virtually all known therapeutic anti-gonadotrophic agents (e.g. androgens, oestrogens, progestins and GnRH analogues) suppress both FSH and LH simultaneously. Thus, hormonal male contraception will create a state of iatrogenic hypogonadotrophic hypogonadism which dictates the use of exogenous androgens (5–7 mg daily) to maintain extra-testicular androgendependent physiological functions, somewhat analogous to the use of oetrogens (50–200 g daily) to provide and regulate menstrual cyclicity in the female combined oral contraceptive pill. In the last 20 years, many phase 1 and 2 dose-finding and proof of principle studies have investigated the efficacy of spermatogenesis suppression and, to a lesser extent contraceptive efficacy (Anderson and Baird, 2002; Kamischke and Nieschlag, 2004). These included androgen-only regimes and androgen combinations with other agents, i.e. progestins and GnRH analogues. 3. Contraceptive regimes 3.1. Androgen only Most early studies have used testosterone alone because of the expediency that gonadotrophin suppression and androgen replacement can be achieved with a single agent. However, oral bioavailability of unmodified testosterone is poor because of hepatic first-pass metabolism and orally active 17 ␣-alkylated testosterone analogues are hepatotoxic. The daily physiological requirement for milligram amounts of testosterone in men can
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only be achieved with depot preparations of injectable testosterone esters or implantable testosterone pellets. 3.1.1. Testosterone enanthate (TE) Intramuscular preparations of esterified testosterone such as TE, is the most commonly-used preparation for physiological androgen replacement therapy in adult hypogonadal patients at a dose of 200 mg every 2 weeks (transdermal and other newer preparations have only become available in the last few years). Early studies in the 1970s have shown that, for suppression of gonadotrophins and spermatogenesis in eugonadal men, doses of TE higher than that for physiological replacement are required. Two landmark multi-national studies sponsored by the World Health Organisation Special Programme of Research, Development, and Research Training in Human Reproduction (Waites, 2003) were conducted between 1986 and 1995 using weekly intra-muscular injections of 200 mg of TE as a prototype male contraceptive to determine the contraceptive efficacy of hormone-induced azoospermia and oligozoospermia. They confirmed that supraphysiological doses of testosterone induced azoospermia in 60% of Caucasian but in 91% of oriental subjects, the remainder becoming severely oligozoospermic with mean sperm concentrations of around 3 million/ml (World Health Organization, 1990). During the 403.7 person-years of exposure accumulated from 655 subjects in 15 centres distributed in 10 countries, a relationship between sperm concentration (the extent of spermatogenesis suppression) and pregnancy rate (contraceptive failure) was demonstrated for the first time. The pregnancy rate for azoospermia was 0.8 (95% confidence interval (CI) 0.02–4.5) per 100 person-years in the first study. In the second study, the pregnancy rate was 0 (95% CI 0–1.6) for azoospermia and 8.1 (95% CI 2.2–20.7) per 100 personyears for oligozoospermia (0.1–3.0 million/ml). The combined failure rate for men with sperm concentrations in the range of 0–3 million/ml was 1.4 (95% CI 0.4–3.7) pregnancies per 100 person-years (World Health Organisation, 1990, 1996), which is comparable to the female oral contraceptive pill and better than the typical first year failure rate of condoms (12%). These important proof-of-principle studies demonstrated that hormonal suppression of spermatogenesis can provide effective and reversible contraception for men with few adverse events. They also suggested that targets of suppression to ensure effective contraceptive protection are either azoospermia or severe oligozoospermia (<1 million/ml). The prototype regime of weekly intramuscular injections of TE highlighted major drawbacks in the androgen-only approach, namely (1) unsatisfactory pharmacokinetics of injectable testosterone esters, available at that time, resulted in widely fluctuating levels of testosterone with frequent supraphysiological peaks; (2) frequent injections were required to prevent troughs falling to levels that allow breakthrough of suppression; (3) relatively high doses of testosterone required to induce and maintain adequate suppression of spermatogenesis were the likely cause of androgen-dependent side effects including acne, weight gain, behavioural change, decreased high density lipoprotein–cholesterol (HDL–C) and increased haemopoiesis. For these reasons longer acting testosterone preparations with
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improved pharmacokinetics and alternative strategies using combinations with other anti-gonadotrophic agents were sought. 3.1.2. Testosterone implants Pellets of crystalline testosterone (one 200 mg pellet releasing 1.3 mg/day) inserted surgically into the subcutaneous tissue of the lower abdominal wall under local anaesthetic have been used for androgen replacement since the 1950s. The quasi zeroorder pharmacokinetics of testosterone implants, maintaining stable testosterone levels for many weeks without supraphysiological peaks, can be exploited to confer dose-sparing advantages in achieving hormonal suppression of spermatogenesis. Thus, a single implantation of 1200 mg (six pellets) has been shown to induce and maintain azoospermia and oligozoospermia for 16 weeks with similar efficacy to TE alone (200 mg weekly), while physiological testosterone levels prevented most androgen-related metabolic side effects (Handelsman et al., 1992). This demonstrated the critical importance of pharmacokinetic properties of androgen formulations in male contraceptive development. 3.1.3. Testosterone undecanoate (TU) TU is an unsaturated ester of testosterone with a long hydrophobic aliphatic fatty acid side chain which renders it highly fat-soluble. Formulation of TU in tea seed oil (125 mg/ml in China) and castor oil (NebidoTM 250 mg/ml, Jenapharm/Schering, Germany) yielded long-acting depot preparations for intra-muscular use. TU (in castor oil) has a long half-life of 70 days with more stable pharmacokinetics when administered at 4–8 weekly intervals. TU (in tea seed oil) 500 mg monthly i.m. can induce azoospermia or oligozoospermia (<3 million/ml) in 97% of Chinese subjects with high contraceptive efficacy (one pregnancy, in 143 personyears exposure-failure rate of 2.3 (95% CI 0.5–4.2) per 100 couple-years) (Gu et al., 2003). These encouraging results are being followed-up by phase 3 studies involving >1000 men in 10 centres in China where a new and more concentrated formulation of TU in soybean oil (250 mg/ml) is also under investigation.
study, four sub-dermal MENT acetate implants (each delivering 400 g/day) have been shown to suppress gonadotrophins and induce azoospermia in 64% of men with a suggestion of reduction in prostate volume by 10–17% after 6 months (von Eckardstein et al., 2003). 3.1.6. Summary The androgen-only approach to male hormonal contraception is attractive conceptually and proof-of-principle studies have confirmed the feasibility of this approach, especially in oriental men. The efficacy, however, is significantly lower in Caucasian men. While newer testosterone formulations may avoid the relatively high dose of older testosterone esters required to suppress spermatogenesis, the spectre of long-term androgen-related side effects remains a significant disincentive to product development unless synthetic androgens with desirable tissue selectivity can be seriously explored. 3.2. Progestin/androgen combinations Exogenous progestins can inhibit gonadotrophin secretion in men, and suppress spermatogenesis. Combining a progestin with androgens for male contraception exploits the synergistic actions of the two steroids so that they can be used at lower doses thus minimising the potential for side effects. The plethora of available synthetic progestin preparations, including oral, injectable and implants, also serves to broaden the choice of potential regimes. Some of the more interesting progestogen/androgen combinations studied to date is summarised. 3.2.1. Depot medroxyprogesterone acetate (DMPA) DMPA has been combined with 19-nortestosterone (19-NT), TE and T implants. Studies with 19-NT and TE in combination with DMPA in Indonesian men documented azoospermia rates of 98%. In Caucasian men the combination of DMPA with T implants achieved lower azoospermia rates similar to TE alone (Handelsman et al., 1996). The main limitation of DMPA is the prolonged period (>6 months) necessary for spermatogenesis recovery following cessation of treatment.
3.1.4. Transdermal testosterone preparations Several novel transdermal delivery systems (patches and gels) of testosterone have become available recently. While selfadministration and maintenance of physiological testosterone blood levels offer obvious convenience and advantages in androgen replacement for hypogonadism, the requirement for daily application and higher levels of variability in skin absorption raises an important issue of compliance not to mention the high incidence of skin irritation with the reservoir patch. Unsurprisingly, transdermal testosterone on its own has not been investigated as a potential contraceptive formulation.
3.2.2. Cyproterone acetate (CPA) CPA combines anti-gonadotrophic and anti-androgenic properties which may be particularly favourable for suppression of spermatogenesis. Oral CPA at doses of 25–100 mg combined with TE induces rapid suppression of spermatogenesis with the time taken to achieve azoospermia being significantly shorter compared to that with TE alone (49 days versus 98 days) (Meriggiola et al., 2003). Whilst encouraging, a dose-dependent decrease in haemoglobin and body weight related to the antiandrogen action of CPA and the potential for hepatic dysfunction limit the prospects of this combination.
3.1.5. 7α-Methyl-19-nortestosterone (MENT) MENT is a highly potent synthetic androgen which is resistant to 5␣-reductase but sensitive to aromatase. This metabolic idiosyncracy underlies the tissue selectivity which confers a prostate sparing profile. In a preliminary dose-finding
3.2.3. Levonorgestrel (LNG) LNG has been extensively studied in combination with a variety of androgens. Initially a dose of 500 g daily with TE 100 mg weekly confirmed greater sperm suppression than with TE alone (azoospermia 67% versus 33%) (Bebb et al.,
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1996). Further study with lower doses of LNG (250 and 125 g) did not compromise suppression rates (Anawalt et al., 1999). Metabolic effects were dose dependent and included lowered HDL–cholesterol and weight gain. Oral LNG 250 g daily and i.m. TU 1000 mg 6-weekly in combination have been compared to TU 1000 mg 6-weekly alone. There was no difference in suppression to azoospermia (50–57%) (Kamischke et al., 2000) suggesting that the addition of LNG did not confer any advantage. Testosterone patches have been combined with oral LNG (125 g daily) and long-acting LNG implants (four rods Norplant II) (Gonzalo et al., 2002). Relatively poor sperm suppression (severe oligozoospermia in <60%) probably relates to the unreliable administration or absorption of T so that circulating levels in the low normal range only can be achieved. This highlights the critical role of testosterone as a necessary suppressor of gonadotrophins in combination contraceptive regimes in addition to its role in androgen replacement. 3.2.4. Desogestrel (DSG) and etonogestrel (ENG) DSG is an oral third generation synthetic progestin with potent progestational activity but lower androgenicity. These potentially favourable properties led to the study of desogestrel in combination with TE. Oral DSG 300 g in combination with various TE doses produced a high rate of azoospermia (Wu et al., 1999). A lowering of HDL–C of 20–25% was observed. A cross-national study confirmed that DSG (150 or 300 g daily) in combination with 400 mg testosterone implants (every 12 weeks) can induce azoospermia in virtually all men in the 300 g group with a significant decline in HDL–C in Caucasian men only (Kinniburgh et al., 2002). ENG is the active metabolite converted by the liver from DSG with dose-equivalent biopotency. ENG has been formulated as a subdermal non-biodegradable implant for female contraception (Implanon® , NV, Organon). Three ENG rods (68 mg ENG per rod) in combination with T implants (400 mg every 12 weeks) (Brady et al., 2004). All nine men became azoospermic, although the time to achieve this varied from 8 to 28 weeks and one subject showed partial recovery after 40 weeks. Treatment did not result in weight gain, change in body composition or decline in HDL–cholesterol. Further study of this promising progestin implant in combination with TU injections is in progress. This effort not only represents the beginnings of public/private collaboration but also indicates for the first time a willingness of industry to invest in hormonal contraceptive products for men. 3.2.5. Norethisterone enanthate Norethisterone (NET) is an androgenic progestin which can be delivered as NET enanthate (NETE), an i.m. aqueous depot preparation available in Europe for female contraception. NETE 400 mg and TU 1000 mg administered at 6-weekly intervals (Kamischke et al., 2002) induced azoospermia in 92% of men. Moderate increases in haemoglobin (within the normal range) and decreases in HDL–C were observed. Dosing interval of the two steroids can be prolonged to 8-weekly without losing efficacy (Meriggiola et al., 2005). This promising regime consisting of two long-acting depot injectable preparations is being further investigated in planned multi-centre studies.
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3.2.6. Summary There is a perception that progestin and androgen combinations are more effective than T alone (Nieschlag et al., 2003), possibly related to an additional action of the progestins in the testis, and therefore, more suited to Caucasians who are less responsive to steroid suppression. However, the small numbers of subjects and relatively short duration of treatment make valid comparisons between regimes difficult, thus limiting the generalisability of these studies. The potential of progestin-related side effects (short- and long-term) merits greater attention. Current research efforts sponsored by industry are directed towards developing a combination of long-acting depot testosterone injections and progestin implants or injections as the first contraceptive product to be marketed. 3.3. GnRH antagonists GnRH antagonists are competitive blockers of GnRH receptor binding and suppress gonadotrophins within 24 h. Studies have shown very rapid spermatogenic suppression with a high rate of azoospermia. Whilst these complex synthetic peptides clearly have contraceptive potential (main advantage being faster suppression than sex steroids), the disadvantages are their high cost, short half-life and the need for frequent subcutaneous injection. Side effects encountered have included local skin reactions at the site of injection. When the GnRH antagonist Nal-Glu and TE were used to initiate spermatogenic suppression, this could then be maintained with TE alone (Swerdloff et al., 1998). New long-acting depot preparations of potent GnRH antagonists may therefore, have a place in male contraception where rapid induction of spermatogenic suppression can subsequently be maintained by testosterone with or without progestins. 4. Ethnic differences There are clear ethnic differences in the response to sex steroid suppression of spermatogenesis between Asian (more responsive) compared to Caucasian men (less responsive) independent of anthropometry and circulating hormone levels. In studies using androgens alone (TE and TU) azoospermia was achieved in >90% of Asian men versus <60% of European or American men. The potential explanations for these differences may include genetic (Wang et al., 1998) and dietary/environmental factors (Santner et al., 1998; Wang et al., 2005) that are not yet fully understood. Intra-ethnic variation is also seen within Caucasian populations. Only 40–60% of men usually suppress to azoospermia while others remain oligozoospermic in response to sex steroids. Gonadotrophindependent and -independent factors have been suggested (Handelsman et al., 1995; McLachlan et al., 2004) but the exact mechanism(s) evades current understanding. 5. Conclusions There is evidence to support couple dissatisfaction with currently available contraceptive methods and choice. A cross-
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cultural survey also found that women felt the contraceptive burden too frequently falls to them and they welcomed the availability of a reversible male contraceptive for which they trust their partners to take (Glasier et al., 2000; Martin et al., 2000). An important aspect of the male hormonal method is the variable and relatively long (8–10 weeks) time lag after commencing treatment until sperm suppression is sufficient for effective contraceptive. However, a similar lag time also applies to vasectomy (irreversible) and a lag of 1 month applies to the female oral contraceptive pill. Another potential drawback is the need for semen analysis to signal sufficient suppression of sperm count, although this can be simplified in future with self-administered dipsticks methods or even dispensed with altogether with more clinical experience in the field. Public-funded research has reached a stage where realisation of male hormonal contraception is within our reach and the pharmaceutical industry is beginning to embark on the necessary steps leading to product development. A progestogen/androgen combination is most likely to be the first product to be marketed. Further development of long-acting depot formulations or oral and non-steroidal compounds will provide a variety of contraceptive formulations that will allow men to have a widened choice, improve acceptability and encourage continued usage. References Anonymous, 1990. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet 336, 955–959. Anonymous, 1996. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil. Steril. 65, 821–829. Anawalt, B.D., Bebb, R.A., Bremner, W.J., Matsumoto, A.M., 1999. A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations. J. Androl. 20, 407–414. Anderson, R.A., Baird, D.T., 2002. Male contraception. Endocr. Rev. 23, 735–762. Bebb, R.A., Anawalt, B.D., Christensen, R.B., Paulsen, C.A., Bremner, W.J., Matsumoto, A.M., 1996. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J. Clin. Endocrinol. Metab. 81, 757–762. Brady, B.M., Walton, M., Hollow, N., Kicman, A.T., Baird, D.T., Anderson, R.A., 2004. Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception. Hum. Reprod. 19, 2658–2667. De Gendt, K., Swinnen, J.V., Saunders, P.T., Schoonjans, L., Dewerchin, M., Devos, A., Tan, K., Atanassova, N., Claessens, F., Lecureuil, C., Heyns, W., Carmeliet, P., Guillou, F., Sharpe, R.M., Verhoeven, G., 2004. A sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc. Natl. Acad. Sci. USA 101, 1327–1332. Glasier, A.F., Anakwe, R., Everington, D., Martin, C.W., van der Spuy, Z., Cheng, L., Ho, P.C., Anderson, R.A., 2000. Would women trust their partners to use a male pill? Hum. Reprod. 15, 646–649. Gonzalo, I.T., Swerdloff, R.S., Nelson, A.L., Clevenger, B., Garcia, R., Berman, N., Wang, C., 2002. Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination with transdermal and injectable testosterone. J. Clin. Endocrinol. Metab. 87, 3562– 3572. Gu, Y.Q., Wang, X.H., Xu, D., Peng, L., Cheng, L.F., Huang, M.K., Huang, Z.J., Zhang, G.Y., 2003. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J. Clin. Endocrinol. Metab. 88, 562–568.
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Hormonal approaches to male contraception: Approaching reality Frederick C.W. Wu ∗ Department of Endocrinology, Manchester Royal Infirmary, University of Manchester, Oxford Rd, Manchester M13 9WL, United Kingdom
Abstract The ‘pre-testicular’ suppression of gonadotrophins is the most likely approach for reversible therapeutic male fertility control to reach imminent clinical application. Maintenance of spermatogenesis depends on adequate gonadotrophin and intratesticular testosterone concentrations. Hormonal contraception for men interrupts this physiological axis by various means of gonadotrophin suppression; this interferes with spermatogonial differentiation and meiosis entry resulting in reversible azoospermia or severe oligozoospermia in virtually all men. Clinical trials have confirmed that high contraceptive efficacy, similar to female hormonal contraceptives, can be reliably attained with few side effects. However, the simultaneous suppression of Leydig cell steroidogenesis mandates the requirement for testosterone replacement in hormonal male contraception. Combination regimens of new synthetic progestins and androgens at various stages of development are being investigated with the lead products poised to go into phase III trials. Heterogeneity in response to spermatogenesis suppression has been observed within and between population; the mechanisms are unclear. This new method of reversible and effective contraception has registered high acceptability in surveys of both men and women. The recent entry of pharmaceutical companies into this area of research and development has considerably enhanced the prospects of translating years of academic efforts into new products which provide added family planning choice for many couples. © 2006 Published by Elsevier Ireland Ltd. Keywords: Contraception; Androgens; Testosterone; Progestins; Hormonal contraception; Spermatogenesis
1. Introduction That one third of couples worldwide (and 41% in the UK in 2001) chooses a male contraceptive method is a testament to substantial male participation in family planning. Yet only two options are currently available to men: a reversible method (condom) that is not reliable and the only reliable method (vasectomy) that is generally not reversible. While younger men without a regular partner are best served by the dual protection against sexually transmitted infections and unintended pregnancy offered by condoms, there is a real and substantial unmet need for men in stable relationships eager to share the responsibility for family planning. In this respect, a new reversible male method as reliable as modern female products will significantly expand the currently limited choice and encourage increased contraceptive uptake and continuation in men. In principle, the series of unique cell types, biologically processes and gonad-specific genes that underlie the physiological functions of the testis (spermatogenesis, spermiogenesis, spermiation), epididymis (sperm volume regulation, surface membrane protein interaction and acquisition of motility), and the
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ejaculated spermatozoa in the female genital tract (acrosome reaction, egg recognition/binding/fusion) should provide numerous potential opportunities for contraceptive targeting. Indeed, in the last decade, an increasing range of key genes and molecules have been identified from knockout animal models of infertility which could provide theoretical candidates for potential contraceptive development (Matzuk and Lamb, 2002). However, the enormous economic investment required in developing preventative medications in the current drug regulatory climate, excessive liability risks and relative lack of public funding all conspire to make it unlikely that completely novel contraceptive products will emerge from basic science leads in the foreseeable future. In contrast, hormone contraception for men relies mainly on off the shelf (and often forgotten) compounds and formulations, some of which have good safety profiles from many years of clinical use in androgen replacement and in female contraception. This relatively ‘low-tech’ approach, bypassing or expediting some of the obstacles inherent to the development of completely new agents, offer realistic prospects of marketing a new reversible and effective contraceptive product within a reasonable time span. Such a method would instantly broaden the contraceptive options for men who seek alternatives to female methods used for many years by their partners, who may have developed side effects, medical contra-indications or simply wish a break; men
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whose partners are lactating in the post-partum period and for those who are undecided or wish to defer vasectomy (Anderson and Baird, 2002). 2. Mechanism of action The aim of male hormonal contraception is to suppress/arrest spermatogenesis reversibly and induce temporary infertility while preserving other androgen-dependent physiological functions without unwanted metabolic effects. Spermatogenesis is regulated by pituitary gonadotrophins (LH and FSH). FSH is required specifically for sertoli cells’ support of the mitotic and meiotic germ cells while testosterone (T) synthesis by the Leydig cells is stimulated by LH. Both FSH and high concentrations of intra-testicular T (as a proxy for LH action) are critical to the quantitative maintenance of spermatogenesis in the adult testis, the actions of both being to some extent interchangeable when either one of the two signals is abrogated. It follows that for the purpose of hormonal contraception, both FSH as well as LH have to be suppressed concurrently in order to turn off spermatogenesis through the intra-testicular testosterone deprivation and FSH deficiency. The sites of spermatogenesis disruption may include (1) a block in the differentiation of type Ap spermatogonia to type B spermatogonia, which diminishes the number of spermatocytes going into meiosis and spermiogenesis; (2) failure of spermiation and (3) increased apoptosis of spermatocytes and spermatids during meiosis (McLachlan et al., 2002; De Gendt et al., 2004). It is fortuitous and fortunate that virtually all known therapeutic anti-gonadotrophic agents (e.g. androgens, oestrogens, progestins and GnRH analogues) suppress both FSH and LH simultaneously. Thus, hormonal male contraception will create a state of iatrogenic hypogonadotrophic hypogonadism which dictates the use of exogenous androgens (5–7 mg daily) to maintain extra-testicular androgendependent physiological functions, somewhat analogous to the use of oetrogens (50–200 g daily) to provide and regulate menstrual cyclicity in the female combined oral contraceptive pill. In the last 20 years, many phase 1 and 2 dose-finding and proof of principle studies have investigated the efficacy of spermatogenesis suppression and, to a lesser extent contraceptive efficacy (Anderson and Baird, 2002; Kamischke and Nieschlag, 2004). These included androgen-only regimes and androgen combinations with other agents, i.e. progestins and GnRH analogues. 3. Contraceptive regimes 3.1. Androgen only Most early studies have used testosterone alone because of the expediency that gonadotrophin suppression and androgen replacement can be achieved with a single agent. However, oral bioavailability of unmodified testosterone is poor because of hepatic first-pass metabolism and orally active 17 ␣-alkylated testosterone analogues are hepatotoxic. The daily physiological requirement for milligram amounts of testosterone in men can
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only be achieved with depot preparations of injectable testosterone esters or implantable testosterone pellets. 3.1.1. Testosterone enanthate (TE) Intramuscular preparations of esterified testosterone such as TE, is the most commonly-used preparation for physiological androgen replacement therapy in adult hypogonadal patients at a dose of 200 mg every 2 weeks (transdermal and other newer preparations have only become available in the last few years). Early studies in the 1970s have shown that, for suppression of gonadotrophins and spermatogenesis in eugonadal men, doses of TE higher than that for physiological replacement are required. Two landmark multi-national studies sponsored by the World Health Organisation Special Programme of Research, Development, and Research Training in Human Reproduction (Waites, 2003) were conducted between 1986 and 1995 using weekly intra-muscular injections of 200 mg of TE as a prototype male contraceptive to determine the contraceptive efficacy of hormone-induced azoospermia and oligozoospermia. They confirmed that supraphysiological doses of testosterone induced azoospermia in 60% of Caucasian but in 91% of oriental subjects, the remainder becoming severely oligozoospermic with mean sperm concentrations of around 3 million/ml (World Health Organization, 1990). During the 403.7 person-years of exposure accumulated from 655 subjects in 15 centres distributed in 10 countries, a relationship between sperm concentration (the extent of spermatogenesis suppression) and pregnancy rate (contraceptive failure) was demonstrated for the first time. The pregnancy rate for azoospermia was 0.8 (95% confidence interval (CI) 0.02–4.5) per 100 person-years in the first study. In the second study, the pregnancy rate was 0 (95% CI 0–1.6) for azoospermia and 8.1 (95% CI 2.2–20.7) per 100 personyears for oligozoospermia (0.1–3.0 million/ml). The combined failure rate for men with sperm concentrations in the range of 0–3 million/ml was 1.4 (95% CI 0.4–3.7) pregnancies per 100 person-years (World Health Organisation, 1990, 1996), which is comparable to the female oral contraceptive pill and better than the typical first year failure rate of condoms (12%). These important proof-of-principle studies demonstrated that hormonal suppression of spermatogenesis can provide effective and reversible contraception for men with few adverse events. They also suggested that targets of suppression to ensure effective contraceptive protection are either azoospermia or severe oligozoospermia (<1 million/ml). The prototype regime of weekly intramuscular injections of TE highlighted major drawbacks in the androgen-only approach, namely (1) unsatisfactory pharmacokinetics of injectable testosterone esters, available at that time, resulted in widely fluctuating levels of testosterone with frequent supraphysiological peaks; (2) frequent injections were required to prevent troughs falling to levels that allow breakthrough of suppression; (3) relatively high doses of testosterone required to induce and maintain adequate suppression of spermatogenesis were the likely cause of androgen-dependent side effects including acne, weight gain, behavioural change, decreased high density lipoprotein–cholesterol (HDL–C) and increased haemopoiesis. For these reasons longer acting testosterone preparations with
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improved pharmacokinetics and alternative strategies using combinations with other anti-gonadotrophic agents were sought. 3.1.2. Testosterone implants Pellets of crystalline testosterone (one 200 mg pellet releasing 1.3 mg/day) inserted surgically into the subcutaneous tissue of the lower abdominal wall under local anaesthetic have been used for androgen replacement since the 1950s. The quasi zeroorder pharmacokinetics of testosterone implants, maintaining stable testosterone levels for many weeks without supraphysiological peaks, can be exploited to confer dose-sparing advantages in achieving hormonal suppression of spermatogenesis. Thus, a single implantation of 1200 mg (six pellets) has been shown to induce and maintain azoospermia and oligozoospermia for 16 weeks with similar efficacy to TE alone (200 mg weekly), while physiological testosterone levels prevented most androgen-related metabolic side effects (Handelsman et al., 1992). This demonstrated the critical importance of pharmacokinetic properties of androgen formulations in male contraceptive development. 3.1.3. Testosterone undecanoate (TU) TU is an unsaturated ester of testosterone with a long hydrophobic aliphatic fatty acid side chain which renders it highly fat-soluble. Formulation of TU in tea seed oil (125 mg/ml in China) and castor oil (NebidoTM 250 mg/ml, Jenapharm/Schering, Germany) yielded long-acting depot preparations for intra-muscular use. TU (in castor oil) has a long half-life of 70 days with more stable pharmacokinetics when administered at 4–8 weekly intervals. TU (in tea seed oil) 500 mg monthly i.m. can induce azoospermia or oligozoospermia (<3 million/ml) in 97% of Chinese subjects with high contraceptive efficacy (one pregnancy, in 143 personyears exposure-failure rate of 2.3 (95% CI 0.5–4.2) per 100 couple-years) (Gu et al., 2003). These encouraging results are being followed-up by phase 3 studies involving >1000 men in 10 centres in China where a new and more concentrated formulation of TU in soybean oil (250 mg/ml) is also under investigation.
study, four sub-dermal MENT acetate implants (each delivering 400 g/day) have been shown to suppress gonadotrophins and induce azoospermia in 64% of men with a suggestion of reduction in prostate volume by 10–17% after 6 months (von Eckardstein et al., 2003). 3.1.6. Summary The androgen-only approach to male hormonal contraception is attractive conceptually and proof-of-principle studies have confirmed the feasibility of this approach, especially in oriental men. The efficacy, however, is significantly lower in Caucasian men. While newer testosterone formulations may avoid the relatively high dose of older testosterone esters required to suppress spermatogenesis, the spectre of long-term androgen-related side effects remains a significant disincentive to product development unless synthetic androgens with desirable tissue selectivity can be seriously explored. 3.2. Progestin/androgen combinations Exogenous progestins can inhibit gonadotrophin secretion in men, and suppress spermatogenesis. Combining a progestin with androgens for male contraception exploits the synergistic actions of the two steroids so that they can be used at lower doses thus minimising the potential for side effects. The plethora of available synthetic progestin preparations, including oral, injectable and implants, also serves to broaden the choice of potential regimes. Some of the more interesting progestogen/androgen combinations studied to date is summarised. 3.2.1. Depot medroxyprogesterone acetate (DMPA) DMPA has been combined with 19-nortestosterone (19-NT), TE and T implants. Studies with 19-NT and TE in combination with DMPA in Indonesian men documented azoospermia rates of 98%. In Caucasian men the combination of DMPA with T implants achieved lower azoospermia rates similar to TE alone (Handelsman et al., 1996). The main limitation of DMPA is the prolonged period (>6 months) necessary for spermatogenesis recovery following cessation of treatment.
3.1.4. Transdermal testosterone preparations Several novel transdermal delivery systems (patches and gels) of testosterone have become available recently. While selfadministration and maintenance of physiological testosterone blood levels offer obvious convenience and advantages in androgen replacement for hypogonadism, the requirement for daily application and higher levels of variability in skin absorption raises an important issue of compliance not to mention the high incidence of skin irritation with the reservoir patch. Unsurprisingly, transdermal testosterone on its own has not been investigated as a potential contraceptive formulation.
3.2.2. Cyproterone acetate (CPA) CPA combines anti-gonadotrophic and anti-androgenic properties which may be particularly favourable for suppression of spermatogenesis. Oral CPA at doses of 25–100 mg combined with TE induces rapid suppression of spermatogenesis with the time taken to achieve azoospermia being significantly shorter compared to that with TE alone (49 days versus 98 days) (Meriggiola et al., 2003). Whilst encouraging, a dose-dependent decrease in haemoglobin and body weight related to the antiandrogen action of CPA and the potential for hepatic dysfunction limit the prospects of this combination.
3.1.5. 7α-Methyl-19-nortestosterone (MENT) MENT is a highly potent synthetic androgen which is resistant to 5␣-reductase but sensitive to aromatase. This metabolic idiosyncracy underlies the tissue selectivity which confers a prostate sparing profile. In a preliminary dose-finding
3.2.3. Levonorgestrel (LNG) LNG has been extensively studied in combination with a variety of androgens. Initially a dose of 500 g daily with TE 100 mg weekly confirmed greater sperm suppression than with TE alone (azoospermia 67% versus 33%) (Bebb et al.,
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1996). Further study with lower doses of LNG (250 and 125 g) did not compromise suppression rates (Anawalt et al., 1999). Metabolic effects were dose dependent and included lowered HDL–cholesterol and weight gain. Oral LNG 250 g daily and i.m. TU 1000 mg 6-weekly in combination have been compared to TU 1000 mg 6-weekly alone. There was no difference in suppression to azoospermia (50–57%) (Kamischke et al., 2000) suggesting that the addition of LNG did not confer any advantage. Testosterone patches have been combined with oral LNG (125 g daily) and long-acting LNG implants (four rods Norplant II) (Gonzalo et al., 2002). Relatively poor sperm suppression (severe oligozoospermia in <60%) probably relates to the unreliable administration or absorption of T so that circulating levels in the low normal range only can be achieved. This highlights the critical role of testosterone as a necessary suppressor of gonadotrophins in combination contraceptive regimes in addition to its role in androgen replacement. 3.2.4. Desogestrel (DSG) and etonogestrel (ENG) DSG is an oral third generation synthetic progestin with potent progestational activity but lower androgenicity. These potentially favourable properties led to the study of desogestrel in combination with TE. Oral DSG 300 g in combination with various TE doses produced a high rate of azoospermia (Wu et al., 1999). A lowering of HDL–C of 20–25% was observed. A cross-national study confirmed that DSG (150 or 300 g daily) in combination with 400 mg testosterone implants (every 12 weeks) can induce azoospermia in virtually all men in the 300 g group with a significant decline in HDL–C in Caucasian men only (Kinniburgh et al., 2002). ENG is the active metabolite converted by the liver from DSG with dose-equivalent biopotency. ENG has been formulated as a subdermal non-biodegradable implant for female contraception (Implanon® , NV, Organon). Three ENG rods (68 mg ENG per rod) in combination with T implants (400 mg every 12 weeks) (Brady et al., 2004). All nine men became azoospermic, although the time to achieve this varied from 8 to 28 weeks and one subject showed partial recovery after 40 weeks. Treatment did not result in weight gain, change in body composition or decline in HDL–cholesterol. Further study of this promising progestin implant in combination with TU injections is in progress. This effort not only represents the beginnings of public/private collaboration but also indicates for the first time a willingness of industry to invest in hormonal contraceptive products for men. 3.2.5. Norethisterone enanthate Norethisterone (NET) is an androgenic progestin which can be delivered as NET enanthate (NETE), an i.m. aqueous depot preparation available in Europe for female contraception. NETE 400 mg and TU 1000 mg administered at 6-weekly intervals (Kamischke et al., 2002) induced azoospermia in 92% of men. Moderate increases in haemoglobin (within the normal range) and decreases in HDL–C were observed. Dosing interval of the two steroids can be prolonged to 8-weekly without losing efficacy (Meriggiola et al., 2005). This promising regime consisting of two long-acting depot injectable preparations is being further investigated in planned multi-centre studies.
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3.2.6. Summary There is a perception that progestin and androgen combinations are more effective than T alone (Nieschlag et al., 2003), possibly related to an additional action of the progestins in the testis, and therefore, more suited to Caucasians who are less responsive to steroid suppression. However, the small numbers of subjects and relatively short duration of treatment make valid comparisons between regimes difficult, thus limiting the generalisability of these studies. The potential of progestin-related side effects (short- and long-term) merits greater attention. Current research efforts sponsored by industry are directed towards developing a combination of long-acting depot testosterone injections and progestin implants or injections as the first contraceptive product to be marketed. 3.3. GnRH antagonists GnRH antagonists are competitive blockers of GnRH receptor binding and suppress gonadotrophins within 24 h. Studies have shown very rapid spermatogenic suppression with a high rate of azoospermia. Whilst these complex synthetic peptides clearly have contraceptive potential (main advantage being faster suppression than sex steroids), the disadvantages are their high cost, short half-life and the need for frequent subcutaneous injection. Side effects encountered have included local skin reactions at the site of injection. When the GnRH antagonist Nal-Glu and TE were used to initiate spermatogenic suppression, this could then be maintained with TE alone (Swerdloff et al., 1998). New long-acting depot preparations of potent GnRH antagonists may therefore, have a place in male contraception where rapid induction of spermatogenic suppression can subsequently be maintained by testosterone with or without progestins. 4. Ethnic differences There are clear ethnic differences in the response to sex steroid suppression of spermatogenesis between Asian (more responsive) compared to Caucasian men (less responsive) independent of anthropometry and circulating hormone levels. In studies using androgens alone (TE and TU) azoospermia was achieved in >90% of Asian men versus <60% of European or American men. The potential explanations for these differences may include genetic (Wang et al., 1998) and dietary/environmental factors (Santner et al., 1998; Wang et al., 2005) that are not yet fully understood. Intra-ethnic variation is also seen within Caucasian populations. Only 40–60% of men usually suppress to azoospermia while others remain oligozoospermic in response to sex steroids. Gonadotrophindependent and -independent factors have been suggested (Handelsman et al., 1995; McLachlan et al., 2004) but the exact mechanism(s) evades current understanding. 5. Conclusions There is evidence to support couple dissatisfaction with currently available contraceptive methods and choice. A cross-
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cultural survey also found that women felt the contraceptive burden too frequently falls to them and they welcomed the availability of a reversible male contraceptive for which they trust their partners to take (Glasier et al., 2000; Martin et al., 2000). An important aspect of the male hormonal method is the variable and relatively long (8–10 weeks) time lag after commencing treatment until sperm suppression is sufficient for effective contraceptive. However, a similar lag time also applies to vasectomy (irreversible) and a lag of 1 month applies to the female oral contraceptive pill. Another potential drawback is the need for semen analysis to signal sufficient suppression of sperm count, although this can be simplified in future with self-administered dipsticks methods or even dispensed with altogether with more clinical experience in the field. Public-funded research has reached a stage where realisation of male hormonal contraception is within our reach and the pharmaceutical industry is beginning to embark on the necessary steps leading to product development. A progestogen/androgen combination is most likely to be the first product to be marketed. Further development of long-acting depot formulations or oral and non-steroidal compounds will provide a variety of contraceptive formulations that will allow men to have a widened choice, improve acceptability and encourage continued usage. References Anonymous, 1990. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet 336, 955–959. Anonymous, 1996. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil. Steril. 65, 821–829. Anawalt, B.D., Bebb, R.A., Bremner, W.J., Matsumoto, A.M., 1999. A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations. J. Androl. 20, 407–414. Anderson, R.A., Baird, D.T., 2002. Male contraception. Endocr. Rev. 23, 735–762. Bebb, R.A., Anawalt, B.D., Christensen, R.B., Paulsen, C.A., Bremner, W.J., Matsumoto, A.M., 1996. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J. Clin. Endocrinol. Metab. 81, 757–762. Brady, B.M., Walton, M., Hollow, N., Kicman, A.T., Baird, D.T., Anderson, R.A., 2004. Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception. Hum. Reprod. 19, 2658–2667. De Gendt, K., Swinnen, J.V., Saunders, P.T., Schoonjans, L., Dewerchin, M., Devos, A., Tan, K., Atanassova, N., Claessens, F., Lecureuil, C., Heyns, W., Carmeliet, P., Guillou, F., Sharpe, R.M., Verhoeven, G., 2004. A sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc. Natl. Acad. Sci. USA 101, 1327–1332. Glasier, A.F., Anakwe, R., Everington, D., Martin, C.W., van der Spuy, Z., Cheng, L., Ho, P.C., Anderson, R.A., 2000. Would women trust their partners to use a male pill? Hum. Reprod. 15, 646–649. Gonzalo, I.T., Swerdloff, R.S., Nelson, A.L., Clevenger, B., Garcia, R., Berman, N., Wang, C., 2002. Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination with transdermal and injectable testosterone. J. Clin. Endocrinol. Metab. 87, 3562– 3572. Gu, Y.Q., Wang, X.H., Xu, D., Peng, L., Cheng, L.F., Huang, M.K., Huang, Z.J., Zhang, G.Y., 2003. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J. Clin. Endocrinol. Metab. 88, 562–568.
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