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Review |
From the * Obstetrics and Gynecology Unit, S.
Orsola Hospital, and University of Bologna, Bologna, Italy; and the
UNDP/UNFPA/WHO/World Bank Special Programme of
Research, Development and Research Training in Human Reproduction, Department
of Reproductive Health and Research, World Health Organization, Geneva,
Switzerland.
| Correspondence to: M. Cristina Meriggiola, MD, I Clinic of Ob Gyn, S. Orsola Hospital, Via Massarenti 13, Bologna, Italy 40138 (e-mail: crismeri{at}med.unibo.it). |
| Received for publication February 3, 2003; accepted for publication March 3, 2003. |
Thanks to public agencies like the World Health Organization (WHO) and the Contraceptive Research and Development Program, the validity of the concept of the hormonal approach to male contraception were proven in large-scale clinical trials. In these studies it was shown that hormones can provide contraceptive protection that promises to be as effective in men as in women (WHO, 1990, 1996). Achievement of azoospermia has been suggested to be the gold standard for this method in order to confer optimal contraceptive protection (WHO, 1990, 1996). Azoospermia achieved with weekly injections of 200 mg of testosterone enanthate (TE) provided a Pearl index (pregnancy per 100 person-years) rating of 0.8 (95% confidence interval [CI] = 0.02–4.5]; WHO, 1990). However, various degrees of severe sperm suppression also have been shown to provide acceptable contraceptive protection. When sperm count is suppressed to azoospermia or severe oligozoospermia (sperm count from 0 to 1 x 106/mL), contraceptive protection is provided to a Pearl index rating of 1.4 per 100 couple-years (95% CI = 0.4–3.7; WHO, 1996). Therefore, induction of azoospermia or sperm suppression to <1 million/mL can be considered an acceptable contraceptive goal.
Studies performed in the last decade have shown that testosterone (T) administration alone can provide almost universal azoospermia in diverse Asian populations, with minimal side effects (WHO, 1990, 1996). Therefore, phase II and III clinical trials are already being planned with androgen regimens in the Asian population. The encouraging preliminary results of these studies offer some promise that an androgen-alone contraceptive may be on the market in those countries within the next few years (Zhang et al, 1999).
Testosterone-alone regimens are not as effective in the Caucasian population as they are in the Asian population, but small-scale clinical trials performed over the last few years have suggested that if a progestin is added to the androgen, profound suppression of sperm production can be achieved in Caucasian men (Meriggiola and Bremner, 1997).
In spite of the fact that all of these studies have shown that hormonal contraception for men is feasible and effective, the lack of involvement of drug companies has prevented the transit of these concepts from small pilot trials to large-scale studies aimed at the development of suitable products for the market. In 1997, a group of leading researchers promulgated a manifesto on male contraception. The aim of this manifesto was to sensitize drug companies, politicians, and research foundations ``to commit themselves to the development of male contraception for the sake of future generations'' (Nieschlag and Behre, 1998). This appeal was finally received and in November 2002 when 2 major pharmaceutical companies committed themselves to the development of a hormonal contraception for men (Schering AG, 2002).
Large-scale clinical trials are now being planned with various combinations of progestins and androgens to confirm and extend the preliminary results obtained in small pilot studies and to eventually test the contraceptive effectiveness of these combinations. Advantages of this hormonal combination include the vast experience of years of clinical use of both classes of compounds and their relatively low cost.
The purpose of this article is to review the literature on androgen-progestin combinations, to understand lessons learned from these trials, and to determine how these results can be applied to the design of large multicenter clinical trials with the ultimate goal of developing an optimal hormonal male contraceptive.
Methods
This review includes all studies reporting the outcome of
androgen-progestin regimens, in terms of sperm suppression, published in the
peer-reviewed literature between 1960 and September 2002. For this review, the
database MEDLINE was searched. English-only publications were included in the
search, and subsequent bibliographies were cross-referenced. Where more than 1
publication reported the same study, the data were analyzed only once. For a
detailed breakdown of the various studies, please refer to the tables. Because
of the apparent ethnic differences in responsiveness to steroids, results from
clinical trials of potential hormonal contraceptive regimens have been
analyzed and reported separately in the Asian and Caucasian populations.
Healthy subjects of all ethnic groups, within an age range of 21–50
years and with normal seminal parameters, were included in the studies. Only
studies in which hormone administration lasted longer than 12 weeks were
included in the analyses. Maximal suppression of sperm count (rate of
azoospermia) was considered for all studies. In most of the papers it
coincided with the end of the study, but in many papers it could not be
detected at which time of the study maximal sperm suppression occurred. Only
rate of azoospermia is considered for analysis in this paper, since the degree
of sperm suppression was not always clearly reported in the results sections
of the various studies. Gonadotropin suppression could not be considered in
this review, since the different gonadotropin assays and their evolution
throughout the years would not allow for a comparison among the studies.
Statistical Analyses
The rates of azoospermia observed in each study were plotted according to
the regimen, and the mean rate of azoospermia was calculated. The total number
of azoospermic men, as well as the total number of treated cases, were also
reported in the text of the figures. These numbers were used for the
comparison between different regimens by evaluating the Yates corrected
chisquared test and the odds ratio (OR) together with the 95% CI. Statistical
evaluations were performed by the SPSS/PC+ statistical package version 5.0
(Dixon et al, 1990; Norusis, 1992).
Mechanisms of Hormonal Suppression of Male Fertility
The mechanism(s) by which gonadal steroids inhibit male fertility is the
suppression of sperm production achieved through inhibition of gonadotropin
secretion. The various progestins have different antigonadotropic potency:
19-nortestosterone derivatives have a stronger suppressive effect on
gonadotropins compared with the progesterone-derived progestins.
The mechanism by which progestins suppress gonadotropins is still unclear. Although previous studies attributed the antigonadotropic effect of progestin to their androgenic activity, more recently a possible direct inhibitory effect of these compounds on gonadotropin secretion has been postulated (McEwen et al, 1983; Couzinet et al, 1996). The direct inhibitory effect of progestins on gonadotropins, independent of estrogens and androgens, could also explain the additive and synergistic effects of this compound when combined with other steroids, in this case androgens. Progesterone receptors have been found both at the hypothalamus and pituitary level in rats and nonhuman primates.
After exogenous administration of sex hormones such as androgens, progestins, or estrogens, Leydig cells decrease in volume; consequently, serum T production also decreases (Flickinger, 1977a, b). T levels fall below physiological levels both intratesticularly and in the peripheral circulation (Morse et al, 1973; McLachlan et al, 2002). Therefore, administration of androgens or androgen-like substances to re-establish peripheral physiological T levels is mandatory for non–T-alone hormonal contraceptive regimens that act through this mechanism to maintain androgen-dependent physiological functions. As a result of FSH and intratesticular T suppression, studies in both animals and humans have demonstrated that after hormone administration, sperm development stops at the pachytene spermatocyte stage, whereas degeneration of later stage spermatids occurs (Terner and MacLaughlin 1973; Hikim et al, 1995). This mechanism maintains spermatogonia and thus implies the potential reversibility of the contraceptive method. According to the degree of T depletion from the testis, remaining spermatids and spermatocytes may complete their development or slough from the seminiferous epithelium. This means that hormone regimens require some time to be fully effective over the human spermatogenic cycle of about 70 days. The mean time reported to induce azoospermia ranged from 6 to 12 weeks in most clinical trials.
After stopping hormone administration, gonadotropin secretion recovers, resulting in full resumption of Leydig cell function and spermatogenesis. The time for spermatogenesis to resume normal levels has varied widely among different studies, ranging from a few weeks to several months, as the result of the long-lasting effect of some steroids, which may accumulate in the subcutaneous tissue. However, it should be emphasized that in all studies performed so far, full recovery of spermatogenesis was always achieved in all subjects. This characteristic gives to hormonal male contraception an important advantage over other currently available forms of contraception such as vasectomy.
Rationale for the Androgen-Progestin Combinations
The rationale for combining androgens with progestins to suppress fertility
in men is based on the additive and synergistic effects that these 2 steroids
have on the suppression of gonadotropins, and thus spermatogenesis. Previous
studies have demonstrated that when given alone at doses that are safe for
administration, currently available progestins do not induce profound
suppression of gonadotropins, and thus spermatogenesis, in men
(Johansson and Nygren, 1973; Morse et al, 1973;
Koch et al, 1976;
Roy et al, 1976; Fredricsson, 1978;
Fogh et al, 1979;
Moltz et al, 1980; Wang and Yeung, 1980;
Fredricsson and Carlstrom,
1981; Kamischke et al,
2000a). Additionally, androgens alone, even when administered at
high, supraphysiological doses, do not uniformly induce a degree of
spermatogenic suppression sufficient for contraception (WHO,
1990,
1996;
Matsumoto, 1990). Moreover,
high T levels may induce changes in some hematocrit and lipid parameters that
may have potential longterm adverse effects
(Bagatell et al, 1994; Meriggiola et al, 1995). The
doses of androgen and progestin can be adjusted to achieve maximal
gonadotropin suppression and, at the same time, avoid induction of
supraphysiological serum androgen levels, thereby improving the safety of the
regimen.
In addition to the effects at the hypothalamus-pituitary level, there are studies that indicate the possibility of a direct inhibitory role of the progestins at the testicular level. A number of studies in animals suggest that progestins may affect spermatogenesis by exerting a direct effect at testicular and posttesticular levels. A variety of mechanism(s) have been suggested to explain this observation. Progestins may reduce the androgen concentrations within the testis by reducing androgen biosynthesis, altering androgen metabolism, and/or acting directly at the receptor level by competitive binding, thereby reducing the effective level of intratesticular androgens (Lobl et al, 1983; Mauvais-Jarvis et al, 1974; Vreeburg et al, 1976; Worgul et al, 1979). Studies in animals suggest that various changes in epididymal structures occur, although their significance remains unclear (Srivastava and Malaviya, 1980; Srivastava, 1981). It should be noted that the above described effects have only been reported in vitro and in vivo at high progestin concentrations, and their relevance to the doses necessary for contraception in men is unclear. The importance of the contribution of local effects relative to the overall contraceptive effects of this regimen is still unknown.
Studies With Androgen-Progestin Combinations
Medroxyprogesterone Acetate—
Medroxyprogesterone acetate (MPA) was developed at the end of the 1950s,
and in 1960 the U.S. Food and Drug Administration approved its use for
regulation of menstrual disorders. Since then a vast amount of literature has
been published on this progestin, which is used in the treatment of a wide
variety of conditions and for contraception in women. In men, MPA has been
used for the treatment of prostatic hypertrophy and hypersexuality and in
experimental male contraception.
Over the last 40 years, 17 papers were published describing studies in which 31 different regimens using MPA were administered to healthy men for suppression of spermatogenesis (Table 1a). These regimens consisted of either the oral or injectable form of MPA given in combination with different T formulations. A total of 307 men completed at least 12 weeks of hormone administration (Table 1b). Altogether, 205 (67%) subjects achieved azoospermia (Table 1c, Figures 1, 2, 3). Three of these studies were performed in Asian populations (Pangkahila, 1991; Lee et al, 1979; WHO, 1993).
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In the Caucasian population, the oral and the depot injectable MPA formulations were administered in combination with oral or injectable T preparations, respectively. Oral MPA was given in combination with oral T, such as methyl-T, or with percutaneous dihydrotestosterone (DHT; Tables 1a and 2; Bain et al, 1980; Guerin and Rollet, 1988; Soufir et al, 1983). Depot medroxyprogesterone acetate (DMPA) injected every 4–6 weeks was given in combination with TE (Alvarez-Sanchez et al, 1977; Brenner et al, 1977; Frick et al, 1977a; Melo and Coutinho, 1977; Alvarez-Sanchez et al, 1979; Faundes et al, 1981; Frick et al, 1982; Wu and Aitken, 1989; Pangkahila et al, 1991; WHO 1993); testosterone propionate (TP; Frick et al, 1977a); testosterone cypionate (TC; Paulsen et al, 1980; Lee et al, 1979); 19-nortestosterone (19-NT); or T pellets (Knuth et al, 1989; Handelsman et al, 1996; WHO 1993; (Tables 1a and 3). Oral combinations were less effective than injectable DMPA (Figure 3) in the suppression of spermatogenesis (P ≤ .001). After administration of DMPA plus injectable T, 57% (75 of 131) of the volunteers achieved azoospermia compared with 22% azoospermic (8 of 36) of the men who received the oral preparation of MPA (Figure 3).
DMPA plus injectable T was administered in a combined-continuous or sequential fashion (Alvarez-Sanchez et al, 1977, 1979; Frick et al, 1977b; Faundes et al, 1981; Frick et al, 1982; Knuth et al, 1989; Table 2). Sequential regimens included an initial period during which the 2 steroids were administered at higher doses, followed by a second phase in which lower steroid doses were administered. With the sequential regimens, profound sperm suppression was achieved by means of the high doses of DMPA and T. Sperm suppression achieved in this phase was more profound than that achieved with the combined-continuous regimens (P ≤ .012; Figure 2). Thirty-five of 46 subjects (76%) became azoospermic after an initial phase of high-dose hormone administration, whereas only 40 of 85 subjects (47%) achieved azoospermia at the end of a combined-continuous DMPA plus T administration (Figure 2). However, in all studies the regimens used in the second phase failed to maintain sperm suppression, and spermatogenesis recovered in most of the subjects in all studies. No major adverse effects were reported with any of these regimens.
Cyproterone Acetate— Cyproterone acetate (CPA) is a synthetic steroid with both progestational and antiandrogenic properties (Neumann and von Berswordt-Wallrabe, 1966; Steinbeck et al, 1971). Because of this combination of activities, CPA has been used in conditions in which a profound suppression of androgen activity is needed in men (eg, hypersexuality or prostate cancer). During these treatments, a decrease of gonadotropin and T levels and a dramatic reduction in sperm production was observed. These observations prompted researchers to test the possibility that CPA could be used for suppression of male fertility. Ten papers have been published in which CPA was given at doses ranging from 200 to 5 mg/d, orally, to test its effectiveness in suppressing spermatogenesis and gonadotropins (Petry et al, 1972; Morse et al, 1973; Koch et al, 1976; Roy et al, 1976; Fredricsson, 1978; Fogh et al, 1979; Roy and Chatterjee, 1979; Moltz et al, 1980; Wang and Yeung, 1980; Fredricsson and Carlstrom, 1981). These studies were also stimulated by the promising results obtained in animals, which suggested that CPA could inhibit fertility through a direct effect at the posttesticular level. Among 76 men who received CPA for 16–26 weeks, azoospermia was only occasionally achieved in a few men and not consistently maintained. In most of the men, sperm suppression was variable and exhibited various degrees of oligozoospermia. In these trials, a decrease of sperm motility and normal morphology was reported. Whether these changes, probably due to a direct effect of CPA at posttesticular level, lead to a significant reduction of fertility potential of these spermatozoa is unclear. However, major side effects of this regimen included a decrease of both libido and sexual potency that was so severe that, in many cases, volunteers were unable to produce an ejaculate for semen analysis.
In 1983, Lohiya and Sharma proposed to combine CPA with T in order to avoid side effects due to androgen depletion. They administered CPA 1 mg/kg IM and TE 2 mg/kg IM every 15 days over a period of 90 days to male Langur monkeys. All animals became azoospermic, and no significant changes of any biochemical parameters were detected. Two years later, the same promising results were reported after administration of 20 mg/d of CPA in combination with 250 mg/fortnight of TE to 6 men (Roy and Prasad, 1985). Five of 6 men became azoospermic, and 1 man had a sperm count <1 million/mL after 20 weeks of administration. In spite of these promising preliminary data, this hormonal combination did not receive further attention, primarily for 2 reasons: 1) these data in men were never published in a scientific peer-reviewed journal, and 2) it seemed somehow illogical to combine an androgen with an antiandrogen. This regimen was explored again 10 years later. The proposed rationale for testing this hormonal combination was based on the peculiar combination of progestogenic and antiandrogenic activity of the progestin. CPA may suppress gonadotropins because of its progestogenic activity as well as act at the testicular and posttesticular level, blocking the stimulatory effect of residual or exogenous intratesticular T on sperm development as the result of its antiadrogenic activity. The lack of any suppressive effect of CPA on plasma sex hormone binding globulin (SHBG) levels could contribute to the avoidance of increased free T levels, which is different than other progestins like levonorgestrel (LNG), which is known to decrease SHBG levels (Meriggiola et al, 2002b).
Four studies have been published (Meriggiola et al, 1996, 1997, 1998, 2002b) in which CPA was given at doses of 100, 50, 25, 12.5, and 5 mg/d in combination with TE 100 or 200 mg/wk or with oral testosterone undecenoate (TU) 160 mg/d to 44 subjects (Table 4). Overall, 23 (52%) subjects became azoospermic, 14 (32%) severely oligozoospermic (<1 million/mL), and in 3 (7%) subjects the sperm count remained above 3 million/mL after 16 weeks of hormone administration (Figure 4a). When the same dose of CPA (25 mg/d) was administered with an oral (TU) or injectable (TE) androgen, the regimen in which oral T was administered seemed to be less effective than that in which IM TE injections were given. One of 8 subjects achieved azoospermia with the oral combination vs 4 of 5 subjects in the CPA plus TE regimen (Figure 4a). Comparing gonadotropin levels between the 2 regimens, it is evident that reduced gonadotropin suppression was achieved with the oral combination (Figure 4b). Although the studies included a very small number of subjects, it would appear that the less profound gonadotropin suppression achieved with oral T may be due to the inconsistent serum T levels achieved after oral TU intake, which may not be able to maintain gonadotropin, and hence sperm suppression (Meriggiola et al, 1997). No major side effects were detected with this regimen. No changes of sexual function or behavior were reported, with the exception of a significant decrease of morning erections in the group that received the highest dose of CPA (100 mg/d). There was a decrease of red cell parameters in all groups, which seemed to be dependent on the dose of CPA and was probably related to its antiandrogenic activity. Further large-size clinical trials may be required to test the safety and efficacy of low doses of CPA with T in multiethnic groups of men.
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19-Nor-Progestins— Based on animal studies and clinical studies in women, 19-norderived progestins are known to be potent in terms of gonadotropin suppression (Couzinet et al, 1996). Among this class of steroidal compounds are norethisterone (NET), norethynodrel, and its dextrorotatory isomer LNG (ie, the biologically active form of this progestin). The progestins of this class are known to be potent suppressors of gonadotropin secretion, and when administered to men these compounds induced a profound suppression of sperm production (Frick, 1973). However, a decrease of libido and sexual potency was also reported, presumably due to the suppression of T production secondary to gonadotropin suppression (Kamischke et al, 2000b). Therefore, like other progestins available thus far, nor-progestins should not be administered alone for male contraception because their residual androgenic activity is not sufficient to maintain androgen-dependent physiological functions like libido or sexual potency (Kamischke et al, 2000a). Also, due to their estrogenic activity or to inadequate androgen replacement, administration of these progestins resulted in a high rate of gynecomastia (Paulsen et al, 1962; Kuhnz et al, 1997). These progestins have therefore been tested in combination with different androgens. Of this group of compounds, LNG and NET, norethisterone enanthate (NETE) and norethisterone acetate (NETA) were the most commonly used progestins in clinical trials. Levonorgestrel seemed to be most attractive because of its potency and the large number of formulations in which it is available for women (oral, injectable, transdermal, subcutaneous, intravaginal, and intrauterine), offering the prospect of different routes of administration for men as well. Ten trials (Fogh et al 1980a, b, c; Bebb et al, 1996; Anawalt et al, 1999; Buchter et al, 1999; Gao et al, 1999; Kamischke et al, 2000b; Pollanen et al, 2001; Gonzalo et al, 2002) have been published in which LNG was administered to normal healthy men to test the effects on sperm suppression (Table 1a). Oral LNG at doses ranging from 125 to 500 µg/d or LNG implants were given in combination with TE or TU injections, oral T or transdermal T, or DHT for at least 6 months (Table 5). Overall, of the 194 subjects treated with these hormonal combinations, 80 (41%) achieved azoospermia (Tables 1b and c; Figure 5). As with other progestins, a combination of oral or transdermal T/DHT with oral LNG (Fogh et al, 1980c; Buchter et al, 1999; Pollanen et al, 2001) tended to be less effective in terms of sperm suppression compared with oral LNG given in combination with injectable T formulations (P < .001; Figure 5; Fogh et al, 1980a, b; Bebb et al, 1996; Anawalt et al, 1999; Gao et al, 1999; Kamischke et al, 2000b; Gonzalo et al, 2002). Fourteen of 74 subjects (19%) who received oral or implant LNG plus oral or transdermal T/DHT became azoospermic compared with the 66 of 120 subjects (55%) that became azoospermic after oral LNG plus injectable TE or TU (Figure 5).
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Four papers have been published in which NET, NETE, or NETA were administered to 95 subjects for 6–9 months (Tables 1a, b, c). In these studies, 79% (75 subjects) became azoospermic (Guerin and Rollet, 1988; Lobel et al, 1989; Kamischke et al, 2001, 2002; Table 6). The combined administration of injectable NETE plus TU was more effective in sperm suppression (91% azoospermic, 49 of 54 subjects) compared with the oral administration of NETA plus oral TU or percutaneous T (63% azoospermic, 26 of 41; P ≤ .001; Figure 6).
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The progestins of this class retain varying degrees of androgenic activity that possibly accumulate with that of the exogenous androgen. The reported decrease of SHBG levels and displacement of T from its binding sites caused by these progestins may further contribute to increased free T levels (Pugeat et al, 1981; Darney, 1995). Together, these characteristics may explain the fact that the adverse effects induced by most of the 19-norderived progestin when combined with androgens are identical to those reported with high-dose androgens, including weight gain, acne, and a decrease in high-density lipoprotein (HDL) cholesterol. Further large-scale studies are required to determine both efficacy and safety of injectable TU in combination with NETE or LNG in multiethnic settings.
Desogestrel— Since the intrinsic androgenicity of progestins like LNG or NET/E/A was thought to contribute to the androgen-related side effects observed with these progestins, the reduction of the androgenic activity in the third generation progestins was thought to provide advantages in terms of safety and possibly of sperm suppression. Six papers (Wu et al, 1999; Anawalt et al, 2000; Kinniburgh et al, 2001; Morton Hair et al, 2001; Kinniburgh et al, 2002; Anderson et al, 2002; Table 7) have been published in which the progestin desogestrel (DSG) at doses of 75, 150, or 300 µg/d or as an implant releasing 68 mg/d of etonogestrel was combined with TE 100 or 50 mg/wk or with 400-mg T pellets (Table 1a). Overall, 162 subjects received 1 of these regimens for 24 weeks. Azoospermia was achieved in 75% of the subjects (122 of 162; Tables 1b and c; Figure 7). With DSG 300 µg plus TE 100 mg/wk, 13 of 16 subjects (81%) became azoospermic, whereas when the dose of TE was reduced to 50 mg/week, azoospermia was achieved in 8 of 8 subjects (100%). Lower doses of DSG (150 µg/d) in combination with 100 or 50 mg/wk TE induced azoospermia in 79% (11 of 14) and 57% (4 of 7) of the subjects, respectively. In one study (Wu et al, 1999) when TE administration was delayed for 3 weeks to allow for the suppression of gonadotropins and depletion of intratesticular T concentrations, no difference in sperm suppression was found compared with the same regimen (DSG 300 µg/d plus TE 100 mg/wk) administered from the beginning: percentage of azoospermia was 75% (6 of 8) vs 88% (7 of 8), and time to azoospermia was 14 ± 2.7 weeks in the 2 groups, respectively. Both studies with DSG and TE reported a decrease of HDL cholesterol that seemed to be dependent on the dose of both the progestin and the androgen (minimum DSG 150 µg/d plus TE 50 mg/wk, and maximum DSG 300 µg/d plus TE 100 mg/wk). These results suggest that DSG retains some androgenicity that, when combined with T, may be sufficient to induce the HDL reduction.
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Discussion
In this paper we have reviewed published studies in which
androgen-progestin hormonal combinations were administered to men for the
purpose of sperm suppression. In the past 40 years (1960–2002) since the
advent of female steroid contraception, 41 articles in which 802 male
volunteers received an androgen-progestin combination have been published in
peer-review journals.
Since the first progestins were administered to men, it has become clear that when administered alone progestins induce symptoms of androgen deficiency due to gonadotropin suppression and possible direct effects on T metabolism. Even nor-progestins that are known to have a strong residual androgenic effect in women cannot maintain androgen-dependent physiological functions in men if given without androgens (Kamischke et al, 2000a). Therefore, for the purpose of male contraception all progestins available must be given in combination with androgens. The theoretical possibility of inducing profound gonadotropin suppression with the progestin alone would allow for the use of an androgen dose that is sufficient to maintain androgen-dependent physiological functions. However, available progestins have not been shown to induce such profound gonadotropin suppression when administered alone. Such a possibility remains open if new progestins are formulated that are more potent in terms of gonadotropin suppression at doses that do not cause adverse effects.
This analysis of the data published in the literature during these 4 decades suggests that when a progestin is administered in combination with an androgen, a profound suppression of spermatogenesis can be induced. Most studies suggest that the suppressive actions of progestin are additive to T. A wide range of degree of sperm suppression has been reported in the various studies with different doses and injection intervals. When optimal regimens were tested, all progestins induced azoospermia or near azoospermia in all men. Therefore, based on the data published so far, no progestin seems to be superior to the others in terms of spermatogenic suppression.
Throughout the different regimens, the low effectiveness of the androgen-progestin combinations that included noninjectable androgens was consistently observed. Thirteen papers have reported on the combined administration of oral progestins with noninjectable androgens (Table 1a). Sperm suppression induced by these noninjectable androgen-progestin regimens is significantly lower compared with that achieved with regimens in which the 2 compounds have been given through injections or implants. The lower levels in serum T levels or wide fluctuations, as in the case of oral T preparations, can explain this low effectiveness. These lower and fluctuating levels may be unable to induce or maintain consistent gonadotropin suppression, as has been suggested by the comparison of gonadotropin levels between 2 groups in which CPA was given in combination with TE or oral TU (Meriggiola et al, 1996, 1997).
A few early studies proposed the idea of using a higher hormonal load to induce profound sperm suppression that can be eventually maintained with lower doses. In these preliminary trials, profound sperm suppression was induced with the initial high dosage. However, the steroid regimen administered to maintain suppression failed to do so (Alvarez-Sanchez et al, 1977, 1979; Frick et al, 1982). More recent studies in which different hormonal combinations have been used both in primates and in men have shown that it is indeed possible to maintain sperm suppression for as long as 32 weeks with lower hormone doses than those used to induce the suppression (Weinbauer et al, 1988; Swerdloff et al, 1998; Costantino et al, unpublished data). However, even these recent reports have given conflicting results (Behre et al, 2001). The use of inadequate regimens for maintenance of sperm suppression may account for the different ability to maintain gonadotropin, and thus sperm suppression, with the 2 regimens. However, this concept remains potentially very interesting and deserves to be explored further as the use of a lower hormonal load for long-term maintenance of sperm suppression may increase safety and decrease the cost, as well as increase acceptability and decrease side effects of the contraceptive.
None of these trials has reported major adverse effects that would discourage continuation of the hormonal combination. However, only years of clinical use will permit evaluation of the potential risks of hormone administration for contraception in men. It is speculated that avoidance of supraphysiological T levels results in a lower incidence of long-term adverse effects on health. When a progestin is added to the androgen for enhancement of sperm suppression, it must be administered at doses that are sometimes higher than those used in women. Therefore, at these dosages some activities of the progestin that are negligible in female contraceptives may reach physiological significance in male contraceptives. The choice of the progestin is also very important. The use of progestins with favorable biological and pharmacological characteristics, which in this case means progestins devoid of strong androgenic or antiandrogenic activities at the doses used for induction of gonadotropin/sperm suppression, will certainly increase the long-term safety of these regimens.
Previous trials have shown that with the steroid formulations currently available, long-acting and depot formulations are more effective in inducing sperm suppression compared with the noninjectable formulations. Previous surveys reported that the majority of men from different countries agreed that injectable contraceptives would be more convenient compared with the currently available male contraceptives (Ringheim, 1999) Therefore, these long-acting androgen-progestin combinations promise to be welcomed by many men as a favorable alternative to currently available methods. A recent survey reported that men of different cultures find the pill more convenient to use compared with injections (Glasier, 1999). As with female contraception, the availability of a wide range of formulations of hormonal male contraceptives will allow for increased acceptability and compliance in men. Therefore, the task of developing noninjectable formulations that can be delivered orally or transdermally will remain a high priority in the male contraceptive agenda.
Conclusions
After so many years since the introduction of the female hormonal
contraception, results of the latest studies have demonstrated that male
hormonal contraception can become a reality. A recent cross-cultural survey
has indicated that the majority of men would be willing to use hormonal
contraceptives and that women would trust their male partners to use them.
Long-acting or depot injectable androgen-progestin formulations provide
optimal sperm suppression with minimal short-term metabolic adverse effects
that promise to result in high long-term safety of these regimens. Phase III
multicenter clinical trials are now awaited for testing the contraceptive
effectiveness of these hormonal regimens. Additionally, more research is
needed to develop new steroid preparations with better biological properties,
such as progestins with more potent gonadotropin activity, selective progestin
modulators or long-acting androgen preparations, or new oral androgen
formulations, to improve the long-term safety of these regimens and increase
choice.
References
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Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. A lower dosage
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