Advances in Male Contraception: Stephanie T. Page, John K. Amory, and William J. Bremner

0163-769X/08/$20.00/0 Printed in U.S.A.
Endocrine Reviews 29(4):465 493 Copyright 2008 by The Endocrine Society doi: 10.1210/er.2007-0041
Advances in Male Contraception

Stephanie T. Page, John K. Amory, and William J. Bremner
Center for Research in Reproduction and Contraception, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195
Despite significant advances in contraceptive options for women over the last 50 yr, world population continues to grow rapidly. Scientists and activists alike point to the devastating environmental impacts that population pressures have caused, including global warming from the developed world and hunger and disease in less developed areas. Moreover, almost half of all pregnancies are still unwanted or unplanned. Clearly, there is a need for expanded, reversible, contraceptive options. Multicultural surveys demonstrate the willingness of men to participate in contraception and their female partners to trust them to do so. Notwithstanding their paucity of options, male methods including vasectomy and condoms account for almost one third of contraceptive use in the United States and other countries. Recent international clinical research efforts have demonstrated high efficacy rates (90 95%) for hormonally based male contraceptives. Current barriers to expanded use include limited delivery methods and perceived regulatory obstacles, which stymie introduction to the marketplace. However, advances in oral and injectable androgen delivery are cause for optimism that these hurdles may be overcome. Nonhormonal methods, such as compounds that target sperm motility, are attractive in their theoretical promise of specificity for the reproductive tract. Gene and protein array technologies continue to identify potential targets for this approach. Such nonhormonal agents will likely reach clinical trials in the near future. Great strides have been made in understanding male reproductive physiology; the combined efforts of scientists, clinicians, industry and governmental funding agencies could make an effective, reversible, male contraceptive an option for family planning over the next decade. (Endocrine Reviews 29: 465 493, 2008)
I. Introduction II. Acceptability of Male Contraception III. Currently Available Male Contraceptive Methods A. Condoms B. Vasectomy IV. Regulation of Testicular Function and Spermatogenesis A. The hypothalamic-pituitary axis: control of gonadotropin secretion B. Testosterone production and androgen action C. Spermatogenesis D. The epididymis V. Male Hormonal Contraception Methods A. Hormonal contraceptive efficacy B. Testosterone alone C. Testosterone-progestin combinations D. Adding GnRH analogs to hormonal contraceptive regimens E. Oral male hormonal contraceptive development F. Reversibility of male hormonal contraception G. Side effects of male hormonal contraceptives H. Selective androgen receptor modulators for male contraception I. Why doesnt hormonal contraception work for all men? VI. Nonhormonal Methods A. Testicular targets B. Epdidymal targets C. Targeting sperm motility or sperm-egg fusion D. Immunological approaches to contraception VII. Conclusions
I. Introduction
ESPITE CURRENTLY AVAILABLE contraceptives, the worlds population exceeds 6.5 billion and is increasing by 75 million yearly (1), and overpopulation continues to be a significant contributor to environmental degradation and human suffering worldwide. Much of our current global population growth is unintended. It is estimated that half of all conceptions are unplanned and half of the resulting pregnancies are undesired (2). In the United States, approximately half of unintended pregnancies are attributable to a failure to use contraception, and the other half to difficulties with contraceptive use or method failure (3). Moreover, in developing countries contraception use is further limited by restricted access to many available methods, both economically and culturally. The contraceptive shortfall results in over 20% of pregnancies ending in abortion (3, 4). In addition, undesired pregnancies result in unwanted children who suffer disproportionately from poverty and neglect (5, 6). Therefore, there is a great need for better access and education
First Published Online April 24, 2008 Abbreviations: DHT, Dihydrotestosterone; DMPA, depomedroxyprogesterone; GAPD, glyceraldehydes 3-phosphate dehydrogenase; GPR, G protein receptor; hCG, human chorionic gonadotropin; HDL, high-density lipoprotein; INSL3, insulin-like factor 3; MENT, 7-methyl-19-nortestosterone; PSA, prostate-specific antigen; sAC, soluble adenylate cyclase; SARM, selective androgen receptor modulator; SFEC, sperm flagellar energy carrier; sNHE, soluble sodiumhydrogen exchanger; TD, testosterone decanoate; TE, testosterone enanthate; TU, testosterone undecanoate. Endocrine Reviews is published by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community.
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Page et al. Advances in Male Contraception
regarding existing contraceptives and more contraceptive options. Women have a wide range of contraceptive choices. Research and family planning organizations have traditionally focused upon female methods of contraception because women bear a disproportionate portion of the health and economic consequences of childbearing and rearing. Consequently, women have many contraceptive choices, ranging from daily oral medications to intrauterine devices implanted every 5 yr to sterilization. In the current era, there are only two forms of male contraception available, condoms and vasectomy, with only the former being reliably reversible. In fact, no new, reversible, male-based methods have become commercially available since the condom was introduced more than 300 yr ago. However, despite few available options, male methods account for approximately 14% of contraception worldwide, with prevalence significantly higher in the more developed world where male-directed methods account for more than 30% of contraception. Funding for the development of male contraceptives has faltered since this topic was last reviewed (7). Although support from some public agencies has continued, albeit at reduced levels, the pharmaceutical industry has largely abandoned this potential market. Three major international pharmaceutical companies have cancelled their programs in male contraception over the last 5 yr, citing corporate changes in direction as the motivating force. However, it is difficult to imagine that other forces have not influenced these decisions, including the perception that the safety standards for regulatory approval of such products would require studies of such numbers and length as to be financially infeasible or lacking in incentive for profit. In addition, despite the environmental and health consequences of the ongoing but largely forgotten population crisis, large nonprofits such as the Bill and Melinda Gates Foundation have focused their resources on other global health concerns. Without the support of these organizations in the long run, progress in the development of effective and available male contraceptives is difficult to imagine. In this article, we will review the mechanism of action and recent advances in male contraception, with particular emphasis on newer regimens that may be nearing introduction to clinical practice. First, however, we will discuss the important question of acceptability, because only a contraceptive that men, and their female partners, will reliably use represents a true advance in the field. We will discuss the physiological challenges of male contraceptive development, hormonal methods of contraception, which likely offer the prospect of reaching the market first, and nonhormonal methods, including immune-based products.
ingness to use a male contraceptive if one were available (9, 10). Additional multinational and multiethnic studies of potential hormonally based male contraceptives demonstrate that most men (11), and their female partners (12), would be willing to use such a method of contraception. In fact, 98% of women in stable relationships would be willing to rely on their male partner to use male contraception (12). Acceptability of male-based contraceptive methods is, however, influenced by economic, cultural, religious, and relationship status. For example, higher income and education status are associated with a great willingness to use male contraception (10). Other studies demonstrate marked cultural differences. For example, men in predominantly Muslim Indonesia were less willing to use a male contraceptive and cited religious beliefs as a major objection (10). Male Australian immigrants were less receptive to the notion of male contraception than those born in Australia (13). Among women with current partners in Hong Kong, only 14% felt that they would rely a male-based method in the future if it were available, whereas in Shanghai 71% of these female respondents would use a male-based method were it available (12). Interestingly, more than 70% of women in both locales thought male contraception was a good idea (12). Clearly, mode of delivery is an important factor in the acceptability of male contraceptive regimens. In large surveys, oral forms of contraceptive delivery are favored by most male respondents (10, 14). Depending on their country of origin, women felt their partners were most likely to use a daily pill or monthly injection (12). Injection-based hormonal regimens, the most clinically studied experimental contraceptive method to date, are acceptable to the majority of participants in male contraceptive studies (15, 16). However, whether the injections are once a month (16) or as far apart as every 12 wk (15), participants find the injection schedule and associated discomfort as the biggest disadvantage to these regimens, and 35 40% cite dissatisfaction with the method as a result (15, 16). A combination of a daily transdermal gel with every 3-month injections was slightly less acceptable to participants, with 45% stating they would use such a regimen if it were commercially available but one third citing that the daily gel interfered with their daily routine, making it less acceptable (17). In summary, most men and their female partners are receptive to the notion, and in fact the practice, of male contraception. Overall, a majority of men feel that the responsibility of contraception falls too much on women (11) and are receptive to male-based methods (10), while 7197% of women believe male hormonal contraception is a good idea (12). The time is ripe, therefore, for introduction of new methods to the marketplace.
III. Currently Available Male Contraceptive Methods A. Condoms
II. Acceptability of Male Contraception
It has been suggested that development of male-based contraceptive methods represents a misdirection of resources (8) because contraception is ultimately in the domain of female reproductive health. However, the appeal of a male contraceptive to both men and women is great. In surveys spanning four continents, a majority of men indicate a will-
Barrier methods have been used to prevent pregnancy since ancient times, but sheath-like condoms, originally made from animal intestines, were developed 300 400 yr ago. Today, barrier methods, including the female as well as male condom, are the only effective means, besides absti-
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nence and lifelong mutual monogamy, of preventing sexually transmitted disease transmission. In particular, although male circumcision has recently been shown to significantly reduce male transmission of HIV (18), the condom remains the most effective way of preventing HIV transmission during sexual contact. Condoms are currently used by approximately 20% of couples using contraception in the United States (19, 20), although the United Nations reports that only 5% of reproductive age women worldwide rely on male condoms for contraception (21). Condoms are associated with few adverse side effects; however, they have a marginal contraceptive efficacy. This is mainly due to improper or inconsistent usage, as demonstrated by comparison of pregnancy rates for typical use (15%) vs. perfect use (2%) for couples using condoms for contraception (22, 23). A significant drawback to condoms is their poor long-term compliance, with more than half of users reporting inconsistent use with every act of intercourse (24). In addition, many men dislike condoms because they feel condoms diminish sexual pleasure (25), again hampering consistent usage. However, even when used correctly, condom breakage and slippage are not infrequent, occurring in up to 2 8% of cases (26 30). Since 1920, most condoms have been made of latex rubber; however, latex condom use has been associated with development of latex allergies in both men and women, which can cause skin irritation and even death (31, 32). As a result of latex allergies, polyurethane condoms have been more recently developed and entered the market in the 1990s. Clinical studies with these condoms have demonstrated a slightly higher rate of condom breakage and slippage when compared with latex condoms (26, 29, 30, 33). In addition, some users have greater difficulty with putting on (33) or unrolling (30) polyurethane condoms compared with latex condoms. Most importantly, however, in general polyurethane and latex condoms have similar efficacy rates (26, 28), with the exception of one study reporting slightly greater efficacy with the latex condom (29). Therefore, despite their increased breakage, polyurethane condoms are an important alternative to latex condoms for couples, particularly those with latex allergies.
B. Vasectomy
a delay in the onset of azoospermia of several months and the lack of complete reversibility. Acute pain, blood loss, and surgical site infections are very rare, particularly with the no-scalpel technique (41). However, whereas postoperative pain usually resolves quickly, 6 15% of men experience some degree of postvasectomy chronic testicular discomfort (43 45). In one study of such men, the majority had relief of their symptoms with reversal of the vasectomy (46). Three to 5% of men with vasectomies eventually request reversal, usually due to remarriage (47, 48). Vasectomy reversal, or vasovasostomy, has the potential to restore fertility; however, rates of pregnancy vary from 30 60% (45). Factors that impact postreversal pregnancy rates include microsurgical technique used and the length of time between the vasectomy and the reversal procedure (45, 49). In 20 30% of men, vasovasostomy is unable to restore patency of the vas if more than 8 yr have elapsed since the original vasectomy (49), and pregnancy rates fall to less than 50%. In fact, 20 40% of all couples remain infertile after vasectomy reversal despite restored patency of the vas (as documented by imaging techniques), possibly due to the presence of antisperm antibodies (50, 51). The type of antibody response may be a key factor. One study found that the presence of IgA antisperm antibodies greatly increased rates of fertility failure after vasovasostomy (52). In summary, for these reasons, vasectomy cannot be considered to be a truly reversible method of male contraception and is most appropriate for men who no longer wish to father children. Vasectomy appears to be safe in regard to overall male health. Earlier reports of associations between vasectomy and cardiovascular disease have proven incorrect (53), and more recent concerns about vasectomy and prostate cancer risk have not been substantiated (35, 43, 45, 54 56). In summary, vasectomy is highly effective and safe. The major drawbacks of vasectomy are a risk of chronic testicular discomfort, the inability of surgery to reliably restore fertility when desired, and economic constraints in developing countries.
IV. Regulation of Testicular Function and Spermatogenesis
Vasectomy is a safe, simple, outpatient surgery performed under local anesthesia in which the ductus deferens is severed and the ends ligated through a small scrotal incision. Approximately 500,000 vasectomies are performed yearly in the United States (34), where approximately 10% of couples using contraception rely on this method (19, 20). Worldwide over 40 million men have undergone the procedure (35), accounting for about 5% of active contraception (21). Vasectomies are highly effective, with a failure rate of less than 1% and a low incidence of complications (36 38). The no scalpel technique was introduced in the early 1990s after development in the Sichuan province in China (39). This technique utilizes a single, midline puncture in the scrotal raphe made with scissors, and in experienced hands it is superior to previous procedures because it minimizes blood loss and risk of infection (40 42). The major drawbacks to vasectomy are
The purpose of this section is to introduce the physiological basis of male fertility, with particular attention to potential contraceptive targets. It is not meant to be a comprehensive review of all factors involved in this process. Developmental aspects of the male reproductive tract have been reviewed recently (57).
A. The hypothalamic-pituitary axis: control of gonadotropin secretion
The hypothalamic-pituitary-testicular axis is a classic endocrine loop, with negative feedback of downstream products playing the pivotal regulatory role in maintaining homeostasis. Testicular production of both hormones and sperm is exquisitely regulated by gonadotropins produced by the pituitary, whereas gonadotropin production is under the direct control of pulsatile GnRH secretion from the hypothalamus (Fig. 1). In turn, steroid and peptide hormones
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FIG. 1. The endocrinology of spermatogenesis and male hormonal contraception. Open arrows denote promotion of spermatogenesis; dashed lines denote inhibition of spermatogenesis and hormone production. A, Diagram of the naturally occurring, normal state. B, Diagram of the impact of hormonal contraceptive interventions on the reproductive axis.
produced in the testes provide inhibitory signals to the pituitary and hypothalamus. It has been known for over 25 yr that both temporal and quantitative changes in GnRH secretion disrupt testicular function (58). GnRH secretion from the hypothalamus is directly related to pulsatile release of LH and FSH in the peripheral circulation (59, 60); thus disrupters of GnRH secretion and action are potential contraceptive targets. Over the last 5 yr there have been rapid advances in understanding of the neuroendocrine control of reproduction upstream of GnRH, and these too represent potential new contraceptive targets that have yet to be tested. Initially, studies into the
genetics of familial hypogonadotropic hypogonadism revealed the critical role of the then orphan G protein receptor GPR54 in gonadotropin secretion (61, 62). Previous studies had demonstrated that the 54-amino acid peptide kisspeptin-54 (also called metastin) is the ligand for GPR54 (63 65). Subsequent investigations have demonstrated that: 1) kisspeptin is expressed in the arcuate, periventricular, and anteroventral periventricular nuclei of the forebrain; 2) GPR54 receptors located on GnRH-secreting neurons in the brain respond to kisspeptin; 3) kisspeptin administration in the brain results in GnRH and gonadotropin secretion in animal models; 4) gonadotropin responses to kisspeptin administration in animals are blocked by administration of a GnRH antagonist; and 5) kisspeptin appears to have direct inhibitory effects on pituitary gonadotropin release through interaction with GPR54 expressed on pituitary gonadotropes (reviewed in Ref. 66). Moreover, the negative feedback of testosterone and estradiol on GnRH secretion is mediated via inhibition of kisspeptin production in the arcuate nucleus of the hypothalamus (67, 68). Most recently, in contrast to acute administration of kisspeptin, which stimulates gonadotropin and testosterone release, chronic administration of kisspeptin lowers serum LH levels in monkeys (69) and leads to testicular atrophy in adult male rats similar to that seen with chronic GnRH infusions (70). Together, these studies directly link kisspeptin-GPR54 to male reproduction and demonstrate the importance of this pathway in upstream regulation of testicular function and sex steroid homeostasis (Fig. 1). Similar to GnRH, the kisspeptin-GPR54 neuroendocrine pathway could be exploited for contraception. Inhibitors of kisspeptin, and/or GPR54 agonists and antagonists, in combination with testosterone, are a theoretically viable contraceptive strategy yet to be tested. Negative feedback to the pituitary and hypothalamus is critical to maintain endocrine homeostasis in the male (Fig. 1). Testosterone is the main testicular steroid, but significant aromatase activity in the testicle and peripheral tissues results in production of estradiol as well. Testosterone clearly inhibits kisspeptin transcription (67) and GnRH and gonadotropin secretion (7174). Some of this inhibition is estrogen independent (7578), but estradiol seems to play an important role in steroid negative feedback in the male, particularly by decreasing LH production (79 83). Aromatase inhibition results in significant increases in LH and FSH secretion in normal men (80); normal levels can be restored with estradiol supplementation in a nonlinear fashion, with higher estradiol levels having increasingly less effect on circulating gonadotropin and testosterone levels (81). Moreover, both aromatase inhibition and medical castration result in similar increases in FSH, despite markedly decreased testosterone levels with medical castration compared with aromatase inhibition; this suggests that, at least acutely, FSH regulation is more dependent on estradiol than testosterone (84, 85). In contrast, dihydrotestosterone (DHT), a nonaromatizable androgen, is a poor inhibitor of gonadotropin production in the male when given at or near physiological doses (83, 86), and 5-reductase blockade with finasteride or dutasteride, which lowers serum DHT concentration by as much as 95%, fails to alter gonadotropin levels (87). However, with chronic administration and supraphysiological dosing, exogenous
DHT inhibits both LH and FSH secretion despite concomitant suppression of testosterone and estradiol (88, 89), demonstrating that aromatization is not an absolute requirement for negative feedback. Like other sex steroids, progesterone is expressed in the male as well as the female, albeit at lower levels (90). The precise role of progesterone in normal male physiology is unknown, but progesterone receptors have been demonstrated in the male hypothalamus, pituitary, and reproductive tract (9193). Mature male progesterone receptor-deficient mice have normal reproductive phenotype, normal serum LH, and mildly decreased FSH levels compared with wild-type animals (94), results which suggest that the physiological role of progestins in the male hypothalamic-pituitary axis is minimal, at least in the rodent. However, progestins enhance male hormonal contraceptive efficacy when combined with androgens (95), an effect attributed to increased hypothalamic-pituitary suppression of gonadotropin secretion either directly or through the androgen receptor. Brady et al. (96) compared the effects of progesterone and the synthetic progestin, desogestrel, on gonadotropin secretion and GnRH responsiveness in normal men. Although both progestins decreased LH and FSH secretion, only progesterone decreased the LH response to GnRH. These results demonstrate that progesterone affects gonadotropin secretion through progesterone receptors and provide evidence for such inhibition at both the hypothalamic and pituitary levels. However, the effects of exogenous progestins on spermatogenesis are greater than can be accounted for by enhanced suppression of gonadotropins alone (97). Therefore, it has been suggested that progestins may act directly on the testes. There is recent evidence directly supporting this hypothesis. First, both membrane-bound and intracellular progesterone receptors have been demonstrated in the human testes (98). Second, Walton et al. (99) recently demonstrated that the exogenous progestin desogestrel, when combined with testosterone and a GnRH antagonist, mediates a direct effect on testicular gene expression. In this context, progestins influenced expression of genes involved in steroidogenesis, Sertoli cell function, and spermatogenesis. Together these data strongly support an effect of progestins on male reproduction independent of their gonadotropin effects. Exploitation of testicular progestin action is an additional mechanism whereby specific progestins could be formulated as male contraceptives. Finally, the nonsteroidal testicular product inhibin B contributes to hormonal feedback in the male. Inhibin B is a dimeric molecule consisting of and subunits and a member of the TGF- family. Inhibin B is predominantly produced by Sertoli cells (100), and inhibin B levels correlate with Sertoli cell number (101). However recent observations in boys with constitutively active LH-receptor mutations resulting in familial male-limited precocious puberty suggest that Leydig cells may produce some inhibin B (102). Indeed, although inhibin B levels rise acutely with FSH administration (103), chronic FSH and spermatogenic suppression results in only a 25% decline in levels, suggesting FSH-independent inhibin B production (104). Similarly, inhibin B levels are low, but detectable, in rare individuals with FSH and FSH receptor mutations (105107). Negative feedback by
inhibin B on FSH production has been demonstrated in 1) normal men, where inhibin B and FSH exhibit an inverse relationship (108, 109); 2) castrate men with very high FSH levels compared with normal men rendered medically castrate (109); 3) men with testicular disorders (103, 110); and 4) male infertility (111) where low inhibin B levels are associated with increased levels of FSH. Together, these data establish the role for inhibin B as a testicular regulator of FSH, as hypothesized by McCullagh (112) over 75 yr ago. Aside from its role in regulating FSH production and as an indicator of Sertoli cell function, no clear role for inhibin B in testicular physiology or spermatogenesis has been established. Theoretically, exogenous inhibin B in conjunction with androgens might further suppress FSH and be an adjunct in a male hormonal contraceptive regimen (Fig. 1). However, to date recombinant inhibin B has not been available for clinical studies, and recent investigations suggest that incomplete FSH suppression may not be pivotal to persistent spermatogenesis in men undergoing male hormonal contraceptive treatment (see Ref. 97 and Section IV.D).
B. Testosterone production and androgen action
Testosterone is produced by the Leydig cells of the testes, primarily in response to LH stimulation. However, there is increasing evidence that there may be non-LH-dependent production of testosterone, which may be critical in maintaining spermatogenesis under conditions of LH inhibition, such as with the hormonal approach to male contraception. LH-receptor (LHR /) knockout mice have low, but detectable levels of circulating testosterone (113, 114). Despite being infertile, a detailed histological examination of testicular tissue from mature LHR / mice revealed low level spermatogenesis that was completely blocked by treatment with an androgen receptor antagonist (113). These results are consistent with low levels of testosterone observed in rodents after hypophysectomy (115, 116). Regulation of non-gonadotropin-dependent testosterone production in men, if it is similar to that in rodents, may be a critical aspect in the development of a universally effective hormonal method of male contraception because this approach relies on blockade of gonadotropin secretion for efficacy. Under normal physiological conditions in young men, 4 6 mg of testosterone is secreted by the testes daily (117119) with a circadian rhythm; the highest level of secretion is in the early morning, and lower levels are found in the circulation during midafternoon (120 122). This pattern is blunted with age, likely due to impairment at multiple levels of the hypothalamic-pituitary-testicular axis (123126). A small percentage of testosterone (1%) is converted to DHT within the testes and elsewhere by the isoenzymes 5-reductase I and II, resulting in circulating DHT levels in the 13 nmol/liter range in normal men. DHT is thought to be a considerably more potent androgen than testosterone, due to its 10-fold greater affinity for the androgen receptor, but its role in spermatogenesis is not known. Significant reductions in serum DHT appear to have a marginal impact on sperm production in normal men (87). In addition, testosterone can be aromatized to estradiol within the testes. The role of estradiol in spermatogenesis is unclear, but increasing evi-
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dence suggests that it may play a role. Men with aromatase deficiency or mutations in the estrogen receptor have impaired spermatogenesis despite otherwise normal secondary sexual development (127130). Moreover, estrogen receptors are expressed in the testes and perhaps on human male germ cells themselves (131133). Both testosterone and its active metabolites therefore appear to be important in qualitatively and quantitatively normal spermatogenesis. Because testicular Leydig cells are the site of testosterone synthesis and secretion under the control of LH, intratesticular testosterone concentrations are 100-fold those of serum (134 138), but the relative importance of this high-androgen environment for spermatogenesis is not well understood. Experimental suppression of LH and FSH levels profoundly decreases testosterone production (137, 139, 140) and dramatically reduces spermatogenesis in men (141, 142). However, results from LH receptor-deficient mice suggest that even markedly reduced levels of androgen can support spermatogenesis (113, 114), although complete blockade of residual androgen action with androgen receptor antagonist flutamide abolished spermatogenesis (113). In addition, using the very effective combination of testosterone enanthate (TE) cyproterone acetate, higher levels of serum testosterone were associated with a lesser degree of spermatogenic suppression (143). These findings have led to the proposal that high levels of exogenous androgens or residual androgen production after gonadotropin withdrawal may be sufficient to support spermatogenesis and result in contraceptive failure (117, 138, 144, 145). However, two recent studies have called this into question (140, 146). In contrast to a rodent model (147), no significant relationship between sperm concentration and intratesticular androgen concentrations was observed in men after prolonged gonadotropin withdrawal in these small studies. Moreover, although it has been suggested that the active metabolite of testosterone, DHT, a more potent androgen, may play a pivotal role in maintaining spermatogenesis during male hormonal contraceptive treatment (117, 138), intratesticular DHT levels did not explain persistent spermatogenesis in these studies. These results are consistent with data in humans where the addition of a 5-reductase inhibitor to a male hormonal contraceptive regimen was not shown to increase the effectiveness of spermatogenic suppression (148, 149). Further investigation into the precise regulation and role of intratesticular androgens in supporting spermatogenesis in men is clearly needed, because targeted disruption of residual androgen production and/or action might be an adjunct to increase effectiveness of current hormonal methods. Classically, androgen action results from ligand binding to the androgen receptor and translocation of the bound, dimerized receptor-ligand complex to the nucleus where it directs androgen-regulated gene transcription via interaction with androgen-response-elements (150). Androgen receptor is expressed in multiple cell types within the testes including Sertoli, Leydig, peritubular myoid, and vascular smooth muscle cells, and on germ cells during the early stages of spermatogenesis (151). Mice completely devoid of androgen receptor throughout development have feminized genitalia, cryptorchid testes, and azoospermia with arrested spermatogenesis at the pachytene spermatocyte stage (152). Due to
the role of androgen receptor signaling in the development of both the external and internal male phenotype, tissuespecific knockouts were required to further delineate the role of androgen receptor in supporting spermatogenesis in specific testicular cell types. Normal fertility is preserved in mice lacking androgen receptor in either germ cells (153) or peritubular myoid cells (154), although in the latter case reduced germ cell numbers, particularly within the epididymis, were noted. In contrast, both Leydig cell and Sertoli cell-specific androgen receptor knockouts are infertile (153, 155157) and have small testes. Interestingly, the level of serum testosterone found in various Sertoli-cell only knockouts varies from low to supraphysiological for unclear reasons (155157). These differences aside, these studies emphasize the critical importance of paracrine actions of androgens within the testes, but the precise mechanism whereby androgen receptor signaling in Leydig and Sertoli cells supports germ cell maturation is not yet clear. Three recent studies examining the transcriptional targets of androgen receptor using Sertolicell only androgen receptor knockouts suggest potential targets, but further functional analyses of these will be required (158 160). In theory, these models suggest that androgen receptor disrupters that could be targeted to specific cell types such as the Sertoli cell might make excellent contraceptives but such compounds have yet to be developed. Data from animals with disrupted androgen receptor and mice treated with androgen receptor blockade with the antagonist flutamide (161) demonstrate that signaling through the androgen receptor is required for spermatogenesis. Modulators of androgen action include tissue-specific expression of coactivators and corepressors as well as genomic variation in the androgen receptor itself. Molecules that bind the androgen receptor yet prohibit or enhance binding of tissuespecific coactivators or corepressors could act as selective androgen receptor modulators (SARMs). Recently, a second, nongenotropic sex steroid receptor-mediated signaling pathway has been proposed that may allow for a second, tissuespecific mechanism for androgen receptor signaling (162 164). Activators of nongenomic estrogen-like signaling, or ANGELS (164, 165), are thought to act predominantly through the MAPK kinase signaling cascade, although their exact mechanism of action and degree of tissue selectivity remain controversial (166). Either SARMs or ANGELS could be employed as part of a hormonal approach to male contraception, allowing for tissue-specific androgen replacement in the setting of reduced gonadotropin and endogenous testosterone production. However, such approaches have yet to be tested in human trials. In addition, naturally occurring variations in the androgen receptor structure could be exploited in the design of such designer androgens. For example, exon 1 of the androgen receptor contains a trinucleotide CAG repeat of variable number, encoding a polymorphic polyglutamine tract and a downstream GGN repeat encoding a polyglycine region (167). The number of CAG repeats is inversely associated with the transcriptional response to androgens in vitro (168, 169) and in vivo (170 172). Impairments in spermatogenesis have been associated with increased CAG repeat length (173, 174), although this is not a consistent finding (175, 176). Expanded GGN repeats are also thought to decrease andro-
gen receptor signaling, but increased repeats were not associated with impaired spermatogenesis (177) unless found in conjunction with longer CAG repeats (178). The crystal structure of the androgen receptor with expanded exon 1 repeats has not been published to date, so the exact impact of these changes on the ligand binding domain is not known. However, given the subtle androgen effects of CAG and GGN repeats observed clinically, exploitation of naturally occurring variations in androgen receptor is unlikely to prove an effective strategy for contraceptive drug design. Over the last few years, a number of testosterone formulations have become available, including long-acting depot injections, implants, transdermal gels, transdermal patches, and buccal formulations (Table 1). Each of these has its own particular pharmacokinetics (179). Using a hormonal approach to contraception, testosterone is administered in part to block gonadotropin secretion but also to maintain nongonadal androgen-dependent functions such as sexual drive and muscle mass. The importance of mimicking normal physiological testosterone secretion patterns in maintaining both nongonadal androgenicity and contraceptive efficacy using a hormonal approach is not known (180), because head to head trials comparing different forms of testosterone delivery are lacking. Long-acting injections, which are currently being tested as part of a large contraceptive efficacy trial, are associated with peaks and troughs, even after multiple injections (181). Although the transdermal preparations have the most physiological pharmacokinetic profiles, patches have been universally disappointing in contraceptive trials (182184), probably due to low levels of serum testosterone. The only large study using transdermal testosterone gel to date, although highly effective, achieved testosterone levels in the slightly supraphysiological range (185). Significant supraphysiological dosing of testosterone
can be associated with side effects including high-density lipoprotein (HDL) suppression, acne, and increased hemoglobin concentrations (186, 187) that would not be desirable in a regimen designed for long-term use, although these are not consistent findings (188). Therefore, the goal of most hormonal regimens under study is to maintain serum testosterone levels within the normal range, delivering approximately 5 mg/d of testosterone.
C. Spermatogenesis
Male contraceptive strategies may generally be divided into approaches that disrupt spermatogenesis, which are largely hormonally based, and those that disrupt sperm-egg interactions by disrupting either sperm motility or processes involved in fertilization. These latter approaches are nonhormonal. Although this is not meant to be a comprehensive review of our current understanding of spermatogenesis, we provide a brief overview of sperm maturation here to put these strategies into context. In particular, there have been substantial developments in delineating the markers and potential of germ cell stem cells recently, and we refer the reader to recent reviews of this field (189, 190). During spermatogenesis, spermatogonia, through multiple mitotic and meiotic divisions, develop into mature spermatozoa. In brief, this process may be divided into four stages (191). First, type A spermatogonia undergo mitosis, resulting in renewal of germline stem cells as well as type B spermatogonia that continue to undergo differentiation. Second, type B spermatogonia undergo meiosis, generating haploid round spermatids. Next, spermiogenesis occurs, wherein round spermatids mature to motile spermatozoa without undergoing further cell division. Spermiogenesis includes formation of the acrosome, nuclear condensation,
TABLE 1. Androgen formulations available for possible incorporation into a male hormonal contraceptive regimen
Generic name Route and interval of administration Published use in a contraceptive regimen (Ref.) Potential concerns as part of a contraceptive regimen
Testosterone undecanoate 17-Methyltestosterone Testosterone enanthate Testosterone decanoate Testosterone undecanoate Testosterone implants Testosterone patch Testosterone gel Dihydrotestosterone gel Testosterone buccal system MENT implant Testosterone 5-reductase inhibitor
Oral, twice daily Oral, daily Intramuscular, 12 wk Intramuscular, 4 6 wk Intramuscular, 8 12 wk Subcutaneous, 4 months Transdermal nonscrotal, daily Transdermal, daily Transdermal, daily Buccal, daily Subcutaneous, 6 months Injection 12 wk, plus daily oral pill
Yes (228, 229, 241, 381) No Yes (141, 142, 143, 238 240, 242, 243, 250, 251, 382) Yes (246) Yes (217, 230, 231, 254 256, 384) Yes (216, 218, 245, 247, 385) Yes (182184) Yes (185, 381) Yes (381, 383) No Yes (215, 298) Yes (148, 149)
Twice daily dosing, short and variable duration Liver toxicity Injections can be painful, high peak levels Injections can be painful, high peak levels Injections can be painful, nonphysiological pharmacokinetics Surgical placement, occasional painful expulsions Poor efficacy, high frequency of skin irritation Possibility of partner transfer, daily application needed Poor efficacy, not aromatized Untested, very limited clinical use Surgical placement, poor sperm suppression, concern regarding bone effects 5-Reductase inhibitor gave no additional contraceptive benefit
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and extensive cellular reorganization including sperm tail development. Finally, interactions with the Sertoli cell mediate the process of spermiation, wherein cytoplasmic material from the spermatid is removed and the mature sperm is released into the lumen of the seminiferous tubule. This entire process is under strict endocrine regulation, and there is potential for contraceptives to target all or part of this process. Although the role of FSH in human spermatogenesis has been debated, it is clear that both FSH and LH are required for quantitatively and qualitatively normal spermatogenesis in men. This has been demonstrated in a series of human studies wherein gonadotropin production and spermatogenesis were suppressed in men using exogenous testosterone and either LH [in the form of human chorionic gonadotropin (hCG)] or FSH were given back in a selective fashion (192 195). Although either gonadotropin alone can reinitiate spermatogenesis, both LH and FSH are required to achieve normal semen parameters. Matthiesson et al. (196) recently expanded upon this work with detailed examination of the relative stages of spermatogenesis affected by selective gonadotropin supplementation using exogenous testosterone plus depomedroxyprogesterone (DMPA) to suppress endogenous testosterone and spermatogenesis. Data from both rodents and monkeys suggested that FSH is more important than LH for spermatogonial maturation, whereas LH and/or intratesticular androgens are needed for normal completion of meiosis and spermiogenesis/spermiation (197200). Surprisingly, after 6 wk of selective LH or FSH withdrawal, only pachytene sperm differed among men lacking FSH (treated with testosterone DMPA hCG) compared with untreated, control individuals; men lacking LH showed no differences compared with untreated men. Moreover, this was despite a 100-fold reduction in intratesticular testosterone in men treated with testosterone DMPA FSH compared with control and hCG-treated men (196). Although the interpretation of these results is limited by the length of treatment and small numbers of individuals studied, they suggest that either FSH or LH/intratesticular androgens are sufficient to support all stages of spermatogenesis, including spermatogonial maturation, meiosis, spermiogenesis, and spermiation. These data emphasize the need for hormonally based male contraceptive strategies to maximally suppress both LH and FSH to optimize spermatogenic suppression.
D. The epididymis
cell. Therefore, the molecules in these Sertoli-germ cell complexes are attractive contraceptive targets if testes specificity could be demonstrated and appropriate agents developed (203). Within the epididymis, sperm undergo further maturation steps allowing for maximal motility and fertilization capacity, as exemplified by the improved fertility rates when recovered spermatozoa are injected intracytoplasmically into the egg or when spermatozoa from further down the cauda are used for in vitro fertilization (204). There have been a number of detailed analyses of the transcriptional profiles of the rodent epididymis, including detailed segmental analyses (205207). It is possible that in the future such analyses will provide novel contraceptive targets, but at this point these data remain largely descriptive and functional analyses of these novel transcripts are required. Similar analyses using proteomics have begun, again perhaps providing novel, organ-specific targets for intervention (208). Suzuki et al. (209) have recently identified an epididymis-specific promoter from the Lipocalin 5 that may be of use in contrasting animal models to assess these targets. Finally, as they travel through the epididymis, maturing sperm encounter an increasingly hyperosmolar environment, yet upon arrival in the female tract these sperm must adopt to the local, hyposmolar environment to remain motile and competent. This requires significant, regulated volume decreases via ion channels acquired during epididymal maturation that might be targets for contraception in either the male or female (210, 211).
V. Male Hormonal Contraceptive Methods
Once spermatogenesis is complete, sperm are released from the Sertoli cells into the lumen of the seminiferous tubules and move through the epididymis before ejaculation. These processes involve additional, as yet poorly characterized events that might provide further targets for contraception. Both FSH and testosterone are thought to play a role in spermiation (201), the release of the spermatid into the tubule lumen, perhaps through regulation of proteins involved in germ-Sertoli cell adherence (197). In rodents, this multiprotein junctional complex appears to involve N-cadherin and a number of other integrins and kinases and is sensitive to phosphorylation (202). Failure of spermiation results in sperm retention and phagocytosis by the Sertoli
It has been known for almost 70 yr that the chronic administration of testosterone to a man suppresses sperm production (212). Because the administration of testosterone alone fails to completely suppress sperm production in some men, progestogens or GnRH antagonists have been combined with testosterone to further suppress pituitary gonadotropins and improve its contraceptive efficacy. These hormonal contraceptive regimens inhibit sperm production and do not incapacitate existing sperm. Because spermatogenesis takes place over 72 d, there is a 2- to 3-month delay in the onset of full contraceptive effect associated with the use of male hormonal contraceptives, a delay that is similar to that seen with vasectomy, but longer than the period of time required for female oral contraceptives to be effective. In addition, there are ethnic differences in the response of sperm concentrations to male contraceptive regimens. For example, study volunteers in Asia exhibit rates of azoospermia in the 90 100% range on testosterone-alone regimens, whereas Caucasian men have rates of azoospermia closer to 60% with the same treatment (142, 213214, 216). The explanation for this difference is unknown, although it is unlikely to be due to different rates of metabolic clearance of testosterone (122), and it complicates extrapolation of rates of suppression of sperm concentrations between populations.
A. Hormonal contraceptive efficacy
The best test of a contraceptive is to study the method in couples who use it as a sole means of contraception. Al-
though the efficacy of condoms and vasectomy is well studied, the only experimental male contraceptive methods to date to undergo efficacy testing are hormonal regimens. Four such male hormonal contraceptive efficacy trials have been published (141, 142, 217, 218), and a fifth multicenter study was recently completed. The first of these tested only the fertility of men who became azoospermic with exogenous testosterone administration (141) and demonstrated that the contraceptive efficacy of testosterone-induced azoospermia is almost perfect. However, this study cannot be used to determine the overall efficacy of testosterone alone as a contraceptive because men who did not achieve azoospermia were not allowed to enter the efficacy phase. The three more recent trials have examined the outcomes of all subjects enrolled and allowed men who suppressed below a threshold sperm concentration (1 to 5 million sperm/ml) to use the method as a sole means of birth control. Analysis of these studies reveals that male hormonal contraception has an overall efficacy of approximately 95%, even when men who do not completely suppress sperm production are included (Table 2). This overall figure is only slightly inferior to the efficacy of female hormonal contraceptives. In these studies, a sperm concentration at or below 1 million sperm/ml of ejaculatesevere oligospermiais associated with a risk of pregnancy of approximately 1% (142). Therefore, uniform suppression of all subjects to a sperm concentration no greater than 1 million sperm/ml is thought to be a reasonable short-term goal for male hormonal contraceptive development (219). Aside from those studies mentioned above, male hormonal contraceptive studies examine the impact of exogenous hormones on sperm production, with effectiveness measured as rates of azoospermia (0 sperm/ ml), severe oligospermia (1 million sperm/ml), or oligospermia (3 million sperm/ml) among users.
B. Testosterone alone
1. Testosterone enanthate (TE). As mentioned above, the World Health Organization (WHO) conducted two seminal, multicenter, male hormonal contraceptive efficacy studies. These trials used the injectable testosterone ester, TE, as a single agent for male contraception. The first study enrolled 271 Asian and Caucasian men who were administered 200 mg TE by weekly injection for 6 months (141). Sixty-five percent of the men became azoospermic using this regimen after a mean of 4 months, and 75% of the remaining men became oligoTABLE 2. Male hormonal contraceptive efficacy trials
Study, year published (Ref.) Length of efficacy phase No. of azoospermic men (%) No. of oligo-spermic men (%)
spermic (3 million sperm/ml). The fertility of 119 of the azoospermic men was then evaluated in a 12-month efficacy phase. In these couples, who used TE as their sole means of contraception during this year, only one pregnancy occurred, corresponding to a pregnancy rate of 0.8 pregnancies per 100 person-years and an efficacy rate of over 99%. The second WHO study tested the fertility of men who became either azoospermic or oligospermic (less than 35 million sperm/ml) on 200 mg of TE weekly (142). The study enrolled 399 men, all but eight (2%) of whom became azoospermic or oligospermic and met criteria for entry into the efficacy phase of the study. In this phase, there were no pregnancies fathered by the men who became azoospermic. In men whose sperm concentration was suppressed to less than 35 million/ml, fertility was reduced to 8.1 pregnancies per 100 person-years. The fertility rate for all men who suppressed enough to enter the efficacy phase was 1.4 per 100 person-years, and the overall failure rate (including the eight men who failed to suppress to less than 5 million sperm/ml) was 5.3%, for an overall contraceptive efficacy of 94.7% (Table 2). These two seminal studies demonstrated that a regimen of weekly TE injections is a reversible and effective contraceptive in the large majority of men and is safe over the 18 months of treatment. The main drawbacks to this approach are the delay in onset of full contraceptive action of 3 4 months, the fact that 2% of men fail to suppress below 3 million sperm/ml and therefore remain potentially fertile, and the potential safety concerns associated with long-term, supraphysiological levels of serum testosterone, the longterm consequences of which are not known. Side effects from weekly injections of 200 mg of TE in healthy men include weight gain, a reversible 25% reduction in testicular volume, a 6% increase in hemoglobin, and a 10 15% decrease in serum HDL cholesterol (142, 187, 220). Importantly, these effects appear to be dose-related (186). There was no evidence that exogenous testosterone administration, despite increasing estradiol levels, increases the risk of blood clotting, which could increase the risk of heart attack or stroke. Indeed, one study suggests that the administration of exogenous testosterone in a male contraceptive regimen may exhibit antithrombotic and antiinflammatory effects (221, 222). Quality of life, sexual function, and well-being are maintained or slightly improved with TE-based male contraceptive regimens (220, 223). Overall, the TE regimen was
No. of couples
No. of failures to suppressa (%)
No. of pregnancies (%)
Total no. of failuresb (%)
Overall contraceptive efficacy (95% CI)
WHO, 1996 (142) Gu et al., 2003 (217) Turner et al., 2003 (218) Total
357 305 53 715
12months 6months 12months
268 (75) 130 (43) 49 (93) 447 (62)
81 (23) 166 (54) 2 (3.6) 249 (35)
8 (2.2) 9 (2.9) 2 (3.6) 19 (2.6)
11 (3.1) 1 (0.3) 0 (0.0) 12 (1.7)
19 (5.3) 10 (3.3) 2 (3.6) 31 (4.4)
94.7(9297) 96.7(9598) 96.4(91100) 95.7(94 97)
CI, Confidence interval. a To a sperm count less than 35 million, depending on study. b Defined as pregnancy and/or failure to suppress to enrollment in the efficacy phase.
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rated better than expected by a majority of men in these studies (224). However, the use of weekly im injections in this regimen led to discontinuation by a small number of men. Although useful as a proof of principle, these landmark studies demonstrated that use of weekly TE alone for contraception is limited by side effects, a 2% failure to adequately suppress spermatogenesis, and the impracticality of weekly injections, and suggested that additional agents would be necessary to improve the hormonal approach to male hormonal contraception. 2. Testosterone undecanoate (TU). TU is a long-chain ester that can be administered orally or by injection (225, 226). In testosterone-deficient men, a single injection maintains serum testosterone levels in the normal range for 6 12 wk (226, 227). Oral administration requires dosing two or three times daily, making it less practical (225), and explaining perhaps the somewhat disappointing results of the only (pilot) male hormonal contraceptive study using oral TU (228). Three small trials using TU injections in normal men for male contraception were initially conducted. In the first study, conducted in China, volunteers received monthly doses of 500 or 1000 mg TU. Eleven of the 12 men in the 500-mg group and all 12 in the 1000-mg group became azoospermic, with the 1000-mg group achieving azoospermia more quickly (229). In the two other pilot studies, conducted in Germany, TU was used alone or in combination with a progestin (see Section V.C) (230, 231). In the arms of these studies in which subjects received only TU, eight of 14 men who were administered 1000 mg TU every 6 wk achieved azoospermia, with four of the remaining six suppressing their sperm concentrations below 3 million sperm/ml. Although the regimens and formulations of TU were slightly different than that used in China, it appears that, as was the case with TE, it remains more difficult to suppress sperm concentrations in nonAsian populations even with long-acting androgens such as TU. Subsequently, a large Chinese efficacy trial studied 308 men treated with monthly injections of 500 mg TU after a 1000-mg loading dose (217). Forty-three percent of men suppressed to azoospermia on this regimen, but only nine (3%) of the men failed to suppress to sperm concentrations below 3 million sperm/ml, the criteria for entering the efficacy phase of the study. During the subsequent 12-month contraceptive efficacy phase, 296 couples used the TU injections as a sole means of contraception. Of these, six men had partial return of sperm production, and there was one pregnancy attributed to the reappearance of sperm while on TU therapy. Overall, this regimen has a 96.7% contraceptive efficacy in Chinese men (Table 2). As with TE, injections of TU at this dosing interval resulted in supraphysiological levels of serum testosterone in some men, and nadir testosterone levels were 31% greater than baseline testosterone levels. Similar to TE, injectable TU was associated with weight gain, a 9% increase in hemoglobin, and a 14% decrease in HDL. However, there were no serious adverse events during treatment, and these changes were reversible. Moreover, most participants found the regimen acceptable (16). A phase III trial of contraceptive efficacy with TU in tea seed oil involving 1000
Chinese couples is currently nearing completion, which will add much to the field. 3. Transdermal testosterone. Scrotal transdermal testosterone patches were introduced in the late 1980s (232). Although testosterone patches are useful for the treatment of male hypogonadism, they have not been effective for male contraception, presumably because the serum testosterone levels are insufficient to completely suppress gonadotropin secretion from the pituitary, even with the addition of a progestin. For example, one study combining a testosterone patch with the progestin levonorgestrel resulted in azoospermia in only two of 11 men and counts below 3 million sperm/ml in three others (182). In a second study, testosterone patches were combined with oral levonorgestrel, but less than 50% of subjects achieved azoospermia (183). Skin reactions to the patch are also a problem. In a third testosterone-patch study, which combined testosterone patches with the progestin desogestrel, only 41% of the subjects achieved azoospermia, and 24% of participants withdrew from the study because of skin irritation attributable to the patches (184). Recently, transdermal testosterone gels have been introduced into the marketplace for the treatment of male hypogonadism (233, 234). We recently reported that, in contrast to the testosterone patch, the combination of testosterone gel plus a long-acting injectable progestin, DMPA, resulted in levels of azo- and oligospermia comparable to previous studies with im testosterone (185). These gels hold promise for contraceptive development because they achieve higher serum testosterone levels and are associated with less irritation of the skin than testosterone patches (233). It is possible that in the future, these gels could be combined with a progestin gel as an all-gel approach to male contraception.
C. Testosterone-progestin combinations
Because progestins inhibit the secretion of gonadotropins from the pituitary, several progestins have been combined with testosterone to improve its contraceptive effect by augmenting suppression of gonadotropins. In addition, it has been hypothesized that progestins might also have a direct inhibitory effect on spermatogenesis, although a recent study in nonhuman primates failed to demonstrate such an effect for the progestin norethisterone (235). Testosterone/progestin regimens were first tested for male hormonal contraception in the 1970s (236). One early case report suggested that the contraceptive efficacy of the early combinations was not ideal, with nine of 100 couples conceiving while on treatment, despite instructions to simultaneously use other methods of contraception and sperm concentrations under 10 million sperm/ml (237). Over the following 35 yr, efficacy of testosterone-progestin-based regimens has greatly improved. However, the use of progestins in men can be associated with side effects such as weight gain, additive suppression of serum HDL cholesterol, and perhaps increases in proinflammatory cytokines associated with increased cardiovascular risk (222); thus current protocols aim to minimize these adverse effects (see Section V.G). Early studies of progestins focused on demonstrating im-
proved sperm suppression compared with testosterone alone, while subsequent studies have aimed at minimizing the doses involved or optimizing the delivery strategy. A randomized, controlled trial of 0.5 mg of oral levonorgestrel with 100 mg of weekly TE showed that the combination was superior to TE alone in achieving azoospermia (67 vs. 33%) by 6 months in Caucasian men (238). Furthermore, the proportion of subjects achieving a sperm concentration of less than 3 million/ml was 94% in the combination group compared with 61% in the TE-alone group. However, the combination regimen resulted in greater weight gain and further decreases in HDL cholesterol when compared with the TEalone group, side effects which have been minimized without compromising effectiveness by lowering the dose of levonorgestrel in subsequent studies (239, 240). Recently, the combination of a long-acting levonorgestrel implant and 1000 mg of TU every 8 wk resulted in azoospermia in 90% of Chinese men, with all subjects suppressing to concentrations fewer than 3 million sperm/ml (241). Another oral progestin, desogestrel, has been tested in male contraceptive regimens with injectable TE (242, 243) or testosterone pellets (400 mg implanted every 12 wk) (244, 245) with overall rates of azoospermia in the 80 90% range in mostly Caucasian populations. The active metabolite of desogestrel is etonogestrel. Oral etonogestrel has been studied in combination with im injections at 4- or 6-wk intervals of the testosterone ester, testosterone decanoate (TD). In a study of 112 subjects, 111 achieved sperm concentrations of less than 1 million sperm/ml (246). Suppression was more rapid in the group receiving TD injections every 4 wk, and side effects were minor. Based upon these results, enthusiasm for the combination of injectable testosterone and a progestin led to two studies combining etonogestrel implants with testosterone. In the first, one or two implanted etonogestrel rods were combined with testosterone pellets and resulted in azoospermia in nine of 14 men in the higher dose etonogestrel group, with 13 of 14 men having sperm counts less than 0.1 million sperm/ml after 24 wk (247). Importantly, there were no significant reductions in HDL cholesterol when the progestin was administered via implant, implying that nonoral administration may be preferable for long-term administration of these compounds. The results from this pilot study were promising enough for a large pharmaceutical company to sponsor a multicenter phase II study of the combination of etonogestrel implants with TD given by im injection every 4 6 wk (248). This combination achieved rates of azoospermia in the 80 90% range, with overall high acceptability and a low incidence of side effects. A follow-up trial of etonogestrel implants combined with TU (which exhibits a half-life superior to that of TD) and involving more than 300 subjects has recently been completed in Europe; these results are not yet published. Success from this trial could in theory result in the first marketed male hormonal contraceptive, although the industry sponsors of this trial (Organon Biosciences and Schering Corporation) may be discontinuing their programs in male contraceptive development. Some progestins such as cyproterone acetate have antiandrogenic properties (249). The antiandrogenic effect of cyproterone may allow it to interfere with testosterone-mediated
spermatogenesis in the testis in addition to its progestogenic inhibition of FSH and LH secretion from the pituitary. In one small trial combining oral cyproterone acetate with 100 mg TE weekly, all men receiving the combination became azoospermic, whereas only three of five in the TE-alone group attained azoospermia (250). In addition, the time required to achieve azoospermia was markedly less in the cyproterone TE groups compared with the testosteronealone group (49 vs. 98 d). This group went on to evaluate lower doses of cyproterone acetate (251), which was also effective, and a completely oral male contraceptive regimen combining cyproterone with twice daily oral TU (228). In the study of the oral regimen, four of eight men suppressed their sperm concentrations below 1 million sperm/ml, with the four remaining subjects suppressing to 1.2 6 million sperm/ml (228). Cyproterone is not currently available in some countries (including the United States). Additionally, a similar antiandrogenic progestogen, dienogest, may be a promising progestin for future clinical trials in male contraception (252). The long-acting injectable progestogen, norethisterone enanthate, has also been tested in male hormonal contraceptive trials (253). In one study, 13 of 14 men who received the combination of 1000 mg TU and 200 mg norethisterone every 6 wk achieved azoospermia after 32 wk of treatment, with HDL suppression and mild weight gain in line with prior studies of testosterone/progestin combinations (231). It has subsequently been demonstrated that high rates of azoospermia (90%) can be maintained when TU and norethisterone enanthate are administered at 8-wk intervals, but not when they are dosed every 12 wk (254). Furthermore, although there is some accumulation of serum testosterone with every 8-wk dosing, the pharmacokinetics of TU are not altered by coadministration of norethisterone (181). This approach, employing an every 8-wk injection schedule, is a significant improvement over the requirement for weekly injections of TE in most prior studies. Alternatively, norethisterone enanthate can also be administered orally in combination with injectable TU (255). Similar to norethisterone enanthate, medroxyprogesterone acetate can be delivered by depot injection (DMPA). Doses identical to those widely used by women for contraception as Depo-Provera (300 mg every 3 months) have been tested in three recent male contraceptive studies. The first was an Australian study combining DMPA with testosterone pellets administered by implantation every 4 6 months (218). In this study, 53 of 55 men achieved sperm concentrations of less than 1 million sperm/ml and entered a 12month efficacy phase in which no pregnancies were observed (Table 2). This important trial was the first testosterone/ progestin efficacy study and confirms that the high rate of pregnancy prevention observed in the original testosteroneonly WHO studies extends to testosterone/progestin combinations. Weight gain and HDL suppression were also very limited in this study. Additionally, a trial of TU at a dose of 1000 mg every 8 wk with DMPA was conducted in China and demonstrated uniform azoospermia in subjects receiving the combination, but not in those receiving TU alone (256). Finally, DMPA injected every 3 months combined with daily transdermal testosterone gel effectively suppressed 19 of 21
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participants to sperm concentrations less than 1 million/ml after 6 months of administration (185). This combination of testosterone plus DMPA is therefore an attractive candidate for larger efficacy studies. In summary, the contraceptive effect of most of the progestins is fairly similar, although smaller doses may be more efficacious for some progestins compared with others and their side effect profiles likely vary (see Section V.G). Combinations of im TU or testosterone pellets and levonorgestrel, etonogestrel, norethindrone, or medroxyprogesterone all result in azoospermia rates of almost 90%. As a result, many researchers now feel that one of these combinations is the most likely to result in a clinically useful contraceptive method. However, larger-scale phase III studies of efficacy at pregnancy prevention will need to be carried out with these regimens before they can be marketed. Suggested guidelines for such a study have been recently outlined (219), and a focus on both pre- and postmarketing side effect profiles is warranted, given the importance of minimizing these in delivery of a long-term medication to a healthy population.
D. Adding GnRH analogs to hormonal contraceptive regimens
GnRH agonists (such as leuprolide) are not effective when used with testosterone for male hormonal contraception (257), perhaps because these agonists tend to allow the continued production of FSH even after chronic administration (257). In contrast to agonists, GnRH antagonists can suppress FSH and LH production within hours of administration and inhibit gonadotropin secretion more completely than agonists. Several trials have investigated the effects of both shortand longer-acting GnRH antagonists as adjuncts in male hormonal contraceptive treatment. Initial very small trials investigated the GnRH antagonist Nal-Glu, administered by daily sc injection, in combination with testosterone to maintain peripheral androgenicity. In the first two trials, 14 of 16 subjects achieved azoospermia by 6 10 wk of treatment (258, 259). But a third small, randomized trial demonstrated no difference in azoospermia with TE plus Nal-Glu compared with TE alone, at least at the doses given (260). Moreover, daily sc injections required for the use of Nal-Glu were not considered to be a feasible part of a long-term contraceptive regimen. It was suggested, therefore, that GnRH antagonists might have a useful role in the induction of azoospermia with maintenance by a combination of hormonal agents. This was demonstrated with Nal-Glu, which induced azoospermia when administered with TE for 12 wk, which was then maintained by TE alone for 20 additional weeks (261). In contrast, the GnRH antagonist cetrorelix, also given by daily injection, combined with the androgen 19-nortestosterone resulted in azoospermia by 12 wk in all six subjects tested; however, azoospermia could not be maintained after the cetrorelix was discontinued (262). It is possible that failure to maintain azoospermia in the second study stemmed from the use of 19-nortestosterone that cannot be aromatized to estrogen, because estrogen may play a role in the feedback suppression of gonadotropin secretion at the pituitary. Indeed, increased
gonadotropin levels were seen associated with spermatogenesis after cessation of cetrorelix in this study (262). Longer-acting GnRH antagonists have recently been developed. A depot formulation of the GnRH antagonist abarelix results in effective gonadotropin suppression for periods up to 1 month (263), but case reports of allergic reactions to this agent may limit its clinical utility. The GnRH antagonist acyline can markedly suppress gonadotropins for up to 2 wk after a single sc administration without significant side effects (264). In a small trial, 12 wk of acyline combined with DMPA and testosterone gel did not demonstrably augment sperm suppression, or the rapidity of sperm suppression, compared with testosterone and DMPA alone (185). These results were surprising because preliminary data demonstrated that administration of acyline in combination with testosterone injections resulted in more rapid gonadotropin suppression than testosterone alone or testosterone plus a progestin (Fig. 2, A. D. Coviello and W. J. Bremner, unpublished data). Additional GnRH antagonists are in development, including orally administered peptide and nonpeptide antagonists (265, 266) and a long-acting (2 yr) GnRH agonist implant that has recently been introduced to the market for treatment of prostate cancer (267). These remain interesting prospects for future contraceptive trials because in theory they could be combined with similarly delivered testosterone formulations without the need for a progestin, perhaps minimizing nonreproductive side effects. In conclusion, while theoretically appealing, GnRH antagonists
FIG. 2. Rate and extent of gonadotropin suppression with various hormonal interventions. Normal healthy men ages 18 55 given TE alone (100 mg im every week), TE plus oral levonorgestrel (LNG, 125 mg oral, daily), TE acyline (300 g/kg sc on day 0 only), or TE LNG acyline (n 7 per group). Error bars represent SEM. Rates of suppression were compared using time-to-event analysis with the event defined as suppression of LH or FSH to 1 IU/liter. Suppression of both LH and FSH was accelerated in both groups receiving acyline (P 0.05) compared with the other two groups. [Data printed with permission of A. D. Coviello and W. J. Bremner.]
have been relatively understudied compared with testosterone-progestin combinations; however, improved methods of delivery may allow for their incorporation into future contraceptive regimens.
E. Oral male hormonal contraceptive development
Although implant and injection-based hormonal contraceptive regimens have been well studied, many men would prefer an oral formulation for contraception (10). The only orally available testosterone replacement products currently approved for use in the United States are alkylated testosterone derivatives such as methyltestosterone, which can cause liver injury and have been associated with hepatomas (268) and thus are not safe for contraceptive use. The testosterone ester TU is an oral testosterone available in many countries and is not associated with the liver injury seen with methyltestosterone. However, the bioavailability of TU is significantly dependent upon the simultaneous ingestion of a fatty meal (269), and it must be dosed two or three times per day to achieve normal serum testosterone levels, thus making it a poor choice for contraceptive purposes. Oral administration of crystalline testosterone does not greatly increase serum testosterone levels due to extensive hepatic first-pass metabolism and low bioavailability (225, 270 272). However, we recently demonstrated that the addition of a 5-reductase inhibitor to orally administered testosterone in an oil emulsion improved the bioavailability of testosterone compared with oral testosterone alone (273, 274). In these studies, serum testosterone levels within the normal range were achieved for 10 h in normal men with reversible, medically induced hypogonadism when a single dose of testosterone was administered orally in oil together with a 5-reductase inhibitor. Although longer-term studies will be required to demonstrate its safety and efficacy, this form of oral testosterone delivery, in combination with an oral progestin and/or GnRH antagonist raises the possibility of a male pill in the future. An additional orally available androgen that holds promise for hormonal contraception has been reported recently. Attardi et al. (275) demonstrated that the 19-nortestosterone derivative dimethandrolone is active in vivo in a rodent model, causing suppression of LH in castrate rats. Moreover, dimethandrolone has both androgenic and progestational activity, at least in vitro, which might increase its potency as a single agent for contraception (275). Such a strategy remains to be tested in men. Similarly, some steroidal and nonsteroidal SARMs, which have some tissue selectivity for androgen action (see Section V.H) (276), are orally active and represent potentially attractive agents for long-term oral use alone or combined with a progestin.
F. Reversibility of male hormonal contraception
was examined. Recovery was defined as attaining a sperm concentration of more than 20 million sperm/ml, consistent with WHO guidelines for normal semen analyses and normal fertility (278). Importantly, in no case did a subject fail to recover. Median time to recovery was 3.4 months. Increased length of recovery time was associated with longer treatment periods and the use of longer-acting testosterone compounds. Prolonged recovery was not, however, associated with inclusion of a progestin in the regimen. Although the additional recovery data provided by two recently completed multicenter trials will be important to increase the absolute numbers of individuals examined, this analysis provides significant reassurance that the hormonal contraceptive approach is truly reversible in men.
G. Side effects of male hormonal contraceptives
A contraceptive for men must be not only efficacious but also fully reversible. Liu et al. (277) recently published a comprehensive analysis of spermatogenic recovery after experimental male hormonal contraceptive treatment including androgens or an androgen plus a progestin for a minimum of 3 months. Data from 1549 men enrolled in 30 studies
Male hormonal contraceptive regimens can have small but significant effects on a number of nonreproductive parameters, and these need to be examined carefully because such regimens are designed for long-term use in large numbers of men. The extent to which these nonreproductive systems are affected appears to be mediated, at least in part, by differences in the progestin component of the regimen and perhaps by the mode of hormonal delivery (injection vs. oral vs. transdermal). Direct comparisons between regimens have, however, rarely been performed, and it is difficult to extrapolate the relative differences between studies performed at various centers. Since efficacy has been established, at least in small studies, dose-reduction and delivery systems designed to minimize the extragonadal effects of male hormonal contraceptive regimens will be an important aspect of drug development over the next decade. It is possible that, analogous to female oral contraceptives that reduce the incidence of some hormone-dependent cancers (279), male hormonal contraceptives could have health benefits for men. In healthy young men, exogenous androgens increase lean body mass and decrease fat mass in a dose-dependent manner (280), whereas androgen replacement in hypogonadal men results in similar improvements in body composition in addition to increasing bone mineral density (281, 282). It is possible that such benefits could occur in men using hormonal contraception over the long term, although these changes may be modulated by the necessary addition of a progestin (283) or other agent. Increases in lean body mass and decreases in fat mass might be beneficial in reducing the incidence of the metabolic syndrome or cardiovascular disease or in maintaining physical function as men age. Moreover, increases in bone mineral density could decrease fracture risk. Long-term trials and data collection will be required to ascertain whether such benefits are conferred when exogenous androgens are given to healthy men. Little is known about the cardiovascular effects of exogenous androgen-based contraceptive regimens, but weight gain and HDL suppression have been consistent findings. However, total cholesterol and the proatherogenic lipid particle low-density lipoprotein are also suppressed by androgens. High doses of testosterone can cause some of these effects, as in the second WHO efficacy trial of high-dosage im TE (200 mg im/wk), where HDL levels declined by 13% and
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weight increased by 4 kg (142). More physiological dosages of testosterone alone cause significantly less HDL suppression and weight gain but are not as effective at suppressing sperm production and thus have limited clinical utility as a contraceptive (183, 238). The mechanism through which androgens alter serum lipids is not fully understood, but likely is a combination of changes in body fat distribution and stimulation of hepatic lipase activity resulting in decreased lipid particle size and increased lipid density (283). Whereas combining physiological doses of testosterone with a progestin dramatically improves sperm suppression, HDL and weight are also adversely affected (183, 238). At least in the case of some regimens, HDL and weight effects have been clearly shown to be related to the progestin dose (238 240, 242). Together, these data suggest that the progestin component of androgen-progestin-based male hormonal contraceptive regimens may negatively affect metabolic parameters in men. Very little is known about the effects of progestins on cardiovascular risk factors in men. In a small study of men (283) and a large study of women (284), progestins were associated with increased total body and abdominal fat and insulin resistance. The route of administration of the progestin may modulate these metabolic effects, because oral administration is associated with first-pass metabolism in the liver, a critical site for cholesterol metabolism and glucose homeostasis. For example, testosterone combined with oral northethisterone and testosterone plus im northethisterone were equally effective in inducing uniform severe oligospermia, but testosterone plus oral northethisterone induced significantly greater HDL suppression (17%) than testosterone plus im northethisterone (10 12%) (255). Similarly, oral desogestrel significantly suppresses HDL (by 20%), but in a separate trial its active metabolite etonogestrel, delivered by implant, did not cause significant HDL suppression (although HDL levels decline by 722% in dosages that effectively induce severe oligospermia) (242, 245247, 285). Inflammation has been implicated in the development of cardiovascular disease, and a number of inflammatory markers including IL-6 and its product, C-reactive protein, are linked to the development of heart disease. In women, exogenous progestins can increase inflammatory markers (284), but there are little data on the inflammatory effects of progestins in men. In a recent study, norethisterone enanthate administered im in combination with testosterone was associated with an increase in proinflammatory IL-6, whereas testosterone alone resulted in decreased IL-6 (222). Perhaps the most worrisome potential drawback to androgen administration in men is inducing or stimulating prostate diseases including benign prostatic hypertrophy or prostate cancer, both major causes of morbidity and mortality in men. The relationship between circulating androgens and the development of prostate disease in men is controversial. Some epidemiological data correlate high serum testosterone levels with prostate cancer risk (286), although these studies have been conflicting (reviewed in Ref. 287). In contrast, other studies have found a relationship between low serum testosterone levels and occult, aggressive prostate cancer (288, 289). Prostate assessments in previous trials of male hormonal
contraception and of androgen therapy in testosterone-deficient men, while reassuring, have been limited to measurement of serum prostate-specific antigen (PSA), and in some cases, prostate volume (217, 218, 256, 285). Limited data in young men acutely administered im TE at doses as high as 500 mg weekly (five times the physiological dose) for 20 wk did not demonstrate significant elevations in PSA (290), but no other measures of prostate function or morphology were assessed. Given the high prevalence of prostate disease in the developed world, even small changes in disease prevalence associated with exogenous androgen administration in young men could be associated with significant harm. Thus, understanding the long-term effects of exogenous but physiologically dosed androgens on prostate health is a key component to hormonal contraceptive development. Moreover, novel combinations such as a GnRH antagonist plus lowdose androgens with or without a 5-reductase inhibitor might minimize prostate stimulation and deserve further clinical evaluation.
H. Selective androgen receptor modulators for male contraception
There has been recent interest in the development of SARMs that provide tissue-selective androgen action (276). Although development is targeted to hypogonadal men, prostate-sparing androgens that inhibit gonadotropin secretion and spermatogenesis while supporting sexual function and maintaining lean body and bone mass would be attractive for long-term contraceptive use. One approach that might achieve these goals is combining testosterone with a 5-reductase inhibitor. 5-Reductase type II is highly expressed in the prostate and is responsible for the conversion of testosterone to the more potent androgen DHT, resulting in tissue-specific amplification of androgen signaling. In older, hypogonadal men, the combination of TE plus finasteride, a specific inhibitor of 5-reductase type II, maintains the beneficial effects of testosterone on bone mineral density (291), strength, physical performance, lipids, and body composition (292) without precipitating the increases in prostate size or PSA noted with administration of TE alone (291). Moreover, results from the Prostate Cancer Prevention Trial (293) suggest that 5-reductase inhibition may have longterm benefits for men by reducing prostate cancer incidence. In addition, it is possible that the addition of a potent 5reductase inhibitor to testosterone might improve contraceptive efficacy by inhibition of 5-reductase activity in the testes because persistent intratesticular DHT levels have been suggested to contribute to the failure to reach azoospermia in some male hormonal contraceptive studies (99, 117, 138). However, contraceptive trials have yet to demonstrate that the addition of a 5-reductase inhibitor to testosterone plus a progestin further blocks spermatogenesis (140, 148). The compound 7-methyl-19-nortestosterone (MENT) is the first steroidal SARM to be tested as part of a male hormonal contraceptive regimen. The 7-methylation of this compound prevents 5-reduction, effectively minimizing the prostatic activity of MENT (294) and perhaps other androgenic side effects attributed to DHT such as male pattern baldness. Such noncontraceptive benefits could significantly
improve the appeal of a male hormonal contraceptive to men. In a study in castrated monkeys, MENT showed a 10-fold greater potency (vs. testosterone) for LH inhibition, but only 2-fold greater potency at stimulating prostate growth (295). In men, MENT has a short half-life, probably due to the fact that MENT does not appear to bind to SHBG (296). Therefore, MENT implants have been synthesized to allow for sustained delivery. These implants suppress gonadotropins and androgens by 80 90% in men (297); as a contraceptive, MENT as a single agent resulted in azoospermia in 73% of those individuals who received four implants (298). Recently, MENT implants have been combined with a progestin for contraception (299). Disappointingly, effective sperm suppression was not maintained beyond 12 wk with combined, implantable MENT plus etonogestrel, likely due to the low levels of MENT in the circulation. Future studies with more sustained delivery of MENT or perhaps other selective steroidal SARMS, combined with a progestin or GnRH antagonist, are still a promising approach to contraceptive development. Like MENT, some anabolic steroids have been recently demonstrated in vitro and in animal models to have some degree of tissue selectivity. These studies come predominantly from efforts aimed at understanding the physiological effects of substances that merit banning in professional sport. Some of these have been shown to have tissue-selective androgen action that may make them candidates both for androgen replacement therapy and as part of a contraceptive regimen. For example, desoxymethyltestosterone appears to be significantly more potent for levator ani muscle than at the prostate (300) in a castrate rat model. Similarly, tetrahydrogestinone is less potent than DHT on the rat prostate at doses capable of maintaining muscle mass (301). Both tetrahydrogestinone (302) and dimethandrolone (275) appear to have significant interaction with both the androgen and progestin receptors. Such properties might provide the benefits of increased gonadotropin and spermatogenic suppression, which characterize combined androgen-progestin regimens. Some of these steroids, particularly dimethandrolone that can be administered orally, warrant further testing in humans as part of a contraceptive strategy. Recently, a number of nonsteroidal small molecule SARMs, which may be compatible with oral administration, have been described (276, 303305). In order for these compounds to act as hormonal contraceptives, they must be potent at the pituitary, muscle, and bone while sparing the prostate. One such compound suppressed spermatogenesis in rats by 75% after 10 wk of treatment (306), and another has been shown to maintain bone density and muscle mass while suppressing LH in castrate rats (307). Some of these compounds are currently undergoing clinical evaluation in humans. Nonsteroidal SARMs are particularly appealing because they might allow for oral administration of the androgen component of future male contraceptive regimens and could, in theory, minimize any adverse effects on the prostate. However, their development as contraceptive agents will require a significant effort on the part of the pharmaceutical industry.
I. Why doesnt hormonal contraception work for all men?
A major mystery in the field of male hormonal contraceptive research is why some men fail to sufficiently suppress their sperm counts despite inhibition of serum gonadotropin secretion to extremely low levels. There are no apparent differences in the gonadotropin levels among men who suppress to azoospermia and those who do not; thus the degree of gonadotropin suppression itself is unlikely to be the explanation for these differences (97, 308, 309). As discussed above, an alternative hypothesis has been that persistent intratesticular DHT levels may support ongoing spermatogenesis in this setting (99, 117, 138); however clinical trials do not support an additional contraceptive benefit with the addition of 5-reductase inhibitors to contraceptive regimens (140, 148). Similarly, residual intratesticular testosterone production in some men despite maximal gonadotropin suppression might support spermatogenesis in those men deemed treatment failures. Indeed, work in the LH-receptor knockout mouse supports the concept of basal, non-LH dependent testosterone production capable of supporting low levels of spermatogenesis (113, 310). However, in two small studies we found no relationship between residual intratesticular testosterone levels and sperm production in men undergoing hormonal contraceptive treatment (134, 146). Larger studies are required to confirm these results, but it is possible that, in contrast to studies in rodents, persistent intratesticular androgen levels after hormonal contraceptive treatment do not explain treatment failures and alternative explanations should be pursued. Clinically, it would be of great use if one could predict treatment failures based upon serum markers, either before or during treatment. Although examined in almost every male contraceptive study, baseline sex steroids, gonadotropins, and sperm concentrations do not appear to be predictive of those men who will achieve adequate sperm suppression with hormonal contraceptive treatment. Insulin-like factor 3 (INSL3) is a recently described protein secreted by the testes and found in abundance in the serum (311). INSL3 secretion is regulated, at least in part, by LH, and may be a marker of Leydig cell function (311, 312). Although the physiological role of INSL3 is not completely understood, some data suggest that INSL3 may play a role in germ cell survival (313). Male hormonal contraceptive treatment results in a significant decrease in circulating INSL3 (311, 312). In a retrospective analysis, we recently showed that higher end-oftreatment INSL3 concentrations after male hormonal contraceptive treatment correlated with persistent spermatogenesis and failure to achieve azoospermia (314). Although these results require further confirmation in a prospective fashion, this is the first demonstration of a serum marker that may be associated with persistent spermatogenesis. Exploring a possible functional role for INSL3 in spermatogenesis will be the subject of future studies in this important area. Genetic polymorphisms may explain the difference between men who suppress to azoospermia and those who do not. No such polymorphisms have been identified to date, although three have been examined. Androgen receptor action is influenced, in part, by two trinucleotide repeats lo-
480
cated in exon 1. Increased numbers of CAG repeats are associated with decreased androgen activity, whereas the effects of GGN repeats are less clear. One study found that a CAG repeat number of greater than 22 was associated with an increased chance of azoospermia in the setting of incompletely suppressed gonadotropins after hormonal contraceptive treatment (315). However, a second study found that the number of neither CAG nor GGN repeats in the androgen receptor appeared to influence individual responsiveness to hormonal suppression of spermatogenesis (316). These authors went on to examine polymorphisms in the CYP3A4 gene, which encodes an important enzyme in the metabolism of testosterone, and again found no relationship between a known polymorphism in CYP3A4 and sperm suppression (316). Clearly, further investigation will be needed to understand the innate differences in the intratesticular environment that allow some men to continue to produce sperm in the extremely low gonadotropin environment of a male contraceptive regimen. These efforts will likely require a coordinated effort among research centers to yield significant results, due to the relatively small, but critical, numbers of men who fall into the category of hormonal contraceptive treatment failures.
VI. Nonhormonal Methods
Nonhormonal approaches to male contraception can target either sperm production (testicular targets) or sperm motility. These are attractive targets because, theoretically, agents targeted to these processes might be very specific, thus lacking the systemic side effects that plague hormonal methods. In addition, it is possible that such agents could have a much more rapid onset of action. However, development in this area has been slow, and only one of these approaches has reached phase II trials in men (gossypol). Both reversibility and efficacy in animal models continues to be an issue for these approaches, but with advances in genetic and proteomic array approaches, new potential targets will continue to emerge.
A. Testicular targets
Two plant extracts, gossypol, a phenolic compound derived from the cotton plant, and triptolide, derived from the Chinese herbal medicine Trypterigium wilfordii, were promising nonhormonal agents evaluated in the 1980s and 1990s in China. Unfortunately, both agents were found to result in significant, serious side effects and in some cases irreversible infertility, and their development as contraceptives has been abandoned. Gossypol affects both spermatogenesis and sperm motility. Of more than 8000 Chinese men treated with oral gossypol, more than 90% achieved sperm concentrations of less than 1 million/ml (317, 318); however, in 20% of cases this effect was not reversible (319). In addition, hypokalemia was a frequent side effect, in some cases resulting in periodic paralysis (320). A subsequent study suggested that these adverse effects of gossypol may be dose-dependent, but reversible infertility still resulted when lower doses were used (321). However, these side effects caused a reevaluation of the preclinical criteria for contraceptive development (320).
T. wilfordii, an herbal medicine with immunosuppressive properties, impairs sperm motility and density when given to rats and men (322). Purification of the active component of T. wilfordii, triptolide, followed (323). Unfortunately, administration of triptolide to rodents resulted in irreversible infertility (324, 325). Moreover, the immunosuppressive effects of triptolide would likely have prohibited its development as a contraceptive. Mild elevations in scrotal temperature, just above that of the body core, can cause germ cell apoptosis (326, 327). Rodent germ cells appear to be particularly susceptible to testicular heat (328, 329). Although exogenous heat alone is not an effective, long-term contraceptive strategy in men (330), it is possible that heat may decrease the time to low sperm concentration when used in combination with hormonal or nonhormonal contraceptive methods (331). In a recent study, heat using a scrotal water bath at 43 C (30 min/d for 6 consecutive days) in combination with exogenous testosterone decreased sperm count and motility and increased germ cell apoptosis during the first 12 wk of treatment compared with testosterone alone (331). However, in contrast to testosterone plus a progestin, most men using heat plus testosterone failed to achieve sperm concentrations below 1 million/ml after 18 wk of treatment. Therefore, heat plus hormone-based regimens are unlikely to be clinically useful at this point. An alternative strategy to nonhormonal contraception is to target nongerm cells critical for spermatogenesis. In theory, this could be either the Leydig or Sertoli cell, however interruption with Leydig cell function would likely result in systemic hypogonadism requiring the addition of exogenous testosterone. Indenopyridines, serendipitously found to have antifertility effects during toxicology screening for new antihistamines, appear to target both Sertoli cells and germ cells (332334). One such indenopyridine, CDB-4022, when used in combination with a GnRH antagonist, induced reversible infertility in male rats (335). Recently, the l-enantiomer of CDB-4022 was tested in adult cynomolgus monkeys (332). Seven days of oral treatment with l-CDB-4022 resulted in severe oligospermia in all four monkeys treated 17 d after initial administration and remained as such for 6 wk total. Reversibility was demonstrated by wk 16, at which time sperm counts were equivalent to vehicle-treated animals. Gonadotropin and sex steroid concentrations were unaffected, and there were no overt toxicities associated with drug administration. Although l-CDB-4022 clearly affected developing spermatocytes, its precise mechanism of action in the monkey is unclear (332). Given that some studies have demonstrated irreversible testicular effects of CDB-4022 administration in rodents, longer-term studies of l-CDB-4022 in nonhuman primates will likely be necessary before testing in humans. However, these are promising preclinical data for a potential oral, nonhormonal male contraceptive. During their development in the seminiferous tubules, spermatids adhere tightly to Sertoli cells via anchoring proteins in junctions known as apical ectoplasmic specializations (apical ES). Oral administration of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (adjudin) to rats has been shown to disrupt the interaction of spermatid-Sertoli cells by interacting with specific proteins in the apical ES and
to result in reversible infertility (336 338). However, in some animals, nonreproductive side effects including liver inflammation and muscle atrophy were noted with adjudin administration. These side effects appear to be overcome by directing adjudin delivery to the testes (339). Mruk et al. (339) developed a mutated FSH molecule, lacking three critical glycosylation sites, and conjugated it to adjudin, allowing for significantly less overall drug exposure for the animals and with consistent achievement of reversible infertility. Moreover, endogenous FSH activity appeared to be maintained. Not only adjudin, but also this novel approach to directing agents to the testes is an exciting new area in contraceptive development; however, caution will be required due to the possibility of developing anti-FSH autoantibodies that might compromise reversibility with long-term use.
B. Epididymal targets
During transit through the epididymis, before ejaculation, spermatozoa undergo maturation; thus the epididymis provides another possibly unique contraceptive target. Murine genetic knockout models have provided a number of putative epididymal targets; however, none have reached clinical testing in humans or nonhuman primates. Epididymal-specific proteins could provide points for pharmaceutical intervention. For example, the G-coupled protein receptor HE6 appears to have epididymal duct-specific expression, and HE6-deficient mice are infertile but otherwise phenotypically normal (340, 341). HE6 appears to be critical to fluid resorption in the efferent epididymal ductules, but its precise mechanism of action is not well known. Nevertheless, G-coupled protein receptors can be excellent targets for drug development. Similarly, CRISP-1, a member of the cystiene-rich secretory protein family, appears to have epididymal-specific expression. CRISP-1 appears to be secreted into the lumen of the epididymis where it is postulated to interact with spermatozoa, preventing the initiation of capacitation during sperm transit and storage (342, 343). Pursuit of these, and other, epididymal proteins as contraceptive targets, however, is still a number of years from clinical use because not only do appropriate inhibitors need to be identified, but their specificity and concentration in the reproductive tract will need to be confirmed.
C. Targeting sperm motility or sperm-egg fusion
Recently, several investigators have focused on inhibition of sperm motility as a promising target for male contraceptive development. Ascent of sperm in the female reproductive tract is dependent on initiation of sperm flagellar beating during ejaculation. Sperm progress between 1 and 3 mm/ min propelled by their flagella, which whip three-dimensionally in an elliptical cone (344). Before fertilization, sperm dramatically increase the frequency and force of their flagellar beating, a process termed hyperactivation, to reach and penetrate the ovum. Blocking sperm motility, hyperactivation, or both has great appeal as a male contraceptive. A drug targeting motility or hyperactivation may not need to cross the blood-testes barrier as long as the drug partitioned into seminal fluid and was ejaculated with the sperm. In addition,
such drugs might have a very rapid onset of action, perhaps allowing for administration immediately before intercourse. Unfortunately, agents that interfere with sperm motility may not always be effective across species. Glycosphingolipids are abundant in sperm, and mice deficient in enzymes involved in glycosphingolipid biosynthesis and metabolism have significantly compromised fertility (345347). Gaucher disease is a rare autosomal recessive glycogen storage disease caused by a deficiency in glycosphingolipid metabolism that can be treated, in part, by an inhibitor of glycosphingolipid synthesis, miglustat (N-butyldeoxynojirimycin) (348 350). Administration of miglustat to normal mice resulted in reversible infertility by markedly affecting sperm motility and acrosome morphology (351). However, we recently demonstrated that, in contrast to the initial findings in mice, administration of daily, oral miglustat to healthy men for 6 wk, at doses similar to that used to treat Gaucher disease, had no effect on sperm motility, morphology, or the acrosome reaction (352). In addition, the initial findings in mice were not reproducible among different strains (353), suggesting that genetic variance plays a key role in spermatic sensitivity to miglustat. One approach to blocking sperm motilityand sperm hyperactivation in particular has focused on a group of four novel sperm-specific transmembrane proteins termed CatSpers (354). These transmembrane proteins assemble, likely as a tetramer in conjunction with the transmembrane protein CatSperbeta (355), and allow for calcium entry into the sperm tail through a bicarbonate-activated, voltage-sensitive channel. The rise in intracellular calcium mediated by the CatSpers is directly responsible for the increase in flagellar beat frequency that characterizes sperm hyperactivation. All four CatSpers are critical for fertility, and mice rendered deficient in even a single CatSper are infertile (354, 356) but otherwise phenotypically normal. Thus, CatSpers are promising targets for male contraceptive development because they are highly specific for sperm. However, antagonists for these channels have not yet been reported in the literature and thus are a long way from clinical use. Potassium chloride cotransporters and ion-specific channels are also thought to play an important role in sperm motility. To maintain their motility, ejaculated sperm undergo regulated volume decrease wherein ions and organic osmolytes are effluxed from the sperm in a regulated fashion to prevent cytoplasmic swelling after exposure to the relatively hyposmolar female reproductive tract (211). The nonselective ion channel blocker quinine maximally inhibits regulated volume decrease (357, 358), but sperm-specific potassium and chloride channels, and effective inhibitors, for human sperm have yet to be identified and may not be equivalent to those in the mouse (357). Additional potential targets for inhibiting sperm motility are the proteins of the principal piece of the flagellum. A recent study used mass spectrometry proteomic analyses of isolated human fibrous sheaths to identify several proteins that colocalize to the fibrous sheath of the flagellum (359). Most of the isolated proteins were known glycolytic enzymes, but the authors also identified a unique adenine nucleotide translocase. This protein, called sperm flagellar energy carrier [SFEC, also termed ADP-ATP carrier protein 4
482
(AAC4)], appears to participate in the transport of ATP within the principal piece. The authors hypothesize that once SFEC has moved ATP to the flagellum core, dynein ATPases allow the microtubules of the flagellum to slide across one another and generate flagellar movement. Structural modeling suggests that SFEC possesses a unique protein motif at the entrance to the nucleotide-binding pocket that might be an attractive drug target. Similarly, the sperm-specific glyceraldehydes 3-phosphate dehydrogenase-S (GAPDS) is bound to the flagellar cytoskeleton and plays a critical role in sperm glycolysis in the mouse (360). GAPDS-deficient male mice are completely infertile, despite normal sperm counts, due to severely impaired motility (360). The human homolog of GAPDS, GAPD2, also appears to be sperm-specific (361). If this is the case, if enzyme-specific inhibitors can be developed that do not interfere with extraspermatic sites of glycosylation, GAPD2 may be an intriguing contraceptive target. Two final intriguing targets for male contraceptive motility research are the unique soluble adenylate cyclase (sAC) and sodium-hydrogen exchanger (sNHE) found in sperm. Increased intracellular cAMP is essential for preparing sperm for fertilization, a process known as capacitation. sAC lacks a transmembrane anchor and produces cAMP in the cytoplasm of the sperm. sAC activity is potentiated by bicarbonate and calcium, known triggers of sperm hyperactivation (362). Therefore, an inhibitor of sAC could utilize two mechanisms to impair fertility: 1) inhibiting sperm motility and hyperactivation; and 2) impairing capacitation. Mice lacking sAC are infertile, and their sperm are immotile due to defects in cAMP production (363, 364). Furthermore, recent work with KH7, a specific inhibitor of sAC, demonstrated that sAC inhibition markedly impairs the ability of mouse sperm to undergo capacitation, achieve a hyperactivated state, and ultimately, fertilize oocytes in vitro (365). Analogous to sAC-null mice, male mice deficient in sNHE are infertile due to immotile sperm (366), and this defect can be overcome in vitro with the addition of cAMP. Wang et al. (367) recently demonstrated that sNHE is required for the full expression of sAC at the protein level and that these two proteins colocalize and form a complex critical for sperm motility. Future work to develop specific inhibitors of sAC and/or sNHE is an intriguing prospect for male contraception. A sperm-specific membrane protein with structural homology to Ig, Izumo, has been recently identified. Data suggest that Izumo is required for sperm-egg fusion (368). Male knockout mice with homozygous Izumo deficiency appear phenotypically normal, with normal sperm numbers, morphology, and motility, yet are infertile. Sperm from Izumodeficient animals could penetrate the zona pellucida of eggs in vitro but could not complete fertilization. However, when intracytoplasmic sperm injection was used to inject Izumodeficient sperm into normal eggs in vitro, the defect was overcome. Its apparent specificity for this critical prefertilization step makes Izumo an attractive target of contraceptive development; however, pharmacological inhibitors of Izumo have yet to be identified. Finally, over the last two decades researchers in India have been developing an injectable intra-vas compound that has
been tested in small phase I and II trials (369, 370). RISUG is a polymer of styrene maleic anhydride dissolved in the vehicle dimethylsulfoxide that is injected into the lumen of the vas deferens using a no-scalpel technique. In the phase II study of 12 men, sustained azoospermia was achieved between 5 and 106 d after the procedure, with the exception of one individual who did not reach azoospermia until d 243, although 100% of his remaining sperm from d 39 onward were nonmotile (370). No pregnancies in the 12 couples studied were reported over the following 12-month period, wherein after the initial 2 months of condom use couples relied only upon the RISUG for contraception. Unfortunately, although RISUG denotes reversible inhibition of sperm under guidance, to date both preclinical and clinical studies have failed to demonstrate reversibility, and the mechanism whereby this might be achieved is not clear. More recent reports from this group have suggested that exposure to the styrene maleic anhydride-dimethylsulfoxide combination within the vas deferens results in irreversible alterations of the sperm membrane via changing the electrostatic and pH environments (371373). Resulting immediate changes in sperm motility and function, if demonstrated clinically, might give such a method an advantage over vasectomy by shortening the postprocedure time to contraceptive efficacy. A phase III trial of this method is apparently under way and hopefully will include data on reversibility. Until such data are published, RISUG should only be considered an experimental alternative to vasectomy.
D. Immunological approaches to contraception
Employing the immune system as a contraceptive by targeting sperm- or egg-specific proteins, or even gonadotropins, has some natural parallel because antisperm antibodies can play a role in infertility. Indeed, sperm antigens have been suggested as ideal targets for contraceptive vaccine development (recently reviewed in Ref. 374). In light of immunological memory, it is difficult conceptually to think of a vaccine approach as a reversible contraceptive method, but a recent study in nonhuman primates suggested that this might be possible. ORand et al. (375) reported that immunization of nine male monkeys with recombinant human eppin resulted in reversible contraception in five of nine animals. Eppin is a testes-epididymal-specific protease inhibitor found on spermatozoa thought to play a role in sperm-semenogelin interaction in the coagulum of human ejaculate (376). Although this represents a novel success in the field of immunocontraception in the male, a number of concerns for further clinical development of this approach were raised in this pilot study. First, booster immunizations were required every 3 wk throughout the treatment to maintain high titer anti-Eppin antibodies, a requirement for contraception. Second, for unknown reasons, two of nine animals failed to mount a significant enough immune response to warrant fertility testing. Finally, two of nine animals failed to sire an offspring after cessation of injections, even after 450 d of observation. It is likely that any vaccine approach to contraception might have similarly inconsistent responses among individuals and that reversibility may also be unpredictable, given the variability in immunogenicity of such a vaccine among individuals. Although controversial, vaccine approaches to contraception
aimed at gonadotropins or GnRH have reached phase I clinical trials in women (377), and a similar approach could in theory also be used in men. Again, variability in the immune response leading to irreversibility and triggering autoimmune disease and perhaps anaphylactic shock has concerned critics in this area (378). In men, GnRH and FSH have been suggested as possible targets for immunocontraception (379), although blockade of the latter would require exogenous testosterone administration for maintenance of androgenicity. Included among most recent work are vaccines aimed at GnRH-1 DNA (380), but there has been very little progress in male contraceptive vaccine development in the last 10 yr, with most work in this area focusing on medical alternatives to castration (permanent sterility) for veterinary use.
introduction, they offer the potential for sperm-specific interventions and thus great promise as reversible contraceptives with minimal side effects suitable for long-term use. Population control remains one of humankinds greatest challenges in the 21st century. The population burden continues to tax our environment and contribute to morbidity and mortality globally. It is the hope of researchers in the field of male contraceptive development that approaches to blocking sperm production and function will bring the dream of the male pill to fruition and significantly impact the health and future of the planet.
Acknowledgments
We thank Dr. Andrea Coviello for permission to include unpublished data (Fig. 2). Received November 26, 2007. Accepted February 26, 2008. Address all correspondence and requests for reprints to: Stephanie T. Page, University of Washington, Box 356138, 1959 NE Pacific Street, Seattle, Washington 98195. E-mail: page@u.washington.edu This work was supported by the National Institute of Child Health and Human Development, a division of the National Institute of Health (NIH), through cooperative agreements U54-HD-12629 and U54 HD42454 as part of the specialized Cooperative Centers Program in Reproductive Research and the Cooperative Contraceptive Research Centers Program (to W.J.B., S.T.P., and J.K.A). In addition, S.T.P. is supported in part by the National Institute of Aging, a Division of the NIH, by Grant K23 AG027238. J.K.A. is supported, in part, by the National Institute of Child Health and Human Development, a Division of the NIH, through Grant K23 HD45386. Disclosures: S.T.P. and J.K.A. have received a lecture fee from Solvay Pharmaceuticals. J.K.A. has been a consultant for the Takeda Pharmaceutical Company. W.J.B. has nothing to disclose.
VII. Conclusions
From a global standpoint, there is clearly a desire and need for more contraceptive options. Couples desire more choices for fertility control, and unplanned pregnancies continue to occur at alarming rates. The hormonal approach to male contraception has made significant progress in the last decade in terms of clinical development. The efficacy of this approach appears to surpass condoms, and these methods seem to appeal to men and their partners. The long experience with female contraceptives sets the bar very high in terms of minimizing side effects for male hormonal contraceptives, thus continued refinements of male hormonal contraceptive regimens to this end are under way. Because the direct health benefits of pregnancy prevention for men are less tangible, male contraceptive development faces additional challenges because agents used for this purpose might be used by healthy individuals over many years. Therefore, acceptance of side effects, or even potential side effects, is very low. New forms of androgen delivery have been introduced over the last 510 yr, including transdermal, oral, and long-acting injectable androgens. These could allow for a very acceptable delivery system for male hormonal contraceptive users. Moreover, the hormonal approach to male fertility control has the potential to further benefit men by contributing to chemoprevention of other diseases, as the female oral contraceptive has. Unfortunately, over the last 2 yr, the major pharmaceutical sponsors of male hormonal contraceptive research have withdrawn their support in this area of product development, making it difficult to complete the final phases of clinical development. Government and not-for-profit sponsors will be needed in this environment to devote the necessary resources for longterm efficacy studies. The potential rewards of preventing unwanted pregnancies and providing more contraceptive choices for couples will hopefully attract visionary leaders to support this mission. Array technology at both the RNA and protein levels is likely to provide an explosion in sperm- and fertilization-specific contraceptive targets in the coming years. Genetic engineering using murine models has already revealed some intriguing nonhormonal targets. Caution must be taken in translating preclinical results, and these methods will require extensive nonhuman primate and human testing. However, although such approaches are a number of years away from clinical
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Endocrine Reviews, June 2008, 29(4):465 493 493 367. Wang D, Hu J, Bobulescu IA, Quill TA, McLeroy P, Moe OW, Garbers DL 2007 A sperm-specific Na/H exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC). Proc Natl Acad Sci USA 104:9325 9330 368. Inoue N, Ikawa M, Isotani A, Okabe M 2005 The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature 434:234 238 369. Guha SK, Singh G, Anand S, Ansari S, Kumar S, Koul V 1993 Phase I clinical trial of an injectable contraceptive for the male. Contraception 48:367375 370. Guha SK, Singh G, Ansari S, Kumar S, Srivastava A, Koul V, Das HC, Malhotra RL, Das SK 1997 Phase II clinical trial of a vas deferens injectable contraceptive for the male. Contraception 56: 245250 371. Chaudhury K, Bhattacharyya AK, Guha SK 2004 Studies on the membrane integrity of human sperm treated with a new injectable male contraceptive. Hum Reprod 19:1826 1830 372. Guha SK 2007 Biophysical mechanism-mediated time-dependent effect on sperm of human and monkey vas implanted polyelectrolyte contraceptive. Asian J Androl 9:221227 373. Kumar S, Chaudhury K, Sen P, Guha SK 2007 Quantitative analysis of surface micro-roughness alterations in human spermatozoa using atomic force microscopy. J Microsc 227:118 123 374. Naz RK 2006 Antisperm immunity for contraception. J Androl 27:153159 375. ORand MG, Widgren EE, Sivashanmugam P, Richardson RT, Hall SH, French FS, VandeVoort CA, Ramachandra SG, Ramesh V, Jagannadha Rao A 2004 Reversible immunocontraception in male monkeys immunized with eppin. Science 306:1189 1190 376. ORand MG, Widgren EE, Wang Z, Richardson RT 2006 Eppin: an effective target for male contraception. Mol Cell Endocrinol 250: 157162 377. Naz RK, Gupta SK, Gupta JC, Vyas HK, Talwar AG 2005 Recent advances in contraceptive vaccine development: a mini-review. Hum Reprod 20:32713283 378. Kumar S 1998 Research into anti-fertility vaccine continues despite protests. Lancet 352:1528 379. Moudgal NR, Jeyakumar M, Krishnamurthy HN, Sridhar S, Krishnamurthy H, Martin F 1997 Development of male contraceptive vaccinea perspective. Hum Reprod Update 3:335346 380. Khan MA, Ferro VA, Koyama S, Kinugasa Y, Song M, Ogita K, Tsutsui T, Murata Y, Kimura T 2007 Immunisation of male mice with a plasmid DNA vaccine encoding gonadotrophin releasing hormone (GnRH-I) and T-helper epitopes suppresses fertility in vivo. Vaccine 25:3544 3553 381. Guerin JF, Rollet J 1988 Inhibition of spermatogenesis in men using various combinations of oral progestagens and percutaneous or oral androgens. Int J Androl 11:187199 382. Seidman SN, Araujo AB, Roose SP, McKinlay JB 2001 Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry 50:371376 383. Pollanen P, Nikkanen V, Huhtaniemi I 2001 Combination of subcutaneous levonorgestrel implants and transdermal dihydrotestosterone gel for male hormonal contraception. Int J Androl 24: 369 380. 384. Meriggiola MC, Costantino A, Cerpolini S, Bremner WJ, Huebler D, Morselli-Labate AM, Kirsch B, Bertaccini A, Pelusi C, Pelusi G 2003 Testosterone undecanoate maintains spermatogenic suppression induced by cyproterone acetate plus testosterone undecanoate in normal men. J Clin Endocrinol Metab 88:5818 5826 385. Brady BM, Walton M, Hollow N, Kicman AT, Baird DT, Anderson RA 2004 Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception. Hum Reprod 19:2658 2667
Endocrine Reviews is published by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.

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Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

II. Acceptability of Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 467

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 469

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 471

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 473

No. of failures to suppressa (%)

No. of pregnancies (%)

Total no. of failuresb (%)

Overall contraceptive efficacy (95% CI)

357 305 53 715

12months 6months 12months

268 (75) 130 (43) 49 (93) 447 (62)

81 (23) 166 (54) 2 (3.6) 249 (35)

8 (2.2) 9 (2.9) 2 (3.6) 19 (2.6)

11 (3.1) 1 (0.3) 0 (0.0) 12 (1.7)

19 (5.3) 10 (3.3) 2 (3.6) 31 (4.4)

94.7(9297) 96.7(9598) 96.4(91100) 95.7(94 97)

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 475

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

D. Adding GnRH analogs to hormonal contraceptive regimens

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 477

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 479

I. Why doesnt hormonal contraception work for all men?

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 481

Endocrine Reviews, June 2008, 29(4):465 493

Page et al. Advances in Male Contraception

Page et al. Advances in Male Contraception

Endocrine Reviews, June 2008, 29(4):465 493 483

13. 14. 15.

31. 32. 33.

95. 96. 97.

120. 121. 122.

111. 112. 113.

189. 190. 191. 192. 193. 194.

177. 178. 179. 180.

203. 204. 205. 206.

211. 212. 213. 214.

220. 221. 222.