FIGURE 142-1. Pooled summary of contraceptive efficacy from two World Health Organization male contraceptive efficacy studies,4,5 where contraceptive failure rate (pregnancy rate) is plotted against the current sperm concentration in the ejaculate. This illustrates a summation of all data pooled from both studies. Data comprise monthly observations of the mean sperm concentration (averaging monthly sperm counts) and whether a pregnancy occurred in that month or not. Pregnancy rate (per 100 person years, Pearl Index) on the Y-axis is plotted against the cumulative sperm density (in million sperm/mL), indicating that contraceptive failure rates are proportional to sperm output. The inset is the same data replotted in discrete sperm concentration bands rather than cumulatively. For comparison, the average contraceptive failure rates in the first year of use10,12 of modern reliable contraceptive methods are indicated by diamond symbols.
The reversibility of hormonal male contraceptive regimens is clearly established by an integrated reanalysis that pooled primary data from over 90% of all hormonal male contraceptive studies reported; it showed that all regimens show full reversibility within a predictable time course6 (Fig. 142-2). This comprehensive review of the recovery of 1549 healthy eugonadal men, aged 18 to 51 years, who underwent 1283.5 man years of treatment and 705 man years of posttreatment recovery, showed the median times for recovery to sperm densities of 10 and 20 million/mL were 2.5 months (2.4 to 2.7) and 3 months (2.9 to 3.1), respectively. Covariables such as age, ethnicity, and hormonal or sperm output kinetics had significant but minor influence on the rate but not the extent of recovery. Acceptability of a hormonal male contraceptive is high across a wide range of countries and cultures. Willingness to use a hypothetical hormonal male contraceptive averaged 55% (range 29% to 71%) in an extensive population-representative survey of 9342 men aged 18 to 50 years from 9 countries (4 European, 3 South American, Indonesia, and the United States), with consistency across a wide range of socioeconomic and cultural settings.138,139 Similar findings are reported in a four-country study (United Kingdom, South Africa, Hong Kong, Shanghai) with 44% to 83% in each center140 and 75% in Australia141 willing to try a hormonal male contraceptive. Female partners from a variety of cultures also indicate high acceptability in a survey of 1894 women in four countries, among whom 40% to 78% would support and trust their male partners in stable relationships to use a hormonal male contraceptive.142 Corroborating the acceptability of hormonal male contraception are findings from experimental studies of prototype regimens for up to 12 months usage in which most participants confirm high levels of satisfaction and willingness to try a commercial product.143,144 Hence, prototype hormonal methods have proven reliability and reversibility and reasonable prospects for being well accepted and safe. Although they are the most likely opportunity in the foreseeable future to develop a practical contraceptive method for men, progress depends on pharmaceutical industry development, but the commitment of drug companies continues to languish.7
FIGURE 142-2. Recovery of spermatogenesis after cessation of treatment with hormonal male contraceptive regimens, modified after an integrated reanalysis of over 90% of all reported studies.6 Data are plotted as a Kaplan-Meier survival plot of the increasing proportion of men recovering to various thresholds over time since last treatment. The data of last treatment are defined as the time elapsed from the end of the last treatment cycle—that is, the latest date of the first missed treatment dose. The thresholds are a sperm concentration of 3, 10, or 20 million sperm/mL in the ejaculate or a return to their own pretreatment baseline sperm concentration. The median time to achieving each threshold is tabulated together with its 95% confidence interval.
STEROIDAL METHODS
Androgen Alone
Testosterone provides both gonadotropin suppression and androgen replacement, making it an obvious first choice as a single agent for a reversible hormonal male contraceptive. Although androgen-induced, reversible suppression of human spermatogenesis has long been known,145–148 systematic studies of androgens for male contraception began in the 1970s.149,150 Feasibility and dose-finding studies,151 mostly using testosterone enanthate (TE) in an oil vehicle as a prototype, showed that weekly IM injections of 100 to 200 mg TE induce azoospermia in most Caucasian men,152 but less frequent or lower doses fail to sustain suppression.153–156 The largest experience with an androgen-alone regimen arises from the two WHO studies in which over 670 men from 16 centers in 10 countries received weekly injections of 200 mg TE. In these studies approximately 60% of non-Chinese and more than 90% of Chinese men became azoospermic, and the remainder were severely oligozoospermic.4,5 The high efficacy among Chinese men has also been replicated using monthly TU injections.134 Effective gonadotropin suppression is a prerequisite for effective testosterone-induced spermatogenic suppression in human135,157–161 and nonhuman primates.162,163 However, the reasons for within- and between-population differences in susceptibility to hormonally-induced azoospermia remain largely unexplained.157 Possible factors include population differences in reproductive physiology of environmental,164,165 genetic,166,167 or uncertain168,169 origin that may lead to differences in suppressibility of circulating gonadotropins and/or depletion of intratesticular androgens. Limited invasive studies measuring intratesticular testosterone (and dihydrotestosterone [DHT]) suggest that the degree of depletion may not predict reliably complete suppression of sperm output,170–172 but other more widely applicable, noninvasive markers of endogenous Leydig-cell function such as circulating epitestosterone173 or 17-hydroxyprogesterone174 or nonsteroidal testicular products such as INSL3175 may be more analytically informative as to the relative roles of gonadotropin suppression and intratesticular androgen depletion. Exogenous testosterone causes suppression of sperm output, with an average of 13 weeks to reach severe oligozoospermia (<1 million/mL) or azoospermia and suppression maintained consistently during ongoing treatment.176 Following cessation of treatment, sperm reappear within 3 months to reach sperm densities of 10 and 20 million/mL at an average of 11.5 and 13.6 weeks, respectively,176 with ultimately full recovery6 (see Fig. 142-2). Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia, or behavioral effects; these side effects were reversible, as were changes in hemoglobin, testis size, and plasma urea. There was no evidence of liver, prostate, or cardiovascular disorders.4,5,177
The pharmacokinetics of testosterone products are crucial for suppressing sperm output. Oral androgens have major first-pass hepatic effects, producing prominent route-dependent effects on hepatic protein secretion (e.g., sex hormone–binding globulin [SHBG], high-density lipoprotein [HDL] cholesterol) and inconsistent bioavailability. Short-acting testosterone products requiring daily or more frequent administration (oral, transdermal patches, or gels) that may be acceptable for androgen replacement therapy are not optimal for hormonal contraception. Weekly TE injections required for maximal suppression of spermatogenesis151 are far from ideal178 and cause supraphysiologic blood testosterone levels, risking both excessive androgenic side effects and preventing maximal depletion of intratesticular testosterone for optimal efficacy.179,180 Other currently available oil-based testosterone esters (cypionate, cyclohexane-carboxylate, propionate) are no improvement over the enanthate ester,181 and longer-acting depot preparations are needed. Subdermal testosterone pellets sustain physiologic testosterone levels for 4 to 6 months,182 and the newer injectable preparations, testosterone undecanoate,134 testosterone-loaded biodegradable microspheres,183 and testosterone buciclate,184 provide 2 to 3 months’ duration of action. Depot androgens suppress spermatogenesis faster at lower doses and with fewer metabolic side effects than TE injections, but azoospermia is still not achieved uniformly,185 although when combined with a depot progestin, this goal is achievable.135
Oral synthetic 17α-alkylated androgens such as methyltestosterone,186 fluoxymesterone,187 methandienone,188 and danazol189,190 suppress spermatogenesis, but azoospermia is rarely achieved and the inherent hepatotoxicity of the 17α-alkyl substitutent191 renders them unsuitable for long-term use in otherwise healthy men. Athletes self-administering supratherapeutic doses of androgens also exhibit suppression of spermatogenesis.188,192 Synthetic androgens lacking the 17α-alkyl substituent have been little studied, although injectable nandrolone esters produce azoospermia in 88% of European men,193,194 whereas oral mesterolone is ineffective.195 On the other hand, nandrolone hexyloxyphenylpropionate alone was unable to maintain spermatogenic suppression induced by a gonadotropin-releasing hormone (GnRH) antagonist196 in a prototype hybrid regime (where induction and maintenance treatment differ), whereas testosterone appears more promising.197 A 7-methyl derivative of nandrolone (7α-methyl-19-nortestosterone [MENT]), which is partly aromatizable but resistant to 5α reduction which amplifies androgenic potency, has been studied as a non-oral androgen for hormonal male contraceptive regimens.198 Although it is prostate sparing,199 dose titration to achieve essential androgen replacement at each relevant tissue is more complex than for testosterone and may be difficult to achieve.200,201 More potent synthetic androgens lacking 17α-alkyl groups,202,203 as well as the recent development of the first nonsteroidal androgens,204 remain to be fully evaluated in the context of male contraception, where aromatizability may be critical in exploiting testosterone’s feedback effects on pituitary gonadotropin secretion.
Antiandrogens have been used to selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects.205 Cyproterone acetate, a steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to androgen deficiency when used alone.206 In contrast, pure nonsteroidal antiandrogens lacking androgenic or gestagenic effects such as flutamide, nilutamide, and bicalutamide (Casodex) fail to suppress spermatogenesis when used alone.207,208 Two studies evaluating the hypothesis that incomplete suppression of spermatogenesis is due to persistence of testicular DHT have reported no additional suppression from administration of finasteride, a type II 5α-reductase inhibitor209,210; however, because testes express predominantly the type I isoforms,211 further studies are required to conclusively test this hypothesis, using an inhibitor of type I 5α-reductase.212
The long-term safety of androgen administration concerns mainly potential effects on cardiovascular and prostatic disease. The explanation for the higher male susceptibility to cardiovascular disease is not well understood, so the risks of exogenous androgens are not clear.213,214 In clinical trials, lipid changes are minimal with depot (non-oral) hormonal regimens.135,173,185,215 Changes in blood cholesterol fractions observed during high hepatic exposure to testosterone and/or progestins, due to either oral first-pass effects or high parenteral doses, have unknown clinical significance. In any case, maintenance of physiologic blood testosterone concentrations is the prudent and preferred objective. The real cardiovascular risks or benefits of hormonal male contraception will require long-term surveillance of cardiovascular outcomes.216
The long-term effects of exogenous androgens on the prostate also require monitoring, since prostatic diseases are both age- and androgen-dependent. Exposure to adult testosterone levels is required for prostate development and disease.217–219 The precise relationship of androgens to prostatic disease, and in particular any influence of exogenous androgens, remains poorly understood. Comprehensive analysis pooling 18 prospective studies shows no relationship between blood testosterone or androgen levels and the subsequent occurrence of prostate cancer.220 A genetic polymorphism, the CAG (polyglutamine) triplet repeat in exon 1 of the androgen receptor, is an important determinant of prostate sensitivity to circulating testosterone, with short repeat lengths leading to increased androgen sensitivity,221 but the relationship of the CAG triplet repeat length polymorphism to late-life prostate diseases remains unclear.222 Among androgen-deficient men, prostate size and PSA concentrations are reduced and returned towards normal by testosterone replacement, without exceeding age-matched eugonadal controls.221,223–225 Even self-administration of massive androgen overdosage does not increase total prostate volume or PSA in anabolic steroid abusers, although central prostate zone volume increases.226 In situ prostate cancer is common in all populations of older men, whereas rates of invasive prostate cancer differ considerably between populations, despite similar blood testosterone concentrations. This suggests that early and prolonged exposure to androgens may initiate in situ prostate cancer, but later, androgen-independent environmental factors promote the outbreak of invasive prostate cancer. Therefore, it is prudent to maintain physiologic androgen levels with exogenous testosterone, which then might be no more hazardous than exposure to endogenous testosterone. Prolonged surveillance comparable with that to quantify small increases in risk of cardiovascular and breast disease in users of female hormonal contraception would be equally essential to monitor both cardiovascular and prostate disease risk in men receiving exogenous androgens for hormonal contraception.
Extensive experience with testosterone in doses equivalent to replacement therapy in normal men indicates minimal effects on mood or behavior.4,5,151,227–229 A careful placebo-controlled crossover study showed that a 1000 mg TU injection in healthy young men produces minor mood changes without any detectable increase in self- or partner-reported aggressive, nonaggressive, or sexual behaviors.230 By contrast, extreme androgen doses used experimentally in healthy men can produce idiosyncratic hypomanic reactions in a minority.231 Aberrant behavior in observational studies of androgen-abusing athletes or prisoners are difficult to interpret, particularly to distinguish genuine androgen effects from the influence of self-selection for underlying psychological morbidity.232
Androgen Combination Regimens
Combination steroid regimens using nonandrogenic steroids (estrogens, progestins) to suppress gonadotropins, together with testosterone for androgen replacement, have shown the most promising efficacy, with enhanced rate and extent of spermatogenic suppression compared with androgen-alone regimens.173,233,234 Synergistic combinations reduce the effective dose of each steroid, and minimizing testosterone dosage could both enhance spermatogenic suppression (if high blood testosterone levels counteract the necessary maximal depletion of intratesticular testosterone235–237) and reduce androgenic side effects.
Progesterone is a key precursor and steroidogenic intermediate for all bioactive natural steroids, and the progesterone receptors A and B are structurally and evolutionarily the closest members of the nuclear receptor superfamily to the androgen receptor. Yet, although progesterone has crucial gestational and lactational roles in female reproductive physiology, it has no well-established role in male reproductive physiology apart from a possible role in sperm function,238 possibly via a nongenomic rather than a classically genomic mechanism.239 Nevertheless, functional nuclear progesterone receptors are expressed in male brain, smooth muscle, and reproductive (but not most nonreproductive) tissues.240 Synthetic progestins, steroidal structural agonistic analogs of progesterone, are potent inhibitors of pituitary gonadotropin secretion and used widely for female contraception and hormonal treatment of disorders such as endometriosis, uterine myoma, and mastalgia. Used alone, progestins suppress spermatogenesis but cause androgen deficiency, including impotence,241,242 so androgen replacement is necessary. Nonhuman primate studies indicate that this is mediated via a central hypothalamic-pituitary site of action rather than direct effects on the testis.243 Extensive feasibility studies concluded that progestin-androgen combination regimens had promise as hormonal male contraceptives if more potent and durable agents were developed.151,244 The most detailed information on androgen-progestin regimens derives from studies with medroxyprogesterone acetate (MPA) combined with testosterone. Monthly injections of both agents or daily oral progestin with dermal androgen gels produce azoospermia in about 60% of fertile men of European background, with the remainder having severe oligozoospermia and impaired sperm function.151,244,245 Nearly uniform azoospermia is produced in men treated with depot MPA and either of two injectable androgens in Indonesian men132,133 or testosterone depot implants in Caucasian men.173 Smaller studies with other oral progestins such as levonorgestrel233,246,247 and norethisterone248,249 combined with testosterone demonstrate similar efficacy to oral MPA, whereas cyproterone acetate with its additional antiandrogenic activity has higher efficacy in conjunction with TE234,250 but not oral testosterone undecanoate.251 Promising findings of highly effective suppression of spermatogenesis are reported with depot progestins in the form of non-biodegradable implants of norgestrel252–254 or etonorgestrel255,256 or depot injectable MPA135,173,257,258 or norethisterone enanthate259,260 coupled with testosterone. The pharmacokinetics of the testosterone preparation is critical to efficacy of spermatogenic suppression, with long-acting depots being most effective and transdermal delivery less effective than injectable testosterone.252 Progestin side effects are few, and sexual function is maintained by adequate androgen replacement dosage. Metabolic effects depend on the specific regimen, with oral administration and higher testosterone doses exhibiting more prominent hepatic effects such as lowering SHBG and HDL cholesterol. After treatment ceases, with depletion or withdrawal of hormonal depots, spermatogenesis recovers completely but gradually, consistent with the time-course of the spermatogenic cycle.6
Estradiol augments testosterone-induced suppression of primate spermatogenesis261 and fertility,262 but estrogenic side effects (gynecomastia) and modest efficacy at tolerable doses make estradiol-based combinations impractical for male contraception.263 The efficacy and tolerability of newer estrogen analogs in combination with testosterone remain to be evaluated.
Gonadotropin-Releasing Hormone Blockade
The pivotal role of GnRH in the hormonal control of testicular function makes it an attractive target for biochemical regulation of male fertility. Blockade of GnRH action by GnRH receptor blockade with synthetic analogs or GnRH immunoneutralization would eliminate luteinizing hormone (LH) and testosterone secretion, requiring testosterone replacement. Many superactive GnRH agonists are used to induce reversible medical castration for androgen-dependent prostate cancer. They cause a sustained paradoxical inhibition of gonadotropin and testosterone secretion and spermatogenesis through pituitary GnRH-receptor down-regulation. When combined with testosterone, GnRH agonists suppress spermatogenesis but rarely achieve azoospermia,235,236,264 making them less effective than androgen-progestin regimens. By contrast, pure GnRH antagonists create and sustain immediate competitive blockade of GnRH receptors265,266 and, in combination with testosterone, are highly effective at suppressing spermatogenesis. Early hydrophobic GnRH antagonists were difficult to formulate and irritating, causing injection-site mast cell histamine release. Newer more potent but less irritating GnRH antagonists produce rapid, reversible, and complete inhibition of spermatogenesis in monkeys267–269 and men270,271 when combined with testosterone. More immediate and effective inhibition of gonadotropin secretion, and thereby more effective depletion of intratesticular testosterone, may account for the striking superiority of GnRH antagonists over agonists. Owing to their highly specific site of action, GnRH analogs have few unexpected side effects. Depot GnRH antagonist plus testosterone formulations suitable for administration at up to 3-month intervals could be promising as a hormonal male contraceptive regimen. Whether GnRH antagonists are more cost effective than progestins as the second, nonandrogenic, component of combination male hormonal contraceptive regimens remains to be established.171,196,258,272 The drawback of high cost might be overcome by hybrid regimens using GnRH antagonists to initiate suppression, followed by a switch to more economical steroids for maintenance of spermatogenic suppression.197 A GnRH vaccine could intercept GnRH in the pituitary-portal bloodstream, preventing its reaching pituitary GnRH receptors. Gonadotropin-selective immunocastration would require androgen replacement in men,273 and pilot feasibility studies in advanced prostate cancer are underway,274 but the prospects for acceptably safe application for male contraception remain doubtful.275 By contrast, there are growing applications for antihormonal contraceptive vaccines in control of companion (pet), agricultural, zoo, feral, and wild animal populations.276,277
Follicle-Stimulating Hormone Blockade
Selective follicle-stimulating hormone (FSH) blockade theoretically offers the opportunity to reduce spermatogenesis without inhibiting endogenous testosterone secretion. FSH action could be abolished by selective inhibition of pituitary FSH secretion with inhibin278 or novel steroids,279 by FSH vaccine,280 or by FSH-receptor blockade with peptide antagonists.281 Although FSH was considered essential to human spermatogenesis, spermatogenesis and fertility persist in rodents282–284 and humans285 lacking FSH bioactivity. Even complete FSH blockade alone might produce insufficient reduction in sperm output and function required for adequate contraceptive efficacy.286 In addition to the usual safety concerns of contraceptive vaccines (e.g., autoimmune hypophysitis, orchitis, immune complex disease), an FSH vaccine might be overcome by reflex increases in pituitary FSH secretion. Hence, effective FSH suppression is a necessary but not sufficient requirement for a hormonal male contraceptive regimen.
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