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HORMONAL METHODS OF MALE CONTRACEPTION
A key strategic issue in developing a hormonal male contraceptive is defining the degree of suppression of sperm output required (63). Two landmark WHO studies involving 671 men from 16 centres in 10 countries established the proof of principle that hormonally-induced azoospermia provides highly reliable, reversible contraception (3, 4). Among the minority (~25%) of men who remained severely oligozoospermic (0.1-3 million sperm/ml) using weekly testosterone enanthate injections, contraceptive failure rate (~8% per annum) was directly proportional to their sperm output. Hence to achieve effective contraception, azoospermia is analogous to anovulation as a sufficient, but not necessary, requirement. Nevertheless reliable contraception by modern standards (64) requires uniform azoospermia as the desirable target for male contraceptive regimens (65). No regimen yet achieves this consistently in all men, although in some Asian countries (e.g. China (3), Indonesia (66, 67)) azoospermia is achieved in close to 100% by a variety of regimens. A study involving 308 Chinese men in 6 centres has shown that monthly injections of testosterone undecanoate provides highly effective and reversible contraception (68). No pregnancies were recorded among men who were azoospermic or severely oligozoospermic (<3 million sperm per mL) providing a 95% upper confidence limit of pregnancy (contraceptive failure) rate of 2.5% per annum. The overall failure rate based on suppression of spermatogenesis was <4%. The prototype regimen was well tolerated apart from injection site discomfort due to large oil injection volume (4 mL) and reversible androgenic effects (acne, weight gain, hemoglobin, lipids). Nevertheless, despite these promising findings, non-Chinese men require combination hormonal regimens involving a 2nd gonadotropin suppressing agent, notably progestins, together with testosterone to ensure adequate spermatogenic suppression. This approach was proven for the depot androgen/progestin combination approach as no pregnancies were observed among 55 couples during 35.5 person-years of exposure (95% upper limit of failure rate ~8%) in a study with satisfactory tolerability and reversibility for a prototype regimen (69). Hormonal methods have proven efficacy and reasonable prospects for safety and are the most likely opportunity in the near future to develop a practical contraceptive method for men but progress depend on pharmaceutical company commitment which has languished (5).
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 (70-73), systematic studies of androgens for male contraception began in the 1970's (74, 75). Feasibility and dose-finding studies (76), mostly using testosterone enanthate (TE) in an oil vehicle as a prototype, showed that weekly im injections of 100-200 mg TE induce azoospermia in most Caucasian men (77) but less frequent or lower doses fail to sustain suppression (78-81). The largest experience with an androgen alone regimen arises from the two WHO studies in which over 670 men from 16 centres in 10 countries received weekly injections of 200 mg TE. In these studies ~60% of non-Chinese and >90% of Chinese men became azoospermic and the remainder were severely oligozoospermic (3, 4). The within and between population differences in susceptibility to hormonally-induced azoospermia remain largely unexplained (82) although possibly relevant population differences in reproductive physiology of environmental (83, 84), genetic (85, 86) or uncertain (87) origin have been described. Azoospermia occurs in 3-4 months and is maintained consistently during ongoing treatment. Following cessation of treatment, sperm reappear within 3 months and normal output by ~6 months. Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia or behavioral effects and these were reversible as were changes in hemoglobin, testis size and plasma urea. There was no evidence of liver, prostate or cardiovascular disorders (3, 4, 88).
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 (eg SHBG, HDL cholesterol) and inconsistent bioavailability. Short-acting testosterone products requiring daily or more frequent administration (oral, transdermal patches or gels) which may be acceptable for androgen replacement therapy are not appropriate for hormonal contraception. Weekly TE injections required for maximal suppression of spermatogenesis (76) are far from ideal (89) and cause supraphysiological blood testosterone levels risking both excessive androgenic side effects and preventing maximal depletion of intratesticular testosterone for optimal efficacy (90). Other currently available oil-based testosterone esters (cypionate, cyclohexane-carboxylate, propionate) are no improvement over the enanthate ester (91), and longer-acting depot preparations are needed. Subdermal testosterone pellets sustain physiological testosterone levels for 4-6 months (92) and the newer injectable preparations testosterone undecanoate (68), testosterone-loaded biodegradable microspheres (93) and testosterone buciclate (94) currently in development promise 2-3 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 (95) although when combined with a depot progestin, this goal is achievable (69).
Oral synthetic 17-a alkylated androgens such as methyltestosterone (96), fluoxymesterone (97), methandienone (98) and danazol (99, 100) suppress spermatogenesis but azoospermia is rarely achieved and the inherent hepatotoxicity of the 17-a alkyl substitutent (101) renders them unsuitable for long-term use. Athletes self-administering supratherapeutic doses of androgens also exhibit suppression of spermatogenesis (98, 102). Synthetic androgens lacking the 17-a alkyl substituent have been little studied although injectable nandrolone esters produce azoospermia in 88% of European men (103, 104) whereas oral mesterolone is ineffective (105). On the other hand, nandrolone hexyloxyphenylpropionate alone was unable to maintain spermatogenic suppression induced by a GnRH antagonist (106) in a prototype hybrid regime (where induction and maintenance treatment differ) whereas testosterone appears more promising (107). A 7-methyl derivative of nandrolone (MENT), which is partly aromatisable but resistant to 5α reductive amplification of androgenic potency, has been studied as a non-oral androgen for hormonal male contraceptive regimens (108). While it is prostate-sparing (109), dose titration to achieve essential androgen replacement at each relevant tissue is more complex than for testosterone and may be difficult to achieve (110). More potent, synthetic androgens lacking 17-a alkyl groups (111, 112) remain to be fully evaluated.
Antiandrogens have been used to selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects (113). Cyproterone acetate, a steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to androgen deficiency when used alone (114). In contrast, pure non-steroidal antiandrogens lacking androgenic or gestagenic effects such as flutamide, nilutamide and casodex fail to suppress spermatogenesis when used alone (115, 116). 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 5a reductase inhibitor (117, 118); however as testes express predominantly the type I isoforms (119), further studies are required to conclusively test this hypothesis.
The safety of androgen administration concerns mainly potential effects on cardiovascular and prostatic disease. As the explanation for the higher male susceptibility to cardiovascular disease is not well understood, the risks of exogenous androgens are not clear (120, 121). In clinical trials, lipid changes are minimal with depot (non-oral) hormonal regimens (69, 95, 122, 123). 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 but, in any case, maintenance of physiological 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 (124).
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 (125-127). The precise relationship of androgens to prostatic disease and in particular any influence of exogenous androgens remains poorly understood. There is little direct relationship between blood testosterone levels and the occurrence of prostatic disease in prospective studies of adults (128). 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 (129), however the relationship of the CAG triplet repeat length polymorphism to late-life prostate diseases remains unclear (130). Among androgen deficient men, prostate size and PSA concentrations are reduced and returned towards normal by testosterone replacement without exceeding age-matched eugonadal controls (129, 131-133). Even self-administration of massive androgen over-dosage does not increase total prostate volume or PSA in anabolic steroid abusers although central prostate zone volumes increases (134). In-situ prostate cancer is common in all populations of older men whereas rates of invasive prostate cancer differ many-fold 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 physiological androgen levels with exogenous testosterone, which then might be no more hazardous than exposure to endogenous testosterone. Prolonged surveillance comparable with that for cardiovascular and breast disease in users of female hormonal contraception would be equally essential to monitor both cardiovascular and prostatic 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 (3, 4, 76, 135-137). By contrast, extreme androgen doses used experimentally in healthy men can produce idiosyncratic hypomanic reactions in a minority (138). Aberrant behaviour in observational studies of androgen-abusing athletes or prisoners are difficult to interpret particularly to distinguished genuine androgen effects from the influence of self-selection for underlying psychological morbidity (139).
Androgen combination regimens
Combination steroid regimens use non-androgenic steroids (estrogens, progestins) to suppress gonadotropins, in conjunction with testosterone for androgen replacement, have shown the most promising efficacy with enhanced rate and extent of spermatogenic suppression compared with androgen alone regimens (122, 140, 141). Synergistic combinations reduce the effective dose of each steroid and minimising testosterone dosage could enhance spermatogenic suppression if high blood testosterone levels counteract the necessary maximal depletion of intratesticular testosterone (142, 143) as well as reducing androgenic side-effects.
Progestins are potent inhibitors of pituitary gonadotropin secretion 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 (144, 145) so androgen replacement is necessary. Extensive feasibility studies concluded that progestin-androgen combination regimens had promise as hormonal male contraceptives if more potent and durable agents were developed (76, 146). 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 ~60% of fertile men of European background with the remainder having severe oligozoospermia and impaired sperm function (76, 146, 147). Nearly uniform azoospermia is produced in men treated with depot MPA and either of two injectable androgens in Indonesian men (66, 67) or testosterone depot implants in Caucasian men (122). Smaller studies with other oral progestins such as levo-norgestrel (140, 148, 149) and norethisterone (150, 151) combined with testosterone demonstrate similar efficacy to oral MPA whereas cyproterone acetate with its additional anti-androgenic activity has higher efficacy in conjunction with TE (141, 152) but not oral testosterone undecanoate (153). Promising findings of highly effective suppression of spermatogenesis are reported with depot progestins in the form of non-biodegradable implants of norgestrel (154) or etonorgestrel (155) or depot injectable medroxyprogesterone acetate (69, 122) or norethisterone enanthate (156) coupled with testosterone. The pharmacokinetics of the testosterone preparation is critical to efficacy of spermatogenic suppression with long-acting depots being most effective while transdermal delivery is less effective than injectable testosterone (154). Progestin side-effects are few and sexual function is maintained by adequate androgen replacement dosage. The metabolic effects depend on 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.
Estradiol augments testosterone-induced suppression of primate spermatogenesis (157) and fertility (158) but estrogenic side-effects (gynecomastia) and modest efficacy at tolerable doses make estradiol-based combinations impractical for male contraception (159). The efficacy and tolerability of newer estrogen analogs in combination with testosterone remain to be evaluated.
GnRH 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 LH and testosterone secretion requiring testosterone replacement. Many superactive GnRH agonists are used to induce reversible medical castration for androgen-dependent prostate cancer by causing a sustained, paradoxical inhibition of gonadotropin and testosterone secretion and spermatogenesis due to pituitary GnRH receptor downregulation. When combined with testosterone, GnRH agonists suppress spermatogenesis but rarely achieve azoospermia (142, 143, 160) being less effective than androgen/progestin regimens. By contrast, pure GnRH antagonists create and sustain immediate competitive blockade of GnRH receptors (161) 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 monkeys (162-164) and men (165, 166) when combined with testosterone. The striking superiority of GnRH antagonists may be due to more secure inhibition of gonadotropin secretion and/or depletion of intratesticular testosterone. Due 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. The drawback of high cost might be overcome by hybrid regimens using GnRH antagonists to initiate and then switching to more economical steroids for maintenance of spermatogenic suppression (107). 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 (167) and pilot feasibility studies in advanced prostate cancer are underway (168) but the prospects for acceptably safe application for male contraception are doubtful.
FSH Blockade
Selective 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 inhibin (169) or novel steroids (170), by FSH vaccine (171) or by FSH receptor blockade with peptide antagonists (172). Although FSH was considered essential to human spermatogenesis, spermatogenesis and fertility persist in rodents (173-175) and humans (176) lacking FSH bioactivity. Hence even complete FSH blockade might produce insufficient reduction in sperm output and function required for adequate contraceptive efficacy (177). In addition to the usual safety concerns of contraceptive vaccines including autoimmune hypophysitis, orchitis or immune-complex disease, an FSH vaccine might be overcome by reflex increases in pituitary FSH secretion.
)HORMONAL METHODS OF MALE CONTRACEPTION
A key strategic issue in developing a hormonal male contraceptive is defining the degree of suppression of sperm output required (63). Two landmark WHO studies involving 671 men from 16 centres in 10 countries established the proof of principle that hormonally-induced azoospermia provides highly reliable, reversible contraception (3, 4). Among the minority (~25%) of men who remained severely oligozoospermic (0.1-3 million sperm/ml) using weekly testosterone enanthate injections, contraceptive failure rate (~8% per annum) was directly proportional to their sperm output. Hence to achieve effective contraception, azoospermia is analogous to anovulation as a sufficient, but not necessary, requirement. Nevertheless reliable contraception by modern standards (64) requires uniform azoospermia as the desirable target for male contraceptive regimens (65). No regimen yet achieves this consistently in all men, although in some Asian countries (e.g. China (3), Indonesia (66, 67)) azoospermia is achieved in close to 100% by a variety of regimens. A study involving 308 Chinese men in 6 centres has shown that monthly injections of testosterone undecanoate provides highly effective and reversible contraception (68). No pregnancies were recorded among men who were azoospermic or severely oligozoospermic (<3 million sperm per mL) providing a 95% upper confidence limit of pregnancy (contraceptive failure) rate of 2.5% per annum. The overall failure rate based on suppression of spermatogenesis was <4%. The prototype regimen was well tolerated apart from injection site discomfort due to large oil injection volume (4 mL) and reversible androgenic effects (acne, weight gain, hemoglobin, lipids). Nevertheless, despite these promising findings, non-Chinese men require combination hormonal regimens involving a 2nd gonadotropin suppressing agent, notably progestins, together with testosterone to ensure adequate spermatogenic suppression. This approach was proven for the depot androgen/progestin combination approach as no pregnancies were observed among 55 couples during 35.5 person-years of exposure (95% upper limit of failure rate ~8%) in a study with satisfactory tolerability and reversibility for a prototype regimen (69). Hormonal methods have proven efficacy and reasonable prospects for safety and are the most likely opportunity in the near future to develop a practical contraceptive method for men but progress depend on pharmaceutical company commitment which has languished (5).
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 (70-73), systematic studies of androgens for male contraception began in the 1970's (74, 75). Feasibility and dose-finding studies (76), mostly using testosterone enanthate (TE) in an oil vehicle as a prototype, showed that weekly im injections of 100-200 mg TE induce azoospermia in most Caucasian men (77) but less frequent or lower doses fail to sustain suppression (78-81). The largest experience with an androgen alone regimen arises from the two WHO studies in which over 670 men from 16 centres in 10 countries received weekly injections of 200 mg TE. In these studies ~60% of non-Chinese and >90% of Chinese men became azoospermic and the remainder were severely oligozoospermic (3, 4). The within and between population differences in susceptibility to hormonally-induced azoospermia remain largely unexplained (82) although possibly relevant population differences in reproductive physiology of environmental (83, 84), genetic (85, 86) or uncertain (87) origin have been described. Azoospermia occurs in 3-4 months and is maintained consistently during ongoing treatment. Following cessation of treatment, sperm reappear within 3 months and normal output by ~6 months. Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia or behavioral effects and these were reversible as were changes in hemoglobin, testis size and plasma urea. There was no evidence of liver, prostate or cardiovascular disorders (3, 4, 88).
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 (eg SHBG, HDL cholesterol) and inconsistent bioavailability. Short-acting testosterone products requiring daily or more frequent administration (oral, transdermal patches or gels) which may be acceptable for androgen replacement therapy are not appropriate for hormonal contraception. Weekly TE injections required for maximal suppression of spermatogenesis (76) are far from ideal (89) and cause supraphysiological blood testosterone levels risking both excessive androgenic side effects and preventing maximal depletion of intratesticular testosterone for optimal efficacy (90). Other currently available oil-based testosterone esters (cypionate, cyclohexane-carboxylate, propionate) are no improvement over the enanthate ester (91), and longer-acting depot preparations are needed. Subdermal testosterone pellets sustain physiological testosterone levels for 4-6 months (92) and the newer injectable preparations testosterone undecanoate (68), testosterone-loaded biodegradable microspheres (93) and testosterone buciclate (94) currently in development promise 2-3 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 (95) although when combined with a depot progestin, this goal is achievable (69).
Oral synthetic 17-a alkylated androgens such as methyltestosterone (96), fluoxymesterone (97), methandienone (98) and danazol (99, 100) suppress spermatogenesis but azoospermia is rarely achieved and the inherent hepatotoxicity of the 17-a alkyl substitutent (101) renders them unsuitable for long-term use. Athletes self-administering supratherapeutic doses of androgens also exhibit suppression of spermatogenesis (98, 102). Synthetic androgens lacking the 17-a alkyl substituent have been little studied although injectable nandrolone esters produce azoospermia in 88% of European men (103, 104) whereas oral mesterolone is ineffective (105). On the other hand, nandrolone hexyloxyphenylpropionate alone was unable to maintain spermatogenic suppression induced by a GnRH antagonist (106) in a prototype hybrid regime (where induction and maintenance treatment differ) whereas testosterone appears more promising (107). A 7-methyl derivative of nandrolone (MENT), which is partly aromatisable but resistant to 5α reductive amplification of androgenic potency, has been studied as a non-oral androgen for hormonal male contraceptive regimens (108). While it is prostate-sparing (109), dose titration to achieve essential androgen replacement at each relevant tissue is more complex than for testosterone and may be difficult to achieve (110). More potent, synthetic androgens lacking 17-a alkyl groups (111, 112) remain to be fully evaluated.
Antiandrogens have been used to selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects (113). Cyproterone acetate, a steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to androgen deficiency when used alone (114). In contrast, pure non-steroidal antiandrogens lacking androgenic or gestagenic effects such as flutamide, nilutamide and casodex fail to suppress spermatogenesis when used alone (115, 116). 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 5a reductase inhibitor (117, 118); however as testes express predominantly the type I isoforms (119), further studies are required to conclusively test this hypothesis.
The safety of androgen administration concerns mainly potential effects on cardiovascular and prostatic disease. As the explanation for the higher male susceptibility to cardiovascular disease is not well understood, the risks of exogenous androgens are not clear (120, 121). In clinical trials, lipid changes are minimal with depot (non-oral) hormonal regimens (69, 95, 122, 123). 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 but, in any case, maintenance of physiological 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 (124).
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 (125-127). The precise relationship of androgens to prostatic disease and in particular any influence of exogenous androgens remains poorly understood. There is little direct relationship between blood testosterone levels and the occurrence of prostatic disease in prospective studies of adults (128). 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 (129), however the relationship of the CAG triplet repeat length polymorphism to late-life prostate diseases remains unclear (130). Among androgen deficient men, prostate size and PSA concentrations are reduced and returned towards normal by testosterone replacement without exceeding age-matched eugonadal controls (129, 131-133). Even self-administration of massive androgen over-dosage does not increase total prostate volume or PSA in anabolic steroid abusers although central prostate zone volumes increases (134). In-situ prostate cancer is common in all populations of older men whereas rates of invasive prostate cancer differ many-fold 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 physiological androgen levels with exogenous testosterone, which then might be no more hazardous than exposure to endogenous testosterone. Prolonged surveillance comparable with that for cardiovascular and breast disease in users of female hormonal contraception would be equally essential to monitor both cardiovascular and prostatic 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 (3, 4, 76, 135-137). By contrast, extreme androgen doses used experimentally in healthy men can produce idiosyncratic hypomanic reactions in a minority (138). Aberrant behaviour in observational studies of androgen-abusing athletes or prisoners are difficult to interpret particularly to distinguished genuine androgen effects from the influence of self-selection for underlying psychological morbidity (139).
Androgen combination regimens
Combination steroid regimens use non-androgenic steroids (estrogens, progestins) to suppress gonadotropins, in conjunction with testosterone for androgen replacement, have shown the most promising efficacy with enhanced rate and extent of spermatogenic suppression compared with androgen alone regimens (122, 140, 141). Synergistic combinations reduce the effective dose of each steroid and minimising testosterone dosage could enhance spermatogenic suppression if high blood testosterone levels counteract the necessary maximal depletion of intratesticular testosterone (142, 143) as well as reducing androgenic side-effects.
Progestins are potent inhibitors of pituitary gonadotropin secretion 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 (144, 145) so androgen replacement is necessary. Extensive feasibility studies concluded that progestin-androgen combination regimens had promise as hormonal male contraceptives if more potent and durable agents were developed (76, 146). 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 ~60% of fertile men of European background with the remainder having severe oligozoospermia and impaired sperm function (76, 146, 147). Nearly uniform azoospermia is produced in men treated with depot MPA and either of two injectable androgens in Indonesian men (66, 67) or testosterone depot implants in Caucasian men (122). Smaller studies with other oral progestins such as levo-norgestrel (140, 148, 149) and norethisterone (150, 151) combined with testosterone demonstrate similar efficacy to oral MPA whereas cyproterone acetate with its additional anti-androgenic activity has higher efficacy in conjunction with TE (141, 152) but not oral testosterone undecanoate (153). Promising findings of highly effective suppression of spermatogenesis are reported with depot progestins in the form of non-biodegradable implants of norgestrel (154) or etonorgestrel (155) or depot injectable medroxyprogesterone acetate (69, 122) or norethisterone enanthate (156) coupled with testosterone. The pharmacokinetics of the testosterone preparation is critical to efficacy of spermatogenic suppression with long-acting depots being most effective while transdermal delivery is less effective than injectable testosterone (154). Progestin side-effects are few and sexual function is maintained by adequate androgen replacement dosage. The metabolic effects depend on 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.
Estradiol augments testosterone-induced suppression of primate spermatogenesis (157) and fertility (158) but estrogenic side-effects (gynecomastia) and modest efficacy at tolerable doses make estradiol-based combinations impractical for male contraception (159). The efficacy and tolerability of newer estrogen analogs in combination with testosterone remain to be evaluated.
GnRH 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 LH and testosterone secretion requiring testosterone replacement. Many superactive GnRH agonists are used to induce reversible medical castration for androgen-dependent prostate cancer by causing a sustained, paradoxical inhibition of gonadotropin and testosterone secretion and spermatogenesis due to pituitary GnRH receptor downregulation. When combined with testosterone, GnRH agonists suppress spermatogenesis but rarely achieve azoospermia (142, 143, 160) being less effective than androgen/progestin regimens. By contrast, pure GnRH antagonists create and sustain immediate competitive blockade of GnRH receptors (161) 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 monkeys (162-164) and men (165, 166) when combined with testosterone. The striking superiority of GnRH antagonists may be due to more secure inhibition of gonadotropin secretion and/or depletion of intratesticular testosterone. Due 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. The drawback of high cost might be overcome by hybrid regimens using GnRH antagonists to initiate and then switching to more economical steroids for maintenance of spermatogenic suppression (107). 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 (167) and pilot feasibility studies in advanced prostate cancer are underway (168) but the prospects for acceptably safe application for male contraception are doubtful.
FSH Blockade
Selective 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 inhibin (169) or novel steroids (170), by FSH vaccine (171) or by FSH receptor blockade with peptide antagonists (172). Although FSH was considered essential to human spermatogenesis, spermatogenesis and fertility persist in rodents (173-175) and humans (176) lacking FSH bioactivity. Hence even complete FSH blockade might produce insufficient reduction in sperm output and function required for adequate contraceptive efficacy (177). In addition to the usual safety concerns of contraceptive vaccines including autoimmune hypophysitis, orchitis or immune-complex disease, an FSH vaccine might be overcome by reflex increases in pituitary FSH secretion.
