Male Infertility Is Reversible

[rhinochaser48]

This isn't news to many of you, and despite what others have said anectodataly, I've always wondered how safe it is in terms of reproduction to shut down the testes and bring them back again and again.

In summary, androgens can cause oligozoospermia (very little sperm in ejaculate), or worse, azoospermia (no sperm in ejaculate). Both are reversible. At worst, you are looking at 3-6 months of infertility after cessation of androgen therapy.

Most men will only experience oligozoospermia, if that, if only using androgens. There must be elevated progesterone in order to achieve true infertility.

I assume this means test + tren would be a guaranteed contraceptive.



http://www.endotext.org/male/male15/maleframe15.htm

David J. Handelsman MB BS, FRACP, Ph.D.
Chapter 15 - MALE CONTRACEPTION
August 16, 2004 Index
Contributors
Search




BACKGROUND

A male contraceptive must reduce the number of fertile sperm in the ejaculate to levels that reliably prevent fertilization (1). Conception can be prevented by diverting or suppressing sperm output and/or inhibiting sperm fertilizing capacity. So far, all male methods depend on reducing female exposure to sperm by traditional drug and device-free methods (abstinence, withdrawal, non-vaginal intercourse), condoms and vasectomy. No new male methods were introduced during the 20th century contrasting with numerous highly reliable, reversible contraceptive female methods developed over the last 4 decades. Unfortunately among existing male contraceptive options, the reversible methods are not reliable and the reliable method is not intentionally reversible. Despite these limitations, male involvement in family planning remains extensive. Globally, one third of couples using family planning rely upon contraceptive methods requiring active male participation (2) reflecting the traditional and ongoing reliance of family planning on male involvement. Greater participation by men in sharing the burdens as well as the benefits of effective family planning requires the development of more effective male methods. Despite strong community interest and medical agreement on the need for new, reversible male contraceptives as well as proof that reversible hormonal suppression of gonadal function is equally feasible for men as for women (3, 4), commercial development by the pharmaceutical industry continues to stagnate (5).

NON-HORMONAL METHODS

Traditional Methods

Periodic abstinence

Although theoretically effective, neither celibacy nor castration is an acceptable or practical contraceptive method. Periodic abstinence, the limiting of sexual intercourse to "safe" days (6), has high contraceptive efficacy if the rules are followed perfectly but the failure rates rise steeply with rule breaking (7). This cost- and device-free method is used by >30 million couples world-wide for family planning (2). The typical use 1st year failure rate is ~20% (7). While inherently safe, it has limited acceptability due to low reliability, inflexibility and interference in the spontaneity of love-making.

Non-vaginal ejaculation

Withdrawal is a traditional male method of contraception whereby intercourse culminates in extra-vaginal ejaculation (8). Often overlooked as a contraceptive method, together with abortion, it was the major pre-industrial method of family planning largely responsible for the demographic transition from high to low birth rates in industrial nation states and continues to be used by 40 million couples (2). This cost- and device-free method has limited reliability in its demanding requirement for skill and self-control. The typical use 1st year failure rate is ~20% (7). While safe and reasonably effective for experienced users, interfering with the pleasurability of coitus leads to a correspondingly high failure rate in practice (9). Other sexual practices that avoid intravaginal ejaculation have also been used traditionally to avoid conception. These include masturbation, oral and anal intercourse, deliberate anejaculation and retrograde ejaculation (10).

Condom

After centuries of use in preventing sexually transmitted infections, now over 45 million couples rely on condoms for contraception (11). Condoms provide safe, cheap, widely available, user-controlled and reversible contraception with few side-effects. In case of latex allergy, non-rubber (polyurethane, natural membrane) condoms can be substituted. Latex condoms are moderately effective at preventing pregnancy with a typical 1st year failure rate of 14% (12). The discrepancy from the estimated 3% perfect-use failure rate is mainly to human error, notably misuse or non-use, rather than mechanical failure (breakage or slippage) (13). The major limitations of condoms for contraception are relatively high failure rates and interference with sexuality. The requirement for regular and correct application during sexual foreplay disturbs the spontaneity of lovemaking and dulls erotic sensation. These aesthetic drawbacks limit the popularity of condoms especially among stable couples (14). Latex condoms are perishable through tears or snagging on nails, clothing or jewellery as well as deterioration from exposure to light, heat, humidity or organic oils. Polyurethane condoms with improved tactile sensitivity were developed in the 1990’s to enhance acceptability (15) but they have shown marginally inferior efficacy compared with latex condoms in prospective randomised controlled clinical trials (16). Although the theoretical requirements for condom use to protect against sexually transmitted infections differ from those to prevent pregnancy, in practice the protections are similar (17). Laboratory testing of condoms standardizes integrity and durability for strength and leakage and, although viral penetration is not routinely tested, synthetic (latex or polyurethane) but not natural membrane condoms are effective (but not perfect) at preventing passage of prototype human pathogenic viruses (18). Using a sensitive biochemical (PSA) marker, even after mechanical condom failure (breakage, slippage) vaginal exposure to semen was still reduced by 50-80% (19). There is now interest in developing novel spermicides with virucidal properties but whether spermicide impregnation improves the contraceptive efficacy of condoms has not been established rigorously. Since non-compliance is the major cause of failure for both methods (13), their efficacy may not be additive.

Vasectomy

Vasectomy, used by over 40 million couples for family planning (2), varies widely between countries depending upon cultural factors, public education and availability of male-oriented facilities (20). For men having completed their family and fit for minor surgery, vasectomy is a very safe and highly effective office procedure (21). Relative contraindications include risks from office-type surgery (bleeding disorders, allergy to local anaesthetic) or scrotal pathology (post-inguinal surgery scarring, keloid-proneness, active genitourinary or groin infections). Conventional vasectomy, usually performed under local anaesthesia via scrotal incisions, excises a segment of vas deferens and interposes a fascial barrier between the occluded cut ends to minimise risk of recanalization (22). The "no-scalpel" technique (23) further minimizes skin incision and reduces immediate side-effects (bleeding, infection) 10-fold to 0.3% compared with conventional vasectomy (24). Additional studies are needed to determine whether cautery further enhances reliability and whether leaving an open testicular end reduces retrograde pressure-related damage (sperm granuloma, epididymal and testicular damage) thereby better preserving reversibility. Vasectomy is highly effective once sperm are cleared from the distal vas deferens, however, flushing with saline or water during surgery does not accelerate sperm clearance (25) although non-irritant spermicides may have promise (26). Additional contraception must continue ideally until azoospermia is demonstrated or, less reliably, at least 3 months (or 20 ejaculations) have passed (27). Contraceptive failures are rare; early failures are due to not awaiting sperm clearance, misidentification or duplication of the vas deferens whereas late failures are due to spontaneous vas recanalization (0.1%). Vasectomy causes no consistent changes in circulating hormones (28), sexual function or risk of cardiovascular or other diseases (29) including prostate, testis or other cancer (21, 30). Sperm antibodies develop in most vasectomized men but have no known deleterious health effects apart from a debatable role in reducing fertility after vasectomy reversal. Vasectomy is a quick, simple, highly effective and convenient method of permanent sterilization; its major drawback as a male contraceptive is its limited reversibility. Elective sperm cryostorage is occasionally useful but may reflect ambivalence about the irreversible intent of vasectomy. Cumulative rate of requests for reversal, mostly prompted by remarriage, are 2.4% at 10 year post-vasectomy but exceed 10% for young men (<25 years at vasectomy) (31) so that requests for, and failed, vasectomy reversal are now a significant cause of male infertility. Following microsurgical vaso-vasostomy, 80-100% have sperm return to the ejaculate ("patency") but normal sperm output is less common and cumulative conception rate at 12 months is only ~50% (31). Reversibility is better with microsurgery, longer testicular vasal stump (32) and in younger men with shorter duration since vasectomy (31); unfavourable predictors include non-microsurgical techniques, older age of wife, sperm antibodies (33) and duration since vasectomy (34) due to long-term epididymal (35) and testicular damage (34, 36). An alternative to surgical vasectomy reversal either instead of, or after failed vaso-vasostomy, is sperm harvesting (epididymis or testis) in conjunction with in-vitro fertilisation. Currently cost-benefit analyses suggest that microsurgical vaso-vasostomy is more cost-effective and safer in both North America (37) and Europe (38) although optimal management depends on local clinical expertise and access to microsurgery and reproductive technologies.

Modern Methods

Vas occlusion

The efficacy, safety, simplicity and acceptability of vasectomy suggest that a reversible mechanical method of vas occlusion would be an attractive male contraceptive option. Since vasectomy reversal is neither cheap nor widely available, more reversible vas occlusion methods are needed (39). A nonsurgical, potentially reversible technique involving percutaneous injections of polymers that harden in-situ to form occluding plugs which may be later removed to restore fertility was reported (40) but, despite preliminary positive findings (41), formal evaluation showed vas occlusion had lower efficacy (inducing azoospermia) than vasectomy (42). Other technical developments including percutaneous injection of sclerosants and transcutaneous delivery of physical agents (ultrasound, lasers) continue to be developed.

Heating

It has long been known (43) that even brief elevations of testicular temperature can profoundly suppress spermatogenesis (44) while sustained elevation may contribute to testicular pathology in cryptorchidism, varicocele and occupational male infertility (45). Clinical studies evaluating the potential for tight scrotal supports as a practical male contraceptive method (46, 47) showed a reversible decrease in sperm output but of inadequate magnitude for reliable contraception. Given the dubious acceptability and safety (48) of heat-induced suppression of sperm output, the feasibility of a male contraceptive method based on testicular heating remains to be established.

Immunocontraception

Sperm vaccines to interrupt fertility have long been of interest (49). Sperm express unique epitopes within the immunologically protected adluminal compartment of the seminiferous tubules at puberty, hence explaining their potential autoimmunogenicity. Sperm autoimmunity may contribute to subfertility after vasectomy reversal and in ~7% of infertile men without adverse effects on general health apart from focal orchitis. Experimental models for an effective sperm vaccine targeting surface-expressed antigens involved in fertilization have been reported. Yet practical application requires resolving problems of the large antigenic load requiring virtually complete functional blockade, variability of individual immune responses, restricted access of antibodies into the seminiferous tubules and epididymis and the risks of autoimmune orchitis or immune-complex disease. The smaller antigenic burden in the female reproductive tract requiring complete neutralization suggests that a sperm vaccine may be more applicable for women (50).

Chemical (Non-hormonal) Methods

The rapidly proliferating germinal epithelium is highly susceptible to cytotoxins such as drugs, heat or ionising irradiation which disrupt mitosis and/or meiosis, resulting in inhibition of spermatogenesis but the mutagenic risk from direct interference with DNA replication precludes their safe use for reversible contraception. The seclusion of functionally immature post-meiotic, haploid sperm during transit through seminiferous tubules and epididymis however offers a target for chemical methods to regulate male fertility. A model rapid-onset oral spermicide was provided by the chlorosugars that showed rapid, irreversible effect on rodent epididymal sperm (51) but proved too toxic for clinical development. Novel leads for male contraceptive development arise from fortuitous observation of existing chemicals (including drugs or natural products) or mechanisms that impair male fertility or arising from functional genomic research (52). Among existing drugs, an orally active spermicide concentrated in semen (53), drugs inhibiting male fertility (54), ejaculation (55) or epididymal sperm function (56) have been identified. Among the numerous plant products and natural medicines reputed to inhibit male fertility, the most widely tested was gossypol, a polyphenolic yellow pigment identified in China as causing epidemic infertility among workers ingesting raw cottonseed oil. In over 10,000 men purified gossypol reduced sperm output to <4 million/ml in >98% within 75 days with suppression maintained by a lower weekly maintenance dose (57). Although an effective male contraceptive, the systemic toxicity of gossypol and irreversibility precluded further clinical development (58). Subsequently, extracts of Tripterygium wilfordii, a traditional Chinese herbal medicine for rheumatoid arthritis and skin disorders, inhibit fertility and impair sperm output and function in rodents and men. Studies aiming to characterise triptolide, an active component as a potential lead for an orally effective sperm function inhibitor are underway (59). Possible leads from serendipitous discovery of genes found to be necessary for normal fertility include inhibition of sperm function by ion channel aberration (60, 61) or of ductular transport of sperm (62). Practical clinical development of these promising leads remains well into the future.

HORMONAL METHODS

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.