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 >40 million couples world-wide for family planning (2). The typical use 1st year failure rate is ~25% (8). While inherently safe, it has limited acceptability due to low reliability, inflexibility and interference in the spontaneity of love-making.

Withdrawal is a traditional male method of contraception whereby intercourse culminates in extra-vaginal ejaculation (9). 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 18-27% in the USA (8, 10) and 10% in France (11). While safe and reasonably effective for experienced users, interfering with the pleasurability of coitus leads to a correspondingly high failure rate in practice (12). 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 (13).

After centuries of use in preventing sexually transmitted infections, now over 50 million couples rely on condoms for contraception (2). 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 15-17% in the USA (8, 10). The discrepancy from the estimated 2% perfect-use failure rate (8) is mainly due to human error, notably misuse or non-use, rather than mechanical failure (breakage or slippage) (14). Differences in contraceptive use behaviours may explain lower reported 1st year failure rates for condoms in France (11). 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 (15). 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 (16) but they have shown reduced efficacy and mechanical performance compared with latex condoms in prospective randomised controlled clinical trials (17). 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 (18). 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 (albeit imperfect) at preventing passage of prototype human pathogenic viruses (19). Using a sensitive and objective biochemical marker for seminal plasma (PSA) exposure in vaginal swabs, even after mechanical condom failure (breakage, slippage) vaginal exposure to semen was still reduced by 50-80% (20). 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 (14), their efficacy may not be additive.

Vasectomy, used by over 40 million couples for family planning (21), varies widely in usage between countries depending upon cultural factors, public education and availability of male-oriented facilities (22). For men having completed their family and fit for minor surgery, vasectomy is a very safe and highly effective office procedure (23, 24). 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). Vasectomy is usually performed under local anaesthesia via scrotal incisions and involves excising a segment of vas deferens. Interposing a fascial barrier between the occluded cut ends significantly reduces the risk of failure due to recanalization (25). The Chinese-developed "no-scalpel" technique (26) minimizes skin incision and reduces immediate side-effects (bleeding, infection) 10-fold to 0.3% compared with conventional vasectomy (27). In the hands of an experienced practitioner, no-scalpel vasectomy with fascial interposition is now the method of choice (28). Additional studies suggest that cautery may further enhances reliability (29, 30) and that leaving an open testicular end reduces retrograde pressure-related complications (pain, sperm granuloma, epididymal and testicular damage) thereby better preserving reversibility (31-33). Vasectomy is highly effective once sperm are cleared from the distal vas deferens. However, flushing with saline or water (34-38) or spermicides (nitrofurazone (39), euflavine (40, 41) or chlorhexidine (42)) during surgery does not accelerate sperm clearance but the evidence remains weak (43). Non-irritant spermicides that inhibit sperm function without chemical sclerosis of the vas that would impair potential reversibility, may have promise (44).

Immediately following vasectomy, additional contraception must continue ideally until azoospermia or near azoospermia (<0.1 million non-motile sperm per mL) is demonstrated usually at 3 months post-vasectomy when at least 95% of men reach this clearance criterion (45-48). Although azoospermia may occur sooner (49), reliable evidence is lacking to support the reliability of earlier timepoints as recanalization, where motile sperm persist in the ejaculate, may occur within the first few weeks after vasectomy (50) and persistence of motile sperm in the ejaculate indicates technical failure. Although detailed information on the rate of sperm clearance from the ejaculate after vasectomy remains sparse, time since vasectomy rather than number of ejaculations is more predictive of sperm clearance (49). Contraceptive failures are rare; early failures are most often due to not awaiting sperm clearance (51) or occasionally misidentification or duplication of the vas deferens whereas late failures are due to spontaneous vas recanalization (~0.1%). Complications of vasectomy include post-surgical bleeding, wound or genito-urinary infections and fistulae as well as chronic scrotal pain  (24, 52) with risk of death estimated at ~1 per million vasectomies in developed countries although higher in developing countries (53).

Vasectomy causes no consistent changes in circulating hormones (54), sexual function or risk of cardiovascular or other diseases (23, 55, 56) including testis cancer (57-59). A small increase in risk of prostate cancer after vasectomy in case-control studies (60, 61), but unaffected by vasectomy reversal (62), appears attributable to surveillance and detection bias, rather than a biological effect (63-65). Sperm antibodies develop in most vasectomized men but have no known deleterious health effects apart from a doubtful role in reducing fertility after vasectomy reversal (66), except where sperm antibody titres are very high (>512) (67).

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 (aged <25 years at vasectomy) (68) so that requests for, and failed, vasectomy reversal are now a significant cause of male infertility. Following microsurgical vaso-vasostomy, 80-100% have any sperm return to the ejaculate ("patency") but normal sperm output is less common and cumulative conception rate at 12 months is only ~50% (68). This discrepancy is most probably attributable to technical limitations of microsurgery as even the lowest reported rates of azoospermia (bilateral non-patency) after microsurgical vaso-vasostomy indicate that nearly half such men have at least one non-patent vas deferens (69) so that re-operation should be a prominent consideration if pregnancy does not ensue. After technical failure, the wife’s age and time since vasectomy appear the dominant predictors of successful reversal (70). Whether robotic microsurgery can improve the technical success of vaso-vasostomy to become a cost-effective and widely available alternative to human microsurgery remains to be established (71, 72). Reversibility is better with microsurgery (69), in younger men with shorter duration since vasectomy (68) and possibly with longer testicular vasal stump (73, 74); unfavourable predictors of a pregnancy outcome include non-microsurgical techniques, older age of wife (especially after 40 yr) (69, 75), high titers of sperm antibodies (67) and long duration since vasectomy (76, 77) due to long-term epididymal (78), vasal (79) and testicular damage (76, 77, 80, 81).  An alternative to surgical vasectomy reversal either instead of, or after failed vaso-vasostomy, is sperm harvesting from epididymis (MESE) or testis (TESE) in conjunction with intracytoplasmic sperm injection (ICSI)/in-vitro fertilisation. Currently cost-benefit analyses suggest that microsurgical vaso-vasostomy is more cost-effective and safer in both North America (82) and Europe (83), with the wife’s age being a key determinant (70), although optimal management depends on local clinical expertise and access to microsurgery and reproductive technologies. 

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 (84). 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 (85) but, despite preliminary positive findings (86), formal evaluation showed vas occlusion had lower efficacy (inducing azoospermia) than vasectomy (87). In a phase II randomized clinical trial a urethane-coated nylon thread intra-vas device was more acceptable with fewer complications but was less effective in producing azoospermia, compared with no-scalpel vasectomy (88). A hydrophilic gel, composed of styrene maleic anhydride in dimethyl sulfoxide, forms a charged spermicidal biopolymer when injected into the vas deferens which is stable but potentially removable. Preliminary non-comparative clinical evaluation showed azoospermia in 12 men with no pregnancies in their wives for 12 months following intravasal injection suggesting vasal occlusion (89); however, subsequent studies indicate persistence of morphologically damaged and non-functional sperm in the ejaculate (90). Other technical developments including percutaneous injection of sclerosants and transcutaneous delivery of physical agents (ultrasound, lasers) continue to be developed.

It has long been known (91) that even brief elevations of testicular temperature can profoundly suppress spermatogenesis (92) while sustained elevation may contribute to testicular pathology in cryptorchidism, varicocele and occupational male infertility (93). Clinical studies evaluating the potential for tight scrotal supports as a practical male contraceptive method (94, 95) showed a reversible decrease in sperm output but of inadequate magnitude for reliable contraception. Given the dubious acceptability and safety (96) of heat-induced suppression of sperm output, the feasibility of a male contraceptive method based on testicular heating remains to be established.

Sperm vaccines to interrupt fertility have long been of interest (97). Sperm express unique epitopes within the immunologically protected adluminal compartment of the seminiferous tubules at puberty, long after the definition of immune self-tolerance 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. Passive immunization may overcome the present limited predictability of active immunization with sperm antigens to reach quickly and maintain, as well as allowing for volitionally controllable offset of effective immunocontraceptive titres (98). The smaller antigenic burden in the female reproductive tract requiring complete neutralization suggests that a sperm vaccine may be more applicable for women (99).

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 in transit through seminiferous tubules and epididymis, however, offers potential targets for chemical methods to regulate male fertility as sperm are stored and mature functionally. Post-testicular targets in particular offer the advantages of fast onset and offset of action compared with hormonal methods; however, specific target identification, selective drug targeting to the epididymis or testis and human dose optimisation remain challenging problems. A model, rapid-onset oral spermicide was first provided by the chlorosugars that showed rapid, irreversible effect on rodent epididymal sperm (100) but proved too toxic for clinical development. More recently, an alkylated iminosugar drugs that inhibit glucosyltransferase, used therapeutically to reduce lysosomal glycosphingolipid accumulation in storage disorder type 1 (Gaucher's disease), was shown to cause male infertility in mice (101) via structural malformation of sperm acrosome, head and mid-piece with consequential impaired motility with the sperm retaining ability to fertilize in-vitro and produce normal offspring (102). Although these effects were reversible on cessation of the drug, prolonged treatment reduced sperm production (103) and the effects were species- and mouse strain-dependent (104) with a pilot clinical study showing that human sperm were unaffected (105).

Novel leads for male contraceptive development arise from fortuitous pharmacological observation of existing chemicals (including drugs or natural products) or mechanisms that impair male fertility notably unexpected sterility in mouse genetic models (106). Among existing drugs, an orally active spermicide concentrated in semen (107), drugs inhibiting male fertility (108), ejaculation (109) or epididymal sperm function (101) 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 (110). Although an effective male contraceptive, the systemic toxicity of gossypol and irreversibility precluded further clinical development (111). 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 (112).

The most rapidly growing area of opportunity arises from serendipitous discoveries of genes found to be necessary for normal fertility, often an unexpected outcome of gene knock-out mouse models (106). This growing list includes inhibition of sperm function, notably flagellar motility, by ion channel aberration (113-123), ductular transport of sperm (124), fertilization (125) or spermiogenesis (126, 127). Practical clinical development of these promising leads remains a challenging task.