Although the twentieth century has seen great strides in the development of female contraception, not a single new agent has been introduced as an approved method for common use for male contraception. Condoms (considered uncomfortable by some) and vasectomy (a permanent invasive procedure) are the only options provided to men, leaving an undue burden on women to bear contraceptive responsibility. Significant developments have, however, been made with regard to hormonal and nonhormonal contraception, and minor, reversible, procedural contraception. This article reviews the currently available, soon to be available, and theoretically possible methods of male contraception.
Key points
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Hormonal contraception has offered the most promising results with the greatest amount of clinical research. It will likely include a combination of androgen and a progesterone analogue with extended-interval depot injections and/or implants, although a tremendous amount of research is ongoing to develop alternative oral or transdermal formulations.
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Inhibition of the testicular retinoic acid pathway through existing agents such as WIN-18,466 or BMS-18943 seems to offer a viable, safe, and reversible mechanism for male contraception although more clinical work needs to be done.
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Interruption of the postepididymal extracellular eppin-semenogelin complex, either through proven immunologic methods or theoretic pharmacologic antagonists, has a promising safety and reversibility profile.
Introduction
Compared with female contraceptive methods, male alternatives are few and relatively underused. Currently, the only readily available methods of contraception for men include vasectomy, condoms, and withdrawal. The first 2 methods account for only 8.9% of global contraceptive use. Surveys have demonstrated that nearly 80% of men believe contraception is a shared responsibility and globally more than 50% of men endorsed interest in an alternative male contraceptive. These studies demonstrate an unmet need for alternative male contraception. This review discusses currently available, soon to be available, and potential targets for male contraception.
Introduction
Compared with female contraceptive methods, male alternatives are few and relatively underused. Currently, the only readily available methods of contraception for men include vasectomy, condoms, and withdrawal. The first 2 methods account for only 8.9% of global contraceptive use. Surveys have demonstrated that nearly 80% of men believe contraception is a shared responsibility and globally more than 50% of men endorsed interest in an alternative male contraceptive. These studies demonstrate an unmet need for alternative male contraception. This review discusses currently available, soon to be available, and potential targets for male contraception.
Currently available methods
Condoms
Reports of barrier methods date back to Imperial Rome; however, the first recorded descriptions of a condom were in the 16th century. For more than 400 years, sheathlike barrier methods of contraception have been used to prevent infection and pregnancy. They have evolved from animal intestines to latex and polyurethane-based products. Compared with other contraceptive methods, condoms offer low cost, ease of use, near absence of side effects, and reduction in transmission of sexually transmitted infections. Although the perfect-use failure rate of condoms is 2% in 1 year of use, with actual use, the failure rate is 17% per year. The relatively high failure rate, coital-dependent slippage, and perceived reduction in pleasure are common reasons for lack of use. Because of their safety and ability to protect against sexually transmitted infections, condoms are likely to remain the recommended method for young men who have not fathered children and are not in a stable monogamous relationship.
Vasectomy
Vasectomy was first described in the early nineteenth century in the United Kingdom as a procedure first performed on dogs. It first came into clinical practice in the late nineteenth century as a treatment of prostatic enlargement as an alternative to castration, and enjoyed moderate popularity as such until it was realized that it offered no benefit in this regard. It was then used in the treatment of postprostatectomy epididymoorchitis and it was not until the 1970s that routine vasectomies stopped being performed with prostatectomies. Oschner first suggested vasectomy as a contraceptive method, not, however, for elective purposes but rather as a eugenic procedure and an alternative to castration for “criminals, degenerates and perverts.” For the first half of the twentieth century, vasectomy was a popular means of eugenic sterilization in the United States and in Europe. In the second half of the twentieth century, as eugenic vasectomy fell out of favor, elective vasectomy became increasingly more popular in the United States and globally.
Compared with elective female sterilization (laparoscopic tubal ligation or transcervical hysteroscopic methods), vasectomy is underused. Globally, 5 times as many female sterilizations are performed as vasectomies despite being associated with increased morbidity and mortality, higher cost, and increased use of general anesthesia. In the United States, nearly 3 times as many couples elect to have tubal sterilization compared with vasectomy. In addition, there are distinct ethnic and socioeconomic differences among those who elect to have male or female sterilization. Vasectomy is most common in non-Hispanic whites (17.4%) with a college education (16.7% compared with 3.0% among those without a high school diploma), whereas tubal sterilization is most common in non-Hispanic blacks (32.7%) and those without a high school education (36.4% compared with 13.0% of college-educated women).
It is estimated that between 175,000 and 550,000 vasectomies are performed annually. It is a highly effective procedure with failure rates typically less than 1%. In the United States, most vasectomies are performed by urologists as an outpatient procedure under local anesthesia. Although vasectomy reversal procedures exist and are practiced regularly by specialists, vasectomy is intended to be a permanent form of contraception. Vasectomy requires a postoperative period of alternative contraception until azoospermia is documented. The most common side effects include a 1% to 2% incidence of symptomatic hematoma, a 3.4% incidence of infections, and a 15% to 52% incidence of chronic scrotal pain. However, a recent prospective study of 625 men followed at 7 months found that 15% had some degree of scrotal pain and only 0.04% had pain severe enough to affect quality of life.
Although the procedure is by no means novel, there are multiple variations in technical approaches, such as no-scalpel vasectomy and other minimally invasive approaches versus scalpel vasectomy. Incisions may be singular and midline or bilateral. Perivasal fascia may be interposed between the 2 cut segments or not. Cautery may be mucosal, intraluminal, extended nondivisional, or not used at all. The testicular end may be left open in an attempt to minimize chronic pain or closed to reduce recanalization or failure. Ligation of the ends may be preformed with clips or suture. The 2012 American Urological Association guidelines on vasectomies found that the evidence studying the effectiveness of these technical variations is limited and only grade C evidence exists. However, the expert opinion was that as long as the procedure is performed through a minimally invasive approach, such as no-scalpel vasectomy or with a small (<10 mm) incision using specialized instruments for vasal isolation, uses mucosal cautery and fascial interposition when the open testicular end is opted for, virtually all of the technical variations have documented approximately less than 1% failure rate and are acceptable as long as the surgeon has a similarly acceptable failure rate.
Hormonal
By far the most widely studied form of male contraception that currently remains unavailable is hormonal contraception. Known since the 1930s and actively pursued since the 1970s, male hormonal contraception is analogous to female hormonal contraception, working primarily through inhibition of the hypothalamic-pituitary-gonadal axis. Sometimes called pretesticular contraception, hormonal contraception inhibits spermatogenesis by inhibiting release of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby decreasing intratesticular testosterone levels. Because viable sperm can exist for up to 8 weeks after production, there is a delay of several months before sufficient oligospermia or azoospermia is achieved, during which alternative contraception must be used. This suppressive effect of testosterone on spermatogenesis can be augmented by the addition of progesterone analogues and GnRH antagonists. Numerous formulations of testosterone in various injectable, implantable, transdermal, or oral forms, along with their modulators in different iterations of doses and frequencies have been studied and published. In developing an alternative male contraceptive, an ideal agent should have the following parameters fulfilled, as outlined by Nieschlag and colleagues ( Fig. 1 ):
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Applied independent of the sexual act
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Acceptable for both partners
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Not interference with libido, potency, and sexual activity
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Have no short-term or long-term toxic side effects
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Have no impact on the eventual offspring
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Rapidly effective and fully reversible
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More effective than condoms
Pure Androgen
High-dose testosterone depot injections alone, for the purpose of achieving azoospermia, have been studied extensively since the 1970s. Unfortunately, most oral testosterone formulations have either poor bioavailability or hepatic toxicity and exogenous administration currently requires depot injections, implants, or transdermal gels to achieve consistent levels without frequent dosing several times a day.
Two large, multinational, multicenter studies sponsored by the World Health Organization published in the 1990s showed that 200 mg intramuscular injections of testosterone enanthate (TE) every week produced azoospermia in 65% of men after 4 months with 0–0.8 pregnancies per 100 person-years and oligospermia (defined as <3 million sperm/mL) in all but 2.2% with associated pregnancy rates of 8.1 per 100 person-years. The combined failure rate of the regimen was 1.4 pregnancies per 100 person-years, comparable with the female contraceptive pill, and improved with increasing severity of azoospermia. Although less than 3 million sperm/mL was seen as sufficiently adequate compared with currently available methods, oligospermia of less than 1 million sperm was seen as ideal.
This regimen was largely well tolerated with minimal reversible side effects seen in a quarter of the subjects (weight gain, acne, increased aggressiveness and libido, hypertension, depression, tiredness, decrease in testicular volume, increase in hemoglobin, and decrease in high-density lipoprotein [HDL]). Largely, the failure in 2% of patients to achieve sufficient oligospermia and the inconvenience of weekly injections along with side effects leading to high attrition rates in the studies were seen as the major disadvantages of this regimen. Some of the side effects seen in these studies were believed to be caused by the unstable pharmacokinetics of early preparations of testosterone leading to the use of testosterone undecanoate (TU) in later studies, which can be administered every 1 to 2 months.
Ethnic Differences
One of the important findings of these studies was an increased effectiveness in East-Asian populations with lower sterilization rates seen in whites after exogenous testosterone administration. This led to the oft-quoted figure of one-third of whites not responding to testosterone alone. The reasons for this are uncertain and may be related to differences observed between these groups in terms of cultural acceptance, general adiposity, testicular parenchymal weight, testosterone production rates, sex-hormone binding globulin affinity, 5α-reductase activity levels, prevalence of certain polymorphisms of the uridine diphosphoglucuronosyl transferase (UDGT) gene responsible for hepatic glucuronidation of testosterone, the number of CAG or GGC repeats at the N-terminus of the androgen receptor affecting affinity for testosterone, or suppressibility of LH.
Certain practical features of this ethnic difference have been noted, such as the observations that addition of progestins closes the gap and that Asian men recover faster after withdrawal of exogenous testosterone. In addition, it has undermined certain uncontrolled studies in East Asia that found high efficacy rates in combined progestin and androgen regimens in that the added benefit of the progestin and applicability to white populations was uncertain given the known difference in response.
Studies of monthly injectable TU in Chinese men have been promising. A recent study of 1045 men found effective suppression to the level of less than 1 million sperm/mL in 94% of men with a pregnancy rate of 1.1 per 100 men after 2 years of study and 1554.1 person-years of exposure. The most common side effects were acne, severe cough after injection, mood or behavior changes, and incomplete recovery of testicular volume in 28% of men at the end of the 12-month recovery phase. Theoretically, this dosing interval could be further extended to 10 to 14 weeks if castor oil were used as a solvent rather than tea seed oil, further adding to patient satisfaction. Although these results are promising, this regimen is unlikely to be as effective in white groups based on the findings from the large multinational World Health Organization (WHO) studies.
Testosterone + Progestin
The addition of progesterone derivatives (called progestins or progestagens) to testosterone increases the rates of spermatogenesis inhibition by further inhibiting pituitary production of gonadotropins and possibly acting directly on germ cells. Progestins alone may be sufficient for inhibiting spermatogenesis; however, without exogenous testosterone, a hypogonadal state would be induced with its resultant undesirable side effects. Together, progestins and testosterone have synergistic effects, affording a lower dose of testosterone to achieve sufficient suppression of spermatogenesis and achieve it in a shorter time than testosterone alone. The lower doses of testosterone required with concomitant progesterone more closely approximates a eugonadal state. This is important because the high doses required for spermatogenesis inhibition in the testosterone-only regimens may actually support spermatogenesis in nonresponders by maintaining intratesticular testosterone levels.
Various progestins have been combined with testosterone including cyproterone acetate, levonorgestrel, desogestrel, etonogestrel, norethisterone enanthate, medroxyprogesterone acetate, and depot medroxyprogesterone acetate (DMPA). As progestins may be formulated in effective oral, injectable, implantable or transdermal forms, testosterone remains the limiting agent with regard to bioavailable formulation when the 2 are combined. Progestins can have proandrogenic (norethisterone) or antiandrogenic (cyproterone) activity, resulting in increased weight gain, lower HDL levels, lower sex-hormone binding globulin levels. They may also promote proinflammatory cytokines that are linked to adverse cardiovascular events, leading to a preferred practice of giving only the minimal necessary dose.
Bebb and colleagues randomized 36 patients to 100 mg of weekly intramuscular TE alone or TE with daily oral levonorgestrel and found that 96% of the combined group achieved oligospermia (defined as <3 million sperm/mL) on average in 9 weeks and 5 weeks faster than with TE alone. This regimen was well tolerated with comparable rates of weight gain, acne, and decrease in HDL between the 2 groups.
In another promising study by Kamischke and colleagues, the dosing interval was spread out to every 6 weeks of intramuscular 1000 mg TU with concomitant depot injections of norethisterone enanthate. With this regimen, 13/14 patients achieved azoospermia with only 1 having insufficient oligospermia of 10 million/mL. Azoospermia was achieved on average by 8 weeks. This regimen was also well tolerated with several volunteers experiencing mild acne, mild nocturnal sweating, and a maximum reversible weight gain of 3.7 kg.
The TU/NET-EN study was the most recent multinational WHO study on combined depot injections of TU and norethisterone enanthate every 2 months. The study was stopped prematurely and results are soon to be published. Patients were enrolled from 2008 to 2010 and the study was discontinued by the review panel in 2011 for concerns of depression, other mood changes, increase in sexual desire, and pain at the injection site at higher rates than expected. In addition, 2 serious adverse events were judged to be either possibly or probably related to the study regimen but the specifics are unavailable for scrutiny at this time. By April 2011, 321 men were enrolled, 110 of whom completed the 12-month efficacy phase and 103 of whom were completing the recovery phase. The regimen was reportedly efficacious with few pregnancies reported; however, because of the previously mentioned concerns and early termination, it is unlikely that this regimen will be further developed clinically.
Oral Testosterone
Oral TU with progesterone has been studied for the purposes of male contraception and was reported as early as 1980. These early studies demonstrated suppression of spermatogenesis, but not to levels sufficient for infertility. Current regimens still require dosing 2 to 3 times a day, making it inconvenient for contraceptive purposes. In 1 small cohort of 8 men taking oral TU with oral cyproterone acetate, oligospermia of less than 3 million sperm/mL and azoospermia was achieved in 75% of men; however, a reversible 1 g/dL decrease in hemoglobin level was seen as well. This induced mild anemia was believed to be caused by the antiandrogenic property of cyproterone acetate, making it fall out of favor relative to the other progestins. Perhaps with future developments and improved pharmacokinetics, male oral contraception may show more promise.
Implants
Crystalline testosterone pellet formulations have been around for more than 70 years and were largely outside clinical focus. With the goal of achieving steady levels of testosterone with zero-order release kinetics, these testosterone implants were rediscovered and investigated for contraceptive purposes. The pellets are made of fused crystalline testosterone and injected subdermally under local anesthesia into the abdominal wall and dissolve without need for removal. They provide the benefit of administration at intervals of up to 6 months apart. Occasionally, they can extrude from the injection site although this occurs relatively infrequently and improves with operator experience.
Handelsman and colleagues demonstrated severe oligospermia of less than 1 million sperm/mL or azoospermia in 9/9 patients after 2 months after 1200 mg of testosterone-only pellet. This small study was done after the first large WHO-sponsored study but before the second in which severe oligospermia of less than 3 million sperm/mL was found to have acceptable pregnancy rates. As a result, Handelsman’s goal was azoospermia, making their rate of 56% seem inadequate. In a follow-up study, they achieved similar results at a lower dose of 800 mg testosterone only, but when DMPA was added, azoospermia was produced in 9 of 10 men, with severe oligospermia in the remaining man. Recovery was seen at 7 months after implant and 2 extrusion episodes occurred in 30 administrations. In yet another study with repeated dosing of this regimen every 4 months in 55 men for 12 months, no pregnancies were seen over the 35.5 person-years studied. Only 2 of 55 men did not achieve azoospermia and did not enter the efficacy phase. They experienced a fairly high attrition rate of 49% but did not attribute this to medical reasons or intolerance of the formulation but rather an absence of a financial incentive strong enough to offset the inconvenience of study participation. In another installment in this series of studies, the addition of implantable estradiol at 10 mg or 20 mg was found to add insignificant rates of azoospermia and had unacceptable side effects of androgen deficiency and estrogen excess.
A separate series of studies by Martin and colleagues of 31 men given 300 mg of testosterone implants with varying doses of oral desogestrel over 8 weeks found no significant adverse metabolic or behavioral effects. Although their objective was primarily to study the hormonal and metabolic effects of this regimen, they were able to demonstrate azoospermia and oligospermia with 300 μg of desogestrel in 10 of 10 patients at 8 weeks.
Given the historical difference in spermatogenesis suppression between white and Asian men, Kinniburgh and colleagues compared daily oral desonogestrel at 150 or 300 μg with 400 mg testosterone pellet implants every 12 weeks between 2 cohorts in Edinburgh, Scotland (n = 30) and Shanghai, China (n = 36). There were slight differences between the 2 in the rate at which severe oligospermia was achieved but overall, each cohort achieved azoospermia with 300 μg desonogestrel by 24 weeks with 90% achieving it by 16 weeks. Paradoxically, the white cohort achieved azoospermia faster and at the lower dose of desonogestrel. The regimen was well tolerated with single individuals experiencing labile mood, worsening acne, hypertension, pellet discomfort, and weight gain, and 2 men experienced pellet expulsion.
Kinniburgh and colleagues also demonstrated no added benefit of the 5α-reductase inhibitor finasteride to spermatogenesis inhibition with a regimen of 150 μg desonogestrel (a known submaximal dose) with 400 mg implantable testosterone. The rationale behind that study was that some of the nonresponders may have increased intratesticular testosterone levels being converted to the more powerful androgen dihydrotestosterone (DHT) by 5α-reductase and supporting spermatogenesis. However, finasteride and other 5α-reductase inhibitors have no action on testosterone directly and thus any intratesticular testosterone present may still support spermatogenesis. In addition, intratesticular testosterone levels may increase as a result of finasteride, counteracting any reduction in DHT. In yet another follow-up study, efficacy of implantable testosterone was also demonstrated with etonogestrel implants. Single etonogestrel implants may be effective for up to 3 years in women, however, 3 pellets at a time were required to achieve sufficient azoospermia. One of 9 men did not sustain azoospermia after 40 weeks, raising the question of relative durability of the etonogestrel implants, which need to be removed surgically.
Transdermal
With the intention of facilitating patient autonomy and allowing self-administration (or user-independent administration), several groups have studied transdermal formulations of testosterone for contraceptive purposes. Historically, these studies have not been promising, even with the addition of a progestin because of low serum levels insufficient for LH and FSH suppression. Guerin and Rollet achieved azoospermia with testosterone gel and oral norethisterone acetate in 12 of 12 volunteers but this was not a durable response and by 3 months the average count was more than 3 million sperm/mL.
Several recent proof-of-concept studies of testosterone gels combined with either progesterone monthly depot injections or gels have been able to achieve severe oligospermia of less than 1 million sperm/mL in approximately 90% in moderate-sized cohorts. Ilani and colleagues achieved this with a nonandrogenic progestin nestoron gel with testosterone gel in 99 patients at around 22 weeks and azoospermia in 78% of patients. This regimen was fairly well tolerated with no severe adverse events and only side effects of mild-to-moderate acne in 21% and headaches in 17%, with the remaining side effects occurring infrequently.
Page and colleagues achieved this using testosterone gel with DMPA every 3 months in 38 men. Although they did not report any azoospermia, they found the addition of the injectable GnRH antagonist acyline to progesterone and testosterone had no improvement. This regimen was also fairly well tolerated but had a high incidence of mild acne (26 of 38 men) as had been seen in previous studies. The primary consideration of testosterone gel is the avoidance of contact with the applied area to female partners and other persons shortly after application because of concern for androgenization.
Addition of GnRH Antagonists
Gonadotropin-releasing hormone (GnRH) antagonists compete with endogenous GnRH but do not activate pituitary receptors and thereby inhibit production and release of FSH and LH. In addition, GnRH agonists have similar effects when given in a nonpulsatile continuous fashion but have proved to be ineffective in demonstrating durable suppression of spermatogenesis and blunt the suppressive effects of androgens.
Similar to progestins, GnRH antagonists have synergy when combined with testosterone in inhibiting spermatogenesis. Several antagonists have been studied in combination with androgens such as Nal-Glu, acyline, cetrorelix, and abarelix.
Bagatell and colleagues found no increased efficacy of daily subcutaneous injections of Nal-Glu to weekly 200 mg intramuscular injections of TE in a study of 22 men. This is not a surprising finding considering that the same dose of TE alone had already been found to be relatively efficacious in previous studies. In a follow-up study of 15 men, the same group found that Nal-Glu combined with TE was an effective induction agent for contraception with weekly low (100 mg) intramuscular TE injections as maintenance for 20 weeks with a failure rate of 6.7%.
Another small study of 6 men induced with cetrorelix and maintained on intramuscular injections of the selective androgen 19-nortestosterone hexyloxyphenylpropionate (19-NT-HPP) every 3 weeks did not show durable spermatogenesis suppression. This was believed to be partly due to the nonaromatizable property of 19-NT, which eliminated the suppressive effects that estradiol has on LH and FSH release seen with testosterone-based regimens.
Although further developments of GnRH/androgen combinations are expected, the disadvantages of GnRH antagonists include their relatively frequent local skin reactions, and cost. These may improve with future developments and do not constitute a reason for abandoning further efforts.
7α-Methyl-19-Nortestosterone
7α-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen resistant to 5α-reductase but sensitive to aromatase. MENT is classified as a selective androgen receptor modulator (SARM), a class of drugs currently under early development. SARMs are of particular interest, not only because of a potentially favorable side effect profile but also because a particular subclass of SARMs called nonsteroidal SARMs exist in oral formulations that may make male hormonal contraception more appealing to a broader group of men. MENT’s properties make it an appealing agent for its minimal effects on prostatic hypertrophy as well increased potency for spermatogenesis inhibition. MENT has already demonstrated efficacy in small studies as a solitary agent in an implantable form for up to 1 year. However, further development is needed as a recent study demonstrated inferiority when combined with implantable etonogestrel compared with an implantable testosterone and etonogestrel combination with regard to rate of azoospermia and durability of severe oligospermia. This was believed to be caused by inadequate release of MENT from the currently manufactured implants and follow-up studies are expected in the near future on improved implants.
Overview of Hormonal Contraceptives
A meta-analysis of 1549 men who underwent 1283.5 man-years of treatment and 705-man-years of recovery showed a median time to recovery of 20 million sperm/mL of 3.4 months and 100% recovered within 24 months. As can be expected, longer-acting preparations, such as TU or implants, were associated with longer recovery and the opposite for shorter-acting agents such as transdermal, TE, or oral formulations. A follow-up meta-analysis confirmed that addition of progesterone increases the rate and extent of spermatogenesis suppression, recommending its addition to any hormonal regimen.
Although most men do not experience loss of testicular volume, a reversible loss of 4 to 5 mL is not uncommon. Alterations in mood such as irritability, depression, lability, or libido changes have been reported in less than 1% to 73% of men. Clearly, the preliminary news of the TU/NET-EN study being prematurely terminated at least partially due to a greater than expected incidence of effects on mood and libido is concerning. However, until final reports are published, it is difficult to draw any conclusions, especially when previous reports have been generally favorable.
Effects on lipids have been variable with generally decreased lipids either isolated to HDL or total lipids or increased total lipids or low-density lipoprotein, alternating between being proatherosclerotic or antiatherosclerotic. This is also balanced by an increased percentage of lean body mass with lower body fat. Overall, the effects of testosterone on cardiovascular health are not known, with conflicting literature suggesting that the effects are likely negligible.
Relatively common complaints pertaining to acne or night sweats may be bothersome to some individuals and should not be a deterrent to use. In a large-scale study of 1045 men, 7% reported acne but none withdrew because of it. Other dermatologic complaints such as skin irritation or injection site tenderness may be more concerning and are limited to the route of administration.
Exogenous testosterone does not increase the risk of prostate hyperplasia and carcinoma, particularly when attempting to achieve a eugonadal state. However, in a patient with known prostate hypertrophy or carcinoma, it would be reasonable to avoid these agents until further data are gathered.
Studies attempting to predict responders from nonresponders by measuring changes in FSH and LH have not been able to differentiate the two. This point has also been rendered moot with the high efficacy rates under regimens using supplemental progestin analogues.
Nonhormonal contraception
Nonhormonal male contraception has been in development for as long as hormonal contraception but with less clinical success. Conceptually, it is appealing for the theoretic lack of systemic side effects seen with hormonal contraception. Unfortunately, less development has taken place than with hormonal contraception and most agents have been plagued by side effects, reversibility, and efficacy issues, leading to few phase 2 or 3 studies.
Pharmacologic
Gossypol
Gossypol is a phenolic compound derived from the cotton plant. It may be second to hormonal contraception in the volume of published literature including phase 3 trials of more than 8000 subjects. It has been studied for its male-specific antifertility effects since the 1970s and is believed to work by inhibiting spermatogenesis and sperm motility. Although highly efficacious in 90%, it has exhibited a narrow therapeutic range with a frequent association with hypokalemia, a 1% incidence of periodic paralysis, and a 5% to 50% incidence of irreversible sterility. Despite numerous attempts at chemical modification and purification of gossypol, it has been all but disqualified from further clinical development for contraceptive purposes.
Triptolide
Triptolide is derived from the Chinese herb Trypterigium wilfordii and belongs to the class of chemicals called diterpene epoxides. Having been used for medicinal and insecticide purposes for centuries, it gained attention for its infertility effects in the 1980s. As an orally administered agent, triptolide impairs sperm motility and has been shown to decrease epididymal sperm counts at the posttesticular level. It was incidentally found in studies of patients with rheumatoid arthritis where it was studied for its immunosuppressive effects. Unfortunately, prolonged exposure was associated with irreversible inhibition of spermatogenesis and further studies as a contraceptive have been all but abandoned.
Indenopyridines
Indenopyridines have been shown to inhibit spermatogenesis in several animal studies since the 1970s. They are believed to affect Sertoli cells and recent primate studies of l -CDB-4022 especially have been promising. Concerns about indenopyridines have centered on Sertoli cell toxicity and irreversibility, which was seen in rat models. l -CDB-4022, as a newer formulation, may have a more favorable profile but further studies are needed to evaluate its safety and efficacy.
Lonidamine derivates
Lonidamine, initially studied for its anticancer properties, was found to be antispermatogenic in the 1970s. Side effects of muscular pain, testicular pain, vomiting, and liver damage halted further development; however, its less toxic derivatives adjudin and gamendazole were also investigated and developed for contraceptive purposes.
Adjudin, formerly called AF-2364, was discovered in the early 2000s. It works primarily through disruption of the adhesion between spermatids and Sertoli cells causing premature spermiation. Because of the localized effect and absence of toxicity to Sertoli cells, this agent has drawn significant attention. By disrupting the sperm-Sertoli cell junction, the developing sperm are depleted but without toxicity or affecting FSH or LH levels, thereby maintaining future fertility. This site of action is also called the apical ectoplasmic specialization (apical ES). Although initial studies were promising with no detectable toxicity and 100% efficacy, in extended studies, 3 of 10 male rats treated with daily adjudin for 29 days developed minimal liver inflammation and skeletal muscle atrophy. No female rats displayed any adverse effects. This prompted a series of studies pairing adjudin with FSH to lower the effective dose as FSH receptors in men are only found in the Sertoli cells. This lowered the minimum dose necessary but proved to be too costly and active efforts are underway to continue to lower the effective dose required.
Gamendazole was another product of the search for a less toxic lonidamine derivative. Although effective at well below toxic doses, gamendazole was irreversible in 43% of rats treated with the dose required to produce 100% infertility.
CDB-4022 is an indenopyridine that also has shown effectiveness in nonhuman primate models in disrupting the Sertoli cell-germ cell junctions. Unlike gamendazole, reversibility was readily achieved at effective doses and it was well tolerated overall with no observable adverse effects.
The lonidamine derivatives are an exciting new class of drugs for male contraception because of their selective activity at the Sertoli cell-germ cell junction, near complete absence of systemic effects, oral dosing with potential for extended dosing intervals, and reversibility.
Testicular retinoic acid inhibition
Vitamin A (retinol or retinoic acid) was first found to be essential to spermatogenesis when Wolbach and Howe demonstrated the devastating effects its absence had on the testes in 1925 when they deprived rats of dietary vitamin A. Through studies of genetically manipulated mice and rats, the significance of retinoic acid and its receptor in spermatogenesis was elucidated and several promising male contraceptive agents working in this pathway have been studied.
WIN 18,446 is a potent bisdichloroacetyl diamine (BDAD) known to have selective and reversible inhibition of spermatogenesis since the 1960s. In a study of 9 men, orally administered WIN 18,446 twice daily for 23 weeks, sperm counts were decreased to 0 to 4 million/mL within 8 to 11 weeks. To our knowledge, this is the only reported clinical study of WIN 18,446 in humans; it was subsequently abandoned because of reports of disulfiram effects. Heller and colleagues made no mention of a disulfiram reaction and the only reported complaint was related to gas and bloating. Regardless, interest in this agent has been renewed and modern studies have found that WIN 18,446 inhibits testicular retinoic acid synthesis from retinol through inhibition of the testis-specific acetaldehyde dehydrogenase ALDH1a2. Blockade of this pathway results in a hormone-independent suppression of spermatogenesis while preserving normal testosterone levels and a eugonadal state. It is thought that WIN 18,446 also inhibits ALDH2 causing the disulfiram effect and that a more refined agent with selectivity for testicular ALDH1a2 would not cause the reported undesirable effects of WIN 18,446. In any event, repeat modern clinical studies of WIN 18,446 are warranted given its favorable safety profile.
Inhibition of testicular retinoic acid production results in decreased expression of the cytoplasmic factor Stra8 (stimulated by retinoic acid gene 8), which inhibits the entry of the spermatogonia into meiosis and thereby inhibits spermatogenesis. This effect can be reversed simply by administering retinoic acid. In addition, Stra8 may become a future pharmacologic target for male contraception.
Besides inhibition of testicular retinoic acid production, advancements have been made in selective inhibition of nuclear retinoic acid receptors (RAR). BMS (Bristol-Meyers-Squibb)-189453 is an arotinoid oral RAR antagonist. Unlike WIN 18,446, which works by depleting testicular retinoic acid and takes up to 16 weeks to produce azoospermia, BMS-189453 has a faster onset of 1 month with durable effects for 4 months after dosing. Although low doses are effective at inhibiting spermatogenesis, high doses in rats are associated with toxicity and death with effects mimicking vitamin A toxicity or excessive retinoid agonists. A repeat efficacy study in rats demonstrated 100% efficacy with no discernible side effects at low doses with almost total reversibility based on histologic appearance.
Calcium channel blockers
Calcium has long been known to be important to sperm motility. However, before the discovery of CatSper (cation channels of sperm) in 2001, little was actually known about sperm calcium regulation. Before this discovery, the effects of nifedipine, verapamil, and other calcium channel blockers on sperm motility were debated and reported on primarily through anecdotal or observational studies. Although numerous CatSper knock-out mice studies exist, little work has been done on developing CatSper blockers or antagonists. Carlson and colleagues reported on a candidate CatSper blocker, HC-056456, with promising in vitro results. Li and colleagues were able to decrease mouse pregnancy rates to 12.5% by immunizing male mice with extracellular epitopes of CatSper. Although CatSper understanding is in its infancy, its blockers offer a promising mechanism for future contraceptive agents.
Sperm Na + /H + exchanger
Similar to CatSper, a novel class of sperm-specific Na + /H + exchangers (sNHE) has been identified and found to be crucial to regulation of the intracellular pH of spermatozoa. Mice with inactivated sNHEs produced morphologically normal sperm with impaired motility resulting in infertility. Further work needs to done on sNHE blockers, but current data allows for optimism about the possibility of these agents.
Inhibitors of glycosphingolipid synthesis
Miglustat, or N -butyldeoxynojirimycin (NB-DNJ), is an alkylated imino sugar that inhibits ceramide-specific glucosyltransferase. It is approved for the treatment of type I Gaucher disease, which results in excess glycosphingolipids. Oral administration of NB-DNJ in mice has demonstrated significant, reversible infertility in a dose-responsive pattern producing morphologically abnormal sperm with impaired motility and ultimately oligospermia. Unfortunately, in a small pilot study of 7 men over 6 weeks, miglustat had no discernible effect on sperm concentration, motility, or morphology despite attaining comparable serum levels. Possibilities for the discordant findings are that there is a species-specific response, 6 weeks was insufficient to detect a significant difference in spermatogenesis, or the dose was insufficient. Although it may seem tempting to use an agent already approved by the US Food and Drug Administration, further work needs to be done to demonstrate efficacy in humans before miglustat is seen as a potential male contraceptive.
Bromodomain BRDT inhibitor (JQ1)
The latest class of agents to find usefulness as male contraceptives are the inhibitors of the testis-specific protein BRDT. BRDT functions to reorganize hyperacetylated histones through recognition modules called bromodomains. Male mice with selective mutation of BRDT were found to have isolated infertility. In a study of healthy men with idiopathic oligospermia or azoospermia, single nucleotide polymorphisms associated with the BRDT gene were found to be a significantly associated factor. BRDT is activated at the onset of meiosis of spermatocytes, making it a desirable target of reversible infertility.
JQ1 is an orally bioavailable triazolothienodiazepine, related to benzodiazepines, and is the first BRDT inhibitor. In mice, its administration results in impaired spermatogenesis, reduced sperm motility, and decreased testicular volume, mimicking the features of BRDT mutated mice. These effects are reversible and have no discernible hormonal or other systemic effects.
Thermal
Although spermatogenesis is negatively affected by temperature increases, heating the scrotum 0.8 to 1.0°C with thermal supports or underwear alone is not a reliable mechanism for contraception. However, in a recent study, the addition of scrotal submersion in a 43°C water bath for 30 minutes per day for 6 days was found to accelerate oligospermia when combined with TU injections every 6 weeks but not to the extent of TU combined with oral levonorgestrel and never to contraceptive levels of less than 1 million sperm/mL. Perhaps future studies will find other contraceptive regimens, hormonal or otherwise, that are enhanced or activated by the addition of heat.
Ultrasound
Ultrasound application for male contraceptive purposes has many appealing conceptual features. First, ultrasound machines are relatively inexpensive and widely available. Second, ultrasound works locally with no systemic effects and, third, it would be appealing to those who are averse to taking medications regularly. In the 1970s, a series of experiments by Fahim demonstrated reversible inhibition of spermatogenesis with ultrasound. However, subsequent efforts to reproduce or study ultrasound-mediated male contraception were not promising. Recently, Tsuruta and colleagues revisited this concept attempting to reproduce Fahim’s results while characterizing and optimizing the ultrasound application. They demonstrated a depletion of rat epididymal sperm reserves within 2 weeks of treatment. VandeVoort studied 4 monkeys using slightly higher settings and demonstrated decreased sperm count and motility and reversibility.
The mechanism of action is uncertain and may be a combined effect of localized tissue heating combined with an additional ultrasound-mediated local phenomenon. Treatments are administered by placing the scrotum in a water bath within the beam filed of an ultrasound transducer. Tsuruta and colleagues used a treatment time of 15 minutes and interval of 2 days between treatments, whereas Vandevoort used a treatment time of 30 minutes and a similar interval of every 2 days for 3 treatments.
Vasal Occlusion/Interruption
Intravas device
Vasectomy alternatives with higher rates of reversal have been sought out since the 1960s. To this end, a class of implants named intravas devices (IVD) was developed. A group in China has developed a urethane device filled with nylon thread that blocks sperm but allows the passage of fluid and is inserted through a small scrotal incision identical to that used for vasectomy. In a randomized control study of 288 patients comparing no-scalpel vasectomy to this device, both groups tolerated the procedure well. However, statistically insignificant inferiority was seen with the device with a contraceptive success rate of 94.3% at 12 months compared with 98.6% for the vasectomy group. Reversal was not studied.
Another group in China developed a nano-SiO 2 -copper polymer composite IVD and studied the effect in 8 dogs over 12 months. After 3 months, no motile sperm were seen and no obvious damage was seen to the testes, epididymis, or vas, histologically suggesting that fertility was preserved and the potential for reversibility was high. In a follow-up study, the same group evaluated the same device in dogs and rabbits randomly assigned to vasectomy, sham procedure, IVD, or reversal for 12 months. Reversal success was measured with birth rates in rabbits, which were 60% for the device reversal but only 80% for the sham reversal, suggesting perhaps an inadequate recovery period, which was not stated.
Reversible inhibition of sperm under guidance
Reversible inhibition of sperm under guidance (RISUG) is the trademark name of an injectable contraceptive technique developed in the 1970s. RISUG involves injection of styrene maleic anhydride (SMA) dissolved in dimethyl sulfoxide (DMSO) into the vas under direct visualization through a small incision. A nonsclerosing porous polymer then forms and disrupts the sperm cell membranes as they traverse the vas, producing damaged, nonviable sperm. Primarily developed in India, several phase 2 studies have demonstrated efficacy of RISUG. In these studies, men attained azoospermia within 1 to 4 months and over 6 months no pregnancies were reported.
In achieving reversal of RISUG, clearly noninvasive methods are preferable to a repeat surgery. In a study of 9 monkeys treated with RISUG for 3 months, 100% reversibility was achieved using a progressive percutaneous method of squeezing the vas toward the inguinal canal, application of electrical stimulation, and digital rectal massage over the ampullary segment of the vas.
In a study of monkeys 1.5 years after RISUG injection, testicular biopsies demonstrated focal changes consistent with vasal occlusion with damage to the seminiferous epithelium; however, most of the testicle showed active and viable spermatogenesis and this was believed to be due to oxidative stress and not from occlusive pressure. Sperm viability and reversibility were evaluated in a later study that showed equivalent reversal to shorter trials.
In a rat study, Lohiya and colleagues demonstrated 100% fertility 3 months after reversal of RISUG with DMSO directly injected into the vas under visualization. In a follow-up study, the same group showed no evidence of DNA damage in a group of similarly treated rats.
RISUG is currently being evaluated in preclinical trials under the trademark name Vasalgel in the United States. Although the proof of principle has been established with intravasal injection of SMA polymer and the results have been promising, significant evaluation still remains to be done with larger multicenter clinical trials. Concerns regarding intravasal SMA center primarily on the teratogenic effects they may have on sperm and reversibility. This method may ultimately be advertised primarily as a vasectomy alternative with higher rates of reversibility but not as high as an ideal reversible contraceptive.
Immunologic
The development of vaccines against sperm or their components has been studied since the 1930s. Female animal studies in the 1950s, 1960s, and 1970s showed effective induced infertility when inoculated with varied sperm preparations. These crude formulations also caused early termination of pregnancy leading to concern about birth abnormalities. Similar to other nonhormonal contraceptive methods, immunologic induction of infertility offers the promise of localized action and absence of systemic effects. Up to 60% of men develop antisperm antibodies after vasectomy without any clinical effects except a lower probability of success after vasectomy reversal.
Primakoff and colleagues demonstrated effective and reversible infertility in both male and female guinea pigs immunized with sperm plasma and inner acrosomal membrane protein PH-20. However, PH-20 immunization is associated with orchitis and little development has taken place since the initial proof-of-principle study.
Eppin (epididymal protease inhibitor) is a protein expressed in the testis and epididymis only. It forms a complex on ejaculated spermatozoa with the major seminal vesicle protein semenogelin and is believed to protect the sperm from microbes and proteolysis and to facilitate sperm motility. In addition, eppin facilitates the cleavage of semenogelin by prostate-specific antigen (PSA) resulting in liquefaction of the coagulum and facilitating spermatozoal motility. In 1 primate study, injections of eppin into male monkeys every 3 weeks produced infertility in 78% with measurably high antieppin antibody titers. Seventy-one percent of those monkeys recovered fertility after cessation of immunizations. Recovery and nonresponsiveness were associated with low titers, suggesting a direct reversible immunologic contraceptive mechanism. It is thought that the antieppin antibody-eppin complex that forms on spermatozoa is equivalent to the eppin-semenogelin complex with regard to intracellular signaling; however, it is not cleaved by PSA like the native complex and, as a result, motility is impaired. Through mechanisms that remain unknown, this complex keeps the intracellular calcium levels low in sperm and prevents capacitation. Clearly, substitution of unpredictable biological inhibition achieved with immunization of the eppin-semenogelin complex for a pharmacologic compound would be more favorable as it would provide more precise regulation with less variability. Efforts are already underway to generate a recombinant semenogelin that would perform the same task as the antieppin antibodies without requiring immune activation.
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