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date: 10 December 2022

Approaches to Contraceptive Methods for Menfree

Approaches to Contraceptive Methods for Menfree

  • Christina WangChristina WangDivision of Endocrinology and the Clinical and Translational Science Institute, The Lundquist Institute and Harbor-UCLA Medical Center
  •  and Ronald S. SwerdloffRonald S. SwerdloffDivision of Endocrinology and the Clinical and Translational Science Institute, The Lundquist Institute and Harbor-UCLA Medical Center

Summary

Unlike female contraception methods, male contraception has had no new approved approaches since the introduction of no-scalpel vasectomy over 40 years ago. Men who wish to share family planning responsibilities have withdrawal or condoms as available reversible methods of contraception. These methods have a high failure rate and are user dependent. While a vasectomy can be surgically reversed, it should be considered a form of permanent contraception because pregnancy in the partner cannot be guaranteed after reversal. Experimental methods, including chemicals to block the vas deferens, are undergoing testing.

Since the 1970s, hormonal male contraception using testosterone alone and testosterone combined with a progestin demonstrated high efficacy and few short-term adverse effects. Long-term adverse effects cannot be determined until a hormonal male contraceptive method is approved, allowing safety studies to be performed. Contraceptive efficacy studies have shown failure rates comparable to those of hormonal female contraception. Current studies focus on user-controlled methods such as daily transdermal gels, oral pills, and long-acting injectables. Large-scale population studies performed in the early 2000s confirmed that over 50% of men surveyed would try a new male contraceptive, preferring an oral pill over injections or implants. These surveys also showed that over 80% of the women welcomed a new method of contraception, and over 90% of them would trust their partner to use the male method consistently. With changes in gender roles and gender equity in relationships, it is anticipated that male participation in family planning methods will be enhanced. Successful efficacy, safety, and reversibility with hormonal male-directed methods may pave the way new, targeted nonhormonal approaches. Once the testicular target is selected, new compounds can be identified based on structure function analyses or high-throughput screening to identify agonists or antagonists of the target.

Subjects

  • Sexual & Reproductive Health

The Need for Contraceptive Methods for Men

The unmet need for contraception for sexually active couples who are not using any contraception was 12.3% in 2010, varying from 6.2% in North America to 10.4% in Latin America, 11.0% in Asia, and 23.2% in Africa (Alkema et al., 2013). The unmet need of the world’s poorest countries remained at 21.6%, about the same from 2012 to 2017, except in African countries such as Kenya (−7.8%) and Malawi (−6.1%), which showed a significant decrease in unmet needs of modern contraception (Cahill et al., 2018). This perceived unmet need is highest in adolescent girls (15–19 years) and greatest in middle- and low-income countries (Deitch & Stark, 2019). It is estimated that the available family planning methods satisfied about 75.7% of women in the reproductive age group globally; less than half of the perceived need was met in Middle and Western Africa (Kantorová et al., 2020). Larger gaps remain in meeting the family planning needs of adolescents (59.2% globally and 38.7% in Western Asia and North Africa) (Kantorová et al., 2021). There are no reports on perceived unmet needs of contraception in men. However, in the National Survey of Family Growth in the United States, men underreported contraceptive use (female sterilization) and overreported “no method used” by their female partner (Aiken et al., 2017). This underreporting may be of importance in future determinants of contraceptive use among men.

Comparison of Contraceptive Failures Rates of Available Female and Male Methods

As noted in Figure 1, the contraceptive efficacy rate of short-acting methods such as the pill, patch, vaginal rings, and injectables (6 to 12 pregnancies per 100 women in a year) is much lower than that of implant and intrauterine devices (< 0.2 to 0.8 pregnancies per 100 women per year). With improvement in adherence to female contraceptive use, the failure rate of reversible methods of contraception (pills, patches, injectables, vaginal rings, intrauterine devices, implants) has declined significantly for all hormonal methods. The probability of failure to protect against pregnancy in the first 12 months of contraceptive use for all methods is 10.3% (6.0% for all female hormonal methods). The failure rate of female methods is higher in multiparous, Black, and Hispanic women; those who are unmarried; and for those below the poverty threshold (Sundaram et al., 2017).

Figure 1. Effectiveness of contraceptive methods.

The male-controlled methods of withdrawal and condoms require the male’s ability to adhere to the process, with in-practice failure rates of 20% for withdrawal and 13% for condoms. In addition, these methods are not acceptable to all couples. Vasectomy, considered a permanent method, has a contraceptive failure rate of 0.15%, lower than that of female sterilization (0.5%). There is a clear discrepancy of the number of available female methods compared to the very limited approaches available for male-directed contraception. The potential impact of new male contraceptive methods (reversible male hormonal contraceptive or reversible vas occlusion) on unintended pregnancies has been studied in Nigeria, South Africa, and the United States. Assuming only 10% of men would take up a new male method, the model estimated that unintended pregnancies would decrease by 3.5% to 5.2% in the United States, 3.2% to 5% in South Africa, and 30.4% to 38% in Nigeria by introducing a new male approach to contraception. Increasing the availability of new male methods should further decrease the rate of unintended pregnancies (Dorman et al., 2018).

Available Male Contraceptive Methods

Unlike approaches to female contraception, contraceptive methods available to men have not changed significantly since the 1970s. The first rubber condoms were made in 1855, and latex condoms were introduced in 1929. Vasectomy was first performed in men in the 19th century and was regarded as a contraceptive method during the Second World War. Globally about 15.7% of married/in-union couples rely on male methods, but their in-practice use varies demographically, with the lowest rates of 5.7% in Africa, increasing to 29.3%–30.2% in North America and Europe; Asia and Latin America are close to the global range (see Figure 2) (Ross & Hardee, 2017).

Figure 2. Contraceptive prevalence for married or in-union women aged 15–49 years, by method and region, 2015.

Note: IDU = intrauterine device.

Source: Ross and Hardee (2017). Creative Commons license.

Withdrawal

Withdrawal is used as a contraceptive method in 3.1% of men globally (Ross & Hardee, 2017). This method requires the male user’s self-control to pull out the penis from the vagina and from the female’s external genitalia before ejaculation. The female partner needs to trust the male partner, and the method is not intended for most couples in casual relationships. There are very few studies on withdrawal (Jones et al., 2009; Rogow & Horowitz, 1995), and typical use failure rate is about 20% (Sundaram et al., 2017). If withdrawal is used as a method of contraception for the couple, alternative methods including emergency contraception should be readily available to the female partner (World Health Organization & Johns Hopkins School of Public Health, 2018).

Condoms

Prevalence

The condom is the most widely used male contraceptive method in the world in 2015 at 7.7%, with the lowest rate of 2.1% in Africa, 7.6% in Asia, 9.6% in Latin America, 10.2% in Oceania, 11.9% in North America, and 16.7% in Europe (Figure 2) (Ross & Hardee, 2017). From 1994 to 2015, condom use rose significantly in developing countries. In more recent data reported by men of reproductive age (15–49 years), condom use was about 10% worldwide (United Nations Department of Economic and Social Affairs Population Division, 2019). Using the 2011–2015 National Survey of Family Growth data in the United States, condom use was reported in 23.8% of women and 33.7% of men. Only 18.2% of women and 23.9% of men reported use of male condoms 100% of the time. Women reported condom breakage or condoms falling off the penis during intercourse. Men with a high educational attainment, those of Hispanic or Black origin, and those with more opposite-sex partners were more likely to use a condom every time they had intercourse (Copen, 2017). For men having casual relationships with multiple partners, condoms have the additional advantage of preventing sexually transmitted infections. Condoms reduce the rate of transmission of human immunodeficiency virus (HIV), human papillomavirus, gonorrhea, chlamydia, syphilis, herpes simplex syphilis, and trichomoniasis (Holmes et al., 2004; Warner et al., 2006). A meta-analysis showed that in heterosexual couples, HIV transmission was reduced by 70% in consistent users but also lower in inconsistent users compared to nonusers (Giannou et al., 2016).

Successful Use Depends on User

Successful use of condoms depends on the skill and experience of the user and the partner. The Right Way to Use a Male Condom (Centers for Disease Control and Prevention, 2016) and Family Planning: A Global Handbook for Providers (World Health Organization & Johns Hopkins School of Public Health, 2018) have pictorial instructions on when and how to put on a condom. The condom is to be placed on the tip of the erect penis and unrolled down the shaft to the base of the penis. Immediately after ejaculation, the penis is withdrawn, and the condom is removed without spillage and disposed of safely. Lubricants when used with condoms should be water-based and applied on the outside of the condom or in the vagina and not on the penis. Common errors include not applying the condom on an erect penis, not using condoms throughout intercourse, not leaving space at the tip, not squeezing air from the tip, putting the condom on inside out, not using water-based lubricants, and incorrect withdrawal. Other problems include breakage, slippage, leakage, and erection problems (Sanders et al., 2012). Providers must discuss with users how to successfully apply the condom and provide them with support in case of problems. The failure rate of condoms in the United States decreased from 18% in 2002 (Trussell, 2011) to about 13% in 2010 (Sundaram et al., 2017).

Types of Condoms

Both latex and polyurethane condoms can be used, but in randomized controlled clinical trials, polyurethane condoms had a higher 6-month failure rate (9.0%) compared to latex condoms (5.4%). Clinical failure with breakage and slippage were also higher with polyurethane (8.4%) compared with latex (3.2%) condoms (Steiner et al., 2003). A systematic review confirmed that the breakage rate was higher with nonlatex condoms, but more men preferred the nonlatex condoms and would recommend nonlatex condoms to other users (Gallo et al., 2006). Condoms made from natural membranes may be more porous and may not reliably prevent sexually transmitted diseases.

Counseling

Condoms have a typical-use contraceptive failure rate of 13%, but the method failure rate is 2% when used consistently and correctly. Correctly applying the condom and using it consistently will improve contraceptive efficacies. Thus, counseling by the provider before condoms are distributed is strongly recommended. Condom use is the only available reversible method of male contraception that has a failure rate lower than 20%, no adverse effects on the male, and the added benefit of preventing sexually transmitted infections.

Vasectomy and Vas Occlusion

Prevalence

Vasectomy (removal of portions of the vas deference) and vas occlusion (introduction of substances into the vas to block sperm transport with the goal that the obstruction may be reversible) may be the best method for men in stable relationships who have completed their desired family size. Though reversal is possible with surgery or assisted reproductive technology, vasectomy should be offered as a permanent method of contraception. A vasectomy is much simpler and cheaper than the female sterilization method, but globally only 2.4% of men used vas occlusion as a method of contraception compared to over 20% that used female sterilization (Ross & Hardee, 2017). By 2019, the vas occlusion prevalence rate had decreased to 0.9%, compared to 11.5% for female sterilization. Vasectomy prevalence is highest in Oceania (7.9%), followed by Europe and North America (2.5%), and has fallen to near 0% in Africa and Western Asia. The reasons for decreasing acceptance rate of both female and male permanent methods may be due to irreversibility of these methods, couples delaying plans to have a family, and the availability of new and safer female methods (Ostrowski et al., 2018). This prevalence is dependent on income with low- to middle-income countries having vas occlusion use of 0.2% compared to 3% in higher-income countries (United Nations Department of Economic and Social Affairs Population Division, 2019).

Methods of Vas Occlusion and Success Rates

No-scalpel vasectomy, first practiced in China (Li et al., 1991), is now the accepted method of vas occlusion (Cook, Pun, et al., 2014). This is a minimally invasive procedure performed under local anesthesia; the no-scalpel method requires specific instruments and sequential steps in which a 1-cm incision/puncture is made that requires no suture. The no-scalpel method requires less operative time and is associated with less pain and lower rates of infection and bleeding; it has become the recommended method of many urologists (Sharlip et al., 2015). In this procedure, the vas deferens is divided and the ends closed by cautery with or without fascial interposition; alternatively the end of the vas end can be left nonoccluded but the abdominal end cauterized with fascial interposition (Cook, Van Vliet, et al., 2014). Postvasectomy semen analysis is recommended to start about 12 weeks or 20 ejaculations after the procedure, and another method of contraception should be used during this waiting period (Griffin et al., 2005; Hancock et al., 2016). Success of vasectomy is defined when one sample of fresh semen shows azoospermia or < 100,000 nonmotile sperm/ml (Coward et al., 2014; Sharlip et al., 2015). Sperm clearance takes time with large variability among men, and the presence of very few nonmotile sperm may be due to the residual sperm in the seminal vesicles or ampullae of the vasa. Vasectomy procedure is considered a failure when motile sperm number is ≥ 100,000/ml beyond 6 months after vasectomy, then repeat vasectomy should be considered (Sharlip et al., 2015). The pregnancy risk is very low after a single semen sample confirming azoospermia, only nonmotile sperm, or ≤ 100,000/ml nonmotile sperm after vasectomy in retrospective studies (Edwards, 1993; Korthorst et al., 2010; O’Brien et al., 1995). A recent report on measuring only sperm concentration in over 9000 postvasectomy semen samples suggested that this was sufficiently robust to confirm success of vasectomy and efforts to detect occasional motile sperm were futile (Tomlinson et al., 2020). Another study questioned the requirement of assessing sperm motility in >6000 postvasectomy semen samples given the low likelihood of finding motile sperm at very low sperm concentrations (when sperm concentration was <1 million or < 0.25 million/ml, only 0.5% and 0.3% of samples had motile sperm) (McMartin et al., 2021). Estimating sperm concentration only would only misclassify success/failure of vasectomy in a very small proportion of men.

Though the recommendation for demonstrating successful absence or near absence of sperm for successful procedure is clearly stated in the guidelines, about half of the men do not complete the postvasectomy semen analysis (Manka et al., 2020; Velez et al., 2021). Despite preoperative counseling, poor compliance with postprocedure semen analyses has been ascribed to distance, time constraint, and forgetfulness to go to a laboratory for semen analyses; thus, sending a sample from home by mail or utilizing available home testing of sperm count kits has been recommended. When the adherence rate of providing a postvasectomy semen sample was compared between postal and nonpostal semen analyses, 79.5% of men adhered to sending semen samples for analyses by postal services, while 59.1% provided sperm counts delivered and tested by nonpostal methods (Atkinson et al., 2021; McMartin et al., 2021). A home testing kit detecting presence of > 250,000 both motile and nonmotile sperm is available and approved by the U.S. Food and Drug Administration for postvasectomy assessment of sperm concentration (Klotz et al., 2008).

Adverse Effects of Vasectomy

After surgery, the person should refrain from ejaculation for about a week, and scrotal support can be used to decrease pain. The complications of hematoma and infections are very rare, occurring in approximately in 1% to 2% of men. Hemospermia may occur after vasectomy; no treatment is required, as this will resolve spontaneously and is not clinically significant. Clinically significant chronic scrotal pain occurs in about 1% to 2% of men after vasectomy, but rarely need opioids for pain relief or surgical reversal (Polackwich et al., 2015; Velez et al., 2021).

Except for scrotal pain, there are very few long-term adverse effects of vas occlusion on general health. The association of vasectomy with prostate cancer, atherosclerosis, and other ailments have no substantial evidence and need not be discussed with the patients (Byrne et al., 2017; Sharlip et al., 2015; Shoag et al., 2017).

Satisfaction

Preoperative anxiety is decreased and satisfaction with vasectomy is increased with prevasectomy counseling that includes decision on vasectomy by the couple, discussion of frequency and nonpersistence of postoperative pain, the expectation of a waiting period when the couple need to use another method of contraception, the need for postvasectomy semen analysis, and the possible but sometimes unsuccessful reversibility of the procedure (Menon, 1998; Sandlow et al., 2001).

Reversal

Reversal of vasectomy is requested in only about 6% of men, mostly due to fertility reasons and uncommonly for postvasectomy pain. Vasectomy reversal is usually performed by a urologist who must discuss with both the patient and the partner about the choice between surgical vasectomy reversal, either with vasovasostomy or vasoepididymostomy or assisted reproductive technology with epididymal sperm aspiration, followed by intracytoplasmic sperm injection and in vitro fertilization. Sperm extraction and cryopreservation can be undertaken at the same time of the vasectomy reversal. In addition, a comprehensive evaluation may guide the urologist to operative planning and outcome of the surgery. Importantly, patency after reversal does not equate pregnancy in the partner (Dubin et al., 2021; Fantus & Halpern, 2021; Namekawa et al., 2018).

The decision of whether to proceed with vasovasostomy or vasoepididymostomy is determined during surgery by examination of the vasal fluid from the testicular end for sperm. If no sperm is found in the vasal fluid, vasoepididymostomy is preferred. There are many anastomosis techniques, and these procedures should be performed by an experienced urologist. The factors affecting patency and pregnancy include the age of the female partner because of decreased fecundity after age of 36 years; the interval between vasectomy and reversal; vasoepididymostomy versus vasovasostomy; and absence of sperm in the epididymal fluid. It takes about 4–6 months after reanastomosis for sperm to appear in the ejaculate. The rates of patency and pregnancy after vasovasostomy are about 90% and up to 73%, respectively. After vasoepididymostomy, the patency rate is about 64% and pregnancy rate about 30%–36%. Complications of vasectomy reversal, which are rare, include infection, prolonged pain, and hematoma. Late failure is usually due to obliteration of the anastomosis site. Repeat vasectomy reversal has a lower patency rate of only about 67% with a pregnancy rate of 25%. Because of the low pregnancy rate, couples should consider sperm extraction either concurrently with vasectomy or as an alternate procedure (Dubin et al., 2021; Fantus & Halpern, 2021).

Future of Vas Occlusion

The current quest for vas occlusion includes a nonsurgical method and reversibility, making vas occlusion a long-acting reversible contraception. Injection of cured-in-place plugs have been tried but not undergone randomized controlled clinical trials (Guha, 1999; Guha et al., 1993; Guha et al., 1997; Waites, 2003; Zhao et al., 1992). More recently, using the same principle, Vasalgel™ has undergone preclinical studies in rabbits and monkeys; it utilizes styrene-alt-maleic acid dissolved in dimethyl sulfoxide, which forms a hydrogel when implanted into the vas deferens. Injection of Vasalgel into the vasa deferentia of male rabbits blocked passage of sperm transit and produced a rapid onset of azoospermia that lasted for 12 months (Waller et al., 2016). Injection of sodium bicarbonate into vasa deferentia 14 months after injection of Vasalgel reversed the obstruction, and semen samples returned to concentrations before vas occlusion. However, sperm progressive motility and acrosome reaction were impaired, suggesting that the residual material in the vas may compromise vas and epididymal function (Waller et al., 2017). When Vasalgel was injected into vasa deferentia of adult male rhesus monkeys, blockage of sperm transit prevented pregnancy when the males cohabitated with female monkeys. However, incorrect placement of Vasalgel led to development of sperm granuloma (Colagross-Schouten et al., 2017). In a survey of 460 college students in the United States, 28.6% of male and 51.4% of female students reported that they would like to encourage the use of intravasal injectable gel. Most would use another method of contraception with intravasal injections because of uncertainties of efficacy (Buck et al., 2020). Adam™ is another hydrogel that is inserted via injection to block sperm from transiting through the vas deferens. The hydrogel is designed to last 12 months, while the hydrogel liquefies and the barrier to sperm flow is removed. There is no report of in vivo studies, but the manufacturer, Contraline Corporation, indicates that a clinical trial may be forthcoming (Long et al., 2021).

Hormonal Male Contraception

Hormonal male contraception utilizes steroid hormone or gonadotropin-releasing hormone (GnRH) analogs that are generally in clinical use and repurposed for male contraception. Thus, in many instances, the preclinical toxicology, dosages, duration of action, formulations, and potential adverse effects are known through clinical trials and used in women and men. Therefore, hormonal contraception clinical trials started in the 1970s, and male contraceptive multicenter clinical trials testing contraceptive efficacy based on testosterone were completed in the 1990s. The assessment of efficacy for male contraceptive clinical trials was initially to make sure sperm output is decreased (spermatogenesis suppression) to a threshold that will prevent pregnancy in the female partner (contraceptive efficacy). Hormonal male contraception is most advanced in the development of new approaches for male-controlled methods. Phase 2 and 3 contraceptive efficacy trials have been reported for contraceptive efficacy, but these contraceptives have not yet been submitted for regulatory approval and are not available for use (Thirumalai & Amory, 2021; Wang et al., 2016).

Principles of Hormonal Male Contraception

The hypothalamic-pituitary-testis axis is illustrated in Figure 3. The hormonal and spermatogenic function of the testis is regulated by hypothalamic GnRH stimulating the pituitary gland to produce and secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the Leydig cells to synthesize and secrete testosterone. Intratesticular concentrations of testosterone are approximately 25–125 times that in the peripheral circulation. Testosterone in the testis diffuses into the interstitial space of the seminiferous tubules to act on the Sertoli cells to promote the differentiation of the spermatogonia to the mature spermatozoa (sperm). At the same time, FSH stimulates the Sertoli cells to secrete the necessary factors to stimulate spermatogenesis. Testosterone and its metabolites, 5α‎-dihydrotestosterone and estradiol, exert negative feedback (Figure 1, dotted lines on the right) both at the hypothalamus and pituitary to regulate the production of LH and FSH to maintain homeostasis of the axis. Inhibin B secreted by the Sertoli cells also has a negative feedback role on secretion of FSH. Hormonal male contraception utilizes the same principles as female hormonal contraception where the exogenous administration of contraceptive agents suppresses the hypothalamic-pituitary-testis axis. Exogenous androgens (mainly testosterone), either alone or in combination with progestins, suppress the production of GnRH from the hypothalamic GnRH neurons and LH and FSH from the pituitary using the negative feedback mechanism (Figure 1, dotted lines on the left). GnRH antagonists suppress the production of LH and FSH at the pituitary level. Reduced LH production results in marked suppression of testosterone production by the Leydig cells, and a very low testosterone concentration within the testis that prevents differentiation and maturation of spermatogonia to spermatozoa. Concurrently, reduced FSH secretion from the pituitary collaborates with the deprivation of intratesticular testosterone by suppressed LH to induce marked suppression of spermatogenesis. Hormonal male methods based on this principle of suppression require an androgen to provide adequate circulating male hormone to the body to sustain the functions of testosterone on reproductive and nonreproductive functions of the male recipient (Thirumalai & Amory, 2021; Yuen et al., 2020). Because hormones have endocrine and paracrine actions, the exogenous administered androgen/progestins act through receptors not only found in reproductive organs (epididymis, seminal vesicle, and prostate) but also in the brain, liver, muscle, adipose tissues, bone, and hematopoietic cells producing beneficial or adverse effects.

Figure 3. Principles of hormonal male contraception.

Note: FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone. The normal hypothalamic-pituitary-testicular axis is shown where large arrows are stimulatory and dotted lines and small arrows are inhibitory. GnRH produced by the hypothalamus stimulates production and secretion of LH and FSH by the hypothalamus. LH stimulates the Leydig cells to produce testosterone which acts on the Sertoli cells within the seminiferous tubules to regulate spermatogenesis. FSH acts also on the Sertoli cells and together with testosterone initiates the progression of spermatogenesis to yield mature spermatozoa. Testosterone exerts negative feedback on the hypothalamus and pituitary to decrease the production and secretion of GnRH, LH, and FSH and suppresses production of testosterone by Leydig cells. Hormonal male contraceptives such as exogenous androgens and progestins suppress the release of GnRH from the hypothalamic neurons and LH and FSH from the pituitary (dotted lines small arrows on the left), depriving the testes of testosterone and FSH and inhibiting the progression of spermatogenesis to produce mature spermatozoa.

Source: Adapted from Thirumalai and Amory (2021). Used with permission.

Hormonal Male Contraceptive Agents

The hormonal male contraceptive agents used include testosterone administered as an injection, implant, or transdermal gel. These testosterone products are usually administered at a higher dose than those used for replacement of testosterone in hypogonadal men. Oral testosterone undecanoate administered alone several times per day was not effective. Addition of another gonadotropin-suppressing agent such as a progestin or GnRH antagonist markedly enhances suppression of LH and FSH. One rationale for addition of a progestin or GnRH antagonist is that the dosage of testosterone may be reduced with possible reduction of adverse effects and more sustained and effective suppression of spermatogenesis. However, the addition of a progestin adds complexities to the combination, because the bioavailability of the progestin may be different from that of testosterone when they are administered at the same time. The progestins that have been tested include levonorgestrel pills, injections, and implants; desogestrel/etonogestrel pills and implants, depo-medroxyprogesterone acetate injections, and cyproterone acetate pills, among others (Table 1). Studies investigating the ability of androgens and androgens plus progestins indicate that they suppress spermatogenesis but to a varying degree based on dosage and combinations (Meriggiola et al., 2003; Wang & Swerdloff, 2004, 2010); those selected for contraceptive efficacy studies are discussed below. Those in current clinical trials (marked with an asterisk in Table 1), including modified androgens, will be discussed in the section on future hormonal male contraceptives.

Table 1. Androgens and Progestins Used in Prior or Current* Hormonal Male Contraceptive Clinical Trials

Androgen

Progestins

Testosterone

Oral: testosterone undecanoate

Injection: testosterone enanthate, decanoate, undecanoate

Transdermal: testosterone gel*, patch, cream

Implants: testosterone, MENT

Oral:

Levonorgestrel*

Desogestrel

Cyproterone acetate (a potent progestin and an anti-androgen)

Injections:

Depo-medroxyprogesterone acetate

Norethisterone enanthate

Levonorgestrel butanoate*

Transdermal:

Nestorone® (segesterone)*

Implants:

Levonorgestrel

Etonogestrel

Modified androgens

Oral: DMAU*; 11β‎-MNTDC*

Injection: DMAU*

Implant: MENT

Note: 11β‎-MNTDC = 11β‎-methyl-19-nortestosterone-17β‎-dodecylcarbonate; DMAU = dimethandrolone undecanoate; MENT = 7α‎-methyl-19-nortestosterone.

* Currently in clinical trials.

Efficacy of Hormonal Male Contraceptive Trials

In the 1970s, supported by the National Institute of Child Health and Human Development (NICHD), U.S. National Institutes of Health (NIH), testosterone enanthate was administered to men as intramuscular injections every 1 or 2 weeks in clinical trials. These studies showed that intramuscular injection of testosterone enanthate at modestly supraphysiologic concentrations suppressed sperm output to severe oligozoospermic levels (arbitrary cutoff ≤ 5 million/ml) (Cunningham et al., 1979; Steinberger & Smith, 1977; Steinberger et al., 1978; Swerdloff et al., 1979). Prompted by the success of spermatogenesis suppression by these early clinical trials, the Task Force on the Methods for the Regulation of Male Fertility of the World Health Organization (WHO) Special Program on Human Reproduction designed and conducted two successful clinical trials. These landmark trials demonstrated that when weekly injections of intramuscular testosterone enanthate (a prototype male hormonal contraceptive) to men suppressed sperm concentrations to azoospermia in the first study (World Health Organization Task Force on Methods for the Regulation of Male Fertility, 1990) and to ≤3 million/ml (oligozoospermia) in the second study (World Health Organization Task Force on the Regulation of Male Fertility, 1996), pregnancy was prevented in the female when the couple was not using another method of contraception for a year (Table 2). It should be noted that that 77% of the men who entered efficacy were azoospermic, 13% fluctuated between azoospermic and oligozoospermic, and 10% were consistently oligozoospermic. Thus, 83% of the exposure to risk of pregnancy in the efficacy phase was contributed by men with consistent azoospermia (World Health Organization Task Force on the Regulation of Male Fertility, 1996). There were relatively few adverse effects, and the contraceptive efficacy was like that of the female oral contraceptive pill or patches. These studies of utilizing androgens alone were very effective in suppression of sperm output. The results were confirmed in two studies in China where men were administered a longer-acting testosterone in clinical trials to test the ability of this product alone to prevent pregnancy in the couple (Table 2) (Gu et al., 2003, 2009).

Table 2. Contraceptive Efficacy in Male Hormonal Contraceptive Clinical Trials

Agents

Sperm concentration threshold (million/ml)

Number enrolled

Number (%) reaching threshold

Number entering efficacy

Pregnancies/failure rate, and Pearl Index [95% CI]

Study reference

TE 200 mg/week

Azoospermia

271

157 (70%)

157

1

0.8 [.0, 4.5]

WHO Task Force on Methods for the Regulation of Male Fertility (1990)

TE 200 mg/week

≤3 (reduced from ≤5)

399

349 (97.8%)

268

4

1.4 [.4, 3.7]

WHO Task Force on the Regulation of Male Fertility (1996)

Testosterone implants 800 or 1200 mg/3 months

≤1

36

21 (72%)

13

0

McLachlan et al. (2000)

Testosterone implants 800 or 1200 mg/4–6 months + DMPA 300 mg/3 months

≤1

55

53 (94%)

51

0

0 [0, 8]

Turner et al. (2003)

TU 1000 mg loading 500 mg/month

≤3

308

299 (97.1%)

296

1

2.3 [.5, 4.2]

Gu et al. (2003)

TU 1000 mg loading 500 mg/month

≤1

1045

855 (95.2%)

855

9

1.1 [.4, 1.8]

Gu et al. (2009)

TU 1000 mg IM and norethisterone enanthate IM 200 mg/8 weeks

≤1

320

274 (95.9%)

266

4

1.57 [.59, 4.14]

Behre et al. (2016)

Testosterone 62–75 mg + Nestorone® 8 mg gel transdermal daily

≤1

420

ongoing

Note: CI = confidence interval; DMPA = Depot Medroxyprogesterone acetate; IM = intramuscular; TE = testosterone enanthate; TU = testosterone undecanoate

Adapted from Wang et al. (2016).

WHO = World Health Organization.

However, because spermatogenesis suppression by testosterone alone appeared to be less complete in non-Asian men (Ilani et al., 2011), recent male hormonal contraceptive trials included a progestin combined with testosterone. A large multicenter study showed that testosterone undecanoate together with norethisterone enanthate injections administered intramuscularly every 8 weeks were very effective in preventing pregnancy in the couple. Unfortunately, this study was stopped not by the independent data and safety monitoring committee but by the sponsor research committee because of high adverse event rates. It should be noted that most of these events were mild and related to injection site pain, mostly from one center. However, mood changes were observed (Behre et al., 2016). The change is mood may be related to the changes in serum testosterone or progestin concentrations or the imbalance of the two. There was no prospective mood assessment of the participants before, during, and after the study. Currently there is an ongoing contraceptive efficacy study utilizing daily application of transdermal testosterone plus Nestorone® gel that aims to recruit about 400 couples that may hold promise for further development to a Phase 3 pivotal trial for regulatory approval (Long et al., 2021).

Factors Affecting Spermatogenesis Suppression

An integrated analysis was performed to identify the determinants of the extent of spermatogenesis suppression. Sperm output data were obtained from 1756 men who participated in 30 contraceptive clinical trials completed between 1999 and 2006. The agents used included testosterone and 7-α‎-methyl-19-nortestosterone (MENT) with or without progestins (Table 1). The most important finding was that coadministration of a progestin increased both the rate and extent of spermatogenesis production. Asian men suppressed sperm output slower initially but ultimately to greater extent than non-Asian men. Younger men and those with lower testosterone level and sperm concentration also showed faster suppression, but the effect size was very small for these factors (Liu et al., 2008).

Studies also examined whether suppression of LH and FSH can predict the suppression of spermatogenesis after a combined testosterone and progestin (Nestorone®) transdermal gel application. Suppression of both LH and FSH within 3 weeks (Mahabadi et al., 2009) was predictive of suppression of sperm output to a very low level in a 6-month study (Ilani et al., 2012). Further detailed analyses showed that serum LH or FSH concentrations above a threshold of 1 IU/L were 97% sensitive in predicting failure of suppression (Roth et al., 2013). The concentrations of the progestin (Nestorone®) in the serum were associated with suppression of sperm output but not testosterone. This suggests that suppression of both LH and FSH is an early indicator of spermatogenesis suppression.

Reversibility of Spermatogenesis Suppression

Hormonal male contraception, like female hormonal contraception, should be reversible when the exogenous sex steroids are withdrawn. This has been shown to be true in an integrated multivariant analysis of 30 hormonal male contraception clinical trials using androgens or androgen-progestin combinations (short and longer acting) to suppress spermatogenesis. The probability of recovery of sperm concentrations after spermatogenesis suppression by hormones to the adult fertile male reference range was 67% within 6 months, 90% within 12 months, and 100% within 24 months. The factors associated with faster recovery included shorter treatment period, shorter-acting testosterone preparations, older age, Asian origin, higher sperm concentration at baseline, faster suppression of spermatogenesis, and lower serum concentration of LH at baseline. This study showed conclusively that male hormonal contraceptive regimens are fully reversible with a predictable time course (Liu et al., 2006). Examination of each of the studies shown in Table 2 confirmed that hormonal male contraception is reversible and that failure of recovery is very uncommon. It should be noted that the longest period of exposure to hormonal male contraceptive is about 30 months; thus, long-term data on reversibility must be collected when these agents are approved, available, and administered for years.

Potential Adverse and Beneficial Effects of Hormonal Male Contraception

The short-term effects of hormonal male contraception are related to its components: androgen and progestins. Testosterone, when administered to healthy men, may result in increased oiliness of skin, acne, weight gain, night sweats, increased or decreased libido, mood changes, (rarely) gynecomastia, and irritability. Supraphysiologic dosages may result in decrease in high-density lipoprotein cholesterol without changes in total or low-density lipoprotein cholesterol or triglycerides, increase in hemoglobin and hematocrit, and suppression of serum sex hormone-binding globulin levels. If testosterone or its ester are used, there is no change in liver or renal function (F. C. Wu et al., 1996). The long-term effects of testosterone or other androgens on the prostate and cardiovascular disease risks (Corona et al., 2015, 2018) are not known until a hormonal male contraceptive product is available in the marketplace and long-term safety studies can better assess risks versus benefits as in hormonal female contraceptives. Based on studies of testosterone replacement in hypogonadal men, the potential benefits may include increase in lean mass and decrease in fat mass and increase in bone density (Ceponis et al., 2017; Corona et al., 2020).

The potential adverse effects of progestin in men are not well defined. This is because the role of progesterone in men is not known. Addition of a progestin to testosterone increased the rate and extent of suppression of spermatogenesis. The potential adverse effects are possibly similar to those in females with weight gain, mood changes, and night sweats (Ilani et al., 2012; Mommers et al., 2008). In general, these adverse effects are usually mild or moderate and rarely cause an early exit from the clinical trial.

Hormonal Male Contraception Currently in Development

Androgen–Progestin Gel: The Male Contraceptive Gel

Supported by the NIH, the NICHD, and the Population Council, the development of a combined testosterone and Nestorone transdermal gel is in a Phase 2b clinical trial. The rationale to use transdermal preparation included the following: (a) Steroid hormones applied on the skin are rapidly absorbed into the subdermal layer where a reservoir is formed and the steroid hormones are released very slowly, resulting in steady levels of these hormone in the circulation; (b) Testosterone gel is favored by hypogonadal men in the United States for hormone replacement; (c) Nestorone is a pure progestin without binding activity on the androgen and estrogen receptor and may have fewer adverse effects than other progestins; (d) Production of transdermal gels does not require expensive equipment; and (e) Provider-independent formulation that can be used at home every day. Testosterone/Nestorone gel was very effective in suppressing LH and FSH in a 3-week study (Mahabadi et al., 2009) This was followed by a 6-month study showing that the combined gel was much more efficacious in suppressing sperm output than testosterone gel alone (Ilani et al., 2012). The daily application of the gel was well tolerated by men and the gel had very few adverse effects except mild acne and weight gain, with no significant effects on hematocrit/hemoglobin and metabolic parameters. Founded on encouraging results from the spermatogenesis study, a multinational, multicenter, hormonal male contraceptive efficacy trial using the daily application of the testosterone/Nestorone gel will complete enrolment in 2022. The primary end point is contraceptive efficacy measured by the failure of preventing pregnancy in the female partner. The clinical centers located in Africa, Europe, and North and South America plan to enroll about 400 couples (Table 2). This study is under way, anticipating completion by the end of 2023. The team is planning discussion with the U.S. Food and Drug Administration in 2022 and a Phase 3 pivotal trial study protocol will be developed in 2022–2023. It should be noted that because the gel is applied on the skin and only about 10% of the testosterone and Nestorone is absorbed, the residual hormone on the skin may be transferred to another person upon close contact. This secondary transfer of the hormones can be very effectively prevented by washing or wearing clothing over the gel application area (Yuen et al., 2019). Using these precautions, secondary exposure of the female partner has been minimized with no related adverse events in the ongoing study.

Orally Bioactive Novel Androgens with Some Progestogenic Activity: The Potential Male Contraceptive Pill

The Population Council developed a modified androgen, MENT, into implants and showed that they were effective in suppressing sperm output (von Eckardstein et al., 2003). A follow-on study compared MENT and MENT together with Levonorgestrel implants. Unexpectedly, the MENT implants did not release adequate amounts of MENT as in prior studies; the result of this study has not been published and MENT implant development is currently on hold.

At the same time, NICHD is developing two modified androgen esters—7-α‎-11β‎-methyl-19-nortestosterone-17β‎-undecanoates (dimethandrolone undecanoate [DMAU]) and 11β‎-methyl-19-nortestosterone-17β‎-dodecylcarbonate (11β‎-MNTDC)—as the prodrug that is converted to the active compounds dimethandrolone (DMA) and 11β‎-methyl-19-nortestosterone (11β‎-MNT) by nonspecific esterases in the body (Attardi, Engbring, et al., 2011; Attardi et al., 2006; Cook & Kepler, 2005). In vitro studies showed that these modified androgens have some progestogenic activity in addition to the potent androgen activity (Attardi et al., 2006; S. Wu et al., 2019). In vivo studies showed that they have strong gonadotropin-suppressive activity and thus suppress endogenous testosterone production. In the rabbit model, administration of oral DMAU was effective in spermatogenesis and sperm output (Attardi, Engbring, et al., 2011). These compounds are not 5-α‎ reduced to dihydrotestosterone-like compounds and may have less stimulatory effect on the prostate than testosterone (Attardi et al., 2010). On the other hand, because they are not readily aromatized (Attardi et al., 2008), their long-term effects on bone health and adiposity have yet to be addressed (Attardi, Marck, et al., 2011). These modified androgens are not hepatotoxic (Hild et al., 2010).

Both DMAU and 11β‎-MNTDC are bioavailable after oral administration and have been tested in men in single-dose, dose-escalating studies as well as a repeat dosing study for 28 days. Both DMAU and 11β‎-MNTDC are effective in suppressing LH and FSH and testosterone at a dose of 200–400 mg per day (Ayoub et al., 2017; Surampudi et al., 2014). These compounds must be administered with food to enhance absorption and attain blood concentration to show an effect on suppression of gonadotropins. They are well tolerated and despite the endogenous testosterone concentration to very low levels, the men maintained normal sexual desire and activity (S. Wu et al., 2019; Yuen et al., 2020). Longer-term studies are necessary to demonstrate suppression of spermatogenesis. As these compounds are not readily converted to estrogens, long-term effects on bone health and fat mass must be assessed, though bone markers did not change significantly in preliminary studies of DMAU (Thirumalai et al., 2021). These compounds have very similar pharmacokinetic and pharmacodynamic profiles; comparison of the nonreproductive effects showed class effects of androgens in increasing weight and hematocrit and decreasing high-density lipoprotein cholesterol and sex hormone binding globulin and no effects on glucose, insulin, or insulin resistance (Yuen et al., 2021).

Future

Hormonal male contraception with an androgen and progestin have been in clinical trials for over five decade. The combined daily testosterone/Nestorone gel, if successful, will need a phase 3 pivotal trial, which may be completed and receive regulatory agency approval before 2030. More long-acting injectable androgen and progestin combinations will follow. These methods, once approved, will pave the way for nonhormonal methods.

Nonhormonal Male Contraception

Targets

The understanding of many mechanisms that can affect spermatogenesis through loss of function mutations in mice and men, regulation of sperm maturation and acquisition of fertilizing capacity in the epididymis and in the female reproductive tract, led to identification of many new targets. These new targets may disrupt sperm production, motility, and morphology, and fertility-related functions are being continuously discovered. Many of these targets have undergone “proof of concept” studies in animal studies but few has gone through preclinical toxicology studies, and none has reached clinical trials (Figure 4). The advantages of nonhormonal methods with a specific target in the male reproductive tract is that the effect will be localized without off-target effects and more rapid acting, and with fewer side effects (Gottwald et al., 2006; Long et al., 2021). These target proteins must be tissue specific, have a crucial role in fertility, be druggable, and be feasible for high-throughput screening to identify new small molecules for drug development (Gottwald et al., 2006).

Figure 4. Potential targets and agents for male contraception during spermatogenesis, sperm maturation in the epididymis, disturbance of sperm function in the female reproductive tract, and interference with binding of sperm to the oocyte.

Source: Adapted from Gottwald et al. (2006). Used with permission.
Spermatogenesis

There are many possible targets that may affect spermatogenesis, spermiogenesis, and spermiation in the testis. The following are selected targets that appear to be promising. The administration of a small molecule, JQ1, that inhibits testis specific bromodomain (BRDT), essential for chromatin remodeling during spermatogenesis, resulted in complete and reversible infertility in mice (Matzuk et al., 2012). BRDT is expressed in spermatocytes and not in spermatogonia, suggesting that BRDT-specific inhibitors will lead to reversible suppression of sperm production (Wisniewski & Georg, 2020). Currents efforts are utilizing DNA-encoded chemical libraries to screen for high affinity and specificity inhibitors of BRDT. Several compounds have been identified that need to be verified for inhibitory activity to BRDT and contraceptive action in animal models (Yu et al., 2021).

Vitamin A–deficient and retinoic acid receptor-α‎ knockout mice showed disrupted spermatogenesis with failure of alignment of spermatids, disturbance of spermiation, sperm release, and germ cell loss leading to infertility. Retinoic acid is essential for commitment of the progenitor germ cell to undergo differentiation, meiosis, spermiogenesis, and spermiation (Griswold, 2016). Administration of a pan–retinoic acid receptor antagonist resulted in reversible infertility in mice (Chung et al., 2011, 2020). Current studies focus on structure activity studies that may provide insight for the design and synthesis of novel retinoic acid-α‎ ligands as potential male contraceptives (Noman et al., 2020). At the same time, other investigators are studying bisdichloroacetyldiamine derivatives that reversibly inhibit retinoic acid synthesis by inhibiting aldehyde dehydrogenase 1A2 (ALDH1A2), resulting in impaired spermatogenesis and infertility in rabbits (Amory et al., 2011). ALDH1A2 concentrations are lower in testis of men with abnormal semen analyses (Nya-Ngatchou et al., 2013) and infertile men (Amory et al., 2014). Novel inhibitors of ALDHA12 are being developed based on binding of inhibitors to ALDH 1A2 to increase both potency and selectivity (Chen et al., 2018).

Indazole and indenopyridine derivatives target the tight junctions between the Sertoli cells and male germ cell. Adjudin (Cheng & Mruk, 2002) and gamendazole (Tash et al., 2008) administered to rats caused infertility, but there are questions about reversibility and these compounds have to cross the blood-testis barrier to reach the Sertoli cells.

Spermiogenesis

Spermiogenesis is specific to male germ cell development. Lack of spermatid maturation 1 (Spem1) results in infertility because of deformed sperm head due to retained cytoplasmic components preventing the straightening of the sperm head (Zheng et al., 2007). These investigators found that Spem1 binds to junction plakoglobin/γ‎-catenin, among other proteins, and disruption of the binding may cause bent-back sperm head. They identified that triptonide (extracted from Tripterygium wilfordii) when administered to mice and monkeys caused presence of deformed sperm that had no progressive motility. These effects on sperm reversed on cessation of treatment (Chang et al., 2021). However, triptonide had been reported to have anticancer and anti-inflammatory activities by inhibiting a number of key signaling pathways including JNK, mTOR, and many others (Dong et al., 2019; Gao et al., 2021; Tan et al., 2021). Another extract of Tripterygium wilfordii, triptolide (Qian, 1987), when administered to rats had minimal effects on spermatogenesis, with normal spermatids and severe impairment of cauda epidydimal sperm (Hikim et al., 2000; Huynh et al., 2000; Lue et al., 1998). However, because of its immunosuppressive and possible toxic effect on organs other than the testis (Noel et al., 2019; Tong et al., 2021; Xi et al., 2017), triptolide was not further developed for male contraception.

Based on gene deletion studies, testis-specific serine kinase 1, 2, and 6 (TSSK1, TSSK2, and TSSK6) knockout mice showed sperm head abnormalities or sperm head to midpiece attachment defects, resulting in infertility without affecting spermatogenesis (Li et al., 2011; Salicioni et al., 2020). Using high-throughput screening of TSSK2, two potent series of inhibitors have been identified and dual inhibitors of these TSSK may be required to achieve contraception (Hawkinson et al., 2017).

Sperm Maturation and Function

When spermatozoa exit the testis and traverse the epididymis, it acquires many proteins on the surface that contributes to the sperm maturation and acquisition of motility. These proteins are targets for male contraception (Drevet, 2018; Sipilä et al., 2009). One of these proteins is Eppin (epididymal protease inhibitor) that binds semenogelin. Eppin has antibacterial activity, modulates the activity of prostate specific antigen, and inhibits sperm motility by decreasing intracellular pH and calcium. Anti-Eppin antibodies at high titers caused reversible contraception in monkeys due to decreased sperm motility (O’Rand et al., 2016). Small molecules (e.g., EP055) that mimic the action of anti-EPPIN antibodies have been developed and are undergoing testing in monkeys (O’Rand et al., 2018).

To enable sperm maturation (capacitation) and penetration of the protective vestment of the oocyte, spermatozoa undergo changes in sperm membrane fluidity, change in intracellular pH and protein tyrosine phosphorylation, and induction of hyperactivated motility (high-amplitude flagella movement). These processes are facilitated by soluble adenyl cyclase (Esposito et al., 2004), Na+/H+ exchangers (Oberheide et al., 2017; Wang et al., 2007), Na/K ATPase α‎4 (Syeda et al., 2020), and other signaling pathways as well sperm-specific voltage gated calcium channel CatSper (CATion channel of SPERm), human potassium channel of sperm (KSper/SLo3/Slo1), and other channels and transporters that allow calcium influx into sperm and intracellular alkalinization (Vyklicka & Lishko, 2020). CatSper is sensitive to progesterone and prostaglandins in primates. Human spermatozoa have Ksper, Slo3, and Slo1 channels and are activated by calcium (Brenker et al., 2014; Mannowetz et al., 2013; Mansell et al., 2014). Inhibitors of these channels and transporters would work both as a male or female contraceptive by causing premature hyperactivation or blocking hyperactivated motility in the female reproductive tract (Lishko & Mannowetz, 2018).

The acrosome reaction and sperm oocyte binding occur at the ampulla of the fallopian tube. ADAM 1a/2/3 (members of ADAM, a family of disintegrins and metalloproteases) are important for sperm migration into the oviduct. While ADAM3 (cyritestin or tMDC1) is important for fertilization in mice, it is nonfunctional in monkeys and men (Frayne & Hall, 1998). The essential factors in fertilization are IZUMO1 (sperm cell surface protein) and its receptor JUNO to ensure adhesion of the gamete cell membranes (Bianchi et al., 2014; Inoue et al., 2011; Okabe, 2018). More recently, other sperm membrane proteins (e.g., fertilization influencing membrane protein; sperm–oocyte fusion required 1; sperm acrosome membrane–associated protein 6; transmembrane protein 95, and cluster of differentiation [CD9 and CD81]) on the oocyte are identified as essential for fertilization without evidence of interaction between these sperm and egg proteins. Compounds that inhibit these actions should be considered female-directed contraceptive agents (Bianchi & Wright, 2020).

Future

There are many new proteins that are potential targets required at specific site of actions during spermatogenesis, spermiogenesis, sperm maturation, and acquisition of fertilizing potential. Drug development aims to produce novel compounds that are druggable and easy to deliver and without off-target effects. New compounds are discovered using (a) structure-activity relationship to modify the target compound (Noman et al., 2020); (b) unbiased approaches with high-throughput drug screen for known and novel compounds (Hawkinson et al., 2017; O’Rand et al., 2011); or (c) DNA-encoded chemistry technology (Yu et al., 2021). Once a lead compound has been selected, large quantities of the lead compound need to be synthesized and used for preclinical toxicology testing and discussion with regulatory agencies before any human trials can begin. Only the Eppin inhibitor has undergone toxicology studies. Thus, nonhormonal contraception will likely follow hormonal male contraception in development and availability.

Will Men Use Male-Directed/Controlled Contraceptive Methods?

The development of contraception has focused on the female because unplanned pregnancies are an enormous physical and socioeconomic burden to the pregnant women. The development of female hormonal contraception expanded the field of reproductive gynecology research that resulted in optimization of the dosages and methods of delivering the steroid hormones, estrogens and progestins, to the body. Studies of the male reproductive system, andrology, lagged until recently when the understanding of the development, function, and regulation of each component responsible for production, transport, and maturation of spermatozoa rapidly expanded. However, new male contraceptive methods have not been approved for the marketplace or made generally available since the development of condoms and vasectomy to provide reversible and more permanent contraception. Clinical trials using testosterone for male contraception began in the 1970s, supported by the NIH (Patanelli, 1978) and other governmental and nongovernmental agencies as well as the WHO (Waites, 1993; Waites et al., 1998; World Health Organization Task Force on Methods for the Regulation of Male Fertility, 1990). Pharmaceutical companies that were manufacturing hormonal female contraception conducted international surveys to explore the landscape of hormonal male contraception to guide their possible involvement in the field (Heinemann, Saad, Wiesemes, & Heinemann, 2005; Heinemann, Saad, Wiesemes, White, et al., 2005; Hoesl et al., 2005). These surveys were done over 16 years ago. A recent systemic review (Heinemann, Saad, Wiesemes, & Heinemann, 2005; Heinemann, Saad, Wiesemes, White, et al., 2005; Hoesl et al., 2005) of 32 studies of male contraceptive drug trials showed that 34% to 82% of men would use a male contraceptive if available. Questioning male willingness to use new undefined male methods varied from 13.6% to 83.0%. From women’s perspective, 42.8% to 94.0% of women would use a novel male method and trusted their partner in using them (Reynolds-Wright et al., 2021). With the changes in gender equity and roles of men and women in a union, these surveys on men’s attitude toward contraception, their role relative to their female partner, and acceptability of different methods should be reexamined in multinational, carefully constructed, large-scale surveys taking into consideration different racial-ethnic group, socioeconomic status, cultural differences, and disparity in access to contraception and medical care.

Assessment of Acceptability and Attitude During Male Contraceptive Clinical Trials

Since the early development of new methods of male contraception, acceptability studies were frequently included in the clinical study design including those on no-scalpel vasectomy, and hormonal method of male contraception. Because no-scalpel vasectomy has less adverse events including pain and other complications of vasectomy, this procedure was adopted by the medical community and by the users (Cook, Pun, et al., 2014; International Planned Parenthood Federation: International Medical Advisory Panel, 1993).

In a carefully designed acceptability study concurrent but independent of the clinical trial assessing contraceptive efficacy of monthly testosterone undecanoate injections in China, all 308 participants in the efficacy study were enrolled in an efficacy study. The latter study consisted of focus group discussion, and in-depth interviews of participants and their female partners enrolled in the study, potential users, principal investigators, provincial and national policy makers, and experts in the development of male contraception methods. Overall men found the method to be acceptable and reported no change in well-being. However, the frequency of the injections and the requirement of monthly semen analyses and the need to use another method of contraception prior to the efficacy study were reported as inconveniences (Zhang et al., 2006). Men in Indonesia participated in an injectable male contraception study because of concerns of economic stability with another child, while their partners thought that a male method would help them prevent pregnancy and associated complications (Solomon et al., 2007). A much smaller, single-center study of 40 men randomized to receive no treatment and 50 men randomized to receive testosterone undecanoate and norethisterone enanthate (administered at intervals of 6, 8, or 12 weeks) or placebo injections found that 92% of the participants indicated that men should share responsibility of family planning, Seventy-five percent said they would try a hormonal contraceptive if available, and 66% who completed the trial found the method acceptable and indicated they would use the method (Meriggiola et al., 2006). Acceptability questionnaires in a multicenter, larger study using the same steroids injected every 8 weeks to prevent pregnancy in the female partner showed that about 82% of the couples were satisfied with the injectable methods and 88% of the male and female partners would use this method of contraception (Behre et al., 2016). Acceptability of daily testosterone gel with a progestin injection was reported as very satisfactory or satisfactory in 50% of men (Amory et al., 2007). With daily testosterone and Nestorone gel application for 6 months, 51% would recommend this for others (Roth et al., 2014), and over 80% of the participants reported overall satisfaction with the daily study gel, 50% would use the gel if available, and over 90% found the gel easy to use (Anawalt et al., 2019). It should be noted that in these studies, men were not using the test compound as a contraceptive method, as the end point was suppression of sperm output. The current ongoing contraceptive efficacy (prevention of pregnancy) study of testosterone and Nestorone gel will assess acceptability of the couple throughout the study and will include and exit interviews with the couples (Long et al., 2021). More recent placebo-controlled studies of prototypes of a potential oral contraceptive pill in very early Phase 1 studies showed that men were significantly more satisfied with the active pills than placebo and over 77% would recommend this method to others (Nguyen et al., 2020). In another study with a prototype male oral contraceptive pill, 75% were satisfied with the pill, 90% would recommend this method to others, and 62.5% would pay for this as a contraceptive method (Nguyen et al., 2021). The primary endpoint of these Phase 1 studies was to assess safety and tolerability of these potential oral contraceptive agents. Study participants of these early clinical trials may not represent the general population, though those enrolled in late-phase studies where prevention of prevention of pregnancy in the female partner is a primary endpoint may better reflect the attitudes of users of new male contraception methods.

Population Surveys

Early studies in small numbers of men (between 100 to 200) in the United States and the United Kingdom reported that over 50% of men would use a male contraceptive pill if available. These men also favored family planning, abortion, and vasectomy as acceptable contraceptive methods. Men considered health risks and effectiveness to be the most important factors for receptivity to male contraception (Gough, 1979; Jaccard et al., 1981). In developing countries, a long-acting, reversible contraceptive method might be preferred by many men (Ringheim, 1993). In a study of 711 men in Zimbabwe, only 14% would consider vasectomy, and 34% reported prior condom use whereas 59% would not use condoms when asked by partner; however, 32% of men would consider using a male contraceptive pill or injection if available (Mbizvo & Adamchak, 1992). A large-scale survey of over 4000 households in Nigeria showed that the male condom was the most acceptable method of contraception (Onwujekwe et al., 2013). In Australia, 75.4% of Australian-born new fathers would consider trying hormonal male contraception (47.5% would probably consider), preferring an oral pill better than a 3-monthly injectable and over an injection every 2 years. This contrasted with only 13.6% of Australian migrant fathers (mainly from Asia) who would probably try hormonal male contraception, preferring an injectable every 2 years over other options (Weston, Schlipalius, Bhuinneain, et al., 2002; Weston, Schlipalius, & Vollenhoven, 2002). In a survey of 400 men in the United Arab Emirates, male contraception was acceptable by 33.3% of men because of religious, cultural, and personal beliefs and poor knowledge of available male contraceptive methods (Ghazal-Aswad et al., 2002). In Ethiopia, male participation in family planning (condom use) was very low (<10%) due to the desire to have more children, fear of side effects, religious reasons, and the notion that contraception is a woman’s responsibility (Kassa et al., 2014).

In a multinational study using a questionnaire-based structured interview administered to about 450 men each in Edinburgh, Cape Town, Shanghai, and Hong Kong, the participants would welcome a new male contraceptive method and 44%–83% would use a contraceptive pill. The pill was preferred over 3-monthly injections, and long-acting implants were least acceptable (Martin et al., 2000). Importantly, 1894 women in the same four cities thought that a male pill was a good idea (>90% in Edinburgh and Cape Town, 87% in Shanghai, and 71% in Hong Kong); only 2% of the women would not trust their partner to use a male pill (Glasier et al., 2000). The best-known survey on hormonal male contraception was supported by a pharmaceutical company to investigate the contraceptive knowledge, desire, and attitude of men in different countries. Over 9000 men (aged 18–50 years) from 9 countries in four continents were surveyed using a structured, standardized interview with identical questions. The participants were selected by random sampling of males from existing community panels representation of the overall population, except in Latin America and Indonesia where interviewers were sent house to house in selected regions. Most men had prior experience with the use of condoms and withdrawal and 47%–83% were currently using contraception. Decision on which method of contraception were made by both partners (54%–82%). Importantly, 28.5% to 71.45% (overall 55%) of the surveyed participants were willing to use a new method of male fertility control. In all participant surveys, a daily oral pill was the preferred method of administration followed by implants or injectables in participants from the United States and Europe, whereas in Latin America and Indonesia, implants were the least preferred (Heinemann, Saad, Wiesemes, & Heinemann, 2005; Heinemann, Saad, Wiesemes, White, et al., 2005).

More recently, smaller qualitative focus group discussions of 80 men and 398 women in two countries in Sub-Sahara Africa suggested that men and women supported development of male contraception, recognized male methods would reduce family burden in women, and provided men more control over their fertility. Concerns included side effects and that men would not use contraception. Different options of delivery methods and duration of action would maximize choice, engage men, and support their contraceptive needs (Cartwright et al., 2020). In a survey directed toward 162 young adult men (18–35 years) in the United States, 45% would use a hormonal male contraception and favored injectables. Men with higher education level or in a relationship were more frequently willing to use a male contraceptive. The main concerns were failure of the method and potential adverse effects (Sax et al., 2021).

Future

Surveys of men and women in the reproductive age group demonstrate that over 50% of men would use a new male contraception, while over 90% of women would welcome a new male method and only 2% of women would not trust their partner in using male contraception. More recent studies in men and women in sub-Saharan Africa as well as in younger adults also suggest that men are willing to try new methods. However, many of the most informative studies were done over 15 years ago. Landscape studies of approval for new methods of male contraception should reexamine factors that may influence acceptability of new male contraceptive methods given the changes in gender roles and equity in family planning. Large-scale acceptability studies in developed and developing countries are being undertaken by the WHO and the Bill and Melinda Gates Foundation and will be a foundation in considerations for development of new male contraceptive approaches. Use of social media to attract and engage potential users will be helpful, if not essential, to prepare for the launch of any new male contraceptive methods.

Why Do New Male Contraception Methods Take Such a Long Time to Develop?

The possible physiological reason is that a man produces many millions of spermatozoa a day. To achieve contraception, the number of spermatozoa must be suppressed to a very low concentration, or sperm motility or sperm function must be completely inhibited consistently every day. Currently male contraceptive clinical trials and research in new specific targets are mainly supported by the NIH. Nongovernmental agencies such as the Male Contraceptive Initiative, the Parsemus Foundation, and recently the Bill and Melinda Gates Foundation support new methods of vas occlusion or drugs that target spermatogenesis or sperm maturation directly. The pharmaceutical industry provided steroid hormones for studies sponsored by the WHO and other organizations. In the 2000s, two pharmaceutical companies (Schering AG and Organon) that were manufacturing female hormonal contraceptives initiated and supported a single study with testosterone decanoate and etonogestrel implants. The study showed that the various combination of the two agents were very effective in suppressing spermatogenesis. but these companies decided not to pursue further studies in male hormonal contraception (Mommers et al., 2008). These medium-size pharmaceutical companies were later acquired by larger multinational companies that have limited interest in contraception despite there being a significant demand and market for reversible and irreversible male contraception (Dorman & Bishai, 2012). The potential impact of a new male contraceptive pill or temporary vas occlusion would result in a meaningful decrease in unintended pregnancies by 3.5% to 5.2% in the United States, 3.2% to 5% in South Africa, and 30.4% to 38% in Nigeria (Dorman et al., 2018). Several reasons provided by the pharmaceutical industry for not engaging in male contraception development included the cost of male contraception development (compared to currently available female methods/products); uncertainty about the potential market for male-directed approaches; the provider that will be prescribing male hormonal agents; the need to monitor sperm concentration, motility, or function to assure efficacy; possible female partner objections to use; uncertainty if the failure rate is acceptable; and possible liability risk when or if conception occurs.

The most advanced clinical trials of new male methods are hormonal contraception and reversible vas occlusion. The hope is that adequate last-phase clinical data will be generated to harness interests of industry to assist in the scale-up and production of the product, accelerate regulatory approval, and distribute the product to be accessible to all men who would like to take responsibility in contraception.

Funding

This work was supported by the Contraceptive Clinical Trials Network, National Institutes of Health (NIH) (contract HHSN275220130024I, task order HHSN 2750007), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (P50 HD098593), and the University of California, Los Angeles Clinical and Translational Science Institute (grant UL1TR001881 from the National Center for Advancing Translational Sciences).

Further Reading

  • Glasier, A. (2010). Acceptability of contraception for men: A review. Contraception, 82(5), 453–456.
  • Johnston, D. S., & Goldberg, E. (2020). Preclinical contraceptive development for men and women. Biology of Reproduction, 103(2), 147–156.
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References