An Update on Male Contraception Research
Background
The global unintended pregnancy rate is ~50%, and it is even higher among adolescents in the U.S. At present, preventing unintended pregnancies is largely the burden on women. Of all modern contraceptive methods available, all but two are for women. Options available for male contraception are still limited to condoms characterized by a high failure rate with typical use and to vasectomy, which is invasive and not easily reversible.
Why is it harder to develop birth control for men than women? There are a couple of reasons. One is that it’s harder from a biological point of view. It comes down to a numbers game: Women produce one egg a month, while men are producing millions of sperm constantly. With women, their normal monthly cycle works in tandem with the birth control pill. There’s nothing equivalent to that in men.
The other is that there’s a different risk–benefit analysis when it comes to men using a contraceptive. When women use a contraceptive, they’re balancing the risks of the drug against the risks of getting pregnant. And pregnancy itself carries risks. But these are healthy men—they’re not going to suffer any risks if they get somebody else pregnant.
For these reasons, family planning continues to be the responsibility of women. In our overpopulated world, the development and commercialization of a male contraceptive method that will allow both men and women to take an active role in family planning is mandatory and further research on this topic is required.
An update on male contraception research making the availability of male hormonal and non–hormonal safe and effective contraceptives would give men the chance to have control over their own fertility and to share the responsibility for family planning. Among the different approaches to control male fertility, hormonal contraception is the closest to possible clinical application.
Action Mechanism of Male Hormonal Contraception
The basic mechanism by which hormones affect fertility in men is through the suppression of luteinizing hormone (LH) and follicle–stimulating hormone (FSH) with subsequent reversible inhibition of testicular function, namely spermatogenesis and testosterone production.
Both the decrease of testosterone and suppression of FSH lead to a decrease of Sertoli cell function essential for germ–cell maturation. To maintain androgen–dependent physiological functions an androgen (usually testosterone) must be part of the contraceptive regimen.
Efficacy Studies of Hormonal Male Contraceptive Regimens
The support of government agencies such as the World Health Organization (WHO), Contraceptive Research and Development (CDRCP), and the National Institute of Child Health and Human Development (NICHD) has led to important progress in this field and numerous studies have confirmed that the hormonal approach is feasible, relatively effective, and acceptable.
Hormonal approaches can successfully block sperm production by interfering with spermatogenesis (the production of sperm). Male contraceptive efforts based on various hormonal regimens achieved overall success rates of ~94% in studies, but these efforts were abandoned due to unwanted side effects. The results were published October 27, 2016 in the Journal of Clinical Endocrinology and Metabolism (JCEM).
These studies all demonstrated that testosterone is efficient in suppressing sperm concentrations. Subsequent trials demonstrated that testosterone alone is not as efficient as testosterone plus a progestin, both in the rate and extent of suppression of spermatogenesis.
In addition to these studies, the feasibility of hormonal contraception for men was tested in a few contraceptive efficacy studies (which evaluated the ability of the formulation to prevent pregnancy). They showed that azoospermia or severe oligozoospermia induced by hormone regimens provide excellent pregnancy protection comparable with female oral hormonal contraception.
Hormonal Topical Gel Combining Testosterone and Nestorone
A hormonal strategy involving a topically applied nestorone–testosterone gel in an ongoing world–wide clinical study remains the most advanced effort to develop a male contraceptive.
Nestorone (segesterone acetate, NES), a 19–norprogesterone–derived progestin characterized by the absence of androgenic, estrogenic, or glucocorticoid effects. It provides inhibition of gonadotropins through a negative feedback mechanism but it also inhibits local testosterone production directly in the testis.
Testosterone gel can be used together with NES gel. This combination used daily in healthy men has shown effective gonadotropin suppression.
In a study of 56 subjects, sperm suppression was significantly more probable in men treated with testosterone plus NES compared with men treated with testosterone (23%). Adverse effects were minimal in all groups with 21% of subjects presenting mild or moderate acne.
Testosterone and NES can be combined into a single gel with reduced volume thus simplifying application and improving adherence.
Hormonal Injectables Using Testosterone Only
Testosterone Enanthate
The U.S. National Institutes of Health began male hormonal contraceptive clinical trials in the 1970s using short–acting testosterone formulations such as testosterone enanthate (TE). These studies demonstrated in healthy male volunteers that intramuscular administration of TE suppresses sperm concentration to very low levels.
TE was also used in two large WHO–supported efficacy studies confirming that testosterone can induce profound suppression of spermatogenesis in men. In 1990, in the first multicenter 12–month study, 271 healthy volunteers received TE weekly and 65% became azoospermic within 120 days. The mean time of recovery of spermatogenesis after stopping testosterone injections was 3.7 months.
The study demonstrated that azoospermia induced by TE injections was able to provide highly effective, sustained, and reversible contraception: among the men who entered the study only one pregnancy was reported.
In the second WHO study, 399 men were enrolled and received weekly intramuscular injections of TE. Men from Asian centers reached azoospermia sooner than men from other centers. Non–suppression occurred in 0.033% of men from non–Asian centers compared with men from the Asian centers. In this study, efficacy was tested in men with different levels of oligospermia. Four pregnancies were reported in oligozoospermic men and no pregnancy was reported in azoospermic men.
Side effects included discomfort at the injection sites, acne, psychological changes, weight gain, polycythemia, and abnormal lipids.
Testosterone Undecanoate
Long–acting intramuscular testosterone undecanoate (TU) was studied as a potential hormonal male contraceptive agent in a large Chinese phase II contraceptive efficacy study. In this trial TU was used in 308 healthy men over the course of 12 months. Overall, the total failure rate of this method was 5.2% and total efficacy was 94.8%.
Spermatogenesis returned to the normal range within the recovery period without any serious adverse events occurring during the study. Side effects included tenderness or discomfort at the injection sites, acne, and self–reported changes in sexual desire.
Another subsequent large multicenter, phase III, WHO–supported, contraceptive efficacy clinical trial was conducted in China enrolling 1045 couples who received treatment with TU over the course of 24 months. Nine pregnancies were reported for a cumulative contraceptive failure rate of 1.0% and 1.1% at the end of months 12 and 24, respectively.
No serious adverse events were reported during the study period. The most frequent complaint was tenderness or discomfort at the injection sites, acne, changes in mood or behavior, and facial swelling or skin rash. Spermatogenesis returned to the normal fertile reference range in all but two participants. This study showed that in the couples who completed the efficacy phase, contraceptive protection was excellent.
Hormonal Injectables Combining Testosterone With Others
Testosterone plus Progestin
Testosterone administration demonstrated contraceptive efficacy but testosterone alone is not as efficient as testosterone plus a progestin in the rate and extension of spermatogenesis suppression. These two steroids have a combined effect resulting in more rapid and profound sperm suppression compared with each compound administered alone.
Adding a progestin also allows the reduction of the testosterone dose therefore reducing possible side effects related to supraphysiological (greater than normally present in the body) doses of testosterone, therefore improving the safety of the regimen.
Various pilot studies using testosterone injections plus different progestins have confirmed the efficacy of these formulations in sperm suppression. Various progestins including medroxyprogesterone acetate (MPA), levonorgestrel pills and implants, desogestrel pills, etonogestrel implants, oral cyproterone acetate, and injectable norethisterone enanthate (NETE) have been studied.
The combination of TU with etonogestrel (active metabolite of desogestrel) was studied in 2008 in a multicenter trial involving 354 men. This trial showed that the combination of etonogestrel subcutaneous implants with TU was associated with sperm suppression to <1 million/ml. This regimen was well–tolerated and provided an effective and reversible suppression of spermatogenesis.
In a small trial the efficacy of a regimen using testosterone pellets (four implants, every 4 or 6 months) and MPA injected every 3 months demonstrated high contraceptive efficacy (no pregnancies occurred in 426 months (35.5 years); 95% confidence interval (CI) for contraceptive failure rate: 0–8%/annum) with satisfactory short–term safety and recovery of spermatogenesis.
Recovery was complete in all but one man with an incidental testicular disorder. Side effects included problems with the pellets, symptoms of androgen deficiency (lower levels of sex hormones), and mood fluctuations.
In 2001 the combination of the injectable preparation of TU plus NETE injected every 6 weeks in 14 subjects was shown to induce profound suppression of spermatogenesis and the absence of serious side effects.
In a subsequent study, the injection interval was increased to 8 weeks and 90% of subjects still achieved azoospermia (lack of sperm) and all were severely oligozoospermic (low sperm count) at <1 million/ml by the end of the 48–week study period. A further increase of the injection interval to 12 weeks led to a decrease in sperm suppression.
After the promising results of these small studies, WHO and CONRAD decided to use this regimen in an efficacy study. The appeal of this regimen was that both TU and NETE are dissolved in castor oil and thus they can be included in one formulation that is injected every 8 weeks providing an acceptable hormonal contraceptive regimen.
A large multinational phase II efficacy trial was carried out to determine the safety and efficacy of this combination regimen for contraception. Participants received injections every 2 months during the suppression and efficacy phases.
Within 24 weeks, 85% of participants suppressed to a sperm concentration ≤1 million/ml. During the efficacy phase, among 83% of male participants, 4 pregnancies occurred in the partners (rate of 0.015%). During the recovery phase, 95% recovered to a total sperm count of at least 39 million per ejaculate.
Reported side effects included acne, increased libido, injection site pain, myalgia, and mood alterations; 6% of men discontinued due to a side effect. The reported frequency of moderate to severe mood changes, which occurred only in a few of the subjects but not all, lead to a stopping of further injections before the planned end of the study.
Testosterone plus gonadotropin releasing hormone (GnRH) antagonists act by competitive binding to receptors and reduce both LH and FSH to undetectable levels. GnRH antagonists are very effective in suppressing spermatogenesis.
Short–term studies have shown that the suppression of spermatogenesis by GnRH antagonists plus testosterone is profound. However, GnRH antagonists are expensive and the majority of them still require frequent subcutaneous injections.
New long–acting depot formulations of GnRH antagonists, such as degarelix, are currently being researched. But until newly developed long–acting formulations are available on the market, these regimens do not represent a realistic option for male contraception.
Oral Formulations: The “Male Pill”
Up to now, studied male hormonal contraceptives are designed to be administered through injections or implants which may be uncomfortable so many men prefer other administration methods such as oral or transdermal self–administration.
The oral delivery of testosterone has been challenging with the problem of hepatoxicity with methyltestosterone or for the necessity of multiple doses per day in the case of TU.
New androgens are currently under development as potential oral male hormonal contraceptives. Dimethandrolone undecanoate (DMAU), a derivative of 19–nortestosterone has both androgenic and progestational activity in preclinical studies.
Recently, it has been studied in 82 healthy men for 28 days was safe, well–tolerated, and demonstrated its ability to suppress serum testosterone, LH, and FSH to levels consistent with effective contraception.
Limitations of oral DMAU are the need for concomitant food administration for effective absorption and androgenic side effects (i.e. weight gain, increased hematocrit, and reduction in HDL–cholesterol).
Another new molecule (11–ßMNTDC) is a derivative of 19–nortestosterone. In preclinical data, it showed serum gonadotropin suppression, and one study in men demonstrated that given in oral doses with food it is well tolerated and able to suppress testosterone.
Side Effects And Risks
In trials which tested testosterone–only regimens, common side effects were acne, altered libido, night sweats, increased weight, and mood changes.
The combination of testosterone with a progestin allowed a reduction of testosterone dose minimizing androgenic side effects. This regimen’s side effects were correlated with the type of progestin used. Progestins derived from nortestosterone more often caused androgen–related adverse side effects such as weight gain, acne, or decreased HDL–cholesterol.
Although side effects were reported in all studies. Active treatment was more frequently associated with mood and libido alterations, acne, weight gain, and night sweats. Adverse side events were reported by 93% of men on active treatment and 81% of men on placebo.
Treatment was associated with a decrease of total cholesterol, HDL–, and LDL–cholesterol, with an increase in the total cholesterol/HDL– cholesterol ratio. No significant changes in prostate volumes were detected. PSA levels did not change throughout the study periods in any study.
Pregnancy and fetal outcomes during and after male hormonal contraceptive treatment are similar to those of the general population. Spontaneous miscarriage rates (6–11%) were comparable to the general population (8–20%). The congenital malformation rate (0.9–1.8%) is consistent with the congenital malformation rate in spontaneous and ART pregnancies (4%).
Factors Influencing Suppression and Reversibility
In the Chinese population, testosterone alone induced azoospermia and thereby effective contraceptive protection in most subjects. In Caucasian men testosterone alone cannot guarantee effective contraception as it produces azoospermia in only two–thirds of volunteers and azoospermia or severe oligospermia in about 95% of subjects.
To achieve uniform azoospermia or severe oligospermia in Caucasian men, testosterone must be combined with a progestin. This combination almost doubles the rate and extent of sperm suppression.
In addition to ethnicity, the dose of testosterone may also modulate the extent of suppression as a higher total administered dose may be related to a higher proportion of incomplete suppression, while higher baseline endogenous testosterone is also associated with slower suppression.
Even after drug and dose optimization, male hormonal contraceptive regimens can have some variability on the extent of sperm suppression depending on body mass index, age, and initial sperm count.
Hormonal male contraceptive regimens have shown full reversibility within a predictable time course. Non–recovery has only been reported twice in men diagnosed with other causes of sterility, such as epididymitis and myotonic dystrophy. Different co–variables can affect the rate but not the extent of recovery.
In 1549 men higher rates of recovery were detected with older age, Asian origin, shorter treatment duration, shorter–acting testosterone preparations, higher sperm concentrations, faster suppression of spermatogenesis, and lower concentrations of LH.
In the longest study of 855 men treated with androgen, the median time to recovery of sperm output was 7.6 months, longer than the median recovery time of 3.4 months previously calculated.
In another study of 354 men administered with combined androgen–progestin therapy, the median recovery time was 3.7 months and all men had recovered after 16 months.
In the most recent study of 266 men treated with NETE and TU, the cumulative rate of recovery to total sperm count of 39 million per ejaculate was 95%.
Volunteers received injections of TU followed by recovery and follow–up period. All sperm counts, in both normal and subnormal volunteers, returned to the starting range confirming the same safe pattern in both groups.
Treatment Acceptability
The ideal male contraceptive method should be independent of the sexual act and without short– or long–term side effects and interference with libido. It should be effective quickly, fully reversible, have no impact on eventual offspring, and be easily accepted by both partners.
Several studies have been performed in different countries to evaluate the level of acceptability of possible male contraceptive methods. In these studies 44–83% of men interviewed welcomed male hormonal methods.
In two different studies performed in Italy and China, men participating in clinical trials on a potential hormonal injectable contraceptive found the method acceptable. In the Italian study 79% of men indicated that they would use the method if available and 74% of subjects reported that their partner would appreciate it.
The transdermal route can improve the acceptance rate of the hormonal contraceptive method in some men over injectable regimens. Of 79 studied subjects 56% were satisfied or extremely satisfied with this gel–gel method and 51% would recommend it to others.
Efficacy Studies of non–hormonal Male Contraceptives
Other strategies focus on non–hormonal targets identified as essential for spermatogenesis via gene disruption technologies. In one study a retinoic acid receptor antagonist rendered mice reversibly sterile by blocking sperm production, but because retinoic acid receptors have other functions (key player in immunity), there are concerns that chronic use may lead to undesirable side effects.
Two other efforts to develop a male contraceptive block sperm functions. The herb Triptonide, originally identified from Chinese folklore, proved to be a reversible non–hormonal contraceptive in male mice and primates.
Inhibitors of the epididymal peptidase inhibitor (EPPIN) block sperm functions in primates. All of these strategies require months of continuous treatment prior to being effective, and require time to be fully reversible after treatment.
Thus, male contraceptive development lacks an on–demand approach where a contraceptive can be taken shortly before sexual intercourse and its effect is transient. Studies for an innovative strategy for an on–demand contraception approach identify sAC inhibitors as leads for on–demand contraceptives for men in the future.
On–Demand Male Contraception via Acute Inhibition of sAC
Among the most advanced research efforts, a small molecule inhibitor against testes–specific bromodomain (amino acid protein) reversibly suppressed spermatogenesis in mice, but it remains unclear whether this bromodomain can be selectively inhibited.
Soluble adenylyl cyclase (sAC) is essential for sperm motility and maturation. In a study published in 2023 in Nature Communications, a single dose of a safe, acutely–acting sAC inhibitor rendered male mice temporarily infertile. The mice exhibited normal mating behavior, and full fertility returned the next day.
Mature sperm are stored dormant where the bicarbonate concentration is actively maintained. Upon ejaculation, mixing with semen exposes the sperm to higher bicarbonate levels which stimulate activity of soluble adenylyl cyclase (sAC). This increase of cAMP is the initial event activating sperm motility, which is necessary to attain fertilizing capacity.
While sAC is found everywhere in the body, there is evidence that sAC isoforms present in sperm may be distinct from the other isoforms. Studies on the sAC present in sperm suggest that contraception for men based on sAC inhibition could be safe and effective if sAC is only transiently blocked.
One study identified numerous inhibitors which can selectively target sperm sAC isoforms, and these inhibitors can be delivered intravaginally as a new strategy for non–hormonal contraception in women.
The data in the 2023 study validates an effective on–demand contraception strategy unlike any other currently used form of birth control which avoids potential consequences of chronic dosing.
Conclusion
Nowadays, despite increases in female contraceptive options, 40–45% of pregnancies across the world are still unplanned. Numerous studies have been performed to develop male hormonal and non–hormonal safe and effective contraceptives.
A variety of new molecules are still under development as oral or transdermal hormonal contraceptives for men demonstrating few side effects. However, despite the significant progress showing efficacy, feasibility, and acceptability of hormonal and non–hormonal regimens, research in this field continues to be slow and has thus far not led to a product approved for clinical use.
A sAC inhibitor formulated into an oral male birth control pill is an innovative, on–demand, non–hormonal strategy representing a previously untested concept in contraception, which has the potential to provide equity between the genders and, like the advent of oral birth control for women, revolutionize family planning.
Sources:
Update on Male Hormonal Contraception
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Male Birth Control Study Killed After Men Report Side Effects
November 3, 2016
https://www.npr.org/sections/health-shots/2016/11/03/500549503/male-birth-control-study-killed-after-men-complain-about-side-effects
On-demand male contraception via acute inhibition of soluble adenylyl cyclase
https://www.nature.com/articles/s41467-023-36119-6
Published: 14 February 2023
Citation:
Balbach, M., Rossetti, T., Ferreira, J. et al. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nat Commun 14, 637 (2023). https://doi.org/10.1038/s41467-023-36119-6