Despite decades of research, male contraceptives remain years away

Contraceptive options for women have been readily available since the 1960s, but the options for men are few — condoms, vasectomy for permanent fertility control and withdrawal for versatile fertility control.

“Women have a limit to their fertility rate based upon the length of pregnancy, but male reproduction does not have the same constraints,” Stephanie T. Page, MD, PhD, of the department of medicine at the University of Washington and Harborview Medical Center in Seattle, told Endocrine Today. “We know that getting men involved in birth control has an important impact. In addition, there are many women who are unable to use birth control, particularly hormonal methods.”

A 2011 study published in Contraception reported that 49% of pregnancies in the United States were unintended in 2006, a trend that remains significantly higher than the rate in many other developed countries.

“For men, there are few reversible choices,” Page said. “Vasectomy is not readily reversible and certainly not reversible for many men due to cost, and condoms have a high failure rate. Clearly, we have a global problem in terms of population growth, and contraception is a big part of any solution.”

Endocrine Today interviewed experts on the state of the research for different contraceptive methods that may, one day, be available for use in men.

Barriers to contraception for men

According to Diana L. Blithe, PhD, director of the Contraceptive Development Research Center Program and the Male Contraceptive Development Program at NIH, the barriers to developing pharmaceutical options for men are high.

Safety must be well established for a medication designed for a healthy population attempting to avoid pregnancy, sometimes for many years.

“You are going to be giving someone a product for lots of years and you don’t want to have any side effects, so you have to demonstrate a high bar of safety in the product,” Blithe said. “I’d say that’s probably the major challenge that we have for female and male methods.”

Regulations that the FDA may put forth, especially for long-term safety and efficacy, are an area of concern for researchers.

“Since there is no product on the market like this, the FDA doesn’t really have a set of guidelines that are already established for [male contraceptives],” Blithe said. “The FDA would be starting from scratch and maybe make a determination based on what they require in women.”

Currently, the FDA requires 20,000 cycles of safety data for female contraceptives, but because men do not cycle it would be difficult to determine the appropriate number of years a pharmaceutical contraceptive would have to be tested in men.

“That’s a question we don’t have the answer to,” Blithe said. “We have to meet with the FDA and get some guidance from them, and then go into studies. We will have to recruit a large number of couples and have them use a drug for a long period of time. The large numbers of use cycles required for women provides a lot of safety data, so we’re talking about several years to be able to generate enough cumulative safety and efficacy data to submit to the FDA.”

Social barriers to contraceptives for men also are of concern, according to Page.

“There’s a perception that men aren’t interested in contraception, that men are more interested in a larger family size,” Page said. “We have good data that shows that that’s not true. There is a bias or a prejudice out there that men aren’t interested. That’s clearly not true with the rates of vasectomy and condom use that men are already using.”

According to Page, multinational, multiethnic surveys have shown men would be willing to use contraceptives in a variety of types.

“About 75% of men are interested in [using contraceptives], and women in committed relationships are willing to trust their partners to do so,” Page said. “There’s certainly a market here for contraceptives for men.”

For whatever reasons, pharmaceutical companies have not shown as much interest in developing methods for use by men in the past few years, according to Doug Colvard, PhD, deputy director for programs at CONRAD, which specializes in reproductive health and HIV prevention.

“There was a period, 5 to 15 years ago, with very active interest,” Colvard said. “Major pharmaceutical companies that were involved in both the United States and Europe had active programs, but they [were discontinued] because they decided to use their funds elsewhere. It’s not one of their priorities.”

Hormonal contraception

Hormonal methods of contraception are a feasible option and effective for suppressing sperm and preventing conception, but it has been difficult to find a regimen with minimal adverse effects, according to Page. One advantage is that hormonal methods would be reversible.

“We’d be asking young men to use these for a number of years, so side effects are clearly an important issue,” Page said. “In fact, like the female pill, the goal of the male contraceptive would be that it would have positive health benefits for men. Any new contraceptive needs to be acceptable to both females and males, and needs to be accessible to have a real global impact both in terms of cost and availability.”

Hormonal contraception for men works by taking advantage of a naturally occurring negative feedback, according to Page.

“We give exogenous hormones [thereby] suppressing pituitary gonadotropin production, which minimizes stimulation of the testes, resulting in significant decreases in intratesticular testosterone and failure of spermatozoa to develop,” Page said. “The key here is that we give exogenous testosterone to block the downstream production of pituitary hormones that are required for spermatogenesis and testosterone production, while the exogenous testosterone supports androgen effects throughout the rest of the man’s body, such as male pattern hair growth and libido.”

Early studies for hormonal contraception for men were conducted in the 1990s and were pioneered by WHO, CONRAD and the pharmaceutical industry. The initial contraceptive effectiveness study involved 271 couples at 10 centers worldwide, and men were assigned relatively high doses of intramuscular testosterone.

“In order for the couple to proceed in the efficacy phase where this was being used as the only contraceptive and the outcome was pregnancy, men had to achieve azoospermia, so zero sperm in their ejaculate,” Page said.

According to Page, 65% of the men went on to the efficacy phase, and only one pregnancy was noted in couples using no other form of birth control through the 12-month phase.

“This was a landmark study, which really showed that rendering men azoospermic was an effective contraceptive,” she said.

In a 2012 study published in The Journal of Clinical Endocrinology & Metabolism, Ilani and colleagues evaluated 99 healthy men randomly assigned to one of three treatment groups applying daily transdermal gels: testosterone 10 g plus placebo (n = 32), testosterone 10 g plus the nonandrogenic progestin nestorone (NES) 8 mg (n = 33) or testosterone 10 g plus NES 12 mg (n = 34).

Of 56 patients who completed at least 20 weeks of treatment, the percentage of men with sperm concentrations of less than 1 million/mL was higher for the testosterone plus NES 8 mg (89%; P < .0001) and testosterone plus NES 12 mg (88%; P < .0002) groups compared with the testosterone plus placebo group (23%). Additionally, more patients became azoospermic in the testosterone plus NES 8 mg (78%; P < .001) and testosterone plus NES 12 mg (69%, P < .008) groups compared with the testosterone plus placebo group (23%). A sperm concentration of more than 15 million/mL was achieved by all participants during the recovery period.

Results of a WHO- and CONRAD-sponsored phase 2 trial designed to assess safety and contraceptive efficacy of a regimen of testosterone undecanoate combined with norethisterone enanthate were much anticipated, but the trial was ended prematurely because of adverse effects; however, according to Colvard, a researcher on the study, researchers said they plan to have a final manuscript published in a peer-reviewed journal in the fall.

“During the trial, one of the external review groups that were looking at the data thought that some of the side effects that the men were experiencing outweighed the study benefits that the men who were continuing the study would provide,” Colvard said.

Despite adverse effects, Colvard said the regimen was highly effective in suppressing sperm production more than 95%, with very few pregnancies during the contraceptive effects of the trial.

“Over 95% of the men who were followed recovered their sperm production after a year,” Colvard said. “Very few who were followed did not recover. The side effects that were of concern were related to emotional disturbances, depression and increased libido, but even those were not unexpected given the previous history of male hormonal contraceptive trials. The review group thought that the risk of additional [side effects] wasn’t worth it for this study.”

Colvard added that although the study was ended prematurely, 80% to 90% of participants reported they were very satisfied with the method.

Nonhormonal contraception

According to Michael G. O’Rand, PhD, of Eppin Pharma Inc., right now, there are no nonhormonal contraceptives in clinical trials, and researchers may not even be close to developing one. The biggest problem in nonhormonal contraception is target selection, which has taken up most of the research. “Of course, there’s the testis, which is an obvious target, but within the testis there are germ cells — should they be used? Or perhaps the supporting cells, Sertoli cells? In addition, we have that large organ called the epididymis, and the epididymis has a number of different cells,” O’Rand said.

According to Polina V. Lishko, PhD, of the University of California, Berkeley, ion channels are essential for sperm physiology, and if certain channels are blocked, sperm can become immotile, which could provide a target for development of nonhormonal contraception.

“If one develops a selective inhibitor for sperm specific ion channels, one can essentially develop new contraceptive,” Lishko said.

Human sperm has three main ion channels, one each for potassium (KSper), protons (Hv1) and calcium (CatSper).

“The [calcium channel] CatSper is present on the sperm tail, and is sperm specific,” Lishko said. “It’s not present in any other part of the body. In male organisms, CatSpers are only expressed in sperm, therefore CatSpers’ inhibition may provide an ideal contraceptive since they likely lack side effects due to their target being restricted to sperm cells only.”

Lishko said if CatSper were removed from the sperm cell, sperm would not be able to fertilize an egg. Once calcium is released into a sperm cell’s tail, it causes the tail to change its bending pattern.

“The standard type of sperm motility is a symmetrical snake-like motion,” she said. “When the calcium rushes in, it starts to bend the tail asymmetrically, which is called hyperactivation, so what’s happened is the sperm cell can produce a more powerful stroke.”

Hyperactivation is essential for sperm cells to penetrate the protective areas of the egg.

“If we can inhibit the CatSper channel activity, we can essentially stop the sperm cell from fertilizing an egg,” Lishko said.

Targeting Eppin

O’Rand and his company are currently working on a nonhormonal method that would target the epididymal protease inhibitor Eppin, a protein present on the surface of the sperm that is present only in males. Although the precise function of Eppin is still open to interpretation, according to O’Rand, the molecule itself is a protease inhibitor, meaning that it inhibits prostate specific antigen (PSA), an enzyme used in detecting prostate cancer.

Eppin also binds semenogelin, a protein that is secreted by the seminal vesicles.

“In the ejaculate, when the sperm first ejaculate, they are in a clot, it’s very viscous and that’s probably another protective mechanism, so the sperm are allowed to be in the vagina and don’t leak out,” O’Rand said. “After about 20 minutes or so, the clot is dissolved, it liquefies, and that liquefication requires the enzyme PSA.”

According to O’Rand, that is the specific function of the enzyme, to dissolve the clot that gives the sperm the ability to freely move through the reproductive tract.

“Part of what happens when semenogelin is mixed in with the ejaculate, is that it binds with Eppin,” O’Rand said. “When they are stuck to each other on the surface of sperm, the sperm don’t swim. This is probably just another protective mechanism in the ejaculate.”

O’Rand and his group immunized male monkeys with recombinant human Eppin to produce antibodies that would then bind with Eppin and prevent its proper functioning.

“We asked the question, if you bind an antibody to Eppin, does anything happen?” O’Rand said. “Sure enough, the monkeys were infertile. When we stopped immunizing them, their fertility returned.”

O’Rand and colleagues aim to find a molecule that could be a substitute for the antibody that would be bio-orally available, last longer and enable them to conduct the toxicology tests required to proceed to a clinical trial.

“I think it will work, and we’re very hopeful that we can develop it in the next few years,” O’Rand said.

Looking to the future

Estimates and opinions about when a contraceptive option will be available for men varies widely. Although development efforts began decades ago, Page said, time-to-approval estimates continue to be 5 to 10 years.

“The real challenge here is trying to understand the biology and why certain men don’t suppress sufficiently to make an effective contraceptive for everyone,” Page said. “There’s been a lot of work in that area, and that still remains a challenge.”

Although most adverse effects in tested methods have not been significant, overcoming FDA challenges is still of great concern.

“What the FDA would want in terms of safety data remains unclear, but it’s an important issue in the development of a contraceptive for men,” Page said. “Finally, we have learned that these different compounds are acceptable to men and their partners. In the female, long-acting reversible contraceptives have been demonstrated to be the most effective agents in terms of preventing pregnancy, and so we need to be working on long-acting compounds as well as short-acting pills to maximize male contraceptive options.” – by Amber Cox

Disclosures: Blithe, Colvard, Lishko and Page report no relevant financial disclosures. O’Rand reports being president and CSO of Eppin Pharma Inc.

Are hormonal methods the most viable option for male contraceptives?

Hormonal strategies are currently the best option for reversible contraception for men.

Research in hormonal methods of male contraception began in the 1970s supported mainly by the Contraceptive Development Branch of National Institute of Child Health and Human Development (NICHD), NIH. The concept was initially based on using available androgens (testosterone) alone and modified by adding a second gonadotropin-suppressing agent (a progestin or a GnRH antagonist) to suppress the secretion of both luteinizing hormone and follicle stimulating hormone and decrease intratesticular testosterone and spermatogenesis. The exogenously administered testosterone maintained libido and other androgenic effects. These early studies provided sufficient preliminary evidence that the World Health Organization and the Contraception Development Program (CONRAD) conducted two multicenter studies in four continents with testosterone enanthate injections as a prototype in the 1990s.

These studies provided data to show that if spermatogenesis is suppressed to very low sperm output, contraceptive efficacy is as good as the female oral contraceptive pill. Subsequent studies in China and Australia confirmed contraceptive efficacy with testosterone undecanoate injections and testosterone implants with depot medroxyprogesterone acetate injections. These and many other trials demonstrated the short-term safety (up to 2 years) and reversibility of male hormonal contraception.

Current studies supported by the Contraceptive Discovery and Development Branch, NICHD, through the male Contraceptive Clinical Trials Network centers are studying new androgens with progestational activity (dimethandrolone), new progestins without androgenic/estrogenic activity (nestorone) and more user-friendly and controlled delivery methods (pills and transdermal gels).

Because steroid hormones have defined mechanisms of action with known on-target and off-target effects, safety has been shown in hypogonadal men (androgens) and women (progestins); successful phase 3 clinical trials have been conducted in China, and the development pathway is faster. Thus hormonal methods are more advanced than non-hormonal methods where first-in-man studies have not yet started. Long-term safety can only be determined in safety studies after a hormonal male product is readily available.

Christina Wang, MD, FRACP, FRCP, and Ronald Swerdloff, MD, are both professors in the department of medicine at Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute. Disclosure: Wang reports various financial ties with Besins Health Care, Clarus Therapeutics, Lipocine and TesoRx. Swerdloff reports various financial ties with Clarus Therapeutics and TesoRx.

Perhaps, but hormonal contraception is not necessarily the best option for men.

Spermatogenesis, like follicle development and ovulation in women, is under systemic endocrine control, which clearly gives the opportunity for hormonal regulation to provide contraception for men, as with the longstanding established methods in women. This approach has been investigated now over several decades with substantial clinical trials supporting the concept that hormonal treatment can suppress gonadotropin secretion and, thus, spermatogenesis and indeed provide contraceptive efficacy. The landmark trials for this were carried out by WHO in the 1990s using the fairly simple regimen of weekly testosterone injections. Subsequent refinements have largely focused on the ability of progestogens to cause profound gonadotropin suppression, with supplementary testosterone to provide physiologic replacement and add to the gonadotropin suppression. Clinical trials in this field are still ongoing. One of the major areas they have highlighted is that a small proportion of men seem to be resistant to this approach, maintaining spermatogenesis at levels higher than are needed for contraceptive efficacy. This remains a very significant issue for the field. The nonhormonal approaches are also very attractive and are based on our rapidly growing understanding of the molecular control of spermatogenesis and of sperm maturation in the epididymis, which provides a further potential target. There have been several very effective approaches demonstrated in animal models, but the key issue here is their translatability to clinical trials, which, in general, has not happened. There remains very great promise here, but it is, at present, unclear which or any of the current approaches will survive the transition to the human. Currently, therefore, the answer to the question “are hormonal methods the most viable option for male contraception?” is “yes,” but whether this will remain the case is a lot less clear.

Richard Anderson, MD, PhD, MRCOG, is head of obstetrics and gynecology at the University of Edinburgh. Disclosure: Anderson reports no relevant financial disclosures.

Hormonal contraception offers men the promise of reversibly regulating their fertility in a safe, reliable, effective manner.

Although once considered a “woman’s issue,” contraception is now thought to be a couple’s shared responsibility. Yet curiously, there are still few options for a male contraceptive beyond the use of condoms, withdrawal and vasectomy. Vasectomy is an effective form of sterilization with failure rates less than 1%. Nevertheless, relatively few men are vasectomized each year, in contrast to the number of tubal ligations performed for female sterilization. The potential of hormonal manipulations to serve as a male contraceptive was first realized in the early 1930s, and over the past 50 years or so andrologists developed approaches to influence the hypothalamic-pituitary-gonadal axis by either inhibiting gonadotropin release or using exogenous testosterone alone or in combination with gonadotropin-releasing hormone (GnRH) antagonists or progestin analogs to inhibit spermatogenesis. Indeed, even today many young men seek treatment for secondary infertility resulting from exposure to exogenous androgen due to prescription drug or anabolic steroid use. Although exogenous testosterone administration alone can produce azoospermia in about 65% of men within 4 months of use with a pregnancy rate less than 1 per 100 person-years, there are ethnic differences in patient response with most of the other men developing severe oligozoospermia. The rate of unwanted pregnancy is about the same as that seen with the female pill for contraception. Side effects are relatively minor with decreased testicular size, acne, polycythemia, decreased HDL levels and behavioral changes (increased libido, aggressiveness, depression) and weight gain among the most common. It is usually reversible, acceptable for both partners and does not impair sexual motivation, erectile function or sexual activity. These characteristics make hormonal contraceptive an attractive choice for men seeking contraception.

The attributes of efficacy, reversibility and safety with few side effects are not shared by the majority of the nonhormonal contraceptives investigated or currently under development. Agents such as triptolide, gossypol and perhaps the indenopyridines are problematic because of toxicity and irreversible sterility. Lonidamines, such as gamendazole and adjudin, have been engineered to be less toxic, but gamendazole also can cause permanent sterility in rats. Other approaches targeting cation channels and Na+/H+ exchangers show promise for the future, as does the recently described bromodomain inhibitor. Less promising are physical alterations, such as heating the scrotum (thermal supports) or using a water bath at 43oC for 30 minutes a day or ultrasound to heat the testis, which seem downright uncomfortable or at best inconvenient. Vasal occlusion with a device or injection of a polymer in the vas is more invasive and not currently an option for men. Given the safety profiles of hormonal contraception, the advantageous characteristics of increased libido and sexual function, together with reversibility and relatively low cost, hormonal contraception is most likely to be the first male contraceptive to be widely used and well accepted in various cultures throughout the world. If an oral approach is employed for a male contraceptive, like the female pill, the more significant challenge is likely patient compliance with timely dosing!

Dolores J. Lamb, PhD, is the director of the Center for Reproductive Medicine at Baylor College of Medicine. Disclosure: Lamb reports financial ties with the American Association of Bioanalysts, the American Board of Bioanalysts, Cellmatix, NIH and the Society for Women in Urology.