Both men and women have been wondering what the holdup is with the male birth control pill. While research has shown promising first steps in understanding the science, that elusive pill is still a few years away.
Gender bias and inequality have been in the headlines a lot in recent months, especially as political talking points boil over from simmer seemingly every night. While most of these sound bites center around how women are typically not earning as much as men — a topic even Endocrine News has broached (“Gender Bias,” December 2015) — there is one area where women come out ahead: birth control.
Specifically, the pill. Why is the birth control pill — arguably the safest and most effective form of contraception — only for women? According to the Centers for Disease Control and Prevention/National Center for Health Statistics, of the 62% of U.S. women using contraception, 17% are using the pill (10% rely on condoms, interestingly enough). Aside from the pill, women have a variety of other options (diaphragms, rings, IUDs, implants, patches).
Meanwhile the only reasonable choice for men is a condom or a vasectomy. So where is that male pill?
Funny you should ask…
So Near, Yet So Far
The male pill has been as elusive as the white rhino. It’s been hotly anticipated for years and always seems to be “just around the corner.” How close are we to seeing the first prescription written for the male contraceptive pill?
Hormonal contraception for men is based on suppressing endogenous production of testosterone and sperm, according to Bradley D. Anawalt, MD, chief of medicine, University of Washington Medical Center and professor and vice chair, University of Washington Department of Medicine, Seattle. “Most of the research has focused on the combination of testosterone plus a progestin, another sex steroid hormone that is found in men and women,” he explains. “Previous studies of male hormonal contraceptives have shown that injectable formulations provide effective contraception that is far superior to the condom and compares favorably to most female contraceptive options.”
“The development of a male pill or another form of male hormone contraception would be the most revolutionary contraceptive development in decades — all new contraceptives that have been developed over the past century have focused on preventing ovulation or fertilization in the woman.” – Bradley D. Anawalt, MD, chief of medicine, University of Washington Medical Center and professor and vice chair, University of Washington Department of Medicine, Seattle
Before there’s a men’s birth control pill, there will more likely be other contraceptives administered via implant, injection, or transdermally, according to Stephanie Page, MD, PhD, Robert B. McMillen Professor in Lipid Research, section chief, Endocrinology and Diabetes, Harborview Medical Center; professor, Division of Metabolism and Endocrinology, University of Washington, Seattle. “This is due to some of the challenges with oral testosterone delivery, which include issues of serum half-life — how long it remains in the blood and therefore how often a pill would need to be dosed — and some potential side effects.”
Anawalt concurs and says that despite the great public interest in a male pill, he predicts that the first reversible male hormonal contraceptive will be one of those methods mentioned above. “Such formulations have already been developed and tested,” he says. “There is currently no safe oral form of testosterone that is effective with a single daily dose.”
Anawalt adds that taking a pill two to three times a day is simply not practical. “However, because of the increasing number of prescription of testosterone products for the treatment of male hypogonadism (or ‘low T’),” he says, “there has been more work done to develop oral forms of testosterone and oral forms of androgens (compounds that act like testosterone in the body). So, the development of a male pill is much more promising.”
Life as We Know It
There is little doubt that the market – and the populace – would welcome a male birth control pill. For one thing, it would take the onus of contraception off of the woman. According to Anawalt, men would welcome a reliable, reversible contraceptive method other than the condom. “Having a male pill available would allow men to participate meaningfully in family planning,” he says. “In addition, the development of a male pill or another form of male hormone contraception would be the most revolutionary contraceptive development in decades — all new contraceptives that have been developed over the past century have focused on preventing ovulation or fertilization in the woman.”
A male pill will need to be nearly side-effect-free in order to make it through the regulatory process, according to Page, since they don’t provide a direct health benefit to their users, whereas female methods that protect a woman from pregnancy, which can be a life-threatening condition in some cases.
Of course, the impact of the male pill – or any reversible method for that matter – would depend on cost, availability, and acceptability. While there probably won’t be a cultural revolution such as the one that occurred with the original pill, a male contraceptive pill will definitely influence cultures, as well population growth. “The market for such a product will likely vary amongst different countries and cultures,” Page says. “For example, there is likely a market within monogamous couples, especially those where the female partner cannot use hormones, and, conversely, among single men who want to control their own fertility.”
Page adds that population growth is a hugely important issue for the next century, both from an environmental and health perspective and that many men want to be partners in contraception, and there is overwhelming data that increased contraceptive availability increases use and reduces unplanned pregnancy. “In this regard, male hormonal contraception could have a big impact if it is readily available, and affordable, to men,” she adds. “Non-hormonal methods are being very actively pursued in the laboratory but there has been almost nothing that has made it to human trials, and nothing yet tested in the U.S. in this space, so that is likely why the research hasn’t garnered as much attention.”
From Bench to Medicine Cabinet
A study published in the October 2015 issue of Science showed that male mice treated with cyclosporine A and FK506, which act as calcineurum inhibitors, resulted in male infertility within two weeks. Fertility returned one week after stopping the treatment. The researchers, led by Haruhiko Miyata of Osaka University in Japan, discovered a protein called calcineurin which is responsible for propelling the sperm through the membrane of a female egg and thus fertilizing it.
“We found that the sperm-specific calcineurin is essential for sperm fertility and its inhibitor could work as male contraceptive in mice,” says one of the study’s authors, Masahito Ikawa, PhD, professor, Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, who adds that since humans also have sperm calcineurin, the same effect would be expected.
“However, there is a problem that the somatic cells also have different type of calcineurin,” Ikawa continues. “The inhibitor we tried (cyclosporine A and tacrolimus) also inhibit somatic ones and lead to immuno-suppression. Therefore, we cannot use these drugs. We hope to find the lead molecules within two to three years and examine their effects in animals in five to six years.”
Another study from 2015 in the journal Andrology examined the protein architecture of sperm and revealed that there may actually be components that serve as a “battering ram” to get the sperm into the egg to fertilize it. The study was led by John Herr, PhD, a professor of cell biology at the University of Virginia, Charlottesville, and was such big news that it was the cover story for the August 2015 issue of Andrology.
“An important component in the quest for a non-hormonal approach to male contraception is the identification of tissue-specific drug targets,” Herr says. “Because the bar is very high for a male contraceptive drug, which treats otherwise healthy subjects, drug targets that are restricted to the testis provide a key strategy to achieve a selective mechanism of drug action. In the SLLP family, SLLP1, 2 & 6, are testis-specific proteins that are restricted to post-meiotic spermatids and sperm in their expression patterns. These proteins provide a means to target the very last step of spermatogenesis: the differentiation of spermatids into sperm.”
Page adds that non-hormonal methods of birth control, such as those that inhibit sperm motility, have great appeal in theory. “There are a number of targets that are being actively pursued: sperm motility, sperm-egg fusion, and various aspects of sperm development,” she explains. “The problems in this area have been a real lack of specificity in the proteins involved in these processes in humans. For example, enzymes that propel sperm are very closely related to enzymes that propel other vital cell types in the body, so designing a drug that only affects that process in sperm is very tricky. Calcineurin is not a sperm-specific protein, but rather quite a ubiquitous one.”
Ikawa and the Osaka University team have partnered with researchers at the Baylor College of Medicine to perform further studies to find specific drugs that inhibit calcineurin, but not somatic cells, with the Baylor College of Medicine in Houston. He adds that even with these further studies he does not see an actual male pill for at least another decade, if not longer.
The Waiting Game
Anawalt is very encouraged by two areas of research that could lead to making the male pill a reality. “The NIH has funded research on novel hormonal compounds that have androgenic and progestinic properties. Some of these novel compounds appear to be highly potent, safe, and effective as an oral pill or capsule,” he explains. “Besides the development of new compounds, the NIH has funded an international study of a testosterone-nesterone gel. This study will shed insight into the effectiveness, safety, and acceptability of a male hormonal contraceptive gel that is applied daily.” This is the type of research that is crucial for the future development of safe, reversible male hormonal contraceptive such as gel, implant, or a male pill.
“The market for [the male pill] will likely vary amongst different countries and cultures. For example, there is likely a market within monogamous couples, especially those where the female partner cannot use hormones, and, conversely, among single men who want to control their own fertility.” – Stephanie Page, MD, PhD, Robert B. McMillen Professor in Lipid Research, section chief, Endocrinology and Diabetes, Harborview Medical Center; professor, Division of Metabolism and Endocrinology, University of Washington, Seattle
Likewise, Page feels that progress is being made on other fronts as well; the FDA is planning to review two oral testosterone products within the next couple of years. “Moreover, despite a current lack of support from the pharmaceutical industry, the NIH has continued to fund a small program testing novel androgens (derivatives of testosterone) and these look promising for once a day oral delivery,” she says. “Thus, the 10-year benchmark that we have talked about for a few years now looks more promising than in the past.”
“We need more creative and talented scientific energy directed at these projects as well as investors who are willing to make this a priority,” Page adds. “These issues will far outlast my time as an investigator, but investing in discovery and delivery is critical to making both short- and long-term impacts on health and choice for families.”
— Newman is the editor of Endocrine News. He wrote about the Endocrine Society’s new Open Access journal in the May issue.
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