Re-conceiving the male “pill”

Since the advent of the birth control pill in 1960, new contraceptives have mostly been hormone-based products for women. But a recent push from researchers may lead to a breakthrough that for decades has seemed just out of reach: a male birth control pill.

While a viable birth control pill for men is still years away, a series of recent discoveries regarding the role of genes in sperm production have changed the way many reproductive biologists are talking about a male pill, lending a tinge of optimism to a field that has seen unfulfilled promises many times in the past.

“This is a field that has made incredible progress in the last five years,” said Jay Bradner, an oncologist at the Dana-Farber Cancer Institute in Boston who is investigating a promising candidate for a male birth control pill. “People should not be surprised to see viable drug molecules emerge from their efforts.”

The optimism stems from genetics-based research revealing new methods of stopping sperm production effectively, but reversibly. It’s a pivot away from the hormone-centered research that led to the first female birth control pill in 1960 and the numerous versions of the pill that have followed. Instead of tinkering with the hormones that send messages between cells, scientists are tinkering with the DNA blueprint contained inside cells.

“The idea of thinking like a geneticist is relatively new in the field of reproductive biology,” said Debra Wolgemuth, a geneticist at Columbia University who is researching another promising drug candidate. “The kinds of approaches and disciplines used in the development of the female pill were quite different from the approaches used today, especially in development of male contraception.”

More than fifty years after the introduction of the pill, few researchers could have predicted that men seeking birth control would still be limited to the same traditional choices: early withdrawal, condoms or a vasectomy. Producing an effective male pill that doesn’t trigger dangerous side effects has proven to be more difficult than anyone would have guessed. One male contraceptive, Gossypol, which was developed in China and used there in the 1970s and early 1980s, caused such adverse effects as diarrhea, heart failure and permanent sterility. Research on Gossypol was abandoned in 1986.

Despite that conspicuous failure, some experts think a male birth control pill made from a mixture of the hormones progestin and testosterone may yet reach pharmacy shelves before a drug with a genetic target. “We know a lot more about how the endocrine system works than how transcription factors work,” said Diana Blithe, who works on contraceptive development at the National Institute of Child Health and Human Development in Rockville, Md. Transcription factors are molecules that block or promote the translation of DNA into proteins.

Even so, researchers are excited about genetics-based approaches to male contraception because they are more specific in the mechanisms they target, and therefore cause fewer side effects, Dr. Bradner says.

While exploring gene switches in cancer cells, Dr. Bradner stumbled upon a drug that inhibits a group of proteins, called bromodomains, that can affect sperm production. Like Post-it notes, bromodomains stick to a chromosome as a reminder to turn on genes that produce other proteins.

The drug — called JQ1 for its discoverer, Jun Qi — inhibits a testis-specific bromodomain called BRDT, according to Dr. Bradner and his research partner, Martin Matszuk of the Baylor College of Medicine. Without BRDT, Dr. Bradner says the “software program” that switches on genes in order to produce sperm encounters an error.

Dr. Bradner and Dr. Matszuk think that their drug will work in humans and have already shown that it works in mice. Studies Dr. Matszuk performed demonstrated that when mice are taken off the drug, they fully regain fertility after one to two months, without suffering any long-term damage.

Similarly, Columbia’s Wolgemuth and her colleagues uncovered an experimental drug abandoned by pharmaceutical giant Bristol-Myers Squibb that could be used as a male contraceptive. The drug, called BMS-189453, interferes with a protein known as RAR-alpha, which, like BRDT, is important to inducing sperm production. Wolgemuth and her Columbia colleague Sanny Chung have shown that the drug can completely disrupt spermatogenesis in mice. Just as importantly, when the mice come off the drug, they are completely fertile again. RAR-alpha is so important to sperm production that even a tiny amount of the drug can cause complete infertility. “We can drop doses so low, we can’t see anything else wrong,” Wolgemuth said.

Other genetic discoveries have also shown promise, though there aren’t yet any drugs to exploit them. Recently, a group led by fertility specialist Moira O’Bryan of Monash University in Melbourne, Australia, revealed that a mutation in the gene RABL2 caused sperm to be produced with tails that were 17 percent shorter than normal. Like birds with clipped wings, the sperm were unable to swim, and therefore could not reach the egg. The mutation also decreased sperm counts by 50 percent.

Even though Wolgemuth and Dr. Bradner have promising drugs, pharmaceutical companies have yet to come knocking at their doors. “When it comes to big pharma, very seldom is a company interested in something that affects healthy people,” said Wolgemuth. And getting from mice to men is a difficult process. The next step for Wolgemuth’s lab is to try the drug in chimps or other primates, which would be very expensive.

Dr. Bradner, meanwhile, is taking a different approach by monitoring the side effects of a compound he describes as “JQ1 2.0” which will enter clinical trials as a cancer medication. As early as 2013, he hopes to begin collecting preliminary information about how safe and effective it is at both treating tumors and, as a side effect, stifling sperm production. If successful, Dr. Bradner’s lab will continue to refine the JQ1 molecule so that it only inhibits BRDT, and not the other bromodomain proteins.

But even if these early trials are successful, a contraceptive pill based on genetics is still unlikely in the near future. Blithe, of the National Institute of Child Health and Human Development, points to the development of the emergency contraceptive Plan B as an example of how long it might take for a male pill to be approved. “It took about 20 years from start to finish, from the time the molecule was first discovered to Food and Drug Administration approval,” she said. A hormone-based medication, a combination of progestin and testosterone that might come in a topical gel, is closer to being approved, but is still in clinical trials and several years away.

After so many years of wrong turns in the search for a male pill, it would be hard for scientists to lower expectations any further. And even if a male pill were successfully brought to the market, there would still be some crucial unresolved questions. Will a male contraceptive pill be acceptable to men? And would women trust men with pregnancy prevention? With all the recent advances made in the genetics of male fertility, we may be getting answers to those questions.