Susan Benoff's research on a potential male birth-control pill began with a puzzling case of infertility. A couple had come into the infertility clinic at North Shore University Hospital in Manhasset, N.Y., seeking to conceive a child through in-vitro fertilization. The couple's earlier attempts to have a child, including artificial insemination with the man's sperm, had all failed. The man's sperm and the woman's egg were normal by every measure, yet the test-tube fertilization also failed: In repeated attempts, the man's sperm were unable to penetrate the eggs. "There was zero percent fertilization," says Benoff, the clinic's research molecular biologist, who investigates the clinic's failures. "The couple was upset, and the physicians were upset."
Benoff began methodically studying the case, trying to find anything that might explain the unusual outcome. She examined the sperm and eggs, she interviewed the couple, and she examined their medical records. One oddity finally caught her eye: The man, who was in his late 30s, was taking a drug called nifedipine for treatment of high blood pressure. Sold under the brand names Procardia and Adalat, it is one of a class of drugs called calcium-channel blockers, which are among the most widely prescribed drugs for the treatment of heart disease and hypertension. The drugs act by stopping the movement of calcium through cell membranes, and Benoff knew that calcium was important in sperm function. It was Benoff's only lead, and she decided to pursue it.
She asked the man's cardiologist to switch him to another hypertension drug. When that was done, the couple was able to conceive a child. It took Benoff months of research to determine that the drug was responsible for the infertility. She realized immediately that it might be possible to develop calcium-channel blockers into a male birth-control pill, a long-sought goal of family-planning advocates. She has since continued the research without major funding, and she has now figured out how the drugs act on sperm. In a recent report, she concluded that calcium-channel blockers induce sperm to produce more cholesterol. That, in turn, hardens their membranes so that when they encounter an egg, they are unable to fuse with it.
The National Institutes of Health thinks the work is so promising that it invited Benoff to visit in January to present her findings. After hearing the presentation, Robert Spirtas, chief of the contraception branch at the National Institute of Child Health & Human Development, said, "She's got an idea that may well be very important. We're going to work with her to try to move it forward."
EAGER CALLERS. Nearly a dozen different calcium-channel blockers, from a variety of manufacturers, are approved for use in the U.S. That translates into a $4 billion-a-year market, according to IMS Health Inc., a drug industry research firm in Plymouth Meeting, Pa. Despite Benoff's findings that the drugs have potential as contraceptives, the companies that make them have shown little interest in the work, she says.
When she first reported her findings in 1994, her phone was "ringing off the hook" with calls from men eager for a male pill, she says. Drug companies took a different view, she says. "I was approached by the companies because they were afraid of lawsuits." More than 4 million Americans, most of them men, are taking drugs that can cause infertility, she says--and they don't know it. Another problem is that drugmakers are afraid of losing the heart market to other medications that are equally effective. "The drug companies were scared," Benoff says. "If patients were frightened, they could go to their physicians and say, `I don't want to take this anymore."' Mary Sawyers, a spokeswoman for Bayer Corp., which sells nifedipine under the brand name Adalat, says: "If we saw it as being effective as a male contraceptive, then we would pursue that. The market would be big, potentially bigger" than the heart market.
In the wake of Benoff's first report, Pfizer Inc., the maker of the Procardia brand of nifedipine, noted in its product description that there had been a "report of reversible reduction of the ability of human sperm...to bind to and fertilize an ovum...." But it's just one sentence in a 3,000-word description of the drug's effects and side effects and easy to miss. "We ourselves have gotten very few reports on this over the years," says Andrew B. McCormick, a Pfizer spokesman. "It does not seem to be an issue with the majority of physicians or patients."
Bayer did not take note of the infertility problem in its product description. Even if Adalat users or their doctors did read all the fine print, they wouldn't find out about Benoff's research. Sawyers says most men who use calcium-channel blockers are older and have already had their children. "I don't know that [infertility] has ever been an issue," she says. "Our lawyers don't know of any lawsuits in that arena."
NO CLUE. The infertility problem extends beyond calcium-channel blockers. Benoff says there are as many as 150 drugs capable of causing infertility in men or women. They include a variety of blood-pressure medications, cancer chemotherapy agents, psychiatric drugs, antibiotics, and recreational drugs, Benoff says. "People mostly don't seem to know about it," she says. "The fact is that the general physician doesn't know about this side effect."
Even some specialists are unaware of the infertility problems Benoff has found. For example, a recent article in the New England Journal of Medicine summarizing research on calcium-channel blockers failed to note that the medication may cause infertility.
Part of the problem, Benoff says, is that drug safety tests are usually run with female lab animals, to find evidence that the drugs might cause birth defects. Those tests sometimes pick up female infertility. But tests with male animals are less common, meaning that problems with male infertility are often not found.
When Benoff first suspected in 1993 that nifedipine might be adversely affecting sperm, she asked colleagues at various clinics to look in their files for any link between calcium-channel blockers and infertility. They soon told her that they were finding similar cases of male infertility in men with normal sperm. Benoff then tried to determine whether they had also found that the effect was reversible--which is exactly what a male contraceptive ought to be. "It was," she says. "When patients were taken off these medications, they regained fertility potential....They were able to get their wives pregnant."
INSTITUTE'S INTEREST. Her first report of those findings is what started her phone ringing. She told callers that more research was needed to develop the drugs into safe, effective contraceptives. But the drug companies that approached her, she says, were not interested in supporting her research.
She reported her most recent findings last fall at the latest meeting of the American Society for Reproductive Medicine in Toronto. The director of the National Institute of Child Health & Human Development heard the presentation, and that led to Benoff's invitation in January to present her findings there. "We think there is a need for a drug like this," says the institute's Spirtas. "There are couples in which the woman can't take hormonal contraceptives and in which, at least in the surveys we've seen, the male partner would be willing to take the contraception."
Spirtas says the institute will work with Benoff to develop a grant proposal and will likely give her funds to pursue the research. Some other male contraceptives, based on testosterone and other hormones, may reach the market sooner, but Benoff's nonhormonal approach could prove to be safer, he says, because it doesn't have the many side effects associated with hormone treatments. With the institute's help, the research could proceed much faster.
Benoff's hunch about the role of calcium-channel blockers in infertility--and her persistence in pursuing it--has put her on the brink of what could be a major advance in contraceptives. By solving the problem of one unhappy couple, she may improve the lives of many others.