A failproof method
Dan Mishell and his researchers continue the quest for more effective ways to prevent the union between sperm and egg.
by Eva EmersonWhen sperm and egg meet, the two may become one-a fertilized egg that, under the right circumstances, will develop into a baby. Interrupting this meeting has long spurred humans to invention, from the snakeskin condoms of the ancient world to today's birth control pills.
Yet, despite progress in preventing unwanted pregnancies, it is not easy to keep sperm and egg apart. With perfect use, the most effective methods-such as The Pill, intrauterine devices, male or female surgical sterilization, Depo-Provera and Norplant-work more than 95 percent of the time. But in the real world, the numbers for average users are not quite as good. And, for barrier methods, it is even worse. To Daniel Mishell, Jr., M.D., the Lyle G. McNeile Professor in Obstetrics and Gynecology and chair of the USC Department of Obstetrics and Gynecology, these discrepancies show why we still need to develop new methods of birth control.
According to an article in U.S. News and World Report, 90 percent of women who want to avoid pregnancy report using birth control, yet six in 10 U.S. pregnancies are unplanned. More than half of the women who terminate their pregnancies say their birth control method failed.
"Only about half the women of reproductive age in the U.S. use one of the five most effective methods of contraception that are currently available," Mishell says. Finding new methods might mean more women will actually use, and benefit from, birth control.
Mishell's flagship in the search for new methods of birth control is a compact, pink-trimmed clinic tucked along a featureless hallway in the Women's and Children's Hospital at the LAC+USC Medical Center. At any given moment, as many as 10 clinical research studies are taking place here. Each morning beginning at 5:30 a.m., study participants arrive for lab tests, exams and quick, often-intimate chats with one of the clinic coordinators.
Over the years, the clinic has tested a wide variety of methods, including birth control pills, the time-released hormone Norplant, the injectable hormone Depo-Provera and intrauterine devices (IUDs). Now, along with continuing studies on these methods, Mishell and his researchers are looking to what may be tomorrow's preferred methods, including contraceptive rings, hormone skin patches and "designer" birth control pills that may help prevent breast cancer while preventing pregnancy.
Much of the USC research has focused on hormone-based methods. "Hormonal methods, together with the IUD, are the most effective methods of reversible birth control," Mishell says.
Hormones are the body's chemical messengers that regulate a woman's fertility cycle. They trigger the release of an egg (ovulation), stimulate the production of sperm-friendly cervical mucus and make sure the uterus is prepared to nurture a fertilized egg. Birth control pills, a mix of synthetic forms of the hormones estrogen and progesterone (called progestins), halt the union of sperm and egg by sending a different message to the body. When using The Pill, women cease to ovulate and produce a type of mucus in the cervix that blocks sperm passage. When it is used correctly, The Pill rivals sterilization in terms of effectiveness.
But The Pill has its drawbacks. Skipping just three pills in a cycle leaves a woman unprotected against pregnancy. The estrogen in the pills puts some women at risk of developing venous blood clots. Progestin-only methods, such as Norplant or Depo-Provera, do not increase risk of blood clots but do create irregular and unpredictable menstruation in most women.
"In general, we keep trying to use lower doses of hormones so there are fewer side effects, while still maintaining the effectiveness," Mishell says. "Another trend is to change the method of delivery of the hormones." Other methods of delivery also offer the advantage of requiring lower levels of hormones than The Pill to be effective.
One of the hormone release methods being studied at the clinic is a transparent, flexible vaginal contraceptive ring that measures about three inches across. Harlene Breaux, a study coordinator at the clinic, explains that the ring is inserted into the vagina, where it steadily releases a mix of hormones. Each month, users remove the ring for one week to allow menstruation. One version of the ring may be reused for up to a year, but this newer, slimmer model is discarded after each month.
While the contraceptive rings have not yet been approved by the U.S. Food and Drug Administration, Breaux says that some of her clinical trial patients "love" the ring. Adds Mishell, "It is easier because you don't have to take a pill everyday and it is relatively easy to insert and remove."
As part of a multi-center study, USC researchers are also testing Cyclo-Provera, a second-generation injectable contraceptive that combines estrogen and a progestin and is already being used in other countries.
One benefit of Cyclo-Provera over the progestin-only Depo-Provera is that women will have regular monthly bleeding. Since many women find birth control that halts their normal monthly cycle unacceptable, Cyclo-Provera may well appeal to a much broader group of women, says Mishell. And since Cyclo-Provera lasts for only one month, the hormones leave a woman's system more quickly than Depo-Provera, which lasts three or more months. Researchers are also looking at whether Cyclo-Provera's natural form of estrogen, called estradiol, will produce fewer harmful side effects than synthetic estrogens.
Mishell has also taken an active role in the clinical investigations of new forms of implantable, long-lasting hormones, with hopes of improving upon the Norplant system. Norplant II, with two matchstick-sized rods instead of the original six, is easier for clinicians to insert and remove than the original and may soon be available for general use. Another kind of implant, a single capsule called Implanon, has recently finished clinical trials, but has yet to be approved by the FDA. Implanon remains in a woman's body for only two years, much less than the five-year lifetime of the Norplant systems.
In the future, another hormone delivery tool may be a skin patch, much like nicotine patches smokers use to help kick the cigarette habit. Still in development, the patch would release hormones through the skin, and would be simple to stick on and take off. Also being considered is what Mishell terms a "designer" birth control pill that work as contraception while also lowering a woman's breast cancer risk. The designer pill is the brainchild of Malcolm Pike, Ph.D., the Flora L. Thornton Chair in Preventive Medicine and chair of the USC Department of Preventive Medicine, who theorizes that such a pill could help prevent breast cancer by decreasing a woman's lifetime exposure to estrogen, which is a known risk factor.
What Mishell does not expect to see any time soon is a form of birth control radically different from what we have today. Despite some progress in the laboratory, efforts to come up with a male birth control pill have been stalled both by scientific obstacles and by questions of its appeal. Frequent injections of testosterone that have been shown to inhibit sperm production have also proved highly variable among users, inconvenient and costly. A daily pill made of testosterone and progestin has been shown to lower sperm counts dramatically, but not yet sufficiently to prevent pregnancy. Put simply, stopping 300 million sperm-the number in a small amount of semen-is a much more daunting task than halting the release of a single egg. "You would have to cut off spermatogenesis completely for a male birth control pill to work. And that has proved difficult," says Mishell.
Likewise, contraceptive vaccines remain a long way from being feasible. Scientists are investigating vaccines that would block the hormones critical in early pregnancy and the production of sperm. But individuals' wide range of responses to the potential vaccine in terms of efficacy and duration, added to safety and cost concerns, makes Mishell doubtful that a vaccine will appear on the market in the next few decades.
In fact, there seems to be less interest in developing new contraceptives because there is less money, and more liability, in bringing a contraceptive to market than for many disease-fighting drugs, says Mishell. This marks a sharp contrast to the atmosphere of the late sixties and early seventies, when Mishell played a leading role in the testing and development of The Pill and more than a dozen companies were heavily invested in new contraceptive technologies. Now, only a handful of companies invest in contraceptive research and the number of research grants has shrunk.
"Birth control is a method for healthy people. So it has many more limits on it than other drugs," Mishell says. Mishell says that even he has seen the effects of the shrinking research dollars. But with more than 30 years of leading clinical investigations into keeping sperm and egg relations cool, he is not about to stop now.