In Our Control (45 page)

When the sperm have reached a certain level of maturity, they move slowly into a long and winding tube called the epididymis, up through the ductus deferens (or vas deferens) to the urethra. Key maturation happens in this part of the body, and because of this the epididymis and ductus deferens are one potential target for chemical intervention. As sperm leave the ductus deferens and enter the urethra, they are joined by seminal fluid.

Sperm have three main parts: the head, the midpiece, and the tail. The design of the tail is unique, enabling it to move at astounding speeds when traveling in the female body. The head, which carries DNA, also houses an enzyme essential for breaking into an egg. The midpiece carries mitochondria, which help to power the tail. Seminal fluid is essential to sperm functioning, providing, among other things, chemicals that make the ejaculate alkaline and help sperm survive in the acidic vaginal climate, and fructose to provide energy for the long swim. When scientists think about male contraceptive drugs, they must decide at which point in this system to chemically intervene.

The goal of hormone drugs is to either eliminate sperm or seriously reduce them. When a man stops making sperm he is said to be “azoospermic.” If his sperm count is simply rendered low enough to prevent pregnancy, he is said to be “oligozoospermic.” Early experiments hoped to completely eliminate sperm, but this proved to be a difficult task, and later scientists readjusted the goal. While most admit that eliminating sperm would be ideal, researchers are also interested in how low sperm volume needs to be to prevent most pregnancies and create a drug with efficacy on par with the female pill.

A major setback to hormonal therapies has been the huge racial and ethnic variation in efficacy. Drug regimens that eliminated sperm in 90 to 100 percent of men in Asian trials had only 60 percent efficacy in white men in North America and Australia.
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While scientists are baffled by this difference, they acknowledge that it means that geographically specific trials aren’t necessarily applicable in other parts of the world. Beyond ethnic and racial differences, scientists struggle to understand why hormonal methods seem to work so well for some men and not for others; an answer to this question remains to be found.

All hormonal therapies require testosterone supplementation. Without
it, patients begin to have sexual side effects, including loss of libido. Testosterone therapy that used testosterone enanthate was tested in two large multicenter trials by the World Health Organization in the 1990s. In the first trial, 200 mg of testosterone was administered in weekly injections to 271 men for six months.
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Of these men, 60 percent became azoospermic, and another 30 percent became oligozoospermic. Only one pregnancy resulted. In the second study, 399 men received 200 mg injections weekly.
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Ninety-eight became either azoospermic or oligozoospermic. In this case, pregnancies were around 8.1 per one hundred people—an efficacy rate that is similar to actual use rates for the female pill. Adverse health effects included a reduction in high-density lipoprotein (so-called good cholesterol), acne, and reversible shrinking of the testicles. Researchers didn’t find significant changes in mood and sexual function or negative impacts on cardiovascular health.

One of the biggest problems with this regimen was practical: weekly injections are simply not a realistic way to deliver birth control to a large population of people in the long term. The high frequency of injections was necessary due to the relative weakness of testosterone enanthate. Other forms of testosterone, including testosterone decanoate (TD)
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and testosterone undecanoate (TU), have been tested because of their longer life in the body. In theory, these versions could be given by injection every month to every three months, making them more similar from an administrative standpoint to Depo-Provera in women. These drugs have been tested alone
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and in combination with progestin therapy.
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Combination therapy, in which testosterone is combined with a variety of progestins, including levonorgestrel, norethisterone, medroxyprogesterone acetate (MPA, the progestin used in Depo-Provera), and desogestrel, has received much preliminary testing. Progestins are administered in a variety of forms, including implants, patch, and gel. Testosterone gel
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or cream, which could be applied frequently by users, might provide a more acceptable alternative to frequent injections.

So how close are any of these options to hitting pharmacy shelves or becoming available in doctors’ offices? It depends who you ask. It has almost become an old joke that the male pill—or more likely injection or implant—is just five years away. In 2005 one group of doctors complained about the modest size and scope of hormone trials, noting, “All trials have
been small, and the power to detect clinically important differences has been poor.”
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Additional complaints returned to a problem that has plagued male birth control for decades: a lack of standardization, particularly as it pertains to defining “oligozoospermia.” Much will depend, in the next few years, on pharmaceutical involvement and other factors that may be subject to economic twists and turns. Currently, trials of a formula combining TU and progestin seem the closest to moving on to phase 3 clinical testing and, perhaps, FDA approval.

All of the current androgen options are fairly imprecise, and as a result, drug potency is decreased and side effects are more numerous. Hormones bind with target tissues through a mechanism that is somewhat like a lock and key; testosterone is a skeleton key, and despite the fact that it doesn’t work as well as we’d like it to, it compensates for the gaps in our steroid knowledge. In future decades new hormonal compounds may allow more specific, finely tuned tools. Selective hormone receptor modulators—drugs that act on certain tissues and not on others—are further along for use in women. The anticancer drug tamoxifen and the menopause drug raloxifene are two female examples. The goal of such medicines is to offer the benefits of hormone therapy—such as increased bone mass in the case of raloxifene—without some of the risks, like breast cancer. The male versions of these drugs are called selective androgen receptor modulators (SARMs).
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One early example of this option for men is the compound 7 alpha-methyl-19-nortestosterone (MENT). Championed by the Population Council, the drug is delivered in implants like the female contraceptives Implanon, Norplant, and Jadelle. Unfortunately, it has proved disappointing in the laboratory. The drug has trouble maintaining efficacy over several months.
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Other SARM options are being explored for the possibility of oral administration, and all of these options are in much more formative stages of development than testosterone therapy.

While androgens and progestins act on FSH and LH, gonadotropin-releasing hormone antagonists (GnRH antagonists) take the process back a step by curtailing the chemicals that trigger FSH and LH.
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This method has two steps: in the first, a GnRH antagonist works to quickly decrease FSH. The second part, a maintenance step, uses testosterone to keep sperm levels low. Should this approach make it to the market, it would
theoretically have a couple of advantages: it would seek to speed up the normally slow onset of azoo- and oligozoospermia, and the testosterone dose needed for maintenance would be lower than testosterone-only therapy, reducing unpleasant side effects.

Hormone treatments have many potential side effects that seem to vary based on the particular androgen or progestin being used. The side effects include acne, weight gain, changes in blood pressure and cardiovascular health, psychological and mood changes, and the potential to increase the risks of certain cancers, most distressingly, prostate cancer. Chemical hormones carry similar risks for women (minus the prostate cancer risk). A significant benefit of hormonal contraception is that in men, as in women, it is entirely reversible for the vast majority of patients.

Nonhormonal Birth Control and the Future of Contraceptive Medicine

All hormonal methods of controlling male fertility draw on previously existing female methods, and while innovative, they don’t constitute a truly radical break with older contraceptive medicine. Nonhormonal alternatives, although much further behind scientifically, provide opportunities for scientists to think in truly creative, groundbreaking ways about reproduction.

There are three stages at which sperm can be stopped in its journey toward egg fertilization: during development in the testicle, in maturation in the epididymis, while moving toward the egg and trying to penetrate its surface (the zona pellucida). Think of it this way: you can stop them at the beginning, middle, or end of their journey.

Gossypol is one compound that works at the beginning. Despite obvious problems, some research on the method continues; Elsimar Coutinho, the Brazilian gynecologist who helped to invent Depo-Provera and start the menstrual suppression craze, has been one advocate of continued work in this field. Coutinho argues that later trials have not revealed the potassium reduction problems seen in earlier trials and theorizes that the original results might have been, at least in part, a by-product of the Chinese diet.
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He also points out that regardless of this, many common drugs can cause potassium reduction. Coutinho thinks that Gossypol might provide a
good, more easily reversible alternative to vasectomy for men who have already had the number of children they desire. While permanent infertility for many remains a serious problem with Gossypol, the chance of renewed potency may be higher than it is with vasectomy reversal. In China, scientists continue to tinker with Gossypol, combining lower doses with hormonal therapy that includes either estrogen or progestin.
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Chinese men participated in trials of another herbal extract, Tripterygium wilfordii, a chemical used to treat rheumatoid arthritis that had the unexpected effect of inducing infertility.
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This compound has similar problems to Gossypol, namely, irreversible infertility and has been similarly disregarded by most of the scientific community.

Both botanicals target the sperm cells. Another approach works on other cells that allow the sperm to develop, such as Leydig or Sertoli cells that make testosterone and prevent the exposure of developing sperm to dangerous toxins. Some versions of this approach, at least as it is imagined now, might require testosterone supplementation and therefore do not truly constitute a nonhormonal method. Methods that try to disrupt the sperm while they are still in the testicle are complicated because it is very difficult to penetrate the blood-testes border, a membrane separating the fragile reproductive cells from the bloodstream.

Because of this, targeting sperm while they are maturing in the epididymis is a promising alternative. The idea with this approach is to “shake the tree”—to release sperm that are immature and therefore incapable of fertilization. Although a number of methods have been proposed, “pursuit of these … is still a number of years from clinical use.”
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Finally, sperm can be prevented from fertilizing an egg by introducing chemicals that act on their ability to swim or penetrate the outer coating of the egg. One potentially innovative approach involves blocking unique calcium channels that exist only on the tails of sperm. Discovered only in the last decade, this possible method has shown promise in tests on mice.
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This sort of therapy still lives in the realm of fantasy, but if realized, it would have the unique advantage of being administered in the form of a pill that either a woman or a man could take before sex to prevent pregnancy.
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Some scientists believe that it might be possible for women to take it after sex, providing a nonhormonal morning-after pill.

Animal tests often prove promising, but human tests tend to have very
different results.
N
-butyldeoxynojirimycin (
N
B-DNJ), a compound that is used to treat Gaucher’s disease, a genetic disorder, showed promise in rendering mice reversibly infertile by forcing the production of inferior sperm.
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However, later tests in humans showed no negative effect on sperm.
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Sperm vaccines provide a completely different sort of nonhormonal option. In this approach, the immune system works as a birth control method, responding to the shot by producing antisperm or antiegg proteins. Eppin is a protease inhibitor found on sperm that has become the subject of early efforts in this arena.
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Tests in monkeys have proved promising, but great concerns exist about moving on to human trials. Vaccine contraceptives are controversial, and there are even greater safety concerns and unknowns than exist with other new methods. Scientists worry about how frequently injections would be required and, more troubling, the failure to restore fertility after discontinuation. A version targeting gonadotropins is in phase 1 trials for women;
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for males, however, immunocontraception is still in very early testing stages and is being studied mostly for use in animals.

If all of this sounds like science fiction, that’s because it essentially is at this point: nonhormonal methods are years behind hormone treatments
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and may prove more difficult and expensive to advance down the scientific pipeline. Even if they work, they will probably bring new and unimagined safety problems. But this type of creative thinking about fertility control is what has been lacking in the past fifty years since the last truly innovative option, Pincus’s pill, was first introduced to the public. Doctors dream of a drug that would encourage male use by offering benefits beyond contraception. Diana Blithe notes, “It would be nice if we could develop methods that also protect the prostate or prevent hair loss.”
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Perhaps changing the context of contraceptive research and development to male bodies will continue to encourage this sort of originality.