What the Dog Saw

millions of women around the world have been given the Pill in such a way as to maximize their pain and suffering. And to what end? To pretend that the Pill was no more than a pharmaceutical version of the rhythm method?

3.

In 1980 and 1981, Malcolm Pike, a medical statistician at the University of Southern California, traveled to Japan for six months to study at the Atomic Bomb Casualties Commission. Pike wasn’t interested in the effects of the bomb. He wanted to examine the medical records that the commission had been painstakingly assembling on the survivors of Hiroshima and Nagasaki. He was investigating a question that would ultimately do as much to complicate our understanding of the Pill as Strassmann’s research would a decade later: why did Japanese women have breast-cancer rates six times lower than American women?

In the late forties, the World Health Organization began to collect and publish comparative health statistics from around the world, and the breast-cancer disparity between Japan and America had come to obsess cancer specialists. The obvious answer—that Japanese women were somehow genetically protected against breast cancer—didn’t make sense, because once Japanese women moved to the United States they began to get breast cancer almost as often as American women did. As a result, many experts at the time assumed that the culprit had to be some unknown toxic chemical or virus unique to the West. Brian Henderson, a colleague of Pike’s at USC and his regular collaborator, says that when he entered the field in 1970, “the whole viral- and chemical-carcinogenesis idea was huge—it dominated the literature.” As he recalls, “Breast cancer fell into this large, unknown box that said it was something to do with the environment—and that word environment meant a lot of different things to a lot of different people. They might be talking about diet or smoking or pesticides.”

Henderson and Pike, however, became fascinated by a number of statistical peculiarities. For one thing, the rate of increase in breast-cancer risk rises sharply throughout women’s thirties and forties and then, at menopause, it starts to slow down. If a cancer is caused by some toxic outside agent, you’d expect that rate to rise steadily with each advancing year, as the number of mutations and genetic mistakes steadily accumulates. Breast cancer, by contrast, looked as if it were being driven by something specific to a woman’s reproductive years. What was more, younger women who had had their ovaries removed had a markedly lower risk of breast cancer; when their bodies weren’t producing estrogen and progestin every month, they got far fewer tumors. Pike and Henderson became convinced that breast cancer was linked to a process of cell division similar to that of ovarian and endometrial cancer. The female breast, after all, is just as sensitive to the level of hormones in a woman’s body as the reproductive system. When the breast is exposed to estrogen, the cells of the terminal-duct lobular unit—where most breast cancer arises—undergo a flurry of division. And during the mid-to-late stage of the menstrual cycle, when the ovaries start producing large amounts of progestin, the pace of cell division in that region doubles.

It made intuitive sense, then, that a woman’s risk of breast cancer would be linked to the amount of estrogen and progestin her breasts have been exposed to during her lifetime. How old a woman is at menarche should make a big difference, because the beginning of puberty results in a hormonal surge through a woman’s body, and the breast cells of an adolescent appear to be highly susceptible to the errors that result in cancer. (For more complicated reasons, bearing children turns out to be protective against breast cancer, perhaps because in the last two trimesters of pregnancy the cells of the breast mature and become much more resistant to mutations.) How old a woman is at menopause should matter, and so should how much estrogen and progestin her ovaries actually produce, and even how much she weighs after menopause, because fat cells turn other hormones into estrogen.

Pike went to Hiroshima to test the cell-division theory. With other researchers at the medical archive, he looked first at the age when Japanese women got their period. A Japanese woman born at the turn of the century had her first period at sixteen and a half. American women born at the same time had their first period at fourteen. That difference alone, by their calculation, was sufficient to explain 40 percent of the gap between American and Japanese breast-cancer rates. “They had collected amazing records from the women of that area,” Pike said. “You could follow precisely the change in age of menarche over the century. You could even see the effects of the Second World War. The age of menarche of Japanese girls went up right at that point because of poor nutrition and other hardships. And then it started to go back down after the war. That’s what convinced me that the data were wonderful.”

Pike, Henderson, and their colleagues then folded in the other risk factors. Age at menopause, age at first pregnancy, and number of children weren’t sufficiently different between the two countries to matter. But weight was. The average post-menopausal Japanese woman weighed a hundred pounds; the average American woman weighed a hundred and forty-five pounds. That fact explained another 25 percent of the difference. Finally, the researchers analyzed blood samples from women in rural Japan and China, and found that their ovaries—possibly because of their extremely low-fat diet—were producing about 75 percent the amount of estrogen that American women were producing. Those three factors, added together, seemed to explain the breast-cancer gap. They also appeared to explain why the rates of breast cancer among Asian women began to increase when they came to America: on an American diet, they started to menstruate earlier, gained more weight, and produced more estrogen. The talk of chemicals and toxins and power lines and smog was set aside. “When people say that what we understand about breast cancer explains only a small amount of the problem, that it is somehow a mystery, it’s absolute nonsense,” Pike says flatly. He is a South African in his sixties, with graying hair and a salt-and-pepper beard. Along with Henderson, he is an eminent figure in cancer research, but no one would ever accuse him of being tentative in his pronouncements. “We understand breast cancer extraordinarily well. We understand it as well as we understand cigarettes and lung cancer.”

What Pike discovered in Japan led him to think about the Pill, because a tablet that suppressed ovulation— and the monthly tides of estrogen and progestin that come with it—obviously had the potential to be a powerful anti-breast-cancer drug. But the breast was a little different from the reproductive organs. Progestin prevented ovarian cancer because it suppressed ovulation. It was good for preventing endometrial cancer because it countered the stimulating effects of estrogen. But in breast cells, Pike believed, progestin wasn’t the solution; it was one of the hormones that caused cell division. This is one explanation for why, after years of studying the Pill, researchers have concluded that it has no effect one way or the other on breast cancer: whatever beneficial effect results from what the Pill does is canceled out by how it does it. John Rock touted the fact that the Pill used progestin, because progestin was the body’s own contraceptive. But Pike saw nothing “natural” about subjecting the breast to that heavy a dose of progestin. In his view, the amount of progestin and estrogen needed to make an effective contraceptive was much greater than the amount needed to keep the reproductive system healthy—and that excess was unnecessarily raising the risk of breast cancer. A truly natural Pill might be one that found a way to suppress ovulation without using progestin. Throughout the 1980s, Pike recalls, this was his obsession. “We were all trying to work out how the hell we could fix the Pill. We thought about it day and night.”

4.

Pike’s proposed solution is a class of drugs known as GnRHAs, which has been around for many years. GnRHAs disrupt the signals that the pituitary gland sends when it is attempting to order the manufacture of sex hormones. It’s a circuit breaker. “We’ve got substantial experience with this drug,” Pike says. Men suffering from prostate cancer are sometimes given a GnRHA to temporarily halt the production of testosterone, which can exacerbate their tumors. Girls suffering from what’s called precocious puberty—puberty at seven or eight, or even younger—are sometimes given the drug to forestall sexual maturity. If you give GnRHA to women of childbearing age, it stops their ovaries from producing estrogen and progestin. If the conventional Pill works by convincing the body that it is, well, a little bit pregnant, Pike’s pill would work by convincing the body that it was menopausal.

In the form Pike wants to use it, GnRHA will come in a clear glass bottle the size of a saltshaker, with a white plastic mister on top. It will be inhaled nasally. It breaks down in the body very quickly.