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AN UNFAMILIAR WILDERNESS: PERIODS, THE PILL, AND HRT

Brave new world: A world or realm of radically transformed existence, especially one in which technological progress has both positive and negative results.

—AMERICAN HERITAGE DICTIONARY

Walking today in an unfamiliar biochemical wilderness, women’s bodies are reacting unpredictably. Breast cancer may very well be one of those reactions.

—JAMES S. OLSON, Bathsheba’s Breast

IN THE COURSE OF A LIFETIME, BREASTS MEET MANY FRIENDS and foes: lovers, babies, ill-fitting undergarments, persistent pollutants, maybe a nipple ring, a baggie of silicone, or a dose of therapeutic radiation. It’s a lot to ask of breasts. Some of them don’t make it to the finish line. Each year in the United States, some seventy-eight thousand women undergo mastectomies of either one or both breasts. Over ten years, that’s enough women to fill the entire city of San Francisco. There are approximately two hundred thousand cases of breast cancer per year and forty thousand deaths in the United States. Globally, breast cancer is the leading cause of cancer-related death in women. One million women get diagnosed each year, and that number is expected to increase 20 percent by 2020. The global rise will largely be due to longer lifespans, obesity, and better screening. In a word, modernity.

Evolutionarily, though, cancer is a fact of life for multicellular organisms. As the pioneering German pathologist Rudolf Ludwig Karl Virchow discovered in 1855, “omnis cellula e cellula,” from one cell grow all cells. We need our cells to divide and replicate. Complex creatures like us would never have seen the sun if it weren’t for the lucky trick of mutations.

Breast cancer has probably been around for as long as there have been breasts. Humans are just about the only free-ranging animal (other than minks) to get it. Domestic pets, if not spayed, get it. Breast tumors can be artificially induced in many other animals in the lab by feeding them strange carcinogens or implanting rogue cells or tissues or messing with their genes.

In some human populations, breast cancer is virtually unknown. Among the Kaingang women in Paraná, Brazil, there is reportedly no breast cancer. Researchers would love to know why. It’s probably a combination of things: the Kaingang women have a shorter life expectancy, they bear many children whom they breast-feed, and they don’t take oral contraceptives or hormone replacement therapy. Also, spending many hours outdoors, they probably get a lot of vitamin D. They probably don’t wear deodorant or underwire bras, both long-held suspects in the breast cancer mystery, but ones that have been reliably exonerated.

Although breast cancer at the rates we know it today is a modern disease, ancient Egyptian doctors were familiar with it. One papyrus recommends applying a plaster made from cow’s brain and wasp dung to tumors for four days. In the Middle Ages, breast cancer was a known and feared disease. The most advanced treatment at the time was the application of insect feces. Anne of Austria, the mother of King Louis XIV, famously suffered from breast cancer. She died in 1666 after caustic remedies of arsenic paste and a butcherous attempt at surgery (without anesthesia, of course). As barbaric as treatments seem today—slash, burn, and poison—we have it a whole lot better than the king’s mum did.

Bernardino Ramazzini was a Renaissance-era doctor who sought to understand the causes of many diseases, not just their treatments. Born in Capri in 1633, shortly after the teachings of Galileo were banned, he is today considered the father of environmental health. In 1705 he published his life’s work, De Morbis Artificum Diatriba, or the Diseases of the Workplace. It’s a lively and, to modern eyes, very amusing work. One of his chapters is titled “Diseases of Cleaners of Privies and Cesspits.” That one makes me appreciate the writer’s life, until I come to “Diseases of Scribes and Notaries.” In it, he writes, “All sedentary workers … suffer from the itch, are a bad colour, and in poor condition.” That one made me get up and go for a hike.

Among the many things that interested Ramazzini were diseases of women, including midwives. In the archaic translation I have, most of the s’s look like f’s, rendering such pronouncements as, “Nurfes … are likewife fubject to various Difeafes in the Courfe of fuckling.” Old-language charms aside, Ramazzini astutely noticed that breast cancer was most common in nunneries. “You’ll scarcely meet with a monastery that has not fresh instances of this cursed [or curfed] plague,” he writes. He admits he does not know the reason, but he calls the breasts and womb the “Fountains of Letchery,” and speculates that it is the “mighty lascivious” among the nuns who will get cancer due to suppression of their sexual drives. Well, he was wrong on the reason, but his observation that nuns were the most vulnerable women remains a critical piece in the modern understanding of this disease.

Women of God did not have a lot of fuckling or suckling going on. What did that mean for the lecherous organs?

Turns out it was a good question. Even W. H. Auden pondered cancer in 1937: “Childless women get it / And men when they retire; / It’s as if there had to be some outlet / For their foiled creative fire.” Eventually, epidemiologists realized it wasn’t foiled creative fire as much as foiled reproduction that caused the trouble. It was childlessness, not celibacy per se, that increased cancer risk. It took centuries to figure out how hormones are made and used in the body, and in fact, we’re still learning. In the nineteenth century, doctors knew that breast tumors were often larger and more aggressive in premenopausal women, and they also figured out that an individual woman’s tumor was sometimes a different size before her period and after. By 1895, a Scottish physician named George Thomas Beatson had experimented with removing the ovaries of cows and pigs. He saw that doing so made their udders shrink, and he speculated that it might make breast tumors shrink as well.

Doubting the conventional wisdom that the nervous system controlled most bodily functions, Beatson presciently observed, “I am satisfied that in the ovary of the female and the testicle of the male we have organs that send out influences more subtle … and more mysterious than those emanating from the nervous system, but possibly much more potent than the latter for good or ill as regards the nutrition of the body.”

Beatson didn’t know those ovarian emanations were estrogen and progesterone. Nor did he know there were hormone receptors in breast tissue and in many tumors, but he witnessed the hormones in action. In the first woman whose ovaries he removed, her breast tumor retreated and she appeared cured. It seemed miraculous, and news of it made a huge splash. Unfortunately, Beatson also did not know that the body partly compensates for the loss of the ovaries by pumping out estrogen and progesterone-related hormones from elsewhere: fat tissues and the adrenal glands. Four years later, his patient’s cancer returned with a vengeance and she died.

It was only the beginning of a long and disappointing legacy of miracle cures turning out not to be so. But Beatson, like Ramazzini before him, was onto something.

Malcolm Pike, whom we met in chapter 7 tinkering around with pregnancy hormones, is a rare academic hybrid. A mathematician born in South Africa in 1935, he first migrated to Britain in 1956, studying with the famed epidemiologist Richard Doll. Epidemiologists are people who use statistics to study disease, and Doll was their dean. He was the man who established that lung cancer was caused by smoking cigarettes, a conclusion that may seem obvious in retrospect, but was far from it at the time. Arriving in California in 1973, Pike soon fell in with a group of American epidemiologists. By this time, breast cancer rates in the United States were increasing between 1 and 2 percent a year, a trend that was both surprising and baffling. In 1940, the number of women coming down with invasive breast cancer on an annual basis was 59 out of 100,000. By 1960, even after adjustments for an aging population, it was 72, and by 1990, it was 105 and rising, to the point where the disease now strikes 129 women per 100,000, or 1 out of every 8 women who reach old age. Worldwide, a quarter of all malignancies are breast cancer. The race was on—and still is—to figure out how breasts became so imperiled so fast.

Interestingly, though, Japanese women developed the disease at rates six times lower than Americans. The epidemiologists wanted to know why. They knew it wasn’t due to genes, because once Japanese women migrated to the United States, their daughters’ cancer rates caught up. Was it a virus, or perhaps something else contagious about the American lifestyle or diet?

Pike was familiar with the work of Beatson, and he suspected clues might be found in the difference between American and Japanese women’s reproductive lives. In 1980, he headed to Hiroshima for six months to study the archives of the Atomic Bomb Casualty Commission. In documenting minute details about survivors of the bomb, the commission’s medical records collected excellent data on everything from a woman’s age of menstruation to the number of children she had.

Pike and a colleague found that Japanese women in 1900 first got their periods at age sixteen and a half on average, meaning their ovaries kicked in more than two years later than those of their American counterparts. Their age at motherhood and the number of children they had were similar, but when Pike looked at weight, the data once again stood out. The average menopausal Japanese woman weighed just 100 pounds; the average American, 145. When Pike analyzed blood samples, he saw that rural Japanese women (and most were rural then) produced only three-fourths as much estrogen as American women.

“We wrote papers explaining that these things, menarche [age at puberty] and weight, might explain half the difference in breast cancer rates between the two countries,” Pike told me during a visit to his office in the Topping Tower of the University of Southern California’s Keck School of Medicine in east LA. As he saw it, American women were simply exposed to more estrogen and progesterone over their lives. Betrayed by their own ovaries and fat cells, these steroidal compounds were somehow causing more cancer.

As early as the 1930s, scientists knew that elevated estrogen levels triggered breast tumors in mice, but it had not yet been proved in humans. In the early days of hormone research, drug companies eyed it and other steroids greedily. Cortisone, for example, mimicking corticosteroids produced in the adrenal glands, was good for treating arthritis. If anyone suspected trouble with estrogen, they looked the other way as it was so promising commercially. Estrogen was known to promote bone density and soften the skin. It could perhaps prevent miscarriage.

Making these steroids in the lab was profitable but complicated. Commercially viable amounts of estrogen could be derived from huge quantities of pregnant horse urine and was first marketed in 1942. It’s still a main ingredient in Premarin, a drug given to menopausal women (more on that later). The first commercially viable quantities of progesterone and testosterone were isolated from wild Mexican yams in the 1940s. Progesterone is a natural hormone made mostly by the corpus luteum in the ovaries, and later, if pregnancy occurs, by the developing placenta.

The word hormone comes from the Greek word meaning “to urge on.” Like other hormones, progesterone travels with its commanding messages through the bloodstream. Among its many powers, it inhibits the release of additional eggs so that we get pregnant only once at a time. During our Pleistocene past, it wouldn’t do for us to be gestating many more than one or two fetuses simultaneously. (This is in contrast to, say, tufted-ear marmosets, who often bear twins and triplets sired by different fathers. The upside to this clever system is that many males in marmoset-land tend to be stellar dads and upstanding citizens, each thinking all babies in the troop are his.)

Progesterone’s uncanny ability to prevent ovulation caught the eye of mid-century drug companies seeking a better source of contraception than condoms, coitus interruptus, or the rhythm method. The latter technique requires timing sex to avoid a woman’s fertile days. Although condoned by the Catholic Church, it was known as Vatican roulette for its failure rate. There was clearly a demand for reliable contraception. But medical progesterone had to be given by daily injection or it wasn’t strong enough. A Big Pharma contest was on to find a way to make it potent enough to deliver by mouth.

Chemist Carl Djerassi, considered the father of the pill, describes the quest in his 1992 memoir, The Pill, Pygmy Chimps and Degas’ Horse. Born the son of a syphilis-specializing physician in Austria in 1923, he fled the Nazis to arrive in New Jersey as a teenager. By his mid-twenties, he was heading a lab in Mexico City for the pharmaceutical company Syntex. There, in 1951, he successfully fabricated a crystalline progesterone by rearranging some of the bonds of another synthetic hormone. “Not in our wildest dreams did we imagine that this substance would eventually become the active progestational ingredient of nearly half the oral contraceptives used worldwide,” he wrote. It would become the pill known as Ortho-Novum.

G. D. Searle brought a similar product to the market first, in 1960, under the name Enovid. It was tested on rats, monkeys, and women in Puerto Rico (because many U.S. states banned birth control at the time). By 1970, ten million healthy American women swallowed a little magic pill every day. That’s when Congress, swamped by complaints of the pill’s side effects—everything from nausea to headaches to fatal blood clots—held a series of safety hearings. As the scientists were learning, the ways hormones worked in the body were far more complicated than they appeared. Drug companies had tweaked the original progesterone-only formulation to include estrogen to prevent “breakthrough” bleeding between periods, a discovery that had been made by accident. But hormone doses in the first combination pills had to be high to ensure protection from pregnancy.

In electrifying testimony, Roy Hertz, a physician and scientist with the National Institutes of Health, denounced the pill as an experimental drug and warned of carcinogenic effects. “Estrogen is to cancer what fertilizer is to the wheat crop,” he declared. Sales immediately dropped 20 percent.

Even though new, differently dosed pills would continue to be very popular, Djerassi knew the days of fast and heady progress in the field of synthetic hormones were ending. In 1973, the famed organic chemist opened a fortune cookie in San Francisco that summed it up: “Your problems are too complicated for fortune cookies.”

AROUND THE SAME TIME AS HIS TRIP TO HIROSHIMA, PIKE wondered if the pill could be contributing to rising breast cancer rates. He knew the pill’s progesterone substantially decreased the risk of ovarian cancer because in preventing the ovaries from releasing eggs, it effectively stopped cellular division and growth. (In the middle of the menstrual cycle, the ovary literally rips open to send forth an egg and then must repair itself.) But progesterone did nothing to prevent cellular changes in the breast, and in fact, it was known to cause changes in the breast. For many years, estrogen was fingered as the primary culprit in breast cancer, because it was known to cause cancer of the uterus in lab studies and also to make human breast cancer cells grow faster in a Petri dish. But it turns out that progesterone is just as bad, and possibly worse, for stimulating cell growth and division.

Whenever a cell divides and replicates, it invites errors, or mutations. Enough mutations (you need a bunch) will send cancer on its inexorable course. Pike’s theory was that the more menstrual cycles a woman has in her lifetime, the more her breasts are flooded with whiplashing hormones. But when a woman is pregnant or breast-feeding—as was normally the case for much of her reproductive life before industrialization, or unless she was a nun—her breast cells usually behaved in cancer-protective ways.

“The problem with women today is they reach puberty at twelve or thirteen and don’t have a baby until they’re thirty-five,” said Pike. “That’s extraordinary! It’s incredibly non-evolutionary!” He’s right; anthropologists have studied the cycling histories of contemporary hunter-gatherer cultures, believing they provide some insight into how early humans lived. Dogon women in Mali don’t reach puberty until the age of sixteen, and soon after, they marry. They spend much of their adult lives either pregnant or nursing (they breast-feed each child an average of two years). They ovulate approximately one hundred times during their life. Women in Western nations ovulate, on average, four hundred times. Today in America, nearly 20 percent of women between the ages of forty and forty-four have never borne a child, a figure that has doubled just since 1976.

Pike scribbled down some charts and pictures for me on scrap paper and printed out articles on his printer. At seventy-four, he is tall and lean and generously bearded, like Santa after a crash diet. When I first Googled him, the top document was a marketing article from the University of Southern California calling him “the dashing Malcolm Pike,” and it stuck in my mind. He speaks in a strong, lilting South African accent and enjoys asking Socratic questions. Having grown up in Johannesburg under apartheid, Pike is an arch proponent of tolerance and open debate. He clearly enjoys taking conventional wisdom apart.

“The pill,” he continued enthusiastically, “gives you hormone levels every day that look like the levels after you’ve ovulated. It was a brilliant pathologist in Scotland who showed us that there’s more cell proliferation in the breasts in the second half of the cycle.”

“I could have told you breast cells are more active after ovulation,” I said, thinking the genius in Scotland was a bit overrated.

The dashing Malcolm Pike raised his eyebrows. “How do you know?”

“Because they hurt! They get bigger. They’re inflamed,” I said.

“Ah!” said Pike. “But how do you know?” he repeated. “How do you know that’s not just water? You can’t feel cell proliferation! We had to see it in a dish!”

Well, I thought, if that’s the way scientists need to do it, fine.

The reason breasts become bigger and more tender after ovulation illustrates how strongly these organs are geared to procreation. Every time an egg pops out of the ovary, the body is preparing for the big event, whether fertilization actually takes place or not. Progesterone courses through our cells to help prepare the uterine wall and to begin growing the dairy machinery in our breasts. It may seem overzealous to do this nine-plus months ahead of time, but in fact the breast needs every possible minute to get up to speed.

In any case, by the mid-1980s, Pike was publishing papers showing that women who began taking the pill as teens, before bearing children, doubled their risk of breast cancer before age forty-five. If they took the pill for eight years before becoming pregnant, they nearly tripled their risk. Captive tigers and lions also suffer from mammary and uterine cancers after taking oral contraceptives.

Between 1986 and 1989, a handful of studies in Europe and New Zealand confirmed Pike’s human data, although other studies showed the pill added a smaller risk of breast cancer. I told Pike I took the pill starting when I was eighteen. By then, in the mid-1980s, manufacturers had introduced lower-dose pills, despite insisting all along that the original formulation was perfectly safe. Today’s oral contraceptives contain one-fifth the hormone levels of the original.

“So has the pill transformed your breast?” he asked, anticipating my question. “We don’t know. How would you ever find out? You have to stick needles in people to look at breast tissue. We’ve been extremely reluctant. If we could look at 180,000 women, we’d understand.”

Just when I was starting to feel the dread of past mistakes, he asked, “How long did you take the pill?”

I shrugged. “About four years,” I said.

“We think the risk of breast cancer goes up for about ten years after you stop,” he explained. “So there’s probably no more risk for you. Now, whether it did you any good, we don’t know.”

Pike was untwisting a green paper clip, working it into a rough quadrangle. “We know it’s protecting you from ovarian cancer.”

I told him that after I stopped the pill, it took me six months to start ovulating again. He looked elated. “That four years you were on the pill was like having four babies when you were young!” he said. As far as my ovaries are concerned, that’s a good thing.

But before breaking out the cigars, Pike turned again to breast cancer. If the pill gave him epidemiological heebie-jeebies, so did hormone replacement therapy, or HRT. Like the pill, this therapy supplied extra daily doses of menstrual hormones, estrogen and later estrogen-plus-progesterone, but to women whose ovaries were no longer making them. As early as 1982, Pike was worried about HRT. He published papers, but, as he tells it, they met with thunderous silence. By 1992, Premarin (the name stands for pregnant mare urine) was one of the most widely prescribed drugs in America, given to 11 million menopausal women and earning its happy makers nearly $2 billion a year. To create the unprecedented demand, drug companies and physicians appealed to women’s vanity and reason, essentially inventing a new pathology called menopause in the same way the surgeons had invented one called micromastia, for small breasts.

As one physician told the New York Times in 1975, “I think of the menopause as a deficiency disease, like diabetes. Most women develop some symptoms, whether they are aware of them or not, so I prescribe estrogens for virtually all menopausal women for an infinite period.”

He had good company. In 1966, the prominent gynecologist Robert Wilson wrote an influential bestseller, Feminine Forever, in which he called menopause a state of “living decay” that makes women fat, moody, and saggy. He wrote that women “rich in estrogen,” by contrast, “tend to have a certain mental vigor that gives them self-confidence, a sense of mastery over their destiny … and emotional self-control.” Estrogen therapy, he wrote, “makes women adorable, even-tempered, and generally easy to live with.”

Not unlike the anthropologists who believe that women’s breasts exist for men, many mid-century doctors thought that women’s moods, sexuality, and general perkiness should be engineered, artificially if need be, to suit male preferences.

By now there has been much debate about whether menopause is evolutionarily adaptive—in other words, is there something useful about it?—or whether we’re really designed by nature to just wither up and die after our ovaries wear out. A common refrain is that we’re more or less supposed to get cancer simply because we live so unnaturally long. I won’t go much into the fray, but one of my favorite rejoinders, the “grandmother hypothesis,” is well defended by anthropologist Sarah Blaffer Hrdy. In her book Mothers and Others, she explains that our ancestors often lived past the age of reproduction, and those grannies were in fact critical to the survival of their progeny for most of human history. Far from being a medical malady, menopause is a highly adaptive mechanism to free up older females to help feed and care for their grandchildren. No creature on the planet is more costly than the human child, who needs a ridiculous amount of time to grow up; without extra hands to supply the thirteen million calories needed until maturity, our species would not have made it this far. Women are supposed to outlive their ovaries after all, concludes Hrdy, with breasts happily intact.

Still, given the choice, who wouldn’t want to have smooth skin and be adorable forever? Estrogen, miracle hormone that it is, does indeed relieve such symptoms as hot flashes, night sweats, and depression, which are experienced to a serious degree by 5 to 15 percent of menopausal women. This is the group that probably should have been targeted for risky drugs, but that wasn’t nearly as profitable as targeting the entire sex.

When uterine cancer was linked to estrogen therapy in 1980, drug makers responded by adding progesterone to the formulations. Then numerous studies in the 1980s and 1990s linked other complications to HRT. In 1991, researchers launched the fifteenyear, $100 million Women’s Health Initiative Study, but they abruptly halted part of it in 2002 when they discovered that the women taking HRT (as opposed to a placebo) had a 26 percent increase in the incidence of breast cancers, a 41 percent increase in the incidence of strokes, and a 29 percent increase in the incidence of heart attacks.

Britain was also conducting studies. Its Million Women Study, the largest study of HRT, yielded data in 2003. Results showed that women who were taking both estrogen and progesterone had a 100 percent increase, or a doubling, in their risk of breast cancer. The main culprit appeared to be progesterone, just as Pike had shown years earlier. Estrogen alone created a smaller breast cancer risk, and more recent studies suggest it might actually protect against breast cancer, but, alas, not against uterine cancer. Typical of the unpredictable ways hormones work their magic (and harm), HRT’s added progesterone helped minimize one cancer (uterine) but exacerbated another—breast cancer. Overall, hormone therapy in Britain caused an additional twenty thousand cases of breast cancer during the decade of the study, which is still a relatively small added risk, but enough to give many women pause.

Although researchers had known for years that synthetic hormones were linked to breast and other cancers, it really wasn’t until these two huge studies in 2002 and 2003 that the knowledge finally stuck. To the dashing Malcolm Pike, that time lag was nothing short of tragedy. “People say, ‘Aren’t you proud? You spotted the danger early,’ and I say, ‘No, because our work didn’t stop it,’ “ he said. “Why?” He shrugged. “Doctors are not particularly nervous, and they like prescribing things,” he said.

But the answer also lies upstream, with the pharmaceutical industry, which has a zeal for profit and a masterful command of the regulatory landscape. These are traits it shares with the chemical industry. Both came of age in America at the same moment in time, often using very similar molecules.

It all adds up to a new ecology of the breast. Here’s the basic cheat sheet for how the risk of breast cancer has changed over the ages. Old days: We did not have so much exposure to cycling estrogens and progesterones (we were thinner, hit puberty later, had more children, dropped dead earlier). Modern times: We’re awash in steroidal hormones. We’re fat and sexually precocious, but have babies late if it all. We take the pill and “bio-identicals,” slather novel, untested chemicals on our bodies, and consume them through food and water. We’re pretty much marinating in hormones and toxins.

Just as our long environmental legacy as synapsids, mammals, and primates shaped our cellular past, our modern environment— in the largest sense of the term—is determining our cellular destiny.

But you don’t have to be in the sway of synthetic or natural hormones to get breast cancer. You don’t even have to be a woman.