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THE PREGNANCY PARADOX

The beginning is glorious … suddenly they begin to grow … breasts fantastic tender apricot breasts, then charming plucky firm tangerines, and then, just as you were on the verge of peaches, oranges, grapefruits, cantaloupes, God knows what other blue ribbon county-fair specimens, your stomach starts to grow and the other fruits are suddenly irrelevant because they’re outdistanced by an honest-to-God Watermelon.

— NORA EPHRON,
Heartburn

OFTEN, WHEN A WOMAN BECOMES PREGNANT, SHE FIRST knows it by her breasts. They hurt and tingle as if someone just plugged them into a sound amp. And they grow, of course, doubling their weight and size, and the nipples enlarge and grow darker. I rejoiced in the physical changes of pregnancy. I loved my new growing shape, even liked the maternity clothes, except the granny underwear. I didn’t gain much weight in pregnancy and it took me a while to start “showing.” I was so thrilled when the first person who didn’t know I was pregnant asked if I was. “I can just tell,” she said knowingly.

I also enjoyed the bigger bustline, no doubt about it. Those new breasts cracked me up. It was as though I’d borrowed someone else’s. I was partly right; the breasts weren’t really the same. They weren’t just my old breasts on hormones. Those county-fair specimens were in fact different breasts. It’s something I’ve said before, but it’s so cool I’ll say it again: these are the only organ in the body that is not fully grown by adulthood. Breasts grow up when there’s a baby cooking one story down.

Biologically, this is interesting. Medically, it’s an epiphany. For at least several decades, researchers have known that the changes wrought by pregnancy protect those breasts from cancer. Lately, they’ve been wondering when we might be able to imitate, bottle, and patent that protection.

That quest has long motivated Irma and Jose Russo, whom we met in the last chapter, and Malcolm Pike, an epidemiologist at University of Southern California and Memorial Sloan Kettering Cancer Center. They and others have been studying the protective effects of hormones on tumors and thinking of ways to mimic pregnancy, because, as Pike puts it, “making every girl have a baby at fifteen is just not going to happen.” Perhaps the most we can ask for is a sort of medically induced hysterical pregnancy, or an immaculate conception minus the baby. If every young woman could just experience a simulated blast of pregnancy juice, she would be protected for life against breast cancer. Sure, she might have some strange cravings (and sore breasts) for a time, but well worth it. Pregnancy hormones, it turns out, are shockingly good cancer-preventing drugs, at least if you get the hit early in your reproductive life.

Here’s what we know: a woman who has her first child before age twenty has about half the lifetime risk of breast cancer as a nonmother or a mother who waits until her thirties to have children.

These statistics have played out in my family as in so many others. My grandmothers and great-grandmothers were unusually early adapters to the modern notion of having children late. My mother’s mother, Carolyn, wanted to be a judge. She graduated from Stanford Law School in 1926. She joked that there were so few women around, she could have a different date every night. Unlike most women of her generation, she was willing and able to put off marriage and children. After Stanford, she shared a law office in San Francisco with her stepfather. In her late twenties, she fell in love and married a young lawyer from Buffalo, New York. At twentyeight, she had her first child, and then two more.

My other grandmother, Florence, a Chicagoan, married long after her compass was pointing firmly to spinsterhood. She fell in love late, with a tall Virginian, and had her first child at age thirtythree. These days that age seems perfectly normal, but in the 1930s the average age of first-time motherhood was 23.7. Before 1960, nearly one-third of American females had their first child before reaching age twenty. The pill changed all that. Since 1970, the percentage of women having their first children at age thirty-five or later has risen eightfold.

Carolyn, my lawyer grandmother, was first diagnosed with breast cancer in her sixties. She recovered, but the disease struck back in her eighties and ultimately killed her. Florence wasn’t so lucky; just before her sixty-first birthday, she died of ovarian cancer, which is often linked genetically to breast cancer. Her mother had died of breast cancer in her fifties, and she had given birth to her first child at age twenty-nine. My mother, in contrast, had her first child, my brother, when she was eighteen, in 1950, well before effective birth control would become widely available to unmarried women. She didn’t get breast or ovarian cancer, but she did succumb to a blood cancer in her sixties. Lately I’ve been wondering if her reproductive history might actually have helped her. Her early pregnancy interrupted her career, but it might have extended her life.

Knowing that I and so many of my peers had our first children well into our thirties, I’m both unsettled and intrigued by the power of pregnancy. The age at first pregnancy is now considered one of the most salient risk factors for breast cancer. In the life cycle of breasts, pregnancy is their defining get-out-of-jail card. If you draw it early, you’ve done as nature intended, and you’re rewarded. If you arrive late or not at all, nature is less forgiving, for reasons scientists are now uncovering.

SO WHAT’S SO GREAT ABOUT PREGNANCY, FROM A BREAST’S PERspective? Aside from the happy boost in bra sizes, the answers aren’t clear. The body is flooded with sky-high levels of estrogen, progesterone, and HCG, or human chorionic gonadotropin. This is what dime-store pregnancy tests measure, since HCG levels spike only in pregnancy. Different scientists disagree on exactly what the magic ingredient or combination of ingredients is and what exactly those hormones are doing. Something about pregnancy rebuilds the breast and armors it, by changing the architecture of either the cells or the proteins around them. One leading theory is that when the breast becomes fully mature by the end of pregnancy, its stem cells, which have been quiet, “differentiate” into cancer-resistant, highperformance dairy equipment. Even after weaning, the protection remains. But when the stem cells are waiting around for decades for their dance card, they’re either weaker or just more likely to proliferate into cancer. And in a woman who’s never been pregnant, her breasts remain undifferentiated for life.

“Women are so delicate,” murmured Jose in his thick accent as he explained this to me.

“Yes, we are,” shrugged Irma. “It’s not sexist. It’s our hormones.”

In addition to studying the “window of vulnerability” that occurs around and after puberty, the Russos are also looking at the long cone of protection around pregnancy. Both pathologists, they are expert at picking out minute changes in tissue and cell structure and, in fact, seem to see things others can’t. They first noticed dramatic changes occurring in rats, in which mammary cell changes are more obvious. Just as in people, lab rats that have been pregnant are less likely to get breast cancer. In one experiment, the Russos exposed “virgin” rats to a cancer-causing chemical. Some rats, however, had been primed with pregnancy-level HCG hormones. As the Russos suspected, those rats were the lucky ones. Their cancer cells divided less, their mammary cells shut down estrogen receptors, and they expressed more cancer-fighting genes.

I COULDN’T HELP BUT WONDER IF THE PREGNANCY-AS-PREVENtion evidence might bolster the theory that many breast cancers are environmental in origin. If the breast is being “armored” in pregnancy, it’s being armored against something. The lab experiments use chemical carcinogens to trigger cancer. The mother rats are protected while the virgin rats aren’t. In humans, known genetic factors account for only about 10 percent of all breast cancers. On the one hand, you could argue that delayed childbirth “causes” cancer. But isn’t that because something else is really causing cancer in unprotected tissue? I asked Irma about this.

She cautioned that we really don’t know what causes breast cancer. But, she said, “from about the ages of twelve to thirty-five, from puberty to first pregnancy in many modern women, is a huge window to get exposed to radiation, alcohol, tobacco, phytoestrogens, xenoestrogens, and all the suspected carcinogens accumulating in the breast. If the same woman gets pregnant or gets the right hormones around puberty or a little later, the breast will mature and be more protected.”

When I visited the Russos’ lab in Philadelphia, their collaborator, Colombian scientist Johana Vanegas, showed me what was actually happening to the cells in the presence of pregnancy hormones. The rats’ mammary glands had been removed and then put through a mini-meat-slicer-type contraption. Then the slices had been dyed dark pink and splayed out on small glass slides. I peered into an Olympus stereomicroscope to see some sections taken from rats that had never been pregnant. These “immature” glands looked like purple flower buds painted with a broad watercolor brush. Next I looked at the HCG-fed glands. These looked very different. The buds had transformed into the tiny petal dots of a pointillist painting. The immature glands represented by the watercolor image, at least in a rat, are called “terminal end buds,” and they represent the undifferentiated state of cancer-vulnerable cells. Watercolor buds: bad. Pointillist petals: good.

The Russos say they can see the same thing happening with human breast sections under a microscope, although it’s a controversial observation. They call the smooth never-pregnant glands “lobule type 1” and the late-pregnancy pointillist florets “lobule type 4.” In the early and mid stages of pregnancy, you get the inbetween lobule types 2 and 3. The higher the number, the more protected the cells. Among other things, lob 1 has more receptors for estrogen and progesterone, which, as we’ve seen, can be an entrance ramp on the cancer highway. Jose points out that the genomic signatures of the different lobes change dramatically as a woman cycles through pregnancy and beyond. Both full-on pregnancy and just a dose of HCG activate good-cop (tumor suppressor) genes, stop cell growth, and turn on other cancer-fighting genes, presumably for life.

Why for life? Because after pregnancy and lactation, the pointillist petals dissolve and revert to smoother buds, but these lobules tend to remain hardy types 2 and 3, say the Russos. If, as they speculate, cancer originates in lobule type 1, that would explain the protection offered by pregnancy: fewer type-1 lobules, fewer chances of cancer.

I’D HAD A GUT SENSE THAT PREGNANCY WAS CHANGING ME IN profound ways. Those mysterious hormones were bathing me in bliss, altering my core chemistry in a way that would prepare me for parenthood. Although I’d felt some ambivalence about what life would be like after having a baby, I’d wanted a child. I’d suffered a couple of years of miscarriages and failed conception, and now I was thirty-four. I’m sure part of my happiness was pure relief. But now I appreciate the power of the hormones, which seem, in retrospect, to have acted on nearly every cell in my body.

The thought of chemically mimicking this experience for a possible faraway health benefit gives me pause. But for some women, such as those who know they are carriers of breast cancer genes, playing with the ephemera of pregnancy might be worth it.

The Russos have begun testing their patented HCG regimen in eighteen high-risk women who have never been pregnant. The women will take HCG for three months, and then the Russos will compare their before-treatment and after-treatment genes to see if they’ve changed from a “high-risk signature” to a low-risk one. Natural HCG is made by the developing embryo, so the Russos get theirs from a synthetic process. HCG has some bizarre properties, including stimulating plant germination. The hormone has been tipping women off to their pregnancy status since 1530 BC, when Egyptians in the eighteenth dynasty watered seeds with their urine. If sacks of wheat and barley sprouted, a woman knew she must be pregnant. Today, some weight-loss clinics administer HCG because it’s believed to help reduce abdominal fat when combined with a calorie-restricted diet (the better to feed a phantom placenta). MTV reality star JWoWW even sells it on the Internet. She gushes, “While on the HCG diet you will sleep sounder and feel better than you did before!”

In the Russos’ trial, the women have noticed getting thicker, luxuriant hair, some weight loss, and a feeling of well-being and energy. “The ladies say they have a glow,” said Irma.

Down at Texas Tech University Health Sciences Center in El Paso, pathologist Raj Lakshmanaswamy is a fan of using therapeutic estrogen rather than HCG to mimic pregnancy. (I know what you’re thinking: if early puberty is any clue, estrogen is bad for breasts, but the reality is more complicated than this. While estrogenic substances may indeed be bad for the youthful, developing breast and the breast that already has tumors, estrogen has been given a worse rap than it deserves. I’ll talk more about this in chapter 12.) Lakshmanaswamy envisions a hormone patch that women can apply for just three months in their early twenties to protect them from breast cancer. “We’re talking about levels equivalent to the low end of pregnancy levels,” he said. “It shouldn’t cause any problems for that short a time. We’re not there yet, but this is my feeling right now, that it can be done.” Unlike the Russos, he hasn’t patented this idea, saying he’s more interested in basic science.

In LA, Malcolm Pike’s team is looking at the breast tissue of women who have already received high doses of pregnancy hormones. These women are patients in fertility clinics who are taking mega hormones to help them “hyper-ovulate,” or produce a large number of eggs for in-vitro fertilization. “Does that change their breast?” asked Pike. “We don’t know. You just have to do the hard thing, which is to study women. We do know egg donors have the breast-stimulating equivalent of three months of pregnancy in just one week of taking hormonal drugs. How does it happen and can you mimic it in smaller doses? They get a tremendous biological effect very, very fast. It’s possible it happens in just two to three days. We need to check them again a year or two later and see if the same differentiation is there.”

A major challenge in developing a fake-pregnancy drug is finding the right dose. “When you’re pregnant, you have astronomical levels of steroids,” Pike continued. “Absolutely astronomical. Before pregnancy, you might have 100 units of estrogen in your blood, and when you’re pregnant, you’d have 10,000 units or more. If I gave you that by mouth, you’d die. So a number of us are fiddling with it. It will still be a long time in the future. It’s the early days yet of chemoprevention.”

THE PREGNANCY EFFECT SOUNDS LIKE A SLAM DUNK: YOU GET high levels of hormones, you’re protected for life! Except that it’s not a slam dunk. There’s a lot of fine print. For example, the abortion exemption. You might think that if these pregnancy hormones are so great, then women who’ve had abortions are also protected, because they too enjoyed the spiking hormones of early pregnancy. The evidence, though, seems to suggest that this does not happen. Some years ago, a distinguished researcher named Janet Daling published results of a study suggesting that women who got abortions before the age of eighteen were more likely to get breast cancer, not less. A few other studies found similar results. The right wing seized upon this data, gleeful to have another reason to condemn abortion. Pro-life groups even sought legal action requiring that abortion be mentioned as a cause of breast cancer to any woman seeking abortion. Early in the George W. Bush administration, the federal National Cancer Institute’s website proclaimed that abortion could increase a woman’s risk of breast cancer.

Then in 2003, the National Cancer Institute convened a panel to sort through the evidence. It concluded that abortion did not increase a woman’s risk, and that studies to the contrary were damaged by “recall bias,” one of the notorious bad sisters of scientific method. Here’s how these studies are typically conducted: You interview a bunch of women, say in their fifties, some of whom have had cancer and some of whom haven’t. The catch is that the ones with cancer are much more likely to come clean about past indiscretions. In other words, as Pike described it to me, “abortion gives you breast cancer if you’re Catholic, but doesn’t if you’re not.” It appears the non-cancer Catholics simply lied about past abortions. Ah, the joys of epidemiology! No wonder these things are hard to sort out.

In any case, no one can claim that abortion protects you from cancer, nor do natural miscarriages. It seems a full-term pregnancy is needed for the breasts to fully differentiate. Which renders the high-dose, short-term faux-pregnancy therapies a big question mark, to say the least.

…

AROUND ABOUT THE 1980S, SOME DOCTORS BEGAN NOTICING AN unexpected pattern: young women who had been pregnant in recent years were getting breast cancer. Rather than being protected by pregnancy, some women were experiencing the opposite. These women tended to be relatively older when they had their first child, and they tended to suffer from premenopausal breast cancer. What if the protective effect of pregnancy was just a myth or, at best, a historical relict?

In the mid-1990s, Pepper Schedin was, like so many other researchers, studying the storied protection offered by pregnancy. Everyone knew the breast goes through massive changes in pregnancy, but Schedin thought it might be worth looking at the massive changes that occur after pregnancy (or for those women who breastfeed their babies, after lactation), when the breast regresses back to a “resting” state. This process is called involution, or the massive loss of cells and structures that were part of the dairy machinery. In fact, 80 percent of the glorious pregnant breast gland simply disappears. Its ability to practically vanish overnight is yet another unique and strange feature of breasts. Schedin thought perhaps this was why mothers might not get breast cancer; perhaps nascent tumors were zapped out during this epic house cleaning.

She ran some experiments and found that while normal cells were indeed killed during involution, breast cancer cells were, startlingly, promoted. “Oh man, was that a surprise,” she said. Just around that time, Schedin was contacted out of the blue by an old friend who had recently borne twins. The friend, who was in her thirties, had just been diagnosed with metastatic breast cancer. “I thought, huh, that’s strange. It went against everything I’d ever heard. Pregnancy was supposed to be protective. Nobody ever mentioned it wasn’t. So I went back and looked in the literature, and there it was: a small body of work on pregnancy-associated breast cancer, and no one knew why it was happening.”

As far back as 1880, Samuel Gross, the surgeon subject of the celebrated Thomas Eakins painting Gross Clinic, noted that after pregnancy, breast cancer “was wonderfully rapid and its course excessively malignant.”

The phone call changed Schedin’s life. She now works in the young woman’s breast cancer program at the University of Colorado’s Anschutz Medical Center in Denver. Her office was decorated with framed photos of mammary gland cells and a giant poster of the well-known U.S. Postal Service breast cancer stamp. On a corner of her desk sat a 1915 microscope that her brother found in a junk shop.

Over the years she has made some interesting discoveries, most having to do with how the molecules of the breast talk to one another during involution. Remember, the breast gland doesn’t just perch in an empty vacuum. It’s a resident in a busy neighborhood filled with fat, collagen, and extracellular matrix, a rainstorm of proteins, hormones, and other material. Schedin has found that during involution, this matrix orchestrates a type of inflammation. Most of us are familiar with inflammation—it’s what happens when a paper cut gets red and swollen or when we bump into the table and get a bruise. Immune cells rush to the injury and help repair it and battle infection. A similar thing happens to the retreating breast gland after lactation: macrophage immune cells swarm in to help clean the old gland and remodel the remaining tissue.

The problem is that sometimes our milk ducts have weird little not-quite-normal growths in them. Usually it’s not a big deal, but sometimes these growths, or lesions, break free of the duct for reasons nobody entirely understands, tap into blood veins for nutrients and oxygen, and grow like bananas. Hello, cancer. This jailbreak appears able to happen during involution, promoted by the inflammatory environment. Schedin calls this the “involution hypothesis.” It’s just a theory, one of several, but she likes it. Older women are more likely to have these precancerous lesions in their ducts (perhaps thanks to their long years of environmental exposures); hence they’re more likely to unleash cancer after their pregnancies.

So while young mothers may indeed be protected by pregnancy, old mothers are not. In fact, mothers who give birth after thirty have a slightly higher risk of breast cancer than women who never have children. That’s right: if you heard nuns had it bad, older moms have it worse. And the types of cancers these moms get are more aggressive. A study in 2011 found that the more times a woman gives birth, the higher her risk of “triple negative” breast cancer. A cancer subtype making up about 10 to 20 percent of all breast cancers, these tumors do not express receptors for estrogen or progesterone, meaning they are more resistant to treatment and more deadly. (By contrast, postmenopausal breast cancers tend to be slower growing and can often be treated with hormonal therapies.) Women who have never given birth have a 40 percent lower risk of this type of breast cancer.

For the legion of us who had kids late in the game: bummer. Fortunately, pregnancy-associated breast cancer, called PABC, is still quite rare. In the United States, about 3,500 cases are reported per year, but under the standard definition a cancer has to be diagnosed within one year of pregnancy. Schedin fiercely disputes this definition and says pregnancy-related factors are still very much at work for many years after delivery. She thinks the risk goes up for five and maybe even ten years after pregnancy. “It’s far more common than the stats let on,” she said.

Sturdy and fit, with shoulder-length brown hair and glasses, she walked me through the eighth-floor lab overlooking east Denver. We passed a bank of freezers calibrated to –80 degrees Celsius (–112 Fahrenheit), the magic temperature for preserving the code of life, the RNA, in tissue samples. The tissue culture room smelled vaguely of cough syrup and sported a photo on the wall of a goofylooking baby wearing a pink hat, below which exhort the words “Find a Cure before I Grow Boobs.” The scientists here know they’re working to help real people, thanks to their partnership with the university hospital and the young women (generally under forty) who proffer their cancer cells for research. In return, the lab tries to come up with therapies that will help these women before another forty years go by in the war against cancer. Schedin called this mission “Bench-to-Bedside.”

If she’s right and inflammation is causing trouble, Schedin wants to know what happens if you reduce it by taking ibuprofen, or fish oil, or other anti-inflammation substances. She’s setting up a trial to find out. Another translation to the real world Schedin is willing to bet on: new mothers should get screened for breast cancer. Right now. They make up another high-risk group, she said, just like women over fifty or women with a family history of the disease.

She finds it unfortunate that the pregnancy-as-protective camp dominates much of the field. A street-tough Chicago girl who litters her words with expletives, Pepper is aptly named. “Not everyone agrees with me, but we need to let the science speak for itself,” she said. “Pregnancy-associated breast cancer is too devastating to ignore.” She’s grateful that her work has led her to think of the breast in a whole new way, as a highly responsive organ whose signals get easily crossed. “I consider the gland plastic and poised to respond to signals because it needs to be quick to respond to pregnancy,” she said.

If the breast needs to be responsive in pregnancy, it’s because it’s preparing for its big-night out, its very raison d’être: breast-feeding. All its 200 million years of evolution and all its individual months and years of construction and signaling and wiring are for this event. Nowhere is the breast more responsive and more conversant and more mind-blowingly intelligent than where there’s an actual baby on tap.