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Not long ago, Marianne Legato recalls, a scientist reported his preliminary findings from tests of a new compound on laboratory ratsall male. "What happens in females?" she asked.
"The same," he replied.
"How do you know?" she inquired.
"Because females respond just like males," he answered.
"But how can you be sure if you haven't tested females?" she pressed. Flustered, he insisted that he "just knew."
"I couldn't understand how he could possibly be so sure," Legato says. "Then, finally, it dawned on me: Dolly the sheep wasn't the first clone, Eve was. This man still assumed that women are essentially small men." (No one ever thinks of the converse: men as large women.)
A lack of actual proof for their premises has never gotten in the way of medical experts' assumption that they "just know" the way women are. Aristotle "just knew" that women nursed their babies with blanched menstrual blood stored in their breasts. Medical illustrators in the Middle Ages "just knew" that women were duplicates of men with an inside-out penis for a vagina, an inverted scrotum for a womb, and testicles for ovaries. Voltaire "just knew" that "the delicacy of women's limbs render them ill-suited to any type of labor or occupation that requires strength or endurance." Physicians of the late nineteenth century "just knew" that removal of a woman's ovaries was the best way to "repair" mental disordersthe reason, according to an 1889 report from the U.S. Surgeon General, for 51 percent of such operations.
Even today doctors routinely perform tests, prescribe drugs, and recommend treatments on the assumption that they will be as effective and beneficial for women as for men. How do they know? The truth is they often don't. From 1977 to 1993 the FDA banned women of childbearing potential from participating in the safety tests of new drugs to prevent possible damage to their unborn children and reproductive capacity. To scientists, this offered an advantage: They did not have to take into account such messy variables as women's fluctuating hormones or monthly cycles. As exclusion of women from all sorts of medical testing became common, this ban extended even to women who'd undergone sterilization or were past reproductive age. In a further attempt to keep the science "clean," laboratory researchers experimented only on male animals. As a result, in the landmark studies that shaped many modern medical practices, females were written outand off.
The landmark Multiple Risk Factor Intervention Trials (known, aptly enough, as Mr. Fit), which studied vulnerability to heart disease, the number-one killer of both sexes, included 12,000 to 15,000 menand no women. The Physician's Health Study of the potential benefits of taking an aspirin a day to lower the risk of heart attack looked at 22,071 physiciansnone of them women. A major evaluation of coffee intake and its impact on stroke and heart attack studied 45,589 menand no women. Only in 1998 did researchers discover that HIV tests misstate a woman's need for treatment. Even when a woman and a man have the same amount of virus in their blood, the woman is at a more advanced state of infection and at much greater risk of developing AIDS. Incredibly, even a study of the impact of obesity on the risk of breast and endometrial cancerfemale diseasesextrapolated from only male subjects.
Agingsomething women do better, or at least longerhas been primarily studied in men. In 1958 the federally sponsored researchers who launched what was to become the Baltimore Longitudinal Study of Aging decided not to include women, even though they make up two thirds of the elderly and more than 70 percent of the old old (those over age eighty-five). The reason was what former congresswoman Patricia Schroeder, one of the first champions of women's health research, dubbed "the rest room excuse."
At the time, the investigators had to work out of a single room at the city hospital. The study participants had access to only one rest room, which they had to share with elderly male patients in an adjacent hospital ward. Rather than ask women subjects to use this facility during overnight evaluations, the scientists excluded them altogether. As the budget for this high-profile project grew, the researchers acquired more spaceand more rest rooms. However, for twenty years their studies included no womenan omission that did not keep the scientists from entitling their initial four-hundred-page report Normal Human Aging.
The very fact that research never took women's menstrual cycling into account has created a black hole in scientific understanding of femaleness. We know that women's bodies work differently at various times of the month, that temperature fluctuates, that fluid volume and weight increase, and that food moves through the digestive system at different rates. But only recently have physicians realized that various diagnostic tests, including cholesterol and blood fat measurements, yield different results at different times of the month and that the timing of medical treatments during a woman's cycle can affect their efficacysometimes with life-or-death implications.
According to an intriguing report at an American Society of Clinical Oncology meeting, women who undergo breast cancer surgery during the second half, or luteal phase, of their monthly cycles (days 14 to 28) are twice as likely to suffer a recurrence as those who are operated on earlier in their cycles. Recent research suggests that women with insulin-dependent diabetes may have higher blood sugar levels during the luteal phase of their cycles because fluctuations in sex hormones affect insulin blood levels.
Many medications also have stronger or weaker effects at different times in a woman's cycle and may require adjustments in dosage. However, the doses of most medicationsalong with their safety and efficacyhave never been tested in women or studied across the menstrual cycle. This may account for the fact that adverse drug reactions, including ones as serious as seizures, are reported twice as often in women.
"More than half of the drugs prescribed today have been tested only in men," says psychiatrist Steven Dubofsky, of the University of Colorado in Boulder, who notes that because of differences in size, absorption, metabolism, and liver function, "there can be tremendous gender differences in both beneficial and adverse effects in women." Yet when Dubofsky tested an experimental medication for Alzheimer's disease, the research review committee banned female participants. "The reason was that women might become pregnantalthough the average age in my study was eighty-two."
Even treatments for problems that are more common in women have rarely been tested in them. Research on aspirin's usefulness in preventing migraine headaches, which strike far more women, included only men. Appetite suppressants and diet drugsused far more often by womenhave been tested almost exclusively in men. Men traditionally were the sole subjects of tests of drugs to treat depression, a disorder that affects twice as many women.
The relatively few studies that have been done on pharmacokinetics (how a drug is absorbed) in women have identified potentially significant gender differences. Women metabolize propranolol, a medication used to treat cardiac arrhythmias, more slowly than men. Blood levels of Inderal, used for migraines or high blood pressure, rise higher in women. Other drugs, including acetaminophen and aspirin, several benzodiazepines (antianxiety agents), and lidocaine (a topical anesthetic and a treatment for certain arrhythmias), take longer to clear a woman's body.
Many medications also interact in ways that have a unique impact on women. Oral contraceptivesused by one in five American women between the ages of eighteen and thirty-fourcan raise blood levels of some psychiatric drugs so high that a woman on the pill may require only a fraction of the standard dose. Other medications, such as the antiseizure drugs carbamazepine and phenytoin, may decrease the effectiveness of birth control pills and increase the chance of an unwanted pregnancy.
When scientists do study the effects of drugs or other treatments on women, they often learn much that can benefit both sexes. Consider the most significant exception to the no-females-allowed approach to health research, the Harvard Nurses' Health Study, which has followed 121,000 women for more than twenty years. Its participants, who have filled out questionnaires and sent in blood samples and even toenail clippings over all these years, have taught us much about many common health threatssome exclusively female, such as the risk of breast cancer from birth control pills (which seems minimal), and some universal, such as the most effective means of preventing colon cancer.
Yet any research investigation that excludes half the human racefemale or maleshortchanges both genders. Learning about human health and longevity by looking only at men, one biologist points out, is like trying to run a successful department store by studying only those that went bankrupt. "More research on women is not a luxury to be indulged in only to pacify feminists, to secure the female vote, or to attract women to a hospital center," says Legato. "Studying women is not so much a service we offer them as an opportunity they offer medical science to improve health care at all levels." Researchers aren't doing women a favor by including them in research protocols. They're doing everyone a service.
The Yentl Syndrome
Felicia, an account manager at a New York advertising agency, worked like a man: Overstressed and underexercised, she put in long hours, smoked a pack and a half of cigarettes a day, and didn't pay much attention to what she ate. At age thirty-four Felicia noticed a burning sensation in her chest when she walked more than a block or two. "I stopped, and it stopped. At first I didn't think it was anything serious. I have a family history of high cholesterol, but I'd never even had a checkup."
Since it was winter, the peak of flu season, Felicia assumed she kept feeling worse because she'd come down with a bug. For ten days she shrugged off chest discomfort, breathlessness, and a throbbing headache. Then one day she walked around a corner in her office and couldn't catch her breath. That's when she got scared. Felicia called her brother-in-law, an intern at a local hospital. At his urging, she went to the emergency room. At first no one suspected a heart attack. "It wasn't like I clutched my chest and fell to the ground," she recalls.
Few women do. And because they don't get the classic symptoms of a heart attack, untold numbers of women complaining of breathlessness or vague pressure in their chest have been sent away from emergency rooms or told to stay home and lie downadvice that may have cost them their lives. Unfortunately, in order to get medical attention, a womanlike Yentl, the girl in Isaac Bashevis Singer's story who had to dress like a boy to study the Torahhas often had to get sick just like a man.
This false and dangerous assumption can occur with many illnesses, but the consequences may be most tragic with heart disease, which many still see as a "guy problem." It is not. Even among women in their forties, heart disease claims more lives each year than breast cancer. Yet a woman's heart, though vulnerable, usually doesn't ache or break like a man's.
Men typically develop the first signs of a heart ailment a decade earlier than womenat thirty-five rather than forty-five. Throughout the reproductive years, estrogen, indeed the best friend a woman's heart could have, prevents the buildup of atherosclerotic plaque in the arteries, boosts levels of the beneficial form of cholesterol, called high-density lipoprotein (HDL), and lowers heart-harming low-density lipoprotein (LDL).
However, estrogen is not a magic potion that guarantees total protection. As Felicia discovered, a woman who has a family history of cardiac disease, high blood pressure, or high cholesterol may develop serious problems even before she reaches menopause. As their estrogen levels fall at midlife, the risk of heart disease rises for all women. After age forty-five, one in nine women has some symptom of heart disease; by sixty-five, one in three does.
"Only in the last eight to ten years have cardiologists realized that heart disease in women has been understudied, underrecognized, underdiagnosed, and undertreated," says Legato. Since then, an explosion of new research has begun to unlock the secrets of a woman's heart. We now know that the same risk factorshigh cholesterol, high blood pressure, and obesityendanger both sexes, but they play out differently in women than men.
A healthy norm for a woman's cholesterol is ten points higher than a man's210 versus 200 milligrams per deciliterbut this figure matters less than her HDL levels. And even then what's normal for a male may spell trouble for a female. "We don't know why, but women with an HDL under 45 mg/dl are at greater risk, while men don't seem to be at risk unless their HDL dips below 35," says Legato.
In women HDL is such a precise indicator of the heart's current and future health that some describe it as a cardiac crystal ball. Total cholesterol, on the other hand, presents a murkier picturemade more complex by menstrual fluctuations. LDL levels decline in the first half of a woman's monthly cycle. In pregnancy, LDL levels increase and remain high until birth. Oral contraceptives, even those with lower estrogen than the original formulations, raise LDL and lower HDL. Menopause brings a rise in LDL and a small decline in HDL. And after age fifty, other blood fatsthe triglyceridesmay be a more telling indicator of risk.
Unlike men, healthy women with high total cholesterol may not benefit as much from some cholesterol-lowering drugs, possibly because these medications cause a drop in helpful HDL as well as harmful LDL. In some studies, lowering total cholesterol by drugs, diet, or both, which does reduce the danger of dying in men, provided similar benefits only for women with actual heart disease. In other women, any treatmentdietary or drugthat pushed down a woman's HDL did little good.
Hypertension, or high blood pressure, a unisex risk factor, is more common in older women, but treating it may not be as beneficial as it is in men. "In men, reducing blood pressure by any means reduces the mortality risk by 15 percent," says Legato. "When we use blood pressure medications to lower mild to moderate hypertension in women, their overall risk of dying for any reason actually increases by 26 percent. We don't know why." A better alternative is exercise, which can bring blood pressure down without the adverse effects of medication and can help lessen another serious risk factor: obesity.
For women, extra pounds clearly spell extra danger. Even those who are moderately overweight (10 to 20 percent above their ideal weight) may have twice the risk of leaner womenparticularly if they put on weight after age eighteen. In women who add a few pounds with every decade, the risk of heart disease increasesespecially if the extra pounds lodge around the waist rather than in the hips and thighs. Apple-shaped women (and men) are at greater risk than pear-shaped ones because midtorso fat seems more likely to move to the bloodstream, where it can build up and clog arteries.
Women also have some unique risk factors, such as age at menopause. In a study of 12,115 Dutch women age fifty to sixty-five, the annual risk of heart disease dropped by 2 percent for every year they continued menstruating. Diabetes is twice as important as a risk factor for heart disease in women as men, and female diabetics have a greater risk of congestive heart failure than males.
Even when women and their doctors recognize that they are at risk, detecting early signs of a problem can be difficult. The first sign of heart disease in a man is usually a heart attack, complete with elephant-on-the-chest, squeezing pain. Women are more prone to "silent" symptoms: shortness of breath, fatigue, discomfort, pressure, nausea, weakness, or pain in seemingly unlikely places, such as the jaw. One woman in her forties had several teeth removed before a cardiologist finally discovered that the sharp twinges of jaw pain had nothing to do with her teeth. The real problem was that her heart was not pumping sufficient blood and oxygen, causing angina that radiated to her jaw.
One form of chest pain, microvascular angina, typically develops in middle-aged, overweight women with high blood pressure and high blood sugar. Notoriously hard to diagnose, women with this conditionsometimes referred to as "Syndrome X"have no telltale signs of blocked arteries. Nonetheless, this ominous condition increases the risk of cardiac danger sixteen times over that of a healthy woman and six times over a man's.
Testing for this and for other types of heart disease in women remains problematic. Standard diagnostic tests, developed through studies in men only, are less precise in detecting heart disease in women. The traditional treadmill or exercise stress test, which records the heart rate during exertion, is the gold standard for evaluating men. But in women it produces a high rate of false positive (erroneously abnormal) results. A thallium stress test, which uses a radioactive isotope that shows up on an X ray, also is less accurate than in men. Cardiologists knowledgeable about gender differences in diagnostic testing generally recommend evaluation of the female heart with an echo stress test, an echocardiogram that uses sound waves to create a 3-D image of the heart at work.
If tests indicate a problem, the next step is an invasive diagnostic procedure called angiography or cardiac catheterization, in which a thin tube is channeled into the heart via an artery in the thigh or arm. As recently as a decade ago, ten times as many men as women (40 percent versus 4 percent) were referred for this definitive test. Women still remain much less likely to undergo angiographya critical prerequisite for angioplasty (balloon surgery to unclog arteries) or coronary bypass surgery.
In the past, women undergoing heart surgery tended to be older and sicker, and their death and complication rates were much higher than men's (though they still fared better than women in comparable condition who didn't undergo surgery). More recent studies have found that advanced age and other medical problems, such as diabetes and hypertension, rather than sex itself, are factors that increase the danger. "We're finding that with earlier diagnosis and intervention and with careful surgical techniquecrucial because of the smaller size of women's blood vesselswomen can do as well as men," says Legato.
Yet women who have heart attacks still are less likely than men to survive over both the short run and the long term. A woman's risk of dying within a month of a heart attack is 75 percent higher than a man's, in part because of a delay in getting help. At the American College of Cardiology meeting in 1998, researchers reported that women typically take an hour longer to get to the hospital than men. And once there, they're often treated less urgently.
According to an analysis of large national databases in the United States, women are 31 percent less likely than men to get clot-dissolving drugs, one of the chief means of limiting the damage of a heart attack, or to receive standard medications like aspirin, the blood thinner heparin, or beta blockers. This gender gap in treatment may be one reason why the death rate for cardiovascular disease has declined faster for men than women in recent years.
However, some advances are offering more hope for women's hearts. Vitamin E intake, according to research in both sexes, can reduce the risk of coronary artery disease in women and men. New medications, such as the blood thinner integrelin, have proved especially effective for women. Women also get as much benefit as men from cardiac rehabilitationan option that cardiologists often didn't even suggest for them in the past. Given the same opportunity to strengthen their hearts, women continue to show improvements for three years after they start an exercise program; men reach a certain performance plateau within months.
Felicia, whose right main coronary artery was 100 percent blocked, is a latter-day success story. A coronary angioplasty opened her blocked arterytemporarily. It's closed down twice since. "Fortunately, my body has grown its own bypass with new blood vessels. I'm much healthier than ever before: I quit smoking; I lost thirty pounds; I work out five or six times a week; I eat no fat. My cholesterol's gone from 480 to around 200. In a way, I'm lucky. I got a wake-up call that made me realize that women aren't immune to heart problemsand that there's a lot we can do to keep our hearts healthy."
"It's All in Your Head"
In the early 1980s, in her third year of medical school, Vicki Ratner, now an orthopedic surgeon in San Jose, developed unremitting pelvic pain along with extreme urinary frequency and urgency. When treatments for a urinary tract infection didn't work, she was referred from one specialist to anotherfourteen in all. "They told me that it was all in my head, that I should find a new boyfriend, that I wasn't cut out to be a doctor, that the only solution was to quit medical school and settle down to a traditional lifestyle." She spent the last two years of medical school in unremitting pain, silently enduring symptoms she'd been convinced were psychosomatic.
Ratner's own search of the medical literature finally led her to an article on a disease she'd never heard of: interstitial cystitis (IC)a bladder inflammation that typically develops in postmenopausal women. "I found fifty cases exactly like mine. I thought: 'This is it!'" But her urologist was so convinced she was too young for this problem that she had to beg for months to undergo a surgical biopsy, which ultimately confirmed her self-diagnosis. Ratner, who eventually found treatments that relieved her symptoms, went on to start a national organization dedicated to helping others with this conditionan estimated 450,000 Americans, almost all of them women. "The problem is that the symptoms of IC look like a urinary tract infection, but the standard diagnostic tests come back negative," says Ratner. And so women, even with severe pain and an urge to urinate up to sixty times a day, are often told the problem is all in their head.
These wordsperhaps the most aggravating uttered by doctorshave echoed in women's ears for years. In a study using videotapes of patient visits, primary-care doctors referred men to medical specialists but suggested that women of the same age with identical symptoms and health histories see a psychotherapist. "There is a reflex in many members of the medical profession to think of women as more emotional," says Legato. "A woman is three times more likely than a man to be told that symptoms are all in her head."
One of her patients, a high-powered corporate attorney in New York City, had developed episodes of very rapid heartbeat at age twenty-five. Her heart would pound so fiercely for hours on end that she felt it would leap out of her chest. Doctor after doctor brushed off her complaints. "I was told that it was because I was working too hard, that I was drinking too much or drinking too little, that I was too anxious," the woman recalls. Finally she decided to attend a talk on women's hearts given by Legato.
"My heart started beating fast during the session, and Dr. Legato looked at me, listened to my symptoms, and said, 'You have a real problem, and you need treatment. I want you in my office tomorrow morning.'" Around-the-clock testing with a portable cardiac monitor revealed a textbook case of a disorder called Wolff-Parkinson-White syndrome, in which a tiny bundle of extraneous muscle cells in the heart causes potentially deadly disturbances in the heart's rhythm. Within two weeks of surgery to correct the defect, the attorney was back at workand she's been feeling "absolutely sensational" ever since.
In twenty years of medical reporting, I've heard variations on this story dozens of times. It took seven years for one woman I interviewed, sandbagged by pain and fatigue, to discover the underlying problem was lupus erythematosus, an autoimmune disorder. Another woman, told that her bouts with diarrhea and stomach pain were wholly psychological, was eventually diagnosed with irritable bowel syndrome, a digestive malady that is three to five times more common in women. Other women, who'd developed genital burning, itching, and excruciating pain during intercourse, were told they were sexually repressed. Several years passed before they learned they had vulvodynia, a little-understood but treatable inflammation of the tissue that surrounds the opening to a woman's vagina and urethra.
Why are women's health complaints so often missed or dissed? "Rather than admitting they just don't know or don't have a test to document and quantify the problem, physicians deny that a problem exists," says Ratner. "They blame the patient by suggesting that the problem is stress-related or all in her head. And it can be hard for a woman to convince a physician that she's in excruciating pain if she looks healthy."
Pain, perhaps the most subjective of symptoms, has long been viewed as a troublesome female complaint. In studies in which women and men have been subjected to the same provocation, women generally give it a higher pain rating. Women also routinely report more pains in more places than men do and experience more pain following injuries such as fractures. The reason may lie in brain chemistry, which fluctuates with the menstrual cycle. Some pain problems, such as migraine headaches, often strike when estrogen, the neurotransmitter serotonin, and the soothing brain chemicals called beta endorphins are low. Many of the pain-that-has-no-name syndromes that doctors once dismissed as psychological have turned out to be real and specificand to have actual names, including endometriosis, dysmenorrhea (menstrual cramps), fibromyalgia (a neuromuscular disorder), mitral valve prolapse, microvascular angina, vulvodynia, irritable bowel syndrome, and interstitial cystitis.
Yet even though these and other painful problems single out women, until 1996 no one had ever studied sex differences in response to pain medications. In a study of forty-eight women and men undergoing removal of their wisdom teeth, researchers at the University of California, San Francisco, discovered that a class of pain relievers called kappa opioids provided much greater and longer-lasting pain relief to the women. "Biologically men and women do not obtain pain relief in the same way," concluded chief researcher Jon Levine, who speculates that the reason may be sex differences in the number of receptors for this type of drug or in basic brain circuitry.
The female-friendly kappa opioids, which do not cause side effects such as sleepiness, nausea, confusion, and addiction (as codeine and morphine, both mu opioids, do), had all but been discarded prior to Levine's research. The reason: They'd been tested only in menwhose continuing complaints of pain after taking kappa opioids were never dismissed as all in their heads.
Is there any proof to back up the premise that it's just like a woman to seek care for phantom pains or trivial or nonexistent health problems? None at all. Researchers from the University of Amsterdam, in a five-year study of more than nine thousand female and male patients seeking primary care, found that fewer than 20 percent of women's "excess" visits involved vague physical symptoms with no known medical cause. The vast majority of the women who sought help had serious, legitimate problems that fully warranted medical attention.
The more frequent problem, says Ratner, is that physicians discount what women are saying so thoroughly that women come to doubt their own judgment. "There's something drastically wrong when male physicians are so ready to trivialize and negate women's experience," she says. "Women have to remember that they are the best judges of their own symptoms. Their lives may depend on it."