Sex and Sickness

A new insight has reached the medical profession: Women are not the same as men. They have different symptoms, respond differently to medication and need to be treated differently. Are we on the verge of a health-care revolution?

Esti Ahronovitz
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Esti Ahronovitz

Last year, a mother from the north of the country called Prof. Marek Glezerman, director of the Hospital for Women at Rabin Medical Center in Petah Tikva. She told him about her daughter, who was suffering repeated epileptic seizures despite the medication she was taking. To the mother's surprise, Prof. Glezerman asked when her daughter got her monthly period. It turned out that she was having attacks on the days leading up to her period. To the mother's delight, she had consulted a doctor with a high awareness of the connection between gender and biological processes in the body. Prof. Glezerman, who chairs the Israel Society for Gender Medicine, is a pioneer in the field in this country. In recent months, he has also served as president of the International Society of Gender Medicine.

"As I see it, it's a simple puzzle," Glezerman explains. "Before menstruation, the ovulation hormone, progesterone, is secreted. One of its characteristics is the breakdown of hydantoins - anti-epileptic drugs." Following the conversation with Glezerman, the neurologists treating the woman's daughter increased the dosage of her medication in the days preceding her period, and she returned to normal. "This is the connection between gender and medication," he explains. "The problem is that doctors don't ask women who come to them with neurological or other problems, when they have their period."

Credit: Yael Bogen

But gender medicine asks exactly this question, and many more. This developing medical field seeks to understand the differences between the male and female body, and how to adapt medical diagnosis and treatment to those differences. "Gender medicine treats both genders with equal seriousness, with an equal desire to improve understanding of the functioning of the body's systems," Glezerman explains.

For many years, those involved in medicine have been aware that the physical differences between women and men affect each differently when it comes to sickness and health. Illnesses develop differently, the symptoms are not the same, nor is the response to medication and other treatments. Yet the road to equality in medicine between men and women is still long: In medical research, physician training, treatment and medication, recognition of the differences is insufficient, usually to the detriment of women's health.

One pioneer in the field of gender medicine is Prof. Marianne Legato, founder and head of the Partnership for Gender-Specific Medicine at Columbia University in New York. After becoming acquainted with her work and publications, Prof. Glezerman founded the Israel Society for Gender Medicine in February 2009, and senior physicians from all over the country are now members. Gender medicine has become an active and exciting area of research. At the fifth annual conference on gender medicine, held in December in Tel Aviv, Israeli doctors presented 60 separate studies in the field.

"A few years from now, all of medicine will look different," Glezerman predicts optimistically. "There will be separate ways of dealing with women and men in cardiology, gastroenterology, nephrology, dermatology, dentistry, ophthalmology and more. It will be taken into account that, while [men and women are] similar morphologically, all the bodily systems actually function differently. We'll ask ourselves why we didn't realize this before."

Male-only research

Indeed, how did we fail to realize this earlier? Most of the medical information accumulated over the decades originates in research pertaining to men only. Women were slighted as research subjects, and thus also as patients. "Medicine treats women on the basis of the premise that a person's gender is of no importance," says Glezerman.

"There is a lot of medical information that needs to be rebuilt, because it did not include women," says Maya Lavie-Ajayi, a psychologist from Ben-Gurion University's social work department who deals with women's sexual health. "The use of the first medication against AIDS, for example, was based on studies done on men only," she says. In 1987, the drug AZT was approved after 63 studies were carried out with it, all on men. Only afterward did it become apparent that the dosage considered safe for a man could be lethal for a woman. Lavie-Ajayi cites another example: A famous major study in 1988 that found that one aspirin a day was beneficial. The study looked at 22,000 men, and not a single woman.

Today it is known that aspirin has a different effect on men, in whom it helps prevent heart attacks, and on women, in whom it has little effect on the heart, but may help prevent strokes.

Researchers preferred to study men, who are considered more physiologically stable than women - who may become pregnant or experience hormonal disruptions during menstruation. The memory of two medical disasters bolstered this approach. The first happened in the 1950s, when as part of a medical trial, pregnant women were given a synthetic hormone called DES. Women who were exposed to DES in utero turned out to be at a much higher risk for vaginal and cervical cancer. A decade later came the thalidomide disaster. This drug was marketed in Europe in the early 1960s to prevent morning sickness in pregnant women after animal trials - but no human trials - had been conducted. Thousands of thalidomide babies were born were severe defects and missing limbs.

"In the wake of these cases," says Glezerman, "in 1977 the U.S. Food and Drug Administration instructed that women not be included in these kinds of trials. The intentions were good, to protect women, but there were also negative consequences: Women were taken out of the research studies, and the drug industry warmly embraced this recommendation."

About a decade ago, a change in legislation in the U.S. obliged researchers to include women in clinical trials, and the FDA directive was annulled. Today, the U.S. Department of Health makes hearings on medications contingent upon the inclusion of women in the research. But still, 75 percent of clinical trials are carried out mainly on men. Glezerman notes that 75 percent of the 442 clinical research studies published in the prestigious New England Journal of Medicine from 1994-99 were based on trials among men only. (The Israeli Health Ministry said this week that in Israel, the issue of gender in medical research is not addressed in any legislation. )

Gender discrimination started even earlier. Irving Zucker and Annaliese Beery of the University of California examined nearly 2,000 medical studies on animals that were published in 2009. In an article they published in June 2010 in Nature, they found that even though animal trials form the basis for the development of treatments for many diseases, in eight out of ten fields, the trials were carried out on more males than females. Moreover, they found that even in research on diseases that have a much higher incidence among women, the proportion of male subjects was much greater.

Prof. Glezerman, why has the female sex been ignored for so many years?

"In the course of human development we've missed a lot, and it took time until we understood how things work and what needs to be done in order to improve things. Revolutions in medicine happen all the time, and this is one of them. The revolution of gender medicine is simply about shifting our point of view and seeing things from a different angle."

Is a significant part of medicine nowadays unsafe for women?

"Certain things are missing in medicine. There's a lack of information, because we project information that we've amassed about men onto women."

A different heart attack

A year ago, Dina (not her real name ), 55, went to a clinic near her home in the south of the country, suffering from chest pain and nausea. The doctor diagnosed it as a pulled muscle and said she could go home. But Dina wasn't persuaded. "I told him I didn't think that was it," she said this week, "and that I wanted him to do an EKG. My daughter, who came with me, also pressed him to do the test." There was no arguing with the EKG results. They showed that Dina was in the midst of a heart attack. An ambulance was summoned to the clinic and Dina was rushed to the nearest hospital.

"Heart disease is perceived as a man's issue," says Glezerman. "And that's true until women reach menopause. Up to that point, more men than women do suffer from heart disease. Women are protected because of the secretion of the sex hormones. But after menopause, that changes and women close the gap very quickly. Today, more women die from heart disease and vascular disease than from all kinds of cancers combined.

"The classic picture of a heart attack," he continues, "is a man clutching his left side and doubling over in intense pain that radiates to the shoulder and arm. But for one out of five women, the symptoms of a heart attack are totally different: the attack develops very gradually and not all at once. The woman complains of shortness of breath, the pain can radiate to the back of the neck, to the back or the jaw. And by the time she gets to the emergency room, the risk that she will be sent home with a diagnosis of hysteria is four times greater than for a man. And even when she obtains a diagnosis, the processes that surround it, the referral to a cardiologist or for catheterization, will take a lot longer than for a man."

Nonetheless, it was in cardiology that the big revolution in gender medicine really began, and where it continues to gain momentum. As a matter of fact, all the members of the International Society of Gender Medicine are cardiologists. For Dr. Tali Porter, director of the intermediary intensive heart-care unit at Beilinson Hospital in Petah Tikva, internist, cardiologist and lecturer at Tel Aviv University, the first step in the gender revolution has to be in education. "I give lectures on gender cardiology, but in my other lectures, too, about radiology, congestive heart failure, heart attacks, I bring in the gender issue. There's an essential difference between women and men."

Dr. Porter, as a woman in such a male-dominated field, would you say you are also motivated by feminism?

"I'm coming from somewhere in the middle, between the studies that point to the difference between a man and woman, and the bra-burners. I think there is more to be learned in order to make medicine right and equal. My philosophy of medicine is personal medicine - Moshe is not Chaim and Chaim is not Dina and so on. And gender is a key, substantial part of this."

Education has to begin with the first doctors to whom the patient turns - the pediatrician, the family doctor, the internist or the gynecologist. "Education doesn't mean telling women 'You're immune from heart disease,' because women also die from heart disease," says Dr. Porter. "When a 45-year-old woman goes to the family doctor and he tells her: 'You're fine,' I expect him to be aware that soon this will all change: Her blood sugar will rise, her blood pressure will go up. Does he understand that the woman in front of him is starting to climb toward men in terms of the heart attack statistics?"

In a June 2010 article in Nature, Alison Kim, Candace Tingen and Teresa Woodruff of Northwestern University in Chicago, ascribe great importance to the difference between men and women when it comes to heart disease. They cite a 2005 survey that found that only 20 percent of American doctors were aware that more women than men die of heart disease. Another survey, from 2006, found that only a few medical schools in the United States included proper training on the medical differences between the sexes as part of their curriculum.

The researchers note that women also suffer more side effects from medication. Nevertheless, only very rarely are different instructions given for treatment of men and women. A study that looked at 300 new medications that came on the U.S. market from 1995-2000 found that even medications with extremely different effects on men and women were sold with no gender-specific dosage instructions. The researchers contend that this statistic partially explains why the rate of women who have negative reactions to prescription medications is 50 percent higher than that of men.

One size doesn't fit all

"The whole pharmacology of medications is different for women and men, because of the different ratio of fat to muscle," explains Dr. Porter. "There are medications that dissipate in fat and medications that don't. Women, by the way, also suffer more often from internal bleeding. A decade ago, when a woman came in with a heart attack, they bombarded her with anti-coagulants, which ended up causing excessive bleeding."

Porter gives several examples of well-known heart medications whose use was completely changed due to new studies that included women. "It used to be common practice to give preventive aspirin to women and men," she says. "But it turns out that aspirin has a different effect on women - it lowers the incidence of stroke but not the incidence of heart attacks."

And she cites another example of medication discrimination: "For years, it was commonly thought that cholesterol-lowering drugs didn't work on women, and were even dangerous for them. This claim was made because none of the studies included enough women to do a proper analysis, until finally new studies came out that showed the opposite result. Today, cholesterol-lowering drugs have revolutionized women's health. They have actually reduced mortality."

An opposite example is a medication called Digoxin, which is used to help control the heart rate. "We're being taught to give it to people whose heart doesn't work well enough, and that's based on a large body of research," says Porter. "But it took years until an extensive examination was done that found that the drug is dangerous to women at a certain dosage. Not that it can't be given to them, but this needs to be checked."

Is there any opposition to gender medicine?

"There are doctors who don't believe in it at all, mostly older doctors. The opponents say that even if there are differences, they shrink over time. I say that the differences are only shrinking because we're working on it all the time."

Prof. Ran Kornowski, director of the catheterization institute in the Beilinson Hospital cardiology department, agrees that in the past two decades, cardiology has vastly changed in its approach to women. He says that many medical centers in the world have established centers specifically dedicated to cardiology for women. His institute is conducting a number of studies in the field.

"Eight years ago we published a report showing that mortality in women who have heart attacks is higher than in men," he says. "They experience it at a later age, and they then have many more background illnesses that complicate the clinical course of the event. The study was subsequently corroborated by other studies around the world."

Another study compared the results of using ordinary heart stents versus those coated with a drug in 4,700 patients treated at the Rabin Medical Center from 2004-2007. The findings were surprising: It was known that women react less well than men to treatment with a stent, but they responded well to the drug-coated stents.

"Women responded even better than men to the new technologies," says Kornowski. "Today, when you submit a proposal for a cardiological study, you wouldn't dream of not including women in it. But there is still more to be done. We have more problems diagnosing heart disease in women than in men, for one thing because the symptoms in women are not that precise or typical. The doctor needs very sharp senses in order to understand that when a woman says, 'I feel weakness,' that it might be a cardiology problem. We've learned over the years to be more sensitive to women's complaints. They're strong, they're used to the burden of work and of the household and they tend not to complain. In other words, we still have plenty to do before we get to a situation where women are treated like men."

Closing the gap

Prof. Glezerman maintains that in nearly every bodily system there are differences between men and women. "Women feel pain differently," he explains. "Women are sensitive to medications in a different way. We know that women have different receptors for different forms of morphine, and therefore there are drugs that affect them differently from men. The same goes for painkillers. But in the pharmacy you don't find different painkillers for men and women. At best, there might be a difference in the dosage."

Men's and women's digestive systems are different, too. "From the beginning all the way to the end of the digestive system, everything works differently for men and women," Glezerman says. "The composition of the saliva is different, the flow of the saliva and the amount of saliva is different, and this affects the rate of digestion. A woman's digestive system is slower and takes twice as long as a man's to relay substances, which of course affects the medications a woman takes."

A 2007 study conducted on around half a million people who served in the Israel Defense Forces found that digestive disorders are more common among females than males, including illnesses of the digestive system, such as ulcers, gallstones, lactose intolerance and irritable bowel syndrome. A study conducted by Dr. Dan Landau, Dr. Yosefa Bar-Dayan and Prof. Yaron Niv of the Rabin Medical Center found a connection between excess weight and these various illnesses among women only.

One of the more interesting areas in regard to gender and the digestive system is colon cancer. Each year, about 3,400 Israelis are diagnosed with this disease. Prof. Yaron Niv, director of the gastroenterology department at Beilinson Hospital, says many studies have shown that this cancer is more common in men under 45, but that women are closing the gap and there is practically an equal incidence of the disease between men and women. A number of studies have led to the theory that during a woman's fertile years, the female hormone estrogen protects against this disease. But in menopause, when the amount of this hormone is reduced, women are more vulnerable to it. The survival rate for women under 45 who are diagnosed and treated for colon cancer is also much higher than for men of the same age. After age 45 there is no difference in the survival rate.

A report last year caused a major stir after a study showed that women who had hormone replacement therapy, often given after menstruation stops, had a lower incidence of colon cancer. Prof. Niv led two studies that looked at men and women's willingness to take part in a survey for early discovery of colon cancer via a blood test.

"In the Galilee, we approached 3,500 people," says Niv. "A thousand declined to participate, and most of them were men." In the second study, which covered 13,000 people in the Tel Aviv area, "we found that 30 percent more women responded positively. It's a paradox: the risk of colon cancer for women, is lower but their readiness to be tested is higher."

What is the psychology behind the findings?

"That men are busier, that they repress more, that they're not as concerned with their health, and that if they don't have a wife who sends them to get tested, they don't go."

Breasts and womb

Niv's finding is not surprising. Surveys conducted by the health maintenance organizations found that two-thirds of visitors to their clinics are women. Women act as the family "health minister": They bring the sick child to the doctor, they accompany older relatives to the clinic and, of course, they also send their spouses to the doctor.

"Men's and women's behavior is different when it comes to health matters," says Prof. Hava Tabenkin, chair of the Health Ministry's National Council for Women's Health. "Generally speaking, men tend to take more risks, and women are more careful. Men drive faster, commit more crimes, smoke more, and they also go to the doctor less frequently. Incidentally, more men than women end up coming to the emergency room. They neglect their health until the situation is serious, and then they come to the emergency room. Even when men come into the clinic, often the first thing they say is, 'My wife sent me.'"

Prof. Tabenkin, do women in Israel suffer discrimination in matters of health?

"There is discrimination against women in regard to health. It might seem that women's health is being addressed, but the concern is not so much with her as with her ability to perpetuate the generation. What do women's health centers focus on? On gynecological issues, on the breasts and womb. Is this women's health? Women's health also relates to many diseases which need to be taken into account."

In Israel, women have a higher life expectancy than men, so the situation can't be all that bad, right?

"Women are certainly aware of their health and therefore their life expectancy is longer. On the other hand, we needn't feel guilty about it. Israeli men's life expectancy is third in the world, so they're not so badly off. One reason is that we're a macho society and the women take good care of the men. If women's status here was higher, I think our life expectancy would be higher."

For Tabenkin, violence against women is also a matter that gender medicine should deal with. "We're trying to promote awareness of the issue among doctors," she says. "Every doctor needs to know how to ask and how to identify a woman who is being subjected to violence. She'll return again and again with unspecific complaints, and you see that she is suffering. Violence affects women's health and it's a very problematic issue, since they are not considered helpless and the doctor cannot report the violence of his own accord. He needs their consent. Many doctors are afraid to ask women if they are exposed to violence, and women don't want it to be written in their records."

Typical depression

And we haven't even talked about depression yet. Just as heart disease is identified with men, depression is most identified with women. Women suffer depression nearly twice as much as men. Today there are approaches that say that while men can also be ill with depression, it is harder to identify because it is manifested differently. Typical female depression is characterized by low functioning, lack of interest, low mood and thoughts of death. Men, on the other hand, will take drugs, become aggressive or possibly workaholic.

"Women have more classic symptoms and they also deal with them more," says psychiatrist Zipora Dolev, who has practiced gender psychiatry for the last decade. Like gender medicine, this field also originated in America. Gender psychiatry primarily deals with the connection between the hormonal changes a woman goes through and changes in her mood. Dr. Dolev cites five hormonal stages that affect a woman's mental state: adolescence, pregnancy, the postpartum months, premenstrual syndrome over the years, and menopause. "Much of the reason that depression is more common in women is these hormonal changes," she says.

And what happens with men?

"In men the hormonal changes are less drastic. In women, each phase is a drama. PMS is drama, childbirth is drama, and menopause is a very big drama."

Sleep cycles are also affected by these hormonal changes. It's no mere cliche that a man just puts his head down on the pillow and falls asleep, while a woman tosses and turns and wakes up every two hours. "There are gender-related sleep disorders," says Dr. Dolev. "We find 50 percent more sleep disorders in women than in men. Sleep disorders often come in a package with menopause and depression, and they have a direct connection to the hormonal changes a woman experiences. It's true that there may be other medical reasons for sleep disorders, but you will also find sleep disorders at the different hormonal stages. In 40 percent of women, sleep disorders are the first symptom of approaching menopause, even before the cessation of menstruation."

Dolev says there is also a close connection between psychiatric drugs and the different hormonal periods. "We know about a connection between the level of estrogen and psychiatric medications. When the estrogen level goes down, at menopause or prior to menstruation, the dosage of psychiatric medication has to be increased. You often see mental illness getting worse just before menstruation or before menopause. And psychiatrists often fail to make the connection. It's not uncommon for me to hear, 'She's taking the medications properly, so why is there a deterioration in her condition?'"

What the future holds

"Before you can solve a problem, you have to realize that there is a problem," says Prof. Glezerman. "Today we are defining the problem and searching for its origins. This requires research and education. I think that after a short process of just a few years, we'll understand that we need to focus on research that will define diseases and syndromes differently for men and women."

You're talking about a real revolution.

"Even now, we're rewriting whole chapters of medicine. A revolution is already happening today. The message is not that a woman should go to the doctor and say, 'Take into account that I'm a woman and give me the right medication,' because the right medication doesn't exist yet. We need to invest in research and teaching."

In the future, will we see two separate tracks in medicine, one for men and one for women?

"Today we're in the same place as 150 years ago, when medicine first understood that a child is not a miniature adult, that the systems in the child's body work differently, and so pediatrics came into being. In the future we will see two tracks, for men and women. We'll see where there are similarities, where there are differences, and we'll proceed accordingly."

Asaf Ronel assisted in the preparation of this article.

Legacy of the caves

Male and female bodily systems are remnants of human and prehuman history, explains Prof. Marek Glezerman. "Our physical systems are a legacy of life in the caves," he says. "Homo sapiens has lived on the earth for half a million years, most of that time in caves, with a very clear division of labor: The man was the hunter and the woman was the gatherer and the one who raised the offspring. These functions had implications for body structure: The hunter had to develop a sense of concentration and focus on the target. Today as well, men are able to concentrate well on one target, but not to do that many things at once. Women did everything: They gathered, they took one baby on their back, held another by the hand and developed an environmental memory. Even now, we men still have no idea where anything is in the house."

Differences in speech capability, says Glezerman, also go back to long ago: "For the hunter, speech was dangerous: Keep quiet, focus, solve the problem. It's still the same today." However, for the women, communication was vital, in order to safeguard them and the children. "Today we know that men have one speech center in the brain and most women have two," says Glezerman. "If a man has a stroke, that affects the speech center and chances of rehabilitating his speech are low, but women have more potential for speech rehabilitation."

Female voices

As with many social processes, in the field of gender medicine the establishment only started to pay attention to the uniqueness of women decades after feminists began protesting women's standing in the medical world. The women's health movement arose in the United States in the late 1960s. An important milestone was the 1973 publication of the book "Our Bodies, Ourselves," which called on women to regain control over their bodies.

Prof. Julie Cwikel, founder and director of the Center for Women's Health Studies and Promotion at Ben-Gurion University, says, "In this book, a group of women got up and said out loud that the health system is not sensitive to women's needs; that there is paternalism, that (male ) doctors are condescending and don't let women express an opinion."

Here is one example from the book of how male doctors' prejudicial ideas about women adversely impact medical treatment. The book names a common condition in women, particularly during menstruation, anemia and iron insufficiency deriving from a decrease in red blood cells. The symptoms can include fatigue, dizziness and shortness of breath. Many male doctors, says "Our Bodies, Ourselves," ascribe these symptoms to emotional disorders. Thus they are likely to tell the woman that she is not suffering from any physical problem.

The entrance of a large number of women into the health professions also contributed substantially to change. "Women began to express their views on women's problems," says Cwikel. "Thirty years ago, for example, Dr. Penny Budoff, the director of the women's health center in Bethpage, New York, said that it just wasn't right that so many women should be put out of commission because of menstrual cramps and no one was addressing this. She spearheaded a research effort and a social struggle in this area."

Cwikel says that in the past, the approach to women's health was "the 'bikini' approach - what the bikini covers are all the areas that need addressing. Today we put the emphasis on multidisciplinary teamwork: Women's health is not only a matter for doctors. It's a democratic approach in planning the solution to health problems, integrating social work, nutrition, physical therapy, psychology and spiritual approaches as well." The feminist approach combines the body and mind, explains Cwikel, and is also beneficial for men.

At the center run by Dr. Cwikel, they continue to make discoveries about health phenomena that are unique to women. "In the field of oncology," she says, "we've heard from women that when they go back to work after chemotherapy, they feel a cognitive decline. Today it is known that about 40 percent of women battling cancer experience something called 'chemo brain.' From listening to women's voices, we developed a research model for diagnosing the phenomenon."



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