When neurobiologist Anat Biegon was studying depression in females 40 years ago at the Weizmann Institute of Science in Rehovot, she asked a colleague what drug dosage was needed to safely anesthetize rats before experimenting on them. Biegon recognized than that women were much more likely than men to suffer from chronically low moods.
She gave the female rodents the recommended amount – and all of them died. The colleague had given the dosage accepted for use on male rats; no special dose had been calculated for female rats because they were considered to be the same as the male gender.
Today, as a professor of neurology and radiology at Stony Brook University in New York (part of the State University of New York), Biegon has established a center for the study of gender, hormones and health at her university. She delivered a solo lecture last month at Hadassah University Medical Center in Jerusalem’s Ein Kerem on “Sex Differences in Medicine? Why Should We Care?,” and has gone far to study the implications of differences between females in males.
Biegon, who at Tel Aviv University studied chemistry for a bachelor’s degree and biochemistry for her master’s degree, branched out into neurobiology in Rehovot and then completed post-doctoral work at Rockefeller University in Manhattan. Since 1990, she has remained in the US, and her main research interests have included brain response to traumatic, ischemic or inflammatory insults; gonadal hormone modulation of brain function in health and disease; and radiopharmaceuticals for non-invasive imaging of neurotransmitter and hormone markers in the brain – all the while keeping an eye on gender differences in these subjects.
“Gender, biological sex and sex hormones affect everything in medicine, including prevalence, disease presentation and outcome, the safety of medical devices and procedures, drug response, metabolism and safety and efficacy,” she said in the English-language speech. Her lecture was based on American statistics but, she said, “the situation in Israel shouldn’t be much different.”
“As many as 66 percent of visits to doctors are by women,” she noted. This is not because women are more fearful of being ill or like to spend their time in health fund clinics. “It’s due to the fact that women live considerably more years than men and they are thus more likely to suffer from age-related, chronic and incurable diseases. In addition, pregnancy, birth, breastfeeding and taking care of children can have adverse effects on women’s health.”
While victims of attention-deficit/hyperactivity disorder (ADHD), autism and traumatic brain injury are predominantly boys/men (75 percent versus 25% in females), autoimmune diseases (in which the immune system attacks bodily tissue or cells because it mistakenly regards them as “foreign”) and others affect mostly females.
While ADHD is more common in boys, and girls have lower ratings on hyperactivity inattention and impulsivity, they tend to have more intellectual impairment in this condition.
“About 90% of sufferers of lupus erythematosus [a complex inflammatory disease causing scaly red patches on the skin, and sometimes affecting connective tissue in the internal organs] are women,” said Biegon. In addition to depression, women suffer more from Alzheimer’s disease, multiple sclerosis, cluster headaches, osteoporosis, fibromyalgia and osteoarthritis. Hip, forearm, spinal and humerus bone fractures occur more in women. “These are generally not killer diseases, but they make life miserable for a long time,” she noted.
“During the course of a woman’s life, affected by reproductive hormones the risk of disease can rise and ebb: For example, during her fertile years a woman is at higher risk of depression; this declines at menopause and then increases when she becomes old-old.”
Even when a woman undergoes a sex change operation, the “liability” of disease can follow her on her path through the other gender.
“Robert Eads, a twice-divorced man with two children who became a transsexual at the age of 45, died of ovarian cancer,” Biegon reported, showing her/his photo. She/he had her breasts removed and took testosterone supplements, but the ovaries were never removed because they were not functional at that age. But he nevertheless succumbed to ovarian cancer at 53. Transgender women who become men take testosterone, which is a precursor of estrogen. So this hormone treatment can also increase the risk of estrogen- linked diseases.”
SYMPTOMS OF the same acute conditions can present themselves differently in men and women, Biegon continued. In men, the first signs of a myocardial infarction (heart attack) in men include sharp pain in the left part of the chest, possibly with the pain radiating down the arm on that side. In women, they could be very different.
“Often, there is no chest pain. There could instead be a cough, feeling tired or pain in the jaw or back. So many women may not know they are having a heart attack, and many physicians in the emergency room may not take their symptoms seriously,” Biegon said.
The emergency room doctor could think a woman was “hysterical” and just give her a Valium pill and send her home. “This situation costs a large number of women’s lives.”
A few weeks ago, the American Heart Association issued an official statement on the matter.
“Cardiovascular disease is the leading cause of mortality in American women. Since 1984, the annual cardiovascular disease mortality rate has remained greater for women than men; however, over the last decade, there have been marked reductions in cardiovascular disease mortality in women. The dramatic decline in mortality rates for women is attributed partly to an increase in awareness, a greater focus on women and cardiovascular disease risk and the increased application of evidence-based treatments for established coronary heart disease. This is our first scientific statement from the American Heart Association on acute myocardial infarction in women,” the association declared.
“Sex-specific differences exist in the presentation, pathophysiological mechanisms and outcomes in patients with acute myocardial infarction. This statement provides a comprehensive review of the current evidence of the clinical presentation, pathophysiology, treatment, and outcomes of women with acute myocardial infarction.”
BIEGON said that although traumatic brain injury is more common in men, the results are usually different in women and men.
The injury usually causes the brain to swell.
The victim undergoes a CT (computerized tomography) scan and is tested with intracranial pressure-measuring devices. The swelling alone can kill.
“But in people with severe brain injury, a quarter of men have swelling that is reduced.
In women, the brain swells much more from the same injury. In women in their reproductive years, under the age of 51, swelling in various female organs – the breasts and abdomen – is common during and after menstruation.
So brain swelling in such women is also greater due to hormones. Post-menopausal women suffer much less brain swelling after traumatic injury to the head. One can’t ignore age in this matter.”
Mortality rates of young girls who suffered traumatic brain injury are more than twice as high as that of boys, she says. “But when they reach puberty, the ratio stabilizes and becomes equal until age 30, but at age 50, men have higher death rates.”
Biegon stressed: “The absence of evidence doesn’t mean evidence of absence. If a study shows no sex difference, it doesn’t mean it is true. One always has to look at the interaction with age. One needs large numbers of women to say something about a gender effect, but often many women are not included.
Researchers compare older and younger men, but not women to men. When you survive brain injury, you are alive. The question is if life is worth living; one might need constant care for disability and even be in a vegetative state.”
AS FOR the safety of medical devices and procedures, coronary angioplasty is claimed to be very safe and effective when arteries in the heart are found to be clogged.
“But this is true for men! Death after angioplasty is less than 1% for men but close to 2% in women. This is a significant difference,” Biegon asserted. “This means more hospitalization and complications in women. The female gender is and independent predictor of lower success for angioplasty and a higher risk of death.”
Drug response also varies according to whether the patient is male or female.
“Women are more likely to suffer adverse effects of drugs than men, and not only because of their average smaller size. ACE inhibitors for treating hypertension have been found to be less effective in women than in men. The use of digitalis, found to be not effective in women in some major studies, has more side effects.”
Digitalis, a natural medicine that strengthens the force of the heartbeat by increasing the amount of calcium in the heart’s cells and controls irregular heart rhythms has been found to cause more deaths in women than in men.
Aspirin has been recommended for preventing myocardial infarction in older people.
“Almost everyone over 60 takes baby aspirin,” said Biegon. “But 32,000 participants studied for the effects of aspirin in preventing the risk of heart attacks were all men. When a different study tested 40,000 women for the same purpose, aspirin made absolutely no difference in preventing MI. Aspirin is Man’s Best Friend but not that of women, who developed only side effects from taking it. Women are often overdosed with medications, and as they tend to suffer from more chronic illnesses at older ages, they are prescribed multiple mediations and suffer from drug-drug interactions.”
Liver enzymes, the lecturer continued, “are induced by testosterone and inhibited by estrogen, so men have a faster oxidating metabolism than women. The effects of barbiturates, for example, are modulated by age and gender. Before puberty, boys and girls spend the same amount of time sleeping.
After puberty, girls and women receiving barbiturate pills sleep significantly more than men, depending on where they are in their menstrual cycle and the involvement of their sex hormones.”
The US Food and Drug Administration, she said, forced a pharmaceutical company to lower the recommended doses of zolpidem (brand names include Ambien, Zonadin, Sanval, Zolsana and Zolfresh), a prescription medication used for the treatment of insomnia and some brain disorders. Younger women need only half the dose as that given to males, as their estrogen affects it, Biegon said.
GENDER DISCRIMINATION in the medical establishment has been quite ludicrous for centuries. In 1859, the American Medical Association said that women’s “psychological condition during part of the month disqualifies them from being doctors.” Only in 1945 did the Harvard Medical School remove a ban on accepting female medical students. In 1977, FDA guidelines excluded “women of childbearing potential” (meaning the ability to become pregnant) from taking part in Phase 1 and Phase 2 clinical trials. Sixteen years later, the US National Institutes of Health issued a requirement to include women in all 93, NIH issues requirement to NIH-sponsored clinical trials, but, said Biegon, “many drug companies ignore this. But things are changing: Last year, the NIH issued a mandate to consider sex as a ‘biological variable’ in all research it funds.” Today, there are a growing number of organizations, professional societies, journals and hospital-based centers dedicated to research and sex differences in medicine.
Still, said Biegon, the “vast majority of medical research today is on males, except for breast cancer and some multiple sclerosis trials. We still don’t know how various drugs affect the fetus and women in pregnancy. Fertile women suffer from allergic, cardiovascular system, skin, endocrine, immune, infectious, respiratory, pain, urogenital and many other conditions, and automatically, doctors say they are not considered safe in pregnancy. “The drug packages say: ‘Consult your doctor about use in pregnancy,’ but what does the doctor know if there are no clinical trials? Sick women do get pregnant, and pregnant women do get sick. They have no access to evidence-based medical care.”
Such women, she continued, “need medications, but they can hardly be given to them due to lack of study. A sick mother is not good for a fetus. If you’re taken off medication because it may harm fetus and then have epileptic seizures, your fetus can suffer from fetal bradycardia [very slow heartbeat] and other serious problems.”
But “many women who are pregnant and have epilepsy are, despite warnings, still taking drugs for the condition, so they should be included in randomized clinical trials to compare them with men. One can do MRI scans of infants and see any effects of the drugs on the fetus and identify blood in the brain. You don’t have to wait for the birth to see any effects. If you see a problem, you can deal with it in utero in prenatal surgery; for example, one can operate in the uterus on fetuses with spina bifida, for example.”
Biegon concluded that medical schools have to teach students differently so they can appreciate sex differences in medicine. “At my school, we will soon start a course on gender- based medicine for fourth-year students.”