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For many years, the majority of medical research was carried out on men, and treatments were prescribed with no regard to the different physiology of both sexes. The solution lies in medicine that is conscious of gender and sex

In the past, men used to go to the tailor to have their suit fitted. They would choose their fabric preference, come to a few fittings and then would enjoy the final product. Now imagine that the man’s life partner also needs a suit. Would he ask the tailor to use his own measurements, reduced by 30 percent and sew an identical suit, with no additional fittings? Is it reasonable for most feminine suits to be sewn based on men’s measurements? Ridiculous, but this is exactly what is still happening in modern medicine. The majority of research on medicine and disease was carried out on men, and the results are applied to women as well.

If the differences between the sexes were limited to the reproductive systems and body weight, there wouldn’t be a significant problem. But this is not the case. There are functional differences between men and women in nearly all of the body’s systems. The differences are sometimes small, but they are important and influence health and disease. The same diseases can appear at different rates in men and women and with different symptoms; the same treatment, given for the same disease, can have different effectiveness for a woman or a man and the intensity of side effects can also be different. Gender medicine deals with these issues. The field inherently deals with improving the quality of medicine for both sexes, however in this article we will focus primarily on its implications for the medical treatment given to women.

 

רישום של גבר ואישה | איור: ProStockStudio, Shutterstock

The differences between sexes affect health and the effect of treatments | ProStockStudio, Shutterstock

Multiple Differences

Whether we become male or female is determined biologically by our sex chromosomes and is usually binary. In contrast, our identity of gender as a man, as a woman or as non-binary is a subjective or social matter on a wide spectrum of variations. The biological sex and gender are inseparably interconnected and this is of utmost importance to how our body functions in sickness and in health.

Women differ from men not only genetically and biologically but also usually in height, weight and almost always in the ratio of body components. Men and women are subject to different hormonal effects starting from the fetal stage and continuously through life. Women have a monthly menstrual cycle, they can undergo pregnancies and lactation periods, and experience menopause – which exists in men as well, but is much rarer. There are also many phenomena and diseases, both physical and mental, that are affected by the menstrual cycle. For example, surgical wounds heal better for women who are in their first half of their menstrual cycle, while during the second half the threshold of pain increases.

As a general rule, women experience pain differently than men. Their threshold of pain is usually lower, but they know how to deal with pain better and react differently to different analgesics. In addition, chronic pain diseases are much more common in women. A migraine, for instance, is a phenomenon that 17 percent of women experience, compared with only 6 percent of men.

Fibromyalgia – a disease characterized by muscle and skeletal pain – is about nine times more common in women than in men. There are also differences relating to gender. Women sometimes communicate pain differently than men, and society, including the medical establishment, tends to relate differently to women’s pain and men’s pain.

תופעות ומחלות רבות, גופניות ונפשיות, מושפעות מהמחזור החודשי | תרשים: PegasuStudio, Shutterstock

Many phenomena and diseases, both physical and mental, are affected by the menstrual cycle | Illustration: PegasuStudio, Shutterstock

“Men only” Medications

An especially important issue is the differences in the function of medications in men and women. The action of drugs in our bodies is highly dependent on how they dissolve and disperse throughout our tissues, namely in water, in fat or in muscle, as well as on the efficiency at which our metabolism processes them and expels them from the body.

In this field of pharmacokinetics, there are many differences between men and women. Take a man and a woman, both in excellent physical shape and an identical body weight of 75 kg, the man’s muscle mass will be greater by about 20 percent, while the woman will have almost twice as much fat tissue than the man. Despite this, most medications today are sold at an identical dosage for both sexes, and in the majority of cases body weight is not accounted for. Where did this come from?

Since its establishment, the FDA (Food and Drug Administration) has approved approximately 1,500 new drug components. Only about a third of them were approved after the year 2000, when the FDA began to fund only clinical research where the treatment was also tested on women. In other words, most medication in use today was never tested on women.

Ignoring women in clinical trials was not necessarily due to deliberate discrimination. It had a lot to do with two medical disasters that occurred in the middle of the previous century. First, in the ‘50s, a significant increase was observed in malignant tumors in the genitals of children of women who had taken a medication to decrease bleeding called DES – a synthetic form of the female hormone estrogen. About ten years later another disaster occurred, where women who had taken the anti-nausea medication Thalidomide gave birth to children with severe deformities of their extremities and suffered an infant mortality rate of about 40 percent.

Following these events, the FDA issued a warning in 1977 not to include women in clinical trials, to prevent possible damage to fetuses. Although the warning was only regarding women of fertile age, the drug manufacturers and many of the independent researchers gave up entirely on including women in their studies. An additional contribution was the fact that research on women tends to be more complicated and expensive due to their more complex hormonal system. Despite much effort put in since by decision makers and medical and research establishments, this skew has not yet been fully corrected. And lastly, many women are not particularly keen on participating in clinical trials.

 

בקבוקון של התרופה DES | צילום: FDA / Science Photo Library

Given to pregnant women and damaged their children. A vial of the medication DES | Photo: FDA / Science Photo Library

Digestion and Metabolism

Most medication is taken orally and is absorbed in the digestive tract. The difference between sexes is already observable here, as the time required for material to pass the digestive system is significantly longer for women than it is in men. This fact is first and foremost important for food digestion, but is also important in the absorption of medication. So here is a small tip: when the direction is to take a certain medication on an empty stomach, it is recommended that women don’t suffice with the usual two-hour fast, but wait an extra half hour to hour between the last meal and taking the medication.

There are many differences in the digestive tract between men and women. Irritable bowel syndrome (IBS) for example, is four times more common in women and some medications for the treatment of the syndrome affect men and women a bit differently. Gallstones are four times more likely to develop in women, especially during periods such as pregnancy, where the level of estrogen increases. Ulcers in the duodenum are twice as common in men, while inflammatory bowel diseases, such as Crohn's and colitis, are 1.5 times more common in women.

The composition of gastric acid is different for men and women. For example, the levels of the enzyme that metabolizes alcohol even before it enters the bloodstream, are five times higher in men, which is why women get more intoxicated than men from the same amount of alcohol. Much like alcohol, certain medications are degraded faster in the stomach in men – such as the sedative Diazepam, Imipramine which is used to treat depression, and Propranolol which reduces blood pressure. In practice, this means that in order to reach the same blood level of these medications, women need a lower dosage, or suffer from stronger side effects.

The most important processes of metabolism are those that occur in the liver. In laboratory experiments, it was discovered that women's liver cells are more sensitive to the damage caused by paracetamol (Acamol) and a few other medications, compared with liver cells from men. Likewise, the first stage of metabolism in the liver is about 50 percent more efficient in women, as is the case for the antipsychotic drug haloperidol. In contrast, the second stage of metabolism, which is also carried out in the liver, is more efficient in men for example – such as for paracetamol.

In addition, there is a difference between the sexes in the efficiency of removing certain medications from the body through the kidneys: for women, this function is about 10 percent slower than in men. This is the case for the removal of Digoxin, a medication for the treatment of heart disease.

תסמונת המעי הרגיז | איור: John Bavosi / Science Photo Library

Four times more common in women. Irritable bowel syndrome | Illustration: John Bavosi / Science Photo Library

What’s the Dosage?

Since most medications have been studied only on men, a grim situation has arised. It is obvious that women, even if their body weight is taken into account, on occasion receive inappropriate dosage of medication. In a review of 5000 studies looking at properties of medications, it was found that 76 out of the 86 medications reviewed elicited negative side effects for women. Taking into account the pharmacokinetic differences between the sexes, there is a 96 percent correlation between them and side effects in women, compared to a mere 29 percent correlation in men. These differences cannot be explained by differences in body weight.

The current situation, where men and women are prescribed the same medications at the same dosage, which is usually not even adapted to body weight, is clearly unreasonable. This may be one of the reasons that women who take medication experience nearly two times more side effects than men.

Side effects are no small matter. About 5 percent of unplanned hospitalizations are related to side effects from medication. Beyond the physical and mental pain they cause, side effects may cause patients to temporarily or permanently stop taking the medication. This impairs the efficiency of treatment and poses a health risk.

The first revolutionary step to solve the problem was taken in 2013, when the FDA recommended drug manufacturers to reduce the dosage of Zolpidem, a medication for sleeping problems, by 50 percent when prescribed to women, unrelated to their body weight. A similar instruction was given a year later for Flurazepam, also used for treating insomnia.

 

 ה-FDA המליץ להפחית את המינון לנשים של חלק מהתרופות לנדודי שינה | צילום: SCIMAT / Science Photo Library

The FDA recommended reducing the dosage of a few insomnia medications for women | Photo: SCIMAT / Science Photo Library

Same organ, different function

In order to better understand the consequences of the differences between the sexes in relation to medical situations, we’ll turn to the brain: the most essential difference is that males and females have different sex chromosomes in their cells. Almost every cell in our bodies is assigned a sex – either male or female, depending on the two sex chromosomes it has. Since the genetic composition serves as a roadmap for all our cells, a difference in the genetic makeup is related to a difference in the functioning of the cells and the systems in which they reside.

In addition, even in the womb the male and female brains develop in completely different hormonal environments. The differences between the sexes are evident by the size of the brain, the composition of the cells in the brain and their organization, in the connection between the cells as well as in the functioning of specific cell groups.

The brain continues to develop after birth, and is continually affected by the environment, gender and expectations and definitions every society has for each gender. All these have developmental consequences that lead to differences in cognition, behavior and function. For example, the hypothalamus is an area in the brain that controls many basic functions, such as eating and sleeping, as well as the functioning of the ovaries and testicles. In a human female, the hormonal stimulation of the ovaries is pulsated, which is why she has a monthly menstrual cycle. In a male, the release of hormones to stimulate the testicles is nearly steady, which is why the production of sperm cells continues pretty much incessantly. The male and female hypothalamus might look identical and secrete the same hormones – but their pattern of function is different, and therefore the way the gonads function is also different.

Another example are the lungs: they are more vulnerable in women than in men, so much so that the risk of a female smoker to develop lung cancer is double that of a man smoking a similar amount of cigarettes.

Cardiovascular diseases can also manifest differently in men and women. The classic signs of a heart attack are well known, but about a fifth of all women who undergo a heart attack present with very different symptoms, which include stomach or chest pain which develop slowly and do not radiate to the left shoulder and arm, but rather to the neck and chin. If the woman and people around her, or the medical staff, do not know to attribute these symptoms to a heart attack, the diagnosis might be delayed, as well as the treatment. The consequences of this could be fatal. In the developed world, more women die each year from coronary disease and vascular diseases than all types of cancer combined. Furthermore, even after a heart attack has been diagnosed, women many times receive inferior care compared to men under the same circumstances. This outrageous fact has no other plausible explanation except misogyny. In Israel the data is more encouraging, both regarding the treatment outcome and the equality of treatment between male and female patients.

 

סריקת גלי מוח | צילום: DC Studio, Shutterstock

The male and female brain differ in size, structure and function. Brainwave scan | Photo: DC Studio, Shutterstock

Fetal programming

Differences between the sexes develop long before birth. Beyond the difference in the genetic makeup of the cells of both sexes, the hormonal environment in the womb where they develop is very different. As a result, their development is different. Furthermore, things affecting the pregnant woman could also reach the fetus, sometimes in an increased fashion, depending on the sex of the fetus. This is true regarding the mother’s diet, environmental toxins, alcohol, smoking, and stress. This is the basis of a process in mammal development termed “fetal programming”.

The COVID pandemic is worth mentioning in this context. The pandemic has brought on an alarming three-fold increase in depression rates, reaching 22 percent in men and 33 in women. The incidence of stress and PTSD has also increased, but with no discernible difference between the sexes.

Stress and depression during pregnancy can affect the fetus as well. This can be observed in hindsight of large disasters in the past: it was found that the children of pregnant women who had lived under continuous or severe stress had a significantly higher chance of developing a wide range of disorders, including mental illness, throughout their lifetime. This was more evident in girls and women.

An important research study carried out in Jerusalem included about 90 thousand subjects, including people who were in their mothers womb during the six day war in 1967, during the Yom Kippur War (1973) or during a calm period. Schizophrenia was significantly more prevalent in children of mothers who were pregnant during wartime, compared to children born to mothers who were pregnant with them during peaceful times. Girls whose mothers were pregnant during wartime were 4.3 times more likely to develop schizophrenia as opposed to boys, whose risk only increased 1.2-fold.

Tamar Wainstock and her colleagues from Ben-Gurion University studied two groups of pregnant women from similar socioeconomic backgrounds who gave birth during the same time period at the same medical center. One group included 1,846 women who lived in the “Gaza envelope” who were exposed to rocket fire and frequent and sudden sirens during their pregnancy. The 2,275 women in the second group lived at an aerial distance of 5-25 kilometers from the border with the Gaza strip and were not exposed to sirens. The children of the first group were, on average, born after a shorter pregnancy, lower birth weight, and with a smaller head circumference. The differences were statistically significant for baby girls, but not the boys.

 

אישה הרה וגבר עוטים מסכות נגד קורונה | איור: MOONG H, Shutterstock

The COVID pandemic, isolation and false information increased rates of stress and depression, that could also affect the fetus | Illustration: MOONG H, Shutterstock

Natural disasters have a similar effect. The COVID pandemic, accompanied by home isolation, physical distancing, spreading of false information and amplifying it on social media, all brought on an increase in rates of stress and depression pregnant women are exposed to, along with their fetuses. Of course not all fetuses are exposed to such situations in the mothers womb during COVID, and not even all of them, rather a larger than usual proportion.

This should suffice to compel us to ready ourselves for the possible mental consequences of the pandemic for those who became pregnant or were born during the pandemic. Mothers need all possible protection and support, for their benefit as well as for their fetuses, to prevent – or at least mitigate – the potential mental damages. This is not a done deal and there are many things that can be done to make it easier for mothers to cope with this period of crisis. Only after recognizing the facts and the risks, is it possible to prepare for them and take precautions to protect against them.

Such precautions include organized dispersal of information that has been fact-checked, a balanced diet of the mother, physical activity, social support of the pregnant woman, decreasing pressures at work and at home, creating support groups, avoiding toxins and monitoring medical treatments. All these could positively affect the programming of the fetus. In addition, the environment that the mothers and children are exposed to after birth should also be taken into consideration.

The prenatal services and pregnancy monitoring services in Israel are indeed very good, but they are also in need of further upgrade, including raising public awareness and the awareness in the medical system to fetal programming. Only if we acknowledge that the treatment of a pregnant woman concerns at least two people – the woman in the present, as well as the future of her fetus or fetuses – we will realize how much of a responsibility we have to provide the mother and her fetus with protection and support. This is truer than ever during times of economic and medical crises such as during the pandemic.