Fine distinctions

Women have two X chromosomes and no Y chromosomes. They also have different primary and secondary sexual characteristics. That is true. But there are also much finer biological distinctions between women and men. “Not only are women usually smaller and lighter and have smaller organs: Their metabolic processes and immune system also work slightly differently,” says Susanna Hofmann, Professor of Lipid Metabolism and Metabolic Diseases at LMU’s Faculty of Medicine. “The fact that such gender-specific differences can be of medical relevance is attributable to complex interaction between genetic, hormonal and cell biological factors,” she says. Hofmann also leads an independent research group on the subject of women and diabetes at the German Research Center for Environmental Health. The group studies gender-specific differences and develops personalized approaches to medicine.

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While many of these interactions are not yet known, numerous research findings are already showing how important it can be for female patients if medicine is aware of the differences. Why? Because besides having different disease risks to men, women also frequently present different symptoms, experience different disease progressions and respond differently to treatments.

Perhaps the best-known example today is the heart attack. In women, it is less common for a heart attack to present with typical symptoms such as chest pains or shortness of breath. Instead, women often experience less specific symptoms: In them, a heart attack may express itself through heavy tiredness, breathlessness, nausea, complaints in the upper abdomen and pain in the upper back. As a result, heart attacks in women are often recognized too late, and more young women die of heart attacks than men in the same age bracket.

Moreover, the belief that heart attacks are a “typically male disease” is only partially true. Since estrogens have a positive impact on the vascular function, female sexual hormones influence the risk of illness in the course of their life. Before menopause, heart attacks are less common in women than in men. However, if the estrogen level declines in the wake of menopause, they are equally at risk. “Their risk of developing metabolic diseases such as diabetes or cardiovascular conditions also increases noticeably in this case.”

Women have a “more attentive” immune response

Unlike the male hormone testosterone, estrogen tends to activate the immune system. Women’s immune system is therefore “more attentive”, with the positive effect that women are better protected against infectious diseases. “We are seeing this now in the mortality statistics from coronavirus infections,” Hofmann notes. “In addition, women produce more antibodies after vaccinations and may therefore be more protected.” However, a more active immune system also tends to attack the body’s own organism, which means that women more frequently suffer from autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Hormonal factors likewise explain why women metabolize medicines differently to men, causing the reaction to active ingredients to vary. Generally, women display a slow gastrointestinal transit compared to men, with delayed gastric emptying and reduced colonic transit time. Thus, active ingredients are broken down more slowly, such that the effect of administered medicines may be amplified or extended. This has been clearly shown in zolpidem, the active ingredient in a sleeping drug, for example. If women take the dose originally determined for male probands, their reactions are still considerably slower even the next morning. Since this discovery, the recommended doses have been adjusted.

“Not all differences between women and men can be traced back to hormones or genes on the sex chromosomes, however,” Susanna Hofmann affirms. “Complex gene expression patterns are also often involved.” Indeed, even minor anatomical differences can mean that it makes sense to vary the way conditions are treated. For example, women have a shorter urethra than men and therefore suffer more frequently from bladder infections. Additionally, lots of drugs raise the sugar content of urine and thereby increase the probability of inflammation. It would therefore often be better to administer different drugs and possibly save female patients many a bout of cystitis.

Getting the dosage right

Gender-specific medical research is still in its early days, though. “Gender-specific differences only came into any kind of focus in the closing decades of the last century,” Hofmann says, formulating a clear demand: “In our research into diseases, drugs and therapies, we need to more systematically address the question of whether gender-specific differences exist.” As early as the preclinical trial stage, this involves testing active ingredients on male and female cells and mice, as well as assembling balanced proband groups for the clinical trials themselves.

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“It is important to spot indications for gender-specific distinctions that could subsequently be of importance to drug dosages as early as possible,” Hofmann stresses. In medical practice, cardiologists and endocrinologists, for example, should then work together to better assess how the hormonal balance influences cardiovascular diseases. “Apart from which,” Hofmann adds, “many standard medical reference works focus on studies that tend to have been normalized around men.”

This being the case, it is important to also place greater emphasis on gender-specific aspects when training future doctors, she notes. More generally, overcoming preconceived ideas about typical “men’s” and “women’s” illnesses would help as well: “For example, many people instinctively associate a man clasping the left side of his chest with a heart attack," Hofmann explains. It follows that knowing more about how heart attacks present in women would help patients themselves and the people around them to more quickly seek the right medical assistance.

In the long term, Susanna Hofmann sees gender-specific medicine as a step toward fully personalized therapy: “Building on what we already know about the more obvious gender-specific differences, we now need to research so many more details and, in future, add in other factors such as age and genetic predispositions.” This more nuanced perspective involves a lot of work and requires the analysis of large sets of data, Hofmann admits. But it will get easier and therefore more important with time. “Medical research in general is already moving more toward individualized medicine, which is already very advanced in the treatment of cancer, for instance,” she says. In this field, immune therapies are now specifically attuned to the patient’s tumor subtypes.

Nicole Lamers

Prof. Dr. Susanna Hofmann is Professor of Lipid Metabolism and Metabolic Diseases at LMU’s Faculty of Medicine. She also leads a research group on the subject of women and diabetes at the German Research Center for Environmental Health.

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