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Women at greater risk of severe diseases
It is not generally known that some potentially severe diseases are more common, or even more severe, in women than in men. Understanding the molecular mechanisms underlying these differences has proved crucial to the development of treatments adapted to the sex of a patient.
Autoimmune diseases are among those that affect women more. This is the case for multiple sclerosis, which attacks the brain and bone marrow and can cause visual disturbances, pain and mobility issues; rheumatoid arthritis, which among other symptoms causes joint pain, stiffness and swelling; or lupus, which may give rise to joint pain, skin rashes or severe kidney disease. As their name suggests, these conditions are due to an immune system that is too strong and turns on the individual, targeting their own tissues and organs: myelin (the sheath that protects nerve fibres) for multiple sclerosis; joints in the case of rheumatoid arthritis; and a variety of organs (joints, skin, kidneys, lungs, etc.) for lupus, etc.
“Women tend to have stronger immune responses than men,” explains the biologist Céline Morey, who is studying the causes of sex bias in autoimmune diseases at the Epigenetics and Cell Fate laboratory (EDC)1. “This enables them to respond better to vaccines and generally to be more resistant to different types of pathogens, such as viruses or bacteria.”
However, this strong immunity has a flipside: an increased predisposition to autoimmune diseases, with 80% of sufferers being female.
XX chromosomes and XXL immunity
In 2024, the researcher and her colleagues demonstrated the implication of a biological phenomenon called “X chromosome inactivation”. Two sex chromosomes – X and Y – determine the gender of a person. Males have a single X (and a Y), while females have two Xs. And the X chromosome – which is larger than Y – is known to be rich in genes involved in the immune system.
From the start of embryonic development and throughout adult life, one of these Xs is silenced at random in each cell of females. This is the X chromosome inactivation process, which places the two sexes on a par in terms of the number of genes expressed on X. However, some of these escape this inactivation, either partially or totally. This may contribute to an overexpression of several genes involved in immunity, making it too reactive.
To verify this hypothesis, Morey and her colleagues triggered defects in the inactivation of one of the two Xs in female mice. These notably affected genes in the family of Toll-like receptors (TLR) which are known to contribute to the onset of autoimmune diseases when they are over-activated. As expected, the rodents developed signs of inflammation typical of lupus, such as an increase in spleen size and in the number of certain immune cells in the blood.
The next step for the scientists was to try and precisely identify those genes that, when strongly inactivated, contribute to the symptoms of lupus. “Targeting these gene sequences could reduce the severity of this disease or prevent its onset in women,” states the scientist. This strategy could also be applied to other autoimmune diseases.
The role of sex hormones
Another type of condition linked to excessive immune response also affects women in particular, namely allergies – where the immune system attacks basically inoffensive substances such as peanut, egg, fish, pollen or dust, etc. The incidence of these diseases has increased exponentially in recent years and now concerns 25%-30% of the population.
The team led by Sophie Laffont-Pradines, immunologist at the Toulouse Institute for Infectious and Inflammatory Diseases2, is focusing on allergic asthma. This inflammation of the bronchopulmonary mucosa is triggered by allergens and causes breathlessness, cough, breathing difficulties and wheezing. “Before puberty, boys are more affected,” explains the biologist, “but in adulthood, twice as many women than men suffer from allergic asthma. Furthermore, they develop more severe forms of the condition”.
What is the reason for this reversal? The work by Laffont-Pradines and her team points to androgens, hormones often referred to as “male” and whose levels rise at puberty in boys but not in girls. During two recent studies involving mice and asthmatic patients, respectively, the scientists demonstrated that androgens provide protection from allergic asthma by directly inhibiting the proliferation and functions of a population of immune cells crucial to the inflammatory response that underlies this disease, i.e. type 2 innate lymphoid cells.
Their findings suggest that sex hormones appear to play a more important role than hitherto suspected regarding gender bias in health, and have also brought some hope: “The development of molecules that can mimic the action of androgens – by binding to their cell receptor – could lead to treatments that are able to reduce the frequency and severity of allergic asthma in women,” explains the immunologist.
More severe cancers
However, there is more than diseases linked to overactive immunity. Some cancers that were previously considered as non-hormone-dependent (i.e. not favoured by sex hormones) may in fact be influenced by them.
This has just been confirmed by the recent work of Véronique Delmas and Lionel Larue, biologists in the Signaling, Radiobiology and Cancer laboratory3. The scientists analysed the incidence of 24 cancers in 185 countries. They observed that between puberty and menopause, a period when women are subject to high levels of oestrogens (female hormones), no fewer than 13 out of the 24 cancers are more common in women than in men of the same age.
“This is especially the case for melanoma, the most severe form of skin cancer, but also for cancers of the thyroid, stomach or salivary glands,” Delmas points out. “Women aged between 20 and 54 years have about twice the risk of developing a melanoma than men in the same age group.”
The researchers also discovered a cascade of hitherto unknown biochemical reactions that link oestrogens to an increased risk of tumour dissemination – and hence a deterioration of these cancers. “Targeting this mechanism regulated by female hormones could open the way towards new therapeutic approaches,” Delmas hopes.
The second disease most feared by the French after cancer is Alzheimer’s, which is caused by a slow degeneration of neurons and affects around one million people in France, 60% of them women, according to the Paris-based Alzheimer’s Research Foundation. Over the course of their lives, women have twice as much risk of developing this condition, which causes a gradual deterioration of memory, language and cognitive abilities. Among the explanations explored by research is the weaker ability of female microglia (a group of cells forming the immune system of the brain) to fight against the formation of amyloid plaque, deposits that accumulate between the neurons and prevent their correct functioning.
Although the initial findings are encouraging, research on diseases showing a sex bias is still in its infancy. ♦
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Long Covid and menstruation
Affecting around 4% of the French, long Covid is defined as a persistence of symptoms for more than three months after an infection. Fatigue, breathlessness, difficulty concentrating and muscle pain are symptoms that are generally the same in women and men. But there is one difference: in women, it also causes more abundant or longer periods.
This has just been revealed in a vast study conducted in more than 12,000 British women by Alexandra Alvergne, at the Institute of Evolutionary Science of Montpellier (ISEM) in southern France4. “This abnormal menstruation may be linked to an over-production of 5α-dihydrotestosterone, a hormone involved in the production and migration of cells in the endometrium (the mucous membrane that coats the inner surface of the uterus) during periods,” explains the scientist. “And these symptoms may be exacerbated by an inflammatory reaction. Indeed, our analyses have shown an increase in the production of molecules favouring inflammation during menstruation among these women affected by long Covid.” All researchers now have to do is to rigorously establish the cause and effect relationship. ♦
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Author
A freelance science journalist for ten years, Kheira Bettayeb specializes in the fields of medicine, biology, neuroscience, zoology, astronomy, physics and technology. She writes primarily for prominent national (France) magazines.