Why brain, liver or kidney are not quite the same depending on whether you are male or female

Some differences between males and females are obvious, and visible to the naked eye. But sexual variation also exists in the cells of non-genital organs, such as the liver and kidneys, which explains why organisms function differently depending on the sex of their owner. What mechanisms make it possible to achieve this difference? At what point in development do they take place? And could we learn from this to better treat women and men, based on their gender?

A study published at the beginning of November in the journal Science reveals the genetic mechanisms allowing these particularities of dimorphic organ cells to be acquired. The researchers carried out a genetic study in humans, rats, mice, rabbits, opossums, hens and chickens. They identified genes sensitive to sexual difference and pinpointed their places and times of expression in five organs: the brain, cerebellum, heart, kidneys and liver.

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If testes and ovaries largely acquire their differences during embryonic development, many morphological differences between males and females only become apparent at sexual maturity. And to the surprise of American researchers, the same is true for non-sexual organs. “We expected to see a gradual increase in sex differences during organ development, but we saw a steep increase around sexual maturity. This research is another piece of the puzzle aimed at understanding why we are sexually dimorphic and how this affects us,” explains Margarida Cardoso Moreira, co-leader of the study, in a press release.

Certain genes are sensitive to sex hormones (androgens for males, estrogens for females), which act as activators or inhibitors of gene expression. Depending on the species, the dimorphic organs are not the same. Thus, the authors found that the livers and kidneys of rats and mice show sexual dimorphism, while for rabbits this difference concerns more the heart. “This has implications for how we use animal models to understand sex differences in humans,” says Margarida Cardoso Moreira. In reality, few genes are thus “sexist” by activating preferentially in one sex and less in the other. The study reveals that the trigger for the acquisition of sexual dimorphism is probably the difference in chromosome lining in the cells, "XX" for females and "XY" for males, as well as sex hormones of which we observe a high concentration from puberty.

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In human medicine, does this mean that for the same pathology, men and women should be treated differently? “The individualization of treatment according to sex is exceptional. The only example to my knowledge concerns a treatment for insomnia, zolpidem, in the United States. The dosage is reduced in women, because they have more adverse effects following a higher concentration of the compound in the blood,” testifies Professor Jean-Christophe Lega, researcher at Lyon 1 University and practitioner in internal medicine at Lyon South hospital center.

Why so little adaptation to the sex of the patient? Catherine Vidal, neurobiologist, honorary director of the Pasteur Institute in Paris and member of the Inserm ethics committee, specifies that “no drug agency other than the American agency has made this decision. In 2019, a new analysis on the same data on zolpidem made it possible to deduce that the differences were due to pharmacokinetics, that is to say the different densities between men and women, and not directly linked to sex . The idea of ​​making gender-specific drugs never came to fruition.” Jean-Christophe Lega adds that “differences between individuals, regardless of sex, have more impact on treatments than differences linked to sex”. He specifies that “the numerous studies show little effect of sex but other factors have more effects such as mass, size, age or geographical origin”.