Sex chromosomes versus hormones: A phenomenological perspective on the current status of mammals and their implications for biomedical research

People have studied men or male animals for a long time. Even as recently as 2009, only 26% of studies using animals included both female and male individuals, according to a review of 10 fields in the biological sciences1. This bias has had serious consequences. Between 1997 and 2000, for instance, eight prescription drugs were removed from the US market, because clinical testing had not revealed women’s greater risk of developing health problems after taking the drugs.

Ever since scientific enquiry began, people have focused mainly on men, or if studies involve animals, on male mice, male rats or whatever it may be. And this has led to gaps in scientists’ understanding of how diseases, and responses to treatment, and many other things might vary between people of different sexes and genders.

To address these specific complaints, it is useful to briefly review current understanding of mammal biology as it pertains to sex and some of the shocking findings that have already surfaced from research comparing two sexes.

Sex has been a part of the evolution of our species. The division of humans and other mammals into two sexes, female and male, derives from the fact that each individual is created by the union of a sperm and an egg. On the basis of the type of germ cell (gamete) that reproducing individuals are able to produce, there are only two sex categories in mammals. Intersex is not a third category of gamete with regards to the kind of gamete individuals can produce. Indeed, understanding of how the mammalian genome evolved and how it functions is based on the foundation of sexual reproduction.

The medical profession and the biomedical community need to identify and address variations between the sex of the person they were assigned when they were born and their current gender identity. When reporting findings, we need to keep in mind the differences between cis gender, trans and non-binary individuals.

Yet we maintain that, in humans and other mammals, the comparison of individuals who have XX chromosomes and ovaries with individuals who have XY chromosomes and testes is a necessary component of basic and clinical research that seeks to improve human health.

Sex chromosomes versus hormones. The biological hypotheses to explain the sex differences in body weight and metabolism in animals and humans have been centered on the action of hormones. And extensive research during the twentieth century supported the idea that, in mammals, almost all sex differences in tissues other than the gonads (the organs that produce the gametes) result from the effects of ovarian and testicular hormones.

Over the past two decades, investigators discovered that sex-chromosome effects in mice contributed to sex differences in other systems. And these sex differences, in turn, affect individuals’ likelihood of developing autoimmune conditions, cardiovascular diseases, cancer and developmental defects in the neural tube, the embryonic precursor to the central nervous system. The X-linked gene Kdm6a, for instance, increases the severity of autoimmune disease, and protects against bladder cancer and an Alzheimer’s-like disease in XX mice7. Similarly, the Y-linked gene Uty protects against pulmonary hypertension in mice13. Sex-chromosome genes also affect mouse behaviour, from the social behaviour of juveniles to responses to pain, as well as the size of certain brain regions7,10.

This work in mice provides clues about where to look for therapeutic targets in the human genome, for diseases that affect women and men differently.

Whether the microglial or T-cell mechanism for the processing of persistent pain is engaged in any one individual seems to be due to testosterone levels being above or below a certain threshold. The differences between men and women in regards to chronic pain can be attributed to a variety of different mechanisms.

Immune function. Numerous studies that involve comparing immune responses in female and male organisms — whether they are fruit flies, fish, lizards, birds or mammals — have shown that females often generate more robust immune responses to antigens than do their male counterparts16. This suggests that sex differences in immune function are evolutionarily conserved, perhaps because of a common need for female individuals to transfer immunity to the next generation (whether through breast milk or a yolk sac), or because of some other sex-specific selective pressure.

All of this suggests that, in mammals, greater activity of the neuroimmune system is somehow involved in the process of brain masculinization — which means that various mental-health disorders that affect boys more than girls could involve disruptions to immune-system processes.

For instance, experiments measuring cellular activity in post-mortem animals have shown that during development, male rodents have a greater number of activated microglia in certain regions of their brains than do female rodents. These activated microglia release more of the signalling molecules that are crucial to forming synapses and controlling cell numbers. Many of the brain regions affected by the selective elimination of cells are also those implicated in mental-health disorders in humans (in both sexes) that originate during development24.

For both sexes, limited information is collected for most research. For studies involving humans, participants are typically asked to identify their sex and/or gender category; for those involving non-human animals, individuals are usually assigned to a sex category depending on the appearance of their genital anatomy.

The term gender can encompass more than the person’s sense of self as a gendered individual. Gender can be understood as a categorization scheme, in which a person can identify as a man or woman (whether cisgender or trans), as non-binary or with one or more other evolving terms. Gender also encompasses roles, norms, relations and opportunities that vary between cultures and over time, and which affect people’s income, autonomy, domestic and public roles, and their access to power and resources.

Various studies have shown that environmental and social factors can affect people’s biology in numerous ways. People’s exposure to sunlight and their levels ofvitamin D can be influenced by gendered dressing patterns. bone density can be influenced by levels of oestrogen or testosterone, but they should not be thought of as a sex-related trait. The pattern of gendered socialization related to dress, indoor and outdoor play, vigilance about cleanliness, and susceptibility to developing immunodeficiency diseases might result in boys and girls having distinct patterns of exposure to microorganisms. Some scholars are focusing on issues around sex and gender and prefer using the hybrid terms gender or sex.

It is a good idea to research on blood donation. In 2017, researchers in Canada published findings that among frequent blood donors, women had low levels of ferritin (a marker of iron levels) more often than did men18. Canadian Blood Services has decided to increase the time between donations for all female donors from 8 to 12 weeks in response to the study. The Canadian Blood Services has intermittently tested ferritin levels in donors’ blood, but only in women.

In order to ensure that all women are treated the same, the organization has decided to focus the policy on the sex category of the donor, rather than looking at the specific factors that are most likely to be linked to low iron levels. The change to donation interval for women — based on a binary analysis — also glosses over the heterogeneous and overlapping nature of the data, including the fact that the frequent donors also included women who did not have low iron levels, and men who did. A more nuanced interpretation of the findings, along with further research that probed the specific sex- and gender-related factors that increase people’s risk of developing low iron levels, could allow policies to be refined in ways that are better oriented to the mechanistic factors that matter most.

Canadian Blood Services recognizes that blood donors are heterogeneous and it uses simple criteria to divide donors into accepted and deferred groups, according to a spokesman for the organization.

NaturePodcast: Science, politics, and the polarized agenda in the debate about T-cell therapy for colon cancer: What can scientists and scientists can do about it?

Someone studying a new T-cell therapy for colon cancer might propose that gonadal hormones might modify the efficacy of the treatment, because T cells possess receptors for both oestrogens and androgens. The researcher could look at correlations between the efficacy of the drug and the levels of hormones in people with colon cancer if they were conducting a study on the subject. If they were working with amouse model of colon Cancer, they could use antagonists or agonists of the relevant hormones to supplement the animal’s diet. A different approach is needed if the researcher is interested in whether the sex of the T-cell donor affects the effectiveness of the treatment.

But all this research is going on within a sociopolitical climate that’s becoming increasingly hostile and polarized, particularly in relation to gender identity. And in some cases, science is being weaponized to push agendas, creating confusion and fear.

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