Sex and gender are explored in research
Biological effects of sex in mammals: A review of recent results in biology and public health including implications for maternal and baby-adult mortality
For as long as scientific inquiry has existed, people have mainly studied men or male animals. 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. The consequences of this bias have been serious. Eight prescription drugs in the US were removed from the market between 1997 and 2000 because clinical testing couldn’t be found that showed a higher risk of health problems for women taking the drugs.
Understanding the effects of sex also anchors discussions about how different gendered environments intersect with biological differences, to amplify or mitigate their effects. Research on animals has been important in developing concepts of sexual differentiation because animals have more flexibility in manipulating single genes or molecule than humans. Moreover, although numerous environmental or social effects can be manipulated and studied in animals, such as diet, stress and levels of interaction with other individuals, animals provide useful models of the biological effects of sex in the absence of hard-to-control human gendered variables, such as cultural norms and expectations around child care and work.
The biological difference between males and females starts with the sex chromosomes which are the only differences between males and females at the beginning of life in mammals. The sex chromosomes are important in determining whether the embryo will be able to develop into an ovarian or testicular embryo because of the type of germ cell and secretory patterns. Sex-chromosome genes and gonadal hormones affect almost everything in the body. The result might be sex differences in tissue development and function, or similar phenotypes based on different underlying mechanisms7.
Sex has been with us since our species originated as a result of sexual reproduction. 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 part of the third category, which deals with the type of gamete individuals can produce. Understanding how the mouse genomes evolved and how they function is based on sexual reproduction.
To serve all individuals equitably — including those who experience an incongruency between the sex they were assigned at birth and their current gender identity, and those who do not find that they align with either the male or female sex category — the medical profession and biomedical community must identify and interrogate these variations in biological attributes and in lived experiences, all of which can influence people’s physiology, risk of developing disease and prognosis8. This includes carefully attending to the distinctions between cisgender, transgender and non-binary individuals when reporting findings.
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 are related to hormones. The biological hypotheses that explain the sex differences in body weight and metabolism were centered on the action of hormones until recently. 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.
Sex differences in many different parts of the body in mice have been linked to sex-chromosome effects. The risk of developing cardiovascular diseases, cancer and a host of other conditions, as well as the likelihood of developing birth defects, are affected by the sex differences. There is an X-linked gene and it protects against bladder cancer and an Alzheimer’s-like disease in mice. Similarly, the Y-linked gene Uty protects against pulmonary hypertension in mice13. Mouse behaviour is affected by sex-chromosome genes from social behaviour of juvenile to responses to pain and the size of certain brain regions.
All of this work in mice provides investigators with clues about where to look for potential therapeutic targets in the human genome, for diseases that tend to affect women and men differently.
The T-cell mechanism for processing persistent pain, whether it’s a microglial or T-cell, may be related to testosterone levels. This dimorphism suggests that different physiological mechanisms could contribute to some of the differences observed in men and women in relation to chronic pain.
Sex and Gender Dependence in the Development of Brain Muscles and Immuno-Inflammatory Disorders in Humans (and Other Non-Human Animals)
During the reproductive years, the amount of antibodies produced by males and females in response to immunological stimuli changes, and is the most robust. This could help explain why females of reproductive age are less likely to get sick from vaccines than males do, and why female responses to vaccines are more durable and cross- reactivity than male responses.
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 most research that considers sex and/or gender, limited information is collected for either attribute. For studies involving humans, participants are typically asked to identify their sex and/or gender category, while for those involving non-human animals, people are usually assigned a sex category based on the appearance of their genital anatomy.
Similarly, the term gender encompasses much more than people’s sense of self as a gendered individual, or their ‘gender identity’. 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. Roles, norms, relations and opportunities that are different in cultures and over time 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. Gendered dressing patterns affect people’s exposure to sunlight7, for instance, affecting their levels of vitamin D, which can in turn influence bone density8,9. In other words, although bone density is affected by levels of oestrogen or testosterone, it should not be understood as solely a sex-related trait, but as something that is shaped by social and environmental factors rooted in gender, too. Similarly, patterns of gendered socialization related to dress, types of play (for example, indoor or outdoor) and vigilance about cleanliness might result in boys and girls having distinct patterns of exposure to microorganisms — which could, in turn, have implications for the maturation of their immune system and susceptibility to developing conditions such as an allergy or autoimmune disorder10. Some scholars focusing on issues around sex and gender use the hybrid terms gender/sex or sex/gender in recognition of such entanglement11,12.
It is possible to take 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 changed its policy on donation intervals after seeing the study and extended the time between donations from 8 to 12 weeks for women. (Since January 2023, Canadian Blood Services has also been intermittently testing ferritin levels in donors’ blood, but only in women.)
By focusing the policy on the sex category of the donor, the organization effectively treats all women as being at the same risk of low iron levels, which is higher than that of men, without attending to the specific factors that are most likely to be mechanistically related to that risk: body size, amount of menstrual blood loss and dietary iron intake. The fact that frequent donors included both women with low iron levels and men with high iron levels also made the change to interval for womenglosses over the heterogeneity of the data. 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.
A spokesperson for Canadian Blood Services said that it recognizes that blood donors are a heterogeneous population and that it uses standardized, simple criteria to divide donors into accepted and deferred groups.
Nature Podcast – Tuning in on the impact of sex and gender in the study of colon cancer treatment using Gonadal Hormones
Someone studying a new colon cancer therapy might propose that gonadal hormones could change the effectiveness of the treatment, because they have both oestrogen and androgens in T cells. A researcher could evaluate correlations between the efficacy of a drug and its levels of hormones in people with colon cancer, if they decided to conduct a study. They might give the animal hormones or give it a pill if they were studying colon cancer in a mouse model. A different approach would be needed if the researcher was interested in whether the sex of the T-cell donor changes the efficacy of the treatment depending on the sex of the recipient.
The tide, however, is turning. Many journals, as well as funders such as the US National Institute of Health, have guidelines and mandates to encourage scientists to consider sex and gender in their work.
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A recent study found that people with low iron levels are treated similar to people with high iron levels regardless of their sex. The study, conducted by the University of Cambridge, found that low iron levels were more likely to be found in men and women with a lower body size. The study’s findings could allow policies to be refined, it added.