Sex talks shouldn’t be toxic
Sex as a Biological Variable: A Baseline Measurement for Comparing Basic Research Results from Humans and Mammalian Individuals
The National Institute of Health implemented extra guidelines to correct the persistent imbalance in 2016 when they included sex as a biological variable in all research. At least with respect to the inclusion of female individuals in basic research, this funding-agency mandate and others like it have been effective. Another bibliometric analysis found that 49% of 720 studies on animals published in 2019 used both males and females3.
Importantly, the study of female and male individuals, as defined here, establishes a baseline measurement against which to compare findings from those who do not fit into a binary categorization scheme.
Sex is a categorization scheme in which individuals are classified into male, female or intersex and a complex constellation of personality characteristics that show considerable variability among individuals. Sex-related factors and traits include anatomical features, hormones, levels of gene expression and physiological, reproductive, metabolic or neurological processes — but no single trait comprehensively defines an individual’s sex. Development processes that occur during sexual differentiation in all animals, and not just humans, are not determined by single genes. Instead, sex phenotypes emerge from the complex interplay of numerous molecular pathways that can be influenced by environmental experiences through epigenetic, endocrine, neurological and other mechanisms across people’s lifespan6.
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 third category with respect to the type of gamete individuals can produce.) Understanding the mammalian genome is based on how sexual reproduction works.
If the medical profession and the biomedical community want to serve all individuals equally, they need to identify and interrogate any variations in sex assigned to them at birth. When reporting findings, it is necessary to understand the differences between cisgender, trans and non-binary individuals.
The comparison of individuals with different types of chromosomes and tests is a necessary part of medical research thatseeks to improve human health.
Sex chromosomes are more important than hormones. The biological hypotheses that explain the sex differences in weight and metabolism in animals and humans used to be 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 have found that similar sex-chromosome effects contribute to sex differences in many other physiological systems in mice. Sex differences affect individuals’ likelihood of developing many diseases, including cardiovascular diseases, Cancer and developmental defects in the neural tube. 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. In mice, the Y-linkedgene Uty protects against pulmonary hypertension. 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.
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.
Pain researchers have proposed various gender-based and sex-based explanations for these differences14, such as that women are more likely than men to go to the doctor, as shown by usage rates for health-care services. The mechanisms for the processing of persistent pain in males and females have been suggested by investigations in male and female mice.
Humans have immunity that is made of self-antigens, such as allergens, cancerous cells, orpathogens. Women have larger immune responses than men and are more prone to develop diseases like asthma, allergies, and skin cancer, but less likely to be diagnosed with certain diseases, such as infectious diseases.
The idea that brain masculinization happens more in boys than girls is suggestive of disrupted immune-system processes.
These findings could offer clues as to why messenger RNAs obtained from the cortex of human male fetuses indicate higher expression levels of genes involved in inflammation than do those obtained from human female fetuses. Men who have been diagnosed with a mental-health issue have moreInflammation in their cortices than those who haven’t been diagnosed.
Gender and Gender in Research: Implications for Blood Donors, Oxygen, Iron and Feline Abundances in Canada
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; for those involving non-human animals, individuals are usually assigned to a sex category depending on the appearance of their genital anatomy.
There is much more to the term gender than just a 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. 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. Girls and boys having different patterns of exposure to organisms, such as spoilage and infections, might be due to the differences in the ways girls and boys dress and play. Some scholars focusing on issues around sex and gender use the hybrid terms gender/sex or sex/gender in recognition of such entanglement11,12.
Take, for example, 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. The study prompted Canadian Blood Services — the organization that manages most of the country’s blood supply — to alter its policy on donation intervals: for all female donors, it has extended the time between donations from 8 to 12 weeks. Canadian Blood Services tests donors blood levels 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 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 probes the specific sex- and gender-related factors that increase peoples’ 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.
Source: We need more-nuanced approaches to exploring sex and gender in research
T-cell therapy for colon cancer: sex and gender effects on the efficacy of the therapy, its protocols, and phenomenology
Someone studying a new T-cell therapy for colon cancer, for example, might propose that gonadal hormones could modify the efficacy of the treatment, because T cells possess receptors for both oestrogens and androgens. If the researcher were to conduct a study in people with colon cancer, they would be able to evaluate the correlation between the efficacy of the drug and the levels of hormones. If they were working with a mouse model of colon cancer, they might use antagonists or agonists of the relevant hormone receptors or give the animals hormone supplements. 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, including those in the Nature Portfolio, and funders, such as the US National Institutes of Health, have developed guidelines and mandates to encourage scientists to consider sex and, where appropriate, gender in their work.
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