Press Release

Biological differences between females, males need to be considered in scientific studies

Washington, DC March 11, 2021

Endocrine Society issues Scientific Statement on sex differences in research

Biological differences between females and males affect virtually every aspect of medicine and biomedical research. In a new Scientific Statement released today, the Endocrine Society called for sex differences to be studied thoroughly to improve public health.

“When we understand the ways sex differences operate at baseline in health, which can either worsen the course of a disease to amplify differences in health outcomes, or protect against it, we can more effectively prevent and treat medical conditions,” said Aditi Bhargava, Ph.D., of the University of California, San Francisco in San Francisco, Calif., and the chair of the writing group that authored the Society’s Scientific Statement.

For instance, SARS CoV-2 infection, cause of the COVID-19 pandemic, disproportionately affects men. A U.S. Centers for Disease Control and Prevention report found the overall case-fatality ratio was about 2.4 times higher in men than women.

Failing to consider sex differences can lead to the failure of promising drug candidates. Drugs are tested in cell lines or animals before drug trials are conducted in humans, and most of these foundational studies rely predominantly on male animals or cell lines. Many published studies that use animal models either do not report the breakdown of animals by sex or do not aggregate results by the sex. Clinical studies similarly fail to consider sex as a variable and instead often report it as a confounding factor.

“Without exploring sex differences, some drug candidates that could be beneficial to women never have the chance to make it to market,” Bhargava said. “The process of developing drugs using only males of a species in pre-clinical studies likely contributes to the higher rates of adverse drug reactions in women compared to men, failure to see efficacy in clinical trials, and translation to therapeutics.”

The statement explores three areas of biological differences between females and males. Imaging has found anatomical and volume differences in the brains of women and men, but these differences do not reveal any functional differences between the sexes. Heart and kidney diseases present differently in women and men. Although twice as many women as men report stress-related diseases, few studies are designed to explore mechanisms that highlight both similarities and difference between the sexes.

Biological sex is often confused with gender in our society. The two sexes are differentiated as females, who have ovaries and produce eggs, and males, who have testes and produce sperm. In mammals, females typically have XX chromosomes and males typically have XY chromosomes. All sex differences in the zygote, or fertilized egg, stem from harboring two different sex chromosomes. Both sexes have all classes of reproductive hormones such as estrogen, progesterone, and testosterone, albeit at different levels. Differences in sexual development may result in a person’s biological sex not aligning with these traditional definitions.

Biological sex is separate from gender identity, which may or may not align with an individual’s biological sex. Transgender or gender diverse individuals should be screened for sex-specific medical conditions such as prostate cancer and cervical cancer based on body parts and tissues that are present, according to the Society’s Clinical Practice Guideline on Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons.

Other authors of the statement are: Arthur P. Arnold, Arpana Gupta and Emeran A. Mayer of the University of California, Los Angeles in Los Angeles, Calif.; Debra A. Bangasser of Temple University in Philadelphia, Penn.; Kate M. Denton and Lucinda M. Hilliard Krause of Monash University in Clayton, Victoria, Australia; Margaret McCarthy of the University of Maryland School of Medicine in Baltimore, Md.; Walter L. Miller of UCSF in San Francisco, Calif.; Armin Raznahan of the National Institutes of Mental Health in Bethesda, Md.; and Ragini Verma of the University of Pennsylvania, Penn.

The authors have no disclosures.

The statement, “Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement,” was published online in the Society’s journal Endocrine Reviews.

About Endocrine Society

Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.

The Society has more than 18,000 members, including scientists, physicians, educators, nurses, and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at Follow us on X (formerly Twitter) at @TheEndoSociety and @EndoMedia.

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