Sex and gender, influenced by genetics, epigenetics, and environmental/social stressors, must be considerations in evaluating every patient.
SPECIAL REPORT: GENDER & SEX ISSUES
Attention to sex and gender differences has been a long time coming. In 1986, the National Institutes of Health required that women and minorities be included in clinical research; this initiative was strengthened with the 1993 FDA Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, which reversed the 1977 directive that women with childbearing potential be excluded from early clinical studies and explicitly called for data to be analyzed for sex differences.
Sex refers to genetic and biological differences, and gender reflects the impact of social constructs/expectations on roles and relationships, behaviors, expression of emotions, and power dynamics. Advancements in personalized medicine that utilize genetic or other biomarker information to make treatment decisions have demonstrated sex differences with some treatments. We now know that the interaction of the genome and the environment or experience can result in epigenetic changes—alterations in gene expression rather than mutations of DNA sequences, which can lead to the formation of inherited phenotypic changes in addition to the traditional genetic basis for inheritance. This increases the complexity of parsing out whether a problem is genome or sex based, related to experienced social constructs and stressors, driven by environmental events impacting a parent that manifested in the offspring, or all of the above.
Thus, some conditions are specific to those born with female sex (eg, ovarian disorders). Some may manifest similarly but are more likely to occur in one gender than the other (eg, depression being twice as likely to occur in women than in men). In some cases, gender differences influence the expression of similar characteristics such as dramatic or erratic features, emotional dysregulation, and interpersonal conflict, diagnosed as borderline personality disorder in women and narcissistic or antisocial personality disorder in men. Furthermore, gender differences increase the risk of various environmental stressors such as childhood trauma/victimization in girls and in LGBTQ+ youth.
Unfortunately, nearly 30 years after mandating evaluation of sex differences, the US Food and Drug Administration has not followed through on requirements for meaningful analysis for sex-related differences in clinical trials. Tracking of menses in premenopausal women in clinical trials is rare, as are comparisons of results in premenopausal women versus postmenopausal women or men. Very little has been done to evaluate gender differences in symptoms and treatments for conditions such as posttraumatic stress disorder (eg, military sexual trauma and/or childhood sexual trauma affecting women versus combat-related trauma in men). Additionally, priority has not been given to finding treatments for conditions disproportionately affecting women, minorities, and LGBTQ+ individuals.
Until gender-sensitive evaluating of clinical presentation, acquiring necessary history, making the correct diagnosis(es), assessing comorbidities, and individualizing treatment are the responsibility of all providers, and assessment of sex and gender differences is ingrained in all research, the needs of our patients will not be met.
The focus of this Special Report will be on how sex and gender, influenced by genetics, epigenetics, and environmental/social stressors, must be considerations in evaluating every patient. Specifically, we must anticipate the potential effect of traumas, understand the impact of gender-based environmental bias/stressors, intervene early, and consider how sex steroids determine the timing of various symptoms, especially in women. Our patients deserve nothing less.
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Dr Clayton is the David C. Wilson Professor and chair of the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, with a secondary appointment as professor of clinical obstetrics and gynecology. She is the author of Satisfaction: Women, Sex, and the Quest for Intimacy, published by Ballantine Books in 2007, and an editor of the 2005 Women’s Mental Health: A Comprehensive Textbook. ❒