Improving clinical outcomes through attention to sex and hormones in research

• Published in: Nature reviews. Endocrinology 2021-10, Vol.17 (10), p.625-635
• Main Authors: Mielke, Michelle M., Miller, Virginia M.
• Format: Article
• Language: English
• Subjects: 631/136; 692/163/2743; 692/308; 692/308/2779; 692/499; Animals; Clinical outcomes; Clinical trials; Complications and side effects; Contraceptives; Dosage and administration; Drug development; Drug metabolism; Drug therapy; Drug-Related Side Effects and Adverse Reactions; Endocrinology; Female; Gender differences; Genetic diversity; Gonadal Steroid Hormones; Health aspects; Health care; Hormone therapy; Hormones; Humans; Male; Medicine; Medicine & Public Health; Men; Menopause; Patient outcomes; Precision Medicine; Receptor mechanisms; Review Article; Sex Characteristics; Sex differences; Social aspects; Steroid hormones; Steroids; Therapeutic targets; Treatment Outcome
• ISSN: 1759-5029; 1759-5037; 1759-5037
• DOI: 10.1038/s41574-021-00531-z

Biological sex, fluctuations in sex steroid hormones throughout life and gender as a social construct all influence every aspect of health and disease. Yet, for decades, most basic and clinical studies have included only male individuals. As modern health care moves towards personalized medicine, it is clear that considering sex and hormonal status in basic and clinical studies will bring precision to the development of novel therapeutics and treatment paradigms. To this end, funding, regulatory and policy agencies now require inclusion of female animals and women in basic and clinical studies. However, inclusion of female animals and women often does not mean that information regarding potential hormonal interactions with pharmacological treatments or clinical outcomes is available. All sex steroid hormones can interact with receptors for drug targets, metabolism and transport. Genetic variation in receptors or in enzymatic function might contribute to sex differences in therapeutic efficacy and adverse drug reactions. Outcomes from clinical trials are often not reported by sex, and, if the data are available, they are not translated into clinical practice guidelines. This Review will provide a historical perspective for the current state of research related to hormone trials and provide concrete strategies that, if implemented, will improve the health of all people. Sex differences can have important implications in research and medical care. This Review will outline our understanding on sex differences, and will offer strategies that, if implemented, will provide information with which to personalize and improve health care for all people. Key points Sex as a biological variable, variation in sex steroidal hormones throughout life and gender as a social construct influence all aspects of health and disease. Inactivation of the X chromosome in XX individuals is random and might cluster within a tissue, resulting in a patchy pattern or mosaicism of X expression in female individuals; it is unclear how this mosaicism affects disease risk and progression across the lifespan. Sex steroids can alter the efficacy of therapeutic interventions via multiple mechanisms and can contribute to adverse drug reactions. Many contraceptives and menopausal hormone therapies are available; better understanding of their metabolism and interaction with genes is needed to develop prescription guidelines and individualized medication approaches. Use of hormones (for example, t