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  • Review Article
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Improving clinical outcomes through attention to sex and hormones in research

Nature Reviews Endocrinology volume 17, pages 625–635 (2021)Cite this article

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Abstract

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.

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, testosterone, 17β-oestradiol or other androgen or oestrogen compounds), surgical history (oophorectomy or orchiectomy), pregnancy history and menopausal status should be routinely collected and considered for potential medication interactions and effects on health.

  • Clinical trial data should be reported by sex so as to improve transparency and reproducibility, and to inform future studies and treatment guidelines.

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Fig. 1: Sex steroids influence cellular processes through both genomic and non-genomic regulation.

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Acknowledgements

The authors are supported in part by grants from the National Institutes of Health/National Institute on Aging (U54 AG044170, RF1 AG055151) and the Mayo Foundation.

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Authors and Affiliations

  1. Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA

    Michelle M. Mielke

  2. Mayo Clinic Specialized Center of Research Excellence, Mayo Clinic, Rochester, MN, USA

    Michelle M. Mielke & Virginia M. Miller

  3. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Michelle M. Mielke

  4. Department of Surgery, Mayo Clinic, Rochester, MN, USA

    Virginia M. Miller

  5. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Virginia M. Miller

  6. Mayo Clinic Women’s Health Research Center, Mayo Clinic, Rochester, MN, USA

    Virginia M. Miller

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Gender Innovations in Science, Health & Medicine, Engineering, and Environment: https://genderedinnovations.stanford.edu/

International Society of Gender Medicine: http://www.isogem.eu/

Organization for the Study of Sex Differences: https://www.ossdweb.org/

Women in Science and Engineering Statistics: https://www.nationalacademies.org/cwsem/women-in-science-and-engineering-statistics

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Mielke, M.M., Miller, V.M. Improving clinical outcomes through attention to sex and hormones in research. Nat Rev Endocrinol 17, 625–635 (2021). https://doi.org/10.1038/s41574-021-00531-z

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