Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries

Author:

Martinez Genesee J.1ORCID,Appleton Malik1,Kipp Zachary A.1ORCID,Loria Analia S.12ORCID,Min Booki3,Hinds Terry D.124ORCID

Affiliation:

1. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States

2. Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States

3. Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

4. Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States

Abstract

The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.

Funder

Center for Strategic Scientific Initiatives, National Cancer Institute

HHS | NIH | National Institute on Minority Health and Health Disparities

HHS | NIH | Office of Extramural Research, National Institutes of Health

Publisher

American Physiological Society

Subject

Physiology (medical),Molecular Biology,Physiology,General Medicine

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