Low glucocorticoids in stress-related disorders: the role of inflammation

Abstract

There is evidence that plasma cortisol concentration can be either increased or decreased in patients with depression and related anxiety and stress-related disorders; the exact pathophysiological mechanisms of this state are not almost clear. Several distinct theories were proposed and mechanisms, which could lead to decreased glucocorticoid signaling and/or levels, were described. However, there is a possible drawback in almost all the theories proposed: insufficient attention to the inflammatory process, which is undoubtedly present in several stress-related disorders, including post-traumatic stress disorder (PTSD). Previous studies only briefly mentioned the presence of an inflammatory reaction’s signs in PTSD, without giving it due importance, although recognizing that it can affect the course of the disease. With that, the state of biochemical changes, characterized by the low glucocorticoids, glucocorticoid receptor’s resistance and the signs of the persistent inflammation (with the high levels of circulating cytokines) might be observed not only in PTSD but in coronary heart diseases and systemic chronic inflammatory diseases (rheumatoid arthritis) as well. That is why the present review aims to depict the pathophysiological mechanisms, which lead to a decrease in glucocorticoids in PTSD due to the action of inflammatory stimuli. We described changes in the glucocorticoid system and inflammatory reaction as parts of an integral system, where glucocorticoids and the glucocorticoid receptor reside at the apex of a regulatory network that blocks several inflammatory pathways, while decreased glucocorticoid signaling and/or level leads to unchecked inflammatory reactions to promote pathologies such as PTSD.

LAY SUMMARY

• This review emphasizes the importance of inflammatory reaction in the development of puzzling conditions sometimes observed in severe diseases including post-traumatic stress disorder — the decreased levels of glucocorticoids in the blood. Following the classical concepts, one would expect an increase in glucocorticoid hormones, since they are part of the feedback mechanism in the immune system, which reduces stress and inflammation. However, low levels of glucocorticoid hormones are also observed. Thus, this review describes potential mechanisms, which can lead to the development of such a state.

Keywords:

• Cytokines
• hypocortisolemia
• inflammation
• monoamine oxidase
• post-traumatic stress disorder
• PTSD

Disclosure statement

The authors declare no conflict of interest and no financial interest in the publication of this manuscript.

Author contribution

All authors contributed to the study concept and the study design. Alexey Sarapultsev, Eliyahu Dremencov, Petr Sarapultsev, Maria Komelkova, Olga Tselikman, and Vadim Tselikman drafted the manuscript, Petr Sarapultsev and Eliyahu Dremencov provided critical revisions. Maria Komelkova created the artwork. All authors approved the final version of the manuscript for submission.

Additional information

Funding

This work was supported by the Ministry of Science and Higher Education of Russian Federation (grants AAAA-A18-118020690020-1 and 17.7255.2017/8.9) and by Slovak Research and Development Agency (Grant APVV-15-0388).

Notes on contributors

Alexey Sarapultsev

Alexey Sarapultsev, MD (Ural State Medical Academy, Ekaterinburg, Russia, 2005), PhD (Tymen State Medical Academy, Tymen, Russia, 2010), ScD (Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia, 2019). Senior researcher, Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia.

Petr Sarapultsev

Petr Sarapultsev, MD (Sverdlovsk State Medical Institute, Sverdlovsk, USSR, 1971), PhD (Sverdlovsk State Medical Institute, Sverdlovsk, USSR, 1983), ScD (Sverdlovsk State Medical Institute, Sverdlovsk, Russia, 1993), Professor (1996). Principal researcher, Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia.

Eliyahu Dremencov

Eliyahu Dremencov, MMedSc (Hebrew University, Jerusalem, Israel, 2000), PhD (Bar-Ilan University, Israel, 2004) is an Independent Research Fellow in the Institute of Molecular Physiology and Genetics (IMPG), Center for Biosciences, and Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Science (since 2013), Head of the IMPG Neuropharmacological Laboratory (2016-), Head of the IMPG (2018-)

Maria Komelkova

Maria Komelkova, MD (Chelyabinsk state University, Chelyabinsk, Russia, 2005), PhD (South-Ural State Medical University, Chelyabinsk, Russia, 2015). Senior researcher, Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia; Senior researcher, School of Medical Biology in the South Ural State University

Olga Tseilikman

Olga Tseilikman, PhD (2001, South Ural State Medical University, Chelyabinsk, Russia), DSc (2005, Omsk State Medical University, Omsk, Russia), is a Professor in the School of Medical Biology, South Ural State University, Chelyabinsk, Russia.

Vadim Tseilikman

Vadim Tseilikman, MSc Chelyabinsk State Pedagogical University, Chelyabinsk Russia, 1982), PhD (Siberian State Medical University, Tomsk, Russia, 1992), DSc (Institute of General Pathology and Pathological Physiology, Moscow, Russia, 1999). Director of School of Medical Biology in the South Ural State University (2017-).