Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Oct 22:15:1459724.
doi: 10.3389/fendo.2024.1459724. eCollection 2024.

Endocrine dysregulation in COVID-19: molecular mechanisms and insights

Cristiana Iosef  1   2   3 , Andrei M Matusa  1 , Victor K M Han  1   2   3 , Douglas D Fraser  1   2   3
Affiliations
Review

Endocrine dysregulation in COVID-19: molecular mechanisms and insights

Cristiana Iosef et al. Front Endocrinol (Lausanne). .

Abstract

This review describes the impact of COVID-19 on the endocrine system, focusing on cortisol signaling and growth factor-induced endocrine resistance. As expected, SARS-CoV-2 infection induces systemic inflammation, resulting in stimulation of the adrenal glands leading to elevated cortisol levels with normal adrenocorticotropic hormone (ACTH) levels. The cytokine storm could also stimulate cortisol production. However, in some instances, cortisol levels rise independently of ACTH due to a phenomenon known as "pseudo-Cushing's syndrome," where adrenal glands become less responsive to ACTH. Plasma proteomic analyses showed that this pattern was variably observed among COVID-19 patients, potentially involving calcium dysregulation and GNAS-regulated activities, ultimately impacting the regulation of microvascular permeability. COVID-19 also exhibited a syndrome resembling endocrine resistance, governed by receptor tyrosine kinase signaling pathways. Mild cases displayed elevated activity of EGFR and MMP9, along with increased expression of survival factors like Bax and Bcl2. In contrast, more severe cases involved IGFR-I and enhanced NOTCH signaling, with altered expression of Bcl2, AKT1, and MAPK8. In summary, these findings describe the complex interplay between COVID-19 and endocrine pathology, particularly endocrine resistance. These insights suggest potential endocrine targets for therapeutic interventions to improve short- and long-term outcomes for COVID-19 patients.

Keywords: COVID-19; adrenal glands; cortisol; disease management; endocrine.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
SARS-Cov2 can induce cortisol excess and Cushing's-like syndrome.
Figure 2
Figure 2
COVID-19 cortisol signaling in a comparative study between patient cohorts from Western and Harvard Universities. Partial data from the two studies (Ref 5, 39) were utilized for bioinformatic analysis to predict various aspects of cortisol signaling as initiated by potassium channels (TREK1). The two datasets were initially analyzed for differential expression using consistent thresholds for fold change (2-fold) and p-value (0.05). Subsequently, a meta-analysis was conducted using upset plot algorithms, enabling a non-directional cross-analysis that identified a pool of common proteins differentially expressed plasma proteins relevant to this study.
Figure 3
Figure 3
Cortisol signaling: candidate biomarkers in COVID-19. The same subset of data (201 proteins) described in the legend of Figure 2 was used for an in-depth bioinformatic analysis focusing on the GNAS protein marker. This specific protein stimulates the activity of adenylate cyclase, an enzyme that plays a crucial role in regulating the production of several hormones that influence the function of endocrine glands, including the thyroid, pituitary gland, ovaries, testes, and adrenal glands.
Figure 4
Figure 4
Candidate biomarkers for COVID-19 endocrine resistance.
Figure 5
Figure 5
Growth factor competition for Ras signaling could lead to endocrine resistance.
See this image and copyright information in PMC

References

    1. Pal R, Banerjee M. COVID-19 and the endocrine system: exploring the unexplored. J Endocrinological Invest. (2020) 43:1027–31. doi: 10.1007/s40618-020-01276-8 - DOI - PMC - PubMed
    1. Sathish T, Cao Y, Kapoor N. Association of sex, age, and comorbidities with mortality in COVID-19 patients: a systematic review and meta-analysis. Int J Infect Dis. (2021) 104:447–59. doi: 10.1159/000512592 - DOI
    1. Patel MA, Knauer MJ, Nicholson M, Daley M, Van Nynatten LR, Cepinskas G, et al. . Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning. Mol Med. (2023) 29:26. doi: 10.1186/s10020-023-00610-z - DOI - PMC - PubMed
    1. Fraser DD, Cepinskas G, Patterson EK, Slessarev M, Martin C, Daley M, et al. . Novel outcome biomarkers identified with targeted proteomic analyses of plasma from critically ill coronavirus disease 2019 patients. Crit Care Explor. (2020) 2:e0189. doi: 10.1097/CCE.0000000000000189 - DOI - PMC - PubMed
    1. Iosef C, Knauer MJ, Nicholson M, Van Nynatten LR, Cepinskas G, Draghici S, et al. . Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function. J Transl Med. (2023) 21:377. doi: 10.1186/s12967-023-04149-9 - DOI - PMC - PubMed