Effects of SARS-CoV-2 on the endocrine system
DOI: 10.32364/2587-6821-2021-5-9-575-578
N.A. Petunina1,2, A.S. Shkoda2, M.E. Telnova1, E.V. Goncharova1, I.A. Kuzina1,
Y.А. El-Taravi1, N.S. Martirosian1,2
1I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow,
Russian Federation
2L.A. Vorokhobov City Clinical Hospital No. 67, Moscow, Russian Federation
SARS-CoV-2 rapidly spread worldwide and resulted in an unprecedented pandemic. Considering the novelty of this disease, its potential effects on the endocrine system remain elusive. This virus is known to utilize the extracellular domain of angiotensin-converting enzyme (ACE) and transmembrane protein TMPRSS2. Broad expression of ACE-2 and TMPRSS2 is a potential cause of extrapulmonary manifestations of SARS-CoV-2, including endocrine ones. The most common presentations are direct or indirect damage of the endocrine part of the pancreas, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, and possible long-term effects on the reproductive system. It was demonstrated that obesity and diabetes increase the risk of severe course and death in COVID-19. Similarly, patients with transitory hyperglycemia have a higher risk of severe disease course. Primary and secondary adrenal insufficiency of various origins potentially accounts for severity. The most common thyroid complications of the COVID-19 infection are euthyroid sick syndrome and transient destructive thyroiditis, including subacut e thyroiditis.
Keywords: SARS-CoV-2, COVID-19, endocrinopathies, diabetes, adrenal insufficiency.
For citation: Petunina N.A., Shkoda A.S., Telnova M.E. et al. Effects of SARS-CoV-2 on the endocrine system. Russian Medical Inquiry. 2021;5(9):575–578 (in Russ.). DOI: 10.32364/2587-6821-2021-5-9-575-578.
In March 2020, the World Health Organization (WHO) had declared the COVID-19 pandemic caused by SARS-CoV-2. At the time of writing this article, the incidence was more than 232 million. SARS-CoV-2 is an RNA virus belonging to the family Coronaviridae that also includes SARS (SARS-CoV) which caused severe acute respiratory syndrome (SARS) outbreak in 2002, and MERS (MERS-CoV), which caused Middle East respiratory syndrome outbreak in 2012. All three RNA viruses belong to the genus Betacoronavirus (molecular mass 26-32 kDa). Phylogenetically, SARS-CoV-2 is related to SARS-CoV. Therefore, an attempt can be made to extrapolate findings accumulated during the SARS outbreak in 2002-2003 on the COVID-19 pandemic. SARS-CoV-2 also provokes acute pneumonitis and numerous extrapulmonary complications (cardiovascular, neurological, gastrointestinal, cutaneous, ocular, reproductive, endocrine, etc.). Coronaviruses are believed to utilize transmembrane proteins to penetrate cells. Angiotensin-converting enzyme-2 (ACE-2) is a well-known receptor for SARS-CoV and SARS-CoV-2. Viruses use their extracellular domain as a surface receptor to bind via their surface spike proteins (S protein) [1]. In addition, SARS-CoV-2 needs TMPRSS2 (a transmembrane protein belonging to the serine protease family required to activate S protein) to penetrate cells. Finally, SARS-CoV-2 can bind with another transmembrane protein, neuropilin-1. This phenomenon also accounts for the high contagiousness of the new virus.
ACE-2 is broadly expressed in various tissues, including the pancreas, thyroid gland, pituitary gland, adrenal glands, gonads, and adipose tissue. This phenomenon is a potential cause of extrapulmonary complications of the COVID-19 infection, including endocrine ones.
Pancreas
Diabetes manifestation with severe metabolic decompensation and diabetic ketoacidosis is reported in healthy (without a history of diabetes) patients with SARS-CoV-2. Considering high ACE-2 expression in the pancreas and the experience with the SARS epidemic (during which new-onset diabetes cases were also described), direct or indirect permanent damage of pancreatic beta-cells can be assumed [2]. A reduced amount of ACE-2 resulting from SARS-CoV-2 infection is accompanied by an increase in angiotensin II activity that, in turn, inhibits insulin secretion by pancreatic beta cells through binding with AT-1 receptors. In addition, local activation of the renin-aldosterone-angiotensin system in the pancreas decreases tissue insulin sensitivity and insulin resistance due to the inhibition of insulin-mediated glucose transport in tissues. Currently, there is no strong evidence of the direct effect of SARS-CoV-2 on pancreatic beta cells. However, fulminant course and lack of circulating antibodies suggest the development of a specific variant of diabetes induced by SARS-CoV-2 [3, 4].
Meanwhile, COVID-19 may be a trigger for T1D or T2D diabetes. Therefore, an international group of diabetes researchers has established a global registry of new-onset COVID-19 related diabetes, CoviDiab [5]. This registry aims to assess the prevalence and characterize new-onset COVID-19 related diabetes to investigate its pathogenesis, therapy, and outcomes. It also collects data on severe metabolic decompensation in patients with existing diabetes with diabetic ketoacidosis, hyperosmolar hyperglycemic state, and severe insulin resistance.
It was demonstrated that diabetes increases the risk of severe course and mortality of the COVID-19 infection [6]. Diabetes in COVID-19 is more common in inpatient departments (31.8%) than in outpatient departments (5.4%). A Chinese study (n=72,314) revealed overall COVID-19 mortality of 2.3% and COVID-19 mortality in diabetes of 7.3%. In 1,590 patients with severe COVID-19 that resulted in ICU admission, mechanical ventilation, or death, 34.6% were diagnosed with diabetes, while in non-severe COVID-19 infection, diabetes was diagnosed in 14.3%.
Several studies evaluated the role of hyperglycemia in the pathogenesis and course of acute respiratory infections [7]. Glucose levels directly correlate with virus concentration in respiratory discharge. Adding glucose to cell culture increased influenza virus replication in vitro. In animal models, diabetes was associated with structural changes in cells, including increased alveolar-capillary membrane permeability and alveolar collapse. IL-6 and D-dimer levels are significantly higher in hyperglycemia than in normoglycemia. Patients with transitory hyperglycemia (similar to patients with diabetes) are at higher risk of severe COVID-19 infection. Meanwhile, glycemic control is beneficial in patients with diabetes and COVID-19. Thereupon, glycemic control and early detection of hyperglycemia are essential for timely and effective treatment.
Hypothalamic-pituitary axis
Individual studies on hypothalamic-pituitary axis dysfunction in SARS are available. ACE-2 and TMPRSS2 in the hypothalamus (particularly in paraventricular nuclei) are highly expressed [8, 9]. Autopsy and immunohistochemistry in five SARS-CoV patients have demonstrated a reduction in the number of TSH- and ACTH-producing cells of the anterior pituitary [10]. A prospective study of 61 SARS-CoV patients (three months after convalescence) has revealed secondary adrenal insufficiency signs in 39%. Two-thirds of these patients did not receive corticosteroids. The authors suggest late complications of SARS-CoV and hypophysitis [11]. In addition, central hypothyroidism was identified in 4.9% (in two patients, it was associated with hypocortisolism. All these abnormalities were transitory, a complete recovery of the hypothalamic-pituitary-adrenal axis occurred within a year.
Chinese researchers isolated SARS-CoV-2 from the cerebrospinal fluid of COVID-19 patients, demonstrating that this virus affects the brain, including the hypothalamic-pituitary region [9].
Therefore, alterations in the hypothalamic-pituitary axis are a likely result of SARS-CoV-2 infection or an indirect result of immune-mediated hypophysitis. Another possible mechanism is progressive hypoxia.
Adrenal glands
Autopsy findings in patients with SARS-CoV infection revealed lymphocytic and monocytic infiltration, adrenal gland necrosis, and small-vessel vasculitis of the adrenal medulla [12]. In addition, antigens and genome sequence of SARS-CoV were isolated. No data on the direct effect of SARS-CoV-2 on the adrenal glands are available. However, this virus provides indirect effects via stress, hypoxia, hypotension, sepsis, and coagulopathy.
Currently, there is no strong evidence of a high risk of COVID-19 severe course in patients with adrenal insufficiency, either primary (Addison's disease) or secondary (congenital adrenal hyperplasia/CAH). Nonetheless, patients with Addison's disease or CAH are at higher risk of infections. Therefore, endocrinological associations recommend following standard principles of a 2-fold escalation of glucocorticoid dose in disease and fever and switch to intramuscular hydrocortisone in vomiting and diarrhea in patients with adrenal insufficiency.
Thyroid gland
Thyroid gland dysfunction was detected in SARS and COVID-19 infection [13]. Autopsy of SARS-CoV patients revealed apoptosis of follicular and parafollicular thyroid gland cells and follicular epithelium desquamation. However, neither viral RNA nor antigens were isolated.
A retrospective study that enrolled 50 patients with the COVID-19 infection has demonstrated that 64% have abnormal thyroid hormone levels, i.e., reduced TSH (34%), free thyroid hormones (8%), or TSH and free thyroid hormones (22%) [14]. Furthermore, the reduction in TSH correlated with COVID-19 severity. Possible causes of low TSH levels are euthyroid sick syndrome, glucocorticoid intake, increase in proinflammatory cytokines, and cytokine storm. In addition, the potential direct effect of SARS-CoV-2 on the hypothalamic-pituitary-thyroid axis is also suggested.
The THYRCOV study included 287 COVID-19 patients. Hypothyroidism was diagnosed in 5.2% and thyrotoxicosis in 20.2%; of them, 42.5% had overt thyrotoxicosis [15].
Subacute thyroiditis with typical clinical presentations that manifested within 5 to 30 days since COVID-19 onset is reported. It is possible that corticosteroids widely used for COVID-19 mask other cases of destructive thyroiditis. Subacute thyroiditis is generally associated with mild COVID-19 [16, 17].
Reproductive system
Analysis of ACE-2 expression patterns in various tissues demonstrated its high expression in the testicles (primarily on Leydig and Sertoli cells, thereby suggesting male reproductive system alteration in the COVID-19 infection.
A study by Song et al. [18] that included 12 seminal fluid samples and 19 testicular biopsies of COVID-19 patients failed to detect SARS-CoV-2 RNA. However, autopsies of patients with SARS-CoV or SARS-CoV-2 identified signs of orchitis with leukocyte infiltration, destruction, low sperm count in the seminiferous tubules, and basal membrane thickening. Another study [19] reports increased LH and prolactin levels but normal testosterone levels in COVID-19 patients.
Currently, there is no strong evidence of the direct effect of SARS-CoV-2 on testicular tissues. An alternative hypothesis suggests immune-mediated or inflammatory testicle damage. Long-term fever results in increased temperature of testicular tissues (whose optimal temperature is <37°C), thereby promoting degeneration and destruction of germ cells and decreasing spermatogenesis. Widely applied corticosteroids also affect spermatogenesis.
Hence, clinical and academic experience illustrates strong correlations between more severe COVID-19 outcomes and diabetes, obesity, and hypertension. However, findings on tissue ACE-2 expression patterns do not provide strong evidence of the direct effect of SARS-CoV-2 on extrapulmonary complication risk. Nevertheless, central hypocortisolism and hypothyroidism are relatively common complications of the COVID-19 infection. In general, these abnormalities are transitory. Meanwhile, some authors report delayed (several months after convalescence) manifestation of hypocortisolism. Significantly, timely diagnosis and treatment improve outcomes. Prospective observational studies are needed to evaluate the risk of reproductive disorders in individuals recovered from COVID-19.
About the authors:
Nina A. Petunina — Dr. Sc. (Med.), Professor, Corresponding Member of the RAS, Head of the Department of Endocrinology of the N.V. Sklifosovskiy Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University); 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation; Head of the Department of Endocrinology of L.A. Vorokhobov City Clinical Hospital No. 67; 2/44, Salyam Adil str., Moscow, 123423, Russian Federation; ORCID iD 0000-0001-9390-1200.
Andrey S. Shkoda — Dr. Sc. (Med.), Professor, Head Doctor, L.A. Vorokhobov City Clinical Hospital No. 67; 2/44, Salyam Adil str., Moscow, 123423, Russian Federation; ORCID iD 0000-0002-9783-1796.
Milena E. Telnova — C. Sc. (Med.), associate professor of the Department of Endocrinology of the N.V. Sklifosovskiy Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University); 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation; ORCID iD 0000-0001-8007-9721.
Ekaterina V. Goncharova — C. Sc. (Med.), associate professor of the Department of Endocrinology of the N.V. Sklifosovskiy Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University); 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation; ORCID iD 0000-0001-6034-9333.
Irina A. Kuzina — assistant of the Department of Endocrinology of the N.V. Sklifosovskiy Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University); 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation; ORCID iD 0000-0001-7923-4894.
Yasmin A. El-Taravi — student, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation.
Narine S. Martirosian — C. Sc. (Med.), associate professor of the Department of Endocrinology of the N.V. Sklifosovskiy Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation; endocrinologist, L.A. Vorokhobov City Clinical Hospital No. 67; 2/44, Salyam Adil str., Moscow, 123423, Russian Federation; ORCID iD 0000-0002-0202-1257.
Contact information: Narine S. Martirosian, e-mail: narinarine@list.ru.
Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.
There is no conflict of interests.
Received 08.08.2021.
Revised 01.09.21.
Accepted 26.09.2021
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