Reviews in Endocrine and Metabolic Disorders https://doi.org/10.1007/s11154-021-09678-6 Basic mechanisms of SARS‑CoV‑2 infection. What endocrine systems could be implicated? Berta Soldevila1 · Manel Puig‑Domingo1 · Mónica Marazuela2 Accepted: 19 July 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 Abstract Although SARS-CoV-2 viral attacks starts by the interaction of spike protein (S Protein) to ACE2 receptor located at the cell surface of respiratory tract and digestive system cells, different endocrine targets, endocrine organs and metabolic condi- tions are of fundamental relevance for understanding disease progression and special outcomes, in particular those of fatal consequences for the patient. During pandemic, moreover, a specific phenotype of COVID-19 metabolic patient has been described, characterized by being at particular risk of worse outcomes. In the present paper we describe the mechanism of viral interaction with endocrine organs, emphasizing the specific endocrine molecules of particular relevance explaining COVID-19 disease evolution and outcomes. Keywords SARS-CoV-2 · COVID-19 · Mechanisms · Endocrine systems · Diabetes mellitus · Pituitary · Thyroid · Calcium · Hypoadrenalism 1 Introduction involvement may take place, either as victims of the viral attack or as suicidal actors amplifying the viral damage, in Endocrine targets are of particular relevance for either particular cytokine storm expansion. SARS-CoV-2 viral entrance to the cells as well as regard- In this paper we aim to make an overview of these two ing modulation of disease expansion in a given host [1]. pivotal positions of the endocrine organs and system in the Lung cells are among others of the respiratory tract, those COVID-19 sanitary earthquake. through which serious disease is initiated. Expression of different molecules in the respiratory tract cells surface is therefore crucial for SARS-CoV-2 viral attack. Besides this 2 COVID‑19 and pathogenic mechanisms respiratory tropism, digestive epithelium is another entrance door for SARS-CoV-2 and part of the initial symptoms are COVID-19 can alter the function of different endocrine clearly related to the viral invasion of the gut system. Once glands and metabolic processes and put patients at risk of the disease has achieved this point, systemic involvement acute or late-onset endocrine or metabolic dysfunction. In may happen and it is at this moment when endocrine organs addition, preexisting endocrine disorders or metabolic pro- cesses can increase the predisposition to develop COVID-19 or a more severe clinical presentation and outcome (Fig. 1). Manel Puig-Domingo and Mónica Marazuela equally contributed as senior authors SARS-Cov-2 infection has a similar mechanism of action than SARS-Cov-1 and this is by via binding to ACE2 pro- * Mónica Marazuela tein, which has an important expression in several endo- monica.marazuela@salud.madrid.org crine tissues including testis, thyroid, adrenal, pituitary, 1 Endocrinology and Nutrition Service, Department hypothalamus and adipose tissue [2]. The SARS-Cov-2 of Medicine, Germans Trias i Pujol Research Institute virus binds to the ACE2 receptor and uses the cellular ser- and Hospital, Universitat Autònoma de Barcelona, Badalona, ine protease TMPRSS2 for S protein priming. Both ACE2 Spain and TMPRSS2 mRNA have been reported in different endo- 2 Department of Endocrinology, Hospital Universitario de crine tissues [2]. The possible mechanisms by which the La Princesa, Instituto de Investigación de La Princesa, SARS-CoV-2 virus, after entering an endocrine gland and Universidad Autónoma de Madrid, Madrid, Spain 13 Vol.:(0123456789) Reviews in Endocrine and Metabolic Disorders Fig. 1  Different pathogenic Pituitary Pancreas mechanisms including direct • Direct viral acon (viral parcles, ACE • Direct viral acon and indirect viral action could receptors) • Hyperglycemia explain why different endo- • Hypophysis • Funconal hypopituitarism crine glands/organs that can be Adipose ssue affected by COVID-19 Thyroid • Chronic inflammatory background • Direct viral acon (Subacute thyroidis) • Reservoir for virus: increase • Trigger to development of autoimmune shedding thyroid disorders • Increased comorbidies • Sick euthyroid syndrome Bone and parathyroid Adrenal No known acon • Direct viral acon • An-COVID anbodies could cross-reactt Testes with ACTH • Effect on all cells in the tess • Crical-illness corcosteroid insufficiency • Presence of ACE-2 and TMPRSS2 (CIRCI) receptors binding the ACE2 receptor, can produce damage include viral effects. In SARS-CoV-1 infection, destruction of characteristically thrombosis and hypoxia that are typical of the follicular epithelium and the parafollicular cells were highly vascularized organs, such as endocrine organs par- reported [8]. ACE2 expression has been found in thyroid ticularly the pituitary. In addition, other mechanisms that follicular cells, and cases of atypical subacute thyroiditis can play a role include immune response against the virus with negative autoantibodies have been found associated and cytokine storm [2]. with SARS-CoV-2 infection [9–12]. This type of thy- roiditis has been traditionally associated to a viral origin. 2.1 Pathogenic mechanisms involved in COVID‑19 A recent report showed scintigraphy findings typical of infection targeting different endocrine organs subacute thyroiditis in one third of patients three months after COVID infection, pointing to a much more preva- The hypothalamic-pituitary (HP) axis may also be a target lent phenomenon than previously thought and it is now of the SARS-CoV-2 [3]. Coronavirus infections can also considered as a sequela associated with COVID-19 [10]. affect the central nervous system, including the hypo- The COVID-19 cytokine storm may eventually precipi- thalamus and pituitary. It is still not well known whether tate the development of autoimmune thyroid disorders the entry is via bloodstream or direct though the cribri- including Graves’ disease, Graves’ ophthalmopathy, and form plate. Direct deleterious effect on these organs is Hashimoto thyroiditis [13]. Nevertheless, the most com- suggested by the fact that SARS-CoV-1 viral particles mon thyroid manifestation in COVID-19 patients, mostly have been detected in autopsy studies involving neuronal in hospitalized patients, is a kind of euthyroid sick syn- degenerated tissue [4]. In this regard, ACE2 and cellular drome, including decrease in T3 and T4 in some occa- serine protease-TMPRSS2 receptors, that are entries of sions, which run in parallel with an increase in cytokines. the SARS-CoV-2 virus, are present in the hypothalamic- These abnormalities could also be very persistent in time pituitary region [5]. SARS-CoV-2 has been reported in as it was also reported in SARS-CoV-1 [14]. Follow-up the cerebrospinal fluid and also in autopsy studies of the studies regarding these abnormalities are still awaiting. hypothalamus in COVID-19 patients [6, 7]. Another pos- A direct cytopathic effect on adrenal cortical cells sible mechanism of pituitary injury during COVID-19 with generation of diverse lesions, including necrosis of is the generation of an immune-mediated hypophysitis, these cells, has been reported in autopsies from SARS- which has also been previously reported in SARS-CoV-1. CoV-1 patients [4]. A similar effect could happen in Moreover, functional hypopituitarism probably related to SARS-CoV-2 virus, as ACE2 receptors are present in the increase in circulating cytokines produced by the viral the adrenal gland. Another possible mechanism that has infection has been reported in both SARS-CoV-1 and been described in SARS-CoV-1 is the homology between SARS-CoV-2 infections. It is interesting that abnormali- certain amino acid sequences of the virus and have with ties related to hypopituitarism can persist long-term after ACTH. In this regard, antibodies that are primarily pro- SARS-CoV-1 infection, even months after the infection duced against SARS-CoV-1 could also cross-react and [1]. This could also be the case in SARS-CoV-2, in which destroy ACTH [15]. This mechanism could happen not follow-up studies of pituitary function are ongoing. only in SARS-CoV-1, as has been described, but also Thyroid dysfunction is a frequent finding in COVID- in SARS-CoV-2 as SARS-CoV-2 is structurally more 19 patients that can be mediated by direct or indirect than 95% homologous to SARS-CoV-1. However, this 13 Reviews in Endocrine and Metabolic Disorders mechanism of production of adrenal insufficiency has study [26], has found that type 2 diabetes people showed not been proved yet in SARS-Cov-2. Moreover, another increased risk of hospitalization, admission to intensive possible mechanism that could provoke adrenal insufic- care and death for COVID-19 in comparison to type 1 ciency in severe forms of COVID-19 is a critical illness diabetes subjects. These later presented few admissions related corticosteroid insufficiency (CIRCI). This condi- into intensive care and deaths compared to type 2. Peo- tion is directly related to the severity of the stress situ- ple with type 2 and type 1 diabetes have a higher risk of ation generated during a critical illness. In this regard, hospitalization, intensive care and mortality compared severe forms of COVID-19 could produce CIRCI and to control population. However, this excess of risk only cause inadequate stress corticosteroid mediated response remained significant in type 2 diabetes after adjustments [16]. for comorbidities and pharmacological treatment. There is no data on the potential direct effect of COVID- Different hypotheses have been formulated to caus- 19 on the parathyroid glands or the bones. Nevertheless, ally explain such an association; one plausible explana- hypocalcaemia is a frequent complication and is a predic- tion that the generalized multisystemic inflammation tor of more severe forms of COVID-19 and an unexpected process observed in SARS-CoV-2 infection potentiates high frequency of silent fractures has been described in these a hyperglycemic state and vice-versa, and this phenom- patients [17]. enon possibly favors viral replication [27]. Additionally, Severity and fatality related to COVID-19 have been abnormal acute glycosylation of the SARS-CoV-2 virus observed more in males than in females [18]. Regarding has been suggested as a potentiator of viral pathogenesis the testis, ACE2 and TMPRSS2 are expressed both in through modification of viral epitopes that otherwise spermatogonia and somatic (Leydig and Sertoli) cells. would have been targeted by the immune system [28]. The testes are probably a high-risk organ for SARS- And also, glycosylated ACE2 on target cells enhances CoV-2 infection. Destruction of germ cells with reduced viral tropism and penetration, leading to a higher inten- sperm cell count [19] and lymphocytic infiltrates in Ser- sity of COVID‐19 infection and severity in hyperglyce- toli and Leydig cells [19, 20] has been reported in the mic people [28]. testis from autopsies of SARS-CoV-1 patients, pointing The virus infects peripheral monocytes in a more effi- to an immune-mediated damage. SARS-CoV-2 viral par- cient way under hyperglycemic conditions and upregu- ticles have also been observed in testis autopsies of these lates ACE2. After this happens, improved cytokine pro- patients [20]. Semen analyses of men with COVID-19 duction by immunocompetent cells take place and can have shown the presence of SARS-CoV-2, but little is turn to an overexaggerated production of what has been yet known about its potential relationship with infertility denominate “cytokine storm”. Thus, an adequate insulin development [21]. In females ACE2 is also expressed in treatment is required to control the glucose availability the ovary, but TMPRSS2 appears to be absent. for activated M1 macrophage and the glycolytic flux that feds the viral replication process. In this regard, the viral 2.2 Pathogenic mechanisms, endogenous enhancement of hypoxia-inducible factor-1a (HIF-1a) is a and exogenous molecules involved in COVID‑19 critical regulator of glycolysis in this situation, in a way infection in different metabolic and endocrine that a metabolic rewiring is produced at the monocyte organs. levels which is beneficial for the viral replication and shedding. 2.2.1 Diabetes In addition, it has been proposed that complement- ing the treatment with an eucaloric ketogenic diet could It is now accepted that diabetes is an important risk fac- be a potential metabolic tool for reducing adenosine tor for COVID-19 infection and the severity of disease triphosphate production from aerobic glycolysis in the [22–24]. A significant part of this risk condition can be M1 macrophage phenotype [29]. This combined thera- attributed solely to hyperglycemia. People with type 1 peutic option could theoretically reduce the overproduc- and type 2 diabetes have an increased risk of hospitaliza- tion of cytokines and, consequently, the accumulation of tion, need of intensive care and mortality from COVID- neutrophils, monocytes, and platelets from the blood. In 19 due to bad glycemic control in a dose-dependent addition, it could be advantageous for the metabolism manner [25]. COVID mortality related to any type of of anti-inflammatory M2 macrophages because these diabetes has been associated with aging, mal gender, low cells predominantly express oxidative phosphorylation socioeconomic conditions, non-white ethnicity, previous enzymes and are best fed by the oxidation of fatty acids cardiovascular disorders, impaired renal function, poor in the mitochondria. glycemic control, as well as to obesity and underweight. Finally, it has been demonstrated that human β-cells According to this phenotype, a nationwide Swedish express viral entry proteins and SARS-CoV-2 indeed 13 Reviews in Endocrine and Metabolic Disorders infects and replicates in cultured human islets. Infec- 3 General mechanisms involving endocrine tion of endocrine pancreas leads to morphological and molecules as SARS‑CoV‑2 viral targets functional changes, including reduced numbers of insu- lin-secretory granules in β-cells and impaired glucose- SARS-CoV-2 viral entry requires at least two host pro- stimulated insulin secretion [30]. teins [39]: the angiotensin converting enzyme-2 (ACE2) and the TMPRSS2 protease. Angiotensin-converting 2.2.2 Obesity enzyme 2 (ACE2) is the only recognized human homo- logue of ACE, the key regulator of blood pressure, and Obesity is an important risk factor for contracting has approximately 42% identical protein sequences. COVID-19, as it is also for other infections either of viral Since its discovery in 2000 [40, 41], ACE2 has been or bacterial origin and also for developing more severe implicated in heart function, hypertension, and diabetes, forms of the disease [31]. Obesity is usually causally with its effects being mediated, in part through its abil- associated with pulmonary dysfunction, thus facilitating ity to convert angiotensin II to angiotensin. ACE2 biol- viral and bacterial infections. Several mechanisms have ogy and crucial contribution to SARS-CoV-2 viral dis- been proposed to explain the higher risk of obesity to ease development will be extensively covered in another contracting COVID-19. One feasible option is related chapter of the present issue. SARS-CoV-2 targets cells to the higher expression of ACE2 in adipocytes which through the viral structural spike protein (S protein) that may facilitate prolonged viral shedding [32, 33]. Another binds to the ACE2 receptor. ACE2 is expressed in human important mechanism involved in the increased severity pancreas, and coronavirus could enter beta-cells bind- in obese people is associated to the COVID-19 driven ing to its receptor, causing acute beta-cell dysfunction, cytokine storm, which is characterized by an overproduc- hyperglycemia and transient diabetes [42]. A chapter in tion of pro-inflammatory cytokines and an increase in this monograph focuses on the study of this mechanism inflammatory cells with a decrease in anti-inflammatory and COVID-19 infection. The transmembrane serine pro- cytokines and regulatory cells [34, 35]. The cytokine tease type 2 (TMPRSS2) in the host cell activates viral storm identified in multiple respiratory viral infections S protein and cleaves ACE2 receptor, further promoting including COVID-19 exhibits an overproduction of inter- viral binding to host cell membrane [39]. feron, tumor necrosis factor α, interleukins, and differ- Other endocrine molecules have been described as virus ent chemokines. Considering that subjects with obesity targets, as neuropilin-1 (NRP1) or human dipeptidyl pepti- have also a pre-set proinflammatory milieu, it is feasi- dase 4 (DPP-4) (Fig. 2). Table 1 summarizes the endocrine ble that COVID-19 could further exacerbate this basal targets effects on COVID-19 of each molecule reported in obesity-related inflammation, exposing them to an abso- this chapter. lute higher level of circulating inflammatory molecules compared to lean human subjects. This seems a plausible 3.1 TMPRSS2 protease mechanistic explanation of the increased risk of severe complications of COVID-19 in subjects with obesity [36]. Transmembrane serine protease type 2 (TMPRSS2) is a cell Obese individuals may exhibit greater viral shedding surface protein primarily expressed across the respiratory and suggesting potential for enhanced viral exposure, espe- digestive tracts. SARS-CoV-2 requires TMPRSS2 as well as cially if several family members are overweight. This ACE2 receptor for entry into epithelial host cells. Both ACE2 may be aggravated in overcrowded multigenerational and TMPRSS2 are present in nasal and bronchial epithelium households, which are more common in the socioeco- and pneumocytes, described as SARS-CoV-2 primary target nomically deprived communities in which obesity is cells in the early infection phase. Furthermore, coronavirus rep- prevalent [37]. In addition, as it has been described lication in the lungs needs TMPRSS2. Experimental studies for influenza infection, obesity not only increases the showed that TMPRSS2-/- knockout mice infected with corona- severity but also enhances viral diversity. The altered virus reduced the severity of the infectious disease with lower microenvironment associated with obesity supports the viral replication in lungs than wild-type mice [43], indicating emergence of a more virulent influenza virus population the critical role of this pathway in coronavirus disease initiation. capable of inducing greater disease severity. This could Gastrointestinal symptoms, such as diarrhea and abdomi- be related to an impaired interferon response in obese nal pain, are observed in COVID-19 patients, often preced- subjects, which has been demonstrated in experimental ing respiratory symptoms. TMPRSS2 is also expressed in models, both in obese mice and obesity-derived human intestinal epithelial cells across the gastrointestinal tract, bronchial epithelial cells [38]. The same could happen which is the target for many enteric viruses. Some studies in COVID-19 infection in humans. have shown that SARS-CoV-2 infects intestinal enteroids 13 Reviews in Endocrine and Metabolic Disorders Fig. 2  Possible endocrine and metabolic targets that have been considered for COVID-19 therapy. Different hormones and Melatonin drugs have been included as possible targets for COVID-19 including melatonin, oxytocin, DPP-4 (human dipeptidyl Oxytocin peptidase 4) inhibitors, GLP-1 (glucagon-like peptide-1) agonists, ACE-2 (angiotensin converting enzyme-2) inhibi- ACE-2 tors, corticosteroids, estrogens, anti-androgens and statins RAAS Corcosteroids Estrogens An-androgens DPP4 GLP-1 Stans cells and TMPRSS2 as well as TMPRSS4 promotes SARS- angiogenesis, tumorigenesis, viral entry, axonal guidance CoV-2 active infection in these cells [44]. Many endocrine and immune function [48] and has been considered as a tissues and organs, such as pancreas, thyroid, testis or pitui- potential therapeutic target in differents pathologies as tary, express TMPRSS2 and this could be related to endo- cancer or autoimmune diseases. NRP1 has been recently crine manifestations of COVID-19 disease [45]. described in experimental studies to be a complimentary Androgens upregulate the transcriptional activity entry mediador factor of SARS-CoV-2 into host cells, in of the TMPRSS2 gene which could contribute to the addition to ACE2 and TMPRSS2, thus acting as a poten- male predominance observed in severe infections [46]. tiator of SARS-CoV-2 infectivity [49, 50]. SARS-CoV-2 TMPRSS2 is also expressed in prostate epithelial cells S protein, which is instrumental for the binding and fusion and, different mutations in its gene, particularly its with host cell membrane, is to get bound to NRP1 after fusion, represents one of the most frequently biologic its cleavage [49]. defects observed in primary prostate cancer. Confirming NRP1 is also used as a surface receptor by different pro- the hypothesis that androgenic upregulation may be of teins, as the vascular endothelial growth factor (VEGF) or importance in disease severity, it has been described that semaphorin 3 family [51]. NRP1 is expressed in vascular patients with prostate cancer treated with androgen dep- endothelial cells and may contribute to the organ tropism rivation seem to be partially protected from SARS-CoV-2 of COVID-19 disease beside the respiratory tract [49, 50]. infection [47]. In this sense, as TMPRSS2 inhibitors are Severe and later stages of the disease are related to vascular currently available for treating prostate cancer, this could dysfunction as arterial injury, increased coagulation or sep- represent an appealing target for the prevention or treat- sis and could be possibly due to NRP1 [52, 53]. ment of COVID-19 disease [39, 46]. NPR1 has been found also to show different degrees of expression in parathyroid, adrenal and testis and a lower 3.2 Neuropilin‑1 expression in thyroid gland compared to the former endo- crine organs. Indeed, it is possible that NRP1 could partici- Neuropilin-1 (NRP1) is a pleiotropic type 1 trans- pate in SARS-CoV-2 attack to the pituitary gland as VEGF membrane protein cell surface receptor involved in receptors are also present in the pituitary [54]. 13 Reviews in Endocrine and Metabolic Disorders Table 1  Endocrine targets with potential usefulness for SARS-CoV-2 treatment Possible action against SARS-CoV-2 Recommendation TMPRSS2 • Viral alternative receptor • No recommendation so far NRP1 • Viral alternative receptor • No recommendation so far Melatonin • Anti-inflammatory and antioxidant effects could be useful • Potentially useful in sleep regulation and neurocognitive in the cytokine storm protector as adjuvant therapy • Improves circadian rhythm, better sleep and shorter ICU stay Oxytocin • Immunomodulatory and anti-inflammatory properties could • No recommendation till clinical trials are conducted reduce cytokine storm • Enhances endothelial integrity and could have cardio-pro- tective properties and reduce thromboembolisms Corticosteroids • Anti-inflammatory action • Highly recommended in severe hospitalized patients Antiandrogens • Decrease TMPRSS2 expression • Antiandrogens should be continued in patients previously treated No recommendation till clinical trials are conducted as primary indication Estrogens • Protective action in endothelial function • Menopausal hormonal therapy should be continued • Stimulate humoral immune response • Hormonal contraception treatment should be discontinued or • Modulate inflammatory response switched to progesterone only contraceptives in hospitalized women • No recommendation till clinical trials are conducted DPP-4 • Potential alternative viral target • DPP-4 inhibitors should be continued if previously indicated • Anti-inflammatory properties • Immunomodulator Facilitates glycaemic control Statins • Promote plaque stabilization • Statins should be continued if previously indicated • Immune and anti-inflammatory effects helpful in the con- tainment of the cytokine storm Hyperglycemia, ketosis and diabetic ketoacidosis have 3.3 Pineal gland been observed in non-previously diabetic patients with COVID-19 [55]. An abnormal allele of NRP1 has been Melatonin, a well-known anti-inflammatory and anti-oxidative described in pancreatic beta cells [56] that could modify molecule, can protect against acute respiratory distress syn- the binding of the S protein of SARS-CoV-2 to NRP1 in drome caused by viral and other pathogens through their known the islets and could potentially cripple the insulin secretory enhancement of increased inflammatory cytokines and reactive pathway causing hyperglycemia or even diabetic ketoaci- oxygen species generation. There are several mechanisms by dosis. The upregulation of NRP1 in diabetic kidney cells which melatonin could have potential benefits in COVID-19 suggests the importance of this protein in SARS-CoV-2 cell infection. In the first place, it could have antiviral activity. In entry as a contributing factor and explains the increased risk studies performed through pharmacology-based platforms, of this infection in patients with diabetes [50]. melatonin has been found to be a potential drug with anti- As previously mentioned, a direct effect of SARS-CoV-2 CoV viruses’ activity [60]. Moreover, melatonin can inhibit virus on adipose tissue is plausible but not well known. In angiotensin II activation and facilitate angiotensin 1–7 action vitro studies have described NRP1 [57], ACE2 protein [58] [61]. Melatonin has also very potent anti-inflammatory and and TMPRSS2 expression [45] in adipocytes and adipose tis- antioxidant effects that could reduce and/or counteract proin- sues. Indeed, human adipose tissues present the highest level of flammatory cytokines during the cytokine storm observed in NPR1 expression among all human tissues examined and high severe COVID-19 cases [62]. Notably, there is a well-known levels of ACE2 protein and TMPRSS2 expression [59], sug- decrease of melatonin synthesis and secretion with aging condi- gesting a possible direct role of SARS-CoV2 in adipose tissue tion, thus favoring a much severe COVID-19 clinical form, as that might explain the severity of the infection in obese patients. the endogenous antioxidant and antiviral action of melatonin A recent study has observed a reduction of the entry and is naturally impaired. Moreover, long standing diabetes can infectivity of SARS-CoV-2 in the cell by inhibiting the inter- be associated with autonomic neuropathy which impairs pro- action between virus S1 protein and NRP1 [49] suggesting foundly melatonin secretion [63]. Thus, melatonin impairment a new therapeutic target pathway. related to aging and/or diabetes may be an important risk factor 13 Reviews in Endocrine and Metabolic Disorders contributing to suffer COVID-19 infection and to develop a T-lymphocytes in the thymus [74]. Therefore, both mecha- more severe outcome. nisms, if sufficiently activated, can be very beneficial, ame- In addition, melatonin regulates the circadian rhythm. liorating and protecting from COVID-19 infection. During the lockdown periods, disruption of the circadian In addition to its effects on the immune system, OXT can rhythmicity has been very frequently described, especially enhance endothelial integrity [75] and has cardio-protective in aged individuals. Chrono-disruption is also very com- properties that could reduce inflammation and promote mon in hospitalized and critically ill patients. In this regard, angiogenesis. These actions are probably very important in treatment with melatonin in intensive care units has been COVID-19 patients as OXT could thus reduce thromboem- found to improve sleep and shorten ICU stay [64]. In a recent bolisms and protect the cardiovascular system, which is a retrospective study melatonin exposure after intubation was major target of this virus [76]. Of particular interest, it is significantly associated with a positive outcome in COVID- the possible modulation of nitric oxide production by OXT, 19 and non-COVID-19 patients requiring mechanical ven- which is a key signaling molecule acting as a host response tilation [65]. modulator in viral infections. Furthermore, melatonin can have neuroprotective proper- OXT could also have a role in some of the comorbidities ties. Cognitive deficits have been reported during COVID- that have been associated with a higher risk of more severe 19 infection [66]. Confusion, forgetfulness, fatigue and low forms of COVID-19. OXT could reduce hyperlipemia and mental energy may be some of the sequela of COVID-19 could also prevent weight gain and attenuate hypertension infection. Melatonin could have potential benefits in these [70]. In addition, OXT has also been involved in the regu- patients as it can improve the quality of sleep and cogni- lation of glucose metabolism and the development of dia- tive performance, mostly if they have required ICU support betes mellitus [77]. In summary, if OXT could ameliorate [67–69]. these comorbidities, it could improve COVID-19 morbidity In summary, melatonin could have potential benefits in and mortality burden. As there are currently no specifically relation to its anti-inflammatory and anti-oxidative proper- effective treatments for COVID-19, OXT could be a safe ties; it could also ameliorate chrono-disruption and have and cheap option and a clinical trial is warranted in these neuroprotective properties that could improve outcomes in patients. COVID-19 patients. Notably, melatonin has a high safety profile, however the specific doses by which melatonin may 3.5 Corticosteroids reduce the severity of COVID-19 are not defined to date and further placebo-controlled randomized clinical trials are Corticosteroids have been used as an anti-inflammatory and needed. immunosuppressive treatment for different diseases of dif- ferent nature. Severe COVID-19 disease is characterized 3.4 Oxytocin by an inflammatory organ injury and a high production of inflammatory endogenous molecules known as cytokine There is probably a dysfunction on the oxytocin (OXT) storm, which may progress to an Acute Respiratory Distress secreting system related to SARS-CoV-2 infection. In this Syndrome (ARDS) as well as to other different organs dam- regard, situations that are known to increase the risk of age, as i.e. vasculitis, kidney damage and myocarditis among developing COVID-19 and also of developing more severe other. Under the basis of its previous utilization in a variety forms, such as age and menopause, are associated with a of diseases, in which a high degree of endogenous inflam- decline in OXT [70]. In addition, evidence of an involve- mation concurs, corticosteroids were postulate as potentially ment of the hypothalamic-pituitary region characterized by useful and in fact they have demonstrated to contribute to an abnormal hyperintensity signal in mammillary bodies and reduce or attenuate the overactivation of the immune system hypothalamus has been reported in T-2 magnetic resonances in COVID-19 patients [78, 79]. of 2 COVID-19 patients [71]. Since the mammillary bodies Data reported regarding the effectiveness of glucocorti- are the center of OXT production, infection of these areas coids for COVID-19 treatment are somehow contradictory could probably lead to changes in OXT activity and secre- [80, 81], probably due to the heterogeneous characteristics tion in COVID-19 patients. of the patients and different classes of glucocorticoids used OXT exerts different roles in the immune system. First, among the studies. However, the Recovery study, published OXT can decrease different cytokines including IL-1 and in July 2020, showed that glucocorticoids, particularly daily IL-6 in the early phases of infectious diseases [72]. Thus, 6 mg of dexamethasone treatment up to 10 days, reduced this could ameliorate COVID-19-related cytokine storm [70]. mortality in severe inpatients with COVID-19 receiving In addition, OXT could also prevent SARS-CoV-2infection invasive mechanical ventilation or oxygen therapy [79]. itself, inducing γ-interferon production [73] and revers- These promising data led to the modification of the stand- ing lymphocytopenia, as it can promote differentiation of ard of care guidance for COVID-19, as shown in the last 13 Reviews in Endocrine and Metabolic Disorders recommendations of the World Health Organization (WHO) Last but not least, low testosterone levels have also been [82] that introduced systemic glucocorticoids in the treat- associated to a poor prognosis and mortality in severe ment of severe and critical COVID-19 patients but not in SARS-CoV-2 men cases [92]. A recent report indicates that patients with mild symptoms. Nowadays, many clinical stud- in a cohort in which the mean age of men was 63 years, ies are ongoing to check the effectiveness of glucocorticoids circulating testosterone was consistently low in those devel- treatment in severe COVID-19 patients. oping a more severe form of the disease [93]. On the other The preferred choice is a compound with a high glucocor- hand, a polymorphism of the androgen receptor gene has ticoid effect and no mineralocorticoid action, such as dexa- been described predisposing some men to develop more methasone. Dexamethasone has a potent anti-inflammatory severe COVID-19 forms. These patients showed high circu- action, but also a very well-known hyperglycaemic effect. lating testosterone levels indicating receptor resistance [94]. As mineralocorticoid action could be harmful due to the Finally, low testosterone could also be related to hypotha- enhancement of RAAS, it may potentially stimulate the viral lamic hypogonadism, as observed in other metabolic, inflam- spread through ACE2 and also has detrimental effects on matory diseases and severe COVID-19 forms. Therefore, the hypertension and cardiac and pulmonary function, therefore information published so far indicates that different factors dexamethasone is a convenient option [83, 84]. interplay in the severity of COVID-19 disease in men, either The use of high doses of glucocorticoids may cause in association with high or low circulating androgens. hyperglycemia in a high percentage of patients by increas- Antiandrogenic treatment, particularly androgen recep- ing hepatic gluconeogenesis [85] and decreasing periph- tor inhibitors as cyproterone, spironolactone, eplerenone or eral glucose use [86]. Indeed, high doses of glucocorticoids flutamide and 5-alpha-reductase inhibitors, as well as finas- exacerbate hyperglycemia in patients with diabetes, previ- teride and dutasteride, seem to protect from COVID-19 in ously diagnosed or undiagnosed, and may precipitate hyper- men. However, this question remains very controversial at the glycemia and steroid-induced diabetes in those patients at moment [95]. Spironolactone and eplerenone have both an risk [87]. Glycemic control in severe COVID-19 in patients antiandrogenic and an antagonistic mineralocorticoid effect, treated with glucocorticoids is a challenge, especially in contributing to cardiovascular protection on these patients, as patients with previous diabetes treated with insulin due to aldosterone represents the bioactive RASS end-product [96]. the aforementioned effects upon glucose metabolism as Dutasteride and finasteride are 5-alpha-reductase inhibitors well as the impact of high circulating concentrations of that block the conversion of testosterone to 5-alpha DHT and cytokines present in severe COVID-19 cases. Diabetes UK mitigate TMPRSS2 expression in prostate cancer [97]. For has published a clinical guideline for the hyperglycemia these effects, they have been proposed as an adjuvant treat- management in COVID-19patients treated with dexametha- ment for SARS-CoV-2 infection, particularly in men with sone [87], recommending glucose monitoring to all patients androgenic alopecia. Different clinical trials using antian- and an initial insulin dose of 0.3 ui/kg/day, which should drogen, aldosterone antagonist or TMPRSS2 inhibitors treat- be quickly adjusted according to daily glucose levels. In ments trials are underway [92]. But, at the moment, results our personal experience, these patients need high insulin are not yet available. Male patients on previous antiandro- doses of about 1–1.3 ui/kg/day on average, and active daily genic therapy for prostate cancer should continue the therapy medical supervision to achieve glycemic goals between with a careful evaluation and follow-up. 7.7–10 mmol/l. Concerning women, the increased risk of developing severe forms and complications of COVID-19 infections is 3.6 Antiandrogens and estrogens mostly related to menopause age [98]. Indeed, estrogens may have a favorable effect against viral infections due to their Gender is one of the determinants for the evolution of severe protective action on endothelial function, the stimulation forms of SARS-CoV-2 infection [88]. Men are more severely of the humoral immune response and the modulation of the affected by COVID-19 than women, even after adjustments inflammatory response [99–102]. Furthermore, the RASS is for age, BMI and comorbidities [89, 90]. A possible explana- favorably modulated by estrogens in women [103, 104], while tion of the worse prognosis in men could be the androgenic- TMPRSS2 expression has a dual correlation with estrogens enhanced expression of TMPRSS2 that facilitate SARS- [105, 106]. In conclusion, estrogens, particularly estradiol, CoV-2 cell entry. However, young men have better outcomes could be eventually protective against COVID-19 and may than older men despite having higher levels of testosterone. prevent severe complications. There are ongoing clinical tri- Among young men, those with androgenic alopecia present a als using estrogens, progesterone and anti-androgens com- higher risk of severe COVID-19 forms and worse outcomes pounds, but no final data are currently available [92]. How- [91], presumably due to increased intracellular conversion ever, it is also crucial to remind that COVID-19 is associated from testosterone to 5-alpha dihydrotestosterone, thus facili- to the development of micro and/or macro thrombotic events tating SARS-CoV-2 to increase infectivity. [107, 108], and this could represent a limitation for estrogens 13 Reviews in Endocrine and Metabolic Disorders utilization in this disease. Regarding women under menopau- comorbid conditions mainly associated with an increased sal hormone replacement therapy (MHT), it has been recom- cardiovascular risk, statins were associated to a reduction of mended to continue treatment, although adding low molecular poor outcomes of COVID-19 disease [8, 9]. Mechanistically, weight heparin treatment in hospitalized cases [109]. How- there is evidence that cholesterol present in the cell mem- ever, the general advice on hormonal contraception treatment brane and the viral envelope could enhance SARS-CoV-2 is to discontinue the therapy or switch to progesterone-only cell entry as it does for other coronaviruses [120–122]. contraceptives in hospitalized women. The known statins cardioprotective effects may have probably been implicated in the protection of COVID-19 3.7 DPP‑4 cardiac injury, as recently reported in a series in which cardiac complications, including myocardial injury was Human dipeptidyl peptidase 4 (DPP-4)/CD26 has also only observed in 7% in those treated and 30% in non-statin been identified as a functional receptor of the S protein of treated patients [123]. Possible mechanisms implicated a MERS-Co-V [110]. MERS-CoV binds to the DPP-4 recep- greater plaque instability related to the COVID-19 inflam- tor-binding domain and interacts with T cells and nuclear mation milieu, especially when cytokine storm is present factors, such as NF-kB, which is critical in the pathogenesis [120], thus treatment with statins in these patients could of inflammatory disorders. DPP-4 is a known regulator of promote additional plaque stability. Moreover, statins have the immune system by activating T cells and enhancing the also immune and anti-inflammatory effects that could con- NF-kB pathway [111]. Transgenic mouse models express- tribute to mitigate the cytokine storm. As a consequence ing human DPP-4 exposed to MERS-CoV had an impaired of these reports, the recommendation for patients on monocyte/macrophage phenotype, CD4 + T cells, and lower statins, is to keep on the statins treatment in case of getting TNF alpha, IL-6 and Arg1 [112]. The human DPP-4/CD26 infected with COVID-19. In patients who haven’t received may also interact with the S1 domain of the viral spike gly- this therapy previously, results of ongoing clinical trials coprotein of SARS-CoV-2, thus allowing an additional way are needed to make a firm recommendation on the ini- for virus entry into the cell [113]. tiation of statins. Nevertheless, their possible actions in Therefore, the question is whether DPP-4 inhibitors cardiac protection, plaque stabilization, anti-inflammatory used currently for type 2 diabetes treatment may not just and immunomodulatory properties make them good can- improve metabolic control in these patients but also con- didates for high-risk COVID-19 patients [120]. tribute to modify COVID-19 attack, either inducing protec- tion or progression of infection. It is tempting to postulate that inhibition of DPP-4 with the current antidiabetic drugs targeting this molecule may impair the virus/DPP-4 inter- 4 Conclusions action, thereby enhancing the cell’s self-defense from virus entrance. However, the binding of SARS-CoV-2 compared COVID-19 pandemic has dramatically impacted the whole to MERS-CoV occurs at residues not located near the DPP-4 society worldwide and almost broken the health care sys- binding pocket of current gliptin drugs; thus, more studies tem of some countries. Since the beginning of the pan- are required to clarify this question [114]. demic, a metabolic and endocrine phenotype of patient has It is also known that DDP-4 inhibition modulates inflam- emerged and required quick adaptation and protection of mation and has anti-fibrotic effects. Depending on the these patients trough specific medical treatment of endocrine potency of these properties, DPP-4 inhibitors may eventually nature. With accumulating evidence generated in the last have some protective effects in case of severe COVID-19 18 months we now know that virtually all endocrine organs infection. The potential decrease of the magnitude COVID- and systems may be affected by the SARS-cov-2 virus. As 19 cytokines storm under DPP-4 inhibitor treatment action a consequence, the knowledge of the main features of endo- sounds attractive but, so far, no data are available to provide crine nature that can be present in everyday patient is cru- a consistent answer. cial for an adequate and successful therapeutic approach. From ACE2, TMPRSS2 to NRP1, many endocrine targets 3.8 Statins and molecules of endocrine nature are at the entrance of the viral attack and can contribute to its expansion and magnifi- A systematic review and meta-analysis found that the use cation of systemic lesions through amplification of cytokine of statins was associated with improved clinical outcomes storm. In this regard, optimization of glycaemic control and in patients with COVID-19 [115]. The results to date have diminution of glycaemic excursions contribute to better out- been controversial, as some studies but not all have found a comes in these patients. 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