Endocrine https://doi.org/10.1007/s12020-021-02734-w POSITION STATEMENT/GUIDELINE COVID-19 and endocrine and metabolic diseases. An updated statement from the European Society of Endocrinology M. Puig-Domingo1 M. Marazuela2 B. O. Yildiz3 A. Giustina ● ● ● 4 Received: 31 March 2021 / Accepted: 16 April 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 Abstract Background COVID-19 has completely changed our daily clinical practice as well as our social relations. Many organs and biological systems are involved in SARS-Cov-2 infection, either due to direct virus-induced damage or to indirect effects that can have systemic consequences. Endocrine system is not only an exception but its involvement in COVID-19 is so relevant that an “endocrine phenotype” of COVID-19 has progressively acquired clinical relevance. Aim We have been appointed by the European Society of Endocrinology (ESE) to update with the current statement ESE members and the whole endocrine community on the emerging endocrine phenotype of COVID-19 and its implication for 1234567890();,: 1234567890();,: the prevention and management of the disease. Conclusions Diabetes has a major role in this phenotype since it is one of the most frequent comorbidities associated with severity and mortality of COVID-19. Careful management including treatment modifications may be required for protecting our patients rather with known diabetes from the most dangerous consequences of COVID-19 or hospitalized with COVID- 19, but also in patients with SARS-CoV-2 induced newly onset diabetes. Obesity increases susceptibility to SARS-CoV-2 and the risk for COVID-19 adverse outcome. Adequate nutritional management needs to be granted to patients with obesity or undernourishment in order to limit their increased susceptibility and severity of COVID-19 infection. Lack of vitamin D, hypocalcemia and vertebral fractures have also emerged as frequent findings in the hospitalized COVID-19 population and may negatively impact on the outcome of such patients. Also, in patients with adrenal insufficiency prompt adaptation of glucocorticoid doses may be needed. Moreover, in this updated statement role of sex hormones as well as peculiar pituitary and thyroid aspects of COVID-19 have been included. Finally, in view of the mass vaccination, potential implications for endocrine patients should be considered. Keywords Covid19 Diabetes mellitus Obesity Vitamin D Pituitary Thyroid ● ● ● ● ● Introduction COVID-19 initially defined as a potentially severe respiratory syndrome caused by severe acute respiratory syndrome cor- * A. Giustina onavirus 2 (SARS-CoV-2) progressively demonstrated to be giustina.andrea@hsr.it a systemic disease with relevant extrapulmonary manifesta- tions which increase the lethality of COVID-19 and mainly 1 Endocrinology and Nutrition Service, Department of Medicine, include vascular, cardiac, kidney, gastrointestinal, and central Germans Trias i Pujol Health Science Research Institute and nervous system complications [1]. Pathophysiologically, Hospital, Universitat Autònoma de Barcelona, Badalona, Spain 2 ubiquitous expression of angiotensin-converting enzyme 2 Department of Endocrinology, Hospital Universitario de la (ACE2), the receptor which is responsible for the entry of Princesa, Instituto de Investigación de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain SARS-CoV-2 at the cellular level [2], widespread endothelial 3 damage, and altered immune response contribute to the Division of Endocrinology and Metabolism, Department of Internal Medicine, Hacettepe University School of Medicine, multiple organ involvement in COVID-19 [3]. Hacettepe Ankara, Turkey During the persisting Coronavirus disease 2019 4 Institute of Endocrine and Metabolic Sciences, Vita-Salute San (COVID-19) outbreak (we are facing the “third wave” of Raffaele University, IRCCS San Raffaele Hospital, Milano, Italy the pandemic) endocrinologists from all over Europe Endocrine discovered themselves to be crucial in the fight against the cohort, 14.8% required hospitalization in the first month COVID-19. In fact, they moved first with self-sacrifice after COVID-19 detection. Data on the presence of diabetes and decision to the first line of care of affected patients, in in COVID-19 patients requiring hospitalization is very collaboration with other physicians such as those in variable among different countries; in this regard China internal medicine and emergency units, but also greatly reported 7.3% [15], while in South Korea it was 17.9% and contributed to the profiling of an endocrine phenotype of 43.3% in US veterans [16]. COVID-19. In fact, in the evolving knowledge about Critically ill patients affected by COVID-19 are older and COVID-19 a major endocrine and metabolic involvement have more previous co-morbidities, mostly of cardiovascular has been progressively better understood with many and metabolic nature, compared to non-ICU patients [17]. endocrine organs, tissues, and molecules being directly or The most frequent phenotype of a COVID-19 patient indirectly affected or negatively influencing outcomes of requiring hospitalization is an aged one (60–70 years) in COVID-19 [4, 5]. which the presence of metabolic co-morbidities included A well-defined endocrine phenotype can be of help in hypertension (between 30 and 55%), diabetes mellitus preserving the health status and prevent adverse COVID-19 (between 15 and 33%), obesity (20–40%), coronary heart outcomes in both the general population and in people diseases (5.8%), and cerebrovascular disease (2.3%) is very affected by different endocrine diseases. People with dia- frequent. This is relatively consistent in western countries betes in particular are at high-risk of severe COVID-19 if while in Chinese series this metabolic phenotype is less fre- infected by SARS-Cov-2, which can also affect directly quently reported and age is lower than in European and beta-cell function. Moreover, other endocrine diseases such American reports [18]. as obesity, hypovitaminosis D and adrenal dysfunctions In a large UK cohort of people dying of COVID-19 in may impact on susceptibility and severity of COVID-19 the hospital, 32% had type 2 diabetes and 1.5% type 1 [6, 7]. Therefore, due to the relevant involvement and diabetes, and among people with diabetes, male sex, older increased responsibility of endocrinologists worldwide in age, renal impairment, non-white ethnicity, socioeconomic the persisting COVID-19 pandemic, as well as to the rapidly deprivation, previous stroke, and heart failure were asso- evolving knowledge on this new disease and its con- ciated with increased COVID-19-related mortality in both sequences, we have been appointed by the European type 1 and type 2 diabetes [19]. Diabetes was also asso- Society of Endocrinology (ESE) to write an update of our ciated with longer hospital stay and the necessity of assisted previously published statement [4] in order to continue to ventilation and ICU admittance [20]. support the ESE members and the whole endocrine com- We now know that mortality in either type 1 or type 2 munity in this critical situation. diabetes has consistently increased during the year of pan- demic, and these diabetic populations died not only because of the presence of the aforementioned co-existing co-mor- COVID-19 and diabetes mellitus bidities but also due to the fact that glycemic control has been recognized as an associated factor to fatality. Thus, Diabetes mellitus and the risk of SARS-CoV-2 mortality in diabetic persons infected with SARS-CoV-2 is infection also related to prior metabolic control, (see below) [21]. Interestingly, use of current antihypertensive drugs Subjects with diabetes mellitus may be at increased risk for included in diabetes treatment, and particularly ACE inhi- infectious diseases which can be decreased, although not bitors, was not associated with increased mortality [22]. completely abolished, by appropriate glycemic control. In this Moreover, the good news is that the use of statins confers context, all people with diabetes (over the age of 2) are certain degree of protection toward mortality, and therefore, recommended influenza vaccinations [8]. A rapidly increasing it is recommended not to withdraw them even when the amount of published data on the incidence of COVID-19 in patient is hospitalized [23]. A retrospective study performed patients with diabetes has accumulated over the last year in Italy indicated that the use of sitagliptin was also asso- clearly indicating that diabetes and obesity are predictors of ciated to a reduced mortality during hospitalization [24]. All worse outcomes and mortality [9–13]. these findings will require to be confirmed in the months to come with more data. Increased risk of morbidity and mortality in patients In summary, according to current evidence, people with with diabetes and COVID-19 diabetes may be at increased risk for SARS-CoV-2 infec- tion, and they are at high risk of medical complications The largest study performed in Catalonia including data of including death. Accordingly, in these patients, active vig- 118,150 COVID-19 patients, found a diabetes prevalence of ilance and testing in outpatient endocrine clinics, as well as 9.3% in the COVID-19 affected population [14]. In this early hospitalization for COVID-19 is recommended [4]. Endocrine Importance of glycemic control in those with should not be stopped at the time of admittance in the COVID-19 and diabetes hospital due to COVID-19 pneumonia [31]. While the restoration of normoglycemia seems to be related COVID-19 and newly onset diabetes to a better prognosis for bacterial infections, in viral disease and especially in COVID-19 diabetic patients, the impact of Diabetes is not only one of the most frequent co-morbidities antihyperglycemic treatments on the outcomes is still under of hospitalized patients with severe COVID-19 but it has evaluation [25]. progressively emerged that a bidirectional relationship In vitro glucose exposure of pulmonary epithelial cells between diabetes and COVID-19 may exist [32]. In fact, significantly increases influenza virus infection and repli- since pancreatic β-cells abundantly express ACE2 receptor, cation and elevated glucose levels impair the antiviral they may be damaged by SARS-CoV-2 with consequent immune response. In viral disease animal models, diabetes worsening of hyperglycemia in patients with known dia- is associated with numerous lung structural changes, betes, often complicated by ketoacidosis or hyperosmolarity including augmented permeability of the vasculature and a with high-dose insulin requirements. Moreover, also new collapsed alveolar epithelium [26]. Hyperglycemia may also onset of diabetes in COVID-19 patients previously non- affect pulmonary function [27, 28], and respiratory dys- diabetic has been consistently reported [32], disclosing a function induced by COVID-19 is exacerbated in patients potential diabetogenic action of SARS-CoV-2 [33]. The with diabetes. In fact, COVID-19 pneumonia radiologic transient or persistent nature of this hyperglycemia in scores are worse in diabetic patients [29]. COVID-19 as well as the true incidence and characteriza- Recently published data indicate that glycemic control is tion of this newly onset diabetes are still not entirely known related to outcomes. Thus, the last A1c previous to the and international registry efforts are ongoing in order to development of COVID-19 has been reported to show a collect and analyze those cases worldwide [32]. linear relationship to outcomes and particularly to mortality when A1c is >10% [19]; these latter figures equally applied Diabetic retinopathy to either type 2 and also type 1 diabetes. Conversely, low A1c has also been related to mortality in type 2 diabetes Microvascular diabetic damage including severe retino- while the relationship is not statistically significant for type pathy and/or nephropathy and/or diabetic foot predicted 1 diabetes. Glycemic factors combined with obesity amplify adverse outcomes in COVID-19 patients [34]. Interest- the deleterious effects upon mortality and severe outcomes, ingly, in a cross-sectional study on 187 hospitalized impacting also individuals <70 years apart from those >80 patients with poorly controlled diabetes and COVID-19, years; this latter fact is particularly relevant in Asian and the presence of retinopathy was independently associated black ethnicities [19]. with intubation (OR slightly lower than 6). Although due to Besides the importance of the A1c previous to SARS- the type of study, the mechanistic association could not be CoV-2 infection, glycemic control and glycemic fluctua- established, it can be speculated that diabetic microangio- tions during the first days of hospital stay have additionally pathy may be surrogate marker of endothelial dysfunction/ been reported as important determinants of hospital length damage representing a risk factor for severe COVID-19 stay, ICU requirement, and mortality with odds ratios ran- tissue damage [35]. ging from 1.97 and 2.73 in Wuhan patients [30]. Moreover, the strength of the association of these outcomes was higher Treatment of people with diabetes infected by if the patients received corticosteroid treatment, thus SARS-CoV-2 requiring intensive insulin treatment. Different factors are influenced by hyperglycemia and People with diabetes who are infected with SARS-CoV-2 play an important role regarding tissue damage in these may experience a worsening of glycemic control during the patients, such as glucose-dependent impaired pulmonary course of the disease, as it occurs with other infectious epi- function, exaggerated inflammasome response, renin- sodes. Implementation of “sick day rules” is therefore angiotensin system dysregulation, aberrant protein gly- necessary to avoid possible decompensation of diabetes. cation including dysfunction of immunoglobulins and Patients with type 1 diabetes should increase frequency of ACE2, increased coagulation activity, potential bacterial blood glucose and urinary ketones measurement in case of superinfection and, as commented below, direct pancrea- fever and hyperglycemia also proactively modify basal tic damage. insulin dose or using correctional bolus in order to maintain Interestingly, it has been reported that treatment with euglycemia and avoid worsening of glycemic control [4]. metformin and statins are associated with lower disease Also, patients under oral hypoglycemic agents may need severity and mortality, suggesting that these treatments more frequent glycemic monitoring and modifications in Endocrine drug doses. If patients on sodium-glucose cotransporter-2 were attributable to cardiometabolic conditions and the top inhibitors are hospitalized, treatment needs to be stopped, due risk factor was obesity accounting for 30.2%. The propor- to a potentially higher risk of ketoacidosis development [36]. tion of COVID-19 hospitalizations attributable to obesity Since recent data seem to indicate the protective effect (BMI:30–40 kg/m2) was similar for the age groups of 18–49 apparently associated with metformin, DPP4, as well as years and ≥65 years whereas severe obesity was a higher statins, if there are no specific contraindications, continuing risk for hospitalization in the youngest age groups (13.5% on these oral compounds may be of benefit for these patients. versus 9.3%), and in women compared to men (13.8% Insulin is the most efficacious agent for the control of versus 9.2%) [39]. Using various inclusion criteria and hyperglycemia in hospitalized seriously sick patients and is definitions for the outcome variables, meta-analyses repor- also the case for COVID-19 infection [4]. In those patients ted increased risk of severe disease and composite poor treated with dexamethasone, insulin requirements are par- outcome in patients with COVID-19 and obesity with odds ticularly high and use to be in the range of 1.2–1.5 units/kg. ratios varying between 1.39 and 2.35 [38]. In general, This dosage should be implemented at the time of initiation available studies consistently indicate increased risk for of corticosteroids to prevent delay in glycemic control. disease severity including hospitalization, ICU admission, In the case of symptomatic COVID-19 without pneu- and IMV need. However, data on mortality are conflicting. monia, if the clinical decision is to follow the patient in a For example, American Heart Association’s COVID-19 non-hospital environment, current antidiabetic treatment Cardiovascular Disease Registry data of 7606 patients with could be maintained provided that close vigilance on pos- 17% mortality ratio showed that severe obesity was asso- sible metabolic deterioration is performed. ciated with increased risk of in hospital death (hazard ratio, 1.26 [95% CI, 1.00–1.58]), particularly in those younger than 50 years [40]. In the UK Biobank study of over COVID-19 and other endocrine and 500,000 individuals where 410 patients died due to metabolic disorders COVID-19, hazard ratios for women and men were 2.21 (1.69; 2.88) and 1.78 (1.44; 2.21) respectively [41]. In Obesity contrast, other studies have failed to show excess mortality associated with obesity in COVID-19 patients [42, 43]. Impact of obesity on clinical outcome of patients with Similar to individual studies, there is a discrepancy in COVID-19 mortality results of meta-analyses. Some report increased risk of mortality with odds ratios varying between 1.37 and Limited data are available regarding susceptibility to SARS- 3.68, whereas others fail to confirm this finding with odds CoV-2 in patients with obesity whereas there are several ratios of 1.05–1.28 [38]. The differences in study popula- reports assessing the burden of obesity on the clinical tions and degree of obesity, healthcare systems, testing course of COVID-19. Most of the earlier studies on strategies, indications for hospitalization, ICU admission, or COVID-19 did not provide information on body mass index IMV might have contributed to the discrepancies of mor- (BMI) or other measures of obesity whereas others reported tality data. Whether obesity survival paradox is relevant conflicting results with similar, lower or higher rates of particularly for COVID-19 patients with mild obesity obesity compared to the general population. A recent ana- remains to be determined [44]. lysis of over 100.000 individuals with an outpatient diag- nosis of COVID-19 in Catalonia, Spain reported a hazard Potential mechanisms linking obesity and poor outcome in ratio of 1.23 (1.21–1.25) for obesity suggesting that indi- COVID-19 viduals with obesity are at increased risk to be infected with SARS-CoV-2 [37]. In a recent meta-analysis of 19 fair to It is well known that obesity, particularly in the severe good quality studies reporting on obesity and at least two form, is commonly associated with pulmonary dysfunction different outcomes, the pooled obesity prevalence rates which might predispose patients to develop respiratory were 32% in hospitalized patients, 41% in patients admitted failure in the case of pneumonia. Most patients with obe- to intensive care unit (ICU), 43% in patients needing sity have co-morbidities including type 2 diabetes, hyper- invasive mechanical ventilation (IMV), and 33% in those tension, cardiovascular disease, and kidney disease which who died [38]. It is important to note that the local obesity could adversely affect the clinical outcome of COVID-19. prevalence in the background population varies by geo- Additionally, several mechanisms have been proposed graphical region and might influence the results in patients about the association between obesity and poor COVID-19 with COVID-19. outcomes. Higher expression of ACE2 in adipose tissue A comparative risk assessment model of over 900,000 may lead to prolonged viral shedding and exposure in COVID-19 hospitalizations in the US showed that 63.5% patients with obesity, increasing the susceptibility to Endocrine SARS-CoV-2 infection and the risk of disease aggravation might eventually increase the number of individuals who [45, 46]. Obesity-driven chronic inflammation, aberrant will likely have a more severe course when infected with cytokine activation, decreased adiponectin and increased COVID-19. Thus, people with obesity should be encour- leptin secretions, and dysfunction of innate and adaptive aged to increase physical activity and gain healthy eating immunity may contribute to worse clinical outcomes in habits, develop strategies to reduce stress and optimize patients with COVID-19. Obesity is also associated with sleep during pandemic. pulmonary dysfunction, hypercoagulability and increased risk of thrombosis, which has emerged as an important factor leading to a more severe clinical course in COVID- COVID-19 and its nutritional consequences 19 patients [47]. Future studies are needed to determine whether these plausible mechanisms are actually linked to COVID-19 may be frequently accompanied by anosmia and COVID-19 outcomes. gastrointestinal disturbances like nausea, vomiting, and diarrhea that affect both, food intake and absorption [1]. Recommendations for people with obesity regarding SARS- These symptoms have been directly related to mucosal CoV-2 infection invasion by the virus and by viral particles. According to the classification of the European Society for Clinical Considering available data consistently suggesting that Nutrition and Metabolism (ESPEN) guidelines and other obesity increases the risk of poor outcome for COVID-19, scientific societies [48, 49], acute Disease Related Mal- measurement of anthropometric parameters should be rou- nutrition (DRM) may account for different reasons, but tinely performed in patients tested positive for SARS-CoV- mainly because of increased energy requirements related to 2 as a part of risk assessment. Patients with obesity and severe inflammation with difficulty to achieve them due to COVID-19 should be considered as a higher risk popula- hyporexia and coexistence of eating difficulties [49]. This tion. Increased vigilance, priority on detection and testing, definition of DRM fits perfectly with what clinicians have close monitoring, and earlier intensive treatment should be seen in COVID-19 patients. In COVID-19, loss of muscle considered in these patients to avoid unfavorable clinical mass and functionality due to the catabolic state caused by outcomes. It is critical that patients with obesity take all the the viral infection is present and directly related to disease possible precautions to avoid infection. Weight manage- severity. Additionally, immobilization and prolonged hos- ment, blood pressure, and blood glucose control have pital stay, aggravates this situation, particularly in those always been important to improve cardiometabolic health patients requiring ICU admission. As age is the most rele- and prevent severe health consequences in obesity, but the vant determining factor for disease severity and mortality, it risk of severe COVID-19 is now another important reason is concordant that many of these patients have a high risk of to focus on these issues. malnutrition due to previous ongoing chronic diseases or It should be considered that persons with obesity who just aging condition before hospital admission, which itself become ill and require hospitalization present challenges in is associated with adverse changes in body composition, the management. These include difficulties in venous such as the gradual loss of skeletal muscle mass and access, position, transport and airway management, diag- impaired muscle function (sarcopenia) [50, 51]. Few stu- nostic imaging problems due to weight limitations of ima- dies, performed mostly in the Chinese population, have ging machines, and the limited number of bariatric beds in evaluated nutritional status in COVID-19 patients, finding a hospitals. Healthcare systems in general are not yet well set risk of malnutrition in ~80% of them during hospitalization up to manage an increasing number of patients with obesity [52, 53]. In about 15% of patients, artificial nutritional in intensive care units and the current crisis highlighted their support is required for hospitalized cases, in particular those limitations even more. with the more severe conditions and those showing high Special attention to obesity is also important in the aspect inflammosome profile, and ICU admittance [54]. of disease prevention. Lockdowns, travel and mobility Anorexia is probably the most prevalent symptom in the restrictions and personal social isolation measures have early phase of the clinical disease, also in milder forms, and been introduced in many countries to reduce the spread of it uses to persist in about 80% of cases for about at least 2 SARS-CoV-2. These measures could result in lifestyle more weeks. Patients describe even aversion to food. Dur- changes that can adversely affect chronic health conditions ing the healing period, a rebound hyperorectic state occurs and increase the susceptibility for weight gain in the long in the majority of cases. Consequently, weight loss is a term for people with normal weight and obesity. Dietary common feature and even in mild cases 3–5 kg of weight habits, physical activity, stress, and sleep characteristics may be lost. Subjects may then recover or even to be could all play a role in weight gain. Social isolation asso- recovered or even gain more weight in the weeks after, in ciated with biological, behavioral and emotional alterations parallel with hyperphagia [54]. The intensity of anorexia Endocrine and its rapid disappearance in the recovery phase clearly vs. non-COVID-19 patients hospitalized with acute respira- suggests that not just the infective catabolic disease state tory disease [58]. with high circulating concentrations of cytokines plays a Several studies have confirmed that calcium levels are role. ACE2 has also been found to be expressed in the lower in patients tested positive to SARS-CoV-2 RT-qPCR human hypothalamus and a case report confirmed viral vs. negative patients and that hypocalcemia is indepen- invasion and replication in the hypothalamus in a post- dently associated with negative outcomes including ICU mortem patient brain [55]. Thus, it has been speculated that admission and mortality [59–61]. viral infiltration at the hypothalamic level may participate in From a pathophysiological perspective, calcium plays a this phenomenon and the virus clearance from the hypo- key role in the action of different enveloped viruses [62] thalamus would contribute to hyperphagia. The disorectic and hypocalcemia has already been reported in patients with situation may, however, last even for 6 months in about SARS [63]. Moreover, widespread lack of vitamin D (see 10% of the patients [54]. below) may contribute relevantly to the high frequency with For those cases requiring admittance to the hospital, full which hypocalcemia is found [64]. nutritional status evaluation during the first days is required Since hypocalcemia occurring in COVID-19 may be severe for detection of potential sarcopenia in apparently frail and potentially life threatening, all patients with postsurgical patients, and prevention of excessive weight loss. Weight hypoparathyroidism should be monitored carefully and never loss in severe cases accounts predominantly for muscle mass, discontinue or down titrate their treatment (e.g., for side while in the recovery phase in which weight regain takes effects) prior to consulting their endocrinologist [65]. More- place, it consists mostly in adipose tissue gains. Thus, the net over, patients with mild hypoparathyroidism not on chronic metabolic balance regarding body composition in these treatment, and particularly those overweight or obese should patients is negative as their metabolic condition worsened. be carefully monitored in areas with high prevalence of In order to prevent sarcopenia development, high protein COVID-19 and eventually adequately treated to prevent acute content diet with at least 1.5 mg/kg of body weight is hypocalcemia [61, 66]. Finally, since hypocalcemia may recommended [48, 49]. Additional nutritional support with negatively impact on cardiac and neurologic outcomes [56], oral supplements or even tube feeding should be imple- calcium evaluation and monitoring in all patients admitted to mented earlier, according to the patient’s diet intake. In the hospital with COVID-19 is recommended. those more severe cases requiring ICU admittance, oral nutrition supplements or parenteral nutrition should be Vitamin D started according to clinical judgment. During long hospital stays, a passive muscle rehabilitation program is also Mediterranean countries, as Italy and Spain, are affected by necessary to prevent muscle mass atrophy. the high prevalence of hypovitaminosis D as a consequence At hospital discharge, both a normocaloric high protein of a change in lifestyle and lack of food fortification with content diet for about 8 weeks, aiming to recover muscle vitamin D at odds with Northern European countries (the lost and preventing excessive adipose tissue regain, as Scandinavian paradox) [67]. Several authors evidenced an well as a personalized muscle exercise program are highly association between COVID-19 prevalence and its severity recommended. with latitude and related sunlight exposure [68, 69]. Moreover, home confinement particularly of elderly sub- jects may contribute to the worsening of the vitamin D Bone and mineral metabolism in COVID-19 status in countries with widespread vitamin D deficiency [70]. Finally, it has been suggested that low vitamin D may Hypocalcemia negatively influence the outcome of patients admitted to ICU in whom vitamin D supplementation could reduce Hypocalcemia has become a major biochemical feature of morbidity and mortality [71]. COVID-19 after being initially reported in a previously Hypovitaminosis D may expose to a high risk of thyroidectomized patient hospitalized with COVID-19 COVID-19 and severe disease since it has been reported to presenting with particularly low calcium levels possibly predispose to systemic infections impairing immune linked to subclinical hypoparathyroidism [56]. In fact, responses [72] with the potential preventive role of vitamin according to our series of more than 500 COVID-19 D supplementation towards respiratory infections [73]. The patients, hypocalcemia is highly prevalent [57], associated specific role of vitamin D in COVID-19 may be due to with inflammatory parameters and independently predicted ACE2 downregulation and its ability to counteract the the need for hospitalization [52]. Subsequently, it has also cytokine storm characteristic in severe COVID-19 cases by been shown that hypocalcemia may be a distinctive feature modulating pro-inflammatory cytokines and regulating of COVID-19 since it is more frequently found in COVID-19 T-cell differentiation into Th2 phenotype [74]. Endocrine Low levels of vitamin D adjusted for confounding factors cortisol dynamics may also be altered in patients with SARS- have been found in different studies from different geo- CoV-2 as ACE receptors have been reported in the adrenal graphical areas in a considerable proportion of hospitalized cortical cells [82]. An acute adrenal insufficiency caused by a COVID-19 patients with average levels lower than the thrombotic event at the adrenal has also been reported [83]. general population [75]. Poor vitamin D status has also been In addition, certain amino acid sequences in the SARS- reported in the majority of the studies to predict disease CoV-1 are molecular mimics of the adrenocorticotropic severity including chest CT stage and mortality risk [69], is hormone (ACTH). This could blunt the stress-induced also associated with severe endocrine co-morbidities of cortisol rise, as antibodies produced against the viral parti- COVID-19 [76, 77]. cles will inadvertently decrease the circulating ACTH [84]. In a Spanish pilot clinical trial, COVID-19 hospitalized However, it is not yet known whether SARS-CoV-2 might patients with pneumonia were randomly assigned to stan- be employing this same strategy as SARS-CoV-1. In dard of care combined or not with calcifediol, and this latter addition, critical-illness related corticosteroid insufficiency significantly reduced the requirement of ICU admission related to COVID-19 can appear. This is a rare condition of with no deaths [78]. relative adrenal insufficiency resulting from inadequate Based on the above, we recommend that granting ade- glucocorticoid-mediated anti-inflammatory activity in rela- quate vitamin D levels in the general population but parti- tion to the severity of stress caused by a critical illness [85]. cularly in high risk (elderly with diabetes and obesity) should It has been hypothesized that patients with adrenal insuf- be a good clinical practice. Supplementation with vitamin D ficiency may be at increased risk of SARS-CoV-2 infection of elderly co-morbid persons at high risk of coexistent since they have an impaired natural immunity with neutrophil COVID-19 and hypovitaminosis D is suggested [79]. and natural killer-cell defective function [86]. Moreover, in patients with adrenal insufficiency, there could be a higher Vertebral fractures (VFs) risk of an adrenal crisis after the infection [87]. However, in a recent survey of more than 200 Italian patients with primary Recently, it was reported a high prevalence (36%) of mor- or secondary adrenal insufficiency on regular follow-up and phometric VFs on lateral chest X rays in a single-center adequately trained, similar incidence of symptoms potentially cross-sectional study, reaching the level of the most frequent related to SARS-CoV-2 infection as well COVID-19 severity co-morbidities in the COVID-19 population [75]. In parti- as compared to controls were reported [88]. cular, VFs did have a strong prognostic impact with a double mortality rate in patients with versus without VFs. Moreover, Recommendations for patients with adrenal insufficiency the mortality rate was significantly higher in patients bearing severe vs. mild and moderate VFs. Also, fractured patients Replacement treatment in hypoadrenalism is a challenge for are older, need more frequent hospitalization and mechanical clinicians and patients, since mimicking physiological serum ventilation vs. non-fracture patients [80]. cortisol fluctuations [89] in the absence of reliable biomarkers The presence of VFs in COVID-19 could negatively for appropriateness, is not easy to achieve [90]. Furthermore, influence respiratory function and increase the risk of pneu- many organic and/or functional factors might influence cor- monia representing a marker of frailty and negative outcome tisol needs. In the context of the COVID-19 pandemic, phy- [80]. Therefore, anti-osteoporotic treatment should not be sicians should be alerted to this treatment issue. discontinued even with the monoclonal antibody denosumab, Patients should be on the replacement treatment that can which has been previously associated with increased risk of better mimic physiologic plasma cortisol concentrations and infections but apparently not of COVID-19 [81]. Finally, proper spacing of the doubled dose of glucocorticoids when lateral chest X-rays are performed in COVID-19 should be achieved [87]. The primary aim of treatment must patients at hospital admission, we suggest that thoracic VFs be not to leave the patients deficient in cortisol while should be searched for and reported for more comprehensive combating the high inflammatory cytokine load caused by profiling of the risk of severe disease. SARS-CoV-2. To avoid a possible increase in morbidity and mortality due to an insufficient compensatory self- Adrenals and pituitary and COVID-19 adjusted rise in the hydrocortisone dose administration, in the case of suspected COVID-19, the “sick days” rule Adrenal insufficiency should be applied as early as even minor symptoms may appear [87]. This means, in the first instance, at least to Regarding cortisol dynamics, autopsy studies performed double the usual doses of glucocorticoid replacement, to on patients who died from SARS-CoV-1 have found degen- avoid adrenal crisis and then tailored to the stress condition. eration and necrosis in the adrenal cortical cells, pointing to a Additionally, patient information must be adequately direct cytopathic effect of the virus. Hence, it is likely that strengthened in the order they maintain adequate stocks of Endocrine hydrocortisone at home (both for oral and systemic manifestations have been disrupted during the pandemic, administration), particularly in view of persisting measures which needs to be tackled despite the restrictions due to the of social confinement. If patients with adrenal insufficiency emergency. Furthermore, many pituitary diseases do have develop COVID-19, heparin should also be introduced due diabetes, obesity, and VFs among their most frequent co- to coagulation abnormalities. morbidities which represent themselves as risk factors for severe COVID-19. Cushing’s syndrome ACE2 and TMPRSS2 receptors are present in hypotha- lamic and/or pituitary tissue of COVID-19 patients [96] and Patients with endogenous (Cushing disease or adrenal SARS-CoV-2 genome has also been found in the hypo- adenoma) but particularly those with exogenous hypercor- thalamus of a postmortem brain of a patient affected with tisolism under treatment with pharmacological doses of COVID-19 [55]. glucocorticoids due to chronic autoimmune diseases as well Recently, cases of pituitary apoplexy have been reported as other inflammatory diseases [91] have also been hypo- associated with COVID-19, and they may be an expression of thesized to be at increased risk of COVID-19 due to the the neurovascular phenotype of COVID-19 in which cere- immunosuppressive steroid action. Moreover, in patients brovascular endothelial damage may lead to progressive vas- under chronic glucocorticoid treatment, a high prevalence cular syndrome or they also are linked to direct viral damage of adrenal insufficiency potentially impacting COVID-19 which can enter the brain through the olfactory nerve, or has been reported [92, 93]. directly reach the median eminence [96]. In addition, SARS- Regarding the diagnosis of patients with endogenous CoV-2 may affect the hypothalamus–pituitary via immune- Cushing´s syndrome, when extensive differential diagnostic mediated hypophysitis, as reported in SARS-CoV 1 [97]. testing is not feasible, it should be deferred. Salivary cor- COVID-19 could also have indirect effects on the HPA axis tisol/cortisone tests should be avoided due to the potential mediated by cytokines that can produce functional hypopi- of viral contamination and infection of laboratory staff. tuitarism. In this regard, two studies have found thyroid Treatment of potential co-morbidities (such as hypertension abnormalities suggestive of central functional hypothyroidism and diabetes) should be optimized and medical treatment and hypoadrenalism in COVID-19 patients [98]. As hypo- must be initiated. Any form of treatment of Cushing’s cortisolism and central hypothyroidism can persist in the long syndrome can be considered, as to switch to a block and term on SARS-CoV-1 survivors [82], it will be interesting to replace regime (metyrapone or ketoconazole plus gluco- monitor the long-term pituitary hormonal profile to estimate corticoid) in order to ease the monitoring [90]. The results any possible pituitary linked morbidity in COVID-19 patients. of a small recently published phone interview conducted in A recent online survey of clinical endocrinologists Northern Italy reported that around 3% of patients with worldwide [99] reported several negative effects of the Cushing’s disease had confirmed COVID-19 vs. <1% of the COVID-19 pandemic on acromegaly care, such as significant general population during the first wave of the pandemic, delay in surgical interventions as for other pituitary adeno- and with severe clinical presentation reported particularly in mas, and as well as major obstacles in the neuroradiological, patients with active disease [94]. These latter findings seem biochemical, and clinical follow-up of their patients. Other to suggest that patients with chronic hypercortisolism may issues pertinent to the COVID-19 pandemic reported by be at high risk of more serious consequences of SARS- clinicians are the potential impact of medical treatment of CoV-2 infection and therefore they should follow strict acromegaly on blood glucose levels [100], as well as the prevention rules. It seems also reasonable that, if cough and/ modality of medical treatment administration possibly or fever occur in patients living in an area of high pandemic favoring self-administered injectable or oral somatostatin spread, they could increase their steroid dose at the stress analogs and the need of improving remote communication glucocorticoid replacement level. These patients should also principally via phone, but also with dedicated software. be proactively informed about the possible risks related to Furthermore, acromegaly as well as Cushing patients are at their condition and counseled about sick days rules. high risk of systemic co-morbidities such as diabetes melli- tus, hypertension, obesity, and fractures [100–102] which may in turn negatively impact the outcomes of COVID-19 Pituitary [4, 5, 25] and therefore should be appropriately controlled in pituitary patients to prevent SARS-CoV-2 infection and Specific involvement of the pituitary gland in the endocrine severe COVID-19 outcomes [99]. phenotype of COVID-19. was recently reported including SARS-CoV-2 infection heavily impacted the functioning pituitary apoplexy, hyponatremia, and possibly hypophysi- of neurosurgical units with prioritization for urgent inter- tis [95]. Moreover, both the diagnosis and treatment of ventions. Unfortunately, prolonged waiting times conversely pituitary diseases and their chronic but also potentially acute have been reported for patients with benign tumors, such as Endocrine generally pituitary adenomas [103]. Moreover, there are risks precipitation of immune-mediated mechanisms, and sick of endonasal surgery linked to aerosolization of SARS-Cov-2 euthyroid syndrome. SARS-CoV-1 autopsies found destruc- during but also following operations [104]. A recent study tion of the follicular epithelium and of the parafollicular cells has evaluated the benefits vs. risks of elective endoscopic [110]. In COVID-19, several cases of atypical subacute endonasal surgery in patients with functioning pituitary thyroiditis, that has traditionally been associated with a viral adenomas resistant to medical treatments [105]. If all pre- origin, have been reported [111]. Subacute thyroiditis related ventive measures are followed, such as, first: COVID-19 to COVID-19 is usually reported to be painless and to present home testing before hospitalization followed by absolute with thyrotoxicosis, which in some cases is followed by home quarantine; second: Covid-19 test the day before sur- hypothyroidism. Patients are reportedly negative for thyroid gery; third: minimized operating team with two neuro- antibodies [112]. In addition, autoimmune thyroiditis or surgeons, an anesthesiologist and two nurses; third: operators Graves’ disease can occasionally be triggered by the “cytokine wearing maximal protective equipment; forth: operation storm” induced by SARS-CoV-2 infection [113]. Possible room closed for the entire intervention; five: avoiding man- complications related to these autoimmune disorders include euvers that could cause droplet formation and six: elimina- thyrotoxicosis, hypothyroidism, and Graves’ ophtalmopathy. tion at end of surgery of disposable “contaminated The most frequent thyroid-related problem in COVID-19 equipment” in a SARS-CoV-2 positive room, thus, pituitary care, particularly in hospitalized patients and in intensive surgery results to be safe for both patients and operators [95]. care units, is sick euthyroidism. In SARS-CoV-1 patients, Prevalence of moderate to mild hyponatremia (serum Na serum T3 and T4 were decreased in 94% and 46% of between 130 and 135 mMol/L), has been reported in around patients in the acute phase and persisted in 90% and 38% in 20–50% of hospitalized patients with COVID-19, which convalescent cases [114]. These alterations were transient sometimes may even be the presenting symptom of the and resolved during follow-up. In COVID‑19, low to nor- disease [95]. Hyponatremia is independently associated mal T3, T4, and TSH without clinically apparent hypo- with old age, male sex, other co-morbidities, the severity of thyroidism have also been reported [115]. Long-term pneumonia, and negative outcomes [106]. follow-up studies on thyroid function are still needed. It has been shown that at least in some cases, hypona- tremia in COVID-19 may be related to inappropriate anti- diuretic hormone secretion syndrome (SIADH) potentially Recommendations for people with thyroid caused by excess IL-6, which can induce the non-osmotic disorders regarding COVID-19 release of vasopressin [107]. SIADH in COVID-19 patients may also be induced by Regarding management of Graves’ disease during COVID-19, treatment with antibiotics, corticosteroids, and positive several medical societies have recommended to take special pressure ventilation. The only available recommendations for care to patients with hyperthyroidism receiving antithyroid the management of hyponatremia in patients with COVID-19 drugs, because symptoms of the rare side effect of agranulo- have been given in a recent consensus of the Spanish Society cytosis can overlap with COVID-19. In the resource-limited for Endocrinology [108] in which it was underlined the need primary care setting a “block and replace” therapy for the for an endocrinological assessment in patients with COVID- treatment of thyrotoxicosis has been proposed [116]. 19 and new onset of hyponatremia since also adrenal and Diagnostic work-up of thyroid nodules, as well as thyr- thyroid dysfunctions may be involved. oid surgery for either benign or malignant thyroid nodules Hyponatremia should also be avoided during the man- for differentiated thyroid cancers, have been generally agement of patients with diabetes insipidus in outpatients, postponed during the COVID-19 pandemic [117] -although since patients may have limited accessibility to blood test- individualized choices based on accurate risk profile ana- ing [109]. This can be done by indicating once a week lysis are recommended, such as prioritizing aggressive aquaresis by omitting one dose of vasopressin. It is also thyroid cancer cases and deferring less aggressive ones. important to monitor weight and drink to thirst. Therefore, in all hospitalized patients with COVID-19, close monitoring and adequate correction of sodium levels, Sex hormones and COVID-19 if indicated, is recommended [109]. Epidemiological evidence suggests similar susceptibility to SARS-CoV-2 in men and women. However, COVID-19 Thyroid disease severity and mortality are higher in men [12]. A meta-analysis of over 3.1 million global cases reported Thyroid dysfunction in COVID -19 can include direct odds ratios of 2.8 and 1.4 for ICU admission and death in destruction of the gland by the SARS-CoV-2 virus, men compared to women [118]. Similarly, a recent Endocrine nationwide analysis of 84,000 patients and 434,000 con- who were not androgen deprived [131]. Most intriguingly, trols in Sweden found that male sex was associated with a recent double-blind placebo-controlled trials showed that 1.6-fold increased risk for non-ICU hospitalization, a selective androgen receptor modulators accelerates viral threefold increased risk of ICU admission, and 1.7-fold clearance and reduce time to clinical remission in male increased risk of mortality after adjustment for confound- patients without prostate cancer hospitalized with mild to ing factors [119]. Given the disparities of clinical out- moderate COVID-19 as well as a novel androgen receptor comes between men and women, the impact of biological inhibitor did show similar positive effects in both males and sex on immune response against COVID-19 infection has females with COVID-19 [132, 133]. become an area of interest. Therefore, a note of caution appears reasonable con- Clinical data suggest that behavioral differences might cerning the use of testosterone particularly in the elderly play a role in the outcome of COVID-19. Higher rates of with the so-called late-onset hypogonadism in whom the smoking [120], various social factors including the com- usefulness of androgen replacement is still debated [134]. pliance to protective measures [121] could contribute to the increased risk of severe disease in men, as well as a higher number of co-morbid diseases [122] and a low likelihood to COVID-19 vaccination and endocrine be treated with vitamin D for osteoporosis [123]. patients Physiological mechanisms that are likely to play a role in sexual dimorphism of COVID-19 outcome include the Since the opportunity of COVID-19 vaccination in some entrance of virus to the body and immunological differ- patients with endocrine diseases such as autoimmune ences. SARS-CoV-2 uses ACE2 and the cell surface thyroiditis has been questioned, the ESE recently released TMPRSS2 to enter the cells. Recently, it has been shown an ad hoc statement [135]. In fact, the approval of the first that androgens regulate transcription of these two host two vaccines in Europe by the EMA and in the US by the entry factors of SARS-CoV-2 in lung epithelial cells partly FDA was based on clinical trials on more than 40,000 and explaining the clinical observation of higher COVID-19 30,000 subjects, respectively. The age of participants morbidity and mortality in men [124]. Furthermore, ACE2 ranged from 16 to over 75 years. Patients with stable is widely distributed throughout the body and higher diabetes and obesity were enrolled in these trials and expression and activity is related to severe COVID-19 similar efficacy and safety were reported as compared to [125]. Sex-based differences and regulation of ACE2 in healthy subjects [136, 137]. Consequently, the ESE various organs might contribute to different clinical mani- statement supported the recommendation that COVID-19 festations in men and women. vaccination should not be handled differently in patients Women and men differ in their immune response to with stable endocrine diseases such as autoimmune thyr- infection [126]. A recent human study has reported that oiditis, Grave’s disease, Addison’s disease, pituitary ade- male patients had higher plasma levels of innate immune nomas, diabetes type 1 and 2 and obesity as compared to cytokines along with more robust induction of nonclassical the general population. The ESE statement recommends to monocytes. Female patients have significantly more robust inform patients with adrenal insufficiency in case of side T-cell activation than male patients during SARS-CoV-2 effects such as fever [135]. infection, which was sustained in old age. A poor T-cell In this regard, a recent survey of more than 100 members response negatively correlates with patients’ age and is was conducted by the Pituitary Society [138] in order to associated with worse disease outcome in male patients, but gain insights on the type of management of glucocorticoid not in female patients. Conversely, higher innate immune treatment that was planned in patients with adrenal insuf- cytokines in female patients have been associated with ficiency undergoing vaccination. Interestingly, around one- worse disease progression, but not in male patients [127]. third of respondents planned to automatically increase Overall, immune responses against SARS-CoV-2 appear to glucocorticoid dose particularly on the day of first vaccine differ between men and women. administration but some also prior to vaccination. The Data from the dermatologic literature suggest that bald majority of respondents were oriented to increase gluco- men are more prone to COVID-19 [128] as well as that corticoid dose in case of fever after vaccination, but many androgenetic alopecia is frequent also in women with also in case of myalgias and arthralgias which have been COVID-19 [129]. However, one of the more impactful reported among side effects of the vaccine. Results of this observations in this field came from patients with prostate survey need to be interpreted in the frame of “expert” cancer. In fact, those patients under androgen deprivation opinions and not of evidence based recommendation which therapy [130] demonstrated in some studies to be less vul- will be based on data from the field, which we recommend nerable to SARS-CoV-2 infection, as compared to patients to collect in an international database. Endocrine Conclusions 3. M. 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