Reviews in Endocrine and Metabolic Disorders https://doi.org/10.1007/s11154-020-09569-2 Endocrine and metabolic aspects of the COVID-19 pandemic Mónica Marazuela 1 & Andrea Giustina 2 & Manuel Puig-Domingo 3 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract COVID-19 infection has tremendously impacted our daily clinical practice as well as our social living organization. Virtually all organs and biological systems suffer from this new coronavirus infection, either because the virus targets directly specific tissues or because of indirect effects. Endocrine diseases are not an exception and some of endocrine organs are at risk of direct or indirect lesion by COVID-19. Although there is still no evidence of higher predisposition to contract the infection in patients with diabetes and/or obesity, the coexistence of these conditions contributes to a worse prognosis because both conditions confer an impaired immunologic system. Cytokines storm can be amplified by these two latter conditions thereby leading to multisystemic failure and death. Glycaemic control has been demonstrated to be crucial to avoiding long hospital stays, ICU requirement and also prevention of excessive mortality. Endocrine treatment modifications as a consequence of COVID-19 infection are required in a proactive manner, in order to avoid decompensation and eventual hospital admission. This is the case of diabetes and adrenal insufficiency in which prompt increase of insulin dosage and substitutive adrenal steroids through adoption of the sick day’s rules should be warranted, as well as easy contact with the health care provider through telematic different modalities. New possible endocrino- logical targets of COVID-19 have been recently described and warrant a full study in the next future. Keywords Covid-19 . Diabetes mellitus . Obesity . Malnourishment . Pituitary . Thyroid . Calcium . Vitamin D . Hypoadrenalism Abbreviations SARS Severe acute respiratory syndrome ACE Angiotensin-converting enzyme SARS-CoV- Severe acute respiratory syndrome ACTH Adrenocorticotropic hormone 2 coronavirus 2 BMI Body mass index TMPRSS2 Transmembrane protease serine 2 COVID-19 Coronavirus disease 2019 DPP4 Human dipeptidyl peptidase 4 H1N1 Influenza A ICUs Intensive care units MERS Middle East respiratory syndrome 1 Introduction Coronavirus disease 2019 (COVID-19) or severe acute respi- ratory syndrome coronavirus 2 (SARS-CoV-2) outbreak re- * Mónica Marazuela quires that endocrinologists move forward, even more, to the monica.marazuela@salud.madrid.org first line of care of our patients, in collaboration with other physicians such as those in internal medicine and emergency 1 Department of Endocrinology, Hospital Universitario de la Princesa, units. This will preserve the health condition and prevent the Instituto de Investigación de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain adverse COVID-19-related outcomes in people affected by 2 different endocrine diseases. People with diabetes in particu- Institute of Endocrine and Metabolic Sciences Vita Salute San Raffaele University; Division of Endocrinology IRCCS San Raffaele lar, are among those in high-risk categories for developing Hospital, Milan, Italy serious illness modality of COVID-19 infection if they get 3 Endocrinology and Nutrition Service, Department of Medicine, the virus, but other endocrine diseases such as obesity, mal- Germans Trias i Pujol Research Institute and Hospital, Universitat nutrition and adrenal insufficiency may also be strongly im- Autònoma de Barcelona, Badalona, Spain pacted by COVID-19 [1, 2] (Fig. 1). Rev Endocr Metab Disord Possible transient hypothalamo- pituitary dysfuncon Dysnatremias more frequent Higher suscepbility and worse outcomes in men Sick euthyroid syndrome Bone Low vitamin D may be linked to more severe disease -Hypocalcemia COVID-19 Probable higher suscepbility in adrenal Worse outcomes in insufficiency diabec paents and Cushing’s syndrome Worse outcomes in obese paents Fig. 1 Different endocrine glands/organs that can be affected by COVID- D may be linked to more severe disease Increased risk of hypocalcemia. 19: 1) Pituitary: possible hypothalamic-pituitary disfunction and alter- 5) Testicle: Higher susceptibility and worse outcomes have been reported ations in antidiuretic hormone metabolism. 2) Thyroid: sick euthyroid in men; 6) Diabetes. Worse outcomes in diabetic patients; 7) Obesity. syndrome; 3) Adrenal: probable higher susceptibility to COVID-19 in Worse prognosis in obese patients adrenal insufficiency and Cushing’s syndrome; 4) Bone. Low vitamin 2 COVID-19 infection and diabetes mellitus Respiratory Syndrome coronavirus (MERS-CoV) outbreaks, the present coronavirus epidemics does not seem to account Individuals with diabetes may be at increased risk of infections, for a much higher capacity to infect people with diabetes [9]. especially influenza and pneumonia. This is why all people with diabetes are recommended pneumococcal and annual influenza 2.1 Increased risk of morbidity and mortality in vaccinations [3]. In general, it is assumed that this risk can be patients with diabetes regarding COVID-19 infection reduced, though not completely eliminated, through good gly- cemic control. Data about the incidence of COVID-19 in pa- Virtually all reports coincide that morbidity and mortality due to tients with diabetes are limited at present, but are increasing COVID-19 infection are increased by the presence of diabetes. steadily every week; early reports have identified diabetes and In the series published by New York city hospitals, diabetes was obesity as predictors of higher incidence [4–7]. However, as more prevalent in those patients requiring admission (31.8%) population testing is still limited, and only in a few countries than in those not requiring admission (5.4%) [8] (Fig. 2). massive COVID-19 screening has been performed, whether or Indeed, diabetes was also reported as an important risk factor not diabetes is associated to a higher risk to contract COVID-19 for worse disease modality and excessive mortality while the is still unknown. The data currently available come mostly from occurrence of the Influenza A (H1N1) pandemic, SARS-CoV hospital consultation cohorts (Fig. 2). and MERSCoV outbreaks [4]. Influenza A (H1N1) pandemic, In this setting, the series by Petrilli et al. [8], in which 4103 tripled the risk of hospitalization and quadrupled the risk of patients were attended and 1999 were admitted to hospital, 15% intensive care unit (ICU) admission when diabetes was present of the overall cohort was found to have diabetes, which is not [3]. Consistent with that, data from China found that diabetes far from the prevalence of diabetes in the general population in accounted for 8%–16% of hospitalized patients [10, 11], being their age range in the US. Thus, confirming what was found diabetes prevalence across China around 5% [12]. with Influenza A (H1N1) pandemic, Severe Acute Respiratory A large report of the Centers for Disease Control and Syndrome coronavirus (SARS-CoV) and Middle East Prevention of the United States showed that 78% of COVID- Rev Endocr Metab Disord Fig. 2 Prevalence of diabetes Hospitalized paents mellitus in hospitalized COVID 34% 19+ versus general population in General populaon different countries The prevalence of diabetes is higher in 19.4% hospitalized patients in USA and Spain, but not in China or Italy 11% 15% 14.3% 8.9% 10.9% 10.3% China USA Spain Italy 19 patients in ICUs had diabetes, cardiovascular diseases in- that elevated blood glucose levels can directly rise glucose cluding hypertension or chronic lung disease [13]. A study concentrations in airway secretion [17]. In vitro glucose expo- performed by the Chinese Centre for Disease Control and sure of pulmonary epithelial cells significantly increases influ- Prevention including 72,314 cases (hospital admitted and am- enza virus infection and replication. In addition, elevated glu- bulatory controlled) reported an overall mortality of 2.3% cose levels impair the antiviral immune response. As a conse- (1023 deaths among 44,672 confirmed cases) and in those hav- quence, patients with diabetes use to have a higher viral ing diabetes it reached 7.3% [1]. An additional report from charge as well as a much severe disease when infected with China including 1590 hospitalized cases analyzed a composite respiratory viruses. These findings are consistent with the re- endpoint including admission to ICU, intensive ventilation, or ports of patients infected with the highly pathogenic avian death, and after adjusting for smoking status and age. It was influenza, in which hyperglycemia was associated with in- found that diabetes significantly increased the risk of severity creased fatal outcome. Hyperglycemia may also affect pulmo- according to the composite endpoint (hazard ratio 1.59, 95% CI nary function, and therefore, respiratory dysfunction induced 1.03–2.45); in this series, 34.6% of severe cases had diabetes by influenza virus is exacerbated in patients with diabetes [18, compared to 14.3% in non-severe cases [14]. 19]. In viral disease animal models, diabetes is associated with General mortality rates are difficult to evaluate due to the numerous lung structural changes, including augmented per- lack of data on non-symptomatic cases, as in most countries meability of the alveolo-capillary membrane and a collapsed universal microbiological screening for COVID-19 has not alveolar epithelium [20]. It is anticipated that glycemic control been implemented, thus leading to an overestimation of the can have beneficial effects in patients with coexistent diabetes prevalence of case fatality. As indicated, in China the overall and viral respiratory diseases such as COVID-19. However, in fatality rate was 2.3% and in people with diabetes it was 7.3% the clinical setting, optimal metabolic control has been diffi- [1]. Data published in Italy, indicate that more than 70% of cult to achieve mostly because of practical limitations encoun- patients who died due to COVID-19 had either diabetes, car- tered during the treatment of this patients’ group [21]. diovascular disease or cancer as comorbidities [7]. Interleukin 6 and D-dimer levels are more elevated in hyper- In summary, according to current accumulated data, persons glycemic patients compared to normoglycemic ones. Both, with diabetes are at increased risk for COVID-19 infection patients with hyperglycemia not previously known as having medical complications including death. Accordingly, an in- diabetes and patients with known diabetes had a higher risk of creased vigilance and testing of people with diabetes in special- severe disease than those without diabetes [22]. This empha- ized outpatient and general medicine clinics for COVID-19 is sizes the importance of early detection of hyperglycemia at the required, as well as a proactive hospitalization policy [15]. hospital setting and the necessity of its prompt and effective treatment with insulin [23–25]. 2.2 Importance of glycemic control in those with coexistence of COVID-19 infection and diabetes 2.3 Treatment for people with diabetes infected by COVID-19 To date, only a limited number of studies have addressed the role of hyperglycemia in the pathogenesis and prognosis of People with diabetes who are infected with COVID-19 may viral respiratory diseases [1, 16]. However, it has been shown probably experience a deterioration of glycemic control, like Rev Endocr Metab Disord in any other infectious episode. Proactive basal insulin dosage regarding metabolic control, but also contributing to modify increase and correctional bolus may be required to maintain COVID-19 attack in these patients, either inducing protection normoglycemia and prevent deterioration of metabolic control or progression of infection (Fig. 3). It is tempting to postulate in those under insulin treatment [15]. that inhibition of DDP-4 with the current antidiabetic drugs Diabetic ketoacidosis coexisting with COVID-19 is partic- such as sitagliptin, vildagliptin or linagliptin may impair the ularly hazardous to treat, because of the risk of pulmonary virus/DPP-4 interaction, thereby protecting the cell from virus fluid accumulation [26]. A report from a Chinese cohort entrance. However, the binding of SARS-CoV-2 and MERS- consisting of 658 patients suggests that COVID-19 infection CoV takes place at residues not located nearby the DPP-4i can cause ketosis per se in non-diabetic persons and may binding pocket of current gliptin drugs, thus requiring more increase the risk of ketoacidosis in those with diabetes [27, studies in order to clarify this question [33]. 28]. It is known that DDP-4 inhibition modulates inflammation In general, mild COVID-19 illness in people with type 2 and has anti-fibrotic effects; depending on the potency of diabetes on oral agents may be allowed to keep their usual these properties, DPP-4 inhibitors may eventually have some treatment, provided that the patient stays under well con- protective effects in case of severe COVID-19 infection. The trol, but treatment modification must be indicated immedi- potential decrease of the magnitude COVID-19 cytokines ately upon clinical judgement, if development of severe storm under DPP-4 inhibitors action sounds attractive but, so COVID-19-related symptoms appear, especially high fever far, no data are available to provide a consistent answer. and potential dehydration. Oral agents, particularly metfor- min and sodium glucose cotransporter-2 inhibitors need to be stopped also, if serious illness condition develops [26]. Insulin is the preferred agent to control hyperglycemia in 3 COVID-19 and obesity hospitalized patients, as it the most efficacious for any in- tercurrent situation, including infections [4]. Although sodi- 3.1 Increased risk of morbidity and mortality in um glucose cotransporter-2 inhibitors may predispose to patients with obesity regarding COVID-19 infection ketoacidosis, a controversial clinical trial with dapaglifozin has been approved in COVID-19 patients with moderate Until recently, there were no specific data in the literature illness including respiratory failure, the DARE-19 study reporting that subjects with obesity have a higher risk of de- (NCT04350593), aiming to evaluate the reduction of dis- veloping severe forms of COVID-19, as first studies from ease progression and death. China [1] and Italy [34] did not provide data on body weight and height. However, last reports have found a strong link 2.4 Role of DPP-4 in COVID-19 as virus target between obesity and admission to critical care as well as the use of invasive mechanical ventilation [35]. In a study from Remarkably, human dipeptidyl peptidase 4 (DPP-4) has Shenzhen (China), obesity was associated with a 142% higher also been identified as a functional receptor of the S- risk of developing severe pneumonia [36]. The Intensive Care protein of MERS-Co-V [29]. MERS-CoV binds to the National Audit & Research Centre in United Kingdom ob- DPP-4 receptor-binding domain and interacts with T cells served that 72.1% of patients with confirmed COVID-19 were and nuclear factors, such as nuclear factor kappa b (NF- overweight or obese and that among patients with body mass kB), a key factor in the pathogenesis of inflammatory index (BMI) >30 who had undergone intensive care, 60.9% of disorders. DPP-4 plays an important role in the regulation them died [37]. Among 4103 patients in New York City, BMI of the immune system by activating T cell repertoire and >40 kg/m2 was the second strongest independent predictor of upregulating nuclear factor kappa b pathway [30]. hospitalization, after old age [8]. In a retrospective single Transgenic mouse models expressing human DPP-4 ex- French center evaluating 124 consecutive patients, obesity posed to MERS-CoV had impaired inflammatory (BMI >30 kg/m2) and severe obesity (BMI >35 kg/m2) were monocyte/macrophage phenotype, CD4+ T cells and low- present in 47.6% and 28.2% of cases admitted to intensive er expression of tumor necrosis factor alpha, interleukin 6 care unit. The need for invasive mechanical ventilation was and Arg1 [31]. Remarkably, it has been recently demon- associated with a BMI ≥35 kg/m2 [38]. Several reports from strated that human DPP-4/CD26 may interact with the S1 around the world have previously identified obesity and se- domain of the viral spike glycoprotein of SARS-CoV-2, vere obesity as risk factors for hospitalization and mechanical thus allowing an additional way for the virus to enter the ventilation in the H1N1 influenza virus [39]. Together, these cell, beside the main one, which is angiotensin-converting data raise the question of whether there is a mechanistic link enzyme (ACE)2 [32]. between obesity and COVID-19 and whether obesity might Thus, the question is whether DPP-4 inhibitors used cur- independently contribute to COVID-19 risk or at least to more rently for treatment of type 2 diabetes play a role not just severe forms of the disease. Rev Endocr Metab Disord Fig. 3 Possible endocrine and metabolic targets that have been Melatonin considered for COVID-19 thera- py. Different hormones and drugs have been included as possible targets for COVI-19 including Oxytocin melatonin, oxytocin, DPP-4 (hu- man dipeptidyl peptidase 4), ACE-2 (angiotensin converting enzyme-2), estrogens and statins DPP4 GLP-1 RAAS ACE-2 Estrogens Stans 3.2 How can obesity impact COVID-19 infection? inflammation loop [42]. In this scenario, inflammatory macro- phage and innate lymphoid subsets replace tissue regulatory The high impact of H1N1 Influenza and now COVID-19 in M2 phenotypic cells. In addition, there are alterations of lym- patients with obesity and severe obesity is probably related to phocyte phenotype with a decrease in T regulatory and Th2 the deleterious effects of obesity on pulmonary function cells and an increase in Th1 an Th17. Viral infection may am- (Fig. 4). Obesity is associated with decreased expiratory reserve plify the already primed organ cytokine response in adipose volume, functional capacity and respiratory system compliance. tissue [42]. In parallel, one of the most important mechanisms Severe obesity causes sleep apnea syndrome and in those with underlying the severity of lung disease in COVID-19 is repre- increased abdominal obesity, pulmonary function is further im- sented by the so called “cytokine storm”, which can lead to paired by decreased diaphragmatic excursion. acute respiratory distress syndrome or even multiple organ fail- In addition, obesity contributes to increase the risk of dif- ure in the worst case. The cytokine storm identified in multiple ferent comorbidities including diabetes, cardiovascular risk respiratory viral infections including COVID-19 exhibits an and thrombosis, which may have a great impact in COVID- overproduction of interferon, tumor necrosis factor α, interleu- 19 infected patients outcomes, thus confirming that obesity kins, and different chemokines. Thus, considering that subjects rises the severity of COVID-19 infection [10, 40]. with obesity have also a pre-set proinflammatory milieu, it is In addition, obesity could increase per se, the risk of differ- expected that COVID-19 could further exacerbate inflamma- ent comorbidities including diabetes, cardiovascular risk and tion exposing them to higher levels of circulating inflammatory thrombosis in COVID-19, which can intensify the severity of molecules compared to lean human subjects. This seems a fea- COVID infection. sible mechanistic explanation of the increased risk of severe When it comes to the immune response, there is a clear complications of COVID-19 in subjects with obesity [43]. association between obesity and chronic inflammation that Obese individuals may exhibit greater viral shedding sug- can modify innate and adaptive immune responses, making gesting potential for enhanced viral exposure, especially if the immune system more vulnerable to infections [41]. several family members are overweight. This may be aggra- Obesity is related to low-grade inflammation that is associated vated in overcrowded multigenerational households, which to adipocyte hypoxia and dysfunction. This results in an exu- are more common in the socioeconomically deprived commu- berant secretion of pro-inflammatory cytokines such as tumor nities in which obesity is prevalent [44]. In addition, in influ- necrosis factor α (TNF- α), interleukin (IL) 1β and interleukin enza infection obesity not only increases the severity but also 6 and adipokines that lead to the recruitment of immune cells enhances viral diversity. The altered microenvironment asso- macrophage, T cell and B-cells, creating an auto-regenerating ciated with obesity supports the emergence of more virulent Rev Endocr Metab Disord OBESITY ↓ Respiratory Comorbidies Viral shedding Chronic inflammaon reserve • Hypertension ↑ Viral load • Altered immune response • ↓ Expiratory • Diabetes • ↑ Inflammatory cells volumen • Insulin resistance • ↓ Regulatory cells • Hypovitaminosis D ↑ Viral diversity ? • ↓ Gas Exchange • ↓ Diaphragmac • ↑ Thrombogenesis excursion • Sleep apnea Il-6, M1 Th1, IFN-α, COVID-19 Th17 IL-1β M2 Treg Th2 T cells M1 Cytokine storm IL-6, IL-7, IFN-α IL-22, TNF-β, MCP-1 Fig. 4 Potential mechanisms that link obesity to worse outcomes in immune response due to altered balance between inflammatory and COVID-19. Obese patients have 1) a impaired respiratory function; 2) regulatory cells. During COVID-19 infection there is also an altered im- associated cardiovascular, metabolic and thrombotic comorbidities which mune response that is amplified by the dysregulated immune system of reduce the capability to cope with COVID-19. In addition, obese patients the obese patients have 3) increased viral shedding and viral load and 4) an amplified influenza virus population capable of inducing greater disease metabolic phenotype is crucial. This includes body mass in- severity. This could be related to an impaired interferon re- dex, waist and hip circumferences and levels of glucose. Such sponse, which is seen in experimental models, both in obese measurements might not be forgotten to be done, both, in the mice and obesity-derived human bronchial epithelial cells primary care setting as well as in the hospital setting to accu- [45]. The same could happen in COVID-19 infection. rately assess the risk of these persons. Finally, subjects with obesity have also mechanical issues It is critical that patients with body mass index greater than related to excessive weight that make difficult an early diag- 40, which has been reported as a critical cut-off for mortality nosis with pulmonary ultrasound and other imaging tech- risk [8], take all the possible precautions to avoid infection. niques, thus leading to a diagnosis of COVID-19 in the ad- Losing weight, lowering blood pressure and controlling blood vanced stage which is most associated to highest mortality. sugar have always been important to prevent severe health con- The lack of medical or intensive care units not designed to sequences, but the risk of severe COVID-19 infection might accommodate optimally patients with severe obesity, the dif- now be another important reason to focus on these issues. ficulty of intubation and insertion of catheters related to excess Persons with obesity who become COVID-19 ill and re- of weight may lead to a slowdown in therapeutic steps, wors- quire treatment in intensive care units present very important ening prognosis in patients with obesity and COVID-19 [46]. challenges in their therapeutic management, as it is more dif- ficult to intubate them. It can also be more difficult to obtain 3.3 Recommendations for people with obesity diagnostic imaging (as there are weight limits on imaging regarding COVID-19 infection machines) and patients are more difficult to position and trans- port by nursing staff. Also, the decision to extubate those There is a need for increased vigilance, priority on detection patients is more challenging when it comes to these patients. and testing, as well as a proactive therapy policy for patients Healthcare systems in general are not yet well set up enough to with obesity and COVID-19 infections. The assessment of manage an increasing number of patients with obesity in ICUs Rev Endocr Metab Disord and the current crisis could probably highlight their limitations and triglycerides [59]. Chronic use of tocilizumab in rheuma- even more. toid arthritis has also been shown to increase lipid parameters, in particular triglycerides [60]. Statins have been postulated as a possible add-on treatment 4 Nutrition & vitamin D and COVID-19 for COVID-19 patients, based on their known immunomodu- latory properties [61]. Statins exert pleiotropic effects on in- Regarding undernourished subjects, COVID-19 infection is flammation and oxidative stress and modulate the immune associated to a high risk of malnutrition development, mostly response at different levels, including immune cell adhesion related to augmenting requirements and the presence of a se- and migration, antigen presentation, and cytokine production vere acute inflammatory status. These patients show also a [62]. Observational studies have reported the effectiveness of hyporexic state, thus contributing to an acute negative nutri- statin treatment in some viral infections including reducing tional balance. Estimated nutritional requirements for these influenza-related hospitalizations and deaths [63]. As statins patients are 25–30 kcal/kg of weight and 1.5 g protein/kg/ are low-cost, extensively tested, well-tolerated drugs in a day [47]. A nutrient dense diet is recommended in hospital- health crisis such as the current COVID-19 pandemic, they ized cases including high protein supplements, administered could be an option when treatment with more expensive drugs in 2–3 intakes per day and containing at least 18 g of protein may not be implemented. Continuation of preexisting statin per intake. If nutritional requirements are not met during hos- therapy must be recommended. pital stay, complementary or complete enteral feeding may be required and, in case that enteral feeding may not be possible due to inadequate gastrointestinal tolerance, the patient should 6 The pituitary and COVID-19 be put on parenteral nutrition. COVID-19 patients’ outcome is expected to improve with an adequate nutritional support. Evidence of altered pituitary function in SARS was first re- Vitamin D deficiency is widespread in Southern Europe ported by Leow et al. [64]. Sixty-one survivors of the SARS where vitamin D fortified food is not widely used [48]. outbreak were evaluated after recovery: 40% had evidence of Vitamin D insufficiency has been reported to increase predis- central mild hypocortisolism and 5% also had central hypo- position to systemic infections and to impair immune response thyroidism [64]. Edema and neuronal degeneration along with or even to enhance the development of autoimmune diseases SARS-CoV genome have been identified in the hypothalamus [49]. Moreover, it has been shown that vitamin D supplemen- on autopsy studies [64]. In the case of COVID-19 both the tation can prevent respiratory infections [50] and poor vitamin hypothalamic and pituitary tissues express ACE2 and could D status may aggravate the health outcome of ICU patients also be viral targets [65]. Currently, we do not have any such while its correction could decrease morbidity and mortality in data in COVID-19; however, considering the high frequency this clinical setting [51]. Therefore, besides the hypothesis that of neurological symptoms, one can assume that SARS-CoV-2 hypovitaminosis D may be a predisposing factor to COVID- may affect the hypothalamus–pituitary as well, directly or via 19 infection and aggressiveness in some European countries immune-mediated hypophysitis [66]. [52], we strongly recommend to maintain vitamin D treatment in those already diagnosed with hypovitaminosis D [53] and 6.1 Recommendations for people with pituitary suggest considering the supplementation with vitamin D of disorders regarding COVID-19 infection elderly comorbid persons at home confinement if they are no yet under supplementation [54, 55]. Studies on levels of Management of pituitary tumors without mass effects and 25 OH Vitamin D and their prognostic role in COVID-19 as without hormonal hypersecretion can be deferred for several well as on potential benefits of vitamin D intervention in this months and if possible, all patients should receive medical clinical setting are underway [56]. therapy [67]. In the case of pituitary tumors (except prolactinomas) with severe visual deterioration, surgery is the treatment of choice, with previous assessment of 5 Lipids and COVID-19 COVID-19 status [68]. Patients with pre-existing endocrine conditions may be vul- Hypertrygliceridemia has been described as a side effect dur- nerable to perturbations in plasma sodium in more severe ing COVID-19 infection, with four cases reported up to date. cases of COVID-19. None of the published reports so far have In two of them hypertrygliceridemia was related with reported a higher prevalence of dysnatremia in COVID-19 lopinavir/ritonavir treatment [57] and in two others, patients [69]. Regarding management of diabetes insipidus, since pa- were receiving a combination of this therapy with tocilizumab tients have limited accessibility to blood testing, the priority [58]. Lopinavir/ritonavir has been previously associated with should be to avoid hyponatremia [70]. This can be performed lipid abnormalities, including elevations of total cholesterol delaying desmopressin to allow regular periods of free water Rev Endocr Metab Disord clearance to prevent dilutional hyponatremia. It is also useful Adrenal insufficiency may confer a potentially increased to measure body weight daily. In addition, patients with dia- risk of acquiring COVID-19 infection, as this condition is betes insipidus who develop respiratory complications of associated to an impaired natural immunity function, with a COVID-19 are at significantly increased risk of dysnatremia defective action of neutrophils and natural killer-cells [75]. and should have a close monitorization [70]. This may explain, in part, the slightly increased rate of infec- tious diseases in these patients, as well as an overall higher mortality. Although patients with adrenal insufficiency may 7 The thyroid and COVID-19 have a greater risk of complications due to the potential for an adrenal crisis to be triggered by the infection, there is still no Data on thyroid involvement by coronavirus are most evidence that those patients have a more severe course of scarce. A study conducted during the SARS outbreak in COVID-19 [76]. 2003 had reported that serum Triiodothyronine and thyrox- Regarding cortisol dynamics, autopsy studies performed ine levels were lower in patients with SARS as compared on patients who died from SARS-CoV showed degeneration to controls, both during the acute and convalescent phases. and necrosis of the adrenal cortical cells, pointing to a direct This could simply imply an underlying euthyroid sick syn- cytopathic effect of the virus. Hence, it is likely that cortisol drome. However, a study of the autopsy in five patients dynamics may be altered in patients with SARS (and also with with SARS has shown marked destruction of the follicular SARS-CoV-2) [65]. In addition, there is an interesting hy- and parafollicular thyroid cells [71] and not a reduction in pothesis that certain amino acid sequences in the SARS- thyroid follicular size associated with euthyroid sick syn- CoV are molecular mimics of the host adrenocorticotropic drome [72]. Destruction of follicular cells may also be hormone (ACTH). This could blunt the stress-induced cortisol identified as a low triiodothyronine and thyroxine profile. rise, as antibodies produced against the viral particles will Data on thyroid function or thyroid pathology are yet not inadvertently destroy the circulating ACTH [77]. However, available in COVID-19 [65]. it is not yet known whether SARS-CoV-2 might be employing Regarding Graves’ disease, COVID-19 can be a precipitat- this same strategy. ing factor for initiation or relapse of the disease (M. The increase in morbidity and mortality in adrenal insuffi- Marazuela, personal experience). Several medical societies ciency could also be accounted by an insufficient compensa- have recommended to take special care to patients with hy- tory self-adjusted rise of the hydrocortisone dosage at the time perthyroidism receiving antithyroid drugs, because symptoms of the beginning of an episode of the infection. In this regard, of the rare side effect of agranulocytosis can overlap with in the case of suspicion of COVID-19, the “sick days” rule COVID-19. In this scenario, if symptoms of COVID-19, should be established as soon as minor symptoms appear [78]. agranulocytosis should be ruled out immediately with a full Additionally, patients are also recommended to have suffi- blood count. cient stock at home of steroid pills and hydrocortisone injec- Diagnostic work-up of thyroid nodules as well as thyroid tions if social confinement is required during the COVID-19 surgery for either benign or malignant thyroid nodules for outbreak. In addition, until there is enough information, pa- differentiated thyroid cancers have been generally postponed tients with AI should observe stringent social distancing. during COVID-19 pandemic [73] -although individualized choices based on accurate risk profile analysis were recom- 8.2 Cushing’s syndrome mended. Interestingly, 1 out of 12 patients who received radioiodine for differentiated thyroid carcinoma also showed Patients with Cushing’s disease, but particularly those under interstitial pneumonia on single photon emission computed supraphysiologic doses of steroids [79] may be also at a higher tomography [74]. risk of COVID-19 infection because of the steroids potential immunosuppressive action. This issue is important, as around 5% of the world’s population is taking chronic corticosteroids 8 The adrenal and COVID-19 and there is a high prevalence of AI among these patients [80]. In these cases, under empiric principles, it might be recom- 8.1 Adrenal insufficiency mendable to follow the same rules as patients with adrenal insufficiency. Life-long replacement treatment aiming to mimic physiologic Regarding diagnosis and therapy of patients with endoge- plasma cortisol concentrations is not easy to be achieved in nous Cushing’s when extensive differential diagnostic testing adrenal insufficiency patients. Many circumstances, either or- is not feasible, it should be deferred. Salivary cortisol/ ganic and/or psychological, might unbalance the physiologic cortisone tests should be avoided due to the potential of viral cortisol requirements. COVID-19 pandemic may be a new contamination and infection of laboratory staff. Treatment of reason for patient and physician concern. potential co-morbidities (such as hypertension and diabetes) Rev Endocr Metab Disord should be optimized and medical treatment must be initiated. inflammatory disease. Regarding SARS-CoV infected mice Any form of treatment can be considered to switch to a block in males, gonadectomy or treatment with an antiandrogen and replace regime (metyrapone or ketoconazole plus gluco- compound did not affect the morbidity and mortality; con- corticoid) in order to ease the monitoring [81]. versely, estrogen depletion by ovariectomy or treatment with an estrogen receptor antagonist dramatically increased both morbidity and mortality suggesting a protective effect for the 9 Calcium & Hypoparathyroidism estrogen receptor signaling pathway [92]. In addition, in ani- and COVID-19 mal experiments, estrogen treatment upregulated estrogen re- ceptor signaling, silenced the cytokine storm and lead to an Several studies showed a key role of calcium in viral fusion improved survival rate. for many enveloped viruses such as SARS-CoV, MERS-CoV SARS-CoV-2 viral entry requires two host proteins [93]: and Ebolavirus. Moreover, calcium promoted their replication the angiotensin converting enzyme-2 (ACE2) and the trans- directly interacting with fusion peptides of these viruses membrane protease, serine 2 (TMPRSS2) Androgen receptor [82–84]. Hypocalcemia had already shown to be common in activity has been considered a requirement for the transcrip- patients with SARS (60% of patients at hospital admission), tion of TMPRSS2 gene [94] and TMPRSS2 is the most fre- although generally mild [85], and in patients with Ebola virus quently altered gene in primary prostate cancer [95]. The mod- disease (62%) [86]. A case of COVID-19 infection has been ulation of TMPRSS2 expression by testosterone has been pos- recently reported as possible precipitating cause of subclinical tulated to contribute to male predominance of COVID-19 in- postsurgical hypoparathyroidism presenting with severe hy- fection [96]. Since TMPRSS2 is expressed also at pulmonary pocalcemia [87]. This case suggested that hypocalcemia may level, the use of TMPRSS2 inhibitors, currently being used for occur also in COVID-19 infection. In fact, very recently we prostate cancer, represents an appealing target for prevention found in a retrospective single Institution study including 531 or treatment for COVID-19 pneumonia [93]. patients with COVID-19 a high prevalence of hypocalcemia Adverse outcomes of COVID-19 in men could also be (in about 80% of cases) on initial hospital evaluation. associated to a higher prevalence of comorbidities, including Hypocalcemic patients were more frequently elderly males hypertension, cardiovascular disease, and lung disease. with linear correlation between calcium levels and LDH and PCR levels. In multivariate analyses, hypocalcemia was an independent risk factor associated with hospitalization where- 11 Ongoing COVID-19 research involving as it predicted ICU admission and mortality only in univariate endocrine targets analysis. [88].Therefore, all patients with postsurgical hypo- parathyroidism should continue their treatment to avoid se- 11.1 Role of ACE2 and inhibitors of the renin- vere acute hypocalcemia, which can be life-threatening, and angiotensin system eventually should be adequately treated [89]. Moreover, mild hypoparathyroid patients not requiring chronic treatment The SARS-CoV binds to the zinc peptidase ACE2, a surface should undergo careful surveillance in areas hit by outbreak molecule that is localized in the endothelial cells of arteries of COVID-19 outbreaks, particularly if overweight/obese and veins, arterial smooth muscle, respiratory tract epitheli- [90]. Finally, since hypocalcemia may have negative impact um, epithelia of the small intestine, and immune cells, to enter on cardiac outcomes [87], calcium evaluation, monitoring and the host cell [97]. With SARS-CoV, it was shown that ACE2 adequate supplementation if needed in all hospitalized patients overexpression facilitated viral entry and replication in cells with COVID-19 infection is recommended. [98]. SARS-CoV-2 probably targets the same spectrum of cells targeted by SARS-CoV, which in the lungs are primarily localized in pneumocytes and macrophages [93]. Acute respi- 10 Androgens and COVID-19 ratory distress syndrome (ARDS), which is the most serious complication of both SARS and COVID-19, is likely ex- Evaluation of the gender-related distribution has revealed that plained by this lung tropism. Moreover, extrapulmonary men had a higher susceptibility to the virus infection and manifestations of COVID-19 may also be related to the sys- worse clinical outcomes and COVID-19 deaths compared temic distribution of ACE2 in the gastrointestinal tract and with women. These gender differences were observed among the heart [15, 99]. There is evidence that ACE2 expression all age groups of adult patients [10, 91]. increases on the cell membrane with the use of ACE inhibi- A possible mechanism that may drive clinical outcomes is tors and angiotensin-receptor blockers [100]. There is a the- a compromised antiviral immune response to SARS-CoV-2 in oretical concern that by increasing ACE2 expression they men. Generally, androgens have an immune suppressive ef- could facilitate the entry of virus into the host cell and in- fect and women are disproportionately affected with crease the chances of infection or its severity [101]. Rev Endocr Metab Disord Unfortunately, data if ACE inhibitors or angiotensin-receptor pulmonary artery, can produce a vasolidatory effect [107]. blockers modify ACE2 levels or activity (or both) are lacking Oxytocin has been postulated as a prospective therapeutic in experimental animal models or in humans [102]. SARS- agent for Covid-19. CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently downregulate ACE2 expression in 11.3 Use of melatonin in COVID 19 order that the enzyme is unable to exert protective effects in organs and this may be in part responsible for organ injury in Viruses induce an explosion of inflammatory cytokines and Covid-19 [102]. At present, we cannot rule out that long-term reactive oxygen species, and melatonin, a well-known anti- intake of ACE inhibitors and/or angiotensin-receptor blockers inflammatory and anti-oxidative molecule, protects against may facilitate SARS-CoV-2 entry and virus replication. acute respiratory distress syndrome caused by viral and other Conversely, it is yet unknown whether intake of ACE inhib- pathogens. Melatonin is effective in critical care patients by itors and/or angiotensin-receptor blockers, when infected, is reducing vessel permeability, anxiety, sedation use, and im- beneficial with regard to pulmonary outcome. Possibly, we proving sleeping quality, which might also be beneficial for are dealing here with a double-edged sword, depending on COVID-19 patients. In addition, melatonin could be an adju- the phase of the disease: increased baseline ACE2 expression vant to prevent pulmonary fibrosis [108]. Notably, melatonin could potentially rise infectivity and ACE inhibitors/ has a high safety profile [109]. There are no reports on the use angiotensin-receptor blockers use would be an addressable of melatonin in COVID-19 to date [108]. risk factor. Conversely, once infected, downregulation of ACE2 may be the hallmark of COVID-19 progression. Compliance with ethical standards Consequently, upregulation by preferentially using renin- angiotensin system blockade and ACE2 replacement in the Conflict of interest The authors have declared that no competing finan- cial interests exist. acute respiratory syndrome phase may turn out to be benefi- cial [103, 104]. 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