Abstract
Endocrine system plays a vital role in controlling human homeostasis. Understanding the possible effects of COVID-19 on endocrine glands is crucial to prevent and manage endocrine disorders before and during hospitalization in COVID-19-infected patients as well as to follow them up properly upon recovery. Many endocrine glands such as pancreas, hypothalamus and pituitary, thyroid, adrenal glands, testes, and ovaries have been found to express angiotensin-converting enzyme 2 receptors, the main binding site of the virus. Since the pandemic outbreak, various publications focus on the aggravation of preexisting endocrine diseases by COVID-19 infection or the adverse prognosis of the disease in endocrine patients. However, data on endocrine disorders both during the phase of the infection (early complications) and upon recovery (late complications) are scarce. The aim of this review is to identify and discuss early and late endocrine complications of COVID-19. The majority of the available data refer to glucose dysregulation and its reciprocal effect on COVID-19 infection with the main interest focusing on the presentation of new onset of diabetes mellitus. Thyroid dysfunction with low triiodothyronine, low thyroid stimulating hormone, or subacute thyroiditis has been reported. Adrenal dysregulation and impaired spermatogenesis in affected men have been also reported. Complications of other endocrine glands are still not clear. Considering the recent onset of COVID-19 infection, the available follow-up data are limited, and therefore, long-term studies are required to evaluate certain effects of COVID-19 on the endocrine glands.
Introduction
Most patients affected by the novel coronavirus disease 19 (COVID-19) are asymptomatic or present with mild flu-like symptoms. Around 14% of cases are severe and 5% are life-threatening (1). SARS-CoV-2 enters the lung, deposits in the lung parenchyma, and afterward enters into the host cells. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) on host cells act as receptors for the virus (2). Viral mRNA has been detected in blood, stool, and urine samples of patients with COVID-19 suggesting that SARS-CoV-2 can interact with ACE2 and TMPRSS2 expressed in other organs as well (3, 4). This interaction leads to multi-organ involvement, including cardiovascular, gastrointestinal, nervous, and endocrine system (4, 5).
Endocrine glands such as pancreas, hypothalamus, pituitary, thyroid, adrenal glands, testes, and ovaries have been found to express ACE2 and TMPRSS2, with the highest concentration in the testes, followed by thyroid, and the lowest in the hypothalamus (6, 7). Since the pandemic outbreak, the aggravation of original endocrine diseases caused by COVID-19 or the adverse prognosis of the disease in patients with endocrine history, such as those with obesity and diabetes mellitus (DM), is under investigation. However, data on new early and late onset manifestations are limited (8, 9, 10, 11).
The aim of this article is to review the early and late endocrine complications of COVID-19 and specifically for (1) glucose metabolism, (2) hypothalamus and pituitary, (3) thyroid gland, (4) adrenal glands, (5) reproductive system, and (6) calcium and vitamin D metabolism.
Methods
Authors collected, analyzed, and present information on early and late endocrine complications of COVID-19. English language literature was searched in PubMed until July 2021 using combinations of relevant terms, such as COVID-19, endocrine, hormones, thyroid, adrenals, reproductive, testes, ovaries, vitamin D, calcium, parathormone, diabetes, pancreas, and glucose. These words were used as MeSH terms, in order to cover other relevant possible words missing. Alike works found in the references of the studies identified were also reviewed.
The early and late endocrine complications of COVID-19 are summarized in Table 1.
Early and late endocrine complications of COVID-19.
| Endocrine gland | Early complications | Late complications | Possible pathophysiological mechanisms |
|---|---|---|---|
| Glucose metabolism | Hyperglycemia on admission/during hospitalization (22, 23, 24, 25) New presentation of DM with DKA or hyperosmolarity (38, 39, 40, 41, 42) Insulin-dependent DM or precipitation of T1DM (47, 48) Aggravation of glycemic control in preexisting DM (26, 42) |
Permanent dysregulation of glucose homeostasis (38) T1DM or T2DM (38, 47, 48) Alteration of pathophysiology of DM (38) |
Pancreatic β-cell loss or malfunction: cytolytic effect of the virus on β-cells (48, 59) Morphological, transcriptional, and functional changes of β-cells by SARS-CoV-2 infection (60, 61, 62) Effect of the virus on exocrine pancreas (pancreatitis) (57, 58) Hyperinflammation/cytokine storm (28, 30) Hypokalemia through reduction of ACE2 expression may decrease insulin secretion (11, 69) Drugs (corticosteroids, antivirals) (11, 34) Cahexia, muscle weakness, rhabdomyolysis lead to decreased insulin sensitivity (35, 36, 37) DPP4 potential SARS-CoV-2 receptor (70, 71, 72, 73) |
| Hypothalamus and pituitary | Possible hyponatremia (75) | No data so far | Possible inappropriate antidiuretic hormone secretion syndrome (75) |
| Thyroid | Low T3 concentrations (77, 78, 79, 80) Thyrotoxicosis (78, 81) Subacute thyroiditis (78, 82, 83, 84, 85, 86) |
Low T3 concentrations (77, 78, 79, 80) Low TSH concentrations (77, 78, 79, 80) Hypothyroidism (78) |
Direct virus effect on follicular cells (89) Immune mechanisms (76) Euthyroid sick syndrome (76, 93) Hypothalamic-pituitary dysfunction due to edema and neuronal degeneration (76) Drugs (glucocorticoids, heparin) (76, 95, 97, 98) |
| Adrenals | Possible adrenal insufficiency (99, 100, 101, 102) | Possible adrenal insufficiency (99, 100, 101, 102) | Adrenal hemorrhage (99, 100) Adrenal micro-infarction (100) Ischemic necrosis (101) Adrenalitis (101) |
| Testes | Semen virus detection (115) | Impaired spermatogenesis (106) | Direct virus effect (89, 106) Seminiferous injuries (106) Reduction in Leydig cells number (106) Inflammation (106) |
| Ovaries | Vaginal fluid positive (118) Increased risk for premature delivery (107, 122) Vertical transmission not confirmed (107, 121) |
Adverse pregnancy outcomes (107, 122) Adverse perinatal outcomes (107, 122) |
Inflammation (107, 122) |
| Calcium and vitamin D | Complicated recovery in patients with vitamin D deficiency and hypocalcemia (124, 125, 126, 127, 128) Vertebral fractures (126) |
Vitamin D deficiency (123) Increased PTH (123) |
Home isolation and low sun exposure during lockdowns (123) |
ACE, angiotensin-converting enzyme; DKA, diabetic ketoacidosis; DM, diabetes mellitus; DPP4, dipeptylpeptidase 4; PTH, parathormone; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TSH, thyroid stimulating hormone; T3, triiodothyronine.
Glucose metabolism
Diabetes mellitus (DM) has been in the highest rank of comorbidities in hospitalized patients with COVID-19 (1, 12). Available evidence indicates that older adults with DM are at greater risk to develop severe COVID-19 disease, subsequent complications, and have increased mortality (13, 14, 15). Diabetic microvascular and macrovascular complications may be responsible for these outcomes (16, 17, 18). Moreover, chronic inflammation and increased thromboembolic risk that exist mainly in diabetic people with obesity may negatively affect the immune response (19, 20, 21). Growing data indicate also that hyperglycaemia on admission and during hospitalization in people with or without diabetes is a predictor of worse prognosis, severity, and mortality of COVID-19 (22, 23, 24, 25, 26). On top of the above, early and late effects of COVID-19 on glucose metabolism are of great interest.
Importantly, COVID-19 may worsen glucose homeostasis. COVID-19 infection is characterized by severe inflammation (27, 28, 29) that may aggravate insulin resistance and subsequent hyperglycaemia through the cytokine storm in conjunction with counterregulatory hormones' dysregulation (30). It has been already documented that viral respiratory infections, even in healthy individuals, can cause acute transient skeletal muscle insulin resistance by increasing interferon-γ production (31). Previous studies suggest that inflammatory cells in severe acute respiratory syndrome and Middle East respiratory syndrome apart from infiltrating the lungs and causing lung injury and acute respiratory distress syndrome (ARDS) can also affect skeletal muscle and liver functions (32). These two organs are responsible for insulin-mediated glucose uptake and gluconeogenesis, and their induced malfunction by inflammation probably results in hyperinsulinaemia and hyperglycaemia (33). Glycemic control seems to play a vital role in regulating the inflammatory response and preserving tissue integrity and physiological function during the critical stages of infection. Interestingly, drugs often used in the treatment of COVID-19, such as corticosteroids or antiviral agents, might further aggravate hyperglycaemia by inducing insulin resistance or even lipodystrophy (11, 34). Furthermore, decreased exercise capacity, cachexia, and muscle weakness in patients during severe infection and long-term hospitalization may diminish insulin sensitivity, especially in survivors of ARDS and sepsis (35, 36). Moreover, rhabdomyolysis has been reported during the infection, which might contribute further to glucose dysregulation (37).
COVID-19 infection may trigger the presentation of new DM cases. Indeed, recent clinical evidence has suggested such an effect of SARS-CoV-2 with presentation of diabetic ketoacidosis (DKA) and hyperosmolarity, usually requiring higher doses of insulin to be controlled (38, 39, 40, 41, 42). German and Italian studies have described higher frequency of DKA and severe DKA in children and youth with new-onset type 1 diabetes mellitus (T1DM) in COVID-19 time, while the incidence of new-onset T1DM in the general population has not changed (43, 44, 45). DKA diagnosis may be attributed to delayed hospital attendance and diagnosis of T1DM because of the overall public health impact (46). On the other hand, the postulation that COVID-19 could precipitate or accelerate T1DM onset is a possibility.
A potential link has been reported in a North West London Study where an apparent increase in DKA was noticed compared with usual admissions at two of the five units. Five out of 30 children with DKA had a positive COVID swab as evidence of SARS-CoV-2 infection or exposure. The authors raised awareness that there may be a link, but the increase in DKA may reflect pandemic-related delayed presentations of new cases of T1DM, resulting in an increased number of presentations with DKA (47). Furthermore, a recent case report presented a 19-year-old German male who was hospitalized with DKA and insulin-dependent DM with the absence of typical diabetic autoantibodies, 5–7 weeks after asymptomatic COVID-19 infection. Authors suggested that SARS-CoV-2 infection might damage β cells in pancreas through a direct cytolytic effect of the virus (48). Increased psychological stress during lockdown could also contribute especially in genetically susceptible individuals. Past coronavirus outbreak studies have also reported higher rates of hyperglycaemia on admission, irrespective of preexisting glycemic status, disease severity, or glucocorticoid use (49, 50).
Of note, several case series of euglycaemic DKA in patients with T2DM and COVID-19 while on sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been reported (51, 52). SGLTis act on glucose and sodium excretion inducing osmotic diuresis and potential dehydration in critically ill patients, especially in a setting of anorexia and vomiting (53). The risk for euglycaemic DKA seems even more enhanced during COVID-19. Specific precipitating factors apart volume depletion by vomiting and anorexia may include a direct cytolytic effect of the virus on β-cells with consequent decreased endogenous insulin secretion and an increased inflammatory response with elevated interleukin-6 contributing to ketoacidosis (54). Furthermore, an international randomized control trial (dapagliflozin in respiratory failure in patients with COVID-19) is ongoing with dapagliflozin in patients with COVID-19 (55) in order to evaluate its safety and efficacy in conjunction with its implications in adults with cardiovascular, metabolic, or renal risk factors. However, early data from this phase 3 trial show that dapagliflozin failed to prevent organ dysfunction and all-cause mortality among hospitalized patients with COVID-19 at risk for developing serious complications, while its safety profile proved to be consistent.
There are several possible underlying pathophysiological mechanisms that would explain the damage of the pancreatic islets by SARS-CoV-2 and the subsequent loss of insulin secretory capacity. The immune response mediated by the virus with release of chemokines and cytokines might affect pancreatic cells and impair their ability to sense glucose concentrations and release appropriate amounts of insulin. Immune response may further impair the ability of liver, muscles, and other peripheral organs to uptake glucose (6, 38). Pancreatic islets express ACE2, facilitating damage during the infection, as indicated by elevated levels of circulating pancreatic enzymes (56, 57, 58). In a recent experimental study with derivatives from human pluripotent stem cells, it was demonstrated that the high expression of ACE2 in β cells and consequently the high β cells' permissiveness to SARS-CoV-2 can induce inflammatory cytokine release, β-cell apoptosis, and decreased insulin secretion (59). These findings were confirmed by a study that presented data from both human pancreatic islet cultures and COVID-19 full-body postmortem examinations. It was shown that SARS-CoV-2 infects and replicates in human islets, inducing morphological, transcriptional, and functional changes with subsequent reduction of insulin-secretory granules and impairment of glucose-dependent insulin secretion of β cells (60).
Two further studies also confirmed infection of β-cells in autopsy samples from people who died of COVID-19 and showed that COVID-19 infection leads to reduced production and release of insulin from pancreatic islet tissue. In particular, they showed that SARS-CoV-2 infection leads to the death of some of those all-important β-cells and causes transdifferentiation of the surviving cells (61, 62). In addition, several studies in mice support the hypothesis that ACE2 is important in β cell homeostasis. High fat diet may lead to reduction of ACE2, while deletion of ACE2 in diabetic mice induces hyperglycaemia, increases β cell oxidative stress, and decreases insulin secretion (63, 64, 65, 66).
In turn, acute hyperglycaemia seems to upregulate ACE2 expression and increase urinary ACE2 activity, which may consequently lead to increase of viral load. It has been shown that urinary ACE2 activity is elevated in patients with T1DM and T2DM, while urinary ACE2/creatinine is positively correlated with fasting blood glucose levels and glycated hemoglobin (HbA1C) (67, 68). In patients with DM, SARS-CoV-2, through reduction of ACE2 expression, results in decreased degradation of angiotensin II, increased secretion of aldosterone, and renal potassium loss. Hypokalemia can lead to further decrease of insulin secretion (69). Dipeptylpeptidase 4 (DPP4) is another possible coronavirus receptor that it is well known to have an important role in glucose homeostasis. Although it is not yet confirmed, DPP4 could also bind to SARS-CoV-2, affecting glucose homeostasis (70, 71, 72, 73).
Given the recent onset of COVID-19 pandemic, it is unclear whether the dysregulation of glucose metabolism induced by this type of coronavirus is permanent and can contribute to the development of overt DM in survivors. Moreover, whether SARS-CoV-2 can induce T1DM or T2DM or a new form of DM is a matter of scientific discussion. Long-term studies are required to evaluate whether the virus has a diabetogenic impact on individuals with higher risk for DM or whether it can totally change the picture of DM pathophysiology.
Hypothalamus and pituitary
There are no sound data indicating specific early or late hypothalamic or pituitary complications from COVID-19. Hypothalamic and pituitary tissues express ACE2 and could be potential SARS-CoV-2 targets either directly or via an immune-mediated process, as already demonstrated with other coronaviruses (2, 8, 9, 11, 74). Survivors of the SARS outbreak after recovery presented mild secondary hypocortisolism (40%) or central hypothyroidism (5%). The potential underlying mechanisms may include edema and neuronal degeneration (74). Hyponatremia is prevalent in around 20–50% of hospitalized patients with COVID-19, associated often with negative outcomes. It has been hypothesized that it could be related to inappropriate antidiuretic hormone secretion syndrome potentially caused by excess levels of interleukins that can induce the non-osmotic release of vasopressin (75). Therefore, even in lack of sound evidence, targeted endocrine work-up especially in patients with unexplained fatigue and mental impairment post COVID-19 should be considered (9).
Thyroid gland
Interesting data have been published recently on the possible thyroid complications of COVID-19 (76). When thyroid function was investigated in 50 patients with COVID-19 for a follow-up period of 3 months post diagnosis, 64% was found to have abnormal thyroid function. Of those, 56% presented lower thyroid stimulating hormone (TSH) levels, while many of them had also decreased triiodothyronine (T3) concentrations compared with a healthy control group. No significant differences in thyroxine (T4) levels were found. Additionally, the degree of the decrease in TSH and T3 was positively correlated with the severity of the disease, as reported in other studies, the more severe the infection, the lower the TSH and T3 levels (77, 78, 79). When the clinical characteristics of deceased and recovered patients with COVID-19 were retrospectively compared, it was found that TSH and free T3 concentrations were significantly lower in the deceased ones (80). Muller et al. (78) found a higher prevalence of thyrotoxicosis (15.3%) in COVID-19 patients compared with only 1.3% in the control group that returned to normal after pneumonia recovery. It should be noted that the definition of thyrotoxicosis is not strict in this study (78). A retrospective study investigated thyroid function in 287 non-critical patients hospitalized for COVID-19 (81), 20.2% of whom had thyrotoxicosis and 5.2% presented with hypothyroidism. Interestingly, it was found that the presence of thyrotoxicosis was significantly associated with increased IL-6 levels (81).
Up to date, eight studies have reported subacute thyroiditis associated with COVID-19 (78, 82, 83, 84, 85, 86, 87, 88). Patients included had an age range from 18 to 68 years, most of them were women of Italian origin. These patients had no serious COVID-19 infection symptoms but only mild fever and mild upper respiratory symptoms, and no one needed treatment in ICU. The symptoms of subacute thyroiditis were the expected and included fever, anterior neck pain, fatigue, tremors, sweating, and palpitations, while the time from COVID-19 diagnosis to typical thyroiditis symptoms ranged from 5 to 42 days. Many of these patients with classic subacute thyroiditis presented specific classic ultrasound patterns (82, 83, 84, 85, 86, 87, 88). Interestingly, diffuse mild hypoechoic or focal markedly hypoechoic areas at thyroid ultrasound or reduced radioisotope thyroid uptake have been also described for atypical thyroiditis (78). Most of these patients received corticosteroids, and the symptoms improved within few days (78, 82, 83, 84, 85, 86, 87, 88). Subacute thyroiditis is thought to follow a viral infection or a post-viral inflammatory response, especially in genetically predisposed individuals (9, 76).
The pathogenesis of thyroid dysfunction post COVID-19 is not completely understood. One hypothesis is the direct influence of SARS-CoV-2 on thyroid gland. In a recently published autopsy study, the SARS-CoV-2 genome was detected in 9 of 25 (36%) thyroid samples. Moreover, strong cytoplasmic staining for SARS-CoV-2 nucleocapsid antigen in thyroid follicular cells was observed (89). Ultrasound findings of thyroid inflammation have been observed in patients with classic subacute or atypical thyroiditis after COVID-19 (76, 78). Of course, there are other recent postmortem reports that did not detect SARS-CoV-2 in thyroid tissues either by immunohistochemistry or PCR analysis (90, 91, 92). Taken all these together and as ACE2 is highly expressed in thyroid tissue, a role of a direct damage by SARS-CoV2 on the thyroid gland is possible. Eventually, the thyroid damage can also be indirect, caused by immune mechanisms, such as the cytokines’ storm (76, 89).
Another potential explanation could be an underlying non-thyroidal illness syndrome or euthyroid sick syndrome, which is often caused by critical illness (93). This is characterized by normal or low serum TSH and T3 levels, with normal or low T4 concentrations. This is a homeostatic mechanism to recover from severe illness (76, 93). An observational study from UK included 334 patients with confirmed COVID-19 without history of thyroid disease. Most of them presented with euthyroidism and mild reductions in TSH and free T4 (FT4) compatible with a non-thyroidal illness syndrome (94). The dysfunction of the hypothalamic-pituitary-thyroid axis might be an additive cause leading to decrease in TSH levels (76). Finally, indirect effects on thyroid or pituitary cells due to systemic immune-mediated post-viral inflammatory response could affect thyroid function (88, 95).
Additionally, drugs used for the management of COVID-19 can potentially affect thyroid function (76). Glucocorticoids could affect serum TSH levels, mainly by inhibiting thyrotropin-releasing hormone secretion in the hypothalamus or by suppressing TSH release in pituitary thyrotroph cells (96, 97). Heparin is indicated for hospitalized COVID-19 patients for thromboembolic event prevention, and it is known that it interferes with the measurement of serum free thyroid hormone due to significant increase of serum non-esterified fatty acid. Heparin causes a displacement of total T4 (TT4) from thyroid binding globulin (TBG), thus resulting in a measurement error increase of FT4. Therefore, in patients treated with heparin, measurement of total thyroid hormone levels, TSH, and TBG could help confirm patient’s thyroid status (76, 98).
Overall, thyroid dysfunction is common in patients with COVID-19 infection. Physicians should be alert and screen COVID-19 patients for early and late thyroid disfunction (8, 9, 10, 11, 76).
Adrenal glands
Adrenal glands play a crucial role in the immune response, as they secrete cortisol and catecholamines. Patients with known adrenal insufficiency and Cushing’s syndrome present higher susceptibility to infections, and special attention is required during the pandemic (8, 9, 10).
Few clinical cases of adrenal hemorrhage as a complication of confirmed COVID-19 infection have been described so far (99, 100). The first one is a 53-year-old Caucasian man from UK who had bilateral pulmonary emboli and a unilateral adrenal haemorrhage during the course of COVID-19 infection. He was treated with intravenous heparin for 5 days and was then converted to oral anticoagulation. He had no clinical or biochemical evidence of adrenal insufficiency (99). Another case is a 66-year-old woman from Israel who presented with acute COVID-19 infection. The patient was already known to have antiphospholipid syndrome and presented with primary adrenal insufficiency due to bilateral adrenal hemorrhage (100).
There are also interesting data from autopsy studies regarding the effect of COVID-19 on adrenal glands (101, 102). In case series of nine full postmortem examinations of patients who died from confirmed COVID-19 in UK between March 1 and April 30, 2020, adrenal micro-infarction was found in three of them (33%) (102). Another autopsy study was performed on 28 deceased patients with confirmed SARS-CoV-2 infection in Western Brazilian Amazon. Adrenal lesions were found in 12 of 28 (42.9%) patients. Ischemic necrosis, cortical lipid degeneration, hemorrhage, or unspecific focal adrenalitis were idenitified, possibly directly linked to the viral infection (101).
To conclude, autopsy and limited clinical data indicate that the adrenal glands may be affected by COVID-19. Hypoadrenalism is life-threatening and therefore adrenal axis testing for COVID-19 patients with clinical suspicion of adrenal insufficiency may be considered.
Testes and ovaries
ACE2 receptors are highly expressed in testes and specifically on the seminiferous duct cells, spermatogonia, Leydig cells, and Sertoli cells (103, 104, 105). In a study with 12 deceased patients, SARS-CoV-2 was detected by PCR in the testes of one patient. However, the testes of most patients displayed seminiferous injuries, reduction in Leydig cells number, and mild inflammation, implying not only direct but also indirect effects due to immune mechanisms (106). In a recently published autopsy study, the SARS-CoV-2 genome was detected in six of nine (67%) of testes (89). Spermatogenesis is impaired in infected men, and delay in sperm maturation might be present. It is well known that spermatogenesis is a temperature-sensitive process; therefore, it may be also affected by high temperature. This can occur even in mild infections (107, 108). In most studies published so far, SARS-CoV- 2 was not detected in the semen of males recovered from COVID-19 (109, 110, 111, 112, 113, 114). There is only one study that reports virus detection within the semen of 6 of 38 patients (115). Most available data do not support a direct effect of SARS-CoV-2 on the testicular tissue or semen. However, the high expression of ACE2 receptors in testes and some recent – autopsy mainly – data maintain such a hypothesis as possible (89, 107, 108).
ACE2 receptors have been detected in the ovaries of both reproductive and postmenopausal women, including oocytes (116, 117). Data on possible effects of SARS-CoV-2 on ovaries are currently lacking, and the exact effect on female fertility still remains unknown. Positive vaginal fluid after infection has been reported in few cases only (118), while other ones failed to detect the virus in the vaginal fluid (119, 120). Larger studies indicate that intrapartum vaginal or orofecal SARS-CoV-2 transmission seems to be unlikely (107, 121). Regarding COVID-19 complications on pregnancy, there is confirmed increased risk for adverse pregnancy and perinatal outcomes, especially among women with certain demographic and health profiles (107, 122).
Calcium and vitamin D metabolism
Vitamin D receptor is expressed in most human tissues, and vitamin D has been implicated in both innate and adaptive immune response (9, 10, 11). Home isolation and low sun exposure during lockdowns might decrease vitamin D levels and impair immunity indirectly. Pizzini et al. reported data on post COVID-19 patients with low vitamin D and increased parathormone levels 8 weeks post symptom onset (123). According to large series of patients with COVID-19, hypocalcemia is highly prevalent and is associated with worse clinical outcomes and the need of hospitalization (124, 125). Various studies from different countries have reported poor vitamin D status, which is associated with disease severity, mortality risk, as well as the development of other endocrine complications of COVID-19 (126, 127, 128). In a Spanish pilot clinical trial, 537 hospitalized patients with COVID-19 pneumonia were randomized to calcifediol or not. Treatment with calcifediol was significantly associated with lower in-hospital mortality during the first 30 days (129). Considering the strong association of vitamin D with immune regulation as well as the above data, supplementation with cholecalciferol could be of some importance according to current recommendations (8, 9).
Recently, a cross-sectional study including patients from a single center reported high prevalence (36%) of morphometric vertebral fractures on lateral chest X-rays of patients with COVID-10 that could negatively influence respiratory function too (126). Physicians may offer therapeutic alternatives in patients with osteoporosis to avoid long-term complications during this era. Subcutaneous use of denosumab could be of some benefit to avoid intravenous administration of bisphosphonates (8, 9, 10).
Conclusions
Data so far have provided evidence for dysregulation of glucose metabolism in patients with or without previous DM. Thyroid dysfunction has been also reported with low T3, low TSH concentrations, or cases of subacute thyroiditis. There are also indications of possible adrenal complications and impaired spermatogenesis in affected men, while early or late complications of other endocrine glands are not clear. Given the very short history of COVID-19 infection, sound conclusions cannot be drawn. Long-term studies are required to evaluate certain effects of COVID-19 on the endocrine glands.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
References
- 1↑
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention. JAMA 2020 323 1239–1242. (https://doi.org/10.1001/jama.2020.2648)
- 2↑
Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM & HCA Lung Biological Network. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020 181 1016 .e19–1035.e19. (https://doi.org/10.1016/j.cell.2020.04.035)
- 3↑
Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020 323 1843–1844. (https://doi.org/10.1001/jama.2020.3786)
- 4↑
Gavriatopoulou M, Korompoki E, Fotiou D, Ntanasis-Stathopoulos I, Psaltopoulou T, Kastritis E, Terpos E, Dimopoulos MA. Organ-specific manifestations of COVID-19 infection. Clinical and Experimental Medicine 2020 20 493–506. (https://doi.org/10.1007/s10238-020-00648-x)
- 5↑
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC & China Medical Treatment Expert Group for Covid. Clinical characteristics of coronavirus disease 2019 in China. New England Journal of Medicine 2020 382 1708–1720. (https://doi.org/10.1056/NEJMoa2002032)
- 6↑
Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infectious Diseases of Poverty 2020 9 45. (https://doi.org/10.1186/s40249-020-00662-x)
- 7↑
Lazartigues E, Qadir MMF, Mauvais-Jarvis F. Endocrine significance of SARS-CoV-2’s reliance on ACE2. Endocrinology 2020 161 108. (https://doi.org/10.1210/endocr/bqaa108)
- 8↑
Puig-Domingo M, Marazuela M, Yildiz BO, Giustina A. COVID-19 and endocrine and metabolic diseases: an updated statement from the European Society of Endocrinology. Endocrine 2021 72 301–316. (https://doi.org/10.1007/s12020-021-02734-w)
- 9↑
Marazuela M, Giustina A, Puig-Domingo M. Endocrine and metabolic aspects of the COVID-19 pandemic. Reviews in Endocrine and Metabolic Disorders 2020 21 495–507. (https://doi.org/10.1007/s11154-020-09569-2)
- 10↑
Lundholm MD, Poku C, Emanuele N, Emanuele MA, Lopez N. SARS-CoV-2 (COVID-19) and the endocrine system. Journal of the Endocrine Society 2020 4 144. (https://doi.org/10.1210/jendso/bvaa144)
- 11↑
Pal R, Banerjee M. COVID-19 and the endocrine system: exploring the unexplored. Journal of Endocrinological Investigation 2020 43 1027–1031. (https://doi.org/10.1007/s40618-020-01276-8)
- 12↑
CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019: United States, February 12–March 28, 2020. Morbidity and Mortality Weekly Report 2020 69 382–386. (https://doi.org/10.15585/mmwr.mm6913e2)
- 13↑
Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KWNorthwell COVID-19 Research Consortium, Barnaby DP, Becker LB & Chelico JD et al.Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020 323 2052–2059. (https://doi.org/10.1001/jama.2020.6775)
- 14↑
Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H, Knighton P, Holman N, Khunti K & Sattar N et al.Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet 2020 8 813–822. (https://doi.org/10.1016/S2213-8587(2030272-2)
- 15↑
Hill MA, Mantzoros C, Sowers JR. Commentary: COVID-19 in patients with diabetes. Metabolism: Clinical and Experimental 2020 107 154217. (https://doi.org/10.1016/j.metabol.2020.154217)
- 16↑
Holman N, Knighton P, Kar P, O’Keefe J, Curley M, Weaver A, Barron E, Bakhai C, Khunti K & Wareham NJ et al.Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet 2020 8 823–833. (https://doi.org/10.1016/S2213-8587(2030271-0)
- 17↑
Wargny M, Potier L, Gourdy P, Pichelin M, Amadou C, Benhamou PY, Bonnet JB, Bordier L, Bourron O & Chaumeil C et al.Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study. Diabetologia 2021 64 778–794. (https://doi.org/10.1007/s00125-020-05351-w)
- 18↑
McGurnaghan SJ, Weir A, Bishop J, Kennedy S, Blackbourn LAK, McAllister DA, Hutchinson S, Caparrotta TM, Mellor J & Jeyam A et al.Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland. Lancet 2021 9 82–93. (https://doi.org/10.1016/S2213-8587(2030405-8)
- 19↑
Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nature Reviews: Immunology 2011 11 98–107. (https://doi.org/10.1038/nri2925)
- 20↑
Knapp S Diabetes and infection: is there a link? A mini-review. Gerontology 2013 59 99–104. (https://doi.org/10.1159/000345107)
- 21↑
Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D, Juenger C, Schnabel RB, Abt TG & Laskowski R et al.Profile of the immune and inflammatory response in individuals with prediabetes and Type 2 diabetes. Diabetes Care 2015 38 1356–1364. (https://doi.org/10.2337/dc14-3008)
- 22↑
Wang S, Ma P, Zhang S, Song S, Wang Z, Ma Y, Xu J, Wu F, Duan L & Yin Z et al.Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study. Diabetologia 2020 63 2102–2111. (https://doi.org/10.1007/s00125-020-05209-1)
- 23↑
Wu J, Huang J, Zhu G, Wang Q, Lv Q, Huang Y, Yu Y, Si X, Yi H & Wang C et al.Elevation of blood glucose level predicts worse outcomes in hospitalized patients with COVID-19: a retrospective cohort study. BMJ Open Diabetes Research and Care 2020 8 e001476. (https://doi.org/10.1136/bmjdrc-2020-001476)
- 24↑
Bode B, Garrett V, Messler J, McFarland R, Crowe J, Booth R, Klonoff DC. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. Journal of Diabetes Science and Technology 2020 14 813–821. (https://doi.org/10.1177/1932296820924469)
- 25↑
Lazarus G, Audrey J, Wangsaputra VK, Tamara A, Tahapary DL. High admission blood glucose independently predicts poor prognosis in COVID-19 patients: a systematic review and dose-response meta-analysis. Diabetes Research and Clinical Practice 2021 171 108561. (https://doi.org/10.1016/j.diabres.2020.108561)
- 26↑
Kim NY, Ha E, Moon JS, Lee YH, Choi EY. Response: acute hyperglycemic crises with coronavirus disease-19: case reports. Diabetes and Metabolism Journal 2020 44 484–485. (https://doi.org/10.4093/dmj.2020.0129)
- 27↑
Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, Qin R, Wang H, Shen Y & Du K et al.Diabetes is a risk factor for the progression and prognosis of COVID -19. Metabolism Research and Reviews 2020 36 e3319. (https://doi.org/10.1002/dmrr.3319)
- 28↑
Zeng Z, Yu H, Chen H, Qi W, Chen L, Chen G, Yan W, Chen T, Ning Q & Han M et al.Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan, China. Critical Care 2020 24 525. (https://doi.org/10.1186/s13054-020-03255-0)
- 29↑
Codo AC, Davanzo GG, Monteiro LdB, de Souza GF, Muraro SP, Virgilio-da-Silva JV, Prodonoff JS, Carregari VC, de Biagi Junior CAO & Crunfli F et al.Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metabolism 2020 32 498–499. (https://doi.org/10.1016/j.cmet.2020.07.015)
- 30↑
Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet 2009 373 1798–1807. (https://doi.org/10.1016/S0140-6736(0960553-5)
- 31↑
Šestan M, Marinović S, Kavazović I, Cekinović Đ, Wueest S, Turk Wensveen T, Brizić I, Jonjić S, Konrad D & Wensveen FM et al.Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity. Immunity 2018 49 164–177. (https://doi.org/10.1016/j.immuni.2018.05.005)
- 32↑
Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Seminars in Immunopathology 2017 39 529–539. (https://doi.org/10.1007/s00281-017-0629-x)
- 33↑
Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. Journal of Clinical Investigation 1989 84 205–213. (https://doi.org/10.1172/JCI114142)
- 34↑
Korytkowski M, Antinori-Lent K, Drincic A, Hirsch IB, McDonnell ME, Rushakoff R, Muniyappa R. A pragmatic approach to inpatient diabetes management during the COVID-19 pandemic. Journal of Clinical Endocrinology and Metabolism 2020 105 dgaa342. (https://doi.org/10.1210/clinem/dgaa342)
- 35↑
Rocheteau P, Chatre L, Briand D, Mebarki M, Jouvion G, Bardon J, Crochemore C, Serrani P, Lecci PP & Latil M et al.Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nature Communications 2015 6 10145. (https://doi.org/10.1038/ncomms10145)
- 36↑
Pfoh ER, Wozniak AW, Colantuoni E, Dinglas VD, Mendez-Tellez PA, Shanholtz C, Ciesla ND, Pronovost PJ, Needham DM. Physical declines occurring after hospital discharge in ARDS survivors: a 5-year longitudinal study. Intensive Care Medicine 2016 42 1557–1566. (https://doi.org/10.1007/s00134-016-4530-1)
- 37↑
Jin M, Tong Q. Rhabdomyolysis as potential late complication associated with COVID-19. Emerging Infectious Diseases 2020 26 1618–1620. (https://doi.org/10.3201/eid2607.200445)
- 38↑
Rubino F, Amiel SA, Zimmet P, Alberti G, Bornstein S, Eckel RH, Mingrone G, Boehm B, Cooper ME & Chai Z et al.New-onset diabetes in Covid-19. New England Journal of Medicine 2020 383 789–790. (https://doi.org/10.1056/NEJMc2018688)
- 39↑
Li H, Tian S, Chen T, Cui Z, Shi N, Zhong X, Qiu K, Zhang J, Zeng T & Chen L et al.Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19. Diabetes, Obesity and Metabolism 2020 22 1897–1906. (https://doi.org/10.1111/dom.14099)
- 40↑
Chee YJ, Ng SJH, Yeoh E. Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Research and Clinical Practice 2020 164 108166. (https://doi.org/10.1016/j.diabres.2020.108166)
- 41↑
Rayman G, Lumb A, Kennon B, Cottrell C, Nagi D, Page E, Voigt D, Courtney H, Atkins H & Platts J et al.Guidance on the management of diabetic ketoacidosis in the exceptional circumstances of the COVID-19 pandemic. Diabetic Medicine 2020 37 1214–1216. (https://doi.org/10.1111/dme.14328)
- 42↑
Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID-19 infection may cause ketosis and ketoacidosis. Diabetes, Obesity and Metabolism 2020 22 1935–1941. (https://doi.org/10.1111/dom.14057)
- 43↑
Kamrath C, Mönkemöller K, Biester T, Rohrer TR, Warncke K, Hammersen J, Holl RW. Ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the COVID-19 pandemic in Germany. JAMA 2020 324 801–804. (https://doi.org/10.1001/jama.2020.13445)
- 44↑
Rabbone I, Schiaffini R, Cherubini V, Maffeis C, Scaramuzza A & Diabetes Study Group of the Italian Society for Pediatric Endocrinology and Diabetes. Has COVID-19 delayed the diagnosis and worsened the presentation of type 1 diabetes in children? Diabetes Care 2020 43 2870–2872. (https://doi.org/10.2337/dc20-1321)
- 45↑
Tittel SR, Rosenbauer J, Kamrath C, Ziegler J, Reschke F, Hammersen J, Mönkemöller K, Pappa A, Kapellen T & Holl RW et al.Did the COVID-19 lockdown affect the incidence of pediatric type 1 diabetes in Germany? Diabetes Care 2020 43 e172–e173. (https://doi.org/10.2337/dc20-1633)
- 46↑
Lazzerini M, Barbi E, Apicella A, Marchetti F, Cardinale F, Trobia G. Delayed access or provision of care in Italy resulting from fear of COVID-19. Lancet Child Adolesc Health 2020 4 e10–e11. (https://doi.org/10.1016/S2352-4642(2030108-5)
- 47↑
Unsworth R, Wallace S, Oliver NS, Yeung S, Kshirsagar A, Naidu H, Kwong RMW, Kumar P, Logan KM. New-onset type 1 diabetes in children during COVID-19: multicenter regional findings in the U.K. Diabetes Care 2020 43 e170–e171. (https://doi.org/10.2337/dc20-1551)
- 48↑
Hollstein T, Schulte DM, Schulz J, Glück A, Ziegler AG, Bonifacio E, Wendorff M, Franke A, Schreiber S & Bornstein SR et al.Autoantibody-negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report. Nature Metabolism 2020 2 1021–1024. (https://doi.org/10.1038/s42255-020-00281-8)
- 49↑
Yang JK, Feng Y, Yuan MY, Yuan SY, Fu HJ, Wu BY, Sun GZ, Yang GR, Zhang XL & Wang L et al.Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabetic Medicine 2006 23 623–628. (https://doi.org/10.1111/j.1464-5491.2006.01861.x)
- 50↑
Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetologica 2010 47 193–199. (https://doi.org/10.1007/s00592-009-0109-4)
- 51↑
Vitale RJ, Valtis YK, McDonnell ME, Palermo NE, Fisher NDL. Euglycemic diabetic ketoacidosis with COVID-19 infection in patients with type 2 diabetes taking SGLT2 inhibitors AACE Clinical Case Reports 2021 7 10–13. (https://doi.org/10.1016/j.aace.2020.11.019)
- 52↑
Fang J, Genco M, Caskey RN. COVID-19 precipitating euglycaemic diabetic ketoacidosis with SGLT2 inhibitor use. European Journal of Case Reports in Internal Medicine 2020 7 001943. (https://doi.org/10.12890/2020_001943)
- 53↑
Hahn K, Ejaz AA, Kanbay M, Lanaspa MA, Johnson RJ. Acute kidney injury from SGLT2 inhibitors: potential mechanisms. Nature Reviews: Nephrology 2016 12 711–712. (https://doi.org/10.1038/nrneph.2016.159)
- 54↑
Palermo NE, Sadhu AR, McDonnell ME. Diabetic ketoacidosis in COVID-19: unique concerns and considerations. Journal of Clinical Endocrinology and Metabolism 2020 105 2819–2829. (https://doi.org/10.1210/clinem/dgaa360)
- 55↑
Scheen AJ SGLT2 inhibition during the COVID-19 epidemic: friend or foe? Diabetes and Metabolism 2020 46 343–344. (https://doi.org/10.1016/j.diabet.2020.06.003)
- 56↑
Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nature Microbiology 2020 5 562–569. (https://doi.org/10.1038/s41564-020-0688-y)
- 57↑
Liu F, Long X, Zhang B, Zhang W, Chen X, Zhang Z. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection. Clinical Gastroenterology and Hepatology 2020 18 2128–2130. (https://doi.org/10.1016/j.cgh.2020.04.040)
- 58↑
Akarsu C, Karabulut M, Aydin H, Sahbaz NA, Dural AC, Yegul D, Peker KD, Ferahman S, Bulut S & Dönmez T et al.Association between acute pancreatitis and COVID-19: could pancreatitis be the missing piece of the puzzle about increased mortality rates? Journal of Investigative Surgery 2020 [epub].(https://doi.org/10.1080/08941939.2020.1833263)
- 59↑
Yang L, Han Y, Nilsson-Payant BE, Gupta V, Wang P, Duan X, Tang X, Zhu J, Zhao Z & Jaffré F et al.A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 2020 27 125–136. (https://doi.org/10.1016/j.stem.2020.06.015)
- 60↑
Müller JA, Groß R, Conzelmann C, Krüger J, Merle U, Steinhart J, Weil T, Koepke L, Bozzo CP & Read C et al.SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nature Metabolism 2021 3 149–165. (https://doi.org/10.1038/s42255-021-00347-1)
- 61↑
Wu CT, Lidsky PV, Xiao Y, Lee IT, Cheng R, Nakayama T, Jiang S, Demeter J, Bevacqua RJ & Chang CA et al.SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metabolism 2021 33 1565–1576.
- 62↑
Tang X, Uhl S, Zhang T, Xue D, Li B, Vandana JJ, Acklin JA, Bonnycastle LL, Narisu N & Erdos MR et al.SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metabolism 2021 33 1577–1591.
- 63↑
Roca-Ho H, Palau V, Gimeno J, Pascual J, Soler MJ, Riera M. Angiotensin-converting enzyme 2 influences pancreatic and renal function in diabetic mice. Journal of Technical Methods and Pathology 2020 100 1169–1183. (https://doi.org/10.1038/s41374-020-0440-5)
- 64↑
Xuan X, Gao F, Ma X, Huang C, Wang Y, Deng H, Wang S, Li W, Yuan L. Activation of ACE2/angiotensin (1–7) attenuates pancreatic β cell dedifferentiation in a high-fat-diet mouse model. Metabolism: Clinical and Experimental 2018 81 83–96. (https://doi.org/10.1016/j.metabol.2017.12.003)
- 65↑
Shoemaker R, Yiannikouris F, Thatcher S, Cassis L. ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice. American Journal of Physiology: Endocrinology and Metabolism 2015 309 E621–E631. (https://doi.org/10.1152/ajpendo.00054.2015)
- 66↑
Lu CL, Wang Y, Yuan L, Li Y, Li XY. The angiotensin-converting enzyme 2/angiotensin (1–7)/Mas axis protects the function of pancreatic β cells by improving the function of islet microvascular endothelial cells. International Journal of Molecular Medicine 2014 34 1293–1300. (https://doi.org/10.3892/ijmm.2014.1917)
- 67↑
Liang Y, Deng H, Bi S, Cui Z, A L, Zheng D, Wang Y. Urinary angiotensin converting enzyme 2 increases in patients with type 2 diabetic mellitus. Kidney and Blood Pressure Research 2015 40 101–110. (https://doi.org/10.1159/000368486)
- 68↑
Cherney DZ, Xiao F, Zimpelmann J, Har RL, Lai V, Scholey JW, Reich HN, Burns KD. Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes. Canadian Journal of Physiology and Pharmacology 2014 92 703–706. (https://doi.org/10.1139/cjpp-2014-0065)
- 69↑
Pal R, Bhansali A. COVID-19, diabetes mellitus and ACE2: the conundrum. Diabetes Research and Clinical Practice 2020 162 108132. (https://doi.org/10.1016/j.diabres.2020.108132)
- 70↑
Drucker DJ The biology of incretin hormones. Cell Metabolism 2006 3 153–165. (https://doi.org/10.1016/j.cmet.2006.01.004)
- 71↑
Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A & Fouchier RA et al.Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013 495 251–254. (https://doi.org/10.1038/nature12005)
- 72↑
Shirato K, Kawase M, Matsuyama S. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. Journal of Virology 2013 87 12552–12561. (https://doi.org/10.1128/JVI.01890-13)
- 73↑
Li Y, Zhang Z, Yang L, Lian X, Xie Y, Li S, Xin S, Cao P, Lu J. The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike. iScience 2020 23 101400. (https://doi.org/10.1016/j.isci.2020.101400)
- 74↑
Chiloiro S, Capoluongo ED, Tartaglione T, Giampietro A, Bianchi A, Giustina A, Pontecorvi A, De Marinis L. The changing clinical spectrum of hypophysitis. Trends in Endocrinology and Metabolism 2019 30 590–602. (https://doi.org/10.1016/j.tem.2019.06.004)
- 75↑
Berni A, Malandrino D, Parenti G, Maggi M, Poggesi L, Peri A. Hyponatremia, IL-6, and SARS-CoV-2 (COVID-19) infection: may all fit together? Journal of Endocrinological Investigation 2020 43 1137–1139. (https://doi.org/10.1007/s40618-020-01301-w)
- 76↑
Chen W, Tian Y, Li Z, Zhu J, Wei T, Lei J. Potential interaction between SARS-CoV-2 and thyroid: a review. Endocrinology 2021 162 004. (https://doi.org/10.1210/endocr/bqab004)
- 77↑
Chen M, Zhou W, Xu W. Thyroid function analysis in 50 patients with COVID-19: a retrospective study. Thyroid 2021 31 8–11. (https://doi.org/10.1089/thy.2020.0363)
- 78↑
Muller I, Cannavaro D, Dazzi D, Covelli D, Mantovani G, Muscatello A, Ferrante E, Orsi E, Resi V & Longari V et al.SARS-CoV-2-related atypical thyroiditis. Lancet 2020 8 739–741. (https://doi.org/10.1016/S2213-8587(2030266-7)
- 79↑
Li T, Wang L, Wang H, Gao Y, Hu X, Li X, Zhang S, Xu Y, Wei W. Characteristics of laboratory indexes in COVID-19 patients with non-severe symptoms in Hefei City, China: diagnostic value in organ injuries. European Journal of Clinical Microbiology and Infectious Diseases 2020 39 2447–2455. (https://doi.org/10.1007/s10096-020-03967-9)
- 80↑
Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H & Wang H et al.Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020 368 1091. (https://doi.org/10.1136/bmj.m1091)
- 81↑
Lania A, Sandri MT, Cellini M, Mirani M, Lavezzi E, Mazziotti G. Thyrotoxicosis in patients with COVID-19: the THYRCOV study. European Journal of Endocrinology 2020 183 381–387. (https://doi.org/10.1530/EJE-20-0335)
- 82↑
Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute thyroiditis after Sars-COV-2 infection. Journal of Clinical Endocrinology and Metabolism 2020 105 276. (https://doi.org/10.1210/clinem/dgaa276)
- 83↑
Ippolito S, Dentali F, Tanda ML. SARS-CoV-2: a potential trigger for subacute thyroiditis? Insights from a case report. Journal of Endocrinological Investigation 2020 43 1171–1172. (https://doi.org/10.1007/s40618-020-01312-7)
- 84↑
Asfuroglu Kalkan E, Ates I. A case of subacute thyroiditis associated with Covid 19 infection. Journal of Endocrinological Investigation 2020 43 1173–1174. (https://doi.org/10.1007/s40618-020-01316-3)
- 85↑
Ruggeri RM, Campennì A, Siracusa M, Frazzetto G, Gullo D. Subacute thyroiditis in a patient infected with SARS-COV-2: an endocrine complication linked to the COVID-19 pandemic. Hormones 2020 1–3 43.
- 86↑
Brancatella A, Ricci D, Cappellani D, Viola N, Sgrò D, Santini F, Latrofa F. Is subacute thyroiditis an underestimated manifestation of SARS-CoV-2 infection? Insights from a case series. Journal of Clinical Endocrinology and Metabolism 2020 105 537. (https://doi.org/10.1210/clinem/dgaa537)
- 87↑
Mattar SAM, Koh SJQ, Rama Chandran S, Cherng BPZ. Subacute thyroiditis associated with COVID-19. BMJ Case Reports 2020 13 e23733645. (https://doi.org/10.1136/bcr-2020-237336)
- 88↑
Campos Barrera E, Alvarez Cisneros T, Davalos Fuentes M. Subacute thyroiditis associated with COVID 19. Case Reports in Endocrinology 2020 2020 8891539. (https://doi.org/10.1155/2020/8891539)
- 89↑
Poma AM, Bonuccelli D, Giannini R, Macerola E, Vignali P, Ugolini C, Torregrossa L, Proietti A, Pistello M & Basolo A et al.COVID-19 autopsy cases: detection of virus in endocrine tissues. Journal of Endocrinological Investigation 2021 [epub]. (https://doi.org/10.1007/s40618-021-01628-y)
- 90↑
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID 19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine 2020 46 846–848. (https://doi.org/10.1007/s00134-020-05991-x)
- 91↑
Bradley BT, Maioli H, Johnston R, Chaudhry I, Fink SL, Xu H, Najafian B, Deutsch G, Lacy JM & Williams T et al.Histopathology and ultrastructural findings of fatal COVID 19 infections in Washington State: a case series. Lancet 2020 396 320–332. (https://doi.org/10.1016/S0140-6736(2031305-2)
- 92↑
Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 autopsies, Oklahoma, USA. American Journal of Clinical Pathology 2020 153 725–733. (https://doi.org/10.1093/ajcp/aqaa062)
- 93↑
Fliers E, Bianco AC, Langouche L, Boelen A. Thyroid function in critically ill patients. Lancet 2015 3 816–825. (https://doi.org/10.1016/S2213-8587(1500225-9)
- 94↑
Khoo B, Tan T, Clarke SA, Mills EG, Patel B, Modi M, Phylactou M, Eng PC, Thurston L & Alexander EC et al.Thyroid function before, during, and after COVID-19. Journal of Clinical Endocrinology and Metabolism 2021 106 e803–e811. (https://doi.org/10.1210/clinem/dgaa830)
- 95↑
Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Frontiers in Immunology 2020 11 1708. (https://doi.org/10.3389/fimmu.2020.01708)
- 96↑
Samuels MH, McDaniel PA. Thyrotropin levels during hydrocortisone infusions that mimic fasting-induced cortisol elevations: a Clinical Research Center Study. Journal of Clinical Endocrinology and Metabolism 1997 82 3700–3704. (https://doi.org/10.1210/jcem.82.11.4376)
- 97↑
Samuels MH Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study. Journal of Clinical Endocrinology and Metabolism 2000 85 1388–1393. (https://doi.org/10.1210/jcem.85.4.6540)
- 98↑
Schatz DL, Sheppard RH, Steiner G, Chandarlapaty CS, de Veber GA. Influence of heparin on serum free thyroxine. Journal of Clinical Endocrinology and Metabolism 1969 29 1015–1022. (https://doi.org/10.1210/jcem-29-8-1015)
- 99↑
Sharrack N, Baxter CT, Paddock M, Uchegbu E. Adrenal haemorrhage as a complication of COVID-19 infection. BMJ Case Reports 2020 13 e239643. (https://doi.org/10.1136/bcr-2020-239643)
- 100↑
Frankel M, Feldman I, Levine M, Frank Y, Bogot NR, Benjaminov O, Kurd R, Breuer GS, Munter G. Bilateral adrenal hemorrhage in coronavirus disease 2019 patient: a case report. Journal of Clinical Endocrinology and Metabolism 2020 105 487. (https://doi.org/10.1210/clinem/dgaa487)
- 101↑
Freire Santana M, Borba MGS, Baía-da-Silva DC, Val F, Alexandre MAA, Brito-Sousa JD, Melo GC, Queiroga MVO, Leão Farias ME & Camilo CC et al.Case report: Adrenal pathology findings in severe COVID-19: an autopsy study. American Journal of Tropical Medicine and Hygiene 2020 103 1604–1607. (https://doi.org/10.4269/ajtmh.20-0787)
- 102↑
Hanley B, Naresh KN, Roufosse C, Nicholson AG, Weir J, Cooke GS, Thursz M, Manousou P, Corbett R & Goldin R et al.Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study. Lancet Microbe 2020 1 e245–e253. (https://doi.org/10.1016/S2666-5247(2030115-4)
- 103↑
Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis dagger. Biology of Reproduction 2020 103 449–451. (https://doi.org/10.1093/biolre/ioaa080)
- 104↑
Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of ACE2 receptor, a target for SARS-CoV-2 infection, in spermatogonia, Leydig and Sertoli cells. Cells 2020 9 920. (https://doi.org/10.3390/cells9040920)
- 105↑
Shen Q, Xiao X, Aierken A, Yue W, Wu X, Liao M, Hua J. The ACE2 expression in sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection. Journal of Cellular and Molecular Medicine 2020 24 9472–9477. (https://doi.org/10.1111/jcmm.15541)
- 106↑
Yang M, Chen S, Huang B, Zhong JM, Su H, Chen YJ, Cao Q, Ma L, He J & Li XF et al.Pathological findings in the testes of COVID-19 patients: clinical implications. European Urology Focus 2020 6 1124–1129. (https://doi.org/10.1016/j.euf.2020.05.009)
- 107↑
Sharma I, Kumari P, Sharma A, Saha SC. SARS-CoV-2 and the reproductive system: known and the unknown! Middle East Fertility Society Journal 2021 26 1. (https://doi.org/10.1186/s43043-020-00046-z)
- 108↑
Tian Y, Zhou LQ. Evaluating the impact of COVID-19 on male reproduction. Reproduction 2021 161 R37–R44. (https://doi.org/10.1530/REP-20-0523)
- 109↑
Song C, Wang Y, Li W, Hu B, Chen G, Xia P, Wang W, Li C, Diao F & Hu Z et al.Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients. Biology of Reproduction 2020 103 4–6. (https://doi.org/10.1093/biolre/ioaa050)
- 110↑
Paoli D, Pallotti F, Colangelo S, Basilico F, Mazzuti L, Turriziani O, Antonelli G, Lenzi A, Lombardo F. Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. Journal of Endocrinological Investigation 2020 43 1819–1822. (https://doi.org/10.1007/s40618-020-01261-1)
- 111↑
Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP, Spivak AM, Alukal JP, Zhang X & Xiong C et al.No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertility and Sterility 2020 113 1135–1139. (https://doi.org/10.1016/j.fertnstert.2020.04.024)
- 112↑
Ma L, Xie W, Li D, Shi L, Ye G, Mao Y, Xiong Y, Sun H, Zheng F & Chen Z et al.Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. Journal of Medical Virology 2021 93 456–462. (https://doi.org/10.1002/jmv.26259)
- 113↑
Guo L, Zhao S, Li W, Wang Y, Li L, Jiang S, Ren W, Yuan Q, Zhang F & Kong F et al.Absence of SARS-CoV-2 in semen of a COVID-19 patient cohort. Andrology 2021 9 42–47. (https://doi.org/10.1111/andr.12848)
- 114↑
Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O, Kruessel JS, Bielfeld AP. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertility and Sterility 2020 114 233–238. (https://doi.org/10.1016/j.fertnstert.2020.05.028)
- 115↑
Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Network Open 2020 3 e208292. (https://doi.org/10.1001/jamanetworkopen.2020.8292)
- 116↑
Reis FM, Bouissou DR, Pereira VM, Camargos AF, dos Reis AM, Santos RA. Angiotensin-(1–7), its receptor mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary. Fertility and Sterility 2011 95 176–181. (https://doi.org/10.1016/j.fertnstert.2010.06.060)
- 117↑
Jing Y, Run-Qian L, Hao-Ran W, Hao-Ran C, Ya-Bin L, Yang G, Fei C. Potential influence of COVID-19/ACE2 on the female reproductive system. Molecular Human Reproduction 2020 26 367–373. (https://doi.org/10.1093/molehr/gaaa030)
- 118↑
Scorzolini L, Corpolongo A, Castilletti C, Lalle E, Mariano A, Nicastri E. Comment on the potential risks of sexual and vertical transmission of COVID-19. Clinical Infectious Diseases 2020 71 2298. (https://doi.org/10.1093/cid/ciaa445)
- 119↑
Qiu L, Liu X, Xiao M, Xie J, Cao W, Liu Z, Morse A, Xie Y, Li T, Lan Zhu L. SARS-CoV-2 is not detectable in the vaginal fluid of women with severe COVID-19 infection. Clinical Infectious Diseases 2020 71 813–817. (https://doi.org/10.1093/cid/ciaa375)
- 120↑
Cui P, Chen Z, Wang T, Dai J, Zhang J, Ding T, Jiang J, Liu J, Zhang C & Shan W et al.Severe acute respiratory syndrome coronavirus 2 detection in the female lower genital tract. American Journal of Obstetrics and Gynecology 2020 223 131–134. (https://doi.org/10.1016/j.ajog.2020.04.038)
- 121↑
Fenizia C, Saulle I, Di Giminiani M, Vanetti C, Trabattoni D, Parisi F, Biasin M, Savasi V, Unlikely S-C. Unlikely SARS-CoV-2 transmission during vaginal delivery. Reproductive Sciences 2021 2. (https://doi.org/10.1007/s43032-021-00681-5)
- 122↑
Lassi ZS, Ana A, Das JK, Salam RA, Padhani ZA, Irfan O, Bhutta ZA. A systematic review and meta-analysis of data on pregnant women with confirmed COVID-19: clinical presentation, and pregnancy and perinatal outcomes based on COVID-19 severity. Journal of Global Health 2021 11 05018. (https://doi.org/10.7189/jogh.11.05018)
- 123↑
Pizzini A, Aichner M, Sahanic S, Böhm A, Egger A, Hoermann G, Kurz K, Widmann G, Bellmann-Weiler R & Weiss G et al.Impact of vitamin D deficiency on COVID-19-A prospective analysis from the covid registry. Nutrients 2020 12 2775. (https://doi.org/10.3390/nu12092775)
- 124↑
Di Filippo L, Formenti AM, Rovere-Querini P, Carlucci M, Conte C, Ciceri F, Zangrillo A, Giustina A. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine 2020 68 475–478. (https://doi.org/10.1007/s12020-020-02383-5)
- 125↑
Sun JK, Zhang WH, Zou L, Liu Y, Li JJ, Kan XH, Dai L, Shi QK, Yuan ST & Yu WK et al.Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging 2020 12 11287–11295. (https://doi.org/10.18632/aging.103526)
- 126↑
Hutchings N, Babalyan V, Baghdasaryan S, Qefoyan M, Sargsyants N, Aghajanova E, Martirosyan A, Harutyunyan R, Lesnyak O & Formenti AM et al.Patients hospitalized with COVID-19 have low levels of 25-hydroxyvitamin D. Endocrine 2021 71 267–269. (https://doi.org/10.1007/s12020-020-02597-7)
- 127↑
Giustina A Hypovitaminosis D and the endocrine phenotype of COVID-19. Endocrine 2021 72 1–11. (https://doi.org/10.1007/s12020-021-02671-8)
- 128↑
De Smet D, De Smet K, Herroelen P, Gryspeerdt S, Martens GA. Serum 25(OH)D level on hospital admission associated with COVID-19 stage and mortality. American Journal of Clinical Pathology 2021 155 381–388. (https://doi.org/10.1093/ajcp/aqaa252)
- 129↑
Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, Martin-Escalante MD, Cortes-Rodriguez B, Zambrana-Garcia JL, Entrenas-Castillo M, Perez-Caballero AI, López-Carmona MD & Garcia-Alegria J et al.Calcifediol treatment and hospital mortality due to COVID-19: a cohort study. Nutrients 2021 13 1760. (https://doi.org/10.3390/nu13061760)