key: cord-0891555-y6b54sxe
authors: Lundholm, Michelle D; Poku, Caroline; Emanuele, Nicholas; Emanuele, Mary Ann; Lopez, Norma
title: SARS-CoV-2 (COVID-19) and the Endocrine System
date: 2020-10-01
journal: J Endocr Soc
DOI: 10.1210/jendso/bvaa144
sha: 3803911c7a55fa861ded1908fa3e069a69f31b25
doc_id: 891555
cord_uid: y6b54sxe

As SARS-CoV-2 (COVID-19) overtakes the world causing moderate to severe disease in about 15% of infected patients, COVID-19 is also been found to have widespread effects throughout the body with a myriad of clinical manifestations including the endocrine system. This manuscript reviews what is known about the impact of COVID-19 on the pathophysiology and management of diabetes (both outpatient and inpatient), pituitary, adrenal, thyroid, bone, and gonadal function. Findings in this area are evolving and long-term effects of infection remain an active area of further research.

With over 28 million confirmed cases worldwide, SARS-CoV-2 (COVID-19) causes moderate to severe pulmonary disease in about 15% of infected patients. COVID-19 also has widespread effects throughout the body with lesser-known clinical manifestations.

Knowledge about the impact of this virus on the endocrine system is emerging and is the focus of this review. PubMed and the Cochrane Library were searched for clinical studies and reviews concerning the effect of COVID-19 on diabetes, adrenal, parathyroid, thyroid, and gonadal axes. Reference searches were conducted in retrieved articles.

Diabetes mellitus (DM) is one of the most prevalent chronic diseases globally estimated to affect about 9.3% of the world's population and only expected to increase in the coming years(1). Such a high prevalence of diabetes in the general population makes it an important comorbidity to consider during the COVID-19 pandemic. Diabetes has been known to increase susceptibility to infections, particularly in the respiratory tract. This was seen in prior coronavirus outbreaks with severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV) (2) (3) (4) . There is also evidence to suggest increased incidence of COVID-19 amongst patients with diabetes (5, 6) . Adequate blood glucose and blood pressure management are key to primary prevention of COVID-19 infection.

Hyperglycemia has harmful effects on innate immunity including dysfunction of phagocytosis, cell-mediated immunity, and neutrophil chemotaxis (7) (8) (9) . Elevated blood glucose levels also affect ACE2 expression, which is the COVID-19 viral binding site for host cell entry (10) . This is thought to account for the increased incidence of COVID-19 infection in patients with diabetes. To prevent infections, outpatient medical therapies should be A c c e p t e d M a n u s c r i p t 4 optimized to target an outpatient plasma glucose goal of 72-144 mg/dL (90-144 mg/dL in the frail or elderly), and a HgA1c of less than 7% (11) . For those who have continuous glucose monitors, time in range should be above 70%, and hypoglycemia less than 4% of the time. All patients are encouraged to follow advice from the government and the Centers for Disease Control and Prevention to minimize exposure by physical distancing. During the pandemic, patients may experience disruptions in their routine care, which may increase utilization of telehealth modalities or self-monitoring. Additionally, disruption to usual diet or exercise patterns may be an opportunity for physicians to promote healthy lifestyle interventions. In the event of COVID-19 infection, patients with diabetes more often develop a severe or critical disease course compared to patients without diabetes (5) . In a recent meta-analysis of 6,452 patients from 30 studies, diabetes was found to be associated with higher mortality, increased severity, and increased frequency of acute respiratory distress syndrome (ARDS) in patients with COVID-19 (12) . In a Chinese Center for Disease Control and Prevention report, the overall COVID-19 case fatality rate more than tripled from 2.3% to 7.3% in patients with diabetes when compared to their general population (13) . For these reasons, physicians should maintain a lower threshold to hospitalize a patient with COVID-19 and diabetes. Even amongst patients with pre-existing diabetes, differences in glycemic management can affect the outcome of COVID-19 disease.

In a study of 187 inpatients with COVID-19, patients with hyperglycemia (>180 mg/dL) showed a higher IL-6 and D-dimer, had more progression of pneumonia on CT scan of the chest, and overall higher mortality when compared to patients with normoglycemia (140-180 mg/dL) (14) . Another larger COVID-19 study compared 282 patients with diabetes and well-controlled blood glucose to 528 patients with poorly-controlled blood glucose (mean blood glucose of 115 mg/dL vs. 196 mg/dL) (15) . The normoglycemic patients had lower A c c e p t e d M a n u s c r i p t 5 incidences of lymphopenia and leukocytosis, lower C-reactive protein, procalcitonin, aspartate transaminase, and D-dimer. Only 12.6% of patients in the well-controlled group developed hypoxia with SpO2 below 95%, compared to 22.7% in the poorly-controlled group. The well-controlled group required less usage of antibiotics, steroids, vasopressors, intubation, and extra-corporeal membrane oxygenation and had a significantly lower death rate (1.1% vs 11.0% with an adjusted HR of 0.13, p<0.001). There was also a significant difference in the rates of complications including ARDS, acute kidney injury, septic shock, and disseminated intravascular coagulation (15) . As more data emerges, it remains clear that diabetes and hyperglycemia have a negative effect in COVID-19 infection and that tight glycemic control remains crucial to prevent poor outcomes and complications.

At this time, there is no evidence to change our outpatient glycemic targets in COVID-19 infection (plasma glucose goal remains 72-144 mg/dL, and a HgA1c goal of less than 7%).

However, blood glucose should be monitored at least twice a day in the setting of infection.

All major classes of antihyperglycemic medications can be continued for patients affected by COVID-19 in the ambulatory setting under the right circumstances. Generally, metformin is held for patients with evidence of organ dysfunction, or even for nausea, vomiting, or diarrhea due to the risk of lactic acidosis (12) . Metformin should not be arbitrarily discontinued because recent studies suggest that metformin may have a positive influence on prognosis for T2DM patients with COVID-19 infection (16) . Sulfonylureas and meglitinides can cause hypoglycemia, and should be held for at-risk patients with poor caloric intake.

SGLT-2 inhibitors can worsen dehydration by increasing urinary excretion of glucose, and have an increased risk of euglycemic ketoacidosis. Consider holding SGLT-2 inhibitor medications in patients at risk of dehydration such as those who cannot maintain adequate A c c e p t e d M a n u s c r i p t 6 fluid intake. Long-or intermediate-acting insulin may be started in patients who have   hyperglycemia, either from held medications or COVID-19 disease. Those patients who are   unable to tolerate oral intake are also candidates for inpatient management as COVID-19 is known to become more severe in this patient population.

Further medication adjustments may be necessary for patients started on hydroxychloroquine due to the potential for hypoglycemia. Although not a dedicated antihyperglycemic agent, multiple case reports have demonstrated hypoglycemia from hydroxychloroquine in patients with and without diabetes alike (17) (18) (19) (20) . Prior cases have suggested a reduced insulin requirement of about 30-35% (18, 21) .

Of special mention, dipeptidyl peptidase-4 (DPP-4) inhibitors are attracting attention as a possible therapeutic agent in COVID-19 (22, 23) . The DPP-4 protein is a known binding site for MERS spike protein, and mice with higher DPP-4 expression had more severe MERS disease(24,25). Viral modeling demonstrates the potential interaction of the COVID-19 spike protein and DPP-4 receptor, but this has not been confirmed experimentally(26). DPP-4 inhibitors may also indirectly affect COVID-19 infection since they are immunosuppressive via reduced T-cell differentiation and reduced pro-inflammatory cytokine production. Prior The renin angiotensin aldosterone system inhibitors boost the expression of ACE2, which was initially thought to increase host alveolar cell susceptibility to COVID-19 invasion and potentially worsen the severity of disease(29). ACE inhibitor and ARB therapy may reduce lung injury by balancing the ratio of angiotensin II and angiotensin 1-7 , since ACE catalyzes production of angiotensin II and ACE2 then degrades this to angiotensin 1-7 (30). When ACE2 is downregulated, such as when COVID-19 binds, then angiotensin II levels are unopposed and lead to vasoconstriction, inflammation, and catecholamine release(31,32). Angiotensin II levels are higher in patients infected with SARS and ARDS, and levels correlate with viral load and acute lung injury (32, 33) . This is the theory behind recombinant soluble ACE2 use as a potential therapy to reduce lung injury in COVID-19. ACE2 trials demonstrate a measurable effect to reduce COVID-19 lung injury in animal models and studies are ongoing in the human population (NCT04375046, NCT04382950) (34, 35) .

Despite hypotheses that ACE inhibitors or ARBs would affect the severity of COVID-19 infection, the data has been inconsistent. Initial observations suggested that patients on renin angiotensin aldosterone system inhibitors had worse outcomes in COVID-19 infection than patients who did not take these medications, but this was heavily confounded by the fact that patients on renin angiotensin aldosterone system inhibitors have more comorbidities such as hypertension, diabetes, kidney disease, or heart failure (36) (37) (38) (39) . When compared to other patients with hypertension, there was no increase in hospital A c c e p t e d M a n u s c r i p t 8 admissions, severity of disease, or mortality for patients on ACE inhibitors or ARBs (40) (41) (42) .

Some data suggests that these drugs may have a positive effect, trending toward reduced hospitalizations and mortality for patients with diabetes (43, 44) . Overall, guidelines from major hypertension societies recommend against discontinuing ACE inhibitors or ARBs due of the risk of worsening the underlying conditions these therapies were intended to treat (45) (46) (47) (48) (49) (50) .

Overall, management of diabetes and COVID-19 in the outpatient setting should focus on tight glycemic control with medication optimization and lifestyle interventions to lower the risk of disease progression, morbidity, and mortality. Providers should consider how well the patient's blood glucose is controlled and if oral intake is adequate when adjusting the outpatient medication regimen. Table 1 provides a summary of common antihyperglycemic medication classes that may be continued in the outpatient setting (as well as inpatient setting) with important considerations. Patients should be discouraged from stopping their medications without consulting their doctor, as this may lead to an exacerbation of their existing medical conditions.

In the inpatient setting, treating hospitalized COVID-19 positive patients who are hyperglycemic can be complex given the severity of their illness (9, 51) . COVID-19 has been associated with direct β-cell damage in addition to immune-mediated destruction of β-cells due to the inflammatory cytokines, including interleukin-1β and tumor-necrosis factor-α.

These patients are also prone to hypokalemia due to downregulation of pulmonary ACE2 and reduced angiotension II degradation leading to increased aldosterone secretion.

Hypokalemia can lead to reduced insulin section. Also aggravating hyperglycemia is A c c e p t e d M a n u s c r i p t 9 treatment of COVID-19 with lopinavir-ritonavir resulting in lipodystrophy and subsequent insulin resistance (52) .

One of the challenges during the COVID-19 pandemic has been the need for clinicians without diabetes expertise to provide diabetes care to COVID-19 positive patients in the hospital. In the management of the hospitalized individuals with or suspected of COVID-19 infection, it is important to have simple and safe diabetes guidelines which will need frequent revision as new evidence emerges. Fortunately, guidelines from the major endocrine and diabetes societies have been published to help manage these patients (53) (54) (55) . These guidelines acknowledge the emphasis on early discharge with a need for close follow up, especially in those newly started on insulin in whom rapid dose reduction is often required.

A significant number of COVID-19 positive patients not previously known to have diabetes present with hyperglycemia so it is important to monitor blood glucose in all admissions. In the inpatient setting, as in the outpatient setting, medication classes may have to be changed. On admission, SGLT-2 inhibitors, metformin and GLP-1 receptor agonists should be discontinued, while DPP-4 inhibitors may be continued if clinically helpful (Table 1) . There are many reports of unusual presentations of diabetic emergencies including people with type 2 diabetes presenting in diabetic ketoacidosis (DKA) or mixed ketoacidosis and hyperosmolar hyperglycemic state (HHS) (5, 56) . It is important to check ketones in all patients who present with an elevated blood glucose. This is even more important if a patient was on an SGLT-2 inhibitor, which has been associated with a potential for increased incidence of euglycemic DKA. If ketones persist despite usual care and glycemic improvement, 10-20% glucose containing solutions should be utilized. Fluid requirement will A c c e p t e d M a n u s c r i p t 10 be variable and may differ if DKA or HHS is present. The concern for pulmonary fluid extravasation (lung leak) or myocarditis will certainly affect fluid requirements (57) . If mild DKA is present, a subcutaneous insulin protocol using rapid acting insulin every 2 hours should be considered to minimize need for an IV insulin drip with frequent glucose monitoring. Subcutaneous insulin protocols for treating mild DKA on the ward or in an observation unit are safe and effective, and demonstrate no difference in mortality, length of hospital stay, total amount of insulin administration or number of hypoglycemic events compared to individuals treated with regular insulin drip (or IV insulin) (58) . A reasonable glucose goal for individuals with COVID-19 in the hospital is 140-180 mg/dL, the same glucose target as for non-COVID hospitalized patients.

In the ICU setting, severe insulin resistance may lead to a high insulin requirement of >20 units insulin/hr. Widely fluctuating insulin doses have been well documented, often in patients on tube feeds. Hypoglycemia is also an important risk, particularly in patients whose continuous tube feeding is interrupted. Hypoglycemia should also be considered if hydroxychloroquine is used, sulfonylureas or meglitinides are used, steroids are being tapered, or if the patient's renal function is declining.

For hyperglycemia outside of the critical care area it is important to test capillary blood glucose using point of care (POC) testing before meals and at bedtime. A basal-bolus regimen based on body weight is recommended with 50% of the insulin as basal and 50% as rapid-acting to cover carbohydrates consumed with correction insulin as needed added to the dose. For individuals on only continuous tube feeding, to minimize the risk of hypoglycemia, the total insulin should be dosed as 40% basal and 60% as rapid-acting, distributed as 15% every 6 hours aligned with POC glucose testing. Blood glucose control in A c c e p t e d M a n u s c r i p t 11 patients receiving only bolus tube feedings can be achieved by using rapid-acting insulin with every four to six hours immediately at the start of the feeding assuring a match of nutrition and insulin. Other dosing considerations include declining renal function and interruption of tube feedings for procedures, high residuals, or a clogged or dislodged feeding tube. Insulin requirements should be assessed daily. If blood glucose is greater than 100-140 mg/dL fasting or greater than 180 mg/dL random/non-fasting, an increase of insulin dosage by 10-20% is indicated. However, if blood glucose is less than 100 mg/dL, a decrease in dose by 10-20% should be considered. Another method can be to take half of the correctional doses over the past 24 hours and add 50% to basal insulin and 50% to short acting insulin. with hypotension requiring vasopressors, with signs of poor perfusion, on acetaminophen use of more than 1000 mg every 6 hours, and significant pitting edema (3+ or greater) as seen in cirrhosis with ascites, congestive heart failure with edema, or nephrotic syndrome.

Numerous studies have shown that adrenal hormones play a crucial role in the immune response. The effect of adrenal hormones cortisol, epinephrine, and norepinephrine on the immune system is complex; this raises the concern that patients with adrenal insufficiency may be at a disadvantage in fighting COVID-19. Investigators have found that while norepinephrine and epinephrine mobilize immune cells into the bloodstream, epinephrine A c c e p t e d M a n u s c r i p t 13 and cortisol are responsible for "trafficking" or directing the cells to become more specific type of immune cells and directing them to tissues where they are needed (60) (61) (62) . It is recognized that a short term increase in blood leukocytes indicates mobilization of cells whereas a decrease represents a trafficking of the cells to target organs such as the lung or skin (61, 63) .

Scientists have studied the extent to which the lack of cortisol in patients with adrenal insufficiency may affect how the immune system responds to stress. Healthy individuals and patients with chronic adrenal insufficiency were exposed to a psychosocial stress test in one study (64) . Both groups showed similar norepinephrine response however epinephrine and cortisol levels were lower in chronic adrenal insufficiency patients and only the healthy individuals demonstrated the expected stress related rise in lymphocytes with a subsequent decrease. The patients with chronic adrenal insufficiency only exhibited the normal poststress migration of lymphocytes if they were given additional steroids to mimic a stress response. There is currently no direct evidence that this altered response worsens the course of patients who contract COVID-19 and have underlying adrenal insufficiency however it certainly raises that concern.

Retrospective studies have shown variable degrees of increased mortality in patients with adrenal insufficiency compared to the general population (65) . Infections, cancer and cardiovascular disease account for the increase in mortality. Furthermore, a retrospective, observational study in patients with Addison's disease found a 5-fold higher mortality from infection, with pneumonia as the major cause (66, 67) . Investigators studied the immune cell make-up of patients with primary adrenal insufficiency due to autoimmune adrenalitis or bilateral adrenalectomy and compared them to healthy subjects (68) . They found natural A c c e p t e d M a n u s c r i p t 14 killer cells were significantly lower in the patients with adrenal insufficiency which, they concluded, has the potential to render patients with adrenal insufficiency more susceptible to invading pathogens. Studies have also suggested that due to underlying depletion of the innate immune system of patients with adrenal insufficiency, steroid replacement regimens that aim to restore a more physiological circadian glucocorticoid rhythm result in reduced susceptibility to infections (69) . There is good evidence that hypercortisolism due to both adrenal and pituitary Cushing's Syndrome is associated with increase in mortality and risks for acute myocardial infarction, A c c e p t e d M a n u s c r i p t 16 venous thromboembolism, stroke and infections (79) . Guidance set forth by expert consensus are recommending patients with Cushing's Syndrome be informed they are at a higher risk of infection from COVID-19 due to an immunocompromised state and therefore should adhere to strict social distancing guidelines and precautions (80) . To date this is based on expert group consensus and not on stronger data or statistics of COVID-19 infections in patients with Cushing's Syndrome. Comorbidities associated with Cushing's disease such as diabetes and hypertension should be aggressively managed since data suggests they adversely affect outcomes in COVID-19 infections (37, 81) . Medical therapy for treatment of Cushing's Syndrome is recommended as first-line therapy during the pandemic.

Transsphenoidal surgery is not recommended unless urgently required during the peak of the pandemic due to the high risk of aerosol formation and risk to health care providers however this is an evolving area and neurosurgical expertise should be requested to weigh risks and benefits (82) . (52, 85) .

There is currently inadequate data regarding COVID-19's impact on the thyroid. ACE2 receptors, the entry site for COVID-19, have been located in the thyroid (86) . Several case reports have described the onset of subacute thyroiditis in patients diagnosed with COVID-19 infection during the pandemic (87) (88) (89) . Given that the etiology of subacute thyroiditis has been attributed to viral infections, it is not surprising that COVID-19 could be an etiology. It is important to note that although infections have been implicated in the genesis of thyroid autoimmunity, having an autoimmune thyroid disease has not been shown to predispose patients to increased infections.

In general, thyroid function should not be assessed during severe clinical illness unless thyroid dysfunction is deemed to be a contributing factor to the underlying clinical picture;

in critical illness such as in some cases of COVID-19 infection, there is an increased risk of non-thyroidal illness syndrome (NTIS) evidenced by decreased free T3, increased reverse T3, with low-normal or decreased free T4 and low-normal TSH (90) . In severe illness, the degree of change in thyroid hormones is related to the severity of illness. A retrospective analysis of thyroid function tests in hospitalized patients with moderate to critical COVID-19 symptoms found decreased TSH and total T3 compared to similarly ill patients with non-COVID-19

pneumonia. The degree of TSH and total T3 suppression correlated with the disease severity; total T4 was not significantly different from the control group and thyroid function tests normalized after recovery (91) . A report on 274 patients showed TSH and free T3 were significantly lower in deceased patients compared to recovered patients (92) . NTIS is thought A c c e p t e d M a n u s c r i p t 18 to be adaptive but might be associated with poor clinical outcomes in certain cases. Current data is inconclusive as to the benefit of treating NTIS, and it has been shown on occasion to be detrimental when thyroid hormone levels have been supplemented in patients with NTIS(90).

Out of 287 patients hospitalized with COVID-19 in Italy, at least 20% had thyrotoxicosis with negative thyroid receptor antibodies and a majority of that subgroup subsequently normalized their thyroid function with resolution of the illness (93) . Of the autopsy data that is currently available in English, there is only one which reported thyroid findings (normal thyroid and MNG in two patients) (94) . For hyperthyroid patients who are being treated with antithyroid drugs, the possibility of agranulocytosis should be kept on the forefront.

Although a rare side effect, with 0.2-0.5% prevalence, agranulocytosis could present with symptoms such as sore throat or fever, also seen in patients with COVID-19, and can occur at any point during treatment. If this occurs, it is imperative to check a complete blood count as soon as possible to ascertain the presence of agranulocytosis (absolute neutrophil count < 500). Once confirmed, immediate cessation of the antithyroid drug is warranted, as is initiation of treatment with antibiotics (95) . 

With the exception of interest in the possible role of Vitamin D in mitigating COVID-19 disease, there is a lack of data on the impact of COVID-19 on the parathyroid gland and bone. Most of the focus has been on access to therapy during the pandemic. There is a valid concern over difficulties in accessing hospital or clinic administered osteoporotic drugs, particularly denosumab (Prolia), which has detrimental effects with delays of more than 6 months between dose administration. To avoid delays in management, expert consensus suggests either setting up low-risk COVID-19 environments and administering denosumab when it is due or switching to bisphosphonates where appropriate (96) . Denosumab is a human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL) that inhibits osteoclast formation, decreases bone resorption, increases bone mineral density and reduces the risk of fracture. There is currently no data to suggest an increased risk of viral infections when denosumab is used for the treatment of osteoporosis (97) . However, hypocalcemia is known to be associated with infections; a recent report of COVID-19 patients showed that lower calcium levels were correlated with worse clinical outcomes (98) . 

Data on COVID-19 and the female gonadal and reproductive function is not available or is limited. Authors recently speculated on possible ways COVID-19 might attack ovarian tissue and endometrial epithelial cells due to the expression of ACE2 in these tissues (86, 105, 106) .

Jing et al. also provides an insightful review on potential COVID-19 targets that may influence reproductive health, also noting ACE2 expression in oocytes, ovary, uterus and vagina (107) .

Men with COVID-19 are at higher risk for worse outcomes and death compared to women despite same prevalence of infection (108) . Sex differences in immune response in general (not specific to COVID-19) have long been studied. Although the process is complex, experts point out that adult females mount a stronger innate and adaptive immune response than males which subsequently results in faster clearance of pathogens but contributes to their increased susceptibility to inflammatory and autoimmune disease(109).

Straub goes in depth into potential causes for the immuno-supportive role of estrogens and complex criteria such as the type of immune stimulus which determine if estrogens play an anti-inflammatory or pro-inflammatory role (110) . A study of male and female mice infected with SARS revealed that male mice were more susceptible to infection compared to female mice (111) . They highlight the protective effect of estrogen signaling in females by noting the increase in mortality of mice after removing this signaling pathway with ovariectomy or treating with estrogen receptor antagonist. A different study in mice infected with influenza A virus found that ovariectomized female mice treated with estradiol reduced the severity of the illness with less morbidity despite same virus titers than placebo treated mice (112) .

A c c e p t e d M a n u s c r i p t 22 This is an area of future research in trying to understand the differences in severity between men and women with COVID-19.

The mRNA for ACE2, the receptor for COVID-19, is expressed in human testes, primarily in spermatogonia, Leydig cells and Sertoli cells (113) . The expression level there is perhaps the highest in the body (114) . In addition, the cellular transmembrane serine protease TMPRSS2, also important for viral cellular entry, is also present in the testes (115) .

control sperm cell differentiation. COVID-19 shares a 76% amino acid sequence identity with SARS, which caused orchitis and widespread germ cell destruction in human testes more than a decade ago (116) . Therefore, there is potential for COVID-19 to invade the testes via ACE2 and interfere with testosterone release and sperm production especially since the blood-testicular barrier may be disrupted in the presence of systemic or local inflammation.

There are several reports of scrotal discomfort, even severe scrotal pain in people with COVID-19 and one report of a case of orchiepididymitis (114, (117) (118) (119) .

Testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin levels were measured in 81 hospitalized confirmed COVID-19 patients, aged 20 to 54 with a median age of 38 years(120). Controls were age matched males who had previously received reproductive function evaluation and were healthy with normal fertility. It is important to remember that any acute illness may lower testosterone levels. Testosterone was nominally but not significantly reduced in the COVID-19 patients compared to controls, but LH was significantly higher. The testosterone to LH ratio was significantly lower in the M a n u s c r i p t 23 infected individuals. This pattern of elevated LH with statistically unchanged testosterone is what might be seen in early gonadal failure and speaks against a direct COVID-19 effect at hypothalamus or pituitary and likely on gonadal Leydig cells. FSH was unchanged. This testicular defect could be caused by direct testicular damage by the virus or by an indirect inflammatory/immune response in the testicles (121) .

Semen was examined for COVID-19 mRNA in 12 affected men aged 22 to 38 years and in testes samples of one 67-year-old who died (122) . Of the 12 survivors, 11 had mild clinical disease and one was asymptomatic. None of the semen samples was positive for COVID-19 mRNA. In another study, no COVID-19 mRNA was found in the semen of 34 men collected between 8 and 75 days (median 31 days) after COVID-19 diagnosis (117) . A third group reported on a population of 18 men who had recovered from COVID-19 infection and a control group of 14 unaffected men (123) . No COVID-19 mRNA could be detected in any of the semen samples. Patients with moderately severe infection had a statistically significant impairment of sperm quality (sperm concentration, total number of sperm per ejaculate, total number of progressive motility, total number of complete motility) compared with men recovered from a mild infection and the control group. Subdividing people who had a fever from those who had not (regardless of the severity of infection) showed that there were significant differences in sperm volume, motility and immotile sperm, though all values were still in the normal range. In contrast, in another study of 38 men providing semen samples, 23 had clinically recovered, while 15 were in the acute stage of the infection.

Semen was COVID-19 positive in six patients including four of 15 patients who were in the acute stage of infection (124) . Therefore, it appears that COVID-19 mRNA can be seen in some men who had infection, though the numbers reported are still small. It also appears A c c e p t e d M a n u s c r i p t 24 that COVID-19 may alter sperm quality, though again the numbers are small. We lack data on those with severe acute infection and the possible effects of drugs used to treat the disease.

The American Society for Reproductive Medicine (ASRM) has regular updates on its website.

At this point, acknowledging that much remains to be learned about COVID-19, ASRM calls "for gradually and judiciously resuming the delivery of reproductive care" (125) .

This paper explores what is presently known about COVID-19 with regard to the endocrine system, particularly as it pertains to diabetes, thyroid and parathyroid disease, adrenal 

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Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery

the covid-19 pandemic adrenal insufficiency

Our Reponse to COVID-19 as Endocrinologists and Diabetaologists

Encountering COVID-19 as Endocrinologists

AACE Position Statement: Coronavirus (COVID-19) and People with Adrenal Insufficiency and Cushing's Syndrome

COVID-19 and endocrine diseases. A statement from the

COVID-19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency

Adverse effects of glucocorticoids: Coagulopathy

The spectrum of haemostatic abnormalities in glucocorticoid excess and defect

Multisystem morbidity and mortality in cushing's syndrome: A cohort study

Endocrinology in the time of COVID-19: Management of Cushing's syndrome

Hypertension in patients with coronavirus disease 2019 (COVID-19): A pooled analysis

Letter: Precautions for Endoscopic Transnasal Skull Base Surgery During the COVID-19 Pandemic

Hypocortisolism in survivors of severe acute respiratory syndrome (SARS)

Molecular mimicry of ACTH in SARS -Implications for corticosteroid treatment and prophylaxis

Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

Sars-COV-2 Infection

SARS-CoV-2: a potential trigger for subacute thyroiditis? Insights from a case report

A case of subacute thyroiditis associated with Covid-19 infection

Thyroid function in critically ill patients

Thyroid Function Analysis in 50 Patients with COVID-19: A Retrospective Study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study

Thyrotoxicosis in Patients with COVID-19: The THYRCOV Study

Autopsy in suspected COVID-19 cases

Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management

Endocrinology in the time of COVID-19: Management of calcium disorders and osteoporosis

Risk for Infections During Treatment With Denosumab for Osteoporosis: A Systematic Review and Meta-analysis

Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease

Vitamin D: Nutrient, hormone, and immunomodulator

Vitamin D and immune function

Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis

The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality

Letter: Covid-19, and vitamin D

Does vitamin D status impact mortality from SARS-CoV-2 infection?

its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary

The vasoactive peptide angiotensin-(1-7), its receptor Mas and the angiotensin-converting enzyme type 2 are expressed in the human endometrium

Potential influence of COVID-19/ACE2 on the female reproductive system

Gender Differences in Patients With COVID-19: Focus on Severity and Mortality

Sex differences in immune responses

The complex role of estrogens in inflammation

Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection

17 -Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs

scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia

ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis †

SARS-CoV-2: diagnostic and design conundrums in the context of male factor infertility

Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS)1

No evidence of severe acute respiratory syndromecoronavirus 2 in semen of males recovering from coronavirus disease 2019

Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis

Orchiepididymitis in a Boy with COVID-19

Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. medRxiv

Could COVID-19 have an impact on male fertility?

Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients

Assessment of SARS-CoV-2 in human semen-a cohort study

Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease

Patient Management and Clinical Recommendations During The Coronavirus (COVID-19) Pandemic -updated