key: cord-0934452-1i0ttim1
authors: Clarke, Sophie A; Abbara, Ali; Dhillo, Waljit S
title: Impact of COVID-19 on the Endocrine System – a mini-review
date: 2021-09-20
journal: Endocrinology
DOI: 10.1210/endocr/bqab203
sha: 66f8a5b2e3a82539f4f9b5b0677208a3753fabec
doc_id: 934452
cord_uid: 1i0ttim1

The Corona Virus Disease 2019 (COVID-19) pandemic continues to exert a significant impact on global healthcare systems, causing devastating mortality and morbidity. As time passes and our understanding of this novel respiratory virus deepens, it is increasingly clear that its effects extend beyond that of the respiratory system. The coronavirus responsible for COVID-19, SARS-CoV-2, obtains cellular access through the angiotensin converting enzyme 2 (ACE2) receptor in a process requiring the transmembrane serine protease 2 (TMPRSS2) protein. Both ACE2 and TMPRSS2 are widely expressed in many endocrine glands. This, along with several case reports of thyroid and pituitary disruption in patients with COVID-19, has resulted in significant interest in its impact on the endocrine system. Indeed, as mortality is abated by the increasing availability of effective vaccines, there is increasing focus on the long-term effects on health in COVID-19 survivors. This review summarises data investigating the effects of COVID-19 on each of the endocrine axes to guide appropriate investigations and optimal management.

SARS-CoV-2 and its variants will impact on global healthcare systems over the upcoming years across the world. Furthermore, the effects of COVID-19 extend beyond the respiratory system, and can be protracted, with ~10% of patients experiencing persistent symptoms at 8 weeks following initial infection 1 . It is therefore vital to deepen our understanding of the disruption of COVID-19 on physiological function.

Whilst early case reports first indicated a potential clinical impact on the endocrine system, there now exists a larger body of research describing the effects of COVID-19 on pituitary, thyroid, adrenal, gonadal and pancreatic endocrine function. However, the contribution of endocrine dysfunction to the symptoms experienced by patients with COVID-19 remains to be fully elucidated. Endocrine disorders are eminently treatable, and their diagnosis and management can result in significant improvements in health and quality of life. Thus, in this review, we appraise the available data investigating the impact of COVID-19 on the endocrine system to aid clinicians in instituting appropriate investigation and management of affected patients.

The SARS-CoV-2 coronavirus, which causes COVID-19, gains cellular access through the angiotensin converting enzyme 2 (ACE2) receptor. The homotrimeric spike glycoprotein, composed of an S1 and S2 subunit, protrudes from the virus surface and is critical for its binding to ACE2 2, 3 . Upon binding to ACE2, the S1 subunit is dissociated with the ACE2 receptor, in a process that requires the presence of transmembrane serine protease 2 (TMPRSS2) 4 (see Figure 1 ). It is known that TMPRSS2 drives oncogenic transcription in prostate cancer, and that TMPRSS2 is regulated by androgens. Indeed, androgen deprivation or antagonism both attenuate SARS-CoV-2 S-mediated cellular entry in vitro 5 .

The resultant conformational change affords the S2 subunit the increased stability necessary for membrane fusion (Figure 1 ) 6 . Binding to the ACE2 receptor is obligatory for SARS-CoV-2 cellular A c c e p t e d M a n u s c r i p t 4 entry. In in vitro studies, the SARS-CoV-2 virus was unable to access HeLa cells that did not express ACE2 proteins 7 , and raising anti-serum to human ACE2 prevented cellular access by SARS-CoV-2 4 .

Additionally, unlike other coronaviruses, SARS-CoV-2 does not appear to utilise other receptors for cellular access, such as dipeptidyl peptidase 4 (DPP4) or aminopeptidase N (APN) 4, 7 .

In humans, ACE2 mRNA is expressed in several endocrine glands including the pancreas, thyroid gland, ovaries and testes 8 (see Figure 2 ). Crucially, TMPRSS2 mRNA also expressed in the pancreas, thyroid gland, ovaries and testes 8 . Thus, the endocrine system not only possesses the requisite ACE2 receptor, but also the TMPRSS2 protein necessary to afford the SARS-CoV-2 virion cellular access. In summary, there is cumulative evidence that the endocrine system is particularly vulnerable to both destruction and alteration in function due to COVID-19.

Although the ACE2 receptor is present in the normal pituitary gland 9 , it is not a region of high expression of ACE2 mRNA or protein 8, 10 . Moreover, post-mortem pituitary tissue from patients with pituitary neuroendocrine tumours also display low ACE2 expression 10 . Nevertheless, SARS-CoV mRNA was detected within the pituitary gland at autopsy 11 , and post-mortem investigation of five patients who died of SARS, demonstrated reduced somatotrope, thyrotrope and corticotrope cell number and immunoreactivity staining for growth hormone (GH), thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) 12 

The pituitary gland has a rich vascular supply; as vascular endothelium has high expression of ACE2 receptors 9 , it is vulnerable to damage during COVID-19 infection. Furthermore, pituitary apoplexy may be precipitated by conditions that alter platelet function and coagulation 13 . Severe illness and sepsis result in a prothrombotic state 14 , but more specifically, patients with COVID-19 have hypercoagulability 15 that is distinct, characterised by thrombocytopenia, high fibrinogen and Ddimer levels, but only minor changes in prothrombin and antithrombin times 16 . Thus, it is conceivable that there is an increased risk of pituitary apoplexy in patients with pituitary tumours with COVID-19 infection, which has been suggested by several case reports. Whilst some of these reports had other risk factors for apoplexy, such as pregnancy 17 , and most were in patients with preexisting pituitary macroadenomas [18] [19] [20] , some were in patients with microadenomas 21, 22 , which is typically less commonly associated with apoplexy.

Whilst there is a paucity of data detailing pituitary function following COVID-19, central hypothyroidism was observed in 4.9% of patients at 3-6 months post-SARS with the majority of patients reverting to euthyroidism by 9 months post-infection 23 

Patients diagnosed with SARS had reduced thyroid function. Furthermore, at post-mortem, both follicular and parafollicular cells of the thyroid gland were extensively damaged in patients who died of SARS 25 . Additionally ACE2 mRNA is present in thyroid follicular cells, highlighting the potential of thyroid cellular access by SARS-CoV-2 26 , but, to date, no evidence of intracellular SARS-CoV-2 has been documented 27 .

Early in the pandemic, several cases of sub-acute thyroiditis were reported [28] [29] [30] [31] . Amongst patients admitted to ITU, those with COVID-19 were more likely to have thyrotoxicosis 32 . Likewise, those with COVID-19 admitted to high intensity ITU had a lower TSH compared to those admitted to low intensity ITU (Table 1) 32 . Interestingly, 6 patients with thyroiditis/thyrotoxicosis after COVID-19 were followed-up at a mean of 55 days. None of them had ever experienced neck pain, and rather than lymphocytosis, had the characteristic lymphopenia associated with COVID-19 32 . In patients with COVID-19 not requiring intensive care admission, overt thyrotoxicosis was observed in 10.8% and 0.7% of patients had hypothyroidism 33 . However, the majority of patients (74.6%) had normal TSH values 33 (Table 1) . Notably, thyrotoxicosis was related to IL-6 levels, suggesting that those with a greater inflammatory response were more likely to develop thyrotoxicosis 33 (Table 1) . By contrast, in a cohort of 334 patients with COVID-19, we observed that no patients had overt thyrotoxicosis, although TSH and fT4 values were reduced compared to baseline 34 (Table 1 ).

In addition to subacute thyroiditis, case reports have emerged of Graves' thyrotoxicosis in patients A c c e p t e d M a n u s c r i p t 7 with COVID-19 35, 36 , one of whom had no previous documentation of autoimmune thyroid disease. Viral infections may trigger the presentation of autoimmune thyroid disease 37 , however it has been posited that the cytokine milieu induced by SARS-CoV-2 renders it a particular trigger for autoimmune thyroid disease 36 . IL-6 levels are characteristically raised by COVID-19 and are elevated in Graves' disease 38 .

Non-thyroidal illness syndrome (NTIS) occurs during physiological stress, and is characterised by an initial reduction in total T3 (TT3) and fT3, with an increase in reverse T3 (rT3) but without a concomitant rise in TSH 39 . Persistent illness results in global reductions in TSH, fT4 and fT3 40 due to a reduction in hypothalamic thyrotropin releasing hormone (TRH) 41 . It is therefore unsurprising that several studies have reported features consistent with NTIS in patients with COVID-19.

Patients with pneumonia due to COVID-19 were observed to have lower serum TSH and TT3 levels than other forms of pneumonia, although there was no difference in total T4 (TT4) values 42 . These differences were resolved at recovery 42 . Whilst a prospective study of 367 patients with mildmoderate COVID-19 failed to demonstrate overt thyrotoxicosis or hypothyroidism, 7.4% had NTIS and 8.2% had thyroid function tests consistent with different stages of thyroiditis 43 (Table 1) .

Notably, NTIS was associated with a higher SARS-CoV-2 viral load, and higher levels of inflammatory markers (Table 1) 43 . Other studies have observed similar findings with an isolated low TSH, or in combination with low fT3, being reported in patients with COVID-19 44, 45 and the degree of reduction being associated with the severity of disease 45, 46 . Finally, survivors of COVID-19 had lower TSH levels than non-survivors (Table 1 ). Moreover, given that corticosteroid use is now gold-standard for patients requiring oxygen supplementation 47 , it should be noted that exogenous steroids can reduce TSH levels 48 and peripheral conversion of T4 to T3, providing an additional mechanism for thyroid dysfunction.

A c c e p t e d M a n u s c r i p t 8 TFTs taken every 3-7 days during Normal TSH at presentation and during admission: n=76 (61%) -n=55 had normal fT4 and fT3 -n=11 had low fT3 alone (4 of these on corticosteroids) -n=10 had low fT3 and fT4 (6 of these on corticosteroids)

Low TSH (<0.4mU/L) at presentation but otherwise normal during admission: n=12 (10%) -n=2 had normal fT4 and fT3 -n=10 had normal fT4 and low fT3 (<2.9pmol/L) Normal TSH at presentation but reduced (<0.4mU/L) during admission:

At presentation, majority of patients were euthyroid

Low TSH with normal fT4 and low fT3 = transient during admission. Low TSH with normal fT4/low fT3 inversely correlated with CRP, IL-6 and cortisol, consistent with immune-mediated response, as opposed to destructive thyroiditis Included patients who received corticosteroids as part of their treatment.

A c c e p t e d M a n u s c r i p t 10 admission n=27 (24%) -n=12 had normal fT4 and fT3 -n=13 had low fT3 alone (10 of these on corticosteroids) -n=2 had low fT3 and fT4 (both on corticosteroids)

fT3 predicted mortality CRP, IL-6 and cortisol higher in pts with low TSH and fT3 TSH and fT3 restored by discharge 

Following the original SARS outbreak, it was reported that hypocortisolism (defined as either 8am cortisol ≤138nmol/L, or stimulated cortisol ≤550nmol/L following 250mcg

Tetracosactide) affected 39.4% of patients at ≥3 months' after acute infection 23 . More A c c e p t e d M a n u s c r i p t 14 recently, the ACE2 receptor has been identified by immunohistochemistry to be present in the adrenal cortex 52 . It was highly prevalent in the zona fasciculata and reticularis (glucocorticoid and androgen production), but not in the zona glomerulosa (mineralocorticoid production) 52 . Furthermore, TMPRSS2 was widely expressed throughout all three zones of the adrenal cortex 52 . At autopsy, adrenal haemorrhage, ischaemic necrosis and focal inflammation were all described in patients who died of COVID-19 52 .

Finally, hyponatremia is commonly observed in patients with COVID-19 with one study finding up to 30% of patients with serum sodium values <135mmol/L 53 and dysnatremia was associated with worse outcomes 54 . Whilst there are several factors that account for this phenomenon, including the syndrome of inappropriate antidiuretic hormone (SIADH) and

hypovolaemia, if present adrenal insufficiency may also present with hyponatraemia 55 .

Adrenal insufficiency secondary to acute adrenal infarction 56 and adrenal haemorrhage [57] [58] [59] have been described in case reports following COVID-19 60 . However, underlying comorbidities, such as antiphospholipid syndrome, may have been contributory in some cases 56 . Adrenal function remains preserved in most patients with acute COVID-19. We observed that serum cortisol within the first 48hrs of admission in patients presenting with COVID-19 was significantly raised 61 . Furthermore, high cortisol concentrations were associated with increased mortality, consistent with activation of the cortisol endocrine axis in acute illness 62 . Conversely, critical illness may result in 'critical illness-related corticosteroid insufficiency' (CIRCI), due to physiological stress suppressing the hypothalamic-pituitaryadrenal axis 63 . However, we did not find an increased proportion of patients with a cortisol <276 nmol/L (10μg/dL) (threshold used to define CIRCI) in patients with COVID-19 62 the testes susceptible to damage by SARS-CoV-2 but that in some patients with COVID-19 significant morphological changes occur which could impair GC function.

In keeping with the histopathological findings, patients with COVID-19 have presented with testicular pain and either epididymo-orchitis, or orchitis in isolation [78] [79] [80] . Likewise, testicular pain was reported by 10.9% of patients with acute COVID-19 in one study 81 (Table 2 ). Over one fifth (22.5%) of 142 men with acute COVID-19 infection had ultrasound evidence of orchitis, or epididymo-orchitis at 1 week to 1 month post hospitalization, with the risk of epididymo-orchitis increasing with severity of COVID-19, and advancing age 82 (Table 2) . By contrast, a study of 253 male patients did not find any features of acute orchitis in patients with COVID-19, however this study relied on physical symptoms / examination for diagnosis rather than ultrasound, and included a younger cohort with a shorter duration of follow-up 83 (Table 2) .

Whilst evidence is mixed regarding the presence of SARS-CoV-2 in semen, COVID-19 may impact testicular function, by way of spermatogenesis, via mechanisms other than the direct effects of the virus in the testes. It is known that fever has a negative impact on spermatogenesis 84 . In a small study of 18 men with COVID-19, those with moderate infection had reduced sperm concentration, reduced total number of sperm per ejaculate and reduced total number of progressive complete motility compared to those with mild disease, and healthy controls 77 (Table 2) . Interestingly, men with fever had reduced semen volume and reduced motility compared to those without 77 (Table 2) . Other studies have also reported both motility and normal morphology of sperm to be reduced in men with COVID-19 85, 75 .

When compared to healthy age-matched controls, sperm concentration and total sperm count were reduced in 55 male patients who had recovered from COVID-19, compared to A c c e p t e d M a n u s c r i p t

18 healthy controls at a median of 80 days post-infection 86 .

Leydig cells are the predominant source of testosterone production in males. In a small study, men with untreated COVID-19 had reduced serum LH, FSH and total testosterone compared to men treated with oral hydroxychloroquine and azithromycin (n=10) or age-matched controls without COVID-19 (Table 2) However, it should be noted that most men with low calculated free testosterone values had either low or normal serum LH values 88 , suggesting that this hypogonadism could be due to hypothalamic-pituitary dysfunction, secondary to reduced GnRH pulsatility, a phenomenon that is known to occur with physiological stressors 89, 90 . Finally a recent prospective study observed that men with severe COVID-19 (n=66) had lower median testosterone values than those with mild disease (admission median testosterone: 1.84 vs 5.24 nmol/L), and that testosterone concentrations were inversely related to cytokines, including interleukin-6, and c-reactive protein (CRP) suggesting that the hypogonadism is immune-mediated 91 ( Table 2) .

Despite acute reduction in testosterone in men with COVID-19, there remains little evidence of a persistent effect beyond recovery. Serum LH, FSH and total testosterone values were all within normal limits at a median of 80 days after acute infection in an uncontrolled study of 66 men who had recovered from COVID-19 86 (Table 2) Prolonged studies required to determine persistent effects in longer-term M a n u s c r i p t 25 Multivariable analysis: Obesity and hypokalemia associated with low testosterone Age >65yrs independent predictor of Sertoli cell dysfunction No relationship between prevalence hypogonadism/Sertoli cell dysfunction and symptoms of 'post-COVID-syndrome' 

In a prospective study from China, median serum anti-Müllerian hormone (AMH) was lower in patients with COVID-19 compared to controls (P<0.05) ( Table 3) . Serum LH, total testosterone and prolactin were higher in the follicular-phase of women with COVID-19 compared to healthy controls. Prolactin is known to be increased during times of stress 100 , which could account for this observation. In another cohort of 62 women with COVID-19, there were no significant changes in estradiol, testosterone, or insulin-like growth factor (IGF-1) during hospitalisation and no differences with disease severity or with inflammatory markers 91 (Table 3 ). Importantly, this study included women of all ages diagnosed with COVID-19 and their menopausal status and other sex hormones were not provided, making it difficult to fully interpret these findings 91 .

A further cross-sectional study of 177 pre-menopausal women diagnosed with COVID-19

found that more women with severe COVID-19 had cycle lengths lasting more than 37 days than those with mild disease (34% vs 19%, P=0.001 ) 101 . In those with available data (n=91), there was no difference in serum AMH, LH, FSH, estradiol, progesterone or testosterone compared to age-matched pre-pandemic historic controls 101 (Table 3) .

Unfortunately, there is scant data on the effects of COVID-19 infection on ovarian function beyond the non-infective impact of the pandemic such as increased psychological stress and weight gain. In an international survey of patients experiencing 'Long COVID', 36.1% reported A c c e p t e d M a n u s c r i p t 28 changes to their menstrual cycle following COVID-19, including new onset of irregular periods, abnormally heavy periods, and post-menopausal bleeding 102 .

In summary, both the acute and chronic effects of COVID-19 on the female HPG axis remain unclear. As the prevalence of COVID-19 appears to be equal between genders 103 Ovaries -persistent effects Davis M a n u s c r i p t 32

Whilst a full discussion regarding the hyperglycaemic effects of COVID-19 is beyond the scope of this mini-review, and has been skilfully covered by others 105, 106 , this section will focus on the potential for islet cell destruction and subsequent impairment of glycaemic control.

During the SARS pandemic, hyperglycaemia in patients not previously known to be diabetic was reported, with 51.3% of 39 non-diabetic patients diagnosed with SARS, meeting diagnostic criteria for diabetes during their inpatient admission 107 . Similarly, reports emerged of patients presenting with ketosis 108 , new onset hyperglycaemia and new diagnoses of diabetes 109, 110 , and patients with type 1 or type 2 diabetes had an increased risk of mortality following COVID-19 111 . Indeed, such is the scale of the problem, that an international registry has been established to investigate the complex interaction between diabetes and COVID-19 112 . SARS-CoV-2 is able to infect and replicate in human endocrine pancreas cells 113 and SARS-CoV-2 viral RNA has been detected in the β cells of patients with COVID-19 at autopsy 114 .

Both the ACE2 receptor and TMPRSS2 protein have been detected in the microvasculature of the pancreas 115, 116 , however there is conflicting evidence regarding the presence of ACE2 receptors in β cells. Several studies have failed to demonstrate the presence of ACE2 in pancreatic β cells 115, 116 , whilst others have observed increased ACE2 expression in pancreatic islets 107, 117 . Recently variable ACE2 expression was found in pancreatic β cells of patients who died of COVID-19, which correlated with the cytokine response 117 .

Ketoacidosis can occur in the context of insufficient pancreatic insulin secretion to meet the glycaemic needs, and is typically observed in T1 diabetes, secondary to autoimmune M a n u s c r i p t 33 destruction of beta cells. However, ketoacidosis has also been reported in patients with T2 diabetes with COVID-19. Indeed, one meta-analysis found that 77% of patients diagnosed with ketoacidosis had T2DM 118 . In the majority of cases, this appeared to be secondary to insulinopenia 119, 120 , however it could also be possible that this is a consequence of the significant insulin resistance observed in patients with COVID-19 106 leading to β cell failure 119 .

Patients presenting with ketoacidosis during the SARS-CoV-2 outbreak were more likely to be older, have T2DM, and in non-white ethnic groups, than historic controls 121 .

Additionally, new onset Type 1 diabetes has been reported following COVID-19 122 , with some remaining islet cell autoantibody negative 123,124 . Thus, the existence of autoantibody-negative insulin-requiring diabetes following COVID-19, together with the histopathological findings, suggests that, at least in some individuals, COVID-19 could be associated with beta cell functional impairment or destruction.

Finally, along with the potential for β cell destruction, a recent small study (n=10-15 per group) from Italy suggested that COVID-19 may disrupt β cell function in patients without known diabetes 125 . Both patients with acute COVID-19 and those recovering from COVID-19 had an increased insulin response to arginine stimulation compared to healthy controls 125 .

suggesting that COVID-19 may cause β cell hypersecretion, which could, in turn, result in relative secretory failure.

Whilst the long-term effects of COVID-19 on hyperglycaemia remain to be fully elucidated, one study found that by 6 months post-admission, 63% of those diagnosed with hyperglycaemia during their admission had recovered euglycaemia 125 . Nevertheless, more than one third still had persistent hyperglycaemia (blood glucose 100-199mg/dL), and ~2% had overt diabetes 125 . Similarly, at 3 years following SARS, 5% of patients diagnosed with new-onset diabetes during their admission still had diabetes 107 . A c c e p t e d M a n u s c r i p t 34 To summarise, SARS-CoV-2 is associated with hyperglycaemia and ketoacidosis occurring more frequently in older patients with T2DM, and can affect those not previously treated with insulin. Whilst this may be due to the stress response that occurs in severe illness (characterised by increased cortisol and glucagon, resulting in a relative insulin deficiency) direct damage to β cell structure and function is possible. Thus, further characterisation of the effects of COVID-19 on dysglycemia in future research will be of clinical relevance.

As we near the conclusion of the second year of the COVID-19 pandemic, it is apparent that its additional impact beyond the respiratory system is clinically important, and may have additional impact on health and quality of life. The endocrine system is particularly vulnerable to perturbation due to COVID-19 infection, with thyroid dysfunction and hyperglycaemia being widely reported. However, much remains to be investigated regarding the impact of COVID-19 on the endocrine system. Specifically, the trajectory of hyperglycaemia that is well documented in the acute phase remains an important focus of investigation, with clear implications for the future metabolic health of COVID-19 survivors. Additionally, gonadal function appears to be vulnerable to disruption, and remains under-researched particularly in women, despite reports of change to menstruation and reproductive health. Finally, as the long-term effects of COVID-19 become an ever-increasing challenge to healthcare systems, the extent to which endocrine dysfunction contributes to 'Long-COVID' is currently unknown, and thus forms a priority area for future research. 

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Protracted ketonaemia in hyperglycaemic emergencies in COVID-19: a retrospective case series

COVID-19 infection may cause ketosis and ketoacidosis

Comparison of diabetic ketoacidosis in adults during the SARS-CoV-2 outbreak and over the same time period for the preceding 3 years

Type 1 diabetes onset triggered by COVID-19

A c c e p t e d M a n u s c r i p t