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      Клинический случай гипопитуитаризма вследствие гипофизита в периоде реконвалесценции после перенесенной инфекции COVID-19 Translated title: Hypophysitis and reversible hypopituitarism developed after COVID-19 infection — a clinical case report

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          Abstract

          ЦЕЛЬ

          ЦЕЛЬ. Представление первого клинического случая частично обратимого гипопитуитаризма у пациентки с подтвержденным гипофизитом после перенесенной инфекции СOVID-19.

          МАТЕРИАЛЫ И МЕТОДЫ

          МАТЕРИАЛЫ И МЕТОДЫ. У пациентки с клиническими проявлениями гипопитуитаризма после перенесенного СOVID-19 были проанализированы клиническая картина, лабораторные показатели и данные МРТ в динамике.

          РЕЗУЛЬТАТЫ

          РЕЗУЛЬТАТЫ. У пациентки 35 лет развились клинические симптомы гипопитуитаризма через 2 мес после подтвержденной инфекции COVID-19. Лабораторное обследование подтвердило пангипопитуитаризм, на МРТ — признаки гипофизита. Через 4 мес симптомы стали менее выраженными и появились признаки восстановления по лабораторному обследованию: уровни кортизола сыворотки крови, адренокортикотропного гормона, пролактина, тиреотропного гормона, свободных тироксина и трийодтиронина — в норме. Однако гипогонадизм и гипокортицизм сохранялись. По данным МРТ проявления гипофизита уменьшились. Полное восстановление гипофизарно-гонадной и гипофизарно-тиреоидной оси зарегистрировано в октябре 2021 г. с восстановлением менструального цикла, но сохраняется вторичный гипокортицизм.

          ВЫВОДЫ

          ВЫВОДЫ. Приводятся доказательства отсроченного поражения гипофиза после заражения вирусом COVID-19 с частичным восстановлением его функции и структуры. На данный момент механизмы воздействия не совсем понятны, необходим дальнейший сбор данных.

          Translated abstract

          AIM

          AIM. To present a clinical case of reversible hypopituitarism due to hypophysitis developed after COVID-19 infection.

          MATERIALS AND METHODS

          MATERIALS AND METHODS. A patient with residual clinical manifestations of hypopituitarism underwent clinical evaluation at the time of symptoms of hypopituitarism and in follow-up. Morning serum cortisol (171–536 nmol/l) was measured by electrochemiluminescence immunoassay. Morning ACTH (7.2–63.3 pg/ml), prolactin (66–436 mU/l), TSH (0.25–3.5 mIU/L), fT4 (9–19 pmol/l) and fT3 (2.6–5.7 pmol/l) were measured by chemiluminescence immunoassay. Data were analyzed throughout the course of the disease.

          RESULTS

          RESULTS. A 35-year-old female developed clinical symptoms of hypopituitarism two months after recovery from a confirmed COVID-19 infection. Laboratory investigation confirmed hypocorticism, hypothyroidism, hypogonadism and the patient was prescribed appropriate hormonal therapy in January 2021. Four months later the symptoms were alleviated (April 2021) and there were signs of recovery shown by imaging and hormonal: morning serum cortisol 227 nmol/l, morning ACTH 33.96 pg/ml, prolactin 68.3 mU/l, TSH 2.626 mIU/L, fT4 10.75 pmol/l, fT3 3.96 pmol/l. Thyroid hormone was discontinued, but hypogonadism and hypocorticism persisted with estradiol — 51.48 pmol/l, 24h urine cortisol level — 41.8 nmol/day. MRI results showed that the signs of hypophysitis were alleviated in comparison with MRI from January 2021. Full recovery of pituitary axis was reported in October 2021, with recovery of normal menstrual cycle. Furthermore, hormonal profile was likewise normal.

          CONCLUSION

          CONCLUSION. This report provides evidence of delayed damage to the pituitary gland after infection with the COVID-19, with recovery of its function and structure. To date, the mechanisms of such an impact are not entirely clear; further collection of data on such cases and analysis is required.

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          COVID-19 and the endocrine system: exploring the unexplored

          Introduction A novel coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected over 2.3 million people, claiming more than 160000 lives in over 200 countries worldwide. Although COVID-19 can be asymptomatic, the primary presentation in symptomatic patients is in the form of viral pneumonia, sometimes complicated by acute respiratory distress syndrome and/or sepsis. In addition, myocarditis and acute kidney injury have also been described in COVID-19. On the contrary, endocrinological manifestations have not yet been reported in patients with COVID-19. The pathogenesis of COVID-19 entails entry of SARS-CoV-2 via the respiratory system and lodgement in the lung parenchyma. Thereafter, it uses angiotensin-converting enzyme 2 (ACE2) as a receptor for ingress into host pneumocytes. In addition, the viral ribonucleic acid (RNA) has also been detected in the plasma or serum of COVID-19 patients, suggestive of viremia [1]. This implies that apart from pneumocytes, the virus is freely available to interact with ACE2 expressed in other tissues. As a matter of fact, a number of endocrine organs do express ACE2, namely pancreas, thyroid, testis, ovary, adrenal glands and pituitary [2]. Even though one could expect endocrine repercussions due to interaction of SARS-CoV-2 with ACE2 expressed on these organs, there are no clinical/pre-clinical data as of yet. However, based on observations drawn partly from studies pertaining to the prior SARS outbreak (in 2003) and partly from animal models, we aim to explore the possible effects of COVID-19 on the endocrine system. COVID-19 and endocrine pancreas ACE2 is expressed in pancreas with mRNA levels being higher in pancreas than in the lungs. The expression is seen on the exocrine pancreas as well as on the islets. Exocrine pancreatic injury is manifested as elevated serum amylase and/or lipase in 1–2% and 17% of patients with non-severe and severe COVID-19, respectively [2]. Although any major illness can be associated with stress-related hyperglycemia, Yang et al. had reported that patients with SARS (caused by SARS-CoV, the ‘cousin’ of SARS-CoV-2) who had never received glucocorticoids had significantly higher fasting plasma glucose levels as compared to patients with non-SARS pneumonia [3]. In another study, SARS-CoV-mediated damage of the pancreatic β-cells was proposed as the plausible mechanism behind the development of ‘acute diabetes’ in patients with SARS [4]. In fact, immunohistochemistry and in situ hybridization have identified SARS-CoV in the pancreas of patients who died of SARS [5]. Thus, although coronavirus does not feature in the list of viruses implicated in the etiopathogenesis of type 1 diabetes mellitus (T1DM), SARS-CoV (and perhaps SARS-CoV-2) could be potential environmental triggers for the development of T1DM. Apart from direct β-cell damage, alterations in self-antigens and subsequent immune-mediated destruction of β-cells could be implicated. In addition, infection of the surrounding exocrine pancreas by SARS-CoV and SARS-CoV-2 might cause a bystander β-cell death via release of mediators such as tumor-necrosis factor-α (TNFα) and interferon-γ [6]. A systemic pro-inflammatory milieu, as evident by high amounts of interleukin-1β, monocyte chemoattractant protein-1 (MCP-1) and inducible protein-10 even in patients with mild COVID-19 might play an additional role to accentuate the process. COVID-19 could also lead to worsening of insulin resistance in patients with pre-existing type 2 diabetes mellitus (T2DM). Apart from inducing a plethora of cytokines, SARS-CoV increases serum levels of fetuin A, a glycoprotein that has been linked with impaired insulin sensitivity [7]. Lopinavir–ritonavir used for the treatment of COVID-19 could lead to lipodystrophy and subsequent insulin resistance. Moreover, COVID-19 is often associated with hypokalemia; this has been attributed to downregulation of pulmonary ACE2, reduced angiotension-II degradation and subsequent increased aldosterone secretion [8]. Hypokalemia, in turn, can worsen glucose control in patients with pre-existing T1DM and T2DM. The presence of diabetes mellitus in patients with COVID-19 is associated with severe disease, acute respiratory distress syndrome (ARDS) and increased mortality. Possible explanations include compromised innate immunity and downregulated ACE2 levels in people with diabetes mellitus [8]. In addition, serum levels of inflammation-related biomarkers (interleukin-6, serum ferritin, C-reactive protein) and coagulation parameter (D-dimer) are higher in COVID-19 patients with underlying diabetes mellitus compared with those without, suggesting that people with diabetes are more susceptible to cytokine storm ultimately leading to ARDS and rapid deterioration [9]. Hitherto available studies do not make any distinction between T1DM and T2DM and it is likely that the COVID-19-related risks holds true for both the disease entities [10]. Nevertheless, it is imperative that people with diabetes mellitus (T1DM and T2DM) take extra precautions and stringently implement social distancing and hand hygiene amid this pandemic. In addition, good glycemic control should be ensured. Certain anti-diabetic drugs like pioglitazone (via peroxisome proliferator-activated receptor γ activation) and liraglutide (via glucagon-like peptide 1 receptor activation) have been shown to upregulate ACE2 in animal models [11, 12]; however, the current evidence does not support any change in the ongoing medications [13]. Similarly, international organizations recommend patients on ACEi/ARBs to carry on with their medications. Obesity has also been found to be associated with severe disease in COVID-19. Adipose tissue express ACE2; with higher adipose tissue, more would be the overall ACE2 expression that would act as receptors for SARS-CoV-2 [14]. As in diabetes mellitus, even in basal state, obese patients have a higher concentration of several pro-inflammatory cytokines such as TNFα, IL-6 and MCP-1, produced by visceral and subcutaneous adipose tissue [15]. This could again predispose an obese individual to an exaggerated cytokine response in the presence of SARS-CoV-2, manifesting as severe disease and ARDS. In addition, obesity is associated with subclinical hypothyroidism and functional hypogonadism that, at least in part, is mediated by cytokines [16, 17]. These could be aggravated amid a pro-inflammatory milieu induced by COVID-19. COVID-19 and gonads A high level of ACE2 expression is seen in the testes; in fact, the mRNA and protein expression of ACE2 in the testis is almost the highest in the human body. Moreover, the Leydig cells, Sertoli cells and the spermatogonia all express ACE2. Nevertheless, serum testosterone levels in COVID-19 needs to be interpreted cautiously, as any acute critical illness can lead to suppression of the hypothalamic–pituitary–testicular axis, biochemically manifesting as low luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone. However, a recent study in 81 men with COVID-19 showed that serum total testosterone (T) was lower (although not statistically significant), while serum LH was significantly higher as compared to 100 age-matched healthy men. Serum T:LH ratio was also significantly lower in COVID-19 patients and was negatively associated with disease severity [18]. Elevated serum LH in men with COVID-19 negates the possibility of suppression of the hypothalamic–pituitary–testicular axis and hints toward primary Leydig cell damage. In accordance with this observation, it is to be noted that orchitis was indeed a known complication of SARS [19]. In addition, SARS-CoV infection was shown to significantly reduce serum testosterone in male mice [20]. Nevertheless, data on female gonadal function in women with COVID-19 (or SARS) is not available. COVID-19 and adrenal gland One of the primary immunoinvasive strategy utilized by the SARS-CoV, like the influenza virus, is to knock down the host’s cortisol stress response. A very interesting hypothesis that had been proposed is the expression of certain amino acid sequences by the SARS-CoV that are molecular mimics of the host adrenocorticotropic hormone (ACTH). This form of molecular mimicry can indeed blunt the stress-induced cortisol rise, as antibodies produced against the viral particles will inadvertently destroy the circulating ACTH [21]. The fact that most of the SARS-CoV-2 proteins are highly homologous (95–100%) to the proteins of the original SARS-CoV makes us wonder whether SARS-CoV-2 might be employing the same strategy of molecular mimicry as well [22]. Therefore, patients with severe COVID-19 may be more prone to develop critical illness-related corticosteroid insufficiency (CIRCI). Data on cortisol dynamics in patients with COVID-19 are however not yet available. Nevertheless, clinicians must be vigilant about the possibility of an underlying relative cortisol deficiency in patients with COVID-19. Notably, indiscriminate use of short-duration, high-dose glucocorticoids during the SARS outbreak was questioned and not found to be universally useful. One recent study in 31 patients with COVID-19 showed that corticosteroid treatment was not associated with virus clearance time, length of hospital stay or duration of symptoms [23]. Another clinical trial on the efficacy and safety of corticosteroids in COVID-19 is currently underway (NCT04273321). Nevertheless, patients with underlying primary adrenal insufficiency (PAI) are at a high risk of lower-respiratory tract infections and hence should take extra precautions amid the ongoing pandemic. They should be aware of sick-day guidelines and increase the dose of corticosteroids by themselves whenever suspected of having COVID-19 to avoid an impending adrenal crisis. PAI patients developing COVID-19 may require parenteral glucocorticoid support; serum potassium should be strictly monitored in such patients, as hypokalemia has been reported in patients with COVID-19 [8]. COVID-19 and the hypothalamus–pituitary Neurological manifestations do occur in patients with COVID-19 and include, among others, hyposmia. Expression of ACE2 by the olfactory epithelial supporting cells could explain much of these olfactory symptoms [24]. The portal of entry of the virus into the central nervous system (CNS) remains uncertain and could be via hematogenous route or directly thorough the cribriform plate. Hypothalamic and pituitary tissues do express ACE2 and can theoretically be the viral targets. In fact, on autopsy studies, edema and neuronal degeneration along with identification of SARS genome have been shown in the hypothalamus. Biochemical evidence of hypothalamo-pituitary involvement in SARS was first reported by Leow et al. in 2005. Sixty-one survivors of SARS were evaluated at 3 months post-recovery and thereafter periodically. Forty percent of patients had evidence of central hypocortisolism, the majority of which (62.5%) resolved within a year. Of note, 87.5% of those with central hypocortisolism had experienced fatigue and/or postural dizziness at the time of initial recruitment. A small percentage of patients (5%) also had central hypothyroidism. The authors had proposed the possibility of a reversible hypophysitis or a direct hypothalamic damage that could have led to a state of hypothalamo-pituitary dysfunction [25]. Currently, we do not have any such data with regard to patients with COVID-19; however, considering the high frequency of neurological symptoms, one can assume that SARS-CoV-2 may affect the hypothalamus–pituitary as well, directly or via immune-mediated hypophysitis. Accordingly, clinicians should have a low threshold to suspect central hypocortisolism in COVID-19 survivors, especially those complaining of unexplained fatigue, lassitude, malaise, orthostatic dizziness, anorexia and apathy. Patients with pituitary–hypothalamic disorders often have underlying diabetes insipidus (DI); COVID-19 in patients with DI can lead to insensible water loss due to fever and tachypnea ultimately resulting in hypernatremia [26]. Hence, the patient and the treating physician need to be cautious in this regard. COVID-19 and thyroid Data on thyroid involvement by coronavirus is most scarce. A study conducted during the SARS outbreak in 2003 had reported that serum T3 and T4 levels were lower in patients with SARS as compared to controls both during the acute and convalescent phases. This could simply imply an underlying sick-euthyroid syndrome. Intensive care patients with sick-euthyroid syndrome tend to have lower mean thyroid weight as a result of reduction in thyroid follicular size associated with depletion of colloid [27]. However, an autopsy study in five patients with SARS has shown marked destruction of the follicular and parafollicular cells of thyroid [28]. Destruction of follicular cells would manifest as low T3 and T4; parafollicular cell damage would theoretically lead to low levels of serum calcitonin. This has been proposed as a plausible mechanism of osteonecrosis of femoral head seen in recovered patients with SARS; calcitonin deficiency leads to disinhibition of osteoclasts leading to osteonecrosis [28]. Data on thyroid function or thyroid pathology are yet not available in COVID-19. The British Thyroid Association and the Society for Endocrinology (BTA/SfE) have issued a consensus statement regarding issues specific to thyroid dysfunction during COVID-19 pandemic. Patients with underlying hypothyroidism or hyperthyroidism are advised to continue their prescribed medications as usual. However, patients on anti-thyroid drugs (ATDs) are at a risk of agranulocytosis, albeit rarely. Symptoms of agranulocytosis often overlap with those of COVID-19, hence, often making it difficult to differentiate one from the other clinically. Hence, it is recommended that patients on ATDs who develop symptoms suggestive of agranulocytosis should immediately discontinue the drug and get a full blood count done at the earliest. Conclusions Amid the ongoing pandemic, endocrine involvement with COVID-19 remains largely unexplored. The aforementioned data pertaining to COVID-19 and the endocrine system are mostly conjectural and factual at this point of time. Validated conclusions must not be drawn based on the presented data, as much of the observations are based on prior experience with SARS and on recent literature derived from small-scale studies. However, the data do provide ample scope for future research. As premature as it may sound, endocrinologists need to be aware of these possibilities in clinical practice, especially while dealing with COVID-19 survivors.
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            COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology

            Introduction Coronavirus disease 2019 (COVID-19) outbreak requires that endocrinologists from all over Europe move on, even more, to the first line of care of our patients, also in collaboration with other physicians such as those in internal medicine and emergency units. This will preserve the health status and prevent the adverse COVID-19-related outcomes in people affected by different endocrine diseases. People with diabetes in particular are among those in high-risk categories who can have serious illness if they get the virus, according to the data published so far from the Chinese researchers, but other endocrine diseases such as obesity, malnutrition, and adrenal insufficiency may also be impacted by COVID-19. Therefore, since the responsibilities of endocrinologists worldwide due to the current COVID-19 outbreak are not minor we have been appointed by the European Society of Endocrinology (ESE) to write the current statement in order to support the ESE members and the whole endocrine community in this critical situation. In addition, endocrinologists, as any other healthcare worker under the current COVID-19 outbreak, will need to self-protect from this viral disease, which is demonstrating to have a very high disseminating and devastating capacity. We urge Health Authorities to provide adequate protection to the whole workforce of health professionals and to consistently test for COVID-19 the exposed personnel. A decrease in the number of healthcare professionals available for active medical practice in case they contract the disease as it is happening in certain countries, is itself, a threat for the healthcare system and the well-being of our patients. The virus seems to have spread from infected animals and human-to-human transmission is now more than evident, with a high suspicion that non-symptomatic individuals act as the major vectors. It spreads like any other respiratory infectious disease, through contaminated air-droplets that come out of the mouth of infected persons when talking, coughing, or sneezing. The virus can survive in the environment from a few hours to a few days, depending on surfaces and environmental conditions, and touching affected surfaces. The mouth, nose, and ocular mucosa appears to be the major way of transmission. Symptoms of COVID-19 infection General symptoms are relatively nonspecific and similar to other common viral infections targeting the respiratory system, and include fever, cough, myalgia, and shortness of breath. The clinical spectrum of the virus ranges from mild disease with nonspecific signs and symptoms of acute respiratory illness, to severe pneumonia with respiratory failure and septic shock. Possibly, an overreaction of the immune system leading to an autoimmune aggression of the lungs could be involved in the most severe cases of acute distress respiratory syndrome. There have also been reports of asymptomatic infection and research in this matter is currently ongoing worldwide to elucidate the real prevalence of the disease and the true relative mortality ratio. COVID-19 infection and diabetes mellitus Increased risk of morbidity and mortality in patients with diabetes regarding COVID-19 infection Older adults and those with serious chronic medical conditions like heart disease, lung disease, and diabetes are at the highest risk for complications from COVID-19 infection. Chronic hyperglycemia negatively affects immune function and increases the risk of morbidity and mortality due to any infection and is associated to organic complications. This is also the case for COVID-19 infection [1]. During the Influenza A (H1N1) pandemic, the presence of diabetes tripled the risk of hospitalization and quadrupled the risk of ICU admission once hospitalized. Among COVID-19 mortality cases in Wuhan, China, major associated comorbidities included hypertension (53.8%), diabetes (42.3%), previous heart disease (19.2%), and cerebral infarction (15.4%) [2]. In addition, as for seasonal influenza, new data regarding COVID-19 indicate that the infection potentiates myocardial damage and identifies underlying heart disorders as a new risk factor for severe complications and worsening of prognosis [3]. Among the confirmed COVID-19 cases in China by Feb 11, 2020, the overall mortality reported is 2.3% [4]. This data refers mostly to hospitalized patients [4, 5]. Among persons with no underlying medical conditions, the reported mortality in China is 0.9%. There is a lack of data regarding the number of non-symptomatic cases, as in most countries universal microbiological screening has not been performed. It is presumed that the prevalence of the infection is probably high or very high in the community, thus leading to an overestimation of the prevalence of case fatality. However, mortality is strongly increased with the presence of comorbid diseases, including previous cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease, hypertension, and cancer, each at 6%. Among 60-year-old people and older, mortality has been reported to be 14.8% in those >80 years, 8% for those between 70 and 79 years and 3.6% in the group of 60–69 years. Compared with non-ICU patients, critically ill patients are older (median age 66 vs. 51 years) and have more previous comorbidities (72% vs. 37%) [6]. Worldwide mortality rates may vary by region, but this information is not yet consistently available and comparable, as public health policies applied and health registers used in every region of the world are not homogeneous. What people with diabetes should do to prevent infection by COVID-19 Social distancing as well as home confinement of the whole population are now widely adopted in many countries in Europe and worldwide as measures hopefully effective in contrast to the spread of infection. We recommend that due to the increased dangers of developing COVID-19, persons with diabetes should strictly adhere to these preventive measures and adopt them also within their homes in order to avoid being in contact with their relatives. Therefore, under these circumstances, it is recommended that people with diabetes try to plan ahead of time what to do in case they get ill. It is important to maintain a good glycemic control, because it might help reduce the risk of infection itself and may also modulate the severity of the clinical expression of the disease. Contact with healthcare providers, such as endocrinologists in the case of type 1 diabetes, and including also internal medicine specialists and general practitioners for type 2 diabetes patients may be advisable. However, routine appointments in person are not recommended for people with diabetes, as they should avoid crowds (waiting rooms). Therefore, we recommend phone calls, video calls, and emails as the main way for patients to keep in touch with their healthcare provider team, in order to guarantee an optimal control of the disease. Moreover, it is advised to ensure adequate stock of medications and supplies for monitoring blood glucose during the period of home confinement. What people with diabetes should do if they are infected by COVID-19 People with diabetes who are infected with COVID-19 may experience a deterioration of glycemic control during the illness, like in any other infectious episodes. Implementation of “Sick day rules” is therefore mandatory to overcome potential diabetes decompensation. Contacting the healthcare provider team by telephone, email, or videoconference is also mandatory in case of possible symptoms of COVID-19 infection in order to seek advice concerning the measures to avoid risk of deterioration of diabetes control or the possibility to be referred to another specialist (pneumologist or infectious disease doctor) or in the Emergency Services of the referral hospital to avoid the most serious systemic complication of the viral infection itself. COVID-19 and other endocrine and metabolic disorders Obesity There is a general lack of data regarding the impact of COVID -19 in people suffering from obesity. However, as for what is currently being the experience in some hospitals in Spain, cases of young people in which severe obesity is present may evolve toward destructive alveolitis with respiratory failure and death (Puig-Domingo M, personal experience). There is no current explanation for this clinical presentation, although it is well known that severe obesity is associated to sleep-apnea syndrome, as well as to surfactant dysfunction, which may contribute to a worse scenario in the case of COVID-19 infection. Also, deterioration of glycemic control is associated with an impairment of ventilatory function and thus may contribute to a worse prognosis in these patients. In addition, type 2 diabetes and obesity may concur in a given patient, which typically is also frequently accompanied by an age >65. In summary, these patients may be at a higher risk of impaired outcomes in the case of COVID-19 infection. Undernourishment Regarding undernourished subjects, COVID-19 infection is associated to a high risk of malnutrition development, mostly related to increased requirements and the presence of a severe acute inflammatory status. These patients show also a hyporexic state, thus contributing to a negative nutritional balance. Estimated nutritional requirements are 25–30 kcal/kg of weight and 1.5 g protein/kg/day [7]. A nutrient dense diet is recommended in hospitalized cases including high protein supplements (2–3 intakes per day) containing at least 18 g of protein per intake. Adequate supplementation of vitamin D is recommended particularly in areas with large known prevalence of hypovitaminosis D and due to the decreased sun exposure [8, 9]. If nutritional requirements are not met, complementary or complete enteral feeding may be required, and in case that enteral feeding may not be possible due to inadequate gastrointestinal tolerance, the patient should be put on parenteral nutrition. COVID-19 patients’ outcome is expected to improve with nutritional support [10]. Adrenal insufficiency Adrenal insufficiency is a chronic condition of lack of cortisol production. Live-long replacement treatment aiming to mimic physiologic plasma cortisol concentrations is not easy for these patients. Based on current data, there is no evidence that patients with adrenal insufficiency are at increased risk of contracting COVID-19. However, it is known that patients with Addison’s disease (primary adrenal insufficiency) and congenital adrenal hyperplasia have a slightly increased overall risk of catching infections. Moreover, primary adrenal insufficiency is associated to an impaired natural immunity function with a defective action of neutrophils and natural killer cells [11]. This may explain, in part, this slightly increased rate of infectious diseases in these patients, as well as an overall increased mortality. This latter could also be accounted by an insufficient compensatory increase of the hydrocortisone dosage at the time of the beginning of an episode of infection. For all these reasons, patients with adrenal insufficiency may be at higher risk of medical complications and eventually at increased mortality risk in the case of COVID-19 infection. So far, there are no reported data on the outcomes of COVID-19 infection in adrenal insufficient subjects. In the case of suspicion of COVID-19, a prompt modification of the replacement treatment as indicated for the “Sick days” should be established when minor symptoms appear. This means in the first instance to at least double the usual doses of glucocorticoid replacement, to avoid adrenal crisis. In addition, patients are also recommended to have sufficient stock at home of steroid pills and injections in order to maintain the social confinement that is required in most of the countries for impeding the COVID-19 outbreak spread. Actions to be taken if infection by COVID-19 is suspected If a person with endocrine and metabolic diseases has fever with cough or trouble breathing and may have been exposed to COVID-19 (if living in or visited a country affected in the 14 days before getting sick, or if having been around a person who may have had the virus), a call to the physician or nurse for advice should be made. Some countries have set up COVID-19 phone lines for the public. The personnel in charge of these phone lines will prioritize arrangements, if needed, regarding what should be the next step in the healthcare protocol. If the person is advised to go to the hospital, it is recommended to put on a face mask. In countries with explosive outbreak, most of the people have already bought a face mask by their own initiative. Fluid samples taken from the nose or throat will be used for microbiologic diagnosis. There is currently no specific treatment for COVID-19, but since the majority of cases are mild, only a limited amount of people will require hospitalization for supportive care. However, in most of the countries in which the outbreak has been declared and recognized, particularly in China, the Northern regions of Italy, Iran, and Spain, the situation has been very challenging and the requirement of hospitalization has led national health systems to the limit of their capacities [12]. What to do in case of confinement at home? Individuals and families affected or suspected to be affected by COVID-19 that stay at home should follow proper measures for infection prevention and control. Management should focus on prevention of transmission to others and monitoring for clinical deterioration, which may prompt hospitalization. Affected persons should be placed in a well-ventilated single room, while household members should stay in a different room or, if that is not possible, maintain a distance of at least one meter from the person affected (e.g., sleep in a separate bed) and perform hand hygiene (washing hands with soap and water) after any type of contact with the affected person or their immediate environment. When washing hands, it is preferable to use disposable paper towels to dry them. If these are not available, clean cloth towels should be used and replaced when wet. To contain respiratory secretions, a medical mask should be provided to the person affected and worn as much as possible. Individuals who cannot tolerate a medical mask should use rigorous respiratory hygiene—i.e., the mouth and nose should be covered with a disposable paper tissue when coughing or sneezing. Caregivers should also wear a tightly fitted medical mask that cover their mouth and nose when in the same room is present the person affected. Conclusions An ESE “decalog” for endocrinologists in the COVID-19 pandemic Adequately protect yourself and ask for COVID-19 testing if exposed. Avoid unnecessary routine appointments in person. Put in place online/email/phone consultation services. Closely monitor glycemic control in patients with diabetes. Recommend to persons with diabetes a strict adherence to general preventive measures. Counsel persons with diabetes about specific measures related to their disease management (sick day rules) in case of infection by COVID-19. Counsel persons with diabetes particularly if aged over 65 and obese about referrals for management in case of suspected infection by COVID-19. Avoid undernourishment with dietary or adjunctive measures if clinically indicated. Closely monitor clinical conditions of patients with adrenal insufficiency. Adapt increased replacement treatment if clinically indicated in patients with adrenal insufficiency.
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              MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and treatment

              Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.
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                Author and article information

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                Journal
                Probl Endokrinol (Mosk)
                Probl Endokrinol (Mosk)
                problendo
                Problems of Endocrinology
                Endocrinology Research Centre
                0375-9660
                2308-1430
                2022
                24 March 2022
                : 68
                : 3
                : 50-56
                Affiliations
                [-1]Национальный медицинский исследовательский центр эндокринологии
                [-2]Национальный медицинский исследовательский центр эндокринологии
                [-3]Национальный медицинский исследовательский центр эндокринологии
                [-4]Национальный медицинский исследовательский центр эндокринологии
                Article
                10.14341/probl12896
                9762539
                35841168
                b4173c2c-26c5-44c9-9b52-b1c409498242
                Copyright © Endocrinology Research Centre, 2022

                This work is licensed under a Creative Commons Attribution 4.0 License.

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