Liver function in transgender persons: Challenges in the COVID-19 era.

Transgender persons constitute a non-negligible percentage of the general population. Physical gender-transitioning in trans persons is mainly achieved with hormonal cross-sex therapy and sex reassignment surgeries that aim to align bodily appearance with gender identity. Hormonal treatment acts via suppressing the secretion of the endogenous sex hormones and replacing them with the hormones of the desired sex. The administration of testosterone is the typical masculinizing treatment in trans men, whilst trans women are routinely treated with estradiol agents in combination with anti-androgens or gonadotrophin-releasing hormone agonists if testes are present. Exogenous androgenic steroids, estradiol agents, and anti-androgens have been implicated in a series of hepatotoxic effects. Thus, liver integrity is a major concern with the long-term administration of cross-sex therapy. Hepatic tissue is susceptible to coronavirus disease 19 (COVID-19) through various pathophysiological mechanisms. Special consideration should be paid to minimize the risk of hepatic damage from the potential cumulative effect of COVID-19 and gender-affirming treatment in transgender patients. Appropriate care is significant, with continuous laboratory monitoring, clinical observation and, if needed, specific treatment, especially in severe cases of infection and in persons with additional liver pathologies. The pandemic can be an opportunity to provide equal access to care for all and increase the resilience of the transgender population.

Pandemic and precocious puberty - a Google trends study.

BACKGROUND: Recent publications from several countries have reported that more young people (mainly girls) are experiencing precocious puberty (PP)/menarche during the coronavirus disease 2019 pandemic compared to the past. This variation is attributed to the stress of confinement, lack of exercise, obesity and disturbed sleep patterns. A common feature of the relevant papers, however, is the small number of reported cases of PP. Studies have shown that searches for diseases on the internet also reflect to some extent the epidemiology of these diseases. AIM: To estimate, through internet searches for PP, any changes in the epidemiology of PP. METHODS: We assessed in Google Trends searches for 21 PP-related terms in English internationally (which practically dwarf searches in other languages), in the years 2017-2021. Additionally, we assessed local searches for selected terms, in English and local languages, in countries where a rise in PP has been reported. Searches were collected in Relative Search Volumes format and analyzed using Kendall's Tau test, with a statistical significance threshold of P < 0.05. RESULTS: Internationally, searches for three PP-related terms showed no noticeable change over the study period, while searches for eight terms showed a decrease. An increase was found over time in searches for nine PP-related terms. Of the 17 searches in English and local languages, in countries where a rise in PP has been reported, 5 showed a significant increase over time. CONCLUSION: Over the study period, more than half of the search terms showed little change or declined. The discrepancy between internet searches for PP and the reported increase in the literature is striking. It would be expected that a true increase in the incidence of PP would also be aptly reflected in Google trends. If our findings are valid, the literature may have been biased. The known secular trend of decreasing age of puberty may also have played a role.

The Mediating Role of Depression and of State Anxiety οn the Relationship between Trait Anxiety and Fatigue in Nurses during the Pandemic Crisis.

The coronavirus pandemic (COVID-19) is a global health crisis with a particular emotional and physical impact on health professionals, especially nurses. The aim of this study was to investigate the prevalence of anxiety, depression and fatigue and their possible relationships among nurses during the pandemic. The study population consisted of nurses from five tertiary-level public hospitals in Athens who completed the Fatigue Assessment Scale (FAS), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) questionnaires. Gender, age and years of work experience were recorded. The study was conducted from mid-November to mid-December 2021. The sample included 404 nurses (69 males and 335 females) with a mean age of 42.88 years (SD = 10.90) and 17.96 (SD = 12.00) years of work experience. Symptoms of fatigue were noted in 60.4% of participants, while 39.7% had symptoms of depression, 60.1% had abnormal scores on state anxiety and 46.8% on trait anxiety, with females showing higher scores on all scales (p < 0.05). High positive correlations (p < 0.01) were found between the FAS, BDI, State Anxiety and Trait Anxiety scales. Regression analysis showed that 51.7% of the variance in FAS scores can be explained by trait anxiety, an additional 6.2% by the BDI and 1.2% by state anxiety. Mediation analysis showed that state anxiety and BDI mediate the relationship between trait anxiety and FAS. Finally, BDI was found to exert a moderating role in the relationship between trait anxiety and fatigue. In conclusion, our study showed that nurses continue to experience high rates of anxiety, depression and fatigue. The variation in fatigue appears to be significantly dependent on trait anxiety. Depressive symptomatology and state anxiety exert a parallel positive mediation on the relationship between trait anxiety and fatigue, with depression exhibiting a moderating role in this relationship.

Endocrine Aspects of ICU-Hospitalized COVID-19 Patients.

The unprecedented scale of the current SARS-CoV-2/COVID-19 pandemic has led to an extensive-yet fragmented-assessment of its endocrine repercussions; in many reports, the endocrine aspects of COVID-19 are lumped together in intensive care unit (ICU) patients and non-ICU patients. In this brief review, we aimed to present endocrine alterations in ICU-hospitalized patients with COVID-19. There are tangible endocrine disturbances that may provide fertile ground for COVID-19, such as preexisting diabetes. Other endocrine disturbances accompany the disease and more particularly its severe forms. Up to the time of writing, no isolated robust endocrine/hormonal biomarkers for the prognosis of COVID-19 have been presented. Among those which may be easily available are admission glycemia, thyroid hormones, and maybe (OH)25-vitamin D3. Their overlap among patients with severe and less severe forms of COVID-19 may be considerable, so their levels may be indicative only. We have shown that insulin-like growth factor 1 may have prognostic value, but this is not a routine measurement. Possibly, as our current knowledge is expanding, the inclusion of selected routine endocrine/hormonal measurements into artificial intelligence/machine learning models may provide further information.

Further understanding of thyroid function in pregnant women.

INTRODUCTION: Normal thyroid status throughout pregnancy is important for both maternal and fetal health. Despite the bulk of contemporary research honing on thyroid function in gestation and the relevant disorders, there are still gaps in our current knowledge about the etiology and treatment of thyroid diseases in pregnant women. AREAS COVERED: This article analyzes the adaptation of the thyroid gland to gestational physiological changes and attempts to explain the effect of several factors on thyroid function in pregnancy. It also stresses proper utilization and interpretation of thyroid tests during pregnancy and underlines the significance of proper screening and treatment of pregnant women aiming at favorable health outcomes. EXPERT OPINION: Appropriate strategies for diagnosing and treating thyroid disease in pregnancy are important. Laboratory thyroid testing plays a leading role, but test results should be interpreted with caution. Given the possible serious maternal and fetal/neonatal complications of thyroid disease in pregnancy, we recommend universal screening with TSH measurements of all pregnant women. Additional assessment with determination of the levels of free thyroid hormones and thyroid antibodies may be necessary under certain conditions. The economic burden of such interventions should be considered.

Testosterone, free, bioavailable and total, in patients with COVID-19.

BACKGROUND: Low testosterone (mainly total testosterone [TTe]) has been noted in patients with COVID-19. Calculated free testosterone (FTe) and bioavailable testosterone (BavTe) may reflect more accurately this hormone's levels. In this study, we sought to assess TTe, FTe as well as BavTe in male patients with COVID-19. METHODS: Sera were collected upon admission from 65 men (10 in the intensive care units [ICU] and 55 in the wards) with polymerase chain reaction - proven COVID-19. A group of age-matched COVID-19-negative men (N.=29) hospitalized in general medical wards served as controls. Age, Body Mass Index (BMI) and 28-day mortality were noted. Measurements included TTe, sex-hormone binding globulin, albumin (the latter two for calculating FTe and BavTe) and laboratory markers of inflammation (white blood cell count [WBC], D-Dimers [D-D], lactate dehydrogenase [LDH], ferritin [Fer] and C-reactive protein [CRP]). RESULTS: Profoundly low TTe, FTe and BavTe were noted in most patients, and were associated with disease severity/outcome (being the lowest in COVID-19 patients in the ICU and overall being lower in non-survivors; analysis of covariance P<0.05). Pearson's correlations for logTe, logFTe or logBavTe versus WBC, D-D, LDH, Ferr or CRP were negative, ranging from -0.403 to -0.293 (P=0.009 to 0.014). CONCLUSIONS: TTe, FTe and BavTe are prone to be low in patients with COVID-19, are negatively associated with disease severity and may be considered to have prognostic value.

COVID-19 and thyroid disease: An infodemiological pilot study.

BACKGROUND: Google Trends searches for symptoms and/or diseases may reflect actual disease epidemiology. Recently, Google Trends searches for coronavirus disease 2019 (COVID-19)-associated terms have been linked to the epidemiology of COVID-19. Some studies have linked COVID-19 with thyroid disease. AIM: To assess COVID-19 cases per se vs COVID-19-associated Google Trends searches and thyroid-associated Google Trends searches. METHODS: We collected data on worldwide weekly Google Trends searches regarding "COVID-19", "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)", "coronavirus", "smell", "taste", "cough", "thyroid", "thyroiditis", and "subacute thyroiditis" for 92 wk and worldwide weekly COVID-19 cases' statistics in the same time period. The study period was split in half (approximately corresponding to the preponderance of different SARS-COV-2 virus variants) and in each time period we performed cross-correlation analysis and mediation analysis. RESULTS: Significant positive cross-correlation function values were noted in both time periods. More in detail, COVID-19 cases per se were found to be associated with no lag with Google Trends searches for COVID-19 symptoms in the first time period and in the second time period to lead searches for symptoms, COVID-19 terms, and thyroid terms. COVID-19 cases per se were associated with thyroid-related searches in both time periods. In the second time period, the effect of "COVID-19" searches on "thyroid' searches was significantly mediated by COVID-19 cases (P = 0.048). CONCLUSION: Searches for a non-specific symptom or COVID-19 search terms mostly lead Google Trends thyroid-related searches, in the second time period. This time frame/sequence particularly in the second time period (noted by the preponderance of the SARS-COV-2 delta variant) lends some credence to associations of COVID-19 cases per se with (apparent) thyroid disease (via searches for them).

Novel appearance of hyperglycemia/diabetes, associated with COVID-19.

In a recent meta-analysis the prevalence of coronavirus disease 2019 (COVID-19)-associated hyperglycemia was 25%, and that of COVID-19-associated new-onset diabetes was 19%. An association between hyperglycemia or new-onset diabetes and COVID-19 has been suggested. In a recent relevant study of critically and non-critically ill patients with COVID-19, we found that indeed beta-cell function was compromised in critically ill patients with COVID-19 and that these patients showed a high glycemic gap. Nevertheless, one quarter of critically ill patients with no history of diabetes have stress hyperglycemia, a finding which could obscure the prevalence of hyperglycemia or new-onset diabetes that could be attributed to COVID-19 per se.

Metformin: Sex/Gender Differences in Its Uses and Effects-Narrative Review.

Metformin (MTF) occupies a major and fundamental position in the therapeutic management of type 2 diabetes mellitus (T2DM). Gender differences in some effects and actions of MTF have been reported. Women are usually prescribed lower MTF doses compared to men and report more gastrointestinal side effects. The incidence of cardiovascular events in women on MTF has been found to be lower to that of men on MTF. Despite some promising results with MTF regarding pregnancy rates in women with PCOS, the management of gestational diabetes, cancer prevention or adjunctive cancer treatment and COVID-19, most robust meta-analyses have yet to confirm such beneficial effects.

Nursing staff fatigue and burnout during the COVID-19 pandemic in Greece.

INTRODUCTION: The coronavirus pandemic (COVID-19) is an unprecedented global health crisis with emotional and physical impact on health care workers. OBJECTIVE: The purpose of this study was to investigate the levels of fatigue and burnout in nursing staff during the pandemic. METHODS: The present study involved nursing staff from hospitals in Greece in February 2021, who completed the Fatigue (FAS) and Burnout (CBI) questionnaires. Gender, age, years of work experience, workplace (COVID-19 or non-COVID-19 wards) and SARS-CoV-2 infection status were recorded. RESULTS: The sample included 593 women and 108 men, with a mean age ± SD: 42.9 ± 9.9 years and 18.14 ± 10.8 years work experience. Slightly more than half, (367, 52.4%) worked in COVID-19 departments. Fifty-six (8%) tested positive for SARS-CoV-2 and 14 of them needed to be treated. The mean ± SD FAS and CBI scores were 25.6 ± 7.4 and 46.9 ± 18.8, respectively (67.9% and 42.9% had scores suggestive of fatigue and burnout, respectively). Women showed higher values in both scales (p < 0.01). Subjects working in COVID-19 wards scored significantly higher on both the FAS and CBI scales; they were also younger and with less work experience (p < 0.01). Staff treated for COVID-19 scored higher on the burnout scale (p < 0.01) than the uninfected staff. Fatigue showed a strong positive correlation with burnout (p < 0.01, r = 0.70). Stepwise multiple regression showed that the variation of fatigue was explained by 47.0% and 6.1% by the scores on the subscales of personal and work-related burnout, respectively. CONCLUSION: In conclusion, high rates of fatigue and burnout were found in the studied population. Nurses working with COVID-19 patients had higher rates of fatigue and burnout compared to those working elsewhere. There was a strong positive correlation (r = 0.70) between burnout and fatigue. Particular attention should be paid to staff who became ill and need to be treated.

Increased Glucocorticoid Receptor Alpha Expression and Signaling in Critically Ill Coronavirus Disease 2019 Patients.

OBJECTIVES: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking. DESIGN: Prospective observational study. SETTING: One academic multidisciplinary ICU. SUBJECTS: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 µg/dL, p < 0.01) compared with the control group. CONCLUSIONS: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins.

Pituitary-Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19.

The hypothalamus-pituitary-adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).

Inherited/Genetically-Associated Pheochromocytoma/ Paraganglioma Syndromes and COVID-19.

In some subjects with inherited pheochromocytoma/paraganglioma (PPG) syndromes, hypoxia-inducible factor 1 alpha (HIF1α) stabilization/activation could lead to an increase in angiotensin converting enzymes (ACE). This would result in the stimulation of angiotensin (AT) II production and, hence, reduce the availability of ACE 2. The latter would provide decreased numbers of binding sites for the spike protein of SARS-CoV-2 and, therefore, result in less points of viral entry into cells. Thus, subjects with HIF1α-associated PPG syndromes may benefit from an inherent protective effect against COVID-19. Such an implication of HIF1α vis-à-vis COVID-19 could open ways of therapeutic interventions.

Dream Recall/Affect and the Hypothalamic-Pituitary-Adrenal Axis.

In this concise review, we present an overview of research on dream recall/affect and of the hypothalamic-pituitary-adrenal (HPA) axis, discussing caveats regarding the action of hormones of the HPA axis (mainly cortisol and its free form, cortisol-binding globulin and glucocorticoid receptors). We present results of studies regarding dream recall/affect and the HPA axis under physiological (such as waking) or pathological conditions (such as in Cushing's syndrome or stressful situations). Finally, we try to integrate the effect of the current COVID-19 situation with dream recall/affect vis-à-vis the HPA axis.

Thyroid hormone alterations in critically and non-critically ill patients with SARS-CoV-2 infection.

OBJECTIVE: Following the evolution of COVID-19 pandemic, reports pointed on a high prevalence of thyroiditis-related thyrotoxicosis. Interpretation of thyroid tests during illness, however, is hampered by changes occurring in the context of non-thyroidal illness syndrome (NTIS). In order to elucidate these findings, we studied thyroid function in carefully selected cohorts of COVID-19 positive and negative patients. DESIGN: Cohort observational study. METHODS: We measured TSH, FT4, T3 within 24 h of admission in 196 patients without thyroid disease and/or confounding medications. In this study, 102 patients were SARS-CoV-2 positive; 41 admitted in the ICU, 46 in the ward and 15 outpatients. Controls consisted of 94 SARS-CoV-2 negative patients; 39 in the ICU and 55 in the ward. We designated the thyroid hormone patterns as consistent with NTIS, thyrotoxicosis and hypothyroidism. RESULTS: A NTIS pattern was encountered in 60% of ICU and 36% of ward patients, with similar frequencies between SARS-CoV-2 positive and negative patients (46.0% vs 46.8%, P = NS). A thyrotoxicosis pattern was observed in 14.6% SARS-CoV-2 ICU patients vs 7.7% in ICU negative (P = NS) and, overall in 8.8% of SARS-CoV-2 positive vs 7.4% of negative patients. In these patients, thyroglobulin levels were similar to those with normal thyroid function or NTIS. The hypothyroidism pattern was rare. CONCLUSIONS: NTIS pattern is common and relates to the severity of disease rather than SARS-CoV-2 infection. A thyrotoxicosis pattern is less frequently observed with similar frequency between patients with and without COVID-19. It is suggested that thyroid hormone monitoring in COVID-19 should not differ from other critically ill patients.

Covid-19 and Growth Hormone/Insulin-Like Growth Factor 1: Study in Critically and Non-Critically Ill Patients.

Objective: We aimed to measure insulin-like growth factor 1 (IGF1) and growth hormone (GH) in critically and non-critically ill patients with Covid-19 and assess them vis-a-vis clinical and laboratory parameters and prognostic tools. Subjects and Methods: We included patients who were admitted to the wards or the ICU of the largest Covid-19 referral hospital in Greece; patients with non-Covid-19 pneumonia served as controls. Apart from the routine laboratory work-up for Covid-19 we measured GH and IGF1 (and calculated normalized IGF-1 values as standard deviation scores; SDS), after blood sampling upon admission to the wards or the ICU. Results: We studied 209 critically and non-critically ill patients with Covid-19 and 39 control patients. Patients with Covid-19 who were ICU non-survivors were older and presented with a worse hematological/biochemical profile (including white blood cell count, troponin, glucose, aminotransferases and lactate dehydrogenase) compared to ICU survivors or Covid-19 survivors in the wards. Overall, IGF-1 SDS was higher in Covid-19 survivors compared to non-survivors (-0.96 ± 1.89 vs -2.05 ± 2.48, respectively, p=0.030). No significant differences were noted in GH between the groups. Nevertheless, in critically ill patients with Covid-19, the prognostic value of IGF-1 (raw data), IGF-1 (SDS) and GH for survival/non-survival was on a par with that of APACHE II and SOFA (with a marginal difference between GH and SOFA). Conclusion: In conclusion, our findings suggest that there might be an association between low IGF1 (and possibly GH) and poor outcome in patients with Covid-19.

COVID-19 and hyperglycemia/diabetes.

In early studies regarding coronavirus disease 2019 (COVID-19), type 2 diabetes mellitus was considered to contribute substantially to the disease's inflammatory response. Subsequently, even hyperglycemia, regardless of insulin resistance or diabetes mellitus, was found to be additionally harmful. Recent studies have shown inflammation of the pancreatic ß cells in COVID-19, even leading to new onset diabetes mellitus. We hereby summarize core literature on glycemia and COVID-19, and present implicated pathways and mechanisms.

Polycystic ovary syndrome: Pathways and mechanisms for possible increased susceptibility to COVID-19.

In 75% of women with polycystic ovary syndrome (PCOS), insulin action is impaired. In obesity, visceral adipose tissue becomes dysfunctional: Chronic inflammation is favored over storage, contributing to the development of metabolic complications. PCOS, metabolic syndrome (MetSy) and non-alcoholic fatty liver disease (NAFLD) apparently share common pathogenic factors; these include abdominal adiposity, excess body weight and insulin resistance. Alterations in the gut microbiome have been noted in women with PCOS compared to controls; these may lead to deterioration of the intestinal barrier, increased gut mucosal permeability and immune system activation, hyperinsulinemia and glucose intolerance, which hamper normal ovarian function and follicular development (all being hallmarks of PCOS). It has been proposed that PCOS may entail higher susceptibility to coronavirus disease 2019 (COVID-19) via its associated comorbidities (NAFLD, obesity, MetSy and alterations in the gut microbiome). Studies have found an association between acute respiratory distress syndrome (seen in severe cases of COVID-19) and the intestinal microbiome. Furthermore, apparently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can gain entry to the gastrointestinal tract via locally-expressed angiotensin converting enzyme type 2 receptors. Excess body weight is associated with more severe COVID-19 and increased mortality. Although robust links between SARS-CoV-2 infection and PCOS/NAFLD/gut microbiome/metabolic consequences are yet to be confirmed, it seems that strategies for adapting the intestinal microbiome could help reduce the severity of COVID-19 in women with PCOS with or without NAFLD, MetSy or obesity.

Post-Traumatic Stress Disorder and Burnout in Healthcare Professionals During the SARS-CoV-2 Pandemic: a Cross-Sectional Study.

INTRODUCTION: Healthcare professionals who are directly involved in the diagnosis, treatment, and general care of patients with SARS-CoV-2 are at risk of developing adverse psychological reactions. A cross-sectional study of healthcare professionals aimed to determine the impact of the SARS-CoV-2 pandemic on the mental health of healthcare professionals in two of the largest referral hospitals in Athens, Greece. METHODS: The study was conducted in the two largest SARS-CoV-2 referral hospitals in Athens, Greece. An assessment and the interrelationship of post-traumatic stress disorder, using the Impact of Event Scale-Revised [IES-R]) and burnout, using the Maslach Burnout Inventory [MBI]) was carried out. RESULTS: A total of 162 subjects were enrolled in the study. Fifty-six (35%) had an IES-R score > 33, suggesting post-traumatic stress disorder. Forty-nine (30%) had an MBI score > 27. Seventy-five (46%) had a personal accomplishment score of < 33 and 46 (28%) had a depersonalization score >10. Stepwise backward logistic regression revealed that the only independent variable that was retained regarding the presence of post-traumatic stress disorder was the emotional exhaustion score of the MBI (at a cut-off of 24 in this scale, the 95% CI of the odds ratio for the presence of post-traumatic stress disorder was 1.077-1.173). CONCLUSIONS: In this sample of first-line Greek healthcare professionals against SARS-CoV-2, most of them were proven to be quite resilient to this challenge. One-third of them had post-traumatic stress disorder, which depended on their degree of emotional exhaustion. Healthcare professionals, as represented by this study, performed their duties without feeling helpless and developing adverse psychological reactions.