Differences in COVID-19 mortality in males and females: is estrogen hormone attributing to sex differences?

OBJECTIVES: Globally, the case fatality ratio is more in males versus females. Some studies have suggested estrogen hormone decreases susceptibility to SARS CoV-2. We have analyzed the observed sex differences in COVID-19 behavior in males and females and the clinical profiles of females of different age groups of COVID-19 patients and discussed their symptoms, laboratory evaluations, and associated comorbidities. MATERIAL AND METHODS: The patients were tested for COVID-19 through real-time RT-PCR (Reverse Transcription Polymerase Chain Reaction) assay. The data obtained were studied for the epidemiological, clinical, and laboratory characteristics from their medical records. RESULTS: The mortality rate in females was 12.33% (36/292) whereas mortality in males was 19.63% (84/428). In between group analysis, 8.7% (14/161) of females died in the <40 years age group versus 16.8% (22/131) in more than 40 years age group whereas in males, the mortality was 13.7% (21/153) in <40 years versus 22.9%(63/275). The mortality rate in women older than 40 years was greater than mortality in younger females emphasizing the protection provided by estrogen hormone in them. The proportion of patients who expired due to COVID-19 significantly differs by age cutoff of 40 years, X2 (1, n=428). The difference is statistically significant at P < 0.05. Males more than 40 years are more likely to expire. CONCLUSION: Sex-related differences in coronavirus pandemic have been found pointing toward the protective role of estrogen hormone and other differences in immunological behavior in males and females. Downregulation of ACE2 expression, thereby reducing viral entry, might also be contributory to decreasing mortality in females.

Post-COVID Parosmia in Women May be Associated with Low Estradiol Levels.

We aimed to investigate the effects of female gender hormones on post-COVID parosmia in females. Twenty-three female patients aged 18-45 who had COVID-19 disease in the last 12 months were included in the study. Estradiol (E2), prolactin (PRL), luteotrophic hormone (LH), follicular stimulating hormone (FSH), and thyroid stimulating hormone (TSH) values were measured in the blood of all participants and a parosmia questionnaire was applied for the subjective evaluation of olfactory function. Values between 4 and 16 were obtained as parosmia score (PS), and the lowest PS showed the most severe complaint. The mean age of the patients was 31 (18-45). According to the PS, patients with a score of 10 or less were classified as Group 1, and patients above 10 were considered Group 2. The age difference between Groups 1 and 2 was statistically significant and younger patients were found to have more complaints of parosmia (25 and 34, respectively, p-value 0.014). It was found that patients with severe parosmia had lower E2 values and there was a statistically significant difference (p-value 0.042) between groups 1 and 2 in terms of E2 values (34 ng/L and 59 ng/L, respectively). There was no significant difference between the two groups in terms of PRL, LH, FSH, TSH levels, or FSH/LH ratio. It may be recommended to measure E2 values in female patients whose parosmia continues after COVID-19 infection. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-03612-9.

Potential immunological effects of gender-affirming hormone therapy in transgender people - an unexplored area of research.

There are well-described sex-based differences in how the immune system operates. In particular, cisgender (cis) females have a more easily activated immune system; associated with an increased prevalence of autoimmune diseases and adverse events following vaccinations. Conversely, cis males have a higher threshold for immune activation, and are more prone to certain infectious diseases, such as coronavirus disease (COVID-19). Oestrogen and testosterone have immune-modulatory properties, and it is likely that these contribute to the sexual dimorphism of the immune system. There are also important immune-related genes located on the X chromosome, such as toll-like receptor (TLR) 7/8; and the mosaic bi-allelic expression of such genes may contribute to the state of immune hyperactivation in cis females. The scientific literature strongly suggests that sex-based differences in the functioning of the immune system are related to both X-linked genes and immune modulation by sex hormones. However, it is currently not clear how this impacts transgender (trans) people receiving gender-affirming hormonal therapy. Moreover, it is estimated that in Australia, at least 2.3% of adolescents identify as trans and/or gender diverse, and referrals to specialist gender-affirming care are increasing each year. Despite the improving social awareness of trans people, they remain chronically underrepresented in the scientific literature. In addition, a small number of case studies describe new onset autoimmune disorders in adult trans females following oestrogen use. However, there is currently minimal long-term research with an immunological focus on trans people. Therefore, to ensure the positive health outcomes of trans people, it is crucial that the role of sex hormones in immune modulation is investigated further.

Premenopausal and postmenopausal women during the COVID-19 pandemic.

The current global COVID-19 mortality rate is estimated to be around 3.4%; however, it is dependent on age, sex, and comorbidities. Epidemiological evidence shows gender disparities in COVID-19 severity and fatality, with non-menopausal females having milder severity and better outcomes than age-matched males. However, the difference vanishes when comparing postmenopausal women with age-matched men. It has been suggested that, to some extent, this is due to the protective role of female hormones, such as anti-Müllerian hormone and oestradiol (E2), in non-menopausal women. Oestrogens have been hypothesized to be crucial in modulating viral infection and the progression of the disease via an action on immune/inflammatory responses and angiotensin-converting enzyme type 2 expression. Hence, the most likely explanation is that, because the levels of oestrogen in females after menopause decrease, oestrogen no longer offers a beneficial effect as seen in younger females. The COVID-19 pandemic has highlighted the serious negative effects arising from the state of E2 deficiency. Therefore, hormone replacement therapy gains further support as the damaging effect of the decline in ovarian function affects many biological systems, and recently with the COVID-19 pandemic, oestrogen's vital role within the immune system has become quite clear. However, additional clinical investigations regarding hormone replacement therapy are urgently needed to further verify the protective and therapeutic effects of E2 on menopausal women with COVID-19.

Bioboard

The following topics are under this section:ASIA-PACIFIC — Identification of Therapeutic Points for Genetically Diverse and Fatal LeukaemiaASIA-PACIFIC — Novel Microfluidic Processes for Drug DevelopmentASIA-PACIFIC — Development of Anti-Microbial Coating against COVID-19ASIA-PACIFIC — Partnership between Arcturus Therapeutics and Duke-NUS Medical School to develop COVID-19 VaccineASIA-PACIFIC — Nanoscopic Insights to Proteins against Huntington’s DiseaseASIA-PACIFIC — Unravelling the Impact of Marine Heatwave on Coral Reef FishesASIA-PACIFIC — Regulation of Plant Pores by MicroRNAsASIA-PACIFIC — Discovering Clues to Longevity in Our GenomeASIA-PACIFIC — Repurposing Nature’s Products to Viable MaterialsASIA-PACIFIC — Reverse Conversion of Oestrogens to AndrogensREST OF THE WORLD — HER2-targeted Antibody Drug Conjugate Shows Promise in Patients with Non-Breast-Gastric CancersREST OF THE WORLD — New Research finds Teeth as a Biological ArchiveREST OF THE WORLD — Finding Treatment for Muscular Dystrophy using CRISPR

Sensitive to Infection but Strong in Defense-Female Sex and the Power of Oestradiol in the COVID-19 Pandemic.

The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17ß-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality are concerned, since the dominant female hormone, oestradiol, has immune-modulatory properties that are likely to be protective against virus infections. It is also known that the X chromosome contains the largest number of immune-related genes, potentially conferring an advantage to women in efficient immune responsiveness. Lifestyle factors are also likely to be contributory. Premenopausal women could possibly face higher exposure to infection (hence higher infection rates) because economic conditions are often less favorable for them with less opportunity for home office work because of jobs requiring mandatory attendance. Due to the additional task of childcare, it is likely that contact times with other people will be longer. Women generally make healthier lifestyle choices, thus reducing the disease burden that confers high risk of mortality in COVID-19 infected men. This narrative review aims to present key concepts and knowledge gaps on the effects of oestrogen associated with SARS-CoV2 infection and COVID-19 disease.

Feminising hormone therapy reduces testicular ACE-2 receptor expression: Implications for treatment or prevention of COVID-19 infection in men.

It has been proposed that men hospitalised with COVID-19 be treated with oestrogen or progesterone to improve COVID-19 outcomes. Transgender women (male-to-female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE-2 expression in testicles of trans-women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans-women undergoing gender-affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-like 3 antibody (Leydig cell) and ACE-2 IHC. Cells per high-powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0-2 scale. On immunohistochemistry staining for Leydig cells and ACE-2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE-2 to protect men from COVID-19 infection.

COVID-19 and pregnancy: are they friends or enemies?

OBJECTIVES: Novel coronavirus disease (COVID-19) is rapidly spreading all over the world. Although in many cases the infection causes very weak symptoms, it can be severe in patient with diverse chronical diseases and immunological compromising patients. Pregnancy is a unique condition in which mother and fetus peacefully collaborate. Diverse endocrine-immune mechanisms, mostly under progesterone control work together to protect the fetus from maternal immunocompetent cell activation driven rejection. The physiological shift to Th2 dominant environment, while favourable for fetus, it makes mothers susceptible to infective pathogens, making pregnancy during COVID-19 pandemic challenging. MATERIALS AND METHODS: Studies involving COVID-19 in pregnancy and those analysing changes of immune system induced by COVID-19 were searched in databases such as PubMed, Scopus, Google Scholar and ScienceDirect. Databases were searched using a keyword COVID-19/coronavirus, that was combined with following terms: immune system, pregnancy, oestrogen, or progesterone. Search included studies published up to 01.07.2020. Almost 1,500 articles were found, but only 18 met criteria. RESULTS: Most frequent symptoms of COVID-19 in mothers infected in the late pregnancy were fever and cough accompanied with lymphopenia and elevated C-reactive protein. Mothers reported to have severe disease had comorbidities and were obese. Low rate of neonatal complications of maternal Sars-Coc-2 infection without neonatal mortality was observed. CONCLUSIONS: Currently available data didn't show significant relationship between COVID-19 severity and pregnancy and there is no strong evidence that mother's infection can lead to adverse pregnancy outcome, but further studies are needed to determinate the possible effects of COVID-19 gained during earlier pregnancy.

Is There a Link between Bisphenol A (BPA), a Key Endocrine Disruptor, and the Risk for SARS-CoV-2 Infection and Severe COVID-19?

Infection by the severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) is the causative agent of a new disease (COVID-19). The risk of severe COVID-19 is increased by certain underlying comorbidities, including asthma, cancer, cardiovascular disease, hypertension, diabetes, and obesity. Notably, exposure to hormonally active chemicals called endocrine-disrupting chemicals (EDCs) can promote such cardio-metabolic diseases, endocrine-related cancers, and immune system dysregulation and thus, may also be linked to higher risk of severe COVID-19. Bisphenol A (BPA) is among the most common EDCs and exerts its effects via receptors which are widely distributed in human tissues, including nuclear oestrogen receptors (ERα and ERß), membrane-bound oestrogen receptor (G protein-coupled receptor 30; GPR30), and human nuclear receptor oestrogen-related receptor gamma. As such, this paper focuses on the potential role of BPA in promoting comorbidities associated with severe COVID-19, as well as on potential BPA-induced effects on key SARS-CoV-2 infection mediators, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Interestingly, GPR30 appears to exhibit greater co-localisation with TMPRSS2 in key tissues like lung and prostate, suggesting that BPA exposure may impact on the local expression of these SARS-CoV-2 infection mediators. Overall, the potential role of BPA on the risk and severity of COVID-19 merits further investigation.

Sexual Dimorphism of Coronavirus 19 Morbidity and Lethality.

The recent coronavirus disease 2019 (COVID-19) pandemic showed a different severity in the disease between males and females. Men have been becoming severely ill at a higher rate than women. These data along with an age-dependent disease susceptibility and mortality in the elderly suggest that sex hormones are the main factors in determining the clinical course of the infection. The differences in aging males versus females and the role of sex hormones in key phenotypes of COVID-19 infection are described in this review. Recommendations based on a dimorphic approach for males and females suggest a sex-specific management the disease.

Ankaferd hemostat (ABS) as a potential mucosal topical agent for the management of COVID-19 syndrome based on its PAR-1 inhibitory effect and oestrogen content.

COVID-19 due to the SARS-CoV-2 infection is a multi-systemic immune syndrome affecting mainly the lungs, oropharyngeal region, and other vascular endothelial beds. There are tremendous ongoing efforts for the aim of developing drugs against the COVID-19 syndrome-associated inflammation. However, currently no specific medicine is present for the absolute pharmacological cure of COVID-19 mucositis. The re-purposing/re-positioning of already existing drugs is a very important strategy for the management of ongoing pandemy since the development of a new drug needs decades. Apart from altering angiotensin signaling pathways, novel drug candidates for re-purposing comprise medications shall target COVID-19 pathobiology, including pharmaceutical formulations that antagonize proteinase-activated receptors (PARs), mainly PAR-1. Activation of the PAR-1, mediators and hormones impact on the hemostasis, endothelial activation, alveolar epithelial cells and mucosal inflammatory responses which are the essentials of the COVID-19 pathophysiology. In this context, Ankaferd hemostat (Ankaferd Blood Stopper, ABS) which is an already approved hemostatic agent affecting via vital erythroid aggregation and fibrinogen gamma could be a potential topical remedy for the mucosal management of COVID-19. ABS is a clinically safe and effective topical hemostatic agent of plant origin capable of exerting pleiotropic effects on the endothelial cells, angiogenesis, cell proliferation and vascular dynamics. ABS had been approved as a topically applied hemostatic agent for the management of post-surgical/dental bleedings and healing of infected inflammatory mucosal wounds. The anti-inflammatory and proteinase-activated receptor axis properties of ABS with a considerable amount of oestrogenic hormone presence highlight this unique topical hemostatic drug regarding the clinical re-positioning for COVID-19-associated mucositis. Topical ABS as a biological response modifier may lessen SARS-CoV-2 associated microthrombosis, endothelial dysfunction, oropharyngeal inflammation and mucosal lung damage. Moreover, PAR-1 inhibition ability of ABS might be helpful for reducing the initial virus propagation and mocasal spread of COVID-19.