The use of oocyte cryopreservation for fertility preservation in patients with sex chromosome disorders: a case series describing outcomes.

PURPOSE: Characterize outcomes among adolescents and young adults (AYAs) with sex chromosome disorders (SCDs) after oocyte cryopreservation (OC) consultation. METHODS: Retrospective case series of all AYA (< 25 years) patients with SCDs seen for OC consultation from 2011 to 2019 at a large, urban, academic fertility center. All AYA patients with an SCD seen for OC consult in the study time period were reviewed and included. Data collected included patient age, SCD type, number of patients who attempted OC, number of cycles attempted, and cycle outcomes. RESULTS: Twenty-two patients were included: 9 with Turner syndrome, 12 with mosaic Turner syndrome, and 1 with 47,XXX. Mean age at consult was 14.7 ± 3.5 years. Fourteen patients elected for OC: 5 with Turner syndrome, 8 with mosaic Turner syndrome, and 1 47,XXX who pursued 31 OC cycles total. Of those 14 patients, 10 underwent retrieval, 9 froze oocytes, and 8 froze mature (MII) oocytes. Seven patients underwent > 1 cycle and 7 had ≥ 1 cancelation. 3/3 patients who pursued cycles after 1st cancelation never got to retrieval. Age, SCD type, and baseline FSH did not predict ability to freeze MIIs. One patient returned after OC and attempted 4 ovulation induction cycles and 2 IVF cycles; all were canceled for low response. CONCLUSIONS: AYA patients with SCDs have a high risk of poor response and cycle cancelation but the majority froze MIIs. Thus, setting expectations is important. A larger sample size is needed to evaluate possible clinical predictors of success.

Risk-focused differences in molecular processes implicated in SARS-CoV-2 infection: corollaries in DNA methylation and gene expression.

BACKGROUND: Understanding the molecular basis of susceptibility factors to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health imperative. It is well-established that males are more likely to acquire SARS-CoV-2 infection and exhibit more severe outcomes. Similarly, exposure to air pollutants and pre-existing respiratory chronic conditions, such as asthma and chronic obstructive respiratory disease (COPD) confer an increased risk to coronavirus disease 2019 (COVID-19). METHODS: We investigated molecular patterns associated with risk factors in 398 candidate genes relevant to COVID-19 biology. To accomplish this, we downloaded DNA methylation and gene expression data sets from publicly available repositories (GEO and GTEx Portal) and utilized data from an empirical controlled human exposure study conducted by our team. RESULTS: First, we observed sex-biased DNA methylation patterns in autosomal immune genes, such as NLRP2, TLE1, GPX1, and ARRB2 (FDR < 0.05, magnitude of DNA methylation difference Δß > 0.05). Second, our analysis on the X-linked genes identified sex associated DNA methylation profiles in genes, such as ACE2, CA5B, and HS6ST2 (FDR < 0.05, Δß > 0.05). These associations were observed across multiple respiratory tissues (lung, nasal epithelia, airway epithelia, and bronchoalveolar lavage) and in whole blood. Some of these genes, such as NLRP2 and CA5B, also exhibited sex-biased gene expression patterns. In addition, we found differential DNA methylation patterns by COVID-19 status for genes, such as NLRP2 and ACE2 in an exploratory analysis of an empirical data set reporting on human COVID-9 infections. Third, we identified modest DNA methylation changes in CpGs associated with PRIM2 and TATDN1 (FDR < 0.1, Δß > 0.05) in response to particle-depleted diesel exhaust in bronchoalveolar lavage. Finally, we captured a DNA methylation signature associated with COPD diagnosis in a gene involved in nicotine dependence (COMT) (FDR < 0.1, Δß > 0.05). CONCLUSION: Our findings on sex differences might be of clinical relevance given that they revealed molecular associations of sex-biased differences in COVID-19. Specifically, our results hinted at a potentially exaggerated immune response in males linked to autosomal genes, such as NLRP2. In contrast, our findings at X-linked loci such as ACE2 suggested a potentially distinct DNA methylation pattern in females that may interact with its mRNA expression and inactivation status. We also found tissue-specific DNA methylation differences in response to particulate exposure potentially capturing a nitrogen dioxide (NO2) effect-a contributor to COVID-19 susceptibility. While we identified a molecular signature associated with COPD, all COPD-affected individuals were smokers, which may either reflect an association with the disease, smoking, or may highlight a compounded effect of these two risk factors in COVID-19. Overall, our findings point towards a molecular basis of variation in susceptibility factors that may partly explain disparities in the risk for SARS-CoV-2 infection.

Why Females Do Better: The X Chromosomal TLR7 Gene-Dose Effect in COVID-19.

A male sex bias has emerged in the COVID-19 pandemic, fitting to the sex-biased pattern in other viral infections. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that the gene-dose of Toll-Like Receptor (TLR) 7 could contribute to the sex-skewed severity. TLR7 is one of the crucial pattern recognition receptors for SARS-CoV-2 ssRNA and the gene-dose effect is caused by X chromosome inactivation (XCI) escape. Female immune cells with TLR7 XCI escape have biallelic TLR7 expression and produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 in plasmacytoid dendritic cells is one of the pattern recognition receptors responsible for IFN production and a delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected to some extend against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect.

The triumvirate of NF-κB, inflammation and cytokine storm in COVID-19.

The coronavirus disease (COVID-19) has once again reminded us of the significance of host immune response and consequential havocs of the immune dysregulation. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inflicts severe complications to the infected host, including cough, dyspnoea, fever, septic shock, acute respiratory distress syndrome (ARDs), and multiple organ failure. These manifestations are the consequence of the dysregulated immune system, which gives rise to excessive and unattended production of pro-inflammatory mediators. Elevated circulatory cytokine and chemokine levels are accompanied by spontaneous haemorrhage, thrombocytopenia and systemic inflammation, which are the cardinal features of life-threatening cytokine storm syndrome in advanced COVID-19 diseases. Coronavirus hijacked NF-kappa B (NF-κB) is responsible for upregulating the expressions of inflammatory cytokine, chemokine, alarmins and inducible enzymes, which paves the pathway for cytokine storm. Given the scenario, the systemic approach of simultaneous inhibition of NF-κB offers an attractive therapeutic intervention. Targeted therapies with proteasome inhibitor (VL-01, bortezomib, carfilzomib and ixazomib), bruton tyrosine kinase inhibitor (acalabrutinib), nucleotide analogue (remdesivir), TNF-α monoclonal antibodies (infliximab and adalimumab), N-acetylcysteine and corticosteroids (dexamethasone), focusing the NF-κB inhibition have demonstrated effectiveness in terms of the significant decrease in morbidity and mortality in severe COVID-19 patients. Hence, this review highlights the activation, signal transduction and cross-talk of NF-κB with regard to cytokine storm in COVID-19. Moreover, the development of therapeutic strategies based on NF-κB inhibition are also discussed herein.

The role of sexual dimorphism in susceptibility to SARS-CoV-2 infection, disease severity, and mortality: facts, controversies and future perspectives.

Former studies have revealed intersex variability in immune response to infectious diseases, including Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological surveillance of the ongoing pandemic has demonstrated a male vulnerability to morbidity and mortality, despite similar infection rates between the two sexes. Divergence in the frequency of comorbidities between males and females, differences in hormonal profile, chromosomal composition and gender behavior have all been proposed as potential causative factors. Data deriving from the immunization process indirectly support the existence of a sex-specific response to SARS-CoV-2, since females apparently produce higher numbers of antibodies while simultaneously exhibiting higher rates of side effects, indicating a stronger immune reactivity to the vaccine's elements. Interpreting intersex differences in immune response to SARS-CoV-2 could lead to a deeper understanding of the COVID-19 pathophysiology and enable healthcare professionals to conduct a more accurate patient risk assessment and better predict the clinical outcome of the disease. This narrative review aims to discuss the pathophysiological and behavioral basis of the disproportionate male morbidity and mortality observed in COVID-19, in the context of most research findings in the field.

Sex, Hormones, Immune Functions, and Susceptibility to Coronavirus Disease 2019 (COVID-19)-Related Morbidity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), uses two primary receptors, type II transmembrane serine protease and angiotensin-converting enzyme-2, for priming and cellular invasion, respectively. Both proteins have been demonstrated to be present in different concentrations in females and males, which may explain a mechanism for the reported higher case-fatality rate in males. Despite the known sex difference in COVID-19 disease mortality, preliminary data suggest there are certain female populations, including pregnant and menopausal women and possibly polycystic ovarian syndrome patients who are more susceptible to COVID-19-related morbidity. This commentary analyzes the interplay between sex differences, hormones, and the immune function in each of these populations with respect to the risk and severity of COVID-19 and proposes biological rationales to explain these differences.

Sex bias of females in survival from cancer and infections. Is X the answer?

Major differences in survival of men and women from infectious diseases and cancers have been highlighted by death rates from COVID-19 infections. In cancer, attention has been focussed on differences in gene expression from X chromosomes in men and women with a preponderance of genes involved in immune responses being expressed in women. Important findings have been that some of the genes are important epigenetic regulators that play fundamental roles in immune responses.

Gender Disaggregation in COVID-19 and Increased Male Susceptibility.

Novel coronavirus disease 2019 (COVID-19) is a growing public health crisis. Despite initial focus on the elderly population with comorbidities, it seems that large studies from the worst affected countries follow a sex-disaggregation pattern. Analysis of available data showed marked variations in reported cases between males and females among different countries with higher mortality in males.  At this early stage of the pandemic, medical datasets at the individual level are not available; therefore, it is challenging to conclude how different factors have impacted COVID-19 susceptibility. Thus, in the absence of patients' level data, we attempted to provide a theoretical description of how other determinants have affected COVID-19 susceptibility in males compared to females.  In this article, we have identified and discussed possible biological and behavioral factors that could be responsible for the increased male susceptibility. Biological factors include - an absence of X-chromosomes (a powerhouse for immune-related genes), a high level of testosterone that inhibits antibody production, and the presence of Angiotensin-converting enzyme 2 (ACE2) receptors that facilitate viral replication. Similarly, behavioral factors constitute - higher smoking and alcohol consumptions, low level of handwashing practices, and high-risk behavior like non-adherence to health services and reluctance to follow public health measures in males. Keywords: COVID-19; gender; males; sex disaggregation; susceptibility.

Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome.

BACKGROUND: The recent emergence of COVID-19 poses a global health emergency. One of the most frequently reported data is sex-related severity and mortality: according to the last available analysis on 239,709 patients in Italy, lethality is 17.7% in men and 10.8% in women, with 59% of total deaths being men. Interestingly, the infection rate is lower in males than in females, with 45.8% and 54.2% of positive cases, respectively, suggesting that gender-related factor may worsen disease evolution. A tentative hypothesis to explain these findings is the role of angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 involved in viral infection. PURPOSE: In this review, we summarize the available evidence pointing to gender-related differences in ACE2 and TMPRSS2 expression, from both genetic and endocrine points of view. RESULTS: Altogether, available evidence points toward two not-mutually exclusive mechanisms in gender susceptibility to COVID-19 by sex hormonal regulation of ACE2 and TMPRSS2. On one hand, ACE2 expression could be increased in women, either by estrogens or constitutively by X chromosome inactivation escape or by reduced methylation, providing a larger reservoir of ACE2 to maintain the fundamental equilibrium of RAS regulatory axis. On the other, low levels of androgens in women may keep at low levels TMPRSS2 expression, representing a further protective factor for the development of COVID-19 infection, despite the increased expression of ACE2, which represents the Trojan horse for SARS-CoV-2 entry. CONCLUSIONS: Both mechanisms consistently point to the role of sex hormones and sex chromosomes in the differential severity and lethality of COVID-19 in men and women.

Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection.

CoV-19/SARS-CoV-2 is a highly pathogenic virus that causes coronavirus-19 disease (COVID-19) an acute respiratory distress syndrome which provokes serious problems for global health. Studies suggest that there are many differences between men and women in the immune response to CoV-19 infection and inflammatory diseases. Women, compared to men, are less susceptible to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes. The presence of two X chromosomes in women emphasize the immune system even if one is inactive. The immune regulatory genes encoded by X chromosome in female gender causes lower viral load levels, and less inflammation than in man, while CD4+ T cells are higher with better immune response. In addition, women generally produce higher levels of antibodies which remain in the circulation longer. The levels of activation of the immune cells are higher in women than in men, and it is correlated with the trigger of TLR7 and the production of IFN. TLR7 is higher in women than in men and its biallelic expression leads to higher immune responses and increases the resistance to viral infections. TLR7 is expressed in innate immune cells which recognizes single strand RNA virus by promoting the production of antibodies against the virus and the generation of pro-inflammatory cytokines including IL-6 and IL-1 family members. Moreover, in women the production of inflammatory IL-6 after viral infection is lower than in males and is often correlated with a better longevity. In addition, on the X chromosome there are loci that code for the genes involved in the regulation of immune cells such as FOXP3, and transcription factor for Treg involved in virus pathogenesis. The X chromosome influences the immune system by acting on many other proteins, including TLR8, CD40L and CXCR3 which can be over-expressed in women, and influence the response to viral infections and vaccinations. However, the biallelic expression of the X-linked genes can promote harmful autoimmune and inflammatory responses. Cardiovascular diseases are more frequent in males and subjects without cardiovascular dysfunctions infected by CoV-19 have a better prognosis, but these effects are still under study. It is hoped that certain drugs, such as CoV-19 receptor blockers, anti-inflammatories (against rheumatic diseases), monoclonal antibodies, anti-IL-1 and anti-IL-6, the remdesevir drug (analogue adenosine, effective against ebola), hydroxychloroquine (for the treatment of malaria) and vaccines, will open up new strategies and new therapeutic ways to combat this terrible virus.