Cardiac and Renal SARS-CoV-2 Viral Entry Protein Regulation by Androgens and Diet: Implications for Polycystic Ovary Syndrome and COVID-19.

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS.

Unraveling the pathogenic interplay between SARS-CoV-2 and polycystic ovary syndrome using bioinformatics and experimental validation.

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among polycystic ovary syndrome (PCOS) is significantly higher than in the general population. However, the mechanisms underlying this remain obscure. This study aimed to explore the mechanisms by identifying the genetic signature of SARS-CoV-2 infection in PCOS. In the present study, a total of 27 common differentially expressed genes (DEGs) were selected for subsequent analyses. Functional analyses showed that immunity and hormone-related pathways collectively participated in the development and progression of PCOS and SARS-CoV-2 infection. Under these, 7 significant hub genes were identified, including S100A9, MMP9, TLR2, THBD, ITGB2, ICAM1, and CD86 by using the algorithm in Cytoscape. Furthermore, hub gene expression was confirmed in the validation set, PCOS clinical samples, and mouse model. Immune microenvironment analysis with the CIBERSORTx database demonstrated that the hub genes were significantly correlated with T cells, dendritic cells, mast cells, B cells, NK cells, and eosinophils and positively correlated with immune scores. Among the hub genes, S100A9, MMP9, THBD, ITGB2, CD86, and ICAM1 demonstrated potential as possible diagnostic markers for COVID-19 and PCOS. In addition, we established the interaction networks of ovary-specific genes, transcription factors, miRNAs, drugs, and chemical compounds with hub genes with NetworkAnalyst. This work uncovered the common pathogenesis and genetic signature of PCOS and SARS-CoV-2 infection, which might provide a theoretical basis and innovative ideas for further mechanistic research and drug discovery of the comorbidity of the two diseases.

Adenovirus-36 infection and obesity: A case control study of Turkish women with polycystic ovary syndrome.

BACKGROUND AND AIMS: Adenovirus-36 (Ad-36) seropositivity has been shown to be involved in the aetiology of obesity. The aim of this study was to examine Ad-36 positivity in obese and normal-weight patients with polycystic ovary syndrome (PCOS). METHODS: There were two groups including 92 and 110 subjects. This study was a prospective case-control study. The enzyme-immunoassay method was used to quantitatively determine antibodies (Abs) specific to human Ad-36 in the serum samples. Age, body mass index (BMI), fasting glucose levels and insulin levels of the participants were recorded. The PCOS and control group patients were divided into two groups: the overweight group with BMI ≥25 kg/m2 and non-obese group with BMI <25 kg/m2. RESULTS: Ad-36 Ab positivity in the PCOS group was found to be significantly higher than that in the control group (p < 0.001). Ad-36 Ab positivity was significantly higher in the PCOS obese group than in the control obese group (p < 0.001). Ad-36 Ab positivity and BMI ≥25 kg/m2 were identified as independent predictors of PCOS in logistic regression analysis. CONCLUSION: Ad-36 Ab positivity was significantly higher in the obese/overweight PCOS patients. Obesity can be prevented in patients with PCOS by treating Ad-36.

Coronavirus Disease 2019 (SARS-CoV-2) and polycystic ovarian disease: Is there a higher risk for these women?

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with acute respiratory distress syndrome and infected patients have a relatively high risk of death. Emerging risk factors for poor outcome in this disease include age, male gender, cardiovascular co-morbidities including hypertension, prior cardiovascular disease, diabetes and more recently obesity. To date there are no data relating to SARS-CoV-2 in PCOS women. The present Clinical Opinion represents a summary of the epidemiological evidence and possible pathophysiological mechanisms regarding PCOS and COVID-19. PCOS women could be more susceptible to infections compared to non-PCOS women. Insulin resistance and the associated hyperinsulinaemia are drivers for enhanced steroidogenesis in women with PCOS. Weight-gain and obesity, through their worsening effects on insulin resistance, thereby drive enhanced steroidogenesis and hyperandrogenism. All these features represent key points to provide an explanation for the possible association between PCOS and SARS-CoV-2. Indeed, androgens may drive clinical results in COVID-19, through the expression of TMPRSS2, a cellular co-receptor necessary for SARS-CoV-2 infection and through androgen-mediated immune modulation. In women with PCOS the endocrine-immune axis leads to immune dysfunction with a state of chronic inflammation, and hyperandrogenism and IR with compensatory hyperglycaemia could play a determining role in the pathophysiogenesis of the infection. However, it is possible that only specific PCOS phenotypes may be more susceptible. In addition, vitamin D deficiency and gut dysbiosis are another important factor potentially involved in the increased risk of developing severe forms of COVID-19 in PCOS women. Further scientific investigations are needed with the aim of understanding which women are most at risk of becoming infected or developing complications, what are the causal mechanisms on which it is possible to intervene with prophylactic and therapeutic measures and what the long-term consequences will be on the health of these patients.

Occasional transsynaptic viral labeling in the central nervous system from the polycystic ovary induced by estradiol valerate.

Increased density of catecholaminergic nerves in the human polycystic ovary has been observed. The aim of the present study was to investigate the distribution of transsynaptically virus-labeled neurons in the central nervous system from the rat polycystic ovary to see whether is it different or not from that of cycling control rats. To induce a polycystic ovary, a single injection of estradiol valerate was given to adult female rats and 30 days later a neurotropic virus was injected into the right ovary. Rats were sacrificed 72 or 96 hours after viral infection. Weight of the ovaries of the estradiol valerate-treated rats was significantly lower compared to controls, and the histology of the ovaries of the treated rats displayed severely atretic large antral follicles. There was almost no viral labeling in the central nervous system from the ovaries showing precystic morphology, in spite of the fact that such altered organs are rich in nerve fibres. It is assumed that presently unidentified factors in the precystic ovary, presumably related to the link between the immune and the nervous system, might be involved in the infectivity of the virus, and thus be responsible for the lack of viral labeling from such an ovary.