Department of Biological Sciences, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia

Corresponding author email: aahmadi1000@hotmail.com

Article Publishing History

INTRODUCTION

Polycystic ovary syndrome (PCOS) is a widespread hormonal health problem which is  engaged in infertility and metabolic disorders, like diabetes and cardiovascular diseases, (Sam, 2007). The prevalence of PCOS among women of reproductive age ranged from 6% to 10%. PCOS’s main characteristics are related to increased androgen production; these constitute oligo and amenorrhoea, impaired fertility, hirsutism, acne, and alopecia (Sam and Dunaif, 2003; Sam, 2007).Besides the severe reproductive consequences, several metabolic features accompany PCOS incorporating insulin resistance; the troubles that cause enhanced risk for glucose intolerance, and insulin independent diabetes, (Kyrou et al., 2000, 2015; Möhlig et al., 2006; Randeva et al., 2012; Pasquali, 2018, Barber et al., 2019; Manisha et al., 2020).

Obesity is a prevalent feature in women with PCOS, as nearly 40% to 80% of women with this disorder are observed to be overweight or obese(Sam, 2007).There are many pathophysiologic factors associated with PCOS development, including increased blood insulin level, which stimulates the overproduction of androgens. The second important factor is the low-grade inflammations that accompany PCOS condition. Studies have reported that women with low-grade inflammation may experience PCOS(Hignett et al., 2011). Genes likewise is a PCOS predisposing factor. The syndrome usually affects mothers, daughters, and sisters in the same family, (Urbanek, 2007). Finally, the immoderate exposure of fetuses to androgens can permanently inhibit normal genes function. The androgens can boost lipid distribution in the abdominal region in a male model pattern, which promotes insulin resistance and low-grade inflammation(Hignett et al., 2011).Renin-angiotensin system (RAS) is an important system that regulates both cardiovascular and kidney function(Unger, 2002; Vejakama et al., 2012). An early study has documented that RAS is linked to hormonal changes and insulin resistance, (Liu, 2007). There is increasing proof that RAS is enhanced in PCOS patients, which may contribute to the overstimulation of the ovary and excess androgen production (Moin et al., 2020).

In March 2020, the World Health Organization (WHO) has been announced the widespread of coronavirus-2 (SARS-CoV-2) disease (COVID-19) as a pandemic (Cucinotta and Vanelli, 2020).Even though the majority of COVID-19 patients are either asymptomatic or with mild symptoms, many others face severe disease with increased mortality (Yuki et al., 2020).A growing body of scientific proof elucidated that the prevalence of serious COVID-19 is remarkably elevated in old versus youth and males versus females (Cai, 2020; Docherty et al., 2020; Guan et al., 2020; Guo et al., 2020; Jin et al., 2020; La Vignera et al., 2020; Wu and McGoogan, 2020).

The researchers documented the presence of certain diseases as risk factors for increased COVID-19 infection and severity. These include diabetes and hypertension. Obesity has also been listed as a risk factor for corona virus infection(Bornstein et al., 2020; Guan et al., 2020; Li et al., 2020).Of particular attention is that the angiotensin-converting enzyme-2 (ACE2) has been utilized by COVID-19 to enter the host target cells and, therefore, significantly impact the RAS pathway(Wiese et al., 2020). Indeed, it is obvious that many risk factors are overlapping between PCOS women and COVID-19 susceptibility. Hence, it may be proposed that the PCOS women are potentially at great than anticipated risk if challenged with a COVID-19 virus infection. This study aims to review PCOS’s comorbid conditions that can predispose to increased risk of acquiring COVID-19 infection or magnifying its complications or even causing death.

Overproduction of Androgens: In PCOS, up to 60 % of androgens are released by the ovaries, whereas the adrenal gland provides the residual 40%. It is known that the fundamental cause of increased androgen production in women with PCOS are androgens from both the ovary as well as the adrenal gland (Cedars et al., 1992).In PCOS females, low concentrations of sex-hormone-binding globulin (SHBG) often lead to elevated serum free androgen. As confirmed in several studies, SHBG concentrations are inversely correlated with serum insulin concentrations or with the extent of insulin sensitivity in females both with and without PCOS. In addition, decreasing insulin secretion in PCOS obese females without affecting the insulin resistance is accompanied by increased serum SHBG concentration (Nestler et al., 1991).

Sex hormones are responsible for the immune response, as estrogen is known to improve immunity, whereas testosterone is known to inhibit it (Strope et al., 2020). Besides, androgens control an essential protease engaged in viral entry, TMPRSS2 (Hägglöf et al., 2014). The experimental studies provided evidence that sex hormones increase the expression and activity of ACE-2 in different tissues, including the cardiac, renal, and adipose tissue(La Vignera et al., 2020).The role of androgen receptor (AR) gene polymorphisms in the development and progression of cardiac complications and hypertension in COVID-19 infected male subjects cannot be ignored because the expression of ACE2 in the cardiac muscle is modulated by the androgens(Dalpiaz et al., 2015).

It has recently been explored that a high prevalence of male pattern baldness (often associated with increased serum androgen) in the hospitalized COVID-19 patients, potentially indicating that androgens could be involved in the incidence of COVID-19(Goren et al., 2020).Therefore, a possible correlation between androgens and the acuteness of COVID-19 seems probable (Goren et al., 2020; McCoy et al., 2020; Wambier and Goren, 2020; Wambier et al., 2020) and may further suggest the hypothesis that PCOS may constitute an additional potential risk for the severity of COVID-19.This assumption is indeed essential because females with PCOS either manifest hyperandrogenism (androgenic alopecia) or under therapy with anti-androgen (spironolactone or finasteride)(Quinn et al., 2014; Kyrou et al., 2015; Teede et al., 2018).

Against this hypothesis, a retrospective cohort study that constitutes forty-five COVID-19 patients at the intensive Care Unit at the University Hospital Hamburg-Eppendorf, Germany, documented that severely COVID-19 diseased men (n=35) showed a severe decline in their serum testosterone and dihydrotestosterone levels. In contrast, the women (n=10) showed increased serum testosterone concentration unaccompanied by any alterations in dihydrotestosterone concentration (Schroeder et al., 2020). Furthermore, in a study of 31 Italian hospital-admitted male patients, a significant gradual decrease in both serum-free and total androgen concentrations was substantially linked with the need for special respiratory care and intensive care (Rastrelli et al., 2020).Perhaps more research will be required to validate the correlation between the amount of serum androgens and the seriousness of COVID-19 infection (Kyrou et al., 2020). Many studies have shown that males are more vulnerable to coronavirus hazards and complications than females. And this was due to the increase in males’ testosterone hormone levels. Females with PCOS who have raised serum testosterone concentration can also be at higher risk for complications of COVID-19.

Microbiome Composition: The results of Torres et al. (2018) showed that females with PCOS have fewer different strains of intestinal microbiome, a finding that seems to be correlated with increased serum concentrations of testosterone. In their study, the researchers analyzed 73 faecal swabs ofPCOS females. Their samples were matched with swabs from 48 women with no PCOS and 42 women with polycystic ovaries, but with no other PCOS characteristics. The study results showed that females with PCOS had the minimal diverse intestinal bacteria, females without the disease had the maximum diverse intestinal bacteria, and females with polycystic ovaries have diversity in the intestinal microbes than females with PCOS. The researchers indicate that testosterone and other androgens can help form the intestinal microbiome, and these alterations can impact the quality of life of PCOS females.

It has been shown that the gut microbiome modifies the immune system, which helps defend against foreign pathogens either by immunity or by competitive exclusion (Cerf-Bensussan and Gaboriau-Routhiau, 2010; Kamada et al., 2013).The normal microflora stimulates interleukins generation in the gut that is defensive against pathogens (Franchi et al., 2012).Not only are the impacts of commensals local, but they can be systemic. The decline in intestinal microbiota owing to antibiotics is consistent with impaired activity of T and B cells versus intranasal influenza(Ichinohe et al., 2011).By rectal administration of toll-like receptor (TLR) agonists, defensive immunity against intranasal influenza is restored, leading to the formation of IL 1-β and IL 18 (Brugger et al., 2016).Scientists have found that citizens in developing countries have a lower mortality rate during COVID-19 relative to developed nations. And the reason for that, scientists have proposed, is the exposure of the inhabitants of these countries to a high microbial load, increasing immunity. Scientists have shown that the richness of the microbiome has a protective effect against external infections, like, COVID-19 (Kumar and Chander, 2020).

In a pilot study including 15 COVID-19 patients, the researchers observed persistent changes compared to controls in the faecal microbiome during the hospitalization period. Alterations of the faecal microbiota were parallel with COVID-19 riskiness levels, (Zuo et al., 2020).A new Wuhan, China, the analysis found a correlation between both the composition of the intestinal microbiota and the susceptibility of healthy subjects to COVID-19 (Gou et al., 2020).The presence of Lactobacillus species in the intestine enhances the production of one of the most important anti-inflammatory cytokines, IL-10, and this is what makes the scientists expect the best with corona treatment. High amounts of pro-inflammatory species bacteria, comprising Klebsiella, Streptococcus, and Ruminococcus gnavus, associated with greater amount of pro-inflammatory cytokines and enhanced complications of illness. These bacteria have been described to be abundant in the proinflammatory gastrointestinal environment of people who suffer from a lot of diseases, such as, diabetes, obesity, irritable bowel disease, and hypertension(van der Lelie and Taghavi, 2020).

The concentration of ACE2, which is the target of the COVID-19 virus, was also increased in the dysbiotic gut environment (Chan et al., 2020). As PCOS is linked with obesity, hyperglycemia, and increased blood pressure, therefore, PCOS females may have the same alterations in the composition of the intestinal microbiome caused by these illnesses and hence they will suffer the severe complications of COVID-19.Women with PCOS have a dysbiotic gut microbiome as well as variation in microbial composition (Morgante et al., 2020).

Obesity And Insulin Resistance: Growing numbers of research have proposed that pro-inflammatory cytokines are implicated in the pathophysiology of PCOS, which is also marked by the existence of low-grade chronic inflammation. In females with PCOS, many inflammatory cytokines have been identified to be linked with insulin resistance (Al-Musawy et al., 2018). The study’s findings indicated that high amounts of interleukin-6 (IL-6) in PCOS females were positively correlated with the ratio of homeostasis model assessment of insulin resistance (HOMA-IR) and total testosterone ratio in both slim and overweight PCOS females (Peng et al., 2016). The majority of females with PCOS are also obese and visceral fat is included in the presence of proinflammatory mediators observed in PCOS women (Sepilian and Nagamani, 2005).

It has been well known that females with PCOS and obesity are exhibiting significant impairment of fat tissue function and overactive secretion of adipokine/cytokine including elevated secretion of IL-6, tumor necrosis factor-α (TNF-α), and leptin, resulting in a prolonged pro-inflammatory condition (Kyrou et al., 2015, 2018).Besides, females with PCOS often have polymorphisms in gene expressing pro-inflammatory cytokines, like TNF-α and IL-6, compared to normal females (Guo et al., 2015; Zhang et al., 2020).IL-6 is an inflammation promoter that regulates the release of many cytokines in females with PCOS (Vural et al., 2010). It controls many ovarian functions including ovulation, conception, and implantation. In PCOS women, serum and granulosa cell IL-6 levels are increased (Lee et al., 2017; Al-Musawy et al., 2018) and studies have confirmed that elevated IL-6 could be correlated with PCOS insulin resistance and hyper androgenism (González et al., 2012).

Preliminary findings from the UK (Intensive Care National Audit & Research Centre, 2020), China (Peng et al., 2020), and the USA (Petrilli et al., 2020) hospitals indicate that obese COVID-19 patients have a poorer prognosis. It is abundantly clear that there are specific mechanisms through which obesity and its consequences such as metabolic and inflammatory alterations, deteriorate the outcome of COVID-19 (Finucane and Davenport, 2020).The initial findings proposed that people with complicatedCOVID-19 appear to be aged men with high blood pressure, hyperglycemia, and increased serum liver enzymes all increase the probability that insulin resistance may exerted an essential function in mediating COVID-19 complications(Finucane and Davenport, 2020).Studies have indicated that the seriousness of COVID-19 may be linked with the predisposition to release inflammatory cytokines (cytokines storm syndrome) including various inflammatory interleukins, like TNF-α, IL-6, and IL-1β in the patient’s lung tissue (Fagone et al., 2020; Mehta et al., 2020).Evidence shows that in a subset of patients with extreme COVID-19 infection, this syndrome can cause self-sustaining hyper-inflammatory responses, priming respiratory, and multiple organ failure (Fagone et al., 2020).Therefore, there may be a link between the cytokine storm syndrome associated with the risk of COVID-19 and the diseases associated with increased release of proinflammatory mediators, including PCOS. To confirm this hypothesis, many studies are needed.

There is another link between PCOS and the risk of experience serious COVID-19 infection, which is also connectedwith obesity and insulin resistance, which is the increased expression of ACE2 (Morgante et al., 2020).Insulin resistance is often reflected in elevated serum insulin levels (Kahn, 2003).A broad “phenome-wide” Mendelian Randomization research reported that the significant lung ACE2 expression is correlated with many diabetes-related features (Rao et al., 2020).PCOS may be a factor that determines the severity of infection with the COVID-19 virus, due to the accompanying obesity and insulin resistance (Frisardi, 2020), the factors that increase the start of the cytokine storm and the consequent inflammation (Fagone et al., 2020), as well as the increased expression of the ACE2 (Frisardi, 2020), which acts as a receptor for the COVID-19 virus to enter the cells.

Vitamin D Level: Several studies have reported on the relationship between vitamin D deficiency and the severity of COVID-19 infection, as studies have linked the rapid spread of the pandemic in Europeespecially Italy, France, Spain, and England to the emergence of the pandemic following the winter and the consequent lack of exposure to sunlight and vitamin D deficiency (Grant et al., 2020; Marik et al., 2020; Panarese and Shahini, 2020; Rhodes et al., 2020).It has also been reported in several studies that vitamin D deficiency is one of the causes of acute respiratory distress syndrome, besides research has also confirmed an increase in COVID-19 deaths among the elderly and patients with metabolic heart diseases, which also coincides with low levels of vitamin D (Grant et al., 2020; Marik et al., 2020; Panarese and Shahini, 2020; Rhodes et al., 2020).Of interest, the elderly people of Italy and Spain, which were between the key epicenters of the COVID-19 outbreak in Europe, recorded especially deficiency of vitamin D(Ilie et al., 2020).

Vitamin D is a famous cytoprotective hormone that influences the innate and adaptive immune reaction, regulates the activity of IL-6, and inhibits the release of pro-inflammatory cytokines from macrophages and respiratory epithelial cells in response to different viruses(Grant et al., 2020; Marik et al., 2020; Silberstein, 2020; Tian and Rong, 2020).Growing results confirm a negative relation among vitamin D and the incidence of multiple manifestations of PCOS, particularly androgen excess, fertility problems, resistance to insulin, and cardio-metabolic disorder(Muscogiuri et al., 2014; Reis et al., 2017).Furthermore, a meta-analysis study indicates that vitamin D supplementation will effectively decrease the serum concentration of total testosterone and C-reactive protein in females with PCOS, although it increases the levels of antioxidant molecules (Azadi-Yazdi et al., 2017; Akbari et al., 2018).From these studies, it can be concluded that women with PCOS may be more susceptible to complications of COVID-19 due to their vitamin D deficiency, which worsens when quarantine and not exposed to the sunlight (Kyrou et al., 2020).

Non-Alcoholic Fatty Liver Disease: Proofs from clinical studies and meta-analyses suggest a high incidence of non-alcoholic fatty liver disease (NAFLD) in females with PCOS, 34% – 70%, compared to 14% – 34% in normal females (Vassilatou et al., 2010; Macut et al., 2016; Wu et al., 2018).Two possible pathophysiological relations between NAFLD and PCOS are insulin resistance and hyperandrogenism. Insulin resistance appears to interact with obesity and hyperandrogenism, thereby impacting NAFLD and PCOS and being impacted by them (Paschou et al., 2020).A recent Cross-sectional study including 98 Mexican women with PCOS at reproductive age (18-44 years) showed that NAFLD was significantly increased in PCOS women than the normal control women at 69.3% versus 34.6%, respectively. Severe steatosis was the most frequent NAFLD stage between PCOS women (Salva-Pastor et al., 2020).

A retrospective longitudinal cohort study assessing NAFLD rates in 63,120 women with PCOS, using a broad primary care database in the United Kingdom, reported that females with PCOS had an elevated NAFLD rate. Besides, an elevated risk of NAFLD was linked to increased serum testosterone (Kumarendran et al., 2018).Females with PCOS had an increased risk of NAFLD, central obesity, hyperlipidemia, insulin resistance, and metabolic syndrome (Kumarendran et al., 2018).

For COVID-19 patients, NAFLD is a major trigger for hospital admission compared to age, sex, obesity, or other coexisting health problems(Bramante et al., 2020).(Bramante et al., 2020) also showed that by managing NAFLD the risk of hospitalization decreased with obesity. The study also suggests the prominent influence of visceral adiposity in COVID-19 pathophysiology, that enhances the prolonged inflammation and clot formation provoked by NAFLD (Bramante et al., 2020). The most important risk causes for bad results duringCOVID-19 infection prove to be obesity and metabolic disorder (Yang et al., 2020).NAFLD is evidence of increased visceral fats, progressive metabolic disorder, and prolonged inflammation (Sheka et al., 2020).Although low expression of ACE2 was normally found in cholangiocytes and hepatocytes, high expression was associated with experimentally induced chronic liver injury and NAFLD (Paizis et al., 2005).Since ACE2 is the way COVID-19 enters the cells, liver injury can lead to increased viral load and worsening outcomes of COVID-19 (Prins and Olinga, 2020; Xu et al., 2020). The hypothesis can be adopted as the women with PCOS being among the most likely to have NAFLD and hence they will also the most likely to have a worse COVID-19 condition.

CONCLUSION

Studies have indicated that women with PCOS have many factors and pathologies that greatly increase the incidence of complications of COVID-19. These factors include excessive androgen production, change in microbiome formation, obesity, insulin resistance, vitamin D deficiency, and NAFLD. These factors cause decreased immunity, increased inflammatory reactions, and increased expression of the ACE2 (the gate that enables the virus to penetrate the cells). Therefore, it is necessary to inform PCOS women to increase precautionary measures. These women with complicated health conditions should receive high-level health care.

REFERENCES

Akbari M, Ostadmohammadi V, Lankarani KB, Tabrizi R, Kolahdooz F, Heydari ST, Kavari SH, Mirhosseini N, Mafi A, Dastorani M, et al. (2018) The effects of vitamin D supplementation on biomarkers of inflammation and oxidative stress among women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials. Hormone and Metabolic Research. 50 (4): 271–279 DOI: 10.1055/s-0044-101355

Al-Musawy S, Al-Saimary I, Flaifil M. (2018) Levels of cytokines profile in polycystic ovary syndrome. Medical Journal of Babylon. 15 (2): 124–128 DOI: 10.4103/MJBL.MJBL_32_18

Azadi-Yazdi M, Nadjarzadeh A, Khosravi-Boroujeni H, Salehi-Abargouei A. (2017) The effect of vitamin D supplementation on the androgenic profile in patients with polycystic ovary syndrome: A systematic review and meta-analysis of clinical trials. Hormone and Metabolic Research. 49 (3): 174–179 DOI: 10.1055/s-0043-103573

Barber T, Hanson P, Weickert M, Franks S. (2019) Obesity and polycystic ovary syndrome: implications for pathogenesis and novel management strategies. Clinical Medicine Insights: Reproductive Health. 13: 1–9 DOI: 10.1177/1179558119874042

Bornstein SR, Dalan R, Hopkins D, Mingrone G, Boehm BO. (2020) Endocrine and metabolic link to coronavirus infection. Nature Reviews Endocrinology. 16 (6): 297–298 DOI: 10.1038/s41574-020-0353-9

Bramante C, Tignanelli C, Dutta N, Jones E, Tamariz L, Clark J, Usher M, Metlon-Meaux G, Ikramuddin S. (2020) Non-alcoholic fatty liver disease (NAFLD) and risk of hospitalization for Covid-19. medRxiv. 2020.09.01.20185850 DOI: 10.1101/2020.09.01.20185850

Brugger S, Bomar L, Lemon K. (2016) Commensal–pathogen interactions along the human nasal passages. PLoS Pathogens. 12 (7): e1005633 DOI: 10.1371/journal.ppat.1005633

Cai H. (2020) Sex difference and smoking predisposition in patients with COVID-19. The Lancet Respiratory Medicine. 8 (4): e20 DOI: 10.1016/S2213-2600(20)30117-X

Cedars M, Steingold K, De Ziegler D, Lapolt P, Chang R, Judd H. (1992) Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: Assessment of the adrenal role in ovarian dysfunction. In Fertility and SterilityFertil Steril.57(3): 495–500. DOI: 10.1016/s0015-0282(16)54890-0

Cerf-Bensussan N, Gaboriau-Routhiau V. (2010) The immune system and the gut microbiota: Friends or foes? Nature Reviews Immunology. 10 (10): 735–744 DOI: 10.1038/nri2850

Chan J, Kok K, Zhu Z, Chu H, To K, Yuan S, Yuen K. (2020) Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerging Microbes and Infections. 9 (1): 221–236 DOI: 10.1080/22221751.2020.1719902

Cucinotta D, Vanelli M. (2020) WHO declares COVID-19 a pandemic. Acta Biomedica. 91 (1): 157–160 DOI: 10.23750/abm.v91i1.9397

Dalpiaz P, Lamas A, Caliman I, Ribeiro R, Abreu G, Moyses M, Andrade T, Gouvea S, Alves M, Carmona A, et al. (2015) Sex hormones promote opposite effects on ACE and ACE2 activity, hypertrophy and cardiac contractility in spontaneously hypertensive rats. PLoS ONE. 10 (5) DOI: 10.1371/journal.pone.0127515

Docherty A, Harrison E, Green C, Hardwick H, Pius R, Norman L, Holden K, Read J, Dondelinger F, Carson G, et al. (2020) Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol. JS Nguyen-Van-Tam. 10: 2020.04.23.20076042 DOI: 10.1101/2020.04.23.20076042

Fagone P, Ciurleo R, Lombardo S, Iacobello C, Palermo C, Shoenfeld Y, Bendtzen K, Bramanti P, Nicoletti F. (2020) Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies. Autoimmunity Reviews. 19 (7): 102571 DOI: 10.1016/j.autrev.2020.102571

Finucane FM, Davenport C. (2020) Coronavirus and obesity: could insulin resistance mediate the severity of Covid-19 infection? Frontiers in Public Health. 8: 184 DOI: 10.3389/fpubh.2020.00184

Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P, Suzuki S, Shaw M, Kim Y, Núñez G. (2012) NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nature Immunology. 13 (5): 449–456 DOI: 10.1038/ni.2263

Frisardi V. (2020) Commentary: coronavirus and obesity: could insulin resistance mediate the severity of Covid-19 infection? Frontiers in Public Health. 8: 351 DOI: 10.3389/fpubh.2020.00351

González F, Nair K, Daniels J, Basal E, Schimke J, Blair H. (2012) Hyperandrogenism sensitizes leukocytes to hyperglycemia to promote oxidative stress in lean reproductive-age women. Journal of Clinical Endocrinology and Metabolism. 97 (8): 2836–2843 DOI: 10.1210/jc.2012-1259

Goren A, Vaño‐Galván S, Wambier C, McCoy J, Gomez‐Zubiaur A, Moreno‐Arrones O, Shapiro J, Sinclair R, Gold M, Kovacevic M, et al. (2020) A preliminary observation: Male pattern hair loss among hospitalized COVID‐19 patients in Spain – A potential clue to the role of androgens in COVID‐19 severity. Journal of Cosmetic Dermatology. 19 (7): 1545–1547 DOI: 10.1111/jocd.13443

Gou W, Fu Y, Yue L, Chen G, Cai X, Shuai M, Xu F, Yi X, Chen H, Zhu Y, et al. (2020)Gut microbiota may underlie the predisposition of healthy individuals to COVID-19-sensitive proteomic biomarkers. medRxiv. 2020.04.22.20076091 DOI: 10.1101/2020.04.22.20076091

Grant W, Lahore H, McDonnell S, Baggerly C, French C, Aliano J, Bhattoa H. (2020) Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 12 (4): 988 DOI: 10.3390/nu12040988

Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, Liu L, Shan H, Lei C, Hui D, et al. (2020) Clinical characteristics of coronavirus disease 2019 in China. New England Journal of Medicine. 382 (18): 1708–1720 DOI: 10.1056/nejmoa2002032

Guo R, Zheng Y, Yang J, Zheng N. (2015) Association of TNF-alpha, IL-6 and IL-1beta gene polymorphisms with polycystic ovary syndrome: a meta-analysis. BMC Genetics. 16 (1): 5 DOI: 10.1186/s12863-015-0165-4

Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, Qin R, Wang H, Shen Y, Du K, et al. (2020) Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes/Metabolism Research and Reviews. 36 (7) DOI: 10.1002/dmrr.3319

Hägglöf C, Hammarsten P, Strömvall K, Egevad L, Josefsson A, Stattin P, Granfors T, Bergh A. (2014) TMPRSS2-ERG expression predicts prostate cancer survival and associates with stromal biomarkers. PLoS ONE. 9 (2): e86824 DOI: 10.1371/journal.pone.0086824

Hignett W, Kyle T, Mba R. (2011) Polycystic ovarian syndrome ( PCOS ) and obesity. Your Weight Matters Magazine. 1–3 Available at: https://www.obesityaction.org/community/article-library/polycystic-ovarian-syndrome-pcos-and-obesity/ [Accessed 31 October 2020]

Ichinohe T, Pang I, Kumamoto Y, Peaper D, Ho J, Murray T, Iwasaki A. (2011) Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proceedings of the National Academy of Sciences of the United States of America. 108 (13): 5354–9 DOI: 10.1073/pnas.1019378108

Ilie P, Stefanescu S, Smith L. (2020) The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research. 32 (7): 1195–1198 DOI: 10.1007/s40520-020-01570-8

Intensive Care National Audit & Research Centre (ICNARC) – Reports. (2020) COVID-19 Report Available at: https://www.icnarc.org/Our-Audit/Audits/Cmp/Reports [Accessed 9 November 2020]

Jin J, Bai P, He W, Wu F, Liu X, Han D, Liu S, Yang J. (2020) Gender differences in patients with COVID-19: focus on severity and mortality. Frontiers in Public Health. 8: 152 DOI: 10.3389/fpubh.2020.00152

Kahn S. (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 46 (1): 3–19 DOI: 10.1007/s00125-002-1009-0

Kamada N, Chen G, Inohara N, Núñez G. (2013) Control of pathogens and pathobionts by the gut microbiota. Nature Immunology. 14 (7): 685–690 DOI: 10.1038/ni.2608

Kumar P, Chander B. (2020) COVID 19 mortality: Probable role of microbiome to explain disparity. Medical Hypotheses. 144: 110209 DOI: 10.1016/j.mehy.2020.110209

Kumarendran B, O’Reilly M, Manolopoulos K, Toulis K, Gokhale K, Sitch A, Wijeyaratne C, Coomarasamy A, Arlt W, Nirantharakumar K. (2018) Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database. PLoS Medicine. 15 (3): e1002542 DOI: 10.1371/journal.pmed.1002542

Kyrou I, Karteris E, Robbins T, Chatha K, Drenos F, Randeva H. (2020) Polycystic ovary syndrome (PCOS) and COVID-19: An overlooked female patient population at potentially higher risk during the COVID-19 pandemic. BMC Medicine. 18 (1): 1–10 DOI: 10.1186/s12916-020-01697-5

Kyrou I, Randeva H, Tsigos C, Kaltsas G, Weickert M. (2000) Clinical problems caused by obesity. MDText.com, Inc. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25905207 [Accessed 31 October 2020]

Kyrou I, Randeva H, Tsigos C, Kaltsas G, Weickert M. (2018)clinical problems caused by obesity. Available at: https://pubmed.ncbi.nlm.nih.gov/25905207/ [Accessed 9 November 2020]

Kyrou I, Weickert M, Randeva H. (2015) Diagnosis and management of polycystic ovary syndrome (PCOS). In Endocrinology and Diabetes: Case Studies, Questions and CommentariesSpringer-Verlag London Ltd; 99–113. DOI: 10.1007/978-1-4471-2789-5_13

Lee J, Tae J, Kim C, Hwang D, Kim K, Suh C, Kim S. (2017) Expression of the genes for peroxisome proliferatoractivated receptor-γ, cyclooxygenase-2, and proinflammatory cytokines in granulosa cells from women with polycystic ovary syndrome. Clinical and Experimental Reproductive Medicine. 44 (3): 146–151 DOI: 10.5653/cerm.2017.44.3.146

van der Lelie D, Taghavi S. (2020) COVID-19 and the Gut Microbiome: More than a Gut Feeling. mSystems. 5 (4): e00453-20 DOI: 10.1128/msystems.00453-20

Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, Shi J, Zhou M, Wu B, Yang Z, et al. (2020) Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. Journal of Allergy and Clinical Immunology. 146 (1): 110–118 DOI: 10.1016/j.jaci.2020.04.006

Liu Z. (2007) The renin-angiotensin system and insulin resistance. Current Diabetes Reports. 7 (1): 34–42 DOI: 10.1007/s11892-007-0007-5

Macut D, Tziomalos K, Božić-Antić I, Bjekić-Macut J, Katsikis I, Papadakis E, Andrić Z, Panidis D. (2016) Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Human Reproduction. 31 (6): 1347–1353 DOI: 10.1093/humrep/dew076

Manisha R, Shane B, Monique L. (2020) Cross-sectional Study on the Knowledge and Prevalence of PCOS at a Multiethnic University. Progress in Preventive Medicine. 5 (2): e0028 DOI: 10.1097/pp9.0000000000000028

Marik P, Kory P, Varon J. (2020) Does vitamin D status impact mortality from SARS-CoV-2 infection? Medicine in Drug Discovery. 6: 100041 DOI: 10.1016/j.medidd.2020.100041

McCoy J, Wambier C, Vano-Galvan S, Shapiro J, Sinclair R, Ramos P, Washenik K, Andrade M, Herrera S, Goren A. (2020) Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19? Journal of Cosmetic Dermatology. 19 (7): 1542–1543 DOI: 10.1111/jocd.13455

Mehta P, McAuley D, Brown M, Sanchez E, Tattersall R, Manson J. (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 395 (10229): 1033–1034 DOI: 10.1016/S0140-6736(20)30628-0

Möhlig M, Flöter A, Spranger J, Weickert M, Schill T, Schlösser H, Brabant G, Pfeiffer A, Selbig J, Schöfl C. (2006) Predicting impaired glucose metabolism in women with polycystic ovary syndrome by decision tree modelling. Diabetologia. 49 (11): 2572–2579 DOI: 10.1007/s00125-006-0395-0

Moin A, Sathyapalan T, Atkin S, Butler A. (2020) Renin-Angiotensin System overactivation in polycystic ovary syndrome, a risk for SARS-CoV-2 infection? Metabolism Open. 7: 100052 DOI: 10.1016/j.metop.2020.100052

Morgante G, Troìa L, De Leo V. (2020) Coronavirus Disease 2019 (SARS-CoV-2) and polycystic ovarian disease: is there a higher risk for these women? The Journal of Steroid Biochemistry and Molecular Biology. 205: 105770 DOI: 10.1016/j.jsbmb.2020.105770

Muscogiuri G, Mitri J, Mathieu C, Badenhoop K, Tamer G, Orio F, Mezza T, Vieth R, Colao A, Pittas A. (2014) Mechanisms in endocrinology: Vitamin D as a potential contributor in endocrine health and disease. European Journal of Endocrinology. 171 (3): R101–R110 DOI: 10.1530/EJE-14-0158

Nestler J, Powers L, Matt D, Steingold K, Plymate S, Rittmaster R, Clore J, Blackard W. (1991) A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 72 (1): 83–89 DOI: 10.1210/jcem-72-1-83

Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, Shaw T, Warner FJ, Zuilli A, Burrell LM, et al. (2005) Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut. 54 (12): 1790–1796 DOI: 10.1136/gut.2004.062398

Panarese A, Shahini E. (2020) Letter: Covid-19, and vitamin D. Alimentary Pharmacology & Therapeutics. 51 (10): 993–995 DOI: 10.1111/apt.15752

Paschou S, Polyzos S, Anagnostis P, Goulis D, Kanaka-Gantenbein C, Lambrinoudaki I, Georgopoulos N, Vryonidou A. (2020) Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Endocrine. 67 (1): 1–8 DOI: 10.1007/s12020-019-02085-7

Pasquali R. (2018) Metabolic syndrome in polycystic ovary syndrome. Frontiers of Hormone Research. 49: 114–130 DOI: 10.1159/000485995

Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX, Huang K, Zeng QT. (2020) Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV. Zhonghua xin xue guan bing za zhi. 48 (6): 450–455 DOI: 10.3760/cma.j.cn112148-20200220-00105

Peng Z, Sun Y, Lv X, Zhang H, Liu C, Dai S. (2016) Interleukin-6 levels in women with polycystic ovary syndrome: A systematic review and meta-analysis. PLoS ONE. 11 (2): e0148531 DOI: 10.1371/journal.pone.0148531

Petrilli C, Jones S, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, Tobin K, Cerfolio R, Francois F, Horwitz L. (2020) Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. BMJ.  369. 2020.04.08.20057794 DOI: 10.1101/2020.04.08.20057794

Prins G, Olinga P. (2020) Potential implications of COVID-19 in non-alcoholic fatty liver disease. Liver International. 40 (10): 2568 DOI: 10.1111/liv.14484

Quinn M, Shinkai K, Pasch L, Kuzmich L, Cedars M, Huddleston H. (2014) Prevalence of androgenic alopecia in patients with polycystic ovary syndrome and characterization of associated clinical and biochemical features. Fertility and Sterility. 101 (4): 1129–1134 DOI: 10.1016/j.fertnstert.2014.01.003

Randeva H, Tan B, Weickert M, Lois K, Nestler J, Sattar N, Lehnert H. (2012) Cardiometabolic aspects of the polycystic ovary syndrome. Endocrine Reviews. 33 (5): 812–841 DOI: 10.1210/er.2012-1003

Rao S, Lau A, So H. (2020) Exploring Diseases/Traits and Blood Proteins Causally Related to Expression of ACE2, the Putative Receptor of SARS-CoV-2: A mendelian randomization analysis highlights tentative relevance of diabetes-related traits. Diabetes Care. 43 (7): 1416–1426 DOI: 10.2337/dc20-0643

Rastrelli G, Di Stasi V, Inglese F, Beccaria M, Garuti M, Di Costanzo D, Spreafico F, Greco G, Cervi G, Pecoriello A, et al. (2020) Low testosterone levels predict clinical adverse outcomes in SARS‐CoV‐2 pneumonia patients. Andrology. 12821 DOI: 10.1111/andr.12821

Reis G, Dos OP, Gontijo N, Rodrigues K, Alves M, Ferreira C, Gomes K. (2017) Vitamin D receptor polymorphisms and the polycystic ovary syndrome: A systematic review. Journal of Obstetrics and Gynaecology Research. 43 (3): 436–446 DOI: 10.1111/jog.13250

Rhodes J, Subramanian S, Laird E, Kenny R. (2020) Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Alimentary Pharmacology & Therapeutics. 51 (12): 1434–1437 DOI: 10.1111/apt.15777

Salva-Pastor N, López-Sánchez GN, Chávez-Tapia N, Audifred-Salomón J, Niebla-Cárdenas D, Topete-Estrada R, Pereznuñez-Zamora H, Vidaltamayo-Ramírez R, Báez-Arellano M, Uribe M, et al. (2020) Polycystic ovary syndrome with feasible equivalence to overweight as a risk factor for non-alcoholic fatty liver disease development and severity in Mexican population. Annals of Hepatology. 19 (3): 251–257 DOI: 10.1016/j.aohep.2020.01.004

Sam S. (2007) Obesity and polycystic ovary syndrome. Obesity Management. 3 (2): 69–73 DOI: 10.1089/obe.2007.0019

Sam S, Dunaif A. (2003) Polycystic ovary syndrome: Syndrome XX? Trends in Endocrinology and Metabolism. 14 (8): 365–370 DOI: 10.1016/j.tem.2003.08.002

Schroeder M, Tuku B, Jarczak D, Nierhaus A, Bai T, Jacobsen H, Zickler M, Mueller Z, Stanelle-Bertram S, Meinhardt A, et al. (2020) The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive Care in Hamburg, Germany: a retrospective cohort study. medRxiv. 2020.05.07.20073817 DOI: 10.1101/2020.05.07.20073817

Sepilian V, Nagamani M. (2005) Adiponectin levels in women with polycystic ovary syndrome and severe insulin resistance. Journal of the Society for Gynecologic Investigation. 12 (2): 129–134 DOI: 10.1016/j.jsgi.2004.09.003

Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. (2020) Nonalcoholic steatohepatitis: A review. JAMA – Journal of the American Medical Association. 323 (12): 1175–1183 DOI: 10.1001/jama.2020.2298

Silberstein M. (2020) Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Medical Hypotheses. 140: 109767 DOI: 10.1016/j.mehy.2020.109767

Strope J, Chau C, Figg W. (2020) Are sex discordant outcomes in COVID-19 related to sex hormones? Seminars in Oncology. 47 (5): 335 DOI: 10.1053/j.seminoncol.2020.06.002

Teede H, Misso M, Costello M, Dokras A, Laven J, Moran L, Piltonen T, Norman R, Andersen M, Azziz R, et al. (2018) Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertility and Sterility. 110 (3): 364–379 DOI: 10.1016/j.fertnstert.2018.05.004

Tian Y, Rong L. (2020) Letter: Covid-19, and vitamin D. Authors’ reply. Alimentary Pharmacology & Therapeutics. 51 (10): 995–996 DOI: 10.1111/apt.15764

Torres P, Siakowska M, Banaszewska B, Pawelczyk L, Duleba A, Kelley S, Thackray V. (2018) Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. The Journal of Clinical Endocrinology & Metabolism. 103 (4): 1502–1511 DOI: 10.1210/jc.2017-02153

Unger T. (2002) The role of the renin-angiotensin system in the development of cardiovascular disease. In American Journal of CardiologyElsevier Inc. 24;89(2A):3A-9A. DOI: 10.1016/S0002-9149(01)02321-9

Urbanek M. (2007) The genetics of the polycystic ovary syndrome. Nature Clinical Practice Endocrinology and Metabolism. 3 (2): 103–111 DOI: 10.1038/ncpendmet0400

Vassilatou E, Lafoyianni S, Vryonidou A, Ioannidis D, Kosma L, Katsoulis K, Papavassiliou E, Tzavara I. (2010) Increased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome. Human Reproduction. 25 (1): 212–220 DOI: 10.1093/humrep/dep380

Vejakama P, Thakkinstian A, Lertrattananon D, Ingsathit A, Ngarmukos C, Attia J. (2012) Reno-protective effects of renin-angiotensin system blockade in type 2 diabetic patients: A systematic review and network meta-analysis. Diabetologia. 55 (3): 566–578 DOI: 10.1007/s00125-011-2398-8

La Vignera S, Cannarella R, Condorelli R, Torre F, Aversa A, Calogero A. (2020) Sex-specific SARS-CoV2 mortality: Among hormone-modulated ace2 expression, risk of venous thromboembolism and hypovitaminosis D. International Journal of Molecular Sciences. 21 (8): 2948 DOI: 10.3390/ijms21082948

Vural P, Deǧirmencioǧlu S, Saral N, Akgül C. (2010) Tumor necrosis factor α (-308), interleukin-6 (-174) and interleukin-10 (-1082) gene polymorphisms in polycystic ovary syndrome. European Journal of Obstetrics and Gynecology and Reproductive Biology. 150 (1): 61–65 DOI: 10.1016/j.ejogrb.2010.02.010

Wambier C, Goren A. (2020) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. Journal of the American Academy of Dermatology. 83 (1): 308–309 DOI: 10.1016/j.jaad.2020.04.032

Wambier C, Goren A, Vaño‐Galván S, Ramos P, Ossimetha A, Nau G, Herrera S, McCoy J. (2020) Androgen sensitivity gateway to <scp>COVID</scp> ‐19 disease severity. Drug Development Research. 81(7):771-776. DOI: 10.1002/ddr.21688

Wiese O, Allwood B, Zemlin A. (2020) COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight? Medical Hypotheses. 144: 110231 DOI: 10.1016/j.mehy.2020.110231

Wu J, Yao X, Shi R, Liu S, Wang X. (2018) A potential link between polycystic ovary syndrome and non-alcoholic fatty liver disease: An update meta-analysis. Reproductive Health. 15 (1): 77 DOI: 10.1186/s12978-018-0519-2

Wu Z, McGoogan J. (2020) Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention. JAMA – Journal of the American Medical Association. 323 (13): 1239–1242 DOI: 10.1001/jama.2020.2648

Xu L, Liu J, Lu M, Yang D, Zheng X. (2020) Liver injury during highly pathogenic human coronavirus infections. Liver International. 40 (5): 998–1004 DOI: 10.1111/liv.14435

Yang J, Hu J, Zhu C. (2020) Obesity aggravates COVID‐19: A systematic review and meta‐analysis. Journal of Medical Virology. jmv.26237 DOI: 10.1002/jmv.26237

Yuki K, Fujiogi M, Koutsogiannaki S. (2020) COVID-19 pathophysiology: A review. Clinical Immunology. 215: 108427 DOI: 10.1016/j.clim.2020.108427

Zhang Y, Che L, Zhang M, He J. (2020) Common cytokine polymorphisms and predisposition to polycystic ovary syndrome: a meta-analysis. Endocrine Journal. 67 (5): 561–567 DOI: 10.1507/endocrj.EJ19-0558

Zuo T, Zhang F, Lui G, Yeoh Y, Li A, Zhan H, Wan Y, Chung ACK, Cheung CP, Chen N, et al. (2020) Basic and translational-alimentary tract alterations in gut microbiota of patients with covid-19 during time of hospitalization. Gastroenterology. 159: 944-955.e8 DOI: 10.1053/j.gastro.2020.05.048