The purpose of this study is to summarize the findings of relevant studies that investigated the association between COVID-19 and PCOS in order to highlight the possible risk factors that may render PCOS patients more liable for morbidity and mortality in cases of COVID-19 infection. In addition to assess whether women with PCOS are at a higher susceptibility and risk for COVID-19 complications.

This systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, ^{15 , 53} with and pre-registered protocol on PROSPERO [CRD42023371956] on January 12, 2023. It investigates available evidence regarding the relationship between COVID-19 and PCOS.

We included papers that investigated the relationship between PCOS and COVID-19 infection and complications. The interest of the investigation is the main impact of PCOS disease on the infection, course, complications, and outcome of COVID-19 disease. The inclusion criteria of this study were: 1) Papers investigating the underlying factors between PCOS and COVID-19 disease, 2) Studies comparing normal and PCOS patients, 3) in vivo studies, 4) English language papers, and 5) Free access papers. Information sources included PubMed, Scopus, Web of Science, Cochrane library, and Google Scholar.

The search for relevant literature was conducted on PubMed, Scopus, Cochrane Library, and Google Scholar, with date restrictions from the beginning of the COVID-19 pandemic December 1, 2019, until November 1, 2022. A detailed overview of the systematic search is provided in Table 1. It is important to note that the search strategy adhered to recent recommendations for systematic reviews. ¹⁶ The first 200 records on Google Scholar were searched, as the relevance of the results significantly decreased beyond this point. We also researched related systematic reviews published in the field to identify potentially relevant full-text articles. After completing the searches, we exported the retrieved references to an EndNote X9 ^® (Alternatively, Zotero could be used as an open-access which can perform the same function) file and removed duplicates. Two independent reviewers (WA, SK) screened the titles and abstracts and assessed potential full texts for eligibility. Studies that met our eligibility criteria were included in our review. Any discrepancies between reviewers were resolved by a third reviewer (MJJT, MTA).

Each paper was independently extracted by two authors to avoid any bias. Characteristics and outcome data from the included papers and any discrepancies were resolved by a third reviewer. Characteristics extracted from trials included: study design, country of participants, main outcome, sample characters, and key findings of the papers. A separate section was also added for quality assessment of the papers.

The quality of the retrieved papers was assessed according to the National Institutes of Health (NIH) quality assessment tool. ¹⁷ Each type of research was assessed to the suitable tool from NIH quality assessment tools. The score of each paper is illustrated in Table 2.

PCOS: Polycystic ovary syndrome, SCARFs: coronavirus-associated receptors and factors

The collected data from the included studies was qualitatively synthesized. No quantitative evaluations were performed due to heterogeneity of the data. In the qualitative synthesis, summarizing was done. Next, the dangers of COVID-19 on PCOS were examined in relation to baseline parameters (age, gender, body mass index (BMI), presenting symptoms, signs and complications).

We retrieved 361 records from our search, 200 duplicates were removed, and the remaining 66 titles and abstracts were screened. Then, 29 potential full texts were assessed, and 11 studies were included in this review. ^{18 – 28} The flow of studies is illustrated in Figure 1.

All included studies are observational studies with a total of 22,155 PCOS patients, from four countries (United Kingdom, India, Slovenia, and Turkey). A retrospective cohort study discussed the susceptibility of COVID-19 in PCOS patients. ²⁷ A total of four papers discussed the biomarkers that were elevated in both PCOS and COVID-19. ^{21 – 24} A retrospective cohort study discussed both biomarkers and COVID-19 susceptibility. ²⁵ A cross sectional study discussed the expression of the SARS-Co-V-2 receptors on the ovarian granulosa cells. ²⁶ In total, four papers, two cohorts ^{20 , 28} and two cross sectionals, ^{18 , 19} discussed the psychological aspect such as depression and anxiety. Despite the heterogeneity of the included studies, they all tend to agree upon the predisposition of PCOS patients to a more severe form of COVID-19 infection.

The overall quality of the included studies was high (9.25 ±1.75). The characteristics and details of the papers included in the systematic review are summarized in Table 2.

The effect of PCOS on the course of COVID-19 infection is reported in only two clinical studies only; Subramanian et al. ²⁶ conducted a retrospective cohort study on 21,292 PCOS patients in the UK, compared to their age-matched 78,310 women without PCOS, to assess the risk of COVID-19 infection in PCOS patient. The study revealed a 51% higher risk of COVID-19 infection in women with PCOS compared to controls (HR =1.51). However, the hazard ratio was reduced to 1.36 after adjustment for BMI, and it was further reduced to 1.28 in the fully adjusted model. ²⁷

Contrary to these observations, Yale et al. conducted a study on 1590 PCOS women who tested positive for COVID-19 infection and concluded no evidence for an increased risk of COVID-19 infection, hospitalization, or mortality in women with PCOS compared to controls. ²⁹

The COVID-19 quarantine had both positive and negative consequences on the mental health of PCOS patients. Atkinson et al. conducted a cross sectional study on 12 PCOS patients in the UK and found that the lockdown caused a detrimental impact on PCOS women’s weight reduction in a variety of ways, including the inability to use exercise facilities such as gyms, pools, and classes, as well as decreased physical activity, which was reported as a major concern of PCOS patients. ¹⁸ A cohort study conducted by Sustarsic et al., also reported that women achieved a 6.8% weight loss before the lockdown, which was decreased to 3.7% during the lockdown. ²⁸ Furthermore, another cohort study on 333 PCOS patients in the UK conducted by Kite et al. discovered increased levels of sleep disruption and insomnia, which correlates with findings of higher levels of stress and despair in these patients during the lockdown. ²⁰

On the other hand, some patients reported positive impact during the quarantine as it breaks the work routine allowing these individuals to adopt new exercise and eating habits, as described by Atkinson et al. ¹⁸

Moin et al. conducted a series of studies investigating the levels of the inflammatory markers and proteins that are characteristically altered in COVID-19 disease in both PCOS and non-PCOS patients. ^{21 – 25} PCOS patients demonstrated an overactivation of the renin-angiotensin-aldosterone system (RAAS) and elevated levels of RAAS-associated proteins. These include renin, angiotensin, and vascular endothelial growth factor (VEGF), together with reduced Angiotensin-converting enzyme 2 (ACE-2) levels, which may lead to more complications and severe outcomes of infection. Furthermore, a study suggests there may be a possible increased susceptibility of COVID-19 in PCOS patients due to decreased serum levels of soluble neuropilin-1 (sNRP1), elevated levels of membrane bound neuropilin-1 and RAAS hyperactivity. ²⁵ A total of 21 out of 60 serum biomarkers of platelet degranulation and coagulation cascade markers and acute phase response proteins were altered in PCOS women when compared to the control group. ²³ A similar study reported that 12 out of 34 protein biomarkers contained within the platelet degranulation and coagulation cascades had different levels between PCOS women and controls. ²²

Naigaonkar et al. found a lower expression of SARS-CoV-2 receptors; Angiotensin converting enzyme 2 (ACE-2), Basigin (BSG), C-type lectin domain family four member M (CLEC4M) and Dipeptidyl peptidase 4 (DPP4), in the ovarian granulosa cells of PCOS patients. ²⁶ In addition, similar or higher expressions of the following proteases: Transmembrane protease serine 2 (TMPRSS2), Furin, Cathepsin B (CTSB), and Cathepsin L (CTSL) was found. The ACE-2 receptor was downregulated in the granulosa cells of PCOS women compared to the control group. The BSG receptor was downregulated in the cells but had a higher expression in the granulosa cells of PCOS women. Additionally, Furin was downregulated in the oocytes and upregulated in the granulosa cells of PCOS women. CTSB was elevated in both the oocytes and granulosa cells of women with PCOS. TMPRSS2 receptor was not expressed in the ovarian granulosa cells. ²⁶

The relationship between vitamin D and macrophage-derived cytokines was revealed in a study by Moin, ²¹ who discovered that PCOS patients had lower vitamin D levels than controls, which is related with noticeably greater levels of baseline macrophage activation markers, such as chemokine CXC ligand 5 (CXCL5), CD163, and matrix metalloproteinase-9 (MMP9), in addition to lower levels of the protective CD200, CD80, and IL12. These findings correlated negatively with the BMI, as when the data was adjusted for BMI, none of these indicators were substantially different between the two groups, implying that the vitamin-D associated rise in inflammatory markers may be accounted for by elevated BMI.

This systematic review shows the relationship between polycystic ovarian syndrome PCOS and COVID-19 infection, complications, and severity. This paper found that BMI was the most important risk factor for COVID-19 susceptibility in PCOS women as it had the highest impact on the hazard ratio of COVID-19 infection in these patients. ²⁷ Furthermore, vitamin D deficiency in these women was linked with increased levels of macrophage derived inflammatory markers. ²¹

In addition, the study revealed an association between PCOS and COVID-19 in terms of higher serum levels of characteristic biomarkers common between the two. ^{22 , 23} Moreover, the study found that PCOS patients suffer from hyperactivity of the RAAS system, which is associated with reduced levels of both sNRP1 and ACE2 in their serum, ^{23 , 24} consequently resulting in an increased susceptibility to COVID-19 infection as well as a more severe form of the disease.

The findings of Naigaonkar et al. stated that the ovarian granulosa cells had decreased expression of SARS-CoV-2 receptors. ²⁶ The majority of findings concerning the impact of the COVID-19 pandemic on the lifestyle and mental health of women with PCOS indicated adverse effects as well.

This systematic review aims to report the relationship between polycystic ovarian syndrome PCOS and COVID-19 infection, complications, and severity. Our search yielded 11 papers investigating the relationship between COVID-19 infection and PCOS. All included papers were observational studies that describe the overlapping risk factors for both diseases.

Starting by susceptibility of PCOS patients to COVID-19 disease, we found that PCOS patients are more prone to COVID-19 infection. A relationship which is attributed to many factors reported by Subramanian et al., who found that BMI had the highest impact on the hazard ratio of severe COVID-19 in PCOS patients. ²⁷ This could be explained by the fact that high BMI levels are associated with increased insulin level, which has been shown to stimulate ovarian androgen production. ³⁰ Additionally, BMI is associated with overexpression of ACE-2 in adipocytes, chronic systemic inflammation, and overactivation of the immune system. ³¹ However, it is noteworthy to mention that Kyrou et al. reported that hyperandrogenism was the main risk factor that could render PCOS patients prone to COVID-19 infection as it increased the ACE-2 expression which could increase the COVID-19 entry into the cell. ⁶

Hyperandrogenism is a common disorder in PCOS patients, and it has been linked to increased severity of SARS-CoV-2 infection. Evidence from literature supports the fact that hyperandrogenism favors COVID-19 infection by causing upregulation of its receptors, increasing the viral entry into host’s cells. ³² One of these receptors is the TMPRSS2 enzyme, which interacts with the viral spike protein facilitating its entry to the pneumocytes. This receptor is controlled by testosterone levels in blood. Another enzyme that is upregulated by the high androgen levels is ACE-2, which acts as a key mediator for the viral entry to the cells. ^{6 , 31} After the viral entry, degradation of ACE-2 by SARS-CoV-2 takes place, strengthening the positive feedback loop of inflammation, and enhancing the acute inflammation observed in severe COVID-19. ³³ On a different note, the findings of Naigaonkar’s study ²⁵ were of importance. The ovarian granulosa cells had decreased expression of SARS-CoV-2 receptors, which could operate as a protective factor against COVID-19 infection to PCOS women’s ovaries. These findings are supported in literature by several studies. ^{34 , 35}

The development of an inflammatory cytokine storm causing multisystem failure, and possibly death, is one of the main complications of COVID-19 illness. ³⁶ PCOS has been linked to higher serum levels of biomarkers and proteins such as platelet degranulation, vascular injury, and acute phase response proteins, all of which are common in both conditions and can introduce patients to a chronic inflammatory state. ⁶ Vitamin D deficiency was reported in nearly 75% of women with PCOS which is connected to increased underlying inflammation and a higher probability of catastrophic COVID-19 outcomes. ^{37 , 38} This could be explained by vitamin D’s role in modulating and regulating cytokine release during inflammation and reducing the severity of infection. ³⁹

These inflammatory and biochemical interactions between PCOS and COVID-19 are of great importance. Novel research suggests a multifactorial relationship between menstrual cycle and COVID-19, especially when considering the systemic hormonal effect of both the hypothalamic-pituitary axis, and the ovarian-endometrial axis. Of these effects, the anti-inflammatory effect of ovarian progesterone is of interest. In normal settings, an inflammatory state such as COVID-19 infection would alter the effect of progesterone on the endometrial shedding resulting in decreased menstrual volume and a prolonged cycle. ^{40 , 41} However, these symptoms can cause confusion in the setting of PCOS for two main reasons: The first is that these symptoms resemble those of PCOS, which might suggest that COVID-19 predisposes to a PCOS-like state, the second is that PCOS patients, being subjected to endometrial progesterone resistance, are at risk of more severe effects of COVID-19 induced inflammation. ³² These findings are of significant importance, but further research is yet to be conducted to confirm and understand these associations between menstrual or ovulatory disorders (such as PCOS) and COVID-19.

Thrombotic events were one of the major complications linked to COVID-19 illness. According to literature, they are linked to specific risk factors such as endothelial injury, obesity, inflammation, complement activation, microvascular damage, and inflammatory mediators. ^{42 , 43} Many of these markers have been found to be higher in PCOS patients, potentially increasing the risk of thrombotic events if COVID-19 infection develops. ^{23 , 27}

Several treatment modalities exist for PCOS, and in the setting of COVID-19, these modalities can alter the course of COVID-19 or be altered by it. One of the commonly administered drugs for COVID-19 patients is Metformin, which helps regulate insulin resistance and moderate BMI and androgen excess. ⁴⁴ Fortunately, Metformin could help reduce COVID-19 severity in patients, due to its anti-viral and anti-inflammatory effects, as shown in a study conducted by Chan et al. ⁴⁵ An interesting study by Jerzak and Szafarowska investigated personalized therapy protocols for pregnant PCOS patients positive for COVID-19. ⁴⁶ Due to the complexity of cases, individualized modalities have been applied, with main components of anti-coagulants as Aspirin and Low Molecular Weight Heparin (LMWH), anti-inflammatory drugs as N-acetylcysteine (NAC), and Metformin. The overall outcome was promising, with little to no symptoms of infection, allowing for preservation of health. ⁴⁶ This points towards the possibility of protecting vulnerable PCOS patients from severe COVID-19 consequences using simple yet effective treatment regimes.

In terms of mental health and lifestyle, the negative effect of COVID-19 pandemic on PCOS patients was the most prevalent. Studies reported that the overall impact of the COVID-19 pandemic on lifestyle and mental health of the PCOS patients was negative, with the exception of better sleep quality. ⁴⁷ In contrast to the previous finding, evidence from cohort research conducted by Kite et al. revealed that restricting measures used during the COVID-19 pandemic had a negative impact on sleep quality, with an increased amount of daytime sleeplessness in PCOS patients. ²⁰ Furthermore, depression is one of the main hazards that threaten PCOS patients, as reported by Wang et al. ⁴⁸ Wang et al. found that women with PCOS had a high prevalence of anxiety and depression. Depression and anxiety levels were elevated during the COVID-19 pandemic as found by a systematic review conducted by Deng et al. ⁴⁹ Deng and his team had gathered information on 5153 COVID-19 patients and found that 45% of COVID-19 patients experienced depression and 47% experienced anxiety. Despite similar conclusions, depression and anxiety levels measurements were dependent on population surveys that can be subjective and may lack standard measurement rules. Another important finding in the present review shows that the COVID-19 pandemic disrupted weight-loss programs, potentially escalating the risks and complications of obesity, as well as increasing BMI, which is the main reason for the increase in severity of COVID-19 complications in PCOS patients, as stated previously. Similarly, weight gain has been reported in numerous investigations on people of various ages and occupations as a global complication of the COVID-19 pandemic lockdown. ^{50 – 52}

The overall COVID-19 complications that are exaggerated in PCOS patients, render these patients vulnerable to true risks, and shed the light on the importance of giving these patients a treatment priority, with more medical attention, thorough management and close follow up when they develop COVID-19. An illustration of the factors intertwining between COVID-19 and PCOS is provided in Figure 2.

The key strength of this review is the ability to cumulatively assess the interaction between PCOS and COVID-19 at both the clinical and molecular levels and evaluate their impact on the severity of the COVID-19. In addition, this review handled both psychological and pathophysiological aspects of the PCOS disease impact on the COVID-19 course, complications and outcomes. Nevertheless, the findings of this review were subject to some limitations, as all included papers were observational studies, risking higher bias and confounding. Moreover, the heterogeneity in diagnosis, measurement of the outcome, and lacking data about mortality and hospitalization emphasize the need for more in-depth investigation to clarify the significance of each contributing factor to this association. Further focused analysis of PCOS patients in the scope of COVID-19 infection is needed to ensure the assessment of all relevant aspects of this risky interaction.