Shanshan Zhang1†
Richard Mprah
Mingming Wang- 1School of Biological Science, Jining Medical University, Rizhao, Shandong, China
- 2Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China
- 3China National Experimental Teaching Demonstration Center for Basic Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, China
The COVID-19 pandemic has left a profound mark on global health, leading to substantial morbidity and mortality worldwide. Beyond the immediate symptoms of infection, the emergence of “long COVID”, the long-term effects of SARS-CoV-2, has become a significant public health concern. Long COVID is a multifaceted condition affecting various organs and systems, including the cardiovascular, digestive, nervous, and endocrine systems. Individuals diagnosed with polycystic ovary syndrome (PCOS) may face an increased risk of severe COVID-19 symptoms and infection. It is crucial to comprehend how long COVID affects PCOS patients to devise effective treatment and care strategies. Here, we review the detrimental effects of COVID-19 and its long-term effects on reproductive health, endocrine function, inflammation, metabolism, cardiovascular health, body composition, lifestyle, and mental health in patients with PCOS. We offer recommendations for the post-covid-19 management of PCOS, emphasizing the necessity of a comprehensive, multidisciplinary approach to patient care. Furthermore, we discuss prospective research directions, highlighting the significance of continued investigations and clinical trials to evaluate treatment approaches for long COVID and its ramifications in individuals with PCOS.
1 Introduction
Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), has been declared a public health emergency of international concern (1). SARS-CoV-2 enters cells by interacting with spike protein S and angiotensin-converting enzyme 2 (ACE2), causing organ dysfunction (2). The COVID-19 pandemic has taken a great toll worldwide, with profound consequences for individuals, organizations, and societies. While the initial focus was on the acute symptoms of the virus, more attention is now being paid to the long-term after-effects of COVID-19 (3).
Even after the virus becomes undetectable in COVID-19 patients, it can continue to replicate for up to four weeks following infection, potentially resulting in long-term effects on various organs and systems. This condition is commonly referred to as ‘‘Long COVID” (4) (Figure 1). The Centers for Disease Control has listed approximately 25 clinical laboratory abnormalities associated with an increase in COVID-19 prevalence, which affects the health-related quality of life and well-being of COVID-19 patients (5, 6). It is estimated that 10-20% of cases across all ages, including children, will develop long COVID (a complex disorder of multiple organ system dysfunction), with most cases occurring in people with mild acute illness (7, 8).
Figure 1. Multisystem symptoms/manifestations of long COVID. Among the various organ systems that long COVID can damage are the respiratory, cardiovascular, neuropsychological, digestive, circulatory, immune, and genitourinary systems, making it a truly multiorgan disease.
Several hypotheses for the pathogenesis of long COVID have been proposed (Figure 2), including the persistence of SARS-CoV-2 in tissues (9), pathological inflammation caused by persistent autoimmune responses and immune disorders (10, 11), long-term tissue damage (12), endothelial dysfunction and coagulation dysfunction (13), and the effects of SARS-CoV-2 on microbiota, including virome (10). Relevant risk factors may include female sex, type 2 diabetes, androgens, early dyspnoea, previous psychiatric disorders, and specific biomarkers (14). However, most of these studies on the mechanism hypothesis are preliminary, and further studies on the pathophysiology of long COVID are urgently needed.
Figure 2. Suggested explanations for the underlying causes of long COVID. There are several hypothesized mechanisms for the pathogenesis of long COVID, including prolonged presence of the virus, direct cell/tissue damage, immune dysregulation, microbiome disruption, autoimmunity, coagulation, and endothelial abnormalities.
Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting 5–20% of females of reproductive age (15). This syndrome can lead to infertility, insulin resistance (IR), obesity, type 2 diabetes, dyslipidaemia, cardiovascular problems, and a series of other health issues (16, 17). The overlap of many PCOS comorbidities with risk factors for severe COVID-19 progression has attracted research attention (Figure 3). Multiple studies have shown that women with PCOS are at a higher risk of contracting the SARS-CoV-2 virus and worsening COVID-19-related outcomes at all ages (18–20). A study of 21,000 patients with PCOS showed that women with PCOS had a 28% higher risk of developing COVID-19 (21). The clinical features of PCOS, such as hyperandrogenism, obesity, IR, chronic low-grade inflammation, and intestinal flora disturbance, may increase the risk of SARS-CoV-2 infection (18, 22). However, the impact of COVID-19 on patients with PCOS has not yet been explored. This review updates our knowledge on this issue, specifically examining the impact of COVID-19 and its subsequent effects on PCOS and its accompanying health issues.
Figure 3. Convergence of post-covid-19 health issues and risk factors associated with PCOS and related problems. Overlapping factors between the common long-term outcomes of COVID-19 and risk indicators for PCOS and its associated health issues.
To gain a comprehensive understanding of the health impact of COVID-19 and its long-term effects on patients with PCOS and to provide guidance for future research and clinical practice, we conducted an extensive literature search of reputable databases, including PubMed and Web of Science. The search terms involved “long-term COVID-19”, “polycystic ovary syndrome”, “epidemiology”, “symptoms”, “mechanism”, “management” and other related terms. Articles were selected based on their relevance to the topic identified in the abstract. The reference lists of articles were also searched to identify relevant literature.
2 Impacts of COVID-19 and its sequelae on PCOS
2.1 Reproductive health
2.1.1 Menstrual irregularities
The female reproductive endocrine system is commonly known to be susceptible to various viruses. Evidence from studies demonstrates that COVID-19 patients underwent different levels of temporary menstrual changes, including longer menstrual cycles and decreased menstrual blood volume (23, 24). Following the COVID-19 pandemic, a study of 1,031 women found that 53% suffered from more severe premenstrual symptoms, 18% experienced new menorrhagia, and 30% experienced new dysmenorrhoea (25). One study revealed a link between menstrual disturbances and the gravity of COVID-19 (24). However, this change is temporary, and most patients return to normal within 1-2 months of discharge.
In addition to SARS-CoV-2 infection, the COVID-19 vaccine also affects the menstrual cycle (26). Studies have shown an increased incidence of changes in the menstrual cycle after COVID-19 vaccination, particularly in menstrual cycle length, menstrual pain, and flow of menstruation (27), which may be attributed to immunological processes (28, 29).
2.1.2 Ovarian dysfunction
To date, no significant studies have reported the influence of COVID-19 on the ovarian reserve, function, or follicular fluid properties. However, clinical studies have shown that ovarian damage can be observed in women with COVID-19, including decreased ovarian reserve and reproductive endocrine disruption. Certain patients exhibit irregular changes in their sex hormone levels, including elevated follicle-stimulating, luteinizing hormones, testosterone, prolactin, and reduced estradiol and progesterone levels, potentially suggesting ovarian suppression (23, 30–32). Elevated levels of luteinizing hormones would stimulate theca cells to secrete more testosterone, potentially leading to secondary ovulation dysfunction at a later time. This situation could be even more problematic for women with PCOS who already have underlying endocrine disorders. Anti-Müllerian hormone (AMH) is secreted by small antral follicles and is an important indicator for evaluating the ovarian reserve. It is not affected by the menstrual cycle, exogenous sex hormones or pregnancy (33). Studies on the effects of COVID-19 on AMH have shown mixed results, with some studies showing no difference in average AMH concentrations in COVID-19 patients compared to controls (23, 34); however, others suggest that COVID-19 infection can lead to ovarian reserve impairment by reducing AMH levels (32, 35).
When the body experiences acute stress, ovarian function is typically suppressed to maintain normal functioning of vital organs, and cases of anovulation have been documented in numerous acute illnesses. SARS-CoV-2 has demonstrated the ability to invade host cells via either the ACE2/transmembrane serine protease 2 (TMPRSS2) pathway or the basigin/cathepsin L (BSG/CTSL) pathway (30). Public datasets have demonstrated that the coexistence of ACE2 and TMPRSS2 expression in ovaries is most prominent in oocytes, whereas a minor expression is also present in granulosa cells (36, 37). A comparison of ACE2-positive and ACE2-negative ovarian cells revealed greater enrichment of various viral infection-related pathways in the former (38), suggesting that SARS-CoV-2 specifically targets certain ovarian cells through the ACE2/TMPRSS2 pathway, thereby suppressing ovarian function.
2.2 Endocrine diseases
2.2.1 The hypothalamic-pituitary-thyroid axis (HPT)
Thyroid dysfunction can exacerbate metabolic disorders, dyslipidaemia, cardiovascular disease risk, and reproductive health disorders in patients (39–41). Endocrine conditions, including thyroid dysfunction, adrenal dysfunction, and hyperandrogenism, have been linked to increased vulnerability to and severity of SARS-CoV-2 infection. Notably, coronavirus directly affects the thyroid gland (42). According to reports, COVID-19 inpatients may experience clinical thyroid dysfunction, such as thyrotoxicosis, hypothyroidism, and subclinical thyroid dysfunction, with the level of thyroid-stimulating hormone indicating the presence of hyperthyroidism or hypothyroidism (43). A study reported that 87% of patients continued to suffer from hypothyroidism even after more than three months following their recovery from COVID-19 (44). Currently, there is no evidence of a direct or indirect effect of SARS-CoV-2 on thyroid function. However, given that SARS-CoV-2 appears to be capable of causing organ damage through autoimmune processes (45), COVID-19-induced thyroid damage via immune system dysregulation cannot be ruled out.
2.2.2 The hypothalamic–pituitary–adrenal axis (HPA)
HPA plays a crucial role in the female reproductive system, and adrenal cortex dysfunction often accompanies variations in reproductive system function (46). Multiple case studies and autopsy results have corroborated the deleterious effect of SARS-CoV-2 on the HPA axis (47–50). A study on the impact of SARS-CoV-2 on the HPA axis found that some COVID-19 patients had lower levels of dehydroepiandrosterone sulfate (DHEAS) and adrenocorticotropic hormone (ACTH) in the morning (51–53). COVID-19 patients may experience central adrenal insufficiency (54). COVID-19, through its cytopathic actions, might enhance the degradation and necrotic processes affecting adrenal cortical cells (55). Physiological stress caused by diseases, such as infection, trauma, surgery, sepsis, and critical illness, can activate the HPA axis, decrease cortisol metabolism and binding proteins, and increase serum cortisol levels (56). An increase in cortisol can trigger many neuroendocrine and immune adaptive adjustments within the body, ultimately resulting in stress responses (57). The pathological changes and physiological stress of the HPA caused by SARS-Cov2 may have negative effects on the reproductive system.
2.3 Metabolic abnormalities
2.3.1 Obesity
Globally, the COVID-19 crisis has profoundly affected both physical and mental health (58). The implementation of COVID-19 restrictions and lockdowns has been associated with weight gain, with nearly 30% of the population experiencing this effect (59). Since the inception of the COVID-19 pandemic, there has been a staggering increase in obesity rates among children aged 2–17 (60). One study indicated that during the pandemic, pre-existing differences in obesity in terms of race, ethnicity, and community socioeconomic status have widened.
Increased SARS-CoV-2 replication enhances the inflammatory immune response, which leads to fat inflammation and IR in obesity (61). Recent evidence suggests that SARS-CoV-2 directly infects human adipocytes and alters cell metabolism in a depot-specific and viral lineage-dependent manner (62). SARS-CoV-2 infection inhibits lipolysis in subcutaneous adipocytes and increases pro-inflammatory gene expression in visceral adipocytes (63, 64). In vitro models suggest that viral infection directly alters the morphology and function of adipocytes (65).
Obesity increases IR and compensatory hyperinsulinaemia, leading to hyperandrogenemia, which in turn increases lipogenesis and decreases lipolysis (66). Obesity can interfere with ovarian function through neuroendocrine mechanisms, leading to ovulation disorders (67). Many bioactive molecules released by adipose tissue interact with multiple molecular pathways involved in IR, inflammation, hypertension, cardiovascular risk, coagulation, and oocyte differentiation and maturation, thereby amplifying and worsening the metabolic and reproductive phenotypes of PCOS (68). Obesity is also an important factor leading to the presence and severity of PCOS in adolescents, and intractable pre-adolescent obesity with severe IR may predict later development of PCOS (69, 70). It is plausible that obesity due to the COVID-19 pandemic may increase the prevalence of PCOS, particularly among adolescents.
2.3.2 IR and β-cell dysfunction
PCOS is associated with severe IR and defective insulin secretion. IR and β-cell dysfunction are considered major drivers of PCOS pathophysiology and are involved in the occurrence of hyperandrogenemia and reproductive dysfunction through multiple mechanisms (71).
COVID-19 patients experience a cytokine storm, with a large number of inflammatory cells affecting the function of the skeletal muscle and liver, the two main insulin-responsive organs responsible for most insulin-mediated glucose uptake (72). Clinical studies have shown that severely ill patients with COVID-19 have a high demand for insulin during peak inflammatory responses, and this significant increase in insulin demand may be due to systemic inflammation and severe IR due to critical illness (73, 74). SARS-CoV-2 induces elevated cytokine levels that promote pancreatic β-cell over-stimulation and IR, resulting in fatigue and subsequent alterations in metabolism (75). COVID-19 can significantly shorten the life expectancy of people with type 2 diabetes (76, 77). It can also cause β-cell dysfunction, IR, and abnormal control of glucose metabolism in COVID-19 patients who have never been diagnosed with diabetes (78). Glucose abnormalities can last for at least 2 months after disease onset (79). It is expected that COVID-19 will further exacerbate IR in patients with PCOS. Montefuscono et al. reported hyperinsulinemia associated with COVID-19, suggesting that COVID-19 may lead to IR, which in turn leads to hyperglycemia (78). He et al. demonstrated that newly developed IR, rather than insulin deficiency, is the mechanism underlying hyperglycaemia after SARS-CoV-2 infection. Another study showed that COVID-19 increased the risk of IR in non-diabetic patients (80). Moreover, this IR condition persists even after the virus has cleared, meaning that COVID-19 patients may face long-term pathological effects. Taken together, the evidence suggests that COVID-19 exacerbates IR in patients with PCOS.
In reviewing the current literature, we found significant limitations and unexplored areas of research on the impact of COVID-19 on IR in PCOS patients. In particular, there have been few studies focusing on the specific effects of COVID-19 on PCOS patients, and few studies have explored its impact on IR, a core pathological process. Most studies have focused on the general clinical presentation of COVID-19, its induced complications, and how it affects a wide range of metabolic diseases, such as diabetes, but have overlooked the unique effects that may occur in this specific population of PCOS. In addition, the current understanding of how COVID-19 specifically acts on the mechanisms of IR in PCOS patients remains unclear. Although some studies have proposed that SARS-CoV-2 may affect insulin sensitivity by damaging islet beta cells and triggering cytokine storms, these hypothetical mechanisms need to be verified and refined by more empirical studies to build a more complete and accurate scientific picture.
2.4 Dysregulation of gut microbiota
Several pieces of scientific evidence strongly support that the microbiome significantly affects the aetiology and sustenance of PCOS, and changes in the intestinal flora may further aggravate metabolic disorders, cytokine storms, endocrine disorders, and hyperandrogenemia in women with PCOS (81, 82). In COVID-19 patients, the composition of the gut microbiota is altered, and in combination with inflammatory cytokines and blood indicators, it mirrors the gravity of illness and immune system dysfunction (83). ACE2 affects the expression of intestinal neutral amino acid transporters (84), thereby regulating the composition of the intestinal microbiota and regulating local and systemic immune responses (85). The ecological imbalance of intestinal flora lasted for up to 30 days after the resolution of the disease (79). The lingering presence of SARS-CoV-2 in the intestines of COVID-19 patients directly leads to the loss of the conjunction-dependent intestinal mucosal barrier in children with multisystem inflammatory syndrome (86), hinting at the possibility that the chronic presence of SARS-CoV-2 in the gastrointestinal tract can provoke alterations in the intestinal microbiome, resulting in long-term outcomes. Sustained changes in the fecal microbiome of COVID-19 patients have been observed, with many bacteria associated with more proinflammatory cytokines and increased disease complications. Given the profound influence of intestinal flora on the pathophysiology of PCOS and changes in intestinal flora in COVID-19 patients, it is reasonable to speculate that the changes in intestinal flora induced by COVID-19 may exacerbate the symptoms and comorbidities of PCOS patients. The potential synergies between the two diseases warrant further investigation, as COVID-19 may exacerbate pre-existing PCOS-related metabolic and endocrine disturbances through dysregulation of the gut microbiome.
However, the literature on this intersecting field remains limited and is filled with gaps. First, there is a lack of studies that specifically examine the effects of COVID-19-induced changes in the gut microbiota of PCOS patients. Most studies have focused on either PCOS or COVID-19 alone, failing to bridge the link between the two diseases through the gut microbiota. Second, the long-term effects of changes in gut microbiota associated with COVID-19 in patients with PCOS are largely unknown. Although some studies have shown that intestinal dysbiosis can persist in the early stages of the disease, its impact on PCOS symptoms, fertility outcomes, and overall quality of life remains to be clarified. In addition, the mechanism of potential interactions between COVID-19, the gut microbiota, and PCOS is unclear. Although ACE2 and its role in regulating gut microbiome composition and immune response provide a promising avenue for exploration, the specific pathways linking COVID-19, gut dysbiosis, and PCOS outcomes require further investigation.
2.5 Low-grade chronic inflammation
Pro-inflammatory cytokines play a pivotal role in the pathophysiology of PCOS, potentially underpinning many of its metabolic abnormalities. These cytokines have been linked to dysfunction and inflammation within adipose tissue (87), IR, and the pathophysiology of diabetes (88) while exerting a regulatory influence on ovarian function and hyperandrogenemia.
In patients with SARS-CoV-2 infection, there is a notable depletion in the absolute number and functional vigor of antiviral cytotoxic lymphocytes (89, 90), alongside severe impairment of specific T-cell subtypes (91). The apparent hyperactivity of the immune system induced by the virus coupled with concurrent bacterial infection can overwhelm its capacity, leading to a chronic inflammatory state with lasting adverse effects. Even after recovery, this persistent inflammatory cascade may manifest as a spectrum of chronic symptoms, including profound fatigue, dyspnoea, and joint discomfort, as well as psychological distress, such as anxiety and depression (79). The COVID-19 cytokine storm is characterized by rapid proliferation and hyperactivation of macrophages and natural killer cells and the overproduction of >150 inflammatory cytokines and chemical mediators released by immune or nonimmune cells (92). Mast cell activation syndrome and lymphopenia (i.e. B-cell and T-cell lymphocyte deficiencies) may be the cause of COVID-19 hyperinflammation and post-covid-19 illness (93, 94). Indeed, increased levels of pro-inflammatory markers (e.g. C-reactive protein, Interleukin-6, and D-dimer) and lymphopenia have been associated with long-term COVID (12).
It is plausible that the infection of SARS-CoV-2 in women with PCOS, who already harbor a background of low-grade inflammation, could further exacerbate this proinflammatory predisposition, thereby compounding various reproductive and metabolic dysfunctions.
2.6 Cardiopulmonary functional capacity
In terms of cardiopulmonary function, COVID-19 typically presents with cough and can precipitate a range of cardiovascular and pulmonary complications, such as diffuse alveolar injury and interstitial pulmonary fibrosis (95). Approximately 50% of patients continue to experience dyspnoea for months after recovery (96, 97). The pathophysiology of lung injury caused by SARS-CoV-2 includes its binding with ACE2 and cytokine storm (51). Decreased cardiorespiratory fitness and disrupted autonomic nervous system function, coupled with irregular heart rate recovery, could be contributing factors to the elevated cardiovascular risk observed in patients with PCOS (98). Concurrently, compromised lung function predisposes patients to glucose intolerance (51), IR (99), type 2 diabetes (100, 101), and cardiovascular diseases (102, 103). These adverse outcomes may stem from the direct impact of hypoxaemia on glucose and insulin regulation (104) as well as the inflammatory mediators and altered insulin signaling associated with pulmonary dysfunction (105, 106), potentially exacerbating the metabolic manifestations of PCOS.
2.7 Fertility outcomes
2.7.1 Assisted reproduction technology (ART)
PCOS is a multifaceted endocrine disorder that often intersects with challenges related to fertility and pregnancy. For many women with PCOS, the path to successful conception often involves ART. Recent investigations into the impact of COVID-19 on in vitro fertilization (IVF) cycles have yielded noteworthy insights. Notably, while COVID-19 did not seem to compromise patients’ physical resilience or ovarian reserve during IVF procedures, there was a discernible decrease in the proportion of high-quality embryos (107). Furthermore, evidence suggests that while acute SARS-CoV-2 infection may not impede immediate ART outcomes, it could potentially exert adverse effects on oocyte production over the long term (i.e. beyond 180 days post-infection) (108). It has also been reported that the sperm concentration of couples was significantly reduced after exposure to COVID-19 (109). Hence, there should be at least three months (the time required for folliculogenesis and spermatogenesis) between a patient’s recovery from COVID-19 and the resumption of IVF treatment.
The onset of the COVID-19 pandemic has precipitated unforeseen disruptions across various spheres, including the delivery of non-emergency healthcare services. Notably, both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology independently recommend the temporary cessation of reproductive health care services (110). This suspension had profound repercussions for individuals and couples awaiting or undergoing fertility treatment. Delays resulting from the pandemic have forced some patients to face age-related limitations enforced by funding agencies, creating formidable barriers to treatment access, and prolonged waiting periods exacerbate anxiety, stress, and despondency among individuals grappling with infertility, consequently diminishing the success rates of ART (111, 112). A recent study revealed that postponing fertility treatment by a mere 12 months could lead to a substantial decrease in the likelihood of achieving a successful live birth through IVF among women aged 38-39 and 40-42, with percentages dropping by 18.8% and 22.4%, respectively (113). Furthermore, the economic and reproductive medicine response to the COVID-19 pandemic has reduced the affordability and accessibility of fertility care and has had a profound impact on IVF live birth rates (114–116).
2.7.2 Pregnancy complications
Epidemiological research has indicated that women with PCOS are more susceptible to COVID-19 than those without (19, 117). Contracting SARS-CoV-2 during pregnancy increases the risk of complications such as spontaneous abortion, premature delivery, intrauterine growth restriction, and maternal renal failure or disseminated intravascular coagulation (118). Furthermore, there is an elevated risk of stillbirth (119). Several preexisting conditions and demographic factors, including chronic hypertension, preexisting diabetes, advanced maternal age, high body mass index, and non-white ethnicity, increase the likelihood of severe COVID-19 during pregnancy. Pregnant women with COVID-19 are more prone to preterm birth, heightened rates of caesarean birth (120), and potentially heightened risks of maternal mortality and ICU admission (121), with newborns being more frequently admitted to neonatal units. Pregnant women with PCOS may fall within the high-risk category for pregnancy-related complications.
2.7.3 Vertical transmission
Vertical transmission, occurring when an infected pregnant woman passes the infection to her fetus or baby during pregnancy, delivery, or the postpartum period, is a significant concern. The transmission route can involve the placenta in utero, during delivery, or through breastfeeding during maternal-infant contact. ACE2, expressed in various maternal tissues including the placenta, human trophoblast ectoderm, fallopian tubes, ovaries, vagina, cervix, and endometrium, plays a role in this transmission process. Studies have reported a combined neonatal vertical transmission rate of SARS-CoV-2 at 3.2%, underscoring the potential for such transmission (122), with the severity of maternal illness linked to the likelihood of vertical foetal transmission (123).
Placental transmission likely serves as the primary mechanism of vertical transmission, with severe/critically ill mothers more prone to placental SARS-CoV-2 positivity (124). Another mechanism briefly considered is the cervicovaginal vertical transmission route, which involves exposure of the newborn to infected cells during delivery (125). However, most studies testing vaginal fluids from infected pregnant women yielded negative results for the virus (126). While breast milk from mothers infected with SARS-CoV-2 (the virus that causes COVID-19) may contain minimal amounts of viral RNA, evidence suggests that breastfeeding rarely leads to transmission of the virus to newborns (127). According to previous reports, 93% (68 out of 73) of infants born to mothers who tested positive for COVID-19 were asymptomatic. However, a small fraction of these infants experiences adverse effects, such as gastric bleeding, multiple organ failure, and, in some cases, mortality (120). Although foetal and neonatal mortality due to COVID-19 during pregnancy is rare, adverse neonatal morbidity may be associated with maternal infection, including respiratory diseases and hyperbilirubinemia, as reported by Norman et al. (128).
2.8 Lifestyle
2.8.1 Physical activity
For patients with PCOS, managing weight is essential not only for symptom improvement and increasing the chances of pregnancy but also for overall health. However, owing to the challenging pathophysiology of PCOS, weight management is exceptionally difficult (129). The social distancing measures implemented during the COVID-19 pandemic, such as closures of social, educational, and recreational facilities, have resulted in behavioral changes that can negatively impact physical activity and promote sedentary behavior, potentially exacerbating chronic health conditions such as obesity (130, 131). The closure of sports and leisure facilities during the pandemic further disrupted weight management efforts in PCOS patients. Additionally, the lingering effects of COVID-19 on patients, including fatigue, respiratory issues, and joint pain, can hinder exercise routines and weight management (6, 132, 133).
2.8.2 Sleep patterns
Sleep patterns have also been significantly affected during the pandemic, with many women with PCOS reporting negative effects on sleep quality (134). Insomnia and poor sleep health are common issues in women with PCOS and are associated with mental health problems, such as anxiety and depression, which exacerbate stress levels (135, 136). Sleep deprivation can also lead to the secretion of proinflammatory cytokines (137), metabolic changes, and disruption of appetite regulation (138–140). These factors are closely linked to the pathogenesis of PCOS.
2.8.3 Dietary habits
Eating disorders and improper diets, especially those that are too low in plant protein and consume carbohydrates with a high glycaemic index, increase the risk of overweight adolescent girls with PCOS (141), causing inflammation, IR, and negatively affecting body composition. A diet lacking quality can lead to an imbalance in the microbiome, subsequently causing intestinal permeability and endotoxaemia. These conditions can exacerbate hyperinsulinaemia, resulting in elevated insulin levels. Such high insulin levels stimulate increased androgen production within ovaries, disrupting the normal follicular development process. This, in turn, worsens the clinical severity of PCOS (142). Additionally, dietary and environmental factors play a pivotal role in the developmental programming of PCOS female susceptibility gene variants (143).
The stress and shopping restrictions caused by isolation lead to changes in people’s eating habits, with a significant increase in sweet preference and frequency of eating (144). Stress causes subjects to overeat and consume super palatable convenience foods high in sugar and/or fat (145), replacing more nutrient-rich foods, and thus reducing dietary protein intake (146, 147). These foods can boost serotonin production, which has a positive effect on mood (148). However, it is associated with an increased risk of obesity, chronic inflammation, metabolic abnormalities, and cardiovascular disease (149), which have been shown to increase the risk of more serious complications from COVID-19 (150). Before the COVID-19 outbreak, the risk of eating disorders was more than four times higher in women with PCOS than in the control group (151). Given that people with PCOS are more prone to uncontrolled and emotional eating, the risk of eating disorders may be further elevated during the pandemic.
2.9 Healthcare systems
Despite the widespread occurrence of PCOS, its fundamental causes and biological mechanisms remain unclear. The approach to managing this condition in routine clinical settings is fragmented, with inconsistencies in the care provided by specialists such as general practitioners, endocrinologists, and gynaecologists (152). Furthermore, significant knowledge deficits persist among medical professionals concerning the diagnosis, treatment strategies, and comprehensive nature of PCOS manifestations (153–155). Previous studies have shown that PCOS patients are dissatisfied with the diagnosis and treatment they receive, and feel the need to seek specialist care for their condition (156). As a result, women with PCOS are often caught in the gap between relevant healthcare services, even without the enormous pressure that the COVID-19 pandemic is putting on clinical practice. Women with PCOS lack sufficient knowledge and access to contemporary healthcare services, a problem that has become even more apparent during the COVID-19 crisis (117).
The COVID-19 pandemic has placed enormous pressure on healthcare services, requiring the reorganization and reprioritization of resources and changes in healthcare delivery models. During the pandemic, PCOS patients face numerous challenges in accessing healthcare support, particularly when it comes to primary care physicians who serve as a crucial source of assistance (157–159). Contacting these professionals or scheduling face-to-face appointments is very challenging, compounding the stress and anxiety associated with PCOS (160–162). The limited availability of primary care, coupled with the suspension of specialized PCOS-related medical services and the uncertainty surrounding their resumption, creates a significant burden for individuals with PCOS, further exacerbating their condition and overall well-being (163, 164). Thus, the role of healthcare workers during the peak of the COVID-19 pandemic cannot be underestimated. The COVID-19 pandemic puts healthcare workers at unprecedented risk and under increased stress due to work (5). Admittedly, the incidence of COVID-19 sequelae among healthcare workers affects their long-term performance, negatively affecting the healthcare environment.
The impact of COVID-19 on access to healthcare and PCOS management varies widely across countries, mainly because of differences in healthcare systems, resources, and pandemic response strategies. Developed countries with strong healthcare systems are generally better able to cope with the surge in COVID-19 cases; however, routine healthcare services have been disrupted even in these countries (165, 166). Telemedicine plays a vital role in maintaining continuity of care, enabling patients to access consultations, laboratory tests, and prescriptions without having to physically visit a healthcare facility (167, 168). Developing countries with weaker healthcare systems face tougher challenges, many of which struggle to provide basic COVID-19 care, let alone maintain services for chronic diseases such as PCOS (169–172). In resource-constrained settings, healthcare providers must prioritize COVID-19 cases over other diseases, and shortages of essential medicines needed for PCOS management are more common in developing countries, further exacerbating the problem for PCOS patients (171–174).
2.10 Psychological impacts
The mental health of women with PCOS is a critical concern, as studies have shown that they are more susceptible to depression, anxiety, and stress than are women without non-PCOS women (175). Recent international guidelines emphasize that women with PCOS are at a higher risk of developing mental health issues such as depression and anxiety, especially during the pandemic. The pandemic has exacerbated the emotional burden experienced by women with PCOS, leading to increased psychological distress (175).
The COVID-19 crisis has not only impacted the physical health of patients with PCOS but has also taken a toll on their mental well-being. Many individuals with PCOS have reported worsening mental health, including feelings of low mood, anxiety, and depression (164). The pandemic has also raised concerns regarding the potential impact of PCOS on the risk of severe COVID-19, causing heightened health anxiety among patients. During this period, it was discovered that conditions commonly associated with PCOS, such as obesity and diabetes, carry an increased risk of severe illness and mortality due to COVID-19. This uncertainty regarding the influence of PCOS on COVID-19 risk has led to significant health anxiety and depression among many patients.
Limited access to primary care and suspension of specialized medical services related to PCOS during the pandemic made patients feel neglected, exacerbating their distress and anxiety (164). The suspension of fertility services caused severe anxiety, psychological stress, and a sense of isolation in some individuals struggling with PCOS (176).
Due to factors such as changes in sleep patterns, mandatory quarantine measures, and socioeconomic impacts, it is anticipated that global efforts to combat COVID-19 will have a negative effect on the mental well-being of the general population. However, individuals with PCOS who are already vulnerable may face potentially greater consequences for their mental health.
The impact of COVID-19 on the mental health of women with PCOS may vary depending on several factors. Women with PCOS often require regular medical follow-ups and symptom management. In countries where access to medical services is limited due to the outbreak, these women may face challenges in managing their condition, leading to increased anxiety and stress. In some countries, rapid response and efficient operation of health services have been achieved through the optimization of diagnosis and treatment processes and the introduction of intelligent management systems, and strong healthcare systems and telemedicine services may alleviate some of these challenges, thereby providing continuity of care and support during the pandemic (177, 178). Conversely, in countries with inefficient health services, patients may have to wait for long periods to access treatment, which not only exacerbates their physical suffering but can also trigger or worsen psychological problems (179–181). In countries with financial worries and limited or disrupted social support due to the pandemic, these women may feel more isolated and experience higher levels of anxiety and depression (182–184). In addition, the severity of the epidemic, awareness of PCOS, cultural attitudes, access to mental health services, and other factors in different countries will also have different impacts on the mental health of women with PCOS (185–187).
3 Interventions and management during the COVID-19 pandemic
3.1 Telemedicine and virtual care
The COVID-19 pandemic has overwhelmed healthcare systems worldwide, dramatically reducing or even eliminating the hospitalizations of individuals with other illnesses, particularly chronic conditions. Undoubtedly, the pandemic has changed the management of chronic diseases, such as PCOS, as well as the daily interactions between patients and healthcare providers. Telemedicine has been widely implemented during this period to effectively manage several chronic noncommunicable diseases, including arterial hypertension (188). Considerable evidence shows that telemedicine is an effective, safe, and satisfactory clinical option for day-to-day management of chronic diseases (114).
One of the most widely adopted areas of telemedicine is outpatient consultation or virtual clinics. Virtual consultations can avoid transportation to hospitals and unnecessary contact with waiting rooms, enabling continuity of care without exposing patients or healthcare professionals to potential risks. Virtual clinics can also prevent unnecessary visits, thereby reducing the number of people in emergency departments and improving the efficiency of medical resource allocation. Clinical practice reports indicate that the consultation rate of virtual clinics is 60–95% of that of regular clinics, and various chronic diseases are satisfactorily controlled through virtual care (189, 190).
Since lifestyle changes are the first-line treatment for PCOS, most patients struggle with adherence to lifestyle management, and mobile services that provide education on lifestyle modifications can be beneficial in treating PCOS. Mobile health apps have been shown to improve body weight and oocyte quality in PCOS patients (191). This reflects the effectiveness of mobile apps in facilitating lifestyle changes in PCOS patients. Telepsychotherapy offers an important additional treatment option for PCOS patients experiencing anxiety and depression during the COVID-19 pandemic. Another study confirmed that mobile health apps based on cross-theoretical models can reduce BMI, anxiety, and depression in PCOS patients and improve exercise and dietary adherence in these individuals in the long term (192).
3.2 Adjustments in reproductive care guidelines
Patients with PCOS have a higher incidence of pregnancy complications, such as preterm labor, caesarean section, miscarriage, gestational diabetes mellitus, gestational hypertension, and preeclampsia. Anatomical, physiological, and immunological changes during pregnancy may lead to a higher risk of severe SARS-CoV-2 infection in pregnant women (193). To address these concerns and prevent potential complications, various fertility societies globally, including the American Society of Reproductive Medicine, Canadian Society of Fertility and Andrology, European Society of Human Reproduction and Embryology, and International Federation of Fertility Societies, issued guidelines during the pandemic (194). These guidelines emphasize the importance of implementing mitigation measures and infection control protocols in fertility care units. Most of these guidelines recommend a temporary halt for new fertility treatments, including ovulation induction, intrauterine insemination, in vitro fertilization, and non-urgent gamete cryopreservation. They also suggested postponing embryo transfers, elective surgeries, and non-emergency diagnostic procedures. A COVID-19 Task Force was established to monitor the situation and provide updated guidance in alignment with local health authorities. Enhanced monitoring of pregnant women with PCOS, particularly those with comorbid conditions, such as hypertension and diabetes, is recommended during prenatal and perinatal care (195).
3.3 Patient education and support
PCOS is a prevalent and intricate disorder linked to metabolic syndrome, obesity, eating disorders, depression, and sleep apnea (196, 197). Prior to the COVID-19 pandemic, a survey revealed that women with PCOS felt that the existing information, resources, and education did not adequately address their needs. They expressed dissatisfaction with early diagnostic care and believed that clinicians lacked sufficient knowledge of their conditions (198, 199). There are evident knowledge gaps and discrepancies among residents and physicians in the diagnosis and treatment of PCOS (154, 155).
Epidemiological studies have shown that women with PCOS are more likely to be infected with SARS-CoV-2 than are women without PCOS (19). Risk factors for severe COVID-19 highly overlap with the common features of PCOS, and COVID-19 may have an impact on all aspects of PCOS care. Additionally, the accompanying hormonal disorders (such as IR or hyperandrogenemia) associated with COVID-19 may further complicate the clinical features of PCOS (19, 117). The elevated risk of COVID-19 poses challenges in accessing timely healthcare for patients with PCOS, making diagnosis and treatment more difficult.
Effective management of PCOS is crucial during the COVID-19 pandemic, necessitating closer monitoring and revision of care plans for this patient population. The challenges posed by the pandemic highlight the need for improved education, resources, and knowledge dissemination among healthcare professionals to ensure optimal care for patients with PCOS.
4 Impact of variants
COVID-19 and its evolving variants have demonstrated a significant impact on human health, especially in those with PCOS, which may in different ways exacerbate existing comorbidities in patients and introduce new health challenges.
Different variants of SARS-CoV-2 have been found to differ significantly in causing COVID-19-related symptoms and in severity (200, 201). Primordial strain infections are associated with a higher proportion of long-COVID symptoms and face a greater burden of disease and health costs than Alpha or Delta variants (202, 203).
Notably, some COVID-19 variants have shown increased transmissibility and virulence compared with the original SARS-CoV-2 strain (204, 205). This property could put people with PCOS - whose immune systems may already be compromised by comorbidities such as obesity, insulin resistance and chronic inflammation - at higher risk of infection.
In addition, SARS-CoV-2 mutants are not only more infectious than wild-type viruses but also have a particular tendency to infect obese individuals (206), which means that PCOS patients with symptoms of obesity need to be closely followed and actively treated.
Different variants can also trigger different immune responses, further affecting the balance of the immune system in PCOS patients (207). For example, certain variants may trigger intense autoantibody production or cytokine storms that exacerbate autoimmune symptoms associated with PCOS, such as hyperandrogenemia and chronic inflammation.
In summary, the impact of COVID-19 variants on PCOS patients is diverse, given their different manifestations of virulence, infectivity, and disruption to various physiological systems (208). This difference may directly lead to further deterioration of reproductive health, metabolic status, mental health, cardiovascular health, and immune system functions. Therefore, it is important to continuously monitor the potential risks of novel COVID-19 variants in PCOS patients and develop personalized management strategies.
5 Future perspectives
As the COVID-19 pandemic continues, its long-term impact, particularly on PCOS patients, highlights the urgency of a multifaceted approach to care (Figure 4). Long COVID exacerbates several challenges faced by women with PCOS, including immune, endocrine, metabolic, neurological, cardiovascular, and gastrointestinal issues. Recognizing this complexity, future research must delve into the mechanisms linking COVID-19 and PCOS to develop tailored interventions.
Figure 4. Therapeutic interventions for patients with PCOS affected by the sequelae of COVID-19. The complexity and wide-ranging impact of COVID-19 after-effects necessitate the use of a multidisciplinary care model for the optimal treatment of PCOS.
One of the crucial aspects of long-term COVID-19 management is the recognition and treatment of psychological issues, such as depression and anxiety, that can arise from the traumatic experience of the pandemic. Seeking counseling and psychological support is vital in helping survivors overcome feelings of despair and anxiety, and in turn, improve their overall quality of life.
Given the heterogeneity of PCOS, personalized treatment regimens are critical (121). Healthcare providers must consider the impact of long COVID on PCOS symptoms and adjust interventions accordingly. Involving people with PCOS in research and clinical trials will contribute to a deeper understanding of the disease and its interactions with COVID-19 (209).
The International Evidence-based Guidelines for the Evaluation and Management of PCOS emphasize the importance of lifestyle interventions, such as diet, exercise, and sleep optimization, for overweight or obese women with PCOS (210). These interventions are essential to improve the metabolic, hormonal, and psychological aspects of the syndrome. However, many women with PCOS may struggle to follow diet and exercise guidelines, especially in the post-pandemic world, where COVID-19 restrictions and concerns about disease transmission continue to affect physical activity levels. Mobile technology can improve compliance with lifestyle management recommendations by providing support and monitoring tools for PCOS patients.
Future research should explore drug treatments that target both PCOS symptoms and boost the immune system or target the virus itself (211). Leveraging current infrastructure, developing scalable healthcare models, and integrating them across disciplines (212) are essential to address the complex interplay between long COVID and PCOS. Long-term follow-up studies and the development of effective treatments are urgently needed, with a focus on the evolving phase of the pandemic, possible complications, vaccination status, and the presence of new viral strains (213).
Improving the diagnosis and treatment of PCOS remains a significant challenge in the healthcare field. Health professionals, especially primary care professionals, must be educated about the standard diagnostic criteria and treatment options. A multidisciplinary collaborative approach involving specialists in gynaecology, endocrinology, family medicine, psychiatry, and nutrition should be implemented. Continuing education programs should be developed for healthcare professionals and patients, including workshops, webinars, and standardized educational materials (214).
Subsequent research priorities should include (i) assessing the long-term effects of COVID-19 in people with or without PCOS; (ii) elucidating the causal mechanisms of COVID-19 and its sequelae affecting PCOS and its complications, including endocrine, immune system, metabolism, and mental stress; (iii) developing and improving scalable diagnostic methods that are highly specific for COVID-19-related PCOS complications; (iv) assessing the effects of vaccination and immunotherapy on PCOS and its complications; (v) identifying new therapeutic solutions or repurposing older drugs that can protect or reverse COVID-19-associated PCOS and its complications; and (vi) testing the feasibility and effectiveness of mobile health applications to improve health-related behaviors in women with PCOS.
In conclusion, a comprehensive and collaborative approach involving health care professionals, researchers, and patients is key to effectively managing the long-term effects of COVID-19 and PCOS. By prioritizing individualized care, psychological support, and ongoing research efforts, we can improve the outcomes and quality of life for those grappling with the aftermath of the pandemic. This approach should encompass lifestyle interventions, innovative technologies, and targeted drug therapies to address the unique challenges posed by the convergence of these conditions. By integrating these strategies, healthcare providers can better support patients in managing their health and well-being in the face of ongoing uncertainty and evolving healthcare needs.
6 Limitations
This review takes a multidisciplinary approach to provide patients with PCOS with a comprehensive perspective on understanding and managing the long-term effects of COVID-19. However, this method has several disadvantages. First, while the review cites a large number of studies, many of the studies on the relationship between long COVID and PCOS are still preliminary, leading to some conclusions that may not be deep or comprehensive enough. Second, the specific pathogenesis of long COVID is not fully understood at present, which limits the depth and accuracy of the review in exploring its mechanisms of influence. Finally, owing to the short duration of the COVID-19 outbreak, long-term follow-up data are relatively scarce, which has hindered the comprehensive assessment of the long-term impact of the long COVID.
7 Conclusion
The COVID-19 pandemic has significantly impacted global health, with long COVID emerging as a major concern. Long COVID affects multiple systems, posing a particular challenge for PCOS patients who may experience aggravated symptoms and complicated management. Current evidence indicates that COVID-19 and its sequelae negatively impact reproductive health, endocrine function, inflammation, metabolism, cardiorespiratory health, body composition, lifestyle, and mental health in patients with PCOS. These mechanisms are multifactorial and include inflammation, lifestyle changes, and comorbidities. Given the lack of effective therapies for PCOS post-COVID-19, a comprehensive multidisciplinary approach is crucial for its management. Future research and clinical trials are needed to evaluate treatment and prevention strategies, emphasizing the importance of personalized care and risk assessment in patients with PCOS and COVID-19.
Author contributions
SZ: Writing – original draft. YQW: Writing – review & editing. RM: Writing – review & editing. MW: Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was financially supported by the National Natural Science Foundation of China (Grant No.82401923) the Natural Science Research of Jiangsu Higher Education Institutions of China (Grant No. 22KJB180007), and Outstanding Talent Research Funding of Xuzhou Medical University (Grant No. RC20552029), the TaiShan Industrial Experts Programme (No. JYHL2022MS20), the Small- and Medium-sized Enterprise Innovation Capability Enhancement Project of Shandong Province (No. 2023TSGC0549).
Acknowledgments
The authors would like to express their sincere gratitude to their respective institutions, Xuzhou Medical University and Jining Medical University, for their support in the literature research and collection. We appreciate the help of Yuanxin Wang, Siyuan Ye and Yinan Cao during the revision phase.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: polycystic ovary syndrome, Long COVID, care strategies, treatment approaches, multidisciplinary management
Citation: Zhang S, Wu Y, Mprah R and Wang M (2024) COVID-19 and persistent symptoms: implications for polycystic ovary syndrome and its management. Front. Endocrinol. 15:1434331. doi: 10.3389/fendo.2024.1434331
Received: 17 May 2024; Accepted: 28 August 2024;
Published: 04 October 2024.
Edited by:
Jeff M. P. Holly, University of Bristol, United KingdomReviewed by:
Saira Rafaqat, Lahore College for Women University, PakistanAhmet Fatih Durmusoglu, Istanbul Medipol University, Türkiye
Bianca Leca, University Hospitals Coventry and Warwickshire NHS Trust, United Kingdom
Copyright © 2024 Zhang, Wu, Mprah and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mingming Wang, wmm@xzhmu.edu.cn
†These authors share first authorship