COVID-19 continues to present a serious gobal health problem. Studies examining the selective effects of Covid-19 in women are scarce. It has not yet been clarified whether there are factor(s) that increase or decrease the susceptibility to COVID-19 in women other than chronic systemic diseases. In order to better understand the interaction between Covid-19 and the female gender, it is necessary to evaluate the risk factors well. In this study, it was aimed to evaluate the frequency and course of COVID-19 in terms of reproductive characteristics and gynecological diseases.
As expected, our study showed that women hospitalized, receiving intensive care support, and receiving antiviral therapy had a more severe illness overall. Severe illness rates were found to be significantly higher than mild illness rates in women who had 2 or more episodes of COVID-19. The result of the study is consistent considering that recurrent virus infections and frequent exposure to the virus may lead to a higher COVID 19 viral load and thus worse clinical outcomes [21].
Although it has been stated in some studies that pregnancy is a risk factor for severe COVID-19, it has been reported that the risk of serious disease increases especially in the postpartum period, when estrogen and progesterone serum levels decrease [22, 23]. Pregnancy is known to affect the immune system in a number of ways. Although the results of the studies are inconsistent, it is generally thought that there is a rather dynamic cooperative adaptation between the maternal and fetal immune systems rather than a particularly broad maternal immune suppression during pregnancy [24]. In our study, it was observed that women with at least one live pregnancy history had significantly milder disease and the probability of mild disease was higher as the parity number increased. While it is difficult to say with certainty that having a pregnancy history protects against severe COVID-19, it is important that a pregnancy history is an indicator of better health. Interestingly, the rates of severe disease in women, who underwent gynecological surgery for benign reasons were significantly lower than the rates of mild and moderate disease. However, since cesarean section constitutes a large part of the benign gynecological surgery history in this study, the results are consistent with the results of the pregnancy history.
In the study, the most common urogenital pathology in women in the pre-COVID-19 period was chronic urinary tract infection. Chronic vaginal infection and PCOS were other common diseases. Interestingly, COVID-19 was significantly more severe in women with a history of chronic urinary tract infections. The urinary tract in men has proven to be a potential target for COVID-19. Studies have shown that COVID-19 infection significantly worsens stress incontinence and overactive bladder scores in both men and women and causes intense inflammatory cytokine release in the bladder [25]. While studies so far have shown that the urinary system is a target for COVID-19, our study has shown that urinary system diseases may be a risk factor. In addition, a history of chronic urinary or vaginal infections may indicate an above-normal immune system sensitivity. Although the mechanism is not clear, it is clear that there is an interaction between COVID-19 and the lower urinary tract.
Chronic inflammation and some endocrine conditions are more commonly associated with COVID-19. The susceptibility and severity of COVID-19 in gynecological diseases such as PCOS and endometriosis have been evaluated in some studies. Niamh Phelan et al., in their study examining the effects of COVID-19 on reproductive health in women, found that 7% of women with COVID-19 had PCOS and 6% had endometriosis [26]. The incidence of PCOS, which is the most common endocrine and metabolic problem in women of reproductive age, is 10–15% [27]. PCOS may increase susceptibility to COVID-19 due to impaired glucose tolerance, an increased prevalence of metabolic syndrome, and hyperandrogenism. It has been reported that PCOS associated with hyperandrogenism leads to an almost 30% higher risk of COVID-19 infection than that in controls, independent of obesity [28]. In addition, it has been shown that polymorphisms in genes encoding proinflammatory cytokines are increased in women with PCOS [29]. In this context, PCOS may be a risk factor that predisposes women to severe COVID-19 due to both a low-level chronic inflammation state and its endocrine pattern. Several cross-sectional and large-scale studies have shown that women with PCOS are at greater risk for COVID-19 and that symptoms are more pronounced [30, 31]. Endometriosis is one of the most common benign gynecological conditions in women of reproductive age. Changes in cell-mediated or humoral immunity in endometriosis, which is thought to be a chronic inflammatory disease, may affect susceptibility and severity to COVID-19 [32, 33]. In a meta-analysis evaluating the relationship between endometriosis and COVID-19, it was emphasized that the risk of women with endometriosis contracting COVID-19 may increase, although it is not statistically significant [34]. In our study population, the rate of PCOS was 11.6% and the rate of endometriosis was 6.3% in women with COVID-19. Although not statistically significant, the rates of PCOS and endometriosis were higher in the severe COVID-19 group, consistent with the literature.
Low and altered expression of ACE2 and TMPRSS 2 in endometrial cells during the menstrual cycle may result in a lower overall risk for COVID-19 infection [35]. However, the expression of these receptors may be altered in cases of AUB and greater susceptibility to COVID-19 may occur. In addition, iron deficiency anemia is an important problem in these women, and anemia may impair the immune response and increase susceptibility to infections [36]. It has been shown that endometrial hyperplasia, one of the most important causes of AUB, increases the risk of COVID-19 infection [37]. In our study, the rate of severe COVID-19 was found to be higher in women with a history of AUB, although it was not statistically significant.
In our study, the rates of severe disease were higher in women, who had received hormone therapy for contraceptive purposes in the three months prior to COVID-19 infection, although it was not statistically significant. In studies conducted with postmenopausal women, the anti-inflammatory effect of hormone therapy was reported in those who used transdermal estrogen instead of oral therapy [38]. In addition, oral estrogen therapy is known to increase inflammatory markers due to its liver first-pass effect [39]. Although our results are compatible with the literature in this respect, there is a need for large-scale studies that evaluate in detail hormone usage, frequency, form and duration.
Interestingly, in this study, the rate of serious disease was found to be lower in women with a history of leiomyoma, although it was not statistically significant. Although many studies suggest that progesterone and estrogen play key roles in the pathogenesis of leiomyomas, their functional roles have not yet been clarified [40]. We do not know whether the higher progesterone levels detected in women with leiomyoma can induce an anti-inflammatory response. The evidence to date does not support a claim that uterine leiomyomas, which have an unclear and complex pathogenesis, protect against severe COVID-19. On the other hand, although the presence of ACE 2 has also been demonstrated in human myometrium and uterine leiomyomas, the presence of TMPRSS2 in these tissues remains unclear [41]. Therefore, the characteristics of the immune response in women with leiomyoma should be investigated in both epidemiological and molecular-based studies.
This study has some limitations. First, due to the study’s design, only self-reports of the participants were used. Existing gynecological histories of the participants were not subject to gynecological examination and hormone levels were not measured. Second, different virus variants may have different characteristics in terms of susceptibility and disease severity, as the timeframe in which participants contracted COVID-19 was not taken into account. Third, a larger sample size is needed to identify those factors that influence the susceptibility and severity of a disease. In addition, the study cannot be generalized as it covers women living in a particular region. On the other hand, this study may provide some degree of insight into the wider issue for future research as it is the first study to evaluate the factors affecting COVID- 19 susceptibility and severity in terms of many gynecological conditions and based on women without additional systemic diseases.
In conclusion, we found that some obstetric and gynecological conditions may affect the susceptibility and severity of COVID-19 in women without a history of systemic disease. Fertility problems may be more serious in women, who are more at risk. Therefore, identifying these women may be important for taking action to protect them. In the future, with larger sample sizes and better designed studies, risk factors for COVID-19 and female gender may be more clearly defined.