Clinical and anamnestic characteristics of isolated and combined genital endometriosis

Endometriosis is a chronic neuroinflammatory disease that affects up to 10% of women worldwide and is associated with chronic pelvic pain and infertility [1]. Several studies have shown that patients with endometrioid foci undergoing diagnostic laparoscopy for other reasons (e.g., acute pain, bleeding, or sterilization) can be asymptomatic [2–4]. These findings suggest a high prevalence of endometriosis in women of reproductive age who do not exhibit a characteristic clinical picture [4]. The frequency of asymptomatic forms of endometriosis varies between 20% and 30%, according to different authors [2]. Despite ongoing research, the ultimate causes of endometriosis remain uncertain [5–7]. It is known that hormonal, immunological, genetic, and other factors contribute to the development of this condition [6, 8, 9]. Currently, noninvasive diagnostic methods, such as magnetic resonance imaging and ultrasound, are actively employed to diagnose endometriosis [9]. However, a definitive diagnosis can only be made if a tissue similar to the endometrium is found outside the uterine cavity during surgery, which often results in significant delays in diagnosis after the onset of initial symptoms [10].

Given the lack of effective tools for identifying endometriosis, it is crucial to study its clinical presentation, which can help diagnose the disease at an early stage [9]. The detection of symptoms or signs such as pelvic pain, infertility, menstrual irregularities, and abnormal uterine bleeding should prompt a thorough and comprehensive examination of patients, thereby minimizing delays in diagnosis and facilitating effective treatment [10].

Endometriosis frequently coexists with other proliferative diseases of the uterus, such as uterine fibroids and endometrial hyperplastic processes. Literature indicates that the co-occurrence of uterine myoma and endometriosis ranges from 35% to 85%, while the incidence of endometrial hyperplastic processes (EHP) alongside endometriosis is 25% [11]. For instance, Strizhakov A.N. et al. found a combination of adenomyosis and uterine leiomyoma in 49% of women studied, while Shchukina et al. reported this in 31.9% of cases [11, 12]. Investigating the characteristic signs of isolated endometriosis and its combination with other proliferative diseases of the female reproductive system is essential for developing a diagnostic algorithm and assessing the risks associated with isolated and combined genital endometriosis. This area is a priority for further research.

Materials and methods

This study included 395 patients diagnosed with genital endometriosis, confirmed through morphological analysis after surgical treatment. Prior to participation, the patients provided informed consent for the processing of their personal data and their use for research purposes. The study was conducted at the perinatal center at St. Ioasaph Belgorod Regional Clinical Hospital.

Data were collected using a specially designed questionnaire that gathered information on medical and biological characteristics, the presence and manifestations of pain syndrome, menstrual and reproductive functions, and concomitant gynecological and extragenital diseases. All data were fully anonymized prior to analysis.

For detailed analysis, patients with genital endometriosis were categorized into four groups: Group 1 included patients with isolated endometriosis (n=103); Group 2 included patients with endometriosis and EHP (n=183); Group 3 included patients with endometriosis and uterine myoma (n=207); and Group 4 included patients with endometriosis, uterine myoma, and EHP (n=98). A comparative analysis of medical-biological and clinical-anamnestic characteristics, as well as risk factors for the development of genital endometriosis, was performed in the studied groups.

Statistical analysis

Statistical analysis was performed using Statistica and Microsoft Excel. The normality of the distribution of continuous variables was tested using the Shapiro–Wilk test. The distribution of continuous variables differed from normal; therefore, parameters such as median (Me) and interquartile range (Q1; Q3) were calculated. In addition, for the convenience of comparing the data obtained with the literature results, the arithmetic mean (M) and standard deviation (SD) are provided for the continuous variables presented in Tables 1 and 2. Counts (n) and percentages (%) were calculated for categorical and ordinal variables. The statistical significance (p) of the differences between the analyzed groups for continuous variables was assessed using the Mann–Whitney U test and Kruskal–Wallis test. The Pearson χ² test was used to compare the groups according to categorical variables. Since four groups were compared in the conducted study, the significance level (p) was recalculated using Bonferroni correction. To obtain a new critical significance level, the traditional type 1 error level (p<0.05) was divided by the number of comparisons. The number of comparison pairs was calculated using the formula m=n(n-1)/2, where n is the number of groups [13]. Thus, considering the Bonferroni correction, the critical level of significance when testing the statistical hypotheses was 0.008.

Results

Statistically significant differences were revealed in the analysis of the age and anthropometric parameters of the study groups. The median age of patients with isolated genital endometriosis was 31 (27–37.5) years. In all analyzed groups of patients with a combination of genital endometriosis and EHP [42 (36; 48) years], uterine myoma [44 (37; 49) years] and EHP with uterine myoma [45 (40; 49) years], the median age was 11–14 years higher than the median age of women with isolated genital endometriosis (p<0.00001) (Table 1). The median body mass index (BMI) of patients in group 1 was 23.84 (20.89; 27.77) kg/m², in group 2 – 27.29 (22.85; 30.48) kg/m², in group 3 – 27.55 (24.03; 31.24) kg/m², in group 4 – 28.22 (24.03; 31.86) kg/m² (p<0.00001).

When analyzing the complaints of the patients in the study groups, no statistically significant differences were found (p>0.008) (Table 2). The patients in all groups were comparable in terms of age at menarche, duration of menstruation, menstrual cycle, as well as the nature of menstruation (p>0.008).

Analysis of reproductive function showed a more frequent (more than 2.5 times) early onset of sexual activity (from 14 to 18 years) in patients with isolated genital endometriosis (59/103 [57.28%], p<0.00001) than in those with a combination of genital endometriosis and proliferative diseases of the female reproductive system. When studying parity, it was revealed that in the 2nd, 3rd, and 4th groups of patients, a significantly higher number of pregnancies (the median in these groups was 3 (1; 4), 3 (1; 5), and 3 (2; 4), respectively), births (the median in these groups was 1 (0; 2), 1 (1; 2), and 1 (1; 2), respectively), and artificial abortions (the median in all groups of patients with combined genital endometriosis was 1 (0; 2)) compared to women with isolated genital endometriosis, where the median number of pregnancies, births, and artificial abortions was 1 (0; 2), 0 (0; 1), and 0 (0; 1), respectively (p<0.00001). Analysis of concomitant and history of gynecological and extragenital diseases did not reveal statistically significant differences between the groups of patients.

Discussion

The study findings revealed that among patients with isolated genital endometriosis, women of early reproductive age and with lower body mass index (BMI) were predominant. When examining reproductive function, it is noteworthy that patients in this group engaged in sexual activity at an earlier age (from 14 to 18 years) more frequently (>2.5 times) compared to those with combined genital endometriosis and proliferative diseases of the female reproductive system. In contrast, among patients with both endometriosis and proliferative uterine diseases, women of late reproductive age with a higher BMI were more prevalent. This group also reported a significantly greater number of pregnancies, births, and artificial abortions than in women with isolated genital endometriosis.

Statistically significant differences in age were identified between the study groups. The median age of women with isolated genital endometriosis was 11–14 years younger than that of women with combined genital endometriosis. Existing literature indicates that endometriosis typically manifests early, while uterine fibroids and EHP tend to develop later, during the premenopausal and menopausal periods [14–17]. In our study, when analyzing the distribution of individuals based on BMI, we observed a predominance of patients with a lower BMI among women with isolated endometriosis. Literature suggests that being underweight is a risk factor for developing endometriosis [18]. The authors attributed this association to a reduced risk of retrograde menstruation in women with lipid metabolism disorders, which is one of the main pathogenetic theories of endometriosis [19]. Obesity can lead to various menstrual cycle disorders (including amenorrhea) and delays in the menstrual cycle, thereby reducing the likelihood of retrograde menstrual reflux [20]. In contrast, according to our data, a higher BMI was found in patients with genital endometriosis and proliferative diseases of the female reproductive system. The literature describes a significant increase in the risk of developing proliferative diseases of the genitals in obese patients [21]. Insulin resistance, impaired hepatic synthesis of sex hormone-binding globulin, and active metabolism of steroid hormones in adipose tissue that arise against the background of lipid metabolism disorders lead to the development of hyperestrogenism, which is one of the main pathogenetic mechanisms for the development of proliferative diseases of the uterus [22–24]. Notably, women with isolated genital endometriosis showed characteristic features of endometriosis, including low BMI and early manifestation of the disease. In contrast, the clinical and anamnestic characteristics of women with a combination of endometriosis and proliferative diseases of the female reproductive system demonstrated features inherent to uterine myoma or EHP (high BMI, late manifestation, a large number of pregnancies, births, and artificial abortions), which is probably associated with the appearance of concomitant proliferative diseases in later reproductive age in patients with asymptomatic forms of genital endometriosis.

In our study, a higher number of pregnancies, births, and artificial abortions were registered in groups of patients with combined proliferative diseases of the uterus than in women with isolated endometriosis due to a higher prevalence of infertility in individuals with isolated endometriosis. The prevalence of isolated genital endometriosis is lower in multiparous women. According to our data, there was a high frequency of induced abortions in women with proliferative genital system diseases. In modern literature, surgical abortion is one of the most traumatic methods of pregnancy termination [25]. During induced abortion, traumatization of the "transition zone" (basal zone, an area in the inner layer of the myometrium) occurs, a key pathogenetic link in the development of proliferative diseases of the endometrium and myometrium [26]. Our analysis allowed us to establish that patients with isolated genital endometriosis had an earlier onset of sexual activity (from 14 to 18 years) 2.5 times more often as patients with genital endometriosis and proliferative diseases of the female reproductive system. According to the literature, the early onset of sexual activity is a risk factor for sexually transmitted diseases [27]. Chronic inflammation caused by immune dysregulation can subsequently lead to the development of infertility, which, according to literature, occurs in 30–50% of patients with genital endometriosis [28]. One of the main challenges in predicting endometriosis in young women is identifying noninvasive markers that can indicate the occurrence and potential development of this condition and its complications. Such markers could contribute to the development of an algorithm capable of altering the disease course. Patients with isolated genital endometriosis typically present at an early reproductive age, have a lower BMI, and have an earlier history of sexual activity. In contrast, women with genital endometriosis, who also have proliferative diseases of the female reproductive system, tend to be older, have a higher BMI, and exhibit a greater number of pregnancies, births, and induced abortions.

Conclusion

Our study identified statistically significant differences in the clinical and anamnestic characteristics of patients with isolated genital endometriosis compared with those with additional proliferative diseases of the female reproductive system. These differences should be considered during the clinical management of these patients. Specifically, given the frequent coexistence of these conditions, it is important to consider the possible presence of asymptomatic forms of genital endometriosis.