Risk Factors Associated with Endometriosis Related Infertility
Muhammad Umer1, Ovais Ullah Shirazi2, Waqas Akram1, Mahtab Ahmad Khan1, Muhammad Nadeem Alvi1, Muhammad Bilal Aslam1, Khadija-TulKubra1, Hassan Ahmad1, Zainab Farooq1, Eman Shahzad Khan1, Mahnoor Asim1, Shaina Rehman1, Hira Foaad1, Itzaz Aslam3, Ali Akhtar1*
¹Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan
²Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Pakistan
³Alliant College of Professional Studies, Lahore, Pakistan
*Corresponding author
Ali Akhtar, Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan
DOI: 10.55920/JCRMHS.2025.11.001505
Abstract
Background: The development of endometrial-like tissue outside the uterus is a distinguishing hallmark of endometriosis, a persistent gynecological illness associated with infertility. Despite the fact that endometriosis is quite widespread, little is known about the precise risk factors that contribute to infertility in these individuals, particularly in resource-limited situations.
Objective: To assess and determine the main risk factors for infertility in endometriosis-affected women that are associated with lifestyle, genetics, and reproduction.
Methods: A cross-sectional observational study was conducted in four tertiary institutions in Lahore, Pakistan, with 200 adult female participants who had a confirmed history of endometriosis and/or infertility. Data was collected using structured questionnaires, and analysis was done using SPSS software. The associations between various risk variables and infertility outcomes were evaluated using regression analysis, chi-square tests, and descriptive statistics.
Results: The study found that a significant portion of individuals had known risk factors for infertility, including persistent pelvic pain (85.5%), a positive family history of endometriosis (78.5%), and extended menstrual flow (84.5%). Regression analysis revealed that alcohol use (p = 0.017), extended menstrual flow (p = 0.007), and family history (p = 0.013) were statistically significant predictors of infertility. Furthermore, a history of infertility and marital status were significantly correlated (p = 0.001). On the other hand, no clear correlations were found between age, low body weight, or contraceptive use.
Conclusion: Family history, delayed menstrual flow, and alcohol consumption are strongly associated with endometriosis-related infertility, although age, BMI, and usage of contraceptives had no discernible effects. Reproductive problems were significantly predicted by marital status and previous infertility, underscoring the necessity of early, focused therapies, especially in settings with limited resources.
Introduction
Infertility is a developing worldwide health concern with a major personal and societal issue. Infertility is a stressful and upsetting illness resulting from endometriosis. Endometriosis is a difficult situation for women who are at age of reproduction, from infertility to persistent discomfort [1, 2]. It is distinguished by endometrial glands and an estrogen-dependent stroma that are mostly, though not solely, located in the pelvic compartment., Endometriosis is defined by endometrial-like tissue outside the uterus, mostly on the rectovaginal septum, ovaries, and pelvic peritoneum, and in rare instances on the diaphragm, pleura, and pericardium[3]. The disease's estimated 5% prevalence, which peaks between the ages of 25 and 35, and 0.1% yearly incidence among women aged 15 to 49 are its defining characteristics[4]. The exact cause of endometriosis is still unclear. Risk factors such as immunological environment, genetic profile, inflammatory conditions and hormonal activities have significant impact on the endometriosis [5]. According to current epidemiological perspectives, one of the initial steps towards the occurrence of endometriosis is thought to be the interconnected relationship between socioeconomic status, family history, constitutional factors, personal habits, reproductive and gynecological status, and environmental factor [6, 7].
A complicated interaction between inflammatory, immunological, angiogenic, and hormonal mechanisms leads to endometriosis. Despite an enormous amount of study, the precise pathophysiology of the disease is still unknown, and there are a number of ideas that contribute to this confusion regarding both the disease's etiology and the most effective medication and surgical treatment options [8].
Table 1:
Table 2: Association Between Demographic and Reproductive Variables (PEARSON X2 test)
Sampson's Theory of Retrograde Menstruation is one of the most commonly recognized theories among the others. According to this idea, some endometrial cells migrate backward via the fallopian tubes into the peritoneal cavity during menstruation, where they implant and develop ectopically [9]. This concept does not well account for deeper or extraperitoneal lesions, but it does assist explain the existence of endometriosis in places like the ovaries or superficial peritoneum [10]. Furthermore, the universality of this idea is called into question by endometriosis instances in premenarchal females and even in men [11]. Additionally, only a small percentage of women develop endometriosis despite the fact that up to 90% of women experience retrograde menstruation, indicating other contributory variables [12].
Researchers like Ivo Brosens and others have put out a modified hypothesis to overcome these constraints. According to their findings, neonatal uterine bleeding may induce the retrograde flow of endometrial-like cells before to the onset of menstruation, which might pave the way for the early development of endometriosis. This idea highlights the complex and dynamic character of the disease and expands our knowledge of early-onset instances, even if it is not yet widely recognized [23].
While there are a number of pharmaceutical and surgical options for managing the symptoms of endometriosis, enhancing reproductive results is still difficult. There is growing evidence that improving reproductive outcomes for impacted persons is mostly dependent on pharmaceutical adherence, nutritional status, and dietary therapies. However, the effectiveness of existing therapies is limited, especially in low-resource settings, by non-adherence to long-term treatment regimens and the absence of integrated care models. Furthermore, few research has taken a complete strategy incorporating both dietary and pharmaceutical methods in the setting of infertility, while individual studies have examined either one.
This research aims to critically provide or evaluate the prevalence, risk factors and an evidence based pharmacological treatment and nutritional strategies to enhance the fertility or optimize fertility outcomes in the patient with endometriosis. By implementing existing evidence and identifying significant gaps, this study objective to inform future therapy guidelines and interdisciplinary intervention models targeted at improving reproductive health in endometriosis patients.
Methodology Section
Study Design: A cross-sectional observational study design was used to assess the endometriosis risk factor associated with infertility.
Study setting: Hospitals in various parts of Lahore, including Surgimed Hospital, General Hospital, Services Hospital, and Hameed Latif Hospital, were the sites of the study.
Study Population and Sample: Two hundred adult female patients with endometriosis or infertility who had a history of endometriosis-related chronic lower back pain were included in the study.
Using Cochran's Formula, the sample size was calculated to be 175; by adding the drop of ratio, the sample size increases to 200. The disease prevalence from the prior study was calculated to be 5%, and the sample size was calculated using a 5% significance level.
Intervention: No variables (such as administering treatment or altering circumstances) were changed or intervened in. We simultaneously observed and gathered data. Finding correlations or patterns rather than cause and effect was probably our aim. Because statistical analysis was used, it is more than just a description and is neither experimental nor quasi-experimental.
Data Collection: A structured questionnaire that was given to patients all at once was used to collect data. Sections on family history and demographic data were included in the questionnaire.
Data Analysis: SPSS software (version) was used to enter and analyse the data that had been gathered. The data was summarised using descriptive statistics. For categorical variables like gender and family history, frequencies and percentages were computed. To investigate relationships between variables, additional statistical tests (such as regression analysis and the PEARSON X2 test) were employed; a p-value < 0.05 was deemed statistically significant.
Table 3: Distribution of demographics with personal Habits.
Table 4: Distribution of demographics with complications and their Association with Risk of Cancer, Infertility, and Prolonged Menstruation
Table 5: Distribution of demographics with pelvic pain and low body weight
Ethical Considerations: The research committee of the University of Central Punjab's Department of Pharmaceutical Sciences in Lahore granted ethical approval. All participants provided written informed consent, and data were anonymized to maintain confidentiality.
Results
The descriptive analysis revealed that the respondents knew a great deal about endometriosis. The majority (95%) agreed that it is a prevalent condition worldwide, and 93% of respondents agreed that advanced stages made conception more difficult. Additionally, according to 83.5% of respondents, it was more prevalent among women with unexplained infertility. However, associations with cardiovascular risk (43%) and malignancy potential (58.5%) were not as well established. Significant percentages of respondents reported a family history of endometriosis (78.5%), infertility (82%), extended menstrual flow (84.5%), and persistent pelvic discomfort (85.5%) as risk factors. On the other hand, having intercourse during menstruation (32.5%) and consuming alcohol (20.5%) were less common.
Using chi-square testing, there was a statistically significant correlation between marital status (p = 0.001) and a history of infertility (p = 0.001) leading to difficulties getting pregnant. Other demographic characteristics such as age (p = 0.256), alcohol usage (p = 0.550), and low body weight (p = 0.364) did not show any significant relationships. Furthermore, neither the history of endometriosis (p = 0.112) nor pelvic discomfort (p = 0.121) differed significantly. These results show that whereas age and BMI were less predictive in this group, relationship status and prior infertility significantly influence reproductive issues.
The distribution of cancer risk according to various reproductive and demographic variables is shown in Table 2. Age group among them showed a statistically significant correlation with cancer risk (χ², p = 0.037). Individuals between the ages of 20 and 40 were more likely to be classified as at risk, with the 20–30 and 30–40 age groups showing the highest percentage. These results imply that women in the reproductive age range are more vulnerable to cancer-related outcomes, which may be due to ovulatory cycles, hormonal changes, or reproductive stresses.
Similarly, there was a significant association (p = 0.007) between the length of infertility and the risk of cancer. Long-term inflammatory disorders linked to infertility or chronic anovulation may contribute to carcinogenic pathways, as evidenced by the increased incidence of cancer risk among women who had been infertile for three years or more.
Additionally, there was a significant correlation between the length of infertility therapy and the risk of cancer (p = 0.043). Women who received therapy for more than six months, especially more than a year, were more likely to get cancer. This might be brought on by long-term exposure to reproductive procedures, hormonal treatments, or the frequent use of ovulation-inducing drugs.
However, there were no statistically significant correlations between cancer risk and other factors such marital status (p = 0.426), low birth weight (p = 0.173), pelvic pain (p = 0.686), intercourse during menstruation (p = 0.167), or family history of disease (p = 0.346).
These variables nonetheless showed clear distribution patterns even if they were not significant, which might have implications in larger cohort studies.
Represents the distribution of cancer risk in relation to several demographic and reproductive factors
The evaluation of personal habits and demographic factors in Table 3 shows a substantial correlation between extended infertility therapy and sexual activity during menstruation.
Intercourse during menstruation was shown to be significantly correlated with the length of infertility therapy; women receiving lengthier treatments were more likely to report engaging in this behavior (OR = 0.631; 95% CI: 0.438–0.910; p = 0.014). According to this research, some behavioral patterns may make infertility-related problems worse and necessitate longer treatment durations.
Some relationships showed intriguing patterns, but some did not approach statistical significance. For example, although the connection was not statistically significant (p = 0.223), women who were single had increased likelihood of being exposed to chemicals (OR = 3.875). Age did not significantly affect the length of infertility or marital status, nor did it significantly affect the usage of alcohol (p = 0.526), chemical exposure (p = 0.348), or intercourse during menstruation (p = 0.216). Together, these results suggest that although demographic traits might not be a reliable indicator of participation in these behaviors, their interaction with medical treatments like infertility therapy may be clinically significant.
Evaluation of demographic variables and personal habits, revealing a significant association between intercourse during menstruation and prolonged infertility treatment.
Table 4 represents The most noteworthy result, which supported the chi-square results from Table 1, was the substantial influence of age on cancer risk (OR = 1.606; 95% CI: 1.029–2.506; p = 0.037). The idea that increasing reproductive age may be linked to cumulative exposure to oncogenic processes was supported by the higher chances of cancer risk among women in the older age groups. Age, marital status, length of infertility, and length of infertility treatment, on the other hand, did not show statistically significant correlations with either infertility or extended menstruation (all p > 0.05).
Longer menstruation seemed to be somewhat more common among those receiving longer treatment durations, and the odds ratios for infertility tended to be higher among women with infertility durations longer than three years, even if these differences were not statistically significant. These trends point to possible underlying relationships that, maybe as a result of sample size limitations, did not achieve statistical significance.
Assessment of demographic predictors for cancer, infertility, and prolonged menstruation, with only age significantly linked to cancer risk
Table 5 show a substantial, statistically significant correlation between age and pelvic discomfort, with younger women reporting higher prevalence, especially those between the ages of 20 and 30 (OR = 2.614; 95% CI: 1.334–5.123; p = 0.005). This might indicate that younger age groups have a greater prevalence of gynecologic disorders such endometriosis, pelvic inflammatory disease, or dysmenorrhea.
Pelvic discomfort was also significantly predicted by the length of infertility (OR = 0.573; 95% CI: 0.336–0.978; p = 0.041). Pelvic pain was more common among women who experienced infertility for longer periods of time; this might be related to structural or chronic inflammatory causes of infertility, such as adhesions or fibroids.
On the other hand, low body weight did not show any statistically significant correlations with any of the independent factors (all p > 0.05). Descriptively, however, women aged 30–40 and those receiving therapy for 3–6 months had somewhat higher risks, indicating potential metabolic or dietary factors affecting both weight and reproductive health.
Analysis of demographic influence on pelvic pain and low body weight, where age and infertility duration significantly predicted pelvic pain.
Discussion
The epidemiology of endometriosis has gotten little attention, despite the fact that it is a disorder that has been extensively studied. The difficulty of correctly is most likely the cause of this. investigating a condition with a wide range of symptoms. Even the gold standard of laparoscopic diagnosis has certain flaws: the accuracy of the diagnosis is limited by the watching surgeon's ability to view and identify the lesions [13]. The environmental risk factors associated with endometriosis, such as lifestyle, reproductive, early life, and other risk factors, were critically analyzed and their relationship to endometriosis was thoroughly summarized [14], According to our study's findings, there is a considerable association between endometriosis-related infertility and certain risk factors, including a family history of the disease, extended menstrual flow, and alcohol use. These relationships were statistically significant. Nevertheless, only two of these variables—alcohol intake and EDCs—exhibited proof of a robust, favorable, and noteworthy correlation with endometriosis. The duration of the menstrual cycle, moderate to frequent alcohol use, and early life characteristics like low birth weight, preterm delivery, and feeding practices were all found to have weak associations with endometriosis [14].
In actuality, a patient's level of discomfort, fertility, or effectiveness with treatment are not correlated with the quantity, location, and size of their lesions [15]. With an average latency of 7–11 years from the start of symptoms to a conclusive diagnosis, the present absence of an effective endometriosis diagnostic results in missing or delayed diagnoses [16]. It was less clear that a significant portion of the women in the endo group (>5%) had additional illnesses such migraine (G43) and dorsalgia (M54). Dorsalgia was shown to have a strong positive genetic connection with endometriosis in a major genetic meta-analysis to determine the common genetic foundation of endometriosis and other disorders [17].
When determining whether to do an endometrial biopsy on women with abnormal uterine bleeding (AUB), especially when there are no other risk factors present, age is a critical issue. Most suggestions, including those made by ACOG (2019) [18] and RTCOG (2022) [19], Some suggest a biopsy at age 35 or 40, while others support screening at age 45 [20, 21]. Because it decreases unnecessary biopsies and improves cost-effectiveness by providing higher specificity with equivalent sensitivity to lower age thresholds, this study supports the adoption of ≥45 years as the best age cut-off [22].
The resolution of infertility in impacted women who become pregnant regardless of the delay to pregnancy may help to explain this. Furthermore, the National Survey for Family Growth found that not all women who report infertility seek medical attention, which is supported by a history of infertility without therapy [23].
Results support many endometriosis risk factors, including gravidity, parity, pelvic discomfort, and a history of infertility. Although it is still difficult, identifying asymptomatic endometriosis in the general population is essential to comprehending the full range of the illness. Such subsets of afflicted women may have a distinct set of risk factors, such as self-reported infertility or longer time to conception, which might provide fresh information on the frequency of endometriosis in the general population, possible etiologies and connections, and its natural history [24].
Endometrial cancer and endometrial intraepithelial neoplasia (EIN) were significantly more common in those aged 45 to 49 [25]. Obesity, diabetes, nulliparity, polycystic ovarian syndrome (PCOS), or abnormal Pap tests in women under 45 were significant risk factors for these conditions. This suggests that age <45 is not a signal unless there are additional risk factors. The study also evaluated the importance of endometrial thickness in line with previous research and found that readings of ≥4 mm and ≥7 mm significantly increased the risk of endometrial disease [26, 27]. While risk factors including nulliparity, menopause, diabetes, and PCOS were found to significantly increase the risk of EIN and cancer, obesity showed a link that diminished after adjusting for confounders like diabetes. Conditions like hypertension and dyslipidemia did not substantially correlate in this group [28].
Additionally, the limited number of users indicates that there was no significant correlation between the use of hormonal contraceptives and an increased risk [29]. The study's best strength is the use of electronic medical data, which allows for in-depth retrospective analysis. Its limitations include its single-institution design and the potential for self-reported medication history inaccuracies.
Despite extensive research, the epidemiology of endometriosis remains poorly known due to the complex nature of symptoms and diagnostic limitations. Despite the desire for histological evidence, this extensive case-control study used surgical observation as the diagnostic criterion to more accurately reflect real-world practice (2,777 patients, including 896 with visible endometriosis lesions) [30]. This study's coverage of all forms of endometriosis allowed for a broader applicability than more limited criteria that only addressed ovarian or deep lesions [31].
The incidence of endometriosis varies by kind of surgery: 50% in diagnostic surgery, 18% in fertility-regulating surgery, and 35% in hysterectomy [6] These differences reflect differing clinical profiles; patients who had diagnostic surgery commonly complained infertility or pain, whereas those who had a hysterectomy were often older and more unwell [32].
Conclusion
According to the study's findings, there is a high association between endometriosis-related infertility and certain risk factors, specifically a family history of the disease, extended menstrual flow, and alcohol use. These relationships were statistically significant. Other variables such as age, BMI, and usage of contraceptives did not significantly affect infertility results, despite the fact that individuals showed a high awareness of endometriosis symptoms and reproductive difficulties. Furthermore, a history of infertility and married status were significant predictors of reproductive difficulties. The study emphasizes the significance of focused risk assessment and early intervention techniques, particularly in resource-constrained settings, to enhance reproductive outcomes for women with endometriosis, even though there were no significant correlations found with certain lifestyle choices and menstrual parameters.
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