CYP19A in visceral fat of patients with endometriosis: a trigger for the disease?

Background Endometriosis is a condition affecting 10% of women of reproductive age. It is characterized by the presence of ectopic endometrial-like tissue, primarily in the pelvic cavity but also in extra pelvic locations such as the upper abdominal organs, abdominal wall, diaphragm, and pleura. Oestrogen-dependent growth of ectopic endometrium causes severe, often cyclical, pain, which is the main symptom in women with endometriosis. Literature shows an inverse relationship between BMI and endometriosis and there is evidence that patients with the lowest BMI (<18.5) had a high risk of developing deeply infiltrating endometriosis, suggesting that a lower BMI also correlates with the stage of the disease. Based on this, it is hypothesized that adipose tissue in patients with endometriosis may be reduced in quantity but present increased inflammation and oestrogen production, due to increased expression of CYP19A1 in visceral fat, a gene that encodes aromatase, which transforms androgens into oestrogens. Previously, CYP19A1 had been studied only in eutopic and ectopic endometrial tissue, where its activity contributes to elevated oestrogen levels and promotes implant growth. Aims of the Study Our primary aim was to assess if CYP19A1 expression is higher in the visceral fat of women with endometriosis versus controls. Additionally, the study aimed to determine if molecules such as IL-6, TNF-α, and IL-10 are expressed at higher levels in the visceral fat of women with endometriosis compared to control subjects. Our secondary goal was to correlate CYP19A1, IL-6, TNF-α, and IL-10 expression in visceral fat with disease stage. Materials and Methods 20 women diagnosed with endometriosis and 20 with benign ovarian cysts were consecutively enrolled between June 2022 and June 2024. All patients were scheduled for laparoscopic surgery and signed written informed consent. Prior to surgery, all women who met the inclusion criteria were asked about their age, body mass index (BMI), and phase of the menstrual cycle. Before surgery, blood samples were collected from each patient, serum was extracted and stored at –80°C. During surgery, ~ 50mm visceral fat sample was taken from the epiploon next to the ovarian cyst, placed in a sterile tube, and stored at –80°C. The histopathological diagnosis was later confirmed by a pathologist. Gene expression of CYP19A1, IL-6, TNF-α, and IL-10 in visceral fat was analysed by isolating mRNA from tissue samples followed by real-time polymerase chain reaction (RT-PCR). Serum TNF-α levels were determined by ELISA test. Results CYP19A1 resulted more expressed in the visceral fat of endometriosis (p = 0,019), as well as TNF-α (p = 0,002). IL-10 resulted more expressed in controls (p = 0,04). There were not significant changes in IL-6 expression in cases and controls. A correlation analysis was performed, and CYP19A1 was the only gene positively correlated with the disease's stage. Serum levels (pg/mL) of TNF-α obtained through ELISA, were higher in endometriosis (p 0,0019). Conclusion This is the first article to demonstrate increased expression of CYP19A1 in visceral fat in patients with endometriosis, with CYP19A levels correlating with disease severity. This is also the first study to demonstrate increased expression of the anti-inflammatory molecule IL-10 in visceral fat in control subjects. Estrogen fuels the disease, and inflammatory cytokines such as IL-6 and TNF-α contribute to its exacerbation. Therefore, the elevated levels of estrogen and inflammatory molecules produced by visceral fat in women with endometriosis may suggest a visceral fat contribution to the pathogenesis of the disease, potentially exacerbating its symptoms.