Endometriosis is a chronic inflammatory disease characterized by the presence of tissue similar to the endometrium outside the uterus 1. The age range of patients diagnosed with endometriosis is between 20–42 years. The prevalence of endometriosis is estimated to be between 2–10% in the female population worldwide, and up to 50% of infertility cases are associated with endometriosis 2.
Potential origins of endometriosis lesions include the transplantation of endometrial tissue through retrograde menstruation and in situ metaplasia of coelomic epithelium. Lesions outside the pelvis may be caused by vascular or lymphatic metastasis 2. Superficial and deep infiltrating endometriosis lesions form through molecular mechanisms involving interactions between adhesion, cell proliferation, systemic and local steroidogenesis, chronic inflammation, immune dysregulation, vascularization, and innervation 3.
The chronic inflammatory response in endometriosis involves both innate and adaptive immune responses influenced by estrogen hormones 4. The initial innate immune response involves macrophage phagocytosis mediated by scavenger receptors and regulated by cytokines. Patients with endometriosis exhibit abnormalities in their innate immune response, where macrophages fail to perform phagocytic functions on endometriosis lesions, particularly during the mediation process by scavenger receptors 5.
The adaptive immune system becomes involved when the innate immune response is insufficient to handle the pathological conditions. The adaptive immune system consists primarily of T and B lymphocytes. In patients with endometriosis, there is an increase in cytokine modulation by T cells and the formation of autoantibodies by B cells 6.
Cytokines are proteins produced by various cells including stromal cells, fibroblasts, and endothelial cells. Interleukin-32 (IL-32) is one among proinflammatory cytokines thought to be involved in the pathogenesis of endometriosis. IL-32 has diverse functions such as regulating the body's immune response during infection, contributing to autoimmune diseases, cancer, and inflammatory reactions 7.
IL-32 is recognized as a proinflammatory cytokines and a potent inducer similar to other proinflammatory cytokines such as TNF-α and IL-8. IL-32 activates specific cytokine signaling pathways including NF-ĸB and p38 mitogen-activated protein kinases. Activation of the NF-ĸB pathway leads to inflammation, invasion of endometriosis cells, angiogenesis, proliferation, and inhibition of apoptosis processes within endometriosis cells 8. Another cytokine pathway activated by IL-32 is the p38 mitogen-activated protein kinases pathway, which results in increased cytokine production, proliferation of endometriosis cells, and reduced apoptosis processes 9.
VEGF is a vasoactive substance involved in various physiological processes in the body, including wound healing and endometrial revascularization. Increased VEGF levels trigger excessive angiogenesis, allowing endometriosis lesions to persist and progress. Activation of VEGF receptors in endothelial cells initiates processes such as endothelial cell proliferation, migration, increased blood vessel permeability, and induction of blood vessel remodeling, ultimately leading to the formation of new blood vessels 10.
Another factor involved in endometriosis pathogenesis is vitamin D deficiency 6. Vitamin D has anti-inflammatory benefits by reducing cytokine production in the body. The most active metabolite of vitamin D is 1,25(OH)2D3, which has been shown to have significant anti-proliferative effects in preclinical models, inhibiting cell differentiation processes, angiogenesis, and inducing apoptosis 11,12.
The role of vitamin D in relation to IL-32 is indirect, involving inhibition of NF-ĸB by direct binding to IKKβ, thereby reducing IL-32 levels 11. Additionally, evidence suggests that vitamin D can affect the normal function of endothelial cells in angiogenesis by suppressing VEGF production through autocrine Wnt/β-catenin pathway inhibition 13.