Association of Vitamin D Level and Its Receptor with Endometriosis

Endometriosis, a condition where endometrial-like tissue grows outside the uterus, often occurs due to retrograde menstruation, where menstrual blood flows backward through the fallopian tubes into the pelvic cavity. This tissue can then implant and grow within the pelvic peritoneum. The survival of these ectopic implants leads to chronic inflammation, adhesion formation, and scarring of surrounding tissues, including the ovaries and fallopian tubes. Symptoms include cyclic pelvic pain, dysmenorrhea, dyspareunia, and infertility.

Ectopic endometrial tissue survival is not attributed to mutations but rather epigenetic changes. Studies have linked this phenomenon to genes such as KRAS (Kirsten Rat Sarcoma Virus Oncogene), involved in cell proliferation and survival. Dysregulated KRAS activity can lead to increased production of MMP-2 and MMP-9 proteins, implicated in angiogenesis and tissue invasion, facilitating the spread of endometrial tissue.

Vitamin D has been shown to modulate immune function and reduce inflammation. Studies suggest that vitamin D deficiency may exacerbate endometriosis symptoms and severity. However, evidence regarding the efficacy of vitamin D supplementation in managing endometriosis symptoms is mixed.

One study found that long-term intake of vitamin D-rich foods was associated with an 18% lower risk of developing endometriosis. Additionally, vitamin D deficiency has been correlated with increased expression of mutated KRAS in colorectal cancer patients, suggesting a potential link between vitamin D status and genetic abnormalities in disease progression.

Further research is needed to fully understand the relationship between vitamin D deficiency and endometriosis severity, particularly in specific populations like the Thai population.

Endometriosis occurs when endometrial-like tissue grows outside the uterus, typically within the pelvic cavity, due to retrograde menstruation through the fallopian tube. The survival and growth of these endometrial cells outside the uterus depend on estrogen, leading to chronic inflammation and symptoms such as cyclic abdominal pain, dyspareunia, and infertility.

The ectopic endometriotic tissue survival outside the uterus is not due to cell mutation but is associated with epigenetic changes. Studies have found a correlation with the KRAS gene, which controls cell division, and abnormal KRAS function reduces cell death, contributing to the development of ectopic endometriotic tissue. This tissue can form in various pelvic locations, including the ovarian follicles and the peritoneal cavity within the cul-de-sac.

Vitamin D is beneficial for the body in several systems, including the endocrine, skeletal, immune, and nervous systems. It is used to treat diseases related to the immune system and inflammation. Patients with infections or autoimmune diseases often undergo vitamin D level testing and supplementation. Vitamin D levels below 20 ng/ml indicate deficiency, 30-50 ng/ml are considered normal, and levels above 100 ng/ml are toxic. Thai people are at risk of deficiency or insufficiency despite being in a region with ample sunlight exposure throughout the year, primarily due to decreased sun exposure behavior. Several studies have found higher rates of deficiency among Thai women compared to men, with varied prevalence across different regions of Thailand.

Studies in Asian countries, including South Korea, Malaysia, and Vietnam, have reported high rates of vitamin D deficiency. In a study across 19 provinces in Vietnam, over half of the women were deficient in vitamin D. Vitamin D deficiency has been linked to various diseases, including musculoskeletal disorders, endocrine disorders, malabsorption syndromes, obesity, chronic kidney disease, cancer, and central nervous system disorders. Age does not seem to correlate with vitamin D levels. Sunscreen use has not been shown to affect vitamin D levels.

In Korea, work-related factors have been found to influence vitamin D levels, while body mass index (BMI) did not correlate with vitamin D levels. However, obesity has been associated with vitamin D deficiency in several studies, including levels of blood lipids.

Vitamin D and its receptor play crucial roles in cellular functions within the immune system, reducing inflammation through various mechanisms. Providing vitamin D to endometrial cells in culture can reduce the production of MMP-2 and MMP-9 proteins. MicroRNA expression associated with the vitamin D receptor increased after vitamin D supplementation. The expression of the vitamin D receptor, assessed by immunohistochemical staining, was significantly correlated with abnormal KRAS gene function in colorectal cancer patients. Moreover, increased expression was found in immunohistochemically stained tissue specimens of ectopic endometriotic tissue in untreated groups compared to those treated with progesterone before surgery. In cultured endometriotic tissue, vitamin D was found to reduce the production of MMP-2 and MMP-9 proteins, leading to decreased inflammation.

Vitamin D also inhibits the action of alpha estrogen receptor in breast cancer cells, and both alpha and beta estrogen receptors are present in ectopic endometriotic tissue. Alpha estrogen receptors are inhibited by progestin drugs used in treatment. An increase in alpha estrogen receptor expression indicates disease progression. Currently, beta estrogen receptors are found to have a greater proportion and a more significant role in various diseases. However, studies have also shown that alpha estrogen receptors may play a role in the development of ectopic endometriotic tissue.

The mechanisms by which vitamin D reduces MMPs and inhibits the action of alpha estrogen receptors are significant. Prolonged chronic inflammation can lead to increased surgical complications or disease progression. Surgical treatment for ectopic endometriotic tissue can help alleviate pain symptoms. The severity of the disease following surgery is assessed using the revised American Society for Reproductive Medicine (rASRM) criteria, considering factors such as lesion size, adhesions, ovarian lesions, and fluid characteristics within lesions. Studies have found a correlation between disease severity according to rASRM and abnormal KRAS gene function. Abnormal KRAS stimulates the production of MMP-2 and MMP-9 proteins, which are involved in angiogenesis, cell invasion, and the spread of cells. Increased levels of MMP-2 and MMP-9 lead to the proliferation of ectopic endometriotic tissue. High levels of MMP protein production have also been associated with resistance to progesterone treatment in endometriotic tissue cells.

Although current studies on vitamin D treatment may show insignificant reduction in pain symptoms, there are studies indicating that long-term consumption of high vitamin D foods can reduce the risk of developing ectopic endometriotic tissue by up to 18%. Vitamin D levels also correlate with the risk of disease. Deficiency or insufficiency of vitamin D over time may be a contributing factor to the growth of ectopic endometriotic tissue and may exacerbate the severity of the disease and associated pain symptoms compared to those with normal vitamin D levels. Considering the impact of vitamin D deficiency on ectopic endometriotic tissue, there are currently no studies investigating vitamin D levels in Thai individuals with more than half of them being deficient. Therefore, this study aims to determine whether there is a correlation between blood vitamin D levels and individuals in Thailand with ectopic endometriotic tissue.

Eligibility Criteria:
Inclusion Criteria Endometriosis Group:

* Women diagnosed with ectopic endometriotic tissue:
* Have a scheduled surgery appointment at Sri Nakarin Hospital.
* Are aged 18 years or older.

Inclusion Criteria Control Group:

* Women undergoing examination at the outpatient department of Sri Nakarin Hospital.
* No history of gynecological diseases or previous treatment for gynecological conditions associated with lower abdominal pain, infections, or abdominal masses at present.
* Have undergone a gynecological examination within the past year, or if examined during the current visit, the results were normal.
* Have undergone an ultrasound examination within the past year, or if examined during the current visit, the ultrasound results were normal.

Exclusion Criteria:

* Received vitamin D supplements within the past 3 months prior to volunteering.
* History of chronic infectious diseases.
* Previously treated for autoimmune diseases.
* History of polycystic ovarian.
* History of bone disorders or receiving medications affecting bones.
* Irregular menstrual cycles or absence of menstruation for more than 3 months up to 1 year.