Association of Vitamin D Level and Its Receptor With Endometriosis

Endometriosis Clinical Trial

Official title:

Association of Vitamin D Level and Its Receptor With Endometriosis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06289257
• Other study ID #: VitDAndEndomet
• Status: Not yet recruiting
• Start date: March 1, 2024
• Est. completion date: September 30, 2024

Study information

• Verified date: February 2024
• Source: Khon Kaen University
• Contact: Vitet Layanun, Doctor of Medicine
• Phone: +66850663130
• Email: jockvitet[@]hotmail.com
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 108
• Est. completion date: September 30, 2024
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Endometriosis

Intervention

Diagnostic Test:
• Vitamin D level
Vitamin D level in blood

Other:
• Vitamin D receptor
Vitamin D receptor in endometriosis tissue

Locations

Country	Name	City	State
Thailand	Department of Obstetrics and Gynecology, Faculty of Medicine, Khonkaen University	Khon Kaen

Sponsors (1)

Lead Sponsor	Collaborator
Khon Kaen University

Country where clinical trial is conducted

Thailand, 

References & Publications (56)

Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, Friedrich M, Taylor RN, Hornung D. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci. 2007 Jul;14(5):486-97. doi: 10.1177/1933719107304565. — View Citation

Anastasi E, Fuggetta E, De Vito C, Migliara G, Viggiani V, Manganaro L, Granato T, Benedetti Panici P, Angeloni A, Porpora MG. Low levels of 25-OH vitamin D in women with endometriosis and associated pelvic pain. Clin Chem Lab Med. 2017 Oct 26;55(12):e282-e284. doi: 10.1515/cclm-2017-0016. No abstract available. — View Citation

Andersen CL, Boisen MM, Sikora MJ, Ma T, Tseng G, Suryawanshi S, Vlad A, Elishaev E, Edwards RP, Oesterreich S. The Evolution of Estrogen Receptor Signaling in the Progression of Endometriosis to Endometriosis-Associated Ovarian Cancer. Horm Cancer. 2018 Dec;9(6):399-407. doi: 10.1007/s12672-018-0350-9. Epub 2018 Oct 9. — View Citation

Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noe M, Horlings HM, Lum A, Jones S, Senz J, Seckin T, Ho J, Wu RC, Lac V, Ogawa H, Tessier-Cloutier B, Alhassan R, Wang A, Wang Y, Cohen JD, Wong F, Hasanovic A, Orr N, Zhang M, Popoli M, McMahon W, Wood LD, Mattox A, Allaire C, Segars J, Williams C, Tomasetti C, Boyd N, Kinzler KW, Gilks CB, Diaz L, Wang TL, Vogelstein B, Yong PJ, Huntsman DG, Shih IM. Cancer-Associated Mutations in Endometriosis without Cancer. N Engl J Med. 2017 May 11;376(19):1835-1848. doi: 10.1056/NEJMoa1614814. — View Citation

Baek JC, Jo JY, Lee SM, Cho IA, Shin JK, Lee SA, Lee JH, Cho MC, Choi WJ. Differences in 25-hydroxy vitamin D and vitamin D-binding protein concentrations according to the severity of endometriosis. Clin Exp Reprod Med. 2019 Sep;46(3):125-131. doi: 10.5653/cerm.2018.00416. Epub 2019 Aug 1. — View Citation

Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, King K, Kvaskoff M, Nap A, Petersen K, Saridogan E, Tomassetti C, van Hanegem N, Vulliemoz N, Vermeulen N; ESHRE Endometriosis Guideline Group. ESHRE guideline: endometriosis. Hum Reprod Open. 2022 Feb 26;2022(2):hoac009. doi: 10.1093/hropen/hoac009. eCollection 2022. — View Citation

Buggio L, Somigliana E, Pizzi MN, Dridi D, Roncella E, Vercellini P. 25-Hydroxyvitamin D Serum Levels and Endometriosis: Results of a Case-Control Study. Reprod Sci. 2019 Feb;26(2):172-177. doi: 10.1177/1933719118766259. Epub 2018 Mar 27. — View Citation

Bulun SE, Yildiz S, Adli M, Chakravarti D, Parker JB, Milad M, Yang L, Chaudhari A, Tsai S, Wei JJ, Yin P. Endometriosis and adenomyosis: shared pathophysiology. Fertil Steril. 2023 May;119(5):746-750. doi: 10.1016/j.fertnstert.2023.03.006. Epub 2023 Mar 15. — View Citation

Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M, Wei J. Endometriosis. Endocr Rev. 2019 Aug 1;40(4):1048-1079. doi: 10.1210/er.2018-00242. — View Citation

Bulun SE. Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, 9th edition. 9 ed: Elsevier; 2023 12/07/2023. 1040 p.

Cashman KD. Global differences in vitamin D status and dietary intake: a review of the data. Endocr Connect. 2022 Jan 11;11(1):e210282. doi: 10.1530/EC-21-0282. — View Citation

Chailurkit LO, Aekplakorn W, Ongphiphadhanakul B. Regional variation and determinants of vitamin D status in sunshine-abundant Thailand. BMC Public Health. 2011 Nov 10;11:853. doi: 10.1186/1471-2458-11-853. — View Citation

Chantalat E, Valera MC, Vaysse C, Noirrit E, Rusidze M, Weyl A, Vergriete K, Buscail E, Lluel P, Fontaine C, Arnal JF, Lenfant F. Estrogen Receptors and Endometriosis. Int J Mol Sci. 2020 Apr 17;21(8):2815. doi: 10.3390/ijms21082815. — View Citation

Cho MC, Kim JH, Jung MH, Cho IA, Jo HC, Shin JK, Lee SA, Choi WJ, Lee JH. Analysis of vitamin D-binding protein (VDBP) gene polymorphisms in Korean women with and without endometriosis. Clin Exp Reprod Med. 2019 Sep;46(3):132-139. doi: 10.5653/cerm.2019.00122. Epub 2019 Aug 13. — View Citation

Delbandi AA, Torab M, Abdollahi E, Khodaverdi S, Rokhgireh S, Moradi Z, Heidari S, Mohammadi T. Vitamin D deficiency as a risk factor for endometriosis in Iranian women. J Reprod Immunol. 2021 Feb;143:103266. doi: 10.1016/j.jri.2020.103266. Epub 2020 Dec 17. — View Citation

Denisova AS, Yarmolinskaya MI, Tkachenko NN. Assessment of 25(OH)D status in patients with genital endometriosis and clinical efficacy of cholecalciferol in the treatment of the disease. JOWD. 2021;70(4):125-33.

Derakhshan M, Derakhshan M, Hedayat P, Shiasi M, Sadeghi E, editors. Vitamin D Deficiency May Be a Modifiable Risk Factor in Women With Endometriosis2018.

Halder SK, Osteen KG, Al-Hendy A. Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells. Hum Reprod. 2013 Sep;28(9):2407-16. doi: 10.1093/humrep/det265. Epub 2013 Jun 27. — View Citation

Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA. Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013 Mar 1;177(5):420-30. doi: 10.1093/aje/kws247. Epub 2013 Feb 3. — View Citation

Hartwell D, Rodbro P, Jensen SB, Thomsen K, Christiansen C. Vitamin D metabolites--relation to age, menopause and endometriosis. Scand J Clin Lab Invest. 1990 Apr;50(2):115-21. doi: 10.3109/00365519009089142. — View Citation

Horikawa A, Kasukawa Y, Hongo M, Kodama H, Sano A, Miyakoshi N. A prospective analysis of concentration of 25-OHD between northern and southern district in Japan in year-round study. Medicine (Baltimore). 2022 Oct 28;101(43):e31340. doi: 10.1097/MD.0000000000031340. — View Citation

Huang X, Yang Y, Jiang Y, Zhou Z, Zhang J. Association between vitamin D deficiency and lipid profiles in overweight and obese adults: a systematic review and meta-analysis. BMC Public Health. 2023 Aug 29;23(1):1653. doi: 10.1186/s12889-023-16447-4. — View Citation

Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E, Hayashi T, Kojima S, Takeyama R, Hashimoto T, Kiyono T, Ikemura M, Taguchi A, Tanaka T, Tanaka Y, Sakata S, Takeuchi K, Muraoka A, Osuka S, Saito T, Oda K, Osuga Y, Terao Y, Kawazu M, Mano H. Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations. Nat Commun. 2019 Dec 19;10(1):5785. doi: 10.1038/s41467-019-13708-y. — View Citation

Jiang Z, Pu R, Li N, Chen C, Li J, Dai W, Wang Y, Hu J, Zhu D, Yu Q, Shi Y, Yang G. High prevalence of vitamin D deficiency in Asia: A systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2023;63(19):3602-3611. doi: 10.1080/10408398.2021.1990850. Epub 2021 Nov 16. — View Citation

Kahlon BK, Simon-Collins M, Nylander E, Segars J, Singh B. A systematic review of vitamin D and endometriosis: role in pathophysiology, diagnosis, treatment, and prevention. F&S Reviews. 2023;4(1):1-14.

Karampela I, Sakelliou A, Vallianou N, Christodoulatos GS, Magkos F, Dalamaga M. Vitamin D and Obesity: Current Evidence and Controversies. Curr Obes Rep. 2021 Jun;10(2):162-180. doi: 10.1007/s13679-021-00433-1. Epub 2021 Apr 1. — View Citation

Ke J, Ye J, Li M, Zhu Z. The Role of Matrix Metalloproteinases in Endometriosis: A Potential Target. Biomolecules. 2021 Nov 22;11(11):1739. doi: 10.3390/biom11111739. — View Citation

Krishnan AV, Swami S, Feldman D. The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer. Steroids. 2012 Sep;77(11):1107-12. doi: 10.1016/j.steroids.2012.06.005. Epub 2012 Jul 16. — View Citation

Kure S, Nosho K, Baba Y, Irahara N, Shima K, Ng K, Meyerhardt JA, Giovannucci EL, Fuchs CS, Ogino S. Vitamin D receptor expression is associated with PIK3CA and KRAS mutations in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2765-72. doi: 10.1158/1055-9965.EPI-09-0490. Epub 2009 Sep 29. — View Citation

Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8. doi: 10.1016/j.pbiomolbio.2006.02.016. Epub 2006 Feb 28. — View Citation

MacLean JA 2nd, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells. 2022 Feb 13;11(4):647. doi: 10.3390/cells11040647. — View Citation

Martelli M, Salvio G, Santarelli L, Bracci M. Shift Work and Serum Vitamin D Levels: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2022 Jul 22;19(15):8919. doi: 10.3390/ijerph19158919. — View Citation

Matasariu DR, Mandici CE, Ursache A, Bausic AIG, Bujor IE, Cristofor AE, Boiculese LV, Grigore M, Bratila E, Lozneanu L. Vitamin D and Mitosis Evaluation in Endometriosis: A Step toward Discovering the Connection? Biomedicines. 2023 Jul 26;11(8):2102. doi: 10.3390/biomedicines11082102. — View Citation

Matsuzaki S, Murakami T, Uehara S, Canis M, Sasano H, Okamura K. Expression of estrogen receptor alpha and beta in peritoneal and ovarian endometriosis. Fertil Steril. 2001 Jun;75(6):1198-205. doi: 10.1016/s0015-0282(01)01783-6. — View Citation

Md Isa Z, Mohd Nordin NR, Mahmud MH, Hashim S. An Update on Vitamin D Deficiency Status in Malaysia. Nutrients. 2022 Jan 27;14(3):567. doi: 10.3390/nu14030567. — View Citation

Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A, Nagai M, Urata Y, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y. Effects of 1,25-Dihydroxy Vitamin D3 on Endometriosis. J Clin Endocrinol Metab. 2016 Jun;101(6):2371-9. doi: 10.1210/jc.2016-1515. Epub 2016 Apr 1. — View Citation

Neale RE, Khan SR, Lucas RM, Waterhouse M, Whiteman DC, Olsen CM. The effect of sunscreen on vitamin D: a review. Br J Dermatol. 2019 Nov;181(5):907-915. doi: 10.1111/bjd.17980. Epub 2019 Jul 9. — View Citation

Orr NL, Albert A, Liu YD, Lum A, Hong J, Ionescu CL, Senz J, Nazeran TM, Lee AF, Noga H, Lawrenson K, Allaire C, Williams C, Bedaiwy MA, Anglesio MS, Yong PJ. KRAS mutations and endometriosis burden of disease. J Pathol Clin Res. 2023 Jul;9(4):302-312. doi: 10.1002/cjp2.317. Epub 2023 Mar 28. — View Citation

Pluchino N, Mamillapalli R, Wenger JM, Ramyead L, Drakopoulos P, Tille JC, Taylor HS. Estrogen receptor-alpha immunoreactivity predicts symptom severity and pain recurrence in deep endometriosis. Fertil Steril. 2020 Jun;113(6):1224-1231.e1. doi: 10.1016/j.fertnstert.2020.01.036. Epub 2020 May 13. — View Citation

Pludowski P, Takacs I, Boyanov M, Belaya Z, Diaconu CC, Mokhort T, Zherdova N, Rasa I, Payer J, Pilz S. Clinical Practice in the Prevention, Diagnosis and Treatment of Vitamin D Deficiency: A Central and Eastern European Expert Consensus Statement. Nutrients. 2022 Apr 2;14(7):1483. doi: 10.3390/nu14071483. — View Citation

Pludowski P. Supplementing Vitamin D in Different Patient Groups to Reduce Deficiency. Nutrients. 2023 Aug 25;15(17):3725. doi: 10.3390/nu15173725. — View Citation

Rajatanavin N, Kanokrungsee S, Aekplakorn W. Vitamin D status in Thai dermatologists and working-age Thai population. J Dermatol. 2019 Mar;46(3):206-212. doi: 10.1111/1346-8138.14742. Epub 2018 Dec 28. — View Citation

Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997 May;67(5):817-21. doi: 10.1016/s0015-0282(97)81391-x. No abstract available. — View Citation

Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics and Gynecology. 1927;14(4):422-69.

Sharpe-Timms KL, Cox KE. Paracrine regulation of matrix metalloproteinase expression in endometriosis. Ann N Y Acad Sci. 2002 Mar;955:147-56; discussion 157-8, 396-406. doi: 10.1111/j.1749-6632.2002.tb02775.x. — View Citation

Somigliana E, Panina-Bordignon P, Murone S, Di Lucia P, Vercellini P, Vigano P. Vitamin D reserve is higher in women with endometriosis. Hum Reprod. 2007 Aug;22(8):2273-8. doi: 10.1093/humrep/dem142. Epub 2007 Jun 4. — View Citation

Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, Adachi S, Takahashi T, Kase H, Tanaka K, Yamamoto T, Motoyama T, Inoue I, Enomoto T. Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. Cell Rep. 2018 Aug 14;24(7):1777-1789. doi: 10.1016/j.celrep.2018.07.037. — View Citation

Tuyen le D, Hien VT, Binh PT, Yamamoto S. Calcium and Vitamin D Deficiency in Vietnamese: Recommendations for an Intervention Strategy. J Nutr Sci Vitaminol (Tokyo). 2016;62(1):1-5. doi: 10.3177/jnsv.62.1. — View Citation

Ueda M, Yamashita Y, Takehara M, Terai Y, Kumagai K, Ueki K, Kanda K, Hung YC, Ueki M. Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis. Gynecol Endocrinol. 2002 Oct;16(5):391-402. — View Citation

Walsh JS, Bowles S, Evans AL. Vitamin D in obesity. Curr Opin Endocrinol Diabetes Obes. 2017 Dec;24(6):389-394. doi: 10.1097/MED.0000000000000371. — View Citation

Wang H, Chen W, Li D, Yin X, Zhang X, Olsen N, Zheng SG. Vitamin D and Chronic Diseases. Aging Dis. 2017 May 2;8(3):346-353. doi: 10.14336/AD.2016.1021. eCollection 2017 May. — View Citation

Wimalawansa SJ. Infections and Autoimmunity-The Immune System and Vitamin D: A Systematic Review. Nutrients. 2023 Sep 2;15(17):3842. doi: 10.3390/nu15173842. — View Citation

Yu K, Huang ZY, Xu XL, Li J, Fu XW, Deng SL. Estrogen Receptor Function: Impact on the Human Endometrium. Front Endocrinol (Lausanne). 2022 Feb 28;13:827724. doi: 10.3389/fendo.2022.827724. eCollection 2022. — View Citation

Zakharova I, Klimov L, Kuryaninova V, Nikitina I, Malyavskaya S, Dolbnya S, Kasyanova A, Atanesyan R, Stoyan M, Todieva A, Kostrova G, Lebedev A. Vitamin D Insufficiency in Overweight and Obese Children and Adolescents. Front Endocrinol (Lausanne). 2019 Mar 1;10:103. doi: 10.3389/fendo.2019.00103. eCollection 2019. — View Citation

Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. Int J Mol Sci. 2023 Apr 10;24(8):6992. doi: 10.3390/ijms24086992. — View Citation

Zheng SH, Chen XX, Chen Y, Wu ZC, Chen XQ, Li XL. Antioxidant vitamins supplementation reduce endometriosis related pelvic pain in humans: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2023 Aug 29;21(1):79. doi: 10.1186/s12958-023-01126-1. — View Citation

* Note: There are 56 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Vitamin D level	Vitamin D status	At enrollment
Secondary	rASRM	Severity of the disease	Intra operation
Secondary	Vitamin D receptor	Tissue staining of Vitamin D antibody	Up to 4 weeks after surgery