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Obstetrics and Gynegology2023№1
The role of vitamin D and...

The role of vitamin D and omega-3 polyunsaturated fatty acid deficiencies in the pathogenesis of polycystic ovary syndrome

DOI
https://dx.doi.org/10.18565/aig.2023.11

Abashova E.I., Yarmolinskaya M.I.

1) D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductology, Saint Petersburg, Russia; 2) I.I. Mechnikov North-Western State Medical University; Ministry of Health of Russia, Saint Petersburg, Russia
Polycystic ovary syndrome (PCOS) occurs in every 5 reproductive-aged women. Women with PCOS are frequently found to have carbohydrate metabolism disorders, overweight, and obesity. The pathogenesis of PCOS is associated with both insulin resistance and a proinflammatory state, oxidative stress, which support the development of metabolic disorders. The role of micronutrients in both the correction of inflammation and oxidative stress and the processes of steroidogenesis, epigenetic regulation, lipid metabolism, and glucose and insulin transport is known. Widespread deficiencies of vitamin D and omega-3 polyunsaturated fatty acids (PUFAs) are the most common conditions associated with the insufficient intake of these micronutrients in the population. Correction of deficiency conditions with the use of vitamins and dietary supplements in women with PCOS is reflected in numerous new studies investigating the benefits of these treatments.
This review summarizes the latest data of randomized controlled trials, meta-analyses, and systematic reviews that analyze the efficacy of vitamin D and omega-3 PUFAs in the treatment of PCOS.
Conclusion: Using the drugs that affect steroidogenesis, insulin resistance, and lipid metabolism and correcting inflammation and oxidative stress in combination with basic treatment and therapeutic lifestyle changes can prevent adverse reproductive and metabolic outcomes in women with PCOS. The data of the presented studies suggest that the use of vitamin D and omega-3 PUFAs may be a useful adjunctive treatment for PCOS.

Authors’ contributions: Abashova E.I. – writing the text; Yarmolinskaya M.I. – editing.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The article has been prepared for publication as part of the fundamental scientific topic – the State Assignment of the Ministry of Science and Higher Education of the Russian Federation "Strategy for maintaining the health of women with gynecological and endocrine diseases in different age periods: a pathogenetic rationale for medical rehabilitation and development new area of organ-sparing surgical interventions” under No. 1021062812154-3-3.2.2.
For citation: Abashova E.I., Yarmolinskaya M.I. The role of vitamin D and omega-3 polyunsaturated fatty acid deficiencies in the pathogenesis of polycystic ovary syndrome.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2023; 1: 101-108 (in Russian)
https://dx.doi.org/10.18565/aig.2023.11

Keywords

polycystic ovary syndrome
PCOS
phenotype
vitamin D
omega-3 polyunsaturated fatty acids
glucose intolerance
insulin resistance
hyperandrogenism
soluble receptor for advanced glycation end products
sRAGE
Full text (in Russian)

References

  1. Teede H.J., Misso M.L., Costello M.F., Dokras A., Laven J., Moran L. et al.; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil. Steril. 2018; 110(3): 364-79. https://dx.doi.org/10.1016/j.fertnstert.2018.05.004.
  2. Министерство здравоохранения Российской Федерации. Клинические рекомендации. Синдром поликистозных яичников. 2021. [Ministry of Health of the Russian Federation. Clinical guidelines. Polycystic Ovary Syndrome. 2021. (in Russian)].
  3. Greenwood E.A., Pasch L.A., Cedars M.I., Legro R.S., Eisenberg E., Huddleston H.G.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Insulin resistance is associated with depression risk in polycystic ovary syndrome. Fertil. Steril. 2018; 110(1): 27 34. https://dx.doi.org/10.1016/j.fertnstert.2018.03.009.
  4. Абашова Е.И., Ярмолинская М.И. Фенотипы СПЯ у женщин репродуктивного возраста: клиника, диагностика, стратегия терапии. Акушерство и гинекология. 2021; 12 (приложение): 4-12. [Abashova E.I., Yarmolinskaya M.I. Phenotypes of polycystic ovary syndrome in women of reproductive age: clinical picture, diagnosis, therapy strategy. Obstetrics and Gynecology. 2021; 12 (Suppl.): 4-12. (in Russian)].
  5. Lim S.S., Hutchison S.K., Van Ryswyk E., Norman R.J., Teede H.J., Moran L.J. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2019; 3(3): CD007506. https://dx.doi.org/10.1002/14651858.CD007506.pub4.
  6. Holick M.F. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev. Endocr. Metab. Disord. 2017; 18(2): 153-65. https://dx.doi.org/10.1007/s11154-017-9424-1.
  7. Суплотова Л.А., Авдеева В.А., Пигарова Е.А., Рожинская Л.Я., Трошина Е.А. Дефицит витамина D в России: первые результаты регистрового неинтервенционного исследования частоты дефицита и недостаточности витамина D в различных географических регионах страны. Проблемы эндокринологии. 2021; 67(2): 84-92. https://dx.doi.org/10.14341/probl12736. [Suplotova L.A., Avdeeva V.A., Pigarova E.A., Rozhinskaya L.Y., Troshina E.A. Vitamin D deficiency in Russia: the first results of a registered, non-interventional study of the frequency of vitamin D deficiency and insufficiency in various geographic regions of the country. Problems of Endocrinology. 2021; 67(2): 84-92. (in Russian)]. https://dx.doi.org/10.14341/probl12736.
  8. Пигарова Е.А., Рожинская Л.Я., Катамадзе Н.Н., Поваляева А.А., Трошина Е.А. Распространенность дефицита и недостаточности витамина D среди населения, проживающего в различных регионах Российской Федерации: результаты 1-го этапа многоцентрового поперечного рандомизированного исследования. Остеопороз и остеопатии. 2020; 23(4): 4-12. https://dx.doi.org/10.14341/osteo12701. [Pigarova E.A., Rozhinskaya L.Y., Katamadze N.N., Povaliaeva A.A., Troshina E.A. Prevalence of vitamin D deficiency in various regions of the Russian Federation: results of the first stage of multicenter cross-sectional randomized study. Osteoporosis and Bone Diseases. 2020; 23(4): 4-12. (in Russian)]. https://dx.doi.org/10.14341/osteo12701.
  9. Stark K.D., Van Elswyk M.E., Higgins M.R., Weatherford C.A., Salem N. Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Prog. Lipid Res. 2016; 63: 132-52. https://dx.doi.org/10.1016/j.plipres.2016.05.001.
  10. Калинченко С.Ю., Соловьев Д.О., Аветисян Л.А., Белов Д.А., Парамонов С.А., Нижник А.Н. Распространенность дефицита омега-3 жирных кислот в различных возрастных группах. Вопросы диетологии. 2018; 8(1): 11-6. https://dx.doi.org/10.20953/2224-5448-2018-1-11-16. [Kalinchenko S.Yu., Solov’ev D.O., Avetisyan L.A. et al. Prevalence of Omega-3 fatty acid deficiency in different age groups. Nutrition. 2018; 8(1): 11-6. (in Russian)]. https://dx.doi.org/10.20953/2224-5448-2018-1-11-16.
  11. Bikle D.D. Vitamin D: production, metabolism and mechanisms of action. In: Feingold K.R., Anawalt B., Boyce A. et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; December 31, 2021.
  12. Charoenngam N., Holick M.F. Immunologic effects of vitamin D on human health and disease. Nutrients. 2020; 12(7): 2097. https://dx.doi.org/10.3390/nu12072097.
  13. Дедов И.И., Мельниченко Г.А., Мокрышева Н.Г., Пигарова Е.А., Поваляева А.А., Рожинская Л.Я., Белая Ж.Е., Дзеранова Л.К., Каронова Т.Л., Суплотова Л.А., Трошина Е.А. Проект федеральных клинических рекомендаций по диагностике, лечению и профилактике дефицита витамина D. Остеопороз и остеопатии. 2021; 24(4): 4-26. https://dx.doi.org/10.14341/osteo12937. [Dedov I.I., Mel’nichenko G.A., Mokrysheva N.G., Pigarova E.A., Povaliaeva A.A., Rozhinskaya L.Y., Belaya Z.E., Dzeranova L.K., Karonova T.L., Suplotova L.A., Troshina E.А. Draft federal clinical practice guidelines for the diagnosis, treatment, and prevention of vitamin D deficiency. Osteoporosis and Bone Diseases. 2021; 24(4): 4-26. (in Russian)]. https://dx.doi.org/10.14341/osteo12937.
  14. Sîrbe C., Rednic S., Grama A., Pop T.L. An update on the effects of vitamin D on the immune system and autoimmune diseases. Int. J. Mol. Sci. 2022; 23(17):9784. https://dx.doi.org/10.3390/ijms23179784.
  15. Davis E.M., Peck J.D., Hansen K.R., Neas B.R., Craig L.B. Associations between vitamin D levels and polycystic ovary syndrome phenotypes. Minerva Endocrinol. 2019; 44(2): 176-84. https://dx.doi.org/10.23736/S0391-1977.18.02824-9.
  16. Shan C., Zhu Y.C., Yu J., Zhang Yi., Wang Y.Y., Lu N. et al. Low serum 25-hydroxyvitamin D levels are associated with hyperandrogenemia in polycystic ovary syndrome: A gross-sectional study. Front. Endocrinol. (Lausanne). 2022; 13: 894935. https://dx.doi.org/10.3389/fendo.2022.894935.
  17. Kakoly N.S., Khomami M.B., Joham A.E., Cooray S.D., Misso M.L., Norman R.J. et al. Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression. Hum. Reprod. Update. 2018; 24(4): 455-67. https://dx.doi.org/10.1093/humupd/dmy007.
  18. Абашова Е.И., Ярмолинская М.И., Булгакова О.Л., Мишарина Е.В., Ткаченко Н.Н., Бородина В.Л. Анализ показателей углеводного профиля у женщин репродуктивного возраста с различными фенотипами синдрома поликистозных яичников. Проблемы репродукции. 2022; 28(4): 31-8. https://dx.doi.org/10.17116/repro20222804131. [Abashova E.I., Yarmolinskaya M.I., Bulgakova O.L., Misharina E.V., Tkachenko N.N., Borodina V.L. Analysis of carbohydrate profile indicators in women of reproductive age with different PCOS phenotypes. Russian Journal of Human Reproduction. 2022; 28(4): 31-8. (in Russian)]. https://dx.doi.org/10.17116/repro20222804131.
  19. Morgante G., Darino I., Spanò A., Luisi S., Luddi A., Piomboni P. et al. PCOS physiopathology and vitamin D deficiency: biological insights and perspectives for treatment. J. Clin. Med. 2022; 11: 4509. https://dx.doi.org/10.3390/jcm11154509.
  20. Shi X.Y., Huang A.P., Xie D.W., Yu X.L. Association of vitamin D receptor gene variants with polycystic ovary syndrome: a meta-analysis. BMC Med. Genet. 2019; 20(1): 32. https://dx.doi.org/10.1186/s12881-019-0763-5.
  21. Aravindhan S., Almasoody M.F.M., Selman N.A., Andreevna A.N., Ravali S., Mohammadi P. et al. Vitamin D receptor gene polymorphisms and susceptibility to type 2 diabetes: evidence from a meta-regression and meta-analysis based on 47 studies. J. Diabetes Metab. Disord. 2021; 20(1): 845-67. https://dx.doi.org/10.1007/s40200-020-00704-z.
  22. Garg D., Grazi R., Lambert-Messerlian G.M., Merhi Z. Correlation between follicular fluid levels of sRAGE and vitamin D in women with PCOS. J. Assist. Reprod. Genet. 2017; 34(11): 1507-13. https://dx.doi.org/10.1007/s10815-017-1011-6.
  23. Абашова Е.И., Ярмолинская М.И., Булгакова О.Л., Мишарина Е.В. Особенности липидного профиля при различных фенотипах синдрома поликистозных яичников у женщин репродуктивного возраста. Журнал акушерства и женских болезней. 2020; 69(6): 7-16. https://dx.doi.org/10.17816/JOWD6967-16. [Abashova E.I., Yarmolinskaya M.I., Bulgakova O.L., Misharina E.V. Lipid profile in women of reproductive age with various polycystic ovary syndrome phenotypes. Journal of Obstetrics and Women's Diseases. 2020; 69(6): 7-16. (in Russian)]. https://dx.doi.org/10.17816/JOWD6967-16.
  24. Merhi Z., Buyuk E., Cipolla M.J. Advanced glycation end products alter steroidogenic gene expression by granulosa cells: an effect partially reversible by vitamin D. Mol. Hum. Reprod. 2018; 24(6): 318-26. https://dx.doi.org/10.1093/molehr/gay014.
  25. Maktabi M., Chamani M., Asemi Z. The effects of vitamin D supplementation on metabolic status of patients with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Horm. Metab. Res. 2017; 49(7): 493-8. https://dx.doi.org/10.1055/s-0043-107242.
  26. Al-Bayyari N., Al-Domi H., Zayed F., Hailat R., Eaton A. Androgens and hirsutism score of overweight women with polycystic ovary syndrome improved after vitamin D treatment: A randomized placebo controlled clinical trial. Clin. Nutr. 2021; 40(3): 870-8. https://dx.doi.org/10.1016/j.clnu.2020.09.024.
  27. Bernasconi A.A., Wilkin A.M., Roke K., Ismail A. Development of a novel database to review and assess the clinical effects of EPA and DHA omega-3 fatty acids. Prostaglandins Leukot. Essent. Fatty Acids. 2022; 183: 102458. https://dx.doi.org/10.1016/j.plefa.2022.102458.
  28. Harris W.S., Tintle N.L., Imamura F., Qian F., Korat A.V.A., Marklund M. et al. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat. Commun. 2021; 12(1): 2329. https://dx.doi.org/10.1038/s41467-021-22370-2.
  29. Zhuang P., Zhang Y., He W., Chen X., Chen J., He L. et al. Dietary fats in relation to cotal and cause-specific mortality in a prospective cohort of 521 120 individuals with 16 years of follow-up. Circ. Res. 2019; 124(5): 757-68. https://dx.doi.org/10.1161/CIRCRESAHA.118.314038.
  30. Khan S.U., Lone A.N., Khan M.S, Virani S.S., Blumenthal R.S., Nasir K. et al. Effect of omega-3 fatty acids on cardiovascular outcomes: a systematic review and meta-analysis. EClinicalMedicine. 2021; 38: 100997. https://dx.doi.org/10.1016/j.eclinm.2021.100997.
  31. Gutiérrez S., Svahn S.L., Johansson M.E. Effects of omega-3 fatty acids on immune cells. Int. J. Mol. Sci. 2019; 20(20): 5028. https://dx.doi.org/10.3390/ijms20205028.
  32. Middleton P., Gomersall J.C., Gould J.F., Shepherd E., Olsen S.F., Makrides M. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst. Rev. 2018; 11(11): CD003402. https://dx.doi.org/10.1002/14651858.CD003402.pub3.
  33. Chiang N., Serhan C.N. Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem. 2020; 64(3): 443-62. https://dx.doi.org/10.1042/EBC20200018.
  34. Mason R.P., Libby P., Bhatt D.L. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler. Thromb. Vasc. Biol. 2020; 40(5): 1135-47. https://dx.doi.org/10.1161/ATVBAHA.119.313286.
  35. Wang R., Feng Y., Chen J., Chen Y., Ma F. Association between polyunsaturated fatty acid intake and infertility among American women aged 20-44 years. Front. Public Health. 2022; 10: 938343. https://dx.doi.org/10.3389/fpubh.2022.938343.
  36. Chiu Y.H., Karmon A.E., Gaskins A.J., Arvizu M., Williams P.L., Souter I. et al. Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. Hum. Reprod. 2018; 33(1): 156-65. https://dx.doi.org/10.1093/humrep/dex335.
  37. Lanza I.R., Blachnio-Zabielska A., Johnson M.L., Schimke J.M., Jakaitis D.R., Lebrasseur N.K. et al. Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet. Am. J. Physiol. Endocrinol. Metab. 2013; 304(12): E1391-403. https://dx.doi.org/10.1152/ajpendo.00584.2012. [Published correction appears Am. J. Physiol. Endocrinol. Metab. 2013; 305(8): E1048].
  38. Salek M., Clark C.C.T., Taghizadeh M., Jafarnejad S. N-3 fatty acids as preventive and therapeutic agents in attenuating PCOS complications. EXCLI J. 2019; 18: 558-75. https://dx.doi.org/10.17179/excli2019-1534.
  39. Muredda L., Kępczyńska M.A., Zaibi M.S., Alomar S.Y., Trayhurn P. IL-1β and TNFα inhibit GPR120 (FFAR4) and stimulate GPR84 (EX33) and GPR41 (FFAR3) fatty acid receptor expression in human adipocytes: implications for the anti-inflammatory action of n-3 fatty acids. Arch. Physiol. Biochem. 2018; 124(2): 97-108. https://dx.doi.org/10.1080/13813455.2017.1364774.
  40. Yang K., Zeng L., Bao T., Ge J. Effectiveness of Omega-3 fatty acid for polycystic ovary syndrome: a systematic review and meta-analysis. Reprod. Biol. Endocrinol. 2018; 16(1): 27. https://dx.doi.org/10.1186/s12958-018-0346-x.
  41. Tosatti J.A.G., Alves M.T., Cândido A.L., Reis F.M., Araújo V.E., Gomes K.B. Influence of n-3 fatty acid supplementation on inflammatory and oxidative stress markers in patients with polycystic ovary syndrome: a systematic review and meta-analysis. Br. J. Nutr. 2021; 125(6): 657-68. https://dx.doi.org/10.1017/S0007114520003207.
  42. Barbe A., Bongrani A., Mellouk N., Estienne A., Kurowska P., Grandhaye J. et al. Mechanisms of adiponectin action in fertility: an overview from gametogenesis to gestation in humans and animal models in normal and pathological conditions. Int. J. Mol. Sci. 2019; 20(7): 1526. https://dx.doi.org/10.3390/ijms20071526.
  43. Shahnazi V., Zaree M., Nouri M., Mehrzad-Sadaghiani M., Fayezi S., Darabi M. et al. Influence of ω-3 fatty acid eicosapentaenoic acid on IGF-1 and COX-2 gene expression in granulosa cells of PCOS women. Iran. J. Reprod. Med. 2015; 13(2): 71-8.
  44. Jo S., Harris W.S., Tintle N.L., Park Y. Association between Omega-3 index and hyperglycemia depending on body mass index among adults in the United States. nutrients. 2022; 14(20): 4407. https://dx.doi.org/10.3390/nu14204407.
  45. Беспалова О.Н., Жернакова Т.С., Шенгелия М.О., Загайнова В.А., Пачулия О.В., Коган И.Ю. Микронутриентный статус женщин с нарушением репродуктивной функции в Северо-Западном регионе Российской Федерации. Акушерство и гинекология. 2022; 10: 93-102. https://dx.doi.org/10.18565/aig.2022.10.93-102. [Bespalova O.N., Zhernakova T.S., Shengelia M.О., Zagaynova V.A., Pachulia O.V., Kogan I.Yu. Micronutrient status of women with impaired reproductive function in the Northwestern region of Russia. Obstetrics and Gynecology. 2022; (10): 93-102. (in Russian)]. https://dx.doi.org/10.18565/aig.2022.10.93-102.
  46. Lu L., Li X., Lv L., Xu Y., Wu B., Huang C. Associations between omega-3 fatty acids and insulin resistance and body composition in women with polycystic ovary syndrome. Front. Nutr. 2022; 9: 1016943. https://dx.doi.org/10.3389/fnut.2022.1016943.
  47. Единые санитарно-эпидемиологические и гигиенические требования к товарам, подлежащим санитарно-эпидемиологическому надзору (конт­ролю). Глава II, раздел 1, Приложение 5. [Unified sanitary-epidemiological and hygienic requirements for goods subject to sanitary and epidemiological supervision (control). Chapter II, Section 1, Appendix 5. (in Russian)].
  48. Bernasconi A.A., Wiest M.M., Lavie C.J., Milani R.V., Laukkanen J.A. Effect of Omega-3 dosage on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional trials. Mayo Clin. Proc. 2021; 96(2): 304-13. https://dx.doi.org/10.1016/j.mayocp.2020.08.034.

Received 17.01.2023

Accepted 23.01.2023

About the Authors

Elena I. Abashova, PhD, Senior Researcher, Department of Gynecology and Endocrinology, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, +7(812)328-98-20, +7(921)945-90-90, abashova@yandex.ru, https://orcid.org/0000-0003-2399-3108, SPIN-код: 2133-0310,
199034, Russia, St. Petersburg, Mendeleevskaya line, 3.
Maria I. Yarmolinskaya, Professor of RAS, Dr. Med. Sci., Professor, Head of the Department of Gynecology and Endocrinology, Head of Center “Diagnostics and treatment of endometriosis”, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology; Professor at the Department of Obstetrics and Gynecology, I.I. Mechnikov North-Western State Medical University, m.yarmolinskaya@gmail.com, https://orcid.org/0000-0002-6551-4147, eLibrary SPIN-код: 3686-3605,
199034, Russia, St. Petersburg, Mendeleevskaya line, 3.

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