About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Logout
Obstetrics and Gynegology2021№12
Estrogen-like and antioxidant properties of...

Estrogen-like and antioxidant properties of resveratrol in clinical pharmacology and therapeutic use

DOI
https://dx.doi.org/10.18565/aig.2021.12.37-48

Kareva E.N., Smetnik A.A.

1) I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), Moscow, Russia; 2) Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia
The article highlights the multi-target properties of trans-resveratrol which is a new generation of phytoestrogens with a high potential in the correction of menopausal disorders in women who cannot be prescribed menopausal hormone therapy. The article presents scientific data confirming that trans-resveratrol has a strong estrogen-like, antioxidant, cardioprotective action, as well as anti-aging and other effects. The clinical properties and mechanisms of resveratrol action are reviewed in terms of its use in gynaecology and clinical pharmacology. The article describes the effects of resveratrol on the manifestations of estrogen deficiency (vasomotor episodes, decreased bone mineral density, metabolic and psychoemotional disorders, and others). The pharmacokinetic properties of resveratrol which may limit its use in clinical practice are highlighted in the article; however, these problems can currently be solved due to the devlopment of new delivery systems. The paper shows the ways to increase the bioavailability of resveratrol which does not exceed 1% when ingested. When the medication is taken sublingually, absorption occurs quickly through the oral mucosa, thereby eliminating the effect on the intestines and metabolism in the liver during the initial passage. Due to the active component delivery systems developed with the help of modern pharmaceutical nanotechnology, it is possible to overcome the low solubility of resveratrol in water, which can significantly increase its absorbability through the oral mucosa and ensure its high bioavailability.
Conclusion: The new medication Feminaspray in the form of a sublingual spray which contains trans-resveratrol, vitamin D3 and vitamin E leads to a statistically significant decrease in the main manifestations of menopausal disorders.

Keywords

menopause
phytoestrogens
resveratrol
hot flushes
alternative therapy
menopausal syndrome
estrogen deficiency
Full text (in Russian)

References

  1. Bowers J.L., Tyulmenkov V.V., Jernigan S.C., Klinge C.M. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology. 2000; 14(10): 3657-67. https://dx.doi.org/10.1210/endo.141.10.7721.
  2. Lai C.Y. Preventing bone loss and weight gain with combinations of vitamin D and phytochemicals. J. Med. Food. 2011; 14(11): 1352-62. https://dx.doi.org/10.1089/jmf.2010.0232.
  3. Карева Е.Н., Федореев С.А., Шимановский Н.Л. Синтетические и растительные лекарственные средства с эстрогеноподобной активностью. Международный медицинский журнал. 2012; 1: 95-100. [Kareva E.N., Fedoreyev S.A., Shimanovsky N.L. Synthetic and herbal drugs with estrogen-like activity. International Medical Journal. 2012; 1: 95-100. (in Russian)].
  4. Филиппова О.В. Фитоэстрогены: перспективы примененения. Эффективная фармакотерапия. 2020; 16(22): 30-6. [Filippova O.V. Phytoestrogens: perspectives of administration. Effective Pharmacothuerapy. 2020; 16(22): 30-6. (in Russian)].
  5. Desmawati D., Sulastri D. Phytoestrogens and their health effect. Open Access Maced. J. Med. Sci. 2019; 7(3); 495-9. https://dx.doi.org/10.3889/oamjms.2019.044.
  6. Koushki M., Amiri-Dashatan N., Ahmadi N., Abbaszadeh H.-A., Rezaei-Tavirani M. Resveratrol: A miraculous natural compound for diseases treatment. Food Sci. Nutr. 2018; 6(8): 2473-2490. https://dx.doi.org/10.1002/fsn3.855.
  7. Pasquariello R. The role of resveratrol in mammalian reproduction. Molecules. 2020; 25(19): 4554. https://dx.doi.org/10.3390/molecules25194554.
  8. Винокурова Е.А., Исмаилова Д.Х., Хвощина Т.Н. Новые возможности персонифицированной менопаузальной фитотерапии ресвератолом. Доктор.Ру. 2021; 20(6): 92-6. https://dx.doi.org/10.31550/1727-2378-2021-20-6-92-96. [Vinokurova E.A., Ismailova D.Kh., Khvoschina T.N. New Possibilities of Personalised Menopausal Phytotherapy with Resveratrol. Doctor.ru. 2021; 20(6): 92-6. (in Russian)]. https://dx.doi.org/10.31550/1727-2378-2021-20-6-92-96.
  9. Zupancic S., Lavric Z., Kristl J. Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature. Eur. J. Pharm. Biopharm. 2015; 93: 196-204. https://dx.doi.org/10.1016/j.ejpb.2015.04.002.
  10. Rotches-Ribalta M., Andres-Lacueva C., Estruch R., Escribano E., Urpi-Sarda M. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol. Res. 2012; 66(5): 375-82. https://dx.doi.org/10.1016/j.phrs.2012.08.001.
  11. Wang P., Sang S. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors. 2018; 44(1): 16-25. https://dx.doi.org/10.1002/biof.1410.
  12. Gambini J., Ingles M., Olaso G., Lopez-Grueso R., Bonet-Costa V., Gimeno-Mallench L. et al. Properties of resveratrol: In vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxid. Med. Cell. Longev. 2015; 2015: 837042. https://dx.doi.org/10.1155/2015/837042.
  13. Delmas D., Aires V., Limagne E., Dutartre P., Mazue F., Ghiringhelli F., Latruffe N. Transport, stability, and biological activity of resveratrol. Ann. N. Y. Acad. Sci. 2011; 1215: 48-59. https://dx.doi.org/10.1111/j.1749-6632.2010.05871.x.
  14. Boocock D.J., Patel K.R., Faust G.E.S., Normolle D.P., Marczylo T.H., Crowell J.A. et al. Quantitation of trans-resveratrol and detection of its metabolites in human plasma and urine by high performance liquid chromatography. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2007; 848(2): 182-7. https://dx.doi.org/10.1016/j.jchromb.2006.10.017.
  15. Ruotolo R., Calani L., Fietta E., Brighenti F., Crozier A., Meda C. et al. Anti-estrogenic activity of a human resveratrol metabolite. Nutr. Metab. Cardiovasc. Dis. 2013; 23(11): 1086-92. https://dx.doi.org/10.1016/j.numecd.2013.01.002.
  16. Baur J.A., Sinclair D.A. Therapeutic potential of resveratrol: The in vivo evidence. Nat. Rev. Drug Discov. 2006; 5(6): 493-506. https://dx.doi.org/10.1038/nrd2060.
  17. Walle T., Hsieh F., DeLegge M.H., Oatis J.E., Walle U.K. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 2004; 32(12): 1377-82. https://dx.doi.org/10.1124/dmd.104.000885.
  18. Boocock D.J., Faust G.E.S., Patel K.R., Schinas A.M., Brown V.A., Ducharme M.P. et al. Phase i dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol. Biomark. Prev. 2007; 16(6): 1246-52. https://dx.doi.org/10.1158/1055-9965.EPI-07-0022.
  19. Patel K.R., Scott E., Brown V.A., Gescher A.J., Steward W.P., Brown K. Clinical trials of resveratrol. Ann. N. Y. Acad. Sci. 2011; 1215: 161-9. https://dx.doi.org/10.1111/j.1749-6632.2010.05853.x.
  20. Amidon G.L., Lennernas H., Shah V.P., Crison J.R. A theoretical basis for a biopharmaceutic drug classification  – The correlation of in-vitro drug product dissolution and in-vivo bioavailability. Pharm. Res. 1995; 12(3): 413-20. https://dx.doi.org/10.1023/a:1016212804288.
  21. Amri A., Chaumeil J.C., Sfar S., Charrueau C. Administration of resveratrol: What formulation solutions to bioavailability limitations? J. Control. Release. 2012; 158(2): 182-93. https://dx.doi.org/10.1016/j.jconrel.2011.09.083.
  22. Sessa M., Balestrieri M.L., Ferrari G., Servillo L., Castaldo D., D’Onofrio N. et al. Bioavailability of encapsulated resveratrol into nanoemulsion-based delivery systems. Food Chem. 2014; 147: 42-50. https://dx.doi.org/ 10.1016/j.foodchem.2013.09.088.
  23. Kuiper G.G.J.M., Carlsson B., Grandien K., Enmark E., Häggblad J., Nilsson S., Gustafsson J.-A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology. 1997; 138(3): 863-70. https://dx.doi.org/10.1210/endo.138.3.4979.
  24. Hewitt S.C., Korach K.S. Estrogen receptors: new directions in the new millennium. Endocr. Rev. 2018; 39(5): 664-75. https://dx.doi.org/10.1210/er.2018-00087.
  25. Leo L., Surico D., Deambrogio F., Scatuzzi A., Marzullo P., Tinelli R. et al. Preliminary data on the effectiveness of resveratrol in a new formulation in treatment of hot flushes. Minerva Ginecol. 2015; 67(5): 475-83.
  26. Chen Y.C., Nagpal M.L., Stocco D.M., Lin T. Effects of genistein, resver- atrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells. J. Endocrinol. 2007; 192(3): 527-37. https://dx.doi.org/10.1677/JOE-06-0087.
  27. Wang Y., Lee K.W., Chan F.L., Chen S., Leung L.K. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol. Sci. 2006; 92(1): 71-7. https://dx.doi.org/10.1093/toxsci/kfj190.
  28. Kulkarni S.S., Cantó C. The molecular targets of resveratrol. Biochim. Biophys. Acta. 2015; 1852(6): 1114-23. https://dx.doi.org/10.1016/j.bbadis.2014.10.005.
  29. Szkudelski T., Szkudelska K. Resveratrol and diabetes: from animal to human studies. Biochim. Biophys. Acta. 2015; 1852(6): 1145-54. https://dx.doi.org/10.1016/j.bbadis.2014.10.013.
  30. Tellone E., Galtieri A., Russo A., Giardina B., Ficarra S. Resveratrol: a focus on several neurodegenerative diseases. Oxid. Med. Cell. Longev. 2015; 2015: 392169. https://dx.doi.org/10.1155/2015/392169.
  31. Signorelli P., Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J. Nutr. Biochem. 2005; 16(8): 449-66. https://dx.doi.org/10.1016/j.jnutbio.2005.01.017.
  32. Szkudelska K., Szkudelski T. Resveratrol, obesity and diabetes. Eur. J. Pharmacol. 2010; 635(1-3): 1-8. https://dx.doi.org/10.1016/j.ejphar.2010.02.054.
  33. Petrovski G., Gurusamy N., Das D.K. Resveratrol in cardiovascular health and disease. Ann. N. Y. Acad. Sci. 2011; 1215: 22-3. https://dx.doi.org/10.1111/j.1749-6632.2010.05843.x.
  34. Baur J.A., Pearson K.J., Price N.L., Jamieson H.A., Lerin C., Kalra A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444(7117): 337-42. https://dx.doi.org/10.1038/nature05354.
  35. Evans H., Howe P., Wong R. Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a 14-week randomised placebo-controlled intervention trial. Nutrients. 2017; 9(1): 27. https://dx.doi.org/10.3390/nu9010027.
  36. de Ligt M., Timmers S., Schrauwen P. Resveratrol and obesity: Can resveratrol relieve metabolic disturbances? Biochim. Biophys. Acta. 2015; 1852(6):1137-44. https://dx.doi.org/10.1016/j.bbadis.2014.11.012.
  37. Zhang J., Chen L., Zheng J., Zeng T., Li H., Xiao H. et al. The protective effect of resveratrol on islet insulin secretion and morphology in mice on a high-fat diet. Diabetes Res. Clin. Pract. 2012; 97(3): 474-82. https://dx.doi.org/10.1016/j.diabres.2012.02.029.
  38. Tome-Carneiro J., Gonzalvez M., Larrosa M., Yáñez-Gascón M.J., García-Almagro F.J., Ruiz-Ros J.A. et al. Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc. Drugs Ther. 2013; 27(1): 37-48. https://dx.doi.org/10.1007/s10557-012-6427-8.
  39. Magyar K., Halmosi R., Palfi A., Feher G., Czopf L., Fulop A. et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 2012; 50(3): 179-87. https://dx.doi.org/10.3233/CH-2011-1424.
  40. Yashiro T., Nanmoku M., Shimizu M., Inoue J., Sato R. Resveratrol increases the expression and activity of the low density lipoprotein receptor in hepatocytes by the proteolytic activation of the sterol regulatory element-binding proteins. Atherosclerosis. 2012; 220(2); 369-74. https://dx.doi.org/10.1016/j.atherosclerosis.2011.11.006.
  41. Zamora-Ros R., Urpi-Sarda M., Lamuela-Raventos R.M., Martínez-González M.Á., Salas-Salvadó J., Arós F. et al. High urinary levels of resveratrol metabolites are associated with a reduction in the prevalence of cardiovascular risk factors in high-risk patients. Pharmacol. Res. 2012; 65(6): 615-20. https://dx.doi.org/10.1016/j.phrs.2012.03.009.
  42. Sabe A.A., Elmadhun N.Y., Dalal R.S., Robich M.P., Sellke F.W. Resveratrol regulates autophagy signaling in chronically ischemic myocardium. J. Thorac. Cardiovasc. Surg. 2014; 147(2): 792-8. https://dx.doi.org/10.1016/j.jtcvs.2013.06.062.
  43. Liel Y., Kraus S., Levy J., Shany S. Evidence that estrogens modulate activity and increase the number of 1,25-dihydroxyvitamin D receptors in osteoblast-like cells (ROS 17/2.8). Endocrinology. 1992; 130 (5): 2597-601.
  44. Uberti F., Morsanuto V., Aprile S., Ghirlanda S., Stoppa I., Cochis A. et al. Biological effects of combined resveratrol and vitamin D3 on ovarian tissue. J. Ovarian Res. 2017; 10(1): 61. https://dx.doi.org/10.1186/s13048-017-0357-9.
  45. Stone A.D., Batie S.F., Sabir M.S., Jacobs E.T., Lee J.H., Whitfield G.K. et al. Resveratrol potentiates vitamin D and nuclear receptor signaling. J. Cell. Biochem. 2015; 116(6): 1130-43. https://dx.doi.org/10.1002/jcb.25070.
  46. Milia R. Improvement of climacteric symptoms with a novel sublingual product containing trans-resveratrol. Progr. Nutr. 2015; 17(1): 68-72.
  47. Zhao L., Cao J., Hu K., He X., Yun D., Tong T., Han L. Sirtuins and their biological relevance in aging and age-related diseases. Aging Dis. 2020; 11(4): 927-45. https://dx.doi.org/10.14336/AD.2019.0820.
  48. Xiang Y., Xu J., Li L., Lin X., Chen X., Zhang X. et al. Calorie restriction increases primordial follicle reserve in mature female chemotherapy-treated rats. Gene. 2012; 493(1): 77-82. https://dx.doi.org/10.1016/j.gene.2011.11.019
  49. Matilla L., Ibarrola J., Arrieta V., Garcia-Peña A., Martinez-Martinez E., Sádaba R. et al. Soluble ST2 promotes oxidative stress and inflammation in cardiac fibroblasts: an in vitro and in vivo study in aortic stenosis. Clin. Sci. (Lond). 2019; 133(14): 1537-48. https://dx.doi.org/10.1042/CS20190475.
  50. Martinez J., Moreno J.J. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem. Pharmacol. 2000; 59(7): 865-70. https://dx.doi.org/10.1016/s0006-2952(99)00380-9.
  51. Garvin S., Ollinger K., Dabrosin C. Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett. 2006; 231(1): 113-22. https://dx.doi.org/10.1016/j.canlet.2005.01.031.
  52. Zhu W., Qin W., Zhang K., Rottinghaus G.E., Chen Y.C., Kliethermes B., Sauter E.R. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr. Cancer. 2012; 64(3): 393-400. https://dx.doi.org/10.1080/01635581.2012.654926.
  53. Blanchard O.L., Friesenhahn G., Javors M.A., Smoliga J.M. Development of a lozenge for oral transmucosal delivery of trans-resveratrol in humans: proof of concept. PLoS One. 2014; 9(2): e90131. https://dx.doi.org/10.1371/journal.pone.0090131.
  54. Юренева С.В., Ильина Л.М., Эбзиева З.Х. Альтернативные методы лечения вазомоторных симптомов в свете доказательной медицины. Акушерство и гинекология. 2016; 6: 32-8. [Yureneva S.V., Ilina L.M., Ebzieva Z.H. Alternative methods of vasomotor symptoms treatment in the light of evidence-based medicine. Obstetrics and gynecology. 2016; 6: 32-8. (in Russian)]. https://dx.doi.org/10.18565/aig.2016.6.32-38.

Received 22.11.2021

Accepted 14.12.2021

About the Authors

Elena N. Kareva, Dr. Med. Sci., Professor of the Department of Pharmacology, I.M.Sechenov First Moscow State Medical University, Ministry of Health of Russia,
+7(499) 248-05-53, kareva_e_n@staff.sechenov.ru, elenakareva@mail.ru, 119435, Moscow, Bolshaya Pirogovskaya str., 2-4.
Antonina A. Smetnik, MD, Ph.D., Head of the Department of Gynecological Endocrinology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, +7(495)531-44-44, a_smetnik@oparina4.ru, https://orcid.org/0000-0002-0627-3902, 117997, Russia, Moscow, Ac. Oparin str., 4. RUS2200265 (v1.0)

Authors’ contributions: Kareva E.N., Smetnik A.A. – development of the concept and plan for the review of publications on the subject of the article, review of publications on the subject of the article, data analysis, writing the text of the article, approval of the article for publication.
Conflicts of interest: The authors declare that they have no competing interests.
Funding: The article was prepared with the support of Abbott Laboratories.
For citation: Kareva E.N., Smetnik A.A. Estrogen-like and antioxidant properties
of resveratrol in clinical pharmacology and therapeutic use.
Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2021; 12: 37-48 (in Russian)
https://dx.doi.org/10.18565/aig.2021.12.37-48

Similar Articles

№11 / 2021
Andreeva E.N., Absatarova Yu.S.
The place of alternative therapy in the algorithms for managing patients with climacteric syndrome in the context of personalized medicine
№12 / 2022
Dikke G.B., Gurskaya T.Yu., Prokofievа S.V., Stolnikova I.I., Andreeva A.S., Repina N.B., Yagovkina N.V., Teplykh S.V., Fedorova E.P.
Efficacy and safety of ultra-low dose vaginal estriol in the therapy of genitourinary syndrome of menopause: a phase III multicenter randomized controlled trial
№9 / 2021
Gavrilov M.V., Puchkina G.A., Ermolenko N.S., Simacheva S.A., Sulima A.N.
Experience with the natural non-hormonal drug Serelis in the therapy of menopausal syndrome in surgical menopausal women
№8 / 2023
Panevin T.S., Smetnik A.A.
Menopause in rheumatology: what is important for gynecologist to know?
№2 / 2023
Tolstov S.N., Salov I.A., Rebrov A.P.
Cardiometabolic risk factors in women undergoing the menopausal transition and the potential of drospirenone-containing contraceptive in the correction of the identified abnormalities
By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.