{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T23:26:52Z","timestamp":1782170812060,"version":"3.54.5"},"reference-count":47,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Phytoestrogen resveratrol (R) has been demonstrated to benefit human reproductive health. However, R bioavailability and pharmacokinetics are still problematic under oral supplementation. We used an experimental vaginal gel with R and hyaluronic acid (HA) to improve bioavailability and pharmacokinetic properties. The study aimed to assess the impact of vaginal R-HA gel on the reproductive system in ovariectomized rats. Methods: The study was carried out on Wistar female rats. It investigated the body weight, tail temperature, vaginal pH, estrogen and progesterone blood levels, and immunohistochemical biomarkers (COX2, Casp-3, Bcl-2, and VEGF). Animals were divided into control animals; ovariectomized rats (OVX); and OVX group treated with vaginal 0.5% R-HA gel (0.5%, 0.1 mL, daily 28 days). Results: The R-HA gel\u2019s therapeutic effect was manifested by slowing weight gain by 17% (p &lt; 0.001), less pronounced symptom of fever at the root of the tail by 9% (p &lt; 0.001) and lowering the vaginal pH to 4.4\u20134.5 compared with OVX rats. The anti-inflammatory effect and the reduction of COX-2 expression in vagina were accompanied by antiapoptotic impact of RA-H on endometrium, associated with the decreased Casp-3 expression (p &lt; 0.001) and elevated Bcl-2 score in endometrial glands (p = 0.01). Together with enhanced VEGF expression in endometrial glands (p &lt; 0.001) and stromal cells (p = 0.007), these changes prevented endometrial atrophy (p &lt; 0.001) after ovariectomy. Thus, this study substantiates the feasibility of developing an innovative topical drug with R and HA for treating hypoestrogenic disorders.<\/jats:p>","DOI":"10.3390\/molecules27154916","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T00:15:26Z","timestamp":1659485726000},"page":"4916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Resveratrol Effects on the Reproductive System in Ovariectomized Rats: Deciphering Possible Mechanisms"],"prefix":"10.3390","volume":"27","author":[{"given":"Ganna","family":"Zaychenko","sequence":"first","affiliation":[{"name":"Pharmacology Department, Bogomolets National Medical University, 01601 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olena","family":"Stryga","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Bogomolets National Medical University, 01601 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Sinitsyna","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Institute of Improvement Qualification of Pharmacy Specialists, National University of Pharmacy, 61002 Kharkiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Doroshenko","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Bogomolets National Medical University, 01601 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9614-4652","authenticated-orcid":false,"given":"Oksana","family":"Sulaieva","sequence":"additional","affiliation":[{"name":"Medical Laboratory CSD, 03122 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetyana","family":"Falalyeyeva","sequence":"additional","affiliation":[{"name":"Medical Laboratory CSD, 03122 Kyiv, Ukraine"},{"name":"Department of Biomedicine, Taras Shevchenko National University of Kyiv, 01033 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-689X","authenticated-orcid":false,"given":"Nazarii","family":"Kobyliak","sequence":"additional","affiliation":[{"name":"Medical Laboratory CSD, 03122 Kyiv, Ukraine"},{"name":"Endocrinology Department, Bogomolets National Medical University, 01601 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.6061\/clinics\/2016(05)09","article-title":"Effect of a gel containing pilocarpine on vaginal atrophy in castrated rats","volume":"71","author":"Sousa","year":"2016","journal-title":"Clinics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2147\/IJWH.S158913","article-title":"Current treatment options for postmenopausal vaginal atrophy","volume":"10","author":"Naumova","year":"2018","journal-title":"Int. J. Women\u2019s Health"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Roby, K.F. (2019). Vaginitis. Reference Module in Biomedical Sciences, Elsevier.","DOI":"10.1016\/B978-0-12-801238-3.11379-0"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tsoumani, M., Nikolaou, P.E., Argyropoulou, A., Tseti, I., Mitakou, S., and Andreadou, I. (2022). Novel Evidence-Based Combination of Plant Extracts with Multitarget Mechanisms of Action for the Elimination of Hot Flashes during Menopause. Molecules, 27.","DOI":"10.3390\/molecules27041221"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40834-017-0050-9","article-title":"Effect of aging on the female reproductive function","volume":"2","author":"Shirasuna","year":"2017","journal-title":"Contracept. Reprod. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kenda, M., Glava\u010d, N.K., Nagy, M., and Dolenc, M.S. (2021). Herbal Products Used in Menopause and for Gynecological Disorders. Molecules, 26.","DOI":"10.3390\/molecules26247421"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3109\/13697137.2015.1129166","article-title":"2016 IMS Recommendations on women\u2019s midlife health and menopause hormone therapy","volume":"19","author":"Baber","year":"2016","journal-title":"Climacteric"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Writing Group for the Women\u2019s Health Initiative Investigators (2002). Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women\u2019s Health Initiative Randomized Controlled Trial. JAMA J. Am. Med. Assoc., 288, 321\u2013333.","DOI":"10.1001\/jama.288.3.321"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.maturitas.2014.07.002","article-title":"Menopausal hormone therapy use in 17 European countries during the last decade","volume":"79","author":"Ameye","year":"2014","journal-title":"Maturitas"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"239","DOI":"10.15761\/CRT.1000239","article-title":"Hormonal treatment of vulvar vaginal atrophy (VVA): Are there options to reduce or avoid systemic adverse effects and risks?","volume":"4","author":"Ruan","year":"2018","journal-title":"Clin. Res. Trials"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3109\/13697137.2014.947254","article-title":"Vaginal administration of estradiol: Effects of dose, preparation and timing on plasma estradiol levels","volume":"18","author":"Santen","year":"2015","journal-title":"Climacteric"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1080\/07853890.2021.1974083","article-title":"Efficacy and safety of prolonged-release hyaluronic acid derivative vaginal application in the postpartum period: A prospective randomised clinical trial","volume":"53","author":"Gustavino","year":"2021","journal-title":"Ann. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ygyno.2020.05.025","article-title":"A single-arm clinical trial investigating the effectiveness of a non-hormonal, hyaluronic acid-based vaginal moisturizer in endometrial cancer survivors","volume":"158","author":"Carter","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3109\/13697137.2012.756466","article-title":"Non-hormonal topical treatment of vulvovaginal atrophy: An up-to-date overview","volume":"16","author":"Sinha","year":"2013","journal-title":"Climacteric"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gonzalez, A., Lee, M., Johnson, B., Booshehri, L., Grady, D., Vaddi, V., Ip, C., Mitchell, C., Krychman, M., and Dardik, R. (2021). Safety and efficacy of a new vaginal gel, Feminilove, for the treatment of symptoms associated with vaginal dryness and vulvovaginal atrophy in women: An in vitro and in vivo study. bioRxiv.","DOI":"10.1101\/2021.08.17.455703"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Novakovic, R., Rajkovic, J., Gostimirovic, M., Gojkovic-Bukarica, L., and Radunovic, N. (2022). Resveratrol and Reproductive Health. Life, 12.","DOI":"10.3390\/life12020294"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kiskova, T., Kubatka, P., B\u00fcsselberg, D., and Kassayova, M. (2020). The Plant-Derived Compound Resveratrol in Brain Cancer: A Review. Biomolecules, 10.","DOI":"10.3390\/biom10010161"},{"key":"ref_18","first-page":"13","article-title":"Health benefits of resveratrol administration","volume":"66","author":"Galiniak","year":"2019","journal-title":"Acta Biochim. Pol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00210-016-1320-9","article-title":"Perspectives and challenges of antioxidant therapy for atrial fibrillation","volume":"390","author":"Gasparova","year":"2017","journal-title":"Naunyn-Schmiedeberg Arch. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111158","DOI":"10.1016\/j.mce.2021.111158","article-title":"Liraglutide improves lipid and carbohydrate metabolism of ovariectomized rats","volume":"524","author":"Model","year":"2021","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ko, S.-H., and Kim, H.-S. (2020). Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women. Nutrients, 12.","DOI":"10.3390\/nu12010202"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nrendo.2017.180","article-title":"Symptoms of menopause\u2014Global prevalence, physiology and implications","volume":"14","author":"Monteleone","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ogc.2019.04.008","article-title":"Menopause","volume":"46","author":"Minkin","year":"2019","journal-title":"Obstet. Gynecol. Clin. N. Am."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1177\/20533691211038455","article-title":"Surgical menopause: A toolkit for healthcare professionals","volume":"27","author":"Garg","year":"2021","journal-title":"Post Reprod. Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.6118\/jmm.20026","article-title":"Clinical Efficacy of Hormonal and Nonhormonal Agents in the Treatment of Vulvovaginal Atrophy","volume":"27","author":"Ilhan","year":"2021","journal-title":"J. Menopausal Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pasquariello, R., Verdile, N., Brevini, T.A.L., Gandolfi, F., Boiti, C., Zerani, M., and Maranesi, M. (2020). The Role of Resveratrol in Mammalian Reproduction. Molecules, 25.","DOI":"10.20944\/preprints202009.0003.v1"},{"key":"ref_27","first-page":"116","article-title":"Resveratrol Treatment Normalizes the Endothelial Function and Blood Pressure in Ovariectomized Rats","volume":"108","author":"Fabricio","year":"2017","journal-title":"Arq. Bras. De Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/GME.0000000000001643","article-title":"Long-term resveratrol supplementation improves pain perception, menopausal symptoms, and overall well-being in postmenopausal women: Findings from a 24-month randomized, controlled, crossover trial","volume":"28","author":"Howe","year":"2021","journal-title":"Menopause"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7460","DOI":"10.1074\/jbc.M411565200","article-title":"Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells","volume":"280","author":"Klinge","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Meng, T., Xiao, D., Muhammed, A., Deng, J., Chen, L., and He, J. (2021). Anti-Inflammatory Action and Mechanisms of Resveratrol. Molecules, 26.","DOI":"10.3390\/molecules26010229"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9932218","DOI":"10.1155\/2021\/9932218","article-title":"Bin Effects and Mechanisms of Resveratrol on Aging and Age-Related Diseases","volume":"2021","author":"Zhou","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.biopha.2017.01.028","article-title":"Effects of polyphenol compounds melanin on NAFLD\/NASH prevention","volume":"88","author":"Belemets","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mongio\u00ec, L.M., La Vignera, S., Cannarella, R., Cimino, L., Compagnone, M., Condorelli, R.A., and Calogero, A.E. (2021). The Role of Resveratrol Administration in Human Obesity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094362"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2553","DOI":"10.1016\/S1569-9056(18)33031-8","article-title":"Cytostatic effect of polyphenol compound melanin in combination with Cisplatin on bladder cancer cell line T24\/83","volume":"17","author":"Yakovlev","year":"2018","journal-title":"Eur. Urol. Suppl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.atherosclerosis.2014.09.001","article-title":"Vascular oxidative stress, nitric oxide and atherosclerosis","volume":"237","author":"Li","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1111\/bph.13492","article-title":"Antioxidant effects of resveratrol in the cardiovascular system","volume":"174","author":"Xia","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"O\u2019Hanlon, D.E., Come, R.A., and Moench, T.R. (2019). Vaginal pH measured in vivo: Lactobacilli determine pH and lactic acid concentration. BMC Microbiol., 19.","DOI":"10.1186\/s12866-019-1388-8"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jsxm.2020.10.016","article-title":"Hyaluronic Acid in Postmenopause Vaginal Atrophy: A Systematic Review","volume":"18","author":"Uggioni","year":"2021","journal-title":"J. Sex. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/ptr.6538","article-title":"Recent advances in the anti-aging effects of phytoestrogens on collagen, water content, and oxidative stress","volume":"34","author":"Liu","year":"2020","journal-title":"Phytother. Res. PTR"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/ijc.10992","article-title":"Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ER alpha","volume":"104","author":"Levenson","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1111\/j.1476-5381.2011.01619.x","article-title":"Genistein aglycone, a soy-derived isoflavone, improves skin changes induced by ovariectomy in rats","volume":"165","author":"Polito","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"481","DOI":"10.2967\/jnumed.113.128751","article-title":"In Vivo Imaging of Brain Estrogen Receptors in Rats: A 16\u03b1- 18 F-Fluoro-17\u03b2-Estradiol PET Study","volume":"55","author":"Khayum","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_43","first-page":"397","article-title":"Pharmacological substantiation for choice the optimal composition of a new vaginal gel with resveratrol and gialuronic acid","volume":"14","author":"Zaychenko","year":"2020","journal-title":"Pharmacol. Drug Toxicol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cyto.2013.10.004","article-title":"Changes in central and peripheral inflammatory responses to lipopolysaccharide in ovariectomized female rats","volume":"65","author":"Iwasa","year":"2014","journal-title":"Cytokine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/humupd\/dmh007","article-title":"Apoptosis in human endometrium and endometriosis","volume":"10","author":"Harada","year":"2004","journal-title":"Hum. Reprod. Update"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Fan, D., Liu, C., Guo, Z., Huang, K., Peng, M., Li, N., Luo, H., Wang, T., Cen, Z., and Cai, W. (2021). Resveratrol Promotes Angiogenesis in a FoxO1-Dependent Manner in Hind Limb Ischemia in Mice. Molecules, 26.","DOI":"10.3390\/molecules26247528"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Breuss, J.M., Atanasov, A.G., and Uhrin, P. (2019). Resveratrol and Its Effects on the Vascular System. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071523"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/4916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:01:04Z","timestamp":1760140864000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/4916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,2]]},"references-count":47,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["molecules27154916"],"URL":"https:\/\/doi.org\/10.3390\/molecules27154916","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,2]]}}}