Phaleria macrocarpa Fruit Flavonoid Extract on Estrogen Receptor Alpha Expression in Ovariectomized Mice

Authors

  • Dyah Ayu Septika Wijaya Master of Midwifery Program, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
  • Sutrisno Sutrisno Departement of Obstetrics and Gynaecology, Faculty of Medicine, Universitas Brawijaya
  • Yahya Irwanto Saiful Anwar General Hospital, Malang, Indonesia
  • Kenty Wantri Anita Department of Clinical Pathology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

DOI:

https://doi.org/10.21776/ub.ijhn.2024.011.01.10

Keywords:

Phaleria macrocarpa, Flavonoid, Estrogen Receptor Alpha

Abstract

Menopause signifies the cessation of ovarian function, presenting significant health challenges for women globally. Hormonal shifts during menopause impact various systems, including cardiovascular and reproductive health. Changes in reproductive organs increase susceptibility to health issues, necessitating effective management strategies. This study used a true experimental method with a randomized post-test-only control group design to investigate the potential of Phaleria macrocarpa fruit extract, which contains flavonoids, to modulate Estrogen Receptor Alpha (ERa) expression in menopausal mice. Following ovariectomy (OVX), mice treated with flavonoid showed increased ERa expression, with the highest expression observed at a dose of P2 (7.5 mg/mice/day), approaching those in non-OVX control (K-) with a percentage difference of 29.82%. Compared to the OVX control group (K+), the percentage increase was 2387.74%. Therefore, the P2 dose is considered the optimum dose. Regression analysis revealed a significant correlation of 43.3% between flavonoid dosage and ERa expression (p < 0.05). These findings suggest flavonoids as promising natural Selective Estrogen Receptor Modulators (SERMs) for managing menopausal symptoms and reducing endometrial disease risk with ERa modulation. Further research is needed to elucidate the mechanisms of flavonoids, including molecular pathways such as ligand binding and transcription, interactions with other hormones like progesterone, long-term effects, and potential clinical applications. To initiate clinical trials, the author established the P1 dose (3.75 mg/mice/day), which demonstrated expression levels approaching the effects produced by P2. Overall, flavonoids offer potential therapeutic benefits in addressing menopausal health concerns, with the identified optimal dosage providing valuable guidance for future studies and clinical interventions.

References

Davis SR, Pinkerton J, Santoro N, Simoncini T. Menopause—Biology, consequences, supportive care, and therapeutic options. Cell [Internet]. 2023 Sep 14 [cited 2024 Mar 8];186(19):4038–58. Available from: https://www.sciencedirect.com/science/article/pii/S0092867423009054

WHO. World Health Organization. 2022 [cited 2024 Feb 14]. Menopause. Available from: https://www.who.int/news-room/fact-sheets/detail/menopause

Peacock K, Carlson K, Ketvertis KM. Menopause. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 May 23]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK507826/

Ilankoon IMPS, Samarasinghe K, Elgán C. Menopause is a natural stage of aging: a qualitative study. BMC Womens Health [Internet]. 2021 Dec [cited 2023 Oct 31];21(1):47. Available from: https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-020-01164-6

Tanmahasamut P, Jirasawas T, Laiwejpithaya S, Areeswate C, Dangrat C, Silprasit K. Effect of estradiol vaginal gel on vaginal atrophy in postmenopausal women: A randomized double‐blind controlled trial. J Obstet Gynaecol Res [Internet]. 2020 Aug [cited 2024 Mar 8];46(8):1425–35. Available from: https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.14336

Badan Pusat Statistik. Proyeksi Penduduk Indonesia 2010-2035. Jakarta: Badan Pusat Statistik; 2013.

The World Bank. World Bank Open Data. 2022 [cited 2024 Feb 16]. World Bank Open Data. Available from: https://data.worldbank.org

Yu K, Huang ZY, Xu XL, Li J, Fu XW, Deng SL. Estrogen Receptor Function: Impact on the Human Endometrium. Front Endocrinol [Internet]. 2022 [cited 2023 Oct 31];13:827724. Available from: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.827724/full

Eyster KM, editor. Estrogen Receptors: Methods and Protocols [Internet]. 2nd ed. New York, NY: Springer New York; 2022 [cited 2023 Oct 31]. (Methods in Molecular Biology; vol. 1366). Available from: https://link.springer.com/10.1007/978-1-4939-3127-9

Nugroho RA. Dasar-dasar endokrinologi. Samarinda: Mulawarman University Press; 2017.

Deligdisch-Schor L, Mareş Miceli A, editors. Hormonal Pathology of the Uterus [Internet]. Cham: Springer International Publishing; 2020 [cited 2023 Oct 31]. (Advances in Experimental Medicine and Biology; vol. 1242). Available from: http://link.springer.com/10.1007/978-3-030-38474-6

Markovac J, Marcus R. The pharmacology of selective estrogen receptor modulators: past and present. In: Principles of Bone Biology [Internet]. Elsevier; 2020 [cited 2023 Oct 31]. p. 863–93. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128148419000373

Fait T. Menopause hormone therapy: latest developments and clinical practice. Drugs Context [Internet]. 2019 Jan 2 [cited 2023 Oct 31];8:1–9. Available from: https://www.drugsincontext.com/menopause-hormone-therapy:-latest-developments-and-clinical-practice

Stubbs C, Mattingly L, Crawford SA, Wickersham EA, Brockhaus JL, McCarthy LH. Do SSRIs and SNRIs reduce the frequency and/or severity of hot flashes in menopausal women. J Okla State Med Assoc. 2017 May;110(5):272–4.

Ariani D, Rulianah N, I.T S, S.R N, W A. Skrining Fitokimia Tanaman Mahkota Dewa (Phaleria macrocarpa [Scheff.] Boerl). First. Yogyakarta: Bintang Semesta Media; 2022.

Ahmad R, Khairul Nizam Mazlan M, Firdaus Abdul Aziz A, Mohd Gazzali A, Amir Rawa MS, Wahab HA. Phaleria macrocarpa (Scheff.) Boerl.: An updated review of pharmacological effects, toxicity studies, and separation techniques. Saudi Pharm J [Internet]. 2023 Jun 1 [cited 2023 Oct 30];31(6):874–88. Available from: https://www.sciencedirect.com/science/article/pii/S1319016423000889

Mustaqim WA, Yus RR, Tamam MB. Phaleria macrocarpa (Scheff.) Boerl. Thymelaeaceae. In: Franco FM, editor. Ethnobotany of the Mountain Regions of Southeast Asia [Internet]. Cham: Springer International Publishing; 2021 [cited 2023 Oct 31]. p. 843–55. (Ethnobotany of Mountain Regions). Available from: https://link.springer.com/10.1007/978-3-030-38389-3_168

Mahayuni AC, Wirasuta IMAG. Aktivitas Antimikroba Ekstrak Buah Mahkota Dewa (Phaleria macrocarpa) sebagai Hand Sanitizer Alami. Pros Workshop Dan Semin Nas Farm [Internet]. 2023 Jan 16 [cited 2023 Oct 31];1:325–38. Available from: https://ejournal1.unud.ac.id/index.php/wsnf/article/view/46

Maharani M. Phaleria macrocarpa for Endometriosis Treatment: A Review. J Med Pharm Allied Sci [Internet]. 2023 Jan 31 [cited 2024 Apr 28];12(1):5582–7. Available from: https://jmpas.com/abstract/1124

Kiyama R. Estrogenic flavonoids and their molecular mechanisms of action. J Nutr Biochem [Internet]. 2023 Apr [cited 2023 Oct 31];114:109250. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0955286322003187

Chantalat E, Valera MC, Vaysse C, Noirrit E, Rusidze M, Weyl A, et al. Estrogen Receptors and Endometriosis. Int J Mol Sci [Internet]. 2020 Apr 17 [cited 2024 Apr 18];21(8):2815. Available from: https://www.mdpi.com/1422-0067/21/8/2815

Sutrisno S, Maharani M. Genistein Ameliorated Vascular Endothelial Growth Factor-A (VEGF-A) and Estrogen Receptor-Alpha (ER-α) in Endometriosis Mice Model, In Vivo and In Silico. Ali MS, editor. Sci World J [Internet]. 2024 Jan 24 [cited 2024 Apr 27];2024:1–7. Available from: https://www.hindawi.com/journals/tswj/2024/5338212/

Han C, Wei Y, Geng Y, Cui Y, Li S, Bao Y, et al. Bisphenol A in utero exposure induces ovary dysfunction in mice offspring and the ameliorating effects of Cuscuta chinensis flavonoids. Environ Sci Pollut Res [Internet]. 2020 Sep [cited 2023 Oct 31];27(25):31357–68. Available from: https://link.springer.com/10.1007/s11356-020-09202-4

Maharani M, Lajuna L, Yuniwati C, Sabrida O, Sutrisno S. Phytochemical characteristics from Phaleria macrocarpa and its inhibitory activity on the peritoneal damage of endometriosis. J Ayurveda Integr Med. 2021;12(2):229–33.

Rodríguez-Landa JF. Considerations of Timing Post-ovariectomy in Mice and Rats in Studying Anxiety- and Depression-Like Behaviors Associated With Surgical Menopause in Women. Front Behav Neurosci [Internet]. 2022 Mar 4 [cited 2023 Oct 31];16:829274. Available from: https://www.frontiersin.org/articles/10.3389/fnbeh.2022.829274/full

Sinyani A, Idowu K, Shunmugam L, Kumalo HM, Khan R. A molecular dynamics perspective into estrogen receptor inhibition by selective flavonoids as alternative therapeutic options. J Biomol Struct Dyn [Internet]. 2023 Jun 13 [cited 2024 Apr 28];41(9):4093–105. Available from: https://www.tandfonline.com/doi/full/10.1080/07391102.2022.2062786

Sutrisno S, Aprina H, Simanungkalit HM, Andriyani A, Barlianto W, Sujuti H, et al. Genistein modulates the estrogen receptor and suppresses angiogenesis and inflammation in the murine model of peritoneal endometriosis. J Tradit Complement Med [Internet]. 2018 Apr 1 [cited 2024 Apr 27];8(2):278–81. Available from: https://www.sciencedirect.com/science/article/pii/S2225411017300366

Domínguez-López I, Yago-Aragón M, Salas-Huetos A, Tresserra-Rimbau A, Hurtado-Barroso S. Effects of Dietary Phytoestrogens on Hormones throughout a Human Lifespan: A Review. Nutrients [Internet]. 2020 Aug 15 [cited 2024 Jul 23];12(8):2456. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468963/

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Published

2024-07-25

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1.
Phaleria macrocarpa Fruit Flavonoid Extract on Estrogen Receptor Alpha Expression in Ovariectomized Mice. IJHN [Internet]. 2024 Jul. 25 [cited 2025 May 25];11(1):110-2. Available from: https://ijhn.ub.ac.id/index.php/ijhn/article/view/748

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