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Research Article


Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction

Yudit Oktanella, Viski Fitri Hendrawan, Gretania Residiwati, Aulia Firmawati, Andre Giovanni, Widjiati Widjiati, Ghina Kamilah, Nur Fitrah Ramadhani Putri, Jamilaturrosyidah Jamilaturrosyidah, Nabilla Rizky Mahalita, Tiara Arum Setyanti, Edo Brendo Stevano.


Abstract
Background:
Polycystic ovary syndrome (PCOS) is associated with anovulation, cystic ovarian morphology, and altered ovarian estrogen signaling. Estradiol benzoate-induced rodent models are useful for reproducing persistent estrus and cystic ovarian morphology, although they do not fully represent the endocrine and metabolic complexity of human PCOS. Gallic acid has antioxidant, anti-inflammatory, and cytoprotective properties that may complement metformin therapy.

Aim:
This study evaluated the adjunctive effect of gallic acid with metformin on ovarian histomorphology, follicular dynamics, and estrogen receptor alpha (ERα) immunoexpression in an estradiol benzoate-induced rat model of PCOSlike ovarian dysfunction.

Methods:
Eighteen female Wistar rats were induced with estradiol benzoate [2 mg/kg body weight (BW), intraperitoneally] for four consecutive days and then randomized into three PCOS-induced groups (n = 6/group): [PCOS control (CP); 1% carboxymethylcellulose sodium], metformin monotherapy (T1; 10 mg/rat/day, approximately 67–77 mg/kg BW/day), and combination therapy (T2; metformin 10 mg/rat/day plus gallic acid 50 mg/kg BW/day). Treatments were administered orally for 14 days. Ovaries were collected for hematoxylin–eosin staining and ERα immunohistochemistry.

Results:
Compared with CP, metformin was associated with improved follicular morphology, and the metformin plus gallic acid group showed the most favorable histological profile. Follicular cyst counts decreased from 2.80 ± 0.54 (CP) to 0.50 ± 0.55 (T1) and 0.16 ± 0.41 (T2). Atretic follicles decreased from 7.50 ± 1.21 (CP) to 5.33 ± 0.20 (T1) and 2.67 ± 0.75 (T2), whereas corpora lutea counts increased from 4.50 ± 0.83 (CP) to 6.33 ± 0.21 (T1) and 11.83 ± 1.45 (T2). ERα-positive area was highest in CP (41.88% ± 4.12%) and was significantly lower in T2 (28.75% ± 2.15%; p <0.05), whereas T1 showed an intermediate, non-significant reduction (35.07% ± 2.29%).

Conclusion:
Within the limitations of this exploratory design, adjunctive gallic acid with metformin improved ovarian histomorphology and reduced ERα immunopositivity relative to the PCOS control group. Further studies including healthy controls, gallic acid monotherapy, endocrine-metabolic profiling, oxidative stress markers, and molecular validation are required to confirm mechanistic effects.

Key words: Estrogen Receptor-α (ERα); Folliculogenesis; Gallic Acid; Metformin; Polycystic Ovary Syndrome (PCOS); Rats.


 
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How to Cite this Article
Pubmed Style

Oktanella Y, Hendrawan VF, Residiwati G, Firmawati A, Giovanni A, Widjiati W, Kamilah G, Putri NFR, Jamilaturrosyidah J, Mahalita NR, Setyanti TA, Stevano EB. Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. Open Vet. J.. 2026; 16(8): 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23

Web Style

Oktanella Y, Hendrawan VF, Residiwati G, Firmawati A, Giovanni A, Widjiati W, Kamilah G, Putri NFR, Jamilaturrosyidah J, Mahalita NR, Setyanti TA, Stevano EB. Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. https://www.openveterinaryjournal.com/?mno=311909 [Access: August 08, 2026]. doi:10.5455/OVJ.2026.v16.i8.23

AMA (American Medical Association) Style

Oktanella Y, Hendrawan VF, Residiwati G, Firmawati A, Giovanni A, Widjiati W, Kamilah G, Putri NFR, Jamilaturrosyidah J, Mahalita NR, Setyanti TA, Stevano EB. Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. Open Vet. J.. 2026; 16(8): 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23


Vancouver/ICMJE Style

Oktanella Y, Hendrawan VF, Residiwati G, Firmawati A, Giovanni A, Widjiati W, Kamilah G, Putri NFR, Jamilaturrosyidah J, Mahalita NR, Setyanti TA, Stevano EB. Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. Open Vet. J.. (2026), [cited August 08, 2026]; 16(8): 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23


Harvard Style

Oktanella, Y., Hendrawan, . V. F., Residiwati, . G., Firmawati, . A., Giovanni, . A., Widjiati, . W., Kamilah, . G., Putri, . N. F. R., Jamilaturrosyidah, . J., Mahalita, . N. R., Setyanti, . T. A. & Stevano, . E. B. (2026) Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. Open Vet. J., 16 (8), 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23


Turabian Style

Oktanella, Yudit, Viski Fitri Hendrawan, Gretania Residiwati, Aulia Firmawati, Andre Giovanni, Widjiati Widjiati, Ghina Kamilah, Nur Fitrah Ramadhani Putri, Jamilaturrosyidah Jamilaturrosyidah, Nabilla Rizky Mahalita, Tiara Arum Setyanti, and Edo Brendo Stevano. 2026. Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. Open Veterinary Journal, 16 (8), 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23


Chicago Style

Oktanella, Yudit, Viski Fitri Hendrawan, Gretania Residiwati, Aulia Firmawati, Andre Giovanni, Widjiati Widjiati, Ghina Kamilah, Nur Fitrah Ramadhani Putri, Jamilaturrosyidah Jamilaturrosyidah, Nabilla Rizky Mahalita, Tiara Arum Setyanti, and Edo Brendo Stevano. "Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction." Open Veterinary Journal 16 (2026), 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23


MLA (The Modern Language Association) Style

Oktanella, Yudit, Viski Fitri Hendrawan, Gretania Residiwati, Aulia Firmawati, Andre Giovanni, Widjiati Widjiati, Ghina Kamilah, Nur Fitrah Ramadhani Putri, Jamilaturrosyidah Jamilaturrosyidah, Nabilla Rizky Mahalita, Tiara Arum Setyanti, and Edo Brendo Stevano. "Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction." Open Veterinary Journal 16.8 (2026), 5285-5293. Print. doi:10.5455/OVJ.2026.v16.i8.23


APA (American Psychological Association) Style

Oktanella, Y., Hendrawan, . V. F., Residiwati, . G., Firmawati, . A., Giovanni, . A., Widjiati, . W., Kamilah, . G., Putri, . N. F. R., Jamilaturrosyidah, . J., Mahalita, . N. R., Setyanti, . T. A. & Stevano, . E. B. (2026) Gallic acid enhances metformin-mediated improvement of ovarian architecture and estrogen receptor alpha expression in an estradiol benzoate-induced rat model of PCOS-like ovarian dysfunction. Open Veterinary Journal, 16 (8), 5285-5293. doi:10.5455/OVJ.2026.v16.i8.23


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