Citrus Compound Naringenin Reduces PCOS-Related Peptide Signaling in Rat Brain | Research

The takeaway

Naringenin, a natural compound found in citrus fruits, significantly reduced the elevated expression of kisspeptin and CGRP genes in the hypothalamus of PCOS rats.

Kiss1 and Cgrp both reduced
Naringenin treatment significantly normalized the expression of two key brain peptide genes — kisspeptin and CGRP — that were abnormally elevated in PCOS rats, suggesting a novel mechanism for this natural compound.

What the researchers found

In the PCOS rat model, hypothalamic expression of both Kiss1 (kisspeptin) and Cgrp (calcitonin gene-related peptide) genes was significantly elevated compared to healthy controls (p≤0.05). Treatment with naringenin at both dose levels (20 mg/kg and 50 mg/kg) significantly reduced Kiss1 and Cgrp gene expression compared to the untreated PCOS group (p≤0.05).

This represents a novel mechanistic finding — while naringenin's effects on PCOS have been previously reported, this is the first demonstration that its benefits may involve modulation of hypothalamic kisspeptin and CGRP signaling pathways.

Why it matters

PCOS affects up to 10% of women of reproductive age and is a leading cause of infertility. Current treatments are limited and often focus on symptoms rather than underlying causes. Kisspeptin is a master regulator of reproductive hormones, and its dysregulation is thought to drive the hormonal imbalances in PCOS. If naringenin can correct kisspeptin signaling, it could represent a natural approach to addressing the root cause of PCOS rather than just managing symptoms.

How the study worked

Twenty female rats (180-200 g) were divided into four groups: control, PCOS (untreated), PCOS + naringenin 20 mg/kg, and PCOS + naringenin 50 mg/kg. PCOS was induced by intramuscular injection of 2 mg estradiol valerate per rat. Control and PCOS groups received saline, while treatment groups received naringenin intraperitoneally. After treatment, hypothalamic tissue was collected and Kiss1 and Cgrp gene expression was measured using real-time PCR.

What this study cannot tell us

This is a small preclinical study with only 20 rats (5 per group), which limits statistical power. The rat PCOS model induced by estradiol valerate may not fully replicate the complex pathophysiology of human PCOS. Only gene expression was measured — protein levels and functional reproductive outcomes (ovulation, hormone levels, fertility) were not assessed. Naringenin was given intraperitoneally rather than orally, which does not reflect how it would be consumed by humans. No dose-response comparison between the 20 and 50 mg/kg groups is detailed.

How to read the evidence

This is a small preclinical animal study with 20 rats investigating a novel mechanism. While the statistical significance is clear, the small sample size, single measurement endpoint (gene expression only), and use of a chemically induced PCOS model limit the evidence strength. The findings are hypothesis-generating rather than clinically actionable.

When this study was published

Published in 2025, this study represents current research into natural compound-based approaches for PCOS. The kisspeptin-PCOS connection is an active area of investigation in reproductive medicine.

The bigger picture

Kisspeptin has emerged as a central player in reproductive neuroendocrinology — it controls the release of gonadotropin-releasing hormone (GnRH), which in turn drives the entire reproductive hormone cascade. Abnormally high kisspeptin signaling in PCOS contributes to the excess luteinizing hormone (LH) that characterizes the condition. CGRP, a vasodilatory peptide, may contribute to ovarian dysfunction. This study connects a dietary phytochemical to these specific neuropeptide pathways, bridging nutritional science and reproductive endocrinology.

Questions still open

Does the reduction in Kiss1 and Cgrp gene expression translate to improved reproductive outcomes like restored ovulation?
Would oral naringenin achieve sufficient hypothalamic concentrations to produce these effects in humans?
Is the kisspeptin-CGRP pathway correction a direct effect of naringenin or secondary to broader estrogenic activity?

Common questions

What are kisspeptin and CGRP, and why do they matter for PCOS?

Kisspeptin is a peptide hormone in the brain that controls the release of reproductive hormones. In PCOS, kisspeptin signaling is abnormally high, which drives excessive production of luteinizing hormone (LH) — a hallmark of the condition. CGRP (calcitonin gene-related peptide) is involved in blood vessel dilation and may affect ovarian blood flow and function. Both being elevated in PCOS suggests they contribute to the hormonal imbalance.

Can eating grapefruit help with PCOS?

While naringenin is found naturally in citrus fruits (especially grapefruit), this study used concentrated doses injected into rats — a very different delivery method than eating fruit. The amount of naringenin in dietary citrus consumption is likely far below what would be needed to reproduce these effects. Human clinical trials would be needed before any dietary recommendations could be made.

Read the original research

Therapeutic Effects of Phytoestrogen Naringenin in Polycystic Ovary Syndrome (PCOS): Involvement of Kisspeptin and Calcitonin Gene Related Peptide Signalling Pathways.

Reports of biochemistry & molecular biology, 14(1), 38-45

View on PubMed ↗Publisher’s paper ↗

Citation

Habibi, Manizheh; Mahmoudi, Fariba; Haghighat, Khadijeh; Khazali, Homayoun. (2025). Therapeutic Effects of Phytoestrogen Naringenin in Polycystic Ovary Syndrome (PCOS): Involvement of Kisspeptin and Calcitonin Gene Related Peptide Signalling Pathways.. Reports of biochemistry & molecular biology, 14(1), 38-45. https://doi.org/10.61882/rbmb.14.1.38