SAT-192 - Gut–Brain Vagal Signaling Modulates HPG Axis Dysfunction in a PCOS-like Mouse Model

Polycystic ovary syndrome (PCOS) is the most common hormonal disorder in reproductive-age women, associated with elevated luteinizing hormone (LH) and suppressed follicle-stimulating hormone (FSH). This disrupted hormonal balance impairs ovulation and fertility. It also reflects dysfunction of the central regulator of reproductive hormone signaling, the hypothalamic–pituitary–gonadal (HPG) axis. Within this axis, pulsatile gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus drives pituitary pulsatile release of LH and FSH. While the hormonal fingerprint of PCOS is well established, the peripheral neural mechanisms that drive and sustain this dysfunction remain poorly understood. Our investigation of gut health in letrozole (LET)-treated mouse model of PCOS-like symptoms revealed significant gut dysbiosis. As the body’s primary communication pathway between the gut and brain, the vagus nerve is uniquely positioned to translate gut disruption into reproductive hormone dysregulation. We therefore hypothesized that vagal signaling contributes to HPG axis dysfunction in PCOS. To test this, peripubertal female mice were assigned to four groups: placebo or LET treatment, each paired with either sham surgery or subdiaphragmatic vagotomy (SDV) to remove vagal input below the diaphragm. As expected, sham LET-treated mice developed a hallmark PCOS-like hormonal profile, with elevated LH, reduced FSH, and an increased LH:FSH ratio. Strikingly, vagotomized LET-treated mice showed reduced LH, restored FSH, and a normalized LH:FSH ratio. To distinguish whether vagal signaling acts at the level of the hypothalamus or pituitary, we used two complementary approaches. Serial blood sampling every six minutes over two hours captured spontaneous LH pulses, a direct readout of hypothalamic GnRH. LET-treated mice with intact vagal signaling exhibited rapid, frequent LH pulses, whereas vagotomy reduced pulse frequency and altered pulse dynamics, indicating modulation at the level of the hypothalamus. In parallel, exogenous GnRH administration directly tested pituitary responsiveness, revealing a blunted response in sham LET-treated mice that was fully rescued by vagotomy. Together, these findings identify gut-to-brain vagal signaling as a previously unrecognized contributor to HPG axis dysfunction in PCOS.

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