Quignon Clarisse, Mansano Naira, Backer Annika, Wray Susan
National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Endocrinology. 2025 Sep 8;166(10). doi: 10.1210/endocr/bqaf136.
Many clinical studies have identified correlations between thyroid dysfunction and reproductive issues, yet the underlying mechanisms behind this interaction remain poorly understood. In this study, we investigated the effect of triiodothyronine (T3) on the activity of gonadotropin-releasing hormone (GnRH) neurons, a key regulator of the central reproductive axis. Dual labeling confirmed that GnRH neurons express thyroid receptor (TR)α and integrin αVβ3 receptors mediating genomic and nongenomic effects of thyroid hormones, respectively. Using calcium imaging in an ex vivo model, we show that T3 induces a rapid and sustained increase of calcium oscillation frequency in GnRH neurons. No change in response was detected after application of T4. The T3 stimulatory effect was not inhibited by a TR-specific antagonist (1-850) but was mimicked by membrane-impermeable T3-BSA, indicating a mechanism independent of nuclear TR signaling. In contrast, the blockade of membrane αVβ3 integrins (with cilengitide) prevented the T3-induced increase in GnRH neurons calcium peak oscillation frequency. Further investigation using modulators of intracellular calcium and calcium entry revealed that binding to αVβ3 integrin can induce distinct calcium responses depending on the ligand, with T3 triggering a complex response involving multiple channels and calcium sources, possibly with compensatory mechanisms. In sum, these results demonstrate for the first time a direct effect of thyroid hormones on GnRH neuronal activity, with T3 stimulating calcium oscillations through the nongenomic αVβ3 integrin pathway. Understanding this thyroid-reproductive axis interaction will help clarify the mechanisms linking thyroid dysfunction to reproductive disorders and pave the way for targeted therapeutic interventions.
许多临床研究已经确定了甲状腺功能障碍与生殖问题之间的相关性，但这种相互作用背后的潜在机制仍知之甚少。在本研究中，我们调查了三碘甲状腺原氨酸（T3）对促性腺激素释放激素（GnRH）神经元活性的影响，GnRH神经元是中枢生殖轴的关键调节因子。双重标记证实，GnRH神经元表达甲状腺受体（TR）α和整合素αVβ3受体，分别介导甲状腺激素的基因组和非基因组效应。在体外模型中使用钙成像，我们发现T3可诱导GnRH神经元中钙振荡频率快速且持续增加。应用T4后未检测到反应变化。T3的刺激作用不受TR特异性拮抗剂（1-850）的抑制，但可被膜不透性的T3-BSA模拟，表明其机制独立于核TR信号传导。相反，膜αVβ3整合素的阻断剂（西仑吉肽）可防止T3诱导的GnRH神经元钙峰振荡频率增加。使用细胞内钙和钙内流调节剂的进一步研究表明，与αVβ3整合素结合可根据配体诱导不同的钙反应，T3触发涉及多个通道和钙源的复杂反应，可能存在补偿机制。总之，这些结果首次证明了甲状腺激素对GnRH神经元活性的直接影响，T3通过非基因组αVβ3整合素途径刺激钙振荡。了解这种甲状腺-生殖轴相互作用将有助于阐明甲状腺功能障碍与生殖疾病之间的联系机制，并为靶向治疗干预铺平道路。
