Hypothalamic insulin-like growth factor-I receptors are necessary for hormone-dependent luteinizing hormone surges: implications for female reproductive aging.
Hypothalamic insulin-like growth factor-I receptors are necessary for hormone-dependent luteinizing hormone surges: implications for female reproductive aging.
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DOI：
10.1210/en.2009-1009
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发表时间：
2010-02
期刊：
影响因子：
4.8
通讯作者：
B. Todd;Z. Merhi;Jun Shu;A. M. Etgen;G. Neal-Perry
中科院分区：
文献类型：
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作者：
B. Todd;Z. Merhi;Jun Shu;A. M. Etgen;G. Neal-Perry
脑IGF-I受体是维持年轻成年雌性大鼠发情周期所必需的。循环和下丘脑IGF-I水平随着年龄的增长而下降，表明IGF-I在生殖衰老的发病中起作用。因此，本研究探讨了脑IGF-I受体在年轻成年和中年大鼠LH峰调节中的潜在作用机制。我们连续输注IGF-I，选择性IGF-I受体拮抗剂JB-1，或车辆到卵巢切除的年轻成年和中年雌性大鼠的第三脑室与雌二醇和孕酮。IGF-I受体的药理学阻断减弱并延迟了年轻成年大鼠的LH峰，这让人想起了预示中年雌性大鼠生殖衰老开始的LH峰模式。单独输注IGF-I对LH峰没有影响，但逆转了年轻女性LH峰的JB-1衰减。在中年大鼠中，输注低剂量的IGF-I部分恢复LH峰幅度，而输注JB-1完全消除了该峰。脑室注射IGF-I或JB-1并没有改变垂体对外源性GnRH的敏感性，也没有改变年轻或中年大鼠下丘脑前基底或中基底的GnRH肽含量。这些研究结果支持了以下假设：脑IGF-I受体信号传导是雌激素正反馈条件下GnRH神经元激活所必需的，中年女性脑IGF-I信号传导减少通过破坏影响GnRH神经元激活和/或GnRH释放的雌二醇敏感过程，部分导致LH峰功能障碍。
Brain IGF-I receptors are required for maintenance of estrous cycles in young adult female rats. Circulating and hypothalamic IGF-I levels decrease with aging, suggesting a role for IGF-I in the onset of reproductive senescence. Therefore, the present study investigated potential mechanisms of action of brain IGF-I receptors in the regulation of LH surges in young adult and middle-aged rats. We continuously infused IGF-I, the selective IGF-I receptor antagonist JB-1, or vehicle into the third ventricle of ovariectomized young adult and middle-aged female rats primed with estradiol and progesterone. Pharmacological blockade of IGF-I receptors attenuated and delayed the LH surge in young adult rats, reminiscent of the LH surge pattern that heralds the onset of reproductive senescence in middle-aged female rats. Infusion of IGF-I alone had no effect on the LH surge but reversed JB-1 attenuation of the surge in young females. In middle-aged rats, infusion of low doses of IGF-I partially restored LH surge amplitude, and infusion of JB-1 completely obliterated the surge. Intraventricular infusion of IGF-I or JB-1 did not modify pituitary sensitivity to exogenous GnRH or GnRH peptide content in the anterior or mediobasal hypothalamus in either young or middle-aged rats. These findings support the hypothesis that brain IGF-I receptor signaling is necessary for GnRH neuron activation under estrogen-positive feedback conditions and that decreased brain IGF-I signaling in middle-aged females contributes, in part, to LH surge dysfunction by disrupting estradiol-sensitive processes that affect GnRH neuron activation and/or GnRH release.