雌性小鼠慢性雄激素过多不会影响促黄体激素脉冲频率或 GnRH 神经元的假定 GABAergic 输入,Journal of Neuroendocrinology

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雌性小鼠慢性雄激素过多不会影响促黄体激素脉冲频率或 GnRH 神经元的假定 GABAergic 输入
Journal of Neuroendocrinology ( IF 3.2 ) Pub Date : 2022-02-26 , DOI: 10.1111/jne.13110
Chris S Coyle ₁ , Melanie Prescott ₁ , David J Handelsman ₂ , Kirsty A Walters ₃ , Rebecca E Campbell ₁

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多囊卵巢综合征 (PCOS) 与雄激素过多有关，并且通常与过度活跃的搏动性促黄体生成素 (LH) 分泌有关。尽管 PCOS 的起源尚不清楚，但来自临床前模型的证据表明大脑中的雄激素信号传导与 PCOS 病理生理学的发展有关。雌性小鼠从 3 周龄开始长期暴露于二氢睾酮 (DHT) 会导致生殖和代谢障碍，这些障碍可通过大脑中的选择性雄激素受体 (AR) 损失而得到改善。这表明高雄激素介导的 PCOS 样病理生理学中的中心驱动机制仍有待确定。急性产前 DHT 暴露也可以模拟 PCOS 的高雄激素血症，这伴随着 LH 脉冲频率增加和促性腺激素释放激素 (GnRH) 神经元的 GABA 能神经支配增加。我们旨在确定雌性小鼠长期暴露于 DHT（模拟 PCOS 的雄激素过多症）对脉动 LH 分泌和 GnRH 神经元推定的 GABA 能输入的影响。为此，GnRH-绿色荧光蛋白 (GFP) 雌性小鼠从出生后第 21 天开始接受 DHT 或空白胶囊 90 天。n = 每组 6 或 7 个）。连续尾尖采血用于测量 LH 动力学，并收集灌注固定的大脑并针对囊泡 GABA 转运蛋白 (VGAT) 进行免疫标记，以评估与 GFP 标记的 GnRH 神经元相关的推定 GABAergic 末端。正如预期的那样，慢性 DHT 导致非周期性并显着增加体重。然而，在卵巢完整的 DHT 治疗的女性和对照组之间，没有发现 LH 脉冲频率或 VGAT 与 GnRH 神经元并列的密度的差异。慢性 DHT 暴露显着增加了下丘脑中表达 AR 的细胞数量，而表达雌激素受体 α 的神经元数量没有变化。因此，尽管从 3 周龄开始长期接触 DHT 会增加大脑中表达 AR 的神经元，与产前雄激素过多相关的 GnRH 神经元网络变化和过度活跃的 LH 分泌并不明显。这些发现表明，在不同发育阶段暴露于雄激素过多导致的生殖障碍涉及独特的中枢机制。

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Chronic androgen excess in female mice does not impact luteinizing hormone pulse frequency or putative GABAergic inputs to GnRH neurons

Polycystic ovary syndrome (PCOS) is associated with androgen excess and, frequently, hyperactive pulsatile luteinizing hormone (LH) secretion. Although the origins of PCOS are unclear, evidence from pre-clinical models implicates androgen signalling in the brain in the development of PCOS pathophysiology. Chronic exposure of female mice to dihydrotestosterone (DHT) from 3 weeks of age drives both reproductive and metabolic impairments that are ameliorated by selective androgen receptor (AR) loss from the brain. This suggests centrally driven mechanisms in hyperandrogen-mediated PCOS-like pathophysiology that remain to be defined. Acute prenatal DHT exposure can also model the hyperandrogenism of PCOS, and this is accompanied by increased LH pulse frequency and increased GABAergic innervation of gonadotrophin-releasing hormone (GnRH) neurons. We aimed to determine the impact of chronic exposure of female mice to DHT, which models the hyperandrogenism of PCOS, on pulsatile LH secretion and putative GABAergic input to GnRH neurons. To do this, GnRH-green fluorescent protein (GFP) female mice received either DHT or blank capsules for 90 days from postnatal day 21 (n = 6 or 7 per group). Serial tail-tip blood sampling was used to measure LH dynamics and perfusion-fixed brains were collected and immunolabelled for vesicular GABA transporter (VGAT) to assess putative GABAergic terminals associated with GFP-labelled GnRH neurons. As expected, chronic DHT resulted in acyclicity and significantly increased body weight. However, no differences in LH pulse frequency or the density of VGAT appositions to GnRH neurons were identified between ovary-intact DHT-treated females and controls. Chronic DHT exposure significantly increased the number of AR expressing cells in the hypothalamus, whereas oestrogen receptor α-expressing neuron number was unchanged. Therefore, although chronic DHT exposure from 3 weeks of age increases AR expressing neurons in the brain, the GnRH neuronal network changes and hyperactive LH secretion associated with prenatal androgen excess are not evident. These findings suggest that unique central mechanisms are involved in the reproductive impairments driven by exposure to androgen excess at different developmental stages.

更新日期：2022-02-26

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