Rometo Adonna M, Krajewski Sally J, Voytko Mary Lou, Rance Naomi E
Department of Pathology, University of Arizona College of Medicine, 1501 North Campbell Avenue, Tucson, Arizona 85724, USA.
J Clin Endocrinol Metab. 2007 Jul;92(7):2744-50. doi: 10.1210/jc.2007-0553. Epub 2007 May 8.
Human menopause is characterized by ovarian failure, gonadotropin hypersecretion, and neuronal hypertrophy in the hypothalamic infundibular (arcuate) nucleus. Recent studies have demonstrated a critical role for kisspeptins in reproductive regulation, but it is not known whether menopause is accompanied by changes in hypothalamic kisspeptin neurons.
Our objective was to map the location of neurons expressing kisspeptin gene (KiSS-1) transcripts in the human hypothalamus and determine whether menopause is associated with changes in the size and gene expression of kisspeptin neurons. In monkeys, our objective was to evaluate the effects of ovariectomy and hormone replacement on neurons expressing KiSS-1 mRNA in the infundibular nucleus.
Hypothalamic tissues were collected at autopsy from eight premenopausal and nine postmenopausal women and from 42 young cynomolgus monkeys in various endocrine states.
We used hybridization histochemistry, quantitative autoradiography, and computer-assisted microscopy.
Examination of human hypothalamic sections revealed that KiSS-1 neurons were located predominantly in the infundibular nucleus. In the infundibular nucleus of postmenopausal women, there was a significant increase in the size of neurons expressing KiSS-1 mRNA and the number of labeled cells and autoradiographic grains per neuron. Similar to postmenopausal women, ovariectomy induced neuronal hypertrophy and increased KiSS-1 gene expression in the monkey infundibular nucleus. Conversely, in ovariectomized monkeys, estrogen replacement markedly reduced KiSS-1 gene expression.
The cynomolgus monkey experiments provide strong evidence that the increase in KiSS-1 neuronal size and gene expression in postmenopausal women is secondary to ovarian failure. These studies suggest that kisspeptin neurons regulate estrogen negative feedback in the human.
人类绝经的特征是卵巢功能衰竭、促性腺激素分泌过多，以及下丘脑漏斗（弓状）核中的神经元肥大。最近的研究表明，亲吻素在生殖调节中起关键作用，但尚不清楚绝经是否伴有下丘脑亲吻素神经元的变化。
我们的目的是绘制人类下丘脑中表达亲吻素基因（KiSS-1）转录本的神经元的位置，并确定绝经是否与亲吻素神经元的大小和基因表达变化有关。在猴子中，我们的目的是评估卵巢切除术和激素替代对漏斗核中表达KiSS-1 mRNA的神经元的影响。
从8名绝经前和9名绝经后妇女以及42只处于不同内分泌状态的幼年食蟹猴的尸检中收集下丘脑组织。
我们使用了杂交组织化学、定量放射自显影和计算机辅助显微镜检查。
对人类下丘脑切片的检查显示，KiSS-1神经元主要位于漏斗核中。在绝经后妇女的漏斗核中，表达KiSS-1 mRNA的神经元大小、标记细胞数量以及每个神经元的放射自显影颗粒数量均显著增加。与绝经后妇女相似，卵巢切除术可诱导猴子漏斗核中的神经元肥大并增加KiSS-1基因表达。相反，在去卵巢的猴子中，雌激素替代可显著降低KiSS-1基因表达。
食蟹猴实验提供了有力证据，表明绝经后妇女中KiSS-1神经元大小和基因表达的增加是卵巢功能衰竭的继发结果。这些研究表明，亲吻素神经元调节人类的雌激素负反馈。
