Rometo A M, Rance N E
Department of Pathology, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
J Neuroendocrinol. 2008 Dec;20(12):1376-81. doi: 10.1111/j.1365-2826.2008.01796.x.
Human menopause is characterised by ovarian failure, gonadotrophin hypersecretion and hypertrophy of neurones expressing neurokinin B (NKB), kisspeptin (KiSS)-1 and oestrogen receptor (ER) alpha gene transcripts within the hypothalamic infundibular (arcuate) nucleus. In the arcuate nucleus of experimental animals, dynorphin, an opioid peptide, is colocalised with NKB, kisspeptin, ER alpha and progesterone receptors. Moreover, ovariectomy decreases the expression of prodynorphin gene transcripts in the arcuate nucleus of the ewe. Therefore, we hypothesised that the hypertrophied neurones in the infundibular nucleus of postmenopausal women would express prodynorphin mRNA and that menopause would be accompanied by changes in prodynorphin gene transcripts. In the present study, in situ hybridisation was performed on hypothalamic sections from premenopausal and postmenopausal women using a radiolabelled cDNA probe targeted to prodynorphin mRNA. Autoradiography and computer-assisted microscopy were used to map and count labelled neurones, measure neurone size and compare prodynorphin gene expression between premenopausal and postmenopausal groups. Neurones expressing dynorphin mRNA in the infundibular nucleus of the postmenopausal women were larger and exhibited hypertrophied morphological features. Moreover, there were fewer neurones labelled with the prodynorphin probe in the infundibular nucleus of the postmenopausal group compared to the premenopausal group. The number of dynorphin mRNA-expressing neurones was also reduced in the medial preoptic/anterior hypothalamic area of postmenopausal women without changes in cell size. No differences in cell number or size of dynorphin mRNA-expressing neurones were observed in any other hypothalamic region. Previous studies using animal models provide strong evidence that the changes in prodynorphin neuronal size and gene expression in postmenopausal women are secondary to the ovarian failure of menopause. Given the inhibitory effect of dynorphin on the reproductive axis, decreased dynorphin gene expression could play a role in the elevation in luteinising hormone secretion that occurs in postmenopausal women.
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）核内表达神经激肽B（NKB）、亲吻素（KiSS）-1和雌激素受体（ER）α基因转录物的神经元肥大。在实验动物的弓状核中，强啡肽（一种阿片肽）与NKB、亲吻素、ERα和孕激素受体共定位。此外，卵巢切除术会降低母羊弓状核中前强啡肽原基因转录物的表达。因此，我们推测绝经后女性漏斗核中肥大的神经元会表达前强啡肽原mRNA，并且绝经会伴随着前强啡肽原基因转录物的变化。在本研究中，使用针对前强啡肽原mRNA的放射性标记cDNA探针，对绝经前和绝经后女性的下丘脑切片进行原位杂交。利用放射自显影和计算机辅助显微镜来定位和计数标记的神经元、测量神经元大小，并比较绝经前和绝经后组之间的前强啡肽原基因表达。绝经后女性漏斗核中表达强啡肽mRNA的神经元更大，呈现出肥大的形态特征。此外，与绝经前组相比，绝经后组漏斗核中用前强啡肽原探针标记的神经元更少。在绝经后女性的内侧视前区/下丘脑前部区域，表达强啡肽mRNA的神经元数量也减少了，而细胞大小没有变化。在其他任何下丘脑区域，未观察到表达强啡肽mRNA的神经元在细胞数量或大小上有差异。先前使用动物模型的研究提供了强有力的证据，表明绝经后女性前强啡肽原神经元大小和基因表达的变化是绝经后卵巢功能衰竭的继发结果。鉴于强啡肽对生殖轴的抑制作用，强啡肽基因表达的降低可能在绝经后女性促黄体生成素分泌升高过程中发挥作用。
