Bouyer K, Faivre-Bauman A, Robinson I C A F, Epelbaum J, Loudes C
UMR 894 INSERM, Centre de Psychiatrie et de Neurosciences, 2ter rue d'Alésia, Paris, France.
J Neuroendocrinol. 2008 Nov;20(11):1278-87. doi: 10.1111/j.1365-2826.2008.01780.x. Epub 2008 Aug 22.
The ultradian pulsatile pattern of growth hormone (GH) secretion is markedly sexually dimorphic in rodents as in primates, but the neuroanatomical mechanisms of this phenomenon are not clear. In the arcuate nucleus of the hypothalamus, GH-releasing hormone (GHRH) neurones receive somatostatinergic inputs through the sst2A receptor (sst2A-R) and the percentage of GHRH neurones bearing sst2A-R is higher in female than in male GHRH-enhanced green fluorescent protein (eGFP) mice. In the present study, we hypothesised that sst2A-R expression on GHRH neurones is modulated by gonadal steroids and constitutes a mechanism for sexually differentiated GH secretion. The distribution of sst2A-R on GHRH neurones was evaluated by immunohistochemistry in adult GHRH-eGFP mice gonadectomised and treated for 3 weeks with oestradiol or testosterone implants. In gonadectomised females supplemented with testosterone, sst2A-R distribution on GHRH neurones was reduced to the level seen in intact males, whereas oestradiol implants were ineffective. Conversely, orchidectomy induced a female 'sst2A phenotype', which was reversed by testosterone supplementation. Changes in the hepatic expression of GH-dependent genes for major urinary protein-3 and the prolactin receptor reflected the altered steroid influence on GH pulsatile secretion. In the ventromedial-arcuate region, GHRH and sst2-R, as well as GHRH and somatostatin expression as measured by the real-time polymerase chain reaction, were positively correlated in both sexes. By contrast, the positive correlation between ventromedial-arcuate GHRH and periventricular somatostatin expression in males was reversed to a negative one in females. Moreover, the positive correlation between periventricular somatostatin and ventromedial-arcuate sst2-R expressions in males was lost in females. These results suggest that, in the adult mouse, testosterone is a major modulator of sst2A distribution on GHRH neurones. This marked sex difference in sst2A-R distribution may constitute a key element in the genesis of the sexually differentiated pattern of GH secretion, possibly through testosterone-modulated changes in somatostatin inputs from hypophysiotrophic periventricular neurones.
与灵长类动物一样，啮齿动物生长激素（GH）分泌的超日节律脉冲模式具有明显的性别差异，但这种现象的神经解剖学机制尚不清楚。在下丘脑弓状核中，生长激素释放激素（GHRH）神经元通过促生长激素神经肽释放抑制因子2A受体（sst2A-R）接受促生长激素神经肽释放抑制因子能的输入，并且在雌性GHRH增强绿色荧光蛋白（eGFP）小鼠中，带有sst2A-R的GHRH神经元的百分比高于雄性。在本研究中，我们假设GHRH神经元上sst2A-R的表达受性腺类固醇调节，并构成了GH分泌性别分化的一种机制。通过免疫组织化学方法，对成年GHRH-eGFP小鼠进行性腺切除，并分别用雌二醇或睾酮植入物处理3周，以评估GHRH神经元上sst2A-R的分布情况。在补充睾酮的去势雌性小鼠中，GHRH神经元上sst2A-R的分布减少到完整雄性小鼠的水平，而植入雌二醇则无效。相反，睾丸切除术诱导出一种雌性“sst2A表型”，补充睾酮可使其逆转。主要尿蛋白-3和催乳素受体的GH依赖性基因在肝脏中的表达变化反映了类固醇对GH脉冲分泌的影响改变。在腹内侧-弓状区域，通过实时聚合酶链反应测量，GHRH和sst2-R以及GHRH和促生长激素神经肽释放抑制因子的表达在两性中均呈正相关。相比之下，雄性腹内侧-弓状GHRH与室周促生长激素神经肽释放抑制因子表达之间的正相关在雌性中则转变为负相关。此外，雄性中室周促生长激素神经肽释放抑制因子与腹内侧-弓状sst2-R表达之间的正相关在雌性中消失。这些结果表明，在成年小鼠中，睾酮是GHRH神经元上sst2A分布的主要调节因子。sst2A-R分布的这种明显性别差异可能是GH分泌性别分化模式形成的关键因素，可能是通过睾酮调节来自垂体营养性室周神经元的促生长激素神经肽释放抑制因子输入的变化实现的。
