Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice
Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice
复制标题
DOI：
10.1210/en.140.11.5348
复制
发表时间：
1999-11-01
期刊：
影响因子：
4.8
通讯作者：
Low, MJ
中科院分区：
文献类型：
--
作者：
Asa, SL;Kelly, MA;Low, MJ
漏斗状多巴胺通过激活乳汁滋养细胞上的多巴胺D2受体(D2R)，强直地抑制垂体腺PRL的表达和分泌。缺乏D2R的突变雌性小鼠在9-12个月龄时会出现持续性的高催乳素血症，但也会出现广泛的垂体促乳素细胞增生和腺垂体肥厚，而年龄匹配的D2R基因缺失的雄性小鼠则没有腺垂体的形态损害。我们现在报道，17到20个月大的雌性和雄性D2R缺陷小鼠都会患上垂体催乳素腺瘤。在接受检查的12只老年雌性小鼠中，所有的小鼠都发生了单激素PRL免疫反应肿瘤，具有PRL染色的典型核旁高尔基图案和网状纤维网络的丢失。其中几个腺瘤比正常腺体大50倍，有明显的鞍上延伸和脑侵犯，但没有远处转移的肉眼证据。他们还患有明显的疱疹，比年轻女性的增生性脑下垂体病变更明显。这些发现表明，神经激素多巴胺抑制的慢性丧失促进了腺垂体催乳素细胞的增殖-肿瘤序列。我们的结果类似于以前的数据，即激素或生长因子长期刺激腺垂体细胞会导致增殖，首先是增生，然后是肿瘤的发展。6只老年雄性DBR缺陷小鼠的脑垂体前部略有增大，大小与正常雌性腺体相似。然而，每个病例都表现为多灶性显微催乳腺瘤，对雌激素受体和Pit-1转录因子有很强的核免疫反应。在没有预先存在或伴随的增生的雄性动物中，腺瘤的意外发展表明，多巴胺抑制的长期丧失也可能通过不同的细胞机制在雄性和雌性动物中引起肿瘤。
Tuberoinfundibular dopamine tonically inhibits PRL expression and secretion from the pituitary gland by the activation of dopamine D2 receptors (D2R) localized on lactotrophs. Mutant female mice that lack D2Rs have persistent hyperprolactinemia but also develop extensive hyperplasia of pituitary lactotrophs and peliosis of the adenohypophysis at 9 to 12 months of age, while age-matched male D2R-deficient mice have no morphologic adenohypophysial lesion. We now report that both female and male D2R-deficient mice 17 to 20 months of age develop pituitary lactotroph adenomas. Of 12 aged female mice examined, all developed monohormonal PRL-immunoreactive neoplasms that had a characteristic juxtanuclear Golgi pattern of PRL staining and loss of the reticulin fiber network. Several of these adenomas were 50-fold larger than normal glands with marked suprasellar extension and invasion of brain but no gross evidence of distant metastases. They also had striking peliosis that was more marked than the lesion seen in the hyperplastic pituitaries of the younger females. These findings demonstrate that a chronic loss of neurohormonal dopamine inhibition promotes the hyperplasia-neoplasia sequence in adenohypophysial lactotrophs. Our results are analogous to previous data indicating that protracted stimulation of adenohypophysial cells by hormones or growth factors results in proliferation with initial hyperplasia followed by the development of neoplasia. Six aged male DBR-deficient mice had slightly enlarged anterior pituitaries similar in size to normal female glands. However, each case exhibited multifocal, microscopic lactotroph adenomas with strong nuclear immunoreactivity for estrogen receptors and Pit-1 transcription factor. The unexpected development of adenomas in males without preexisting or concomitant hyperplasia suggests that prolonged loss of dopamine inhibition may also cause neoplasia by distinct cellular mechanisms in male and female animals.