Asa S L, Kelly M A, Grandy D K, Low M J
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Ontario, Canada.
Endocrinology. 1999 Nov;140(11):5348-55. doi: 10.1210/endo.140.11.7118.
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 D2R-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.
结节漏斗部多巴胺通过激活位于催乳素细胞上的多巴胺D2受体（D2R），对垂体催乳素的表达和分泌起持续性抑制作用。缺乏D2R的突变雌性小鼠会出现持续性高催乳素血症，且在9至12月龄时会出现垂体催乳素细胞广泛增生以及腺垂体血囊肿，而年龄匹配的雄性D2R缺陷小鼠则没有腺垂体形态学病变。我们现在报告，17至20月龄的雌性和雄性D2R缺陷小鼠都会发生垂体催乳素细胞腺瘤。在检查的12只老龄雌性小鼠中，全部都发生了单激素催乳素免疫反应性肿瘤，这些肿瘤具有特征性的催乳素染色核旁高尔基体模式以及网状纤维网络的缺失。其中一些腺瘤比正常腺体大50倍，有明显的鞍上扩展并侵犯脑组织，但没有远处转移的明显证据。它们还伴有明显的血囊肿，比年轻雌性增生性垂体中的病变更明显。这些发现表明，神经激素多巴胺抑制的长期丧失会促进腺垂体催乳素细胞的增生-肿瘤形成序列。我们的结果与先前的数据相似，表明激素或生长因子对腺垂体细胞的长期刺激会导致细胞增殖，最初是增生，随后发展为肿瘤形成。6只老龄雄性D2R缺陷小鼠的垂体前叶略有增大，大小与正常雌性腺体相似。然而，每例均表现为多灶性、显微镜下可见的催乳素细胞腺瘤，对雌激素受体和Pit-1转录因子有强核免疫反应性。雄性小鼠在没有先前存在或伴随增生的情况下意外发生腺瘤，这表明多巴胺抑制的长期丧失也可能通过雄性和雌性动物不同的细胞机制导致肿瘤形成。
