Dubuis J M, Deal C L, Drews R T, Goodyer C G, Lagacé G, Asa S L, Van Vliet G, Collu R
Research Unit on Reproductive and Developmental Biology, Research Center, Hôpital Ste-Justine, Montreal, Canada.
Clin Endocrinol (Oxf). 1995 May;42(5):539-49. doi: 10.1111/j.1365-2265.1995.tb02675.x.
The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 8-year old boy with a 5-year history of growth acceleration and acromegalic gigantism at presentation. Elevated basal GH (mean 28 micrograms/l) and PRL (mean 120 micrograms/l) plasma levels were observed, as well as paradoxical responses of GH to L-dopa, TRH and oral glucose administration; PRL was reduced by L-dopa and slightly increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (microM) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high levels of the AC-stimulatory G protein alpha subunit Gs alpha and very low amounts of the AC-inhibiting G protein alpha subunit Gi3 alpha and of the phospholipase C-stimulating G protein alpha subunit Gq alpha were found in the tumour. After bromocriptine, baseline AC activity was normalized and could no longer be stimulated; Gs alpha and Gi3 alpha levels were unchanged while those of Gq alpha were normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analysis did not reveal any mutations in the hot spots of G protein alpha subunits (alpha s, alpha i2, alpha o2 and alpha 11) genes or in the H-ras and p53 genes. Gs alpha and GH transcription factor-1 (pit-1) expression were evaluated by amplification of cDNA. While the mRNA expression of pit-1 decreased after bromocriptine treatment, that of Gs alpha increased. These data suggest the possibility of an oncogenic process involving overexpression of Gs alpha, resulting in chronic activation of adenylate cyclase. Furthermore, our results suggest that the anti-secretory and anti-proliferative effects of bromocriptine may be mediated through a decrease in Pit-1 secondary to the inhibition of adenylate cyclase activity.
乳腺生长激素细胞腺瘤的病理生理学仍不清楚。我们研究了一名8岁男孩的乳腺生长激素细胞腺瘤，该男孩就诊时已有5年生长加速和肢端肥大性巨人症病史。观察到基础血浆生长激素（平均28微克/升）和催乳素（平均120微克/升）水平升高，以及生长激素对左旋多巴、促甲状腺激素释放激素（TRH）和口服葡萄糖给药的反常反应；左旋多巴可降低催乳素水平，TRH可使其略有升高；生长激素释放激素（GHRH）可刺激生长激素和催乳素的释放。需要进行两次手术才能切除这个非常大的肿瘤，患者在第二次手术前接受了溴隐亭治疗。在基础条件下以及刺激或抑制后，对培养的肿瘤外植体的激素分泌进行了评估。高水平的生长激素和催乳素分泌可持续24天。此外，GHRH和TRH对这两种激素均产生剂量相关的刺激作用，而生长抑素和多巴胺仅在非常高的（微摩尔）浓度下才能有效抑制基础或刺激后的激素释放。通过测定肿瘤组织中的鸟苷三磷酸结合（G）蛋白水平和腺苷酸环化酶（AC）活性来研究细胞内事件。在溴隐亭治疗前，肿瘤中的AC活性非常高，并且可被各种药物进一步刺激；在肿瘤中发现了非常高水平的AC刺激型G蛋白α亚基Gsα，以及非常少量的AC抑制型G蛋白α亚基Gi3α和磷脂酶C刺激型G蛋白α亚基Gqα。溴隐亭治疗后，基线AC活性恢复正常，且不再能被刺激；Gsα和Gi3α水平未改变，而Gqα水平恢复正常。通过聚合酶链反应扩增后进行单链构象多态性分析，对肿瘤DNA进行筛查，未发现G蛋白α亚基（αs、αi2、αo2和α11）基因或H-ras和p53基因热点区域的任何突变。通过cDNA扩增评估Gsα和生长激素转录因子-1（Pit-1）的表达。溴隐亭治疗后，Pit-1的mRNA表达下降，而Gsα的表达增加。这些数据提示存在一个涉及Gsα过表达的致癌过程，导致腺苷酸环化酶的慢性激活。此外，我们的结果提示溴隐亭的抗分泌和抗增殖作用可能是通过抑制腺苷酸环化酶活性继发Pit-1减少来介导的。
