Mazzuco Tânia L, Chabre Olivier, Feige Jean-Jacques, Thomas Michaël
Institut National de la Santé et de la Recherche Médicale, Equipe Mixte 01-05, 38054 Grenoble, France.
J Clin Endocrinol Metab. 2006 Jan;91(1):196-203. doi: 10.1210/jc.2005-1975. Epub 2005 Oct 25.
Aberrant expression of LH/human chorionic gonadotropin (hCG) receptor has been suggested in several cases of bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The cortisol production is then directly controlled by endogenous secretion of LH/hCG. However, the direct involvement of this aberrant LH/hCG receptor expression in the development of the hyperplasia has not been demonstrated. Moreover in most cases, whenever investigated, the aberrant expression of LH/hCG receptor has been associated with the ectopic expression of other G protein-coupled receptors such as gastric inhibitory polypeptide, serotonin, or vasopressin receptors.
The aim of this study was to explore the action of LH/hCG receptor on the development of adrenal hyperplasia.
The ectopic expression of this single nonmutated gene transduced into bovine adrenocortical cells was sufficient to induce not only the aberrant cortisol secretion but also hyperproliferation and benign transformation. The cells were transplanted beneath the kidney capsule of adrenalectomized immunodeficient mice. Only the cells expressing the LH/hCG receptor gene formed an enlarged tissue with a high proliferation rate. The tissue expressing LH/hCG receptor was responsible for elevated plasma cortisol and decreased plasma ACTH levels in transplanted mice. These animals displayed physiological changes similar to those of patients with Cushing's syndrome, including muscle atrophy, thin skin, spleen atrophy, and hyperglycemia.
These results demonstrate that a single genetic event such as the inappropriate expression of the nonmutated LH/hCG receptor gene is sufficient to initiate the phenotypic changes that cause the development of a benign adrenocortical tumor.
在几例伴有库欣综合征的双侧大结节性肾上腺增生病例中，已发现黄体生成素/人绒毛膜促性腺激素（LH/hCG）受体存在异常表达。此时，皮质醇的产生直接受LH/hCG内源性分泌的控制。然而，这种异常的LH/hCG受体表达在增生发展过程中的直接作用尚未得到证实。此外，在大多数病例中，一旦进行研究，LH/hCG受体的异常表达都与其他G蛋白偶联受体的异位表达相关，如胃抑制多肽、5-羟色胺或血管加压素受体。
本研究旨在探讨LH/hCG受体在肾上腺增生发展过程中的作用。
转导至牛肾上腺皮质细胞中的这个单一非突变基因的异位表达不仅足以诱导异常的皮质醇分泌，还能导致细胞过度增殖和良性转化。将这些细胞移植到肾上腺切除的免疫缺陷小鼠的肾包膜下。只有表达LH/hCG受体基因的细胞形成了一个增大的组织，且增殖率很高。表达LH/hCG受体的组织导致移植小鼠血浆皮质醇升高和血浆促肾上腺皮质激素水平降低。这些动物表现出与库欣综合征患者相似的生理变化，包括肌肉萎缩、皮肤变薄、脾脏萎缩和高血糖。
这些结果表明，单一的基因事件，如非突变的LH/hCG受体基因的不适当表达，足以引发导致良性肾上腺皮质肿瘤发展的表型变化。
