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Submitted on September 1, 2005
Accepted on October 17, 2005
Institut National de la Santé et de la Recherche Médicale, Equipe Mixte 105, Département Réponse et Dynamique Cellulaires, Commissariat à l'Energie Atomique, 17 rue des Martyrs, 38054 Grenoble, Cedex 09, France and Service d'Endocrinologie, Département de Diabétologie, Urologie, Néphrologie et Endocrinologie, Centre Hospitalier Universitaire, Grenoble, France
* To whom correspondence should be addressed. E-mail: michael.thomas{at}cea.fr.
Context: Aberrant expression of LH/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.
Objective: The aim of this study was to explore the action of LH/hCG receptor on the development of adrenal hyperplasia.
Results: The ectopic expression of this single non-mutated 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.
Conclusions: These results demonstrate that a single genetic event such as the inappropriate expression of the non-mutated LH/hCG receptor gene is sufficient to initiate the phenotypic changes that cause the development of a benign adrenocortical tumor.
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