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      Clinical and Subclinical ACTH-Independent Macronodular Adrenal Hyperplasia and Aberrant Hormone Receptors

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          ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a very rare cause of endogenous Cushing’s syndrome (CS). In this review, the clinical characteristics, the pathophysiology, and the management of AIMAH are described. AIMAH typically presents with overt CS, but subclinical oversecretion of cortisol has been increasingly described. The diagnosis is suspected by adrenal nodular enlargement on conventional imaging following the demonstration of ACTH-independent hypercortisolism. Final diagnosis is established by histological examination of the adrenal tissue. Bilateral adrenalectomy is the treatment of choice but unilateral adrenalectomy has been proposed in selected cases. In patients with subclinical CS, the decision to treat should be individualized. The pathophysiology of this condition has begun to be elucidated in recent years. Diverse aberrant membrane-bound receptors expressed in a non-mutated form in the adrenal gland have been found to be implicated in the regulation of steroidogenesis in AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. A protocol designed to screen patients for the presence of these aberrant receptors should be undertaken in all patients with AIMAH. The identification of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specific antagonists.

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          Most cited references 83

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          A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.

          Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4. Testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone (LH). The LH receptor is a member of the family of G-protein-coupled receptors, and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist. A single A-->G base change that results in substitution of glycine for aspartate at position 578 in the sixth transmembrane helix of the LH receptor was found in affected individuals from eight different families. Linkage of the mutation to FMPP was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LH receptor.
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            Leuprolide acetate therapy in luteinizing hormone--dependent Cushing's syndrome.

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              Regulation of Expression ofobmRNA and Protein by Glucocorticoids and cAMP


                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                October 2005
                26 October 2005
                : 64
                : 3
                : 119-131
                Division of Endocrinology, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, Canada
                88818 Horm Res 2005;64:119–131
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 1, References: 123, Pages: 13
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