Transient pregnancy-induced Cushing's Syndrome with Aberrant Adrenal hCG receptor

U Plöckinger; N Tiling; O Blankenstein; K von Weizsäcker; B Allolio; M Kroiss; K Hauptmann; W Saeger; C Radke; T Steinmüller; N Rahman; M Chrusciel; M Doroszko; A Lacroix; I Huhtaniemi; M Quinkler

doi:10.1055/s-0034-1372154

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Transient pregnancy-induced Cushing's Syndrome with Aberrant Adrenal hCG receptor

U Plöckinger ¹, N Tiling ¹, O Blankenstein ², K von Weizsäcker ³, B Allolio ⁴, M Kroiss ⁴, K Hauptmann ⁵, W Saeger ⁶, C Radke ⁷, T Steinmüller ⁸, N Rahman ⁹, M Chrusciel ⁹, M Doroszko ⁹, A Lacroix ¹⁰, I Huhtaniemi ¹¹, M Quinkler ¹²

¹Charité-Universitätsmedizin Berlin, Interdisziplinäres Stoffwechsel-Centrum: Endokrinologie, Diabetes und Stoffwechsel, Berlin, Germany
²Labor-Berlin, Berlin, Germany
³Charité-Universitätsmedizin Berlin, Klinik für Geburtsmedizin, Berlin, Germany
⁴Universitätsklinikum Würzburg, Medizinische Klinik I, Würzburg, Germany
⁵Charité-Universitätsmedizin Berlin, Institut für Pathologie, Berlin, Germany
⁶Universitätsklinikum Hamburg-Eppendorf, Institut für Pathologie, Hamburg, Germany
⁷DRK Kliniken Berlin, Institut für Pathologie, Berlin, Germany
⁸DRK Kliniken Berlin, Chirurgische Klinik, Berlin, Germany
⁹Institute of Biomedicine, Department of Physiology, Turku, Finland
¹⁰L'Université de Montreal, Centre Hospitalier, Montreal, Canada
¹¹Imperial College London, Faculty of Medicine, Department of Surgery and Cancer, London, United Kingdom
¹²Charité-Universitätsmedizin Berlin, Klinik für Endokrinologie und Stoffwechsel, Berlin, Germany

Abstract

Introduction: ACTH-independent Cushing's syndrome (CS) can be associated to the expression of ectopic- or overexpression of eutopic adrenal receptors. These receptors activate adenylate cyclase and subsequently stimulate steroid synthesis, resulting in ACTH-independent CS and growth promotion with hyperplasia or macronodular adrenal changes. Excess cortisol (Co)-secretion better correlates with variations of ligands for the aberrant receptors than the suppressed circulating ACTH.

Results: We report a 22 y-old pat. with repeated, transient pregnancy-induced CS due to LH/hCG stimulated Co-secretion. The 1^st pregnancy was characterized by biochemical hypercortisolism [urinary free cortisol 5fold ULN, non-suppressibility of Co by dexamethasone] and an enlarged left adrenal. After preterm parturition CS and adrenal hyperplasia resolved spontaneously. Testing for aberrant adrenal regulation of Co-secretion was neg. except for vasopressin-increased Co-secretion (1700%, yet at a low level, while ACTH still suppressed). Stimulation with hCG, [ßhCG = 890 IU/ml (ULN at 12^th w of pregnancy ˜12000 IU/ml)] induced hypercortisolism. 1 y later, during an extra-uterine pregnancy, hypercortisolism recurred and normalized after termination of the pregnancy. 6 mo later, after bilateral adrenalectomy, adrenal histology was normal. In vitro adrenal LH-, vasopressin 1A- and 2 receptor mRNA expression was pos. while LHR-expression was neg. by IHC. rhCG stimulation of prim. cells increased 11-desoxy-Co, Co, corticosterone, androstenedione and cAMP.

Conclusion: We demonstrated the role of hCG as activating ligand for ACTH-independent Co-secretion. The need for long-term/high-dose stimulation by LH/hCG for the induction of Co-secretion explains transient pregnancy-induced CS while hypercortisolism is not observed during a normal menstrual cycle. The regression of adrenal hyperplasia after delivery suggests a primary role of chronic stimulation of aberrant receptors by hCG in adrenal hyperplasia.