Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome
Creators: name: Plöckinger, Ursula
name: Chrusciel, Marcin
name: Doroszko, Milena
name: Saeger, Wolfgang
name: Blankenstein, Oliver
name: Weizsäcker, Katharina
name: Kroiss, Matthias
name: Hauptmann, Kathrin
name: Radke, Cornelia
name: Pöllinger, Alexander
name: Tiling, Nikolaus
name: Steinmuller, Thomas
name: Huhtaniemi, Ilpo
name: Quinkler, Marcus
name: Bertherat, Jerome
name: Lacroix, André
name: Rahman, Nafis
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2017
Subjects: subject: pregnancy
subject: cushing syndrome
subject: hydrocortisone
subject: adrenal glands
subject: mutation
subject: chorionic gonadotropin
subject: corticotropin
subject: dexamethasone
subject: adrenal gland hyperfunction
subject: genes
subject: hyperplasia
subject: labor
subject: pro-opiomelanocortin
subject: receptors lh
subject: zona glomerulosa
subject: zona reticularis
subject: corticosterone
subject: v1a receptors
subject: birth
subject: cortisol secretion
subject: beta catenin
subject: avpr1a gene
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit

description: Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). Objective: To determine the role of LHCGR in transient, pregnancy-induced CS. Design, Setting, Patient, and Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Main Outcome Measures and Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)–increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone–positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient’s adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. Conclusion: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR- positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus.