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
