LAUSR

Abstract Background: Fewer than 200 cases of Cushing syndrome (CS) during pregnancy are reported in the literature, and most are patients who developed Cushing disease prior to pregnancy. Rare cases of pregnancy-induced ACTH-independent CS feature hCG stimulation of cortisol production from pre-existing adrenal adenomas with ectopic LH/hCG receptors (LHCGR). We describe a case of ACTH-independent CS from adrenocortical micronodular hyperplasia presenting during pregnancy. Case: A previously healthy 23-year-old G1P0 woman presented at 17 weeks gestational age (GA) with rapid 50-pound weight gain, diabetes, hypertension, proximal muscle weakness, violaceous abdominal and underarm striae, and facial swelling, which began shortly following conception. Biochemical analysis revealed a urinary free cortisol of 403 mcg/24 h, a midnight salivary cortisol of 0.71 mcg/dL and an ACTH of <5 pg/mL. She had no family history of CS or other endocrinopathies. MRI without contrast showed normal appearing adrenal glands without nodularity. Her presentation and biochemistry suggested ACTH-independent CS. Due to her severe clinical symptoms, absence of adenomas on imaging, and lack of affordable medical options, she underwent bilateral adrenalectomy at 20 weeks GA. In the weeks following bilateral adrenalectomy, the diabetes and cushingoid features resolved. She underwent urgent Caesarean section for non-reassuring fetal heart tones at 29 weeks GA, and the boy was discharged home after 2 months in the neonatal intensive care unit. Her adrenal tissue demonstrated multiple unpigmented 2-16 mm nodules, and immunohistochemistry showed increased expression of steroidogenic enzymes, including CYP11B1, HSD3B2, and CYP17A1 throughout the nodular tissue with suppressed expression in the non-nodular tissue. Similarly, transcriptional analysis of a nodule revealed 3.7- to 5.3-fold increased mRNA expression of CYP11B1, HSD3B2 and CYP17A1 compared to control normal adrenal tissue. LHCGR mRNA expression was 17.2-fold higher in the adrenal nodule compared to controls. When isolated adrenal cells derived from a nodule were treated with hCG, cortisol secretion increased 2.1-fold (to 86 pg/h/mg protein) from baseline but not in control adrenal cells, suggesting that elevated hCG due to pregnancy may have mediated the CS through stimulation of aberrantly expressed LHCGR in the patient’s adrenal glands. Significance: Pregnancy-induced ACTH-independent CS is a rare condition that may be caused by aberrant expression of LHCGR in the adrenal cortex, resulting in increased steroidogenesis and cortisol excess due to high hCG levels during pregnancy.