Prolactin receptor overexpression in pregnancy-associated Cushing syndrome and functional implications

Cushing syndrome (CS) during pregnancy is rare but is associated with substantial maternal and fetal risks. Although aberrant activation of G protein-coupled receptors (GPCRs), particularly the luteinizing hormone/human chorionic gonadotropin receptor, has been implicated in pregnancy-related hypercortisolism, non-GPCR mechanisms remain incompletely defined. We report a case of adrenocorticotropic hormone-independent CS during pregnancy caused by a cortisol-producing adrenocortical adenoma. Integrative molecular analyses of the resected tumor, including ribonucleic acid sequencing and immunohistochemistry, demonstrated increased expression of the prolactin receptor (PRLR) compared with adjacent normal adrenal tissue. PRLR is a member of the type I cytokine receptor family and is expressed in normal adrenal glands; however, its potential role in adrenal tumors has not been well characterized. To examine its functional relevance, primary cell cultures derived from independent cortisol-producing adenomas from nonpregnant women were treated with recombinant prolactin (PRL). PRL induced a dose-dependent increase in both cortisol secretion into the culture medium and intracellular cortisol levels. Following unilateral adrenalectomy, hypercortisolism resolved, and maternal and neonatal outcomes were favorable. These data provide molecular and functional evidence supporting a contributory role of PRLR in pregnancy-associated hypercortisolism, potentially triggered by physiological PRL elevations during gestation.