A retrospective study of severity-dependent HPG Axis suppression by glucocorticoids in Chinese women with Cushing...

Cushing syndrome (CS) is a severe endocrine disorder caused by prolonged exposure to glucocorticoid excess. Among its diverse complications, reproductive and sexual disorders arehighly prevalent, impacting patients' quality of life. Despite this clinical significance, clinicalstudies specifically investigating the hypothalamic-pituitary-gonadal (HPG) axis status in femalepatients with CS remain insufficient, highlighting the urgent need for thorough evaluation.

This retrospective cross-sectional study evaluated the HPG axis status in 137 women diagnosed with CS between 2007 and May 2024, comprising adrenal CS, Cushing's disease (CD) and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), with reproductive hormone profiles compared across the three subtypes. Linear regression analysis was employed to assess the association between reproductive hormone levels and the severity of hypercortisolism. In a subgroup of 45 women with available steroid profiles quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), plasma androgens were evaluated through receiver operating characteristic (ROC) curve analysis to determine their diagnostic power. Additionally, the relative susceptibility of the thyroid axis and the gonadal axis to hypercortisolism was comparatively examined.

Among the three CS subtypes, female patients with EAS exhibited markedly elevated ACTH, serum cortisol, and 24-hour urinary free cortisol (24h-UFC), alongside markedly elevated testosterone and reduced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Linear regression analysis revealed significant positive associations between serum cortisol with testosterone, whereas inverse correlations were observed with LH and FSH, particularly in postmenopausal women. Furthermore, plasma androgens, including testosterone, androstenedione (A2), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS), demonstrated superior diagnostic power in discriminating CD from adrenal CS. Additional comparative analyses between the thyroid axis and the gonadal axis indicated that the latter exhibited greater susceptibility to hypercortisolism.

Our findings demonstrate that a severity-dependent glucocorticoid suppression of HPG axis function across CS subtypes, with the most pronounced effects observed in EAS, which may facilitate clinical identification.