Role of Adrenal Steroid Metabolites in Osteoporosis in Patients with Autonomous Cortisol Secretion
Background: Autonomous cortisol secretion (ACS), results from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, how other adrenal steroid metabolites affect bone status is unclear. Methods: ACS was diagnosed at serum cortisol after 1-mg dexamethasone suppression test (DST-cortisol) = 1.8 ?g/dL. Using liquid chromatography-tandem mass spectrometry, we measured 21 plasma steroid metabolites in 73 patients with ACS and 85 with non-functioning adrenal tumors (NFAT). We also examined expression of steroidogenic enzymes and relevant steroid metabolites in some of CPA tissues. Results: In discriminant and principal component analysis, steroid profiles distinguished between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite; 11-deoxycorticosterone (11-DOC), with lower androgen metabolites; dehydroepiandrosterone-sulfate and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol was negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC was negatively correlated with lumbar spine-bone mineral density (r = -0.603), while androsterone-glucuronide was positively correlated with TBS (r = 0.681), which was supported by Bayesian kernel machine regression analysis. There were no such correlations in postmenopausal women and men. The CPA tissues showed increased levels of 11-DOC, with increased expression of CYP21A2, which is essential for 11-DOC synthesis. The adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, which is required for androgen synthesis. Conclusion: This study provides the first evidence that unbalanced production of adrenal steroid metabolites, which are derived from both adrenal tumors and non-tumor tissues, play a role in the pathogenesis of endogenous SIOP in premenopausal women with ACS.