自主分泌的皮质醇（autonomous cortisol secretion，ACS）由皮质醇产生性腺瘤（cortisol-producing adenomas，CPA）引起，导致内源性类固醇诱导的骨质疏松症（steroid-induced osteoporosis，SIOP）。然而，内源性SIOP的风险不能仅通过皮质醇过多来解释，其他类固醇代谢产物如何影响骨骼状况尚不清楚。 ACS的诊断标准是1mg地塞米松抑制试验（dexamethasone suppression test，DST）后血清皮质醇≥ 1.8μg/dL（DST-皮质醇）。利用液相色谱串联质谱法对73例ACS患者和85例非功能性肾上腺肿瘤（non-functioning adrenal tumors，NFAT）患者进行了21种血浆类固醇代谢产物的测定。对部分CPA组织进行了甾类激素代谢酶和相关代谢产物的分析。 判别分析和主成分分析可区分产前绝经女性ACS组和NFAT组之间的甾类代谢谱。ACS产前绝经女性的11-去氧皮质酮（11-deoxycorticosterone，11-DOC）矿皮质激素代谢物水平较高，雄激素代谢物去氢表雄酮硫酸酯（dehydroepiandrosterone-sulfate）和雄酮-葡萄糖苷酸酯（androsterone-glucuronide）水平较低。在ACS产前绝经女性中，DST-皮质醇与骨小梁分数（trabecular bone score，TBS）呈负相关。此外，11-DOC与腰椎骨密度呈负相关，而androsterone-glucuronide与TBS呈正相关。CPA组织显示随着CYP21A2表达增加，11-DOC水平增加，CYP21A2对11-DOC合成至关重要。非肿瘤性肾上腺组织萎缩，CYB5A表达减少，CYB5A对雄激素合成至关重要。 本研究表明，来自肾上腺肿瘤和非肿瘤组织的肾上腺类固醇代谢产物不平衡的产生，对于ACS产前绝经女性内源性SIOP的发病机制有贡献。 本研究得到了JSPS KAKENHI、Secom Science and Technology Foundation、Takeda Science Foundation、Japan Foundation for Applied Enzymology、AMED-CREST、JSTA-STEP、JST-Moonshot和Ono Medical Research Foundation的支持。版权所有©2023年作者。Elsevier B.V.出版，保留所有权利。

Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear.ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues.Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis.This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS.JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.