Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
EBioMedicine. 2023 Sep;95:104733. doi: 10.1016/j.ebiom.2023.104733. Epub 2023 Aug 3.
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.
自主皮质醇分泌（ACS）是由产生皮质醇的腺瘤（CPA）引起的，导致内源性类固醇诱导的骨质疏松症（SIOP）。然而，内源性 SIOP 的风险不能仅用皮质醇过多来解释，其他类固醇代谢物如何影响骨骼状态尚不清楚。
使用 1 毫克地塞米松抑制试验（DST-皮质醇），将血清皮质醇≥1.8μg/dL 诊断为 ACS。在 73 例 ACS 患者和 85 例无功能性肾上腺肿瘤（NFAT）患者中，使用液相色谱串联质谱法测量了 21 种血浆类固醇代谢物。分析了一些 CPA 组织中的类固醇生成酶和相关类固醇代谢物的表达。
判别分析和主成分分析在绝经前妇女中区分了 ACS 和 NFAT 组的类固醇谱。ACS 的绝经前妇女表现出更高水平的盐皮质激素代谢物 11-脱氧皮质酮（11-DOC）和更低水平的雄激素代谢物脱氢表雄酮硫酸酯和雄酮葡萄糖醛酸。在 ACS 的绝经前妇女中，DST-皮质醇与小梁骨评分（TBS）呈负相关。此外，11-DOC 与腰椎骨密度呈负相关，而雄酮葡萄糖醛酸与 TBS 呈正相关。CPA 组织中 CYP21A2 的表达增加，导致 11-DOC 水平升高，CYP21A2 是 11-DOC 合成所必需的。肾上腺非肿瘤组织萎缩，导致雄激素合成所需的 CYB5A 表达减少。
本研究表明，肾上腺肿瘤和非肿瘤组织来源的肾上腺类固醇代谢物的不平衡产生，导致 ACS 绝经前妇女内源性 SIOP 的发病机制。
JSPS KAKENHI、Secom 科学与技术基金会、武田科学基金会、日本应用酶学基金会、AMED-CREST、JSTA-STEP、JST-Moonshot 和小野制药研究基金会。
