Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Eur J Endocrinol. 2012 Dec 10;168(1):67-74. doi: 10.1530/EJE-12-0594. Print 2013 Jan.
Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop.
Investigation of regulation of steroidogenesis in a case of PPNAD with virilization.
A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues.
Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue.
PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas.
原发性色素性结节性肾上腺皮质病（PPNAD）可导致类固醇激素过度产生。cAMP 蛋白激酶 A 调节亚单位 1A（PRKAR1A）的突变是 PPNAD 的致病原因。PPNAD 中的类固醇生成可以通过局部糖皮质激素反馈环进行修饰。
研究一例男性化的 PPNAD 中类固醇生成的调节。
一名 33 岁女性因高雄激素血症导致原发性不孕就诊。检测到睾酮水平升高和亚临床 ACTH 非依赖性库欣综合征，从而发现肾上腺肿瘤，诊断为 PPNAD。异常表达激素受体的体内评估显示，对已知刺激无类固醇反应。基因分析显示 PRKAR1A 蛋白截断 Q28X 突变。肾上腺切除术后，类固醇水平恢复正常。培养肿瘤细胞，测量 ACTH 和地塞米松对其类固醇生成反应，并与正常肾上腺和肾上腺皮质癌细胞进行比较。定量分析 PPNAD、正常肾上腺和肾上腺腺瘤组织中 17β-羟甾类脱氢酶（17β-HSD）类型 3 和 5 以及类固醇受体的表达水平。
与正常肾上腺细胞类似，分离的 PPNAD 细胞在 ACTH 刺激下均表现出增加的类固醇生成酶表达和类固醇分泌。在所研究的肾上腺细胞类型中，地塞米松不影响类固醇的产生。与对照肾上腺组织相比，PPNAD 相关腺瘤中 17β-HSD 类型 5 的表达水平更高。
PPNAD 相关腺瘤通过肾上腺雄激素过度产生导致男性化和不孕。这可能是由于类固醇生成的控制机制与无大腺瘤的 PPNAD 描述的机制不同所致。
