Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg ON1 Herestraat 49 - Box 901, 3000 Leuven, Belgium.
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands.
Endocrinology. 2024 Aug 27;165(10). doi: 10.1210/endocr/bqae119.
Biological sex affects the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, how androgen deprivation affects this axis remains largely unknown. In this study, we investigated the effect of androgen status on different components of the HPA axis in male mice. Two weeks of androgen deprivation did not affect total plasma corticosterone levels but led to increased pituitary ACTH levels. Stress-induced total plasma corticosterone levels were increased, whereas the suppression of corticosterone after dexamethasone treatment under basal conditions was attenuated. Androgen-deprived mice displayed a 2-fold increase in plasma levels of corticosteroid binding globulin (CBG). A similar increase in CBG was observed in global androgen receptor knock-out animals, compared to wild-type littermates. Androgen deprivation was associated with a 6-fold increase in CBG mRNA in the liver and enhanced transcriptional activity at CBG regulatory regions, as evidenced by increased H3K27 acetylation. We propose that the induction of CBG as a consequence of androgen deprivation, together with the unaltered total corticosterone levels, results in lower free corticosterone levels in plasma. This is further supported by mRNA levels of androgen-independent GR target genes in the liver. The reduction in negative feedback on the HPA axis under basal condition would suffice to explain the enhanced stress reactivity after androgen deprivation. Overall, our data demonstrate that, in mice, tonic androgen receptor activation affects CBG levels in conjunction with effects on gene expression and HPA-axis reactivity.
生物性别会影响下丘脑-垂体-肾上腺（HPA）轴的活性。然而，雄激素剥夺如何影响该轴仍知之甚少。在这项研究中，我们研究了雄激素状态对雄性小鼠 HPA 轴不同成分的影响。两周的雄激素剥夺不会影响总血浆皮质酮水平，但会导致垂体 ACTH 水平升高。应激诱导的总血浆皮质酮水平升高，而在基础条件下用地塞米松处理时皮质酮的抑制作用减弱。去势小鼠的血浆皮质类固醇结合球蛋白（CBG）水平增加了 2 倍。与野生型同窝仔相比，全身性雄激素受体敲除动物也观察到 CBG 增加相似。与对照组相比，雄激素剥夺与肝脏中 CBG mRNA 增加 6 倍以及 CBG 调节区域的转录活性增强相关，这表现为 H3K27 乙酰化增加。我们提出，由于雄激素剥夺而诱导的 CBG 与总皮质酮水平不变一起导致血浆中游离皮质酮水平降低。这进一步得到了肝脏中雄激素非依赖性 GR 靶基因 mRNA 水平的支持。基础状态下 HPA 轴负反馈的减少足以解释雄激素剥夺后的应激反应增强。总的来说，我们的数据表明，在小鼠中，持续的雄激素受体激活会影响 CBG 水平，同时还会影响基因表达和 HPA 轴反应。
