Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids

内源性糖皮质激素具有多种生理作用，并且是代谢，免疫，心血管功能，骨骼肌肉健康和中枢神经系统活动的重要调节剂。合成的糖皮质激素类药物由于其有效的抗炎活性而受到广泛关注，并已成为一类重要的药物，用于增强内源性糖皮质激素活性，用于治疗多种慢性炎症。由于对糖皮质激素敏感途径的持续失调，长期使用合成糖皮质激素与许多不良反应有关。如果不考虑内源性糖皮质激素的明显昼夜节律，可能导致超生理性糖皮质激素暴露或严重抑制内源性糖皮质激素分泌，并被认为是慢性糖皮质激素治疗期间不良反应发生的原因。此外，鉴于合成的糖皮质激素对下丘脑-垂体-肾上腺（HPA）轴具有有效的反馈作用，因此可能引起HPA轴活动的个体差异的生理因素，例如性别，年龄和疾病状态，也可能对治疗。我们使用啮齿动物HPA轴的半机械数学模型来研究HPA轴调节中的假定性别差异和个体变异性如何影响长期合成暴露对内源性糖皮质激素昼夜节律的影响。模型模拟表明，对于相同的药物暴露量，考虑到肾上腺敏感性的差异以及对下丘脑和垂体的负反馈，模拟的女性表现出比男性更少的内源性抑制作用。模拟显示，HPA轴网络中的稳态调节变异性和慢性应激诱导的调节适应性可能导致合成暴露对内源性糖皮质激素的昼夜节律的影响存在实质性差异。一般而言，我们的结果提供了关于如何以个性化方式操纵合成糖皮质激素的剂量和暴露情况的信息，以保留内源性糖皮质激素在慢性治疗期间的昼夜动态，从而有可能将与长期使用相关的不良反应的发生率最小化糖皮质激素 模拟表明，HPA轴网络中的稳态调节变异性和慢性应激诱导的调节适应性可能导致合成暴露对内源性糖皮质激素的昼夜节律的影响存在实质性差异。一般而言，我们的结果提供了关于如何以个性化方式操纵合成糖皮质激素的剂量和暴露情况的信息，以保留内源性糖皮质激素在慢性治疗期间的昼夜动态，从而有可能将与长期使用相关的不良反应的发生率最小化糖皮质激素 模拟表明，HPA轴网络中的稳态调节变异性和慢性应激诱导的调节适应性可能导致合成暴露对内源性糖皮质激素的昼夜节律的影响存在实质性差异。一般而言，我们的结果提供了关于如何以个性化方式操纵合成糖皮质激素的剂量和暴露情况的信息，以保留内源性糖皮质激素在慢性治疗期间的昼夜动态，从而有可能将与长期使用相关的不良反应的发生率最小化糖皮质激素