Kinetic modelling of testosterone-related differences in the hypothalamic-pituitary-adrenal axis response to stress

The sex hormone testosterone (TTS) and the hypothalamic-pituitary-adrenal (HPA) axis mutually control one another's activity, wherein TTS suppresses corticotrophin releasing hormone (CRH) stimulated HPA axis activity, whereas the activation of HPA axis has an inhibitory effect on TTS secretion. With an intention to explain these phenomena, a network reaction model is developed from the previously postulated stoichiometric models for HPA activity where main dynamic behaviors are controlled by two catalytic steps (one autocatalytic and one autoinhibitory) with respect to cortisol, both found experimentally. The capacity of the model to emulate TTS effects on HPA axis dynamics and its response to acute CRH-induced stress is examined using numerical simulations. Model predictions are compared with empirically obtained results reported in the literature. Thus, the reaction kinetic examinations of nonlinear biochemical transformations that constitute the HPA axis, including the negative feedback effect of TTS on HPA axis activity, recapitulates the well-established fact that TTS dampens HPA axis basal activity, decreasing both cortisol level and the amplitude of ultradian cortisol oscillations. The model also replicates TTS inhibitory action on the HPA axis response to acute environmental challenges, particularly CRH-induced stress. In addition, kinetic modelling revealed that TTS induced reduction in ultradian cortisol amplitude arises because the system moves towards a supercritical Hopf bifurcation as TTS is being increased.