Loop Modeling of the Reciprocal Inhibition Between HPA and HPG Endocrine Axes Reveals Transitions to Bistability and Critical Bifurcation Parameters

Endocrine axes are pathways of interactions involved in various aspects of the organism’s functioning, also implicated in deviations from physiological states leading to pathological conditions. The hypothalamic–pituitary–adrenal (HPA) axis releases corticosteroid hormones promoting adaptation to environmental stimuli (acute stress) or inducing altered conditions due to long-term noxious solicitations (chronic stress). The HP–gonadal (HPG) axis regulates reproductive activities by releasing gonadal steroids. These axes have been shown to engage in reciprocal inhibition under certain conditions, particularly when they rise beyond normal ultradian and circadian fluctuations. Based on the literature data, we reconstructed a neuroendocrine network responsible for this type of interaction. Thereafter, we developed a model of the HPA-HPG inhibition based on a series of nonlinear interactions represented by a system of differential equations in the Matlab environment. The quantitative analysis of the system’s behavior revealed the occurrence of bifurcations leading to bistable behavior, allowing us to detect bifurcation parameters. Bifurcation arises as the system’s components increase hypersensitivity and sustained activity in response to activating inputs. This involves transition from a single low-activity attractor to two distinct attractors, with a new high-activity state representing a breakdown of homeostasis. These results provide insights into the potential involvement of the HPA-HPG interaction in neuroendocrine disorders, and the identification of therapeutic targets from bifurcation parameters.