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1. Introduction

The theory of dynamical compensation (sometimes also referred to as dynamic compensation) describes a dual effect of certain (especially glandotropic) hormones on both organ size and hormone output. The method is based on mathematical modelling and computer simulations of endocrine feedback loops that are, unlike previous approaches, targeted at different time scales ^[1]. On a short scale of minutes to hours, the hormonal function is modelled, and on a long scale of months and years, the growth of a gland is described. Feedback loops represented on both time scales are coupled with common components, e.g. controlling hormones.

2. Endocrine gland mass

This theory can explain the automatic and optimal control of endocrine organ growth. E. g., a low adrenal cell count results in a low secretory capacity of the adrenals. As a consequence, the cortisol secretion is rather low, resulting in increased ACTH production by the anterior pituitary gland. Consecutively, the elevated ACTH concentration not only stimulated increased production and release of cortisol but also the growth of the adrenal glands. This dynamical compensation adjusts the organ size to the individual demand ^[1].

3. Clinical aspects

The theory explains multiple clinical phenomena, e.g. adrenal atrophy and insufficiency in steroid-treated patients, increased adrenal secretory capacity in chronic stress and allostatic load and congenital adrenal hyperplasia due to reduced capacity of the 21-hydroxylase and other steroidogenic enzymes.

4. Paradoxical reduced ACTH in chronic stress

In chronic allostatic load (depression, panic disorders, anorexia, post-traumatic stress disorder, etc.), the pituitary gland’s response to a stimulation test with corticotropin-releasing hormone (CRH) is reduced ^[2]. This phenomenon appears paradoxical and has previously been poorly understood. It can be elegantly explained by dynamical compensation: as the regulatory circuits are coupled, the allostatic load resulting from stress causes an increase in adrenal mass. The consequent increase in adrenal secretory output, in turn, inhibits the secretion of ACTH. Consequently, a reduced amount of ACTH is released, even after stimulation with CRH ^[3].

Figure 1. The dynamics of functional adrenal mass can explain the paradoxically reduced CRH-stimulated ACTH release in chronic stress. A simple model without dynamical compensation (A) is unable to describe the observed endocrine pattern. Due to dynamical compensation, the secretory capacity of the adrenal glands is increased (B), which inhibits the secretion of ACTH despite stimulation with CRH [from Karin and Alon 2020, CC BY 4.0 licence].

5. Chronobiology

Dynamical compensation also explains the circannual rhythms of certain hormones, e.g. cortisol, thyroid hormones, IGF-1 and sex hormones. It has been observed that the central and peripheral hormones of the respective feedback loops have an opposed pattern in the rhythm of a year. Dynamical compensation, which accounts for fluctuations in organ mass that are delayed by several months, provides a simple and convincing explanation of the temporal patterns ^[4].