Hypothalamic–pituitary–adrenal (hPA) axis

The HPA axis controls the secretion and synthesis of glucocorticoids, a class of steroid hormones that influence energy substrate metabolism. The most significant glucocorticoid in humans is cortisol. Cells in paraventricular nucleus of the hypothalamussecrete corticotrophin discharging hormone (CRH), a peptide that acts synergistically with arginine vasopressin to stimulate discharge of adrenocorticotrophic hormone (ACTH) from corticotrophs. This is cleaved from a huge precursor, pro-opiomelanocortin. In reaction to ACTH, cells in the adrenal cortex secrete and synthesize glucocorticoids. The negative feedback by cortisol functions at the hypothalamus, hippocampus, and pituitary which is as shown in figure below.

A circadian rhythm in cortisol outcome is driven by a brain biological clock situated in the suprachiasmatic nucleus acting on CRH-secreting cells. In humans ACTH pulses are utmost early in the morning and decline via the day to arrive at a low point around midnight. The Cortisol secretion follows a similar prototype. This daily rhythm is influenced by the timing of light & dark, sleep & meals.

The effect of cortisol is mediated by two receptors, that is the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These are members of a nuclear receptor superfamily which involves receptors for other steroids and for thyroid hormones. Whenever unbound, MRs and GRs are present in the cytoplasm, it complexed with heat shock proteins, molecular chaperones which stabilize the receptors into their functional configuration. The Glucocorticoids like cortisol disperse readily across the cell membranes. Binding of cortisol causes the receptor to translocate into the nucleus wherever it binds to particular series of DNA, hormone responsive elements, thereby raising or reducing the transcription of particular genes which is shown in figure below.

Mineralocorticoid receptors are in peak numbers in limbic structures. The Glucocorticoid receptors are more pervasive, and expressed in glia and also in neurons. Since MRs has a high cortisol affinity they are typically engaged at basal concentrations of the steroid. By contrary, GRs have a low affinity therefore are only engaged whenever the cortisol concentration is high, like early morning. This means that cortisol affects various target tissues based on its concentration. The corticotrophs of the anterior pituitary, CRH-secreting neurons of the hypothalamus, and hippocampal neurons express GRs. Whenever the concentration of cortisol is high these GRs are activated and they restrain transcription of the genes for CRH and arginine vasopressin. This is one method for negative feedback control of the glucocorticoid concentrations.