HPA Axis Regulation and ACTH Control

The hypothalamic-pituitary-adrenal (HPA) axis is the regulatory loop that controls glucocorticoid secretion. The hypothalamus releases corticotropin-releasing hormone, which drives the anterior pituitary to secrete adrenocorticotropic hormone (ACTH); ACTH then stimulates the adrenal cortex to make cortisol, and cortisol feeds back to restrain the axis.

Definition

HPA axis regulation is the coordinated control of cortisol secretion by corticotropin-releasing hormone from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary, and negative feedback from circulating cortisol, organized around a circadian rhythm and responsive to stress.

Scope

This topic covers the structure and dynamics of the HPA axis: the hypothalamic and pituitary signals, the actions of ACTH on the adrenal cortex, the circadian and stress-related patterns of activity, and the negative-feedback regulation that keeps cortisol within range. The downstream actions of cortisol itself are covered in the glucocorticoid topic.

Core questions

• How do CRH, ACTH, and cortisol form a closed feedback loop, and what does negative feedback achieve?
• How does ACTH act on the adrenal cortex to stimulate steroidogenesis?
• How do circadian timing and stress modulate the set point and output of the axis?

Key concepts

• Corticotropin-releasing hormone (CRH)
• Adrenocorticotropic hormone (ACTH)
• Pro-opiomelanocortin (POMC) precursor
• Melanocortin 2 receptor (MC2R) on the cortex
• Stimulation of steroidogenesis (StAR, cAMP)
• Negative feedback by cortisol
• Circadian rhythm of the axis
• Stress activation

Mechanisms

Neurons in the hypothalamic paraventricular nucleus release corticotropin-releasing hormone (and vasopressin as a co-secretagogue) into the hypophyseal portal blood, stimulating corticotroph cells of the anterior pituitary to cleave the precursor pro-opiomelanocortin and secrete ACTH. ACTH reaches the adrenal cortex and binds the melanocortin 2 receptor on zona fasciculata cells, raising cAMP and acutely promoting cholesterol delivery via the StAR protein to drive cortisol synthesis, while chronically maintaining the steroidogenic machinery and cortical mass. Circulating cortisol exerts negative feedback at both the pituitary and hypothalamus, suppressing ACTH and CRH and thereby closing the loop. The axis operates with a circadian rhythm, generating the early-morning cortisol peak, and is activated by physical and psychological stressors that increase CRH and ACTH drive.

Clinical relevance

The HPA axis framework explains the distinction between primary adrenal failure (low cortisol with high ACTH) and central, pituitary or hypothalamic, causes (low cortisol with inappropriately low ACTH), and why exogenous glucocorticoids suppress the axis through feedback. This entry describes physiology and the conceptual basis of these states for reference; it gives no dosing and is not guidance for managing any individual.

Evidence & guidelines

The architecture and feedback dynamics of the HPA axis are established physiology reviewed in the context of the stress response (Charmandari et al., 2005; de Kloet et al., 2005). The clinical correlates of axis failure are summarized in reviews of adrenal insufficiency (Charmandari et al., 2014), which fall outside this entry's physiological scope and are cited for orientation.

History

Geoffrey Harris established in the mid-twentieth century that the hypothalamus controls the anterior pituitary through portal blood, the conceptual foundation of the axis. Guillemin and Schally subsequently isolated hypothalamic releasing hormones, and Wylie Vale's group characterized corticotropin-releasing hormone in 1981, completing the molecular description of the axis from hypothalamus to adrenal cortex.

Key figures

• Geoffrey Harris
• Roger Guillemin
• Andrew Schally
• Wylie Vale
• George Chrousos

Seminal works

• charmandari-2005
• dekloet-2005

Frequently asked questions

What does ACTH do at the adrenal gland?

ACTH binds the melanocortin 2 receptor on cortical cells, raising cAMP and stimulating cholesterol delivery through the StAR protein, which acutely drives cortisol synthesis and chronically maintains the steroidogenic capacity and size of the cortex.

How does negative feedback work in the HPA axis?

Cortisol acts back on the pituitary and hypothalamus to suppress ACTH and CRH secretion. As cortisol rises, this feedback dampens the drive to the adrenal cortex, keeping cortisol within a regulated range.