ACTH Cortisol and the HPA Axis explained | Osmosis

Short summary

This Osmosis video from Elsevier explains the hypothalamic pituitary adrenal axis, detailing how corticotropin releasing hormone CRH triggers ACTH release, how ACTH acts on the adrenal cortex, and how cortisol mediates immune and metabolic effects. It also covers adrenal cortex anatomy, the processing of the ACTH precursor, and the feedback loops that regulate this hormonal cascade.

• ACTH is produced from the large precursor Preproopiomelanocortin and stored in corticotroph granules until release.
• The hypothalamus secretes CRH into the portal system to stimulate ACTH release from the anterior pituitary.

Overview

This Osmosis video from Elsevier provides a comprehensive walkthrough of the hypothalamic pituitary adrenal axis, detailing how corticotropin releasing hormone CRH stimulates adrenocorticotropic hormone ACTH release, how ACTH drives adrenal steroid production, and how cortisol coordinates immune and metabolic responses.

ACTH synthesis and processing

ACTH is generated in corticotroph cells from a large precursor called Preproopiomelanocortin POMC. The precursor contains a short leader peptide that is cleaved to form Propiomelanocortin and then POMC. POMC is further processed to yield ACTH among other peptide hormones. ACTH is stored in granules within corticotrophs and released in pulsatile bursts rather than a steady stream.

The HPA axis and receptor signaling

The hypothalamus releases corticotropin releasing hormone CRH into the hypophyseal portal system, a network of capillaries linking the hypothalamus to the anterior pituitary. CRH binds to receptors on corticotroph cells, triggering ACTH secretion. ACTH then travels via the bloodstream to the adrenal glands and binds to the ACTH receptor MC2R, a seven pass transmembrane receptor on adrenocortical cells. This receptor activates intracellular signaling pathways that culminate in steroid synthesis.

Adrenal cortex anatomy

The adrenal gland comprises an inner medulla and an outer cortex divided into three zones. The outermost zona glomerulosa secretes mineralocorticoids, the middle zona fasciculata secretes glucocorticoids with cortisol as the principal one, and the innermost zona reticularis produces androgens. ACTH primarily drives cortisol production in the fasciculata, while other factors more directly regulate mineralocorticoids in the glomerulosa.

Cortisol actions and broad effects

Glucocorticoids like cortisol have potent anti inflammatory and metabolic effects. After cortisol passes through cell membranes, it binds to intracellular glucocorticoid receptors present in nearly every cell. This binding suppresses inflammation by reducing brain prostaglandins and leukotrienes and inhibiting Interleukin 2 production in white blood cells. Metabolically, cortisol promotes lipolysis in adipose tissue, supports gluconeogenesis in the liver, and increases insulin resistance in peripheral tissues. It also modulates vascular responsiveness, supports brain function under stress, and influences memory and mood. Cortisol can hinder bone formation by affecting osteoblasts, reduce collagen synthesis, and impair wound healing by inhibiting fibroblasts. Cortisol’s systemic actions help maintain glucose homeostasis and blood pressure during stress, while excess cortisol can contribute to metabolic disturbances and immune suppression.

Feedback regulation

Multiple negative feedback loops control the axis. Glucocorticoids signal the hypothalamus to reduce CRH production, which in turn lowers anterior pituitary ACTH release. Cortisol can also directly inhibit ACTH synthesis in corticotroph cells and may influence the synthesis of the ACTH precursor PREPROOPIOMELANOCORTIN. These mechanisms prevent excessive hormonal output and stabilize cortisol levels across the day and in response to stress.

Melanocortin signaling and clinical relevance

Beyond stimulating the adrenal cortex via MC2R, ACTH can activate other melanocortin receptors, including MC1, which is involved in skin pigmentation. Excess ACTH can lead to skin bronzing in certain disorders, highlighting the pleiotropic roles of the same peptide in different tissues.

Wrap up

In sum, the video maps the pathway from hypothalamus to adrenal cortex, clarifying how ACTH triggers glucocorticoid production and how cortisol orchestrates anti inflammatory and metabolic responses while exercising tight hormonal control through feedback loops.