Adrenocorticotropic hormone, also known as adrenocorticotropin, corticotropin, or simply ACTH, is a peptide hormone that helps regulate the release of hormones by the adrenal glands which sit above the kidneys. Secretion of ACTH is dependent on the hypothalamic-pituitary axis.
The hypothalamus, which is at the base of the brain, secretes corticotropin releasing hormone, or CRH, into the hypophyseal portal system - which is a network of capillaries linking the hypothalamus to the anterior part of the pituitary gland.
In the anterior pituitary, there are many different types of cells, each responsible for producing a type of hormone.
The corticotropin releasing hormone binds to a surface protein of one of these cell types, called corticotroph cells, and stimulates them to release ACTH.
Inside corticotroph cells, ACTH is synthesized from a large precursor molecule called pre- proopiomelanocortin, or pre- POMC.
Pre- proopiomelanocortin has a short tail called a leader or signal peptide which is cleaved off to form proopiomelanocortin, or POMC, and POMC is then split into multiple peptide hormones, and one of them is ACTH.
ACTH is then stored inside granules within the corticotroph cells, where it waits until it’s released into the blood.
Normally, ACTH is released in a pulsatile manner throughout the day and peaks in the morning around 6am but it is also secreted in response to various forms of stressful stimuli.
For example, the hypothalamus senses when there’s hypoglycemia or low blood sugar, and in response it secretes more corticotropin releasing hormone.
Another example, is during an infection, where pro-inflammatory cytokines, act on the hypothalamus and anterior pituitary to cause ACTH secretion.
Now, when ACTH is released it travels to the adrenal glands, which sit above each kidneys and binds to the ACTH receptor, also called melanocortin receptor 2, located in the membrane of their target cells which are adrenocortical cells.
Each gland is made up of an inner medulla, which secretes catecholamines, and an outer cortex.
The adrenal cortex itself is divided into three zones, each one secreting a different steroid hormone. The outermost zone is the zona glomerulosa, which secretes mineralocorticoids. Next, there’s the zona fasciculata, which secretes glucocorticoids, of which, cortisol is the most important one. And finally, there’s the zona reticularis that secretes androgens.
Zooming back into the adrenocortical cells, the ACTH receptor is a seven pass transmembrane receptor, meaning they are really long proteins that have one end that sits outside the cell and binds ACTH, then the snake- like protein dips in and out of the cell membrane seven times, and finally ends on the inside of the cell.
The end of the protein within the cell activates intracellular proteins. When ACTH binds to the ACTH receptor, it causes the adrenocortical cells to release corticosteroid hormones - mainly glucocorticoids, which have anti- inflammatory and metabolic effects, but also mineralocorticoids to some extent, which influence electrolyte and fluid balance.
Glucocorticoids are a class of steroid hormones, and the most important glucocorticoid in humans is cortisol.
Once it’s made, cortisol travels via the blood and binds to the glucocorticoid receptors, which are generally intracellular receptors within nearly every cell in the body. Cortisol helps to regulate both the immune response as well as cellular metabolism.
With regard to the immune response, cortisol promotes an overall anti- inflammatory state, by inhibiting the two main products of inflammation - prostaglandins and leukotrienes - as well as inhibiting interleukin-2 production by white blood cells.
In adipose tissue, cortisol triggers lipolysis, which is the breakdown of fats for energy, which can be used by other cells throughout the body.
In the liver, it promotes gluconeogenesis, which is the production of new glucose molecules, and increased glycogen storage.
