Primary adrenal insufficiency

Primary adrenal insufficiency occurs when the adrenal glands fail to produce key hormones like glucocorticoids and mineralocorticoids.

It can be acute, also known as adrenal crisis, and chronic, which is referred to as Addison disease.

Now, each of the two adrenal glands sits on top of a kidney and has two main parts:

The inner part, the medulla, produces the hormones epinephrine and norepinephrine.

On the flip side, the outer part, the cortex, has three layers.

The outermost layer, the zona glomerulosa, produces mineralocorticoids, such as aldosterone. With mineralocorticoids, “mineralo-” refers to minerals, because these hormones help regulate sodium and potassium levels.

The middle layer, the zona fasciculata, produces glucocorticoids, like cortisol. With glucocorticoids, “gluco-” refers to glucose, because they help increase blood glucose levels.

The innermost layer, the zona reticularis, produces androgens, such as dehydroepiandrosterone, which is a precursor of testosterone.

Now, the inner and middle layers of the cortex are mainly under the control of the hypothalamus-pituitary-adrenal axis.

The hypothalamus releases corticotropin-releasing hormone, which stimulates the corticotrophs in the anterior pituitary gland. Corticotrophs then produce pro-opiomelanocortin or POMC.

Next, corticotrophs cleave this protein into melanocyte-stimulating hormone and adrenocorticotropic hormone or ACTH.

Melanocyte-stimulating hormone stimulates the melanocytes in the skin to release melanin, which can darken skin pigmentation.

On the flip side, ACTH travels through the bloodstream to the adrenal glands, where it stimulates the zona reticularis to release androgens and the zona fasciculata to release cortisol, which plays a big role in metabolism.

On one hand, cortisol signals the liver to convert amino acids into glucose; on the other, it reduces glucose uptake in peripheral tissues. Together, these actions raise blood sugar levels.

Cortisol also promotes protein synthesis in the liver, while breaking down proteins in muscles.

In addition, it increases the breakdown of triglycerides in fat tissue, releasing free fatty acids into the bloodstream for energy.

By balancing glucose, protein, and fat metabolism, cortisol helps mobilize sources during stressful situations, like when you are tackling the USMLE exam.

Also, it helps regulate the immune response and reduces inflammation to prevent overreaction when you are under stress.

On the other hand, the zona glomerulosa is controlled by the renin-angiotensin-aldosterone system.

When blood pressure or sodium levels drop, the juxtaglomerular cells in the kidneys release renin into the bloodstream.

In the bloodstream, renin cleaves angiotensinogen into angiotensin I, which is later converted by angiotensin-converting enzyme or ACE, into angiotensin II.

Angiotensin II raises blood pressure through two mechanisms.

First, it triggers vasoconstriction of small arterioles, subsequently increasing peripheral vascular resistance.

Also, angiotensin II stimulates the zona glomerulosa to release aldosterone.

In the kidneys, aldosterone increases sodium and water uptake, boosting the intravascular volume and maintaining blood pressure.

At the same time, it stimulates potassium excretion. That’s why high potassium levels can also trigger aldosterone release.

In primary adrenal insufficiency, the hypothalamus and pituitary gland work normally, but the adrenal glands fail to respond, resulting in glucocorticoid and mineralocorticoid deficiency.

In secondary adrenal insufficiency, the hypothalamus sends signals, but the pituitary gland drops the ball and doesn’t pass it to the adrenal glands.