Understanding Cortisol: The Key Hormone of the Adrenal Glands

Cortisol, often referred to as the "stress hormone," plays a crucial role in regulating various bodily functions, including metabolism, immune response, and blood pressure. Produced by the adrenal glands, cortisol secretion is primarily controlled by the hypothalamic-pituitary-adrenal (HPA) axis. This intricate system ensures that cortisol levels fluctuate in response to the body's needs, with a typical daily rhythm characterized by high levels in the morning and lower levels at night.

One of the notable aspects of cortisol management is the measurement of urinary free cortisol (UFC). This method collects urine over a 24-hour period to assess glucocorticoid excess, as UFC accounts for approximately 1% of the total cortisol produced by the adrenal glands. The convenience of this test lies in its ability to bypass the fluctuations seen in serum cortisol levels due to variations in cortisol-binding globulin (CBG).

To understand how cortisol is synthesized, it is essential to consider the role of adrenocorticotropic hormone (ACTH), released by the anterior pituitary. ACTH is produced in response to corticotropin-releasing hormone (CRH) from the hypothalamus. When ACTH binds to its receptors on adrenal cortex cells, it activates pathways that increase the conversion of cholesterol to cortisol. Remarkably, this process can elevate cortisol levels within just five minutes after an increase in ACTH.

The synthesis of cortisol involves several key enzymes and intermediates, beginning with the transport of cholesterol into the mitochondria facilitated by the steroid acute regulatory (StAR) protein. The rate-limiting step in cortisol biosynthesis is the cleavage of the cholesterol side chain by the enzyme CYP11A1. Other enzymes, such as CYP17A1 and HSD3B2, play critical roles at various points in the steroidogenic pathway, influencing whether a steroid will be committed to cortisol or sex steroid precursors.

Cortisol's regulation is not only complex but also tightly controlled, as it exerts feedback effects on the hypothalamus and anterior pituitary to inhibit the production of CRH and ACTH. This feedback loop ensures that the body maintains appropriate levels of cortisol. Additionally, the circadian rhythm affects cortisol secretion, with levels peaking in the morning and gradually declining throughout the day. Given cortisol's short half-life of approximately one to two hours in the serum, random measurements of cortisol are generally ineffective for diagnostic purposes; instead, tests are typically scheduled for specific times during the day to capture the expected fluctuations.