Sources and Initial Stage of Biosynthesis
Absolutely all corticosteroids derive from a single molecule: cholesterol ($C_{27}$). Adrenal cortex cells obtain cholesterol from two main sources: by taking up cholesterol esters circulating in the blood as part of low-density lipoproteins (LDL), or by utilizing their own intracellular stores of deposited esters.
The synthesis process is localized in different compartments of the adrenal cortex cells. It is triggered by corticotropin (adrenocorticotropic hormone, ACTH). This regulatory hormone performs a dual function: first, it stimulates the release of free cholesterol from its esters, and second, it activates the corticosteroid synthesis cascade itself.
The first biochemical step is the conversion of 27-carbon cholesterol into 21-carbon pregnenolone. The mechanism of this reaction involves the oxidation of the 20th carbon atom ($C_{20}$) followed by the cleavage of a 6-carbon fragment from the side chain of the cholesterol molecule.
Path Divergence: Progesterone and Hydroxylases
The resulting pregnenolone ($C_{21}$) serves as an intermediate. It is rapidly converted into progesterone ($C_{21}$), which acts as a biochemical "crossroads." The future fate of progesterone and the final product depend on the set of enzymes present in a specific cell and the sequence of reactions.
The key enzymes at this stage are hydroxylases. Their task is to sequentially attach hydroxyl (–OH) groups to the steroid core.
The main pathways of progesterone conversion:
- Cortisol synthesis ($C_{21}$): The main glucocorticoid is formed through the sequential action of three enzymes. First, progesterone undergoes hydroxylation by 17-hydroxylase, then 21-hydroxylase acts, and the process is completed by 11β-hydroxylase.
- Aldosterone synthesis ($C_{21}$): To produce the primary mineralocorticoid, progesterone is hydroxylated by only two enzymes: first 21-hydroxylase, and then 11β-hydroxylase.
- Androgen synthesis: An alternative pathway producing steroids containing 19 carbon atoms ($C_{19}$). Testosterone is a prominent final product of this pathway.
Regulation, Transport, and Catabolism
The rate at which cortisol is synthesized and secreted is a strictly regulated parameter in the body. This is managed by the hypothalamic-pituitary-adrenal (HPA) axis, which operates via a negative feedback mechanism: once hormone levels reach the target threshold, further synthesis is inhibited.
Once secreted by the adrenal glands, steroid hormones enter the bloodstream. Due to their lipophilic nature, they cannot dissolve freely in plasma; therefore, they are transported exclusively bound to specific carrier proteins.
Used hormones undergo elimination. The primary site of their catabolism is the liver. It is here that inactivation reactions of corticosteroids take place. The main biochemical reactions at this stage are hydroxylation and oxidation, rendering them biologically inactive and preparing them for excretion from the body.