The conversion of cholesterol in the zona fasciculata occurs sequentially, resulting in the production of pregnenolone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol. There is also a minor pathway in the zona fasciculata that bypasses 17-hydroxylation, leading to the conversion of progesterone to 11-deoxycorticosterone (DOC) and then corticosterone. Although this pathway is not significant in humans, it becomes more prominent when there is a lack of active CYP11B1 (11-hydroxylase activity). Elevated levels of DOC, which acts as a weak mineralocorticoid, can cause hypertension.

The transportation of cortisol in the bloodstream primarily involves its binding to corticosteroid-binding globulin (CBG) or albumin. CBG, also known as transcortin, binds around 90% of cortisol, while albumin binds approximately 5% to 7%. The liver is responsible for the inactivation of cortisol and the conjugation of active and inactive steroids with glucuronide or sulfate. This process allows for easier excretion of these steroids by the kidneys. The circulating half-life of cortisol is approximately 70 minutes.

The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the reversible inactivation of cortisol by converting it to cortisone. This inactivation occurs in cells that express the mineralocorticoid receptor (MR) and are also involved in steroidogenesis.

The enzymes involved in steroidogenesis can be classified into two superfamilies. Most of these enzymes belong to the cytochrome P-450 monooxidase gene family, also known as CYPs. These enzymes are located either in the inner mitochondrial matrix, where they use molecular oxygen and a flavoprotein electron donor, or in the smooth endoplasmic reticulum, where they utilize a different flavoprotein for electron transfer. Different CYP enzymes can function as hydroxylases, lyases (desmolases), oxidases, or aromatases. Two of these enzymes, CYP17 and CYP11B2 (aldosterone synthase), have multiple functions. CYP17 acts as both a 17-hydroxylase and a 17,20-lyase (desmolase), while CYP11B2 has functions as an 11-hydroxylase, 18-hydroxylase, and 18-oxidase.

The other enzymes involved in steroidogenesis belong to three hydroxysteroid dehydrogenase (HSD) families. The 3β-HSDs have two isoforms that convert the hydroxyl group on carbon 3 of the cholesterol ring to a ketone and shift the double bond from the 5-6 (Δ5) position to the 4-5 (Δ4) position. All active steroid hormones must be converted to Δ4 structures by 3β-HSD. The 17β-HSDs, consisting of at least five members, can function as either oxidases or reductases. They primarily act on sex steroids and can have activating or deactivating effects. Lastly, the 11β-HSDs have two isoforms that catalyze the interchange between cortisol (active) and cortisone (inactive).
Inthezonafasciculata,cholesterolisconvertedsequentially to pregnenolone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol (Figs. 43.8 43.9 ). A parallel pathway in the zona fasciculata involves a pathway that bypasses 17-hydroxylation, in which progesterone is converted to 11-deoxycorticosterone (DOC) and then to corticosterone (see
Fig. 43.9C ). This pathway is minor in humans, but in the absence of active CYP11B1 (11-hydroxylase activity), the production of DOC is significant. Because DOC acts as a weak mineralocorticoid ( 43.3 ), elevated levels of DOC cause hypertension.
Transport and Metabolism of Cortisol
Cortisol is transported in blood predominantly bound to corticosteroid-binding globulin [CBG] (also called transcortin), which binds about 90% of cortisol, and albumin, which binds 5% to 7% of cortisol. The liver is the predominant site of steroid inactivation. It both inactivates cortisol and conjugates active and inactive steroids with glucuronide or sulfate so that they can be excreted more readily by the kidney. The circulating half-life of cortisol is about 70 minutes.
Cortisol is reversibly inactivated by conversion to cortisone. This action is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Inactivation of cortisol by 11β-HSD2 occurs in cells that also express the mineralocorticoid receptor (MR)and are
Steroidogenicenzymesfallintotwosuperfamilies.Mostbelongtothecytochrome P-450 monooxidase gene family andarethusreferredtoasCYPs. Theseenzymesarelocatedeitherintheinnermitochondrialmatrix,wheretheyusemolecularoxygenandaflavoproteinelectrondonor,orinthesmoothendoplasmicreticulum,wheretheyuseadifferentflavoproteinforelectrontransfer.DifferentCYPenzymesactashydroxylases,lyases(desmolases),oxidases,oraromatases.Twooftheseenzymeshavemultiplefunctions.CYP17hasbotha17-hydroxylasefunctionanda17,20-lyase(desmolase)function.CYP11B2,alsocalledaldosterone synthase, hasthreefunctions:11-hydroxylase,18-hydroxylase,and18-oxidase.
Theotherenzymesinvolvedinsteroidogenesisbelongtothreehydroxysteroid dehydrogenase (HSD)families.3β-HSDs havetwoisoformsthatconvertthehydroxylgrouponcarbon3ofthecholesterolringtoaketoneandshiftthedoublebondfromthe5-6(Δ5) positiontothe4-5(Δ4) position.AllactivesteroidhormonesmustbeconvertedtoΔ4structuresby3β-HSD.The17β-HSDs haveatleastfivemembersandcanactaseitheroxidasesorreductases.17β-HSDsprimarilyactonsexsteroidsandcanbeactivatingordeactivating.Finally,the11β-HSDs havetwoisoformsthatcatalyzetheinterchangebetweencortisol(active)andcortisone(inactive).