Adrenal Cortex Hormone Biosynthesis
Overview
- Adrenal cortex hormones, which are steroid hormones that regulate water and salt balance, blood sugar, and sexual characteristics, among other actions.
- Production of these hormones occurs in the mitochondria and smooth endoplasmic reticulum, and requires several enzymes, most of which belong to the family of cytochrome P-450 oxidases.
- As we'll see, some key enzymes are only present in specific layers, which is why the layers produce different hormones.
- Adrenal capsule and cortex sublayers:?
– The zona glomerulosa, which produces mineralocorticoids.
– The zona fasciculata, which produces glucocorticoids.
– The zona reticularis, which produces androgens.
Pathways
- Begin at the top of the diagram with cholesterol, which is the precursor for all steroid hormones.
– The adrenal gland can synthesize cholesterol, but the primary source of cholesterol is circulating LDL.
Show that cortisol entry into adrenocortical cell mitochondria is facilitated by a transport protein called the steroidogenic acute regulatory protein – StAR*.
Show that cholesterol side chain cleavage* cleaves cholesterol to form
pregnenolone.
– This step occurs in all layers of the adrenal cortex, and is upregulated by ACTH.
- From here, the pathway depends on the available enzymes.
We'll first follow the pathway that leads to the production of aldosterone, the primary mineralocortioid, in the zona glomerulosa.
So, show that pregnenolone is oxidized by 3 beta-hydroxysteroid dehydrogenase (3B-HDS)* to form
progesterone.
- Be aware that 3 beta-hydroxysteroid dehydrogenase, which plays a role in each layer of the adrenal cortex, is the only non-P-450 enzyme we'll see in this diagram; we'll come back to this point, later.
Next, show that, within the zona glomerulosa, 21 alpha-hydroxylase* converts progesterone to
11-deoxycortisterone (DOC), which is a weak mineralocorticoid.
Then, 11 beta-hydroxylase* converts 11-deoxycorticosterone to
corticosterone.
Lastly, show that aldosterone synthase,* which is only present in the zona glomerulosa, converts corticosterone to
aldosterone, the main mineralocorticoid.
Show that angiotensin II facilitates aldosterone production* in both early and late stages of aldosterone synthesis: like ACTH, it increases cholesterol side chain cleavage enzyme activity, and, it uniquely increases the activity of aldosterone synthase.
Be aware that elevated potassium* also increases aldosterone synthesis.
Now, let's learn about cortisol production in the zona fasciculata.
First, return to progesterone, and show that, in the presence of 17 alpha-hydroxylase,* which is present in the zona fasciculata, progesterone is converted to
17-hydroxyprogesterone.
- Pause and show another pathway to 17-hydroxyprogesterone formation:
– Return to pregnenolone, and show that
17 alpha-hydroxylase converts it to
17-hydoxypregnenolone, which, in the presence of
3 beta-hydroxysteroid dehydrogenase, is converted to
17-hydroxyprogesterone!
Next, show that, in the presence of 21 alpha-hydroxylase*, 17-hydroxyprogesterone is converted to
11-deoxycortisol.
Then, show that 11 beta-hydroxylase* adds a hydroxl to 11-deoxycortisol to produce
cortisol, the primary glucocorticoid.
Finally, let's see the pathway for adrenal androgen biosynthesis.
Return to 17-hydroxypregnenolone, and show that, in the presence of 17 alpha-hydroxylase*, it is converted to
dehydroepiandrosterone (DHEA).
– Be aware that some texts show this step occurring via 17,20 desmolase, aka, 17,20-lase; however, because these enzymes are encoded by the same gene as 17 alpha-hydroxylase, we can consider them to be the same enzyme for simplicity.
Next, show that DHEA is converted to Androstenedione (A4) by 3 beta-hydroxysteroid dehydrogenase*.
- Pause to show another pathway to A4:
– 17-hydroxyprogesterone, which we saw in the pathway to cortisol biosynthesis, can be converted to androstenedione by 17 alpha-hydroxylase.
- Show that androstenedione is a precursor to testosterone, which is only minimally produced by the adrenal glands.
Sex steroids in the Peripheral Tissues
- Relatively weak adrenal androgens are converted to stronger sex hormones in the peripheral tissues:
– Androstenedione and testosterone are converted to
estrone and
estradiol, respectively, via
aromatase.
– Testosterone is converted to
dihydrotestosterone (DHT) via
5 alpha-reductase.
Be aware that, although the adrenal glands are not the primary source of androgens in adult males, they are a significant source of androgens in children and women.*
Key Enzymes
3 beta-hydroxysteroid dehydrogenase*, which we indicated is involved in the production of all three hormone groups (mineralocorticoids, glucocorticoids, and androgens).
–
Non-P-450 enzyme.
- The rest of the enzymes we'll show are P-450 enzymes and the gene names for each of these enzymes (some texts refer to them this way).
Cholesterol side-chain-cleavage*, aka, P-450SCC, gene name CYP11A1.
– Recall that this enzyme was involved in the very early steps of steroid hormone biosynthesis, so it is a rate-limiting enzyme for all steroid hormones.
– Be aware that this enzyme is sometimes called cholesterol desmolase.
11 beta-hydroxylase*, aka, P-450-C11, gene name CYP11B1.
– Notice that this enzyme is active in the formation of both aldosterone and cortisol, but not the androgens.
– Another way to think of this is that this enzyme is only present in the zona glomerulosa and zona fasciculata.
17 alpha-hydroxylase*, aka, P450-C17, gene name CYP17.
– This enzyme is active in the production of cortisol and androgens, but not in the production of aldosterone
– 17 alpha-hydroxylase is not significantly present in the zona glomerulosa.
21 alpha-hydroxyalse*, aka, P-450-C21, gene name CYP21A2.
– Notice that this enzyme is involved in the production of aldosterone and cortisol.
Aldosterone synthase*, aka, P-450-Aldo, gene name CYP11B2.
– Recall that this enzyme is only present in the zona glomerulosa, and is responsible for the final steps of aldosterone synthesis.
Enzyme Deficiencies
- Generally speaking, when one enzyme is absent, its downstream hormone products are not synthesized, but upstream precursors and, therefore, other hormones, are produced in excess.
– We'll address the causes and consequences of these deficiencies elsewhere (i.e., congenital adrenal hyperplasia).
- Deficiency of 11 beta-hydroxylase:
– Both
aldosterone and cortisol levels are decreased.
–
Upstream hormones, such as 11-deoxycortisol, are increased.
– 11-deoxycortisol is a weak mineralocorticoid, but show that, in excessive quantities, it can cause
hypertension, hypokalemia, and reduced renin activity (remember that blood pressure follows aldosterone).
–
Androgen production is increased due to excessive quantities of "upstream" hormones in the shared pathway.
In females, increased androgen production leads to virilzation (the development of "masculine" characteristics, like increased muscle mass and body hair); in male children, look for precocious puberty.
- Deficiency of 17 alpha-hydroxylase:
–
Decreased cortisol and androgen production, and, therefore, increased mineralocorticoid production.
– Increased mineralocorticoid production (i.e., DOC) leads to
hypertension and hypokalemia.
– Congenital 17 alpha-hydroxylase deficiency produces ambiguous genitalia with undescended testes in males, and in females, lack of secondary sex characteristics.
- Deficiency of 21 alpha-hydroxylase:
– Reduced mineralocorticoid and cortisol production.
– Thus, potassium levels, renin action, and androgen levels will be elevated, but
blood pressure will be low due to decreased mineralocorticoid action.
– Indicate that reduced aldosterone will cause
salt wasting, and, in females, increased androgen secretion will cause
virilization.
- Shortcut:
- Notice that androgens are increased when the deficient enzyme ends in 1 (both 11 beta-hydroxylase and 21 alpha-hydroxylase deficiencies lead to virilization).
- When the deficient enzyme starts with 1, hypertension can occur (both 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies are associated with increased blood pressure).
Key Drugs:
- Ketoconazole, which is an antifungal drug, blocks steroid hormone synthesis by inhibiting cholesterol side chain cleavage.
- Metyrapone blocks cortisol production via inhibition of 11 beta-hydroxylase; thus, it is used to treat hypercortisolemia.
- Anastrozole and letrozole inhibit aromatase, thereby inhibiting estrone and estradiol production; these drugs can be used as part of anti-breast cancer treatments.
- Finasteride blocks 5 alpha-rectuase, and, therefore, conversion of testosterone to dihydrotestosterone; finasteride, aka, propecia, is used to treat enlarged prostate and male hair loss.
For full references, please see the tutorial on Adrenal Cortex Hormone Biosynthesis.
