1. Steroidgenesis and Congenital Adrenal Hyperplasia
Clinical Chemistry by Marshall, 7th edition
Pages
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and Technology

2. Cholesterol is the precursor of all classes of steroid hormones:
Glucocorticoids (for example, cortisol)
Mineralocorticoids (for example, aldosterone),
sex hormones—androgens, estrogens, and progestins
Synthesis and secretion occur in the adrenal cortex (cortisol, aldosterone, and androgens), ovaries and placenta (estrogens and progestins), and testes (testosterone)
Steroid hormones are transported by the blood from their sites of synthesis to their target organs

3. Because of their hydrophobicity, they must be complexed with a plasma protein
Plasma albumin can act as a nonspecific carrier, and does carry aldosterone
However, specific steroid-carrier plasma proteins bind the steroid hormones more tightly than does albumin, for example, corticosteroid-binding globulin (transcortin) is responsible for transporting cortisol

4. Synthesis of steroid hormones
Synthesis involves shortening the hydrocarbon chain of cholesterol, and hydroxylation of the steroid nucleus
The initial and rate-limiting reaction converts cholesterol to the 21-carbon pregnenolone
It is catalyzed by the cholesterol side-chain cleavage enzyme complex (desmolase)—a CYP mixed function oxidase of the inner mitochondrial membrane
NADPH and molecular oxygen are required for the reaction
The cholesterol substrate can be newly synthesized, taken up from lipoproteins, or released from cholesteryl esters stored in the cytosol

5. An important control point is the movement of cholesterol into mitochondria
This process is mediated by StAR (steroidogenic acute regulatory protein
Pregnenolone is the parent compound for all steroid hormones
Pregnenolone is oxidized and then isomerized to progesterone
Progesterone is further modified to the other steroid hormones by hydroxylation reactions that occur in the ER and mitochondria
Like desmolase, the enzymes are CYP proteins

6. Action of ACTH on Cortisol Production
Gs AC
growth
ATP
cyclic AMP
cholesterol
ester
free cholesterol
PKA
IGF-II
P450scc
pregnenolone
cortisol

9. Adrenal steroidgenesis

10. Congenital Adrenal hyperplasia
A defect in the activity or amount of an enzyme in this pathway can lead to:
1. Deficiency in the synthesis of hormones beyond the affected step
An excess in the hormones or metabolites before that step
Because all members of the pathway have potent biologic activity, serious metabolic imbalances occur if enzyme deficiencies are present
Collectively these disorders are known as the congenital adrenal hyperplasias

11. Congenital adrenal hyperplasia (CAH)
21-Hydroxylase deficiency, with an incidence accounts for around 95% of all cases of CAH
It is caused by mutation in the CYP21 gene
The majority of the remaining 5% are due to deficiency of 11β-hydroxylase

12. Congenital adrenal hyperplasia
21-Hydroxylase deficiency is often incomplete, and adequate cortisol synthesis can be maintained by increased secretion of ACTH by the pituitary
This is what causes hyperplasia of the glands
Because of the metabolic block, the substrate of the enzyme (17α-hydroxyprogesterone) accumulates and there is increased formation of adrenal androgens

13. 21 hydroxylase defeciency
Female infants affected by CAH may be born with ambiguous genitalia
when the enzyme deficiency is only partial the condition may not present until early adulthood with hirsutism, amenorrhoea or infertility (late-onset CAH)

14. 21 hydroxylase defeciency
Males may present with pseudoprecocious puberty in their second or third year of life
In about one-third of neonates with 21 hydroxylase deficiency, the enzyme deficiency is complete
Complete deficiency present shortly after birth with a life-threatening salt-losing state, in which cortisol and aldosterone production are insufficient to maintain normal homoeostasis.

15. Diagnosis is made by demonstrating an elevated concentration of 17α-hydroxyprogesterone (17-OHP) in the plasma at least two days after birth
Treatment involves replacement of glucocorticoid or mineralcorticoid
This should suppress the excessive ACTH production and hence the excessive androgen synthesis

16. 11β-hydroxylase deficiency
Partial 11β-hydroxylase deficiency is also more common than complete deficiency of the enzyme
Increased androgen production causes virilization, which tends to be more severe than in 21-hydroxylase deficiency (but again is not present in males at birth)

17. 11β-hydroxylase deficiency
Hypertension develops, owing to the accumulation of 11-deoxycorticosterone
The diagnosis rests on the demonstration of an increased plasma concentration of either 11-deoxycortisol or its urinary metabolite
Treatment is with cortisol alone

18. Synthesis of testosterone

19. Conversion of testosterone into DHT