Steroidgenesis and Congenital Adrenal Hyperplasia Clinical Chemistry by Marshall, 7th edition Pages 149-150 Mahmoud A. Alfaqih BDS PhD Jordan University of Science and Technology

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

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

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

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

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

Adrenal steroidgenesis

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

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

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

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)

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.

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

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)

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

Synthesis of testosterone

Conversion of testosterone into DHT