17 alpha-hydroxylase deficiency pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
Overview
Pathogenesis
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene CYP17A1, which encodes for the enzyme 17α-hydroxylase. It produces decreased synthesis of both cortisol and sex steroids, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild hypocortisolism, ambiguous genitalia in genetic males or failure of the ovaries to function at puberty in genetic females, and hypertension (respectively). This form of CAH results from deficiency of the enzyme 17α-hydroxylase (also called CYP17A1). It accounts for less than 5% of the cases of congenital adrenal hyperplasia. 17α-hydroxylase deficiency impairs the efficiency of cortisol synthesis, resulting in high levels of ACTH secretion and hyperplasia of the adrenal glands. Clinical effects of this condition include overproduction of mineralocorticoids and deficiency of prenatal and pubertal sex steroids. CYP17A1 functions in steroidogenesis, where it converts pregnenolone and progesterone to their 17-hydroxy forms. The enzyme itself is attached to the smooth endoplasmic reticulum of the steroid-producing cells of the adrenal cortex and gonads. CYP17A1 functions as both a 17α-hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations in cortisol and sex steroid synthesis:
- As 17α-hydroxylase it mediates pregnenolone → 17-hydroxypregnenolone
- and progesterone → 17-hydroxyprogesterone.
- As 17,20-lyase it mediates 17-hydroxypregnenolone → DHEA.
- An expected second 17,20-lyase reaction (17-hydroxyprogesterone → androstenedione) is mediated so inefficiently in humans as to be of no known significance.
Mineralocorticoid Effects
Genetics
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is inherited in an autosomal recessive manner. The most common abnormal alleles of this condition impair both the 17α-hydroxylase activity and the 17,20-lyase activity of CYP17A1.
