Congenital Adrenal Hyperplasia: Pathophysiology

A block in one of the enzymes that build cortisol removes the negative feedback on ACTH and diverts the accumulating precursors into androgens; the severity of the block determines the form of the disease.

From enzyme block to androgen excess

In the pathway that builds glucocorticoids in the zona fasciculata cells, 5 key enzymes are involved, and the most common mutation affects the 21-hydroxylase P450. The substrate of 21-hydroxylase in the glucocorticoid pathway is 17-hydroxyprogesterone, or 17-OHP. When 21-hydroxylase activity is missing or reduced, 17-OHP accumulates and is shunted into the androgenic pathway, which causes virilization (the development of male characteristics) through over-production of androgen.

Because there is not enough cortisol, the ACTH level is very high in these patients, which causes hyperplasia of the adrenal cortex and hyperpigmentation.

Different mutations leave different amounts of residual 21-hydroxylase activity, and the level of enzymatic activity is correlated with the onset of the disease. On this basis there are two forms of 21OHD CAH. Classical 21OHD CAH was described first and has an early onset at birth; it tends to result from two severely affected genes. Non-classical 21OHD CAH, also known as late-onset CAH, was described later and has a later onset during adolescence, because its mutations leave a low level of 21-hydroxylase activity where the salt-wasting classical form leaves almost none, and the simple-virilizing form only a little. Non-classical 21OHD CAH is more common than the classical form and tends to result from two mildly affected genes, or from one severely affected and one mildly affected gene.

A severe lack of 21-hydroxylase, which can be seen in classical 21-OHD CAH, can interfere with the normal pathway of production of mineralocorticoids. The result of aldosterone deficiency in these patients is called salt wasting.

Salt wasting happens mainly due to the lack of aldosterone, but another mechanism that can exacerbate this condition is the antagonistic effect of 17-OHP on the receptors of aldosterone in the distal convoluted tubules.

In vitro studies show that only 1% activity is enough for the formation of enough aldosterone, so salt wasters are the patients with a complete lack of 21-hydroxylase activity: they are the severely affected phenotypes of CAH, in whom almost no residual activity remains.

The activity of the adrenocortical region is initiated during fetal life at the 7th week of gestation, and the critical time for sexual differentiation is between the 9th and 12th week of gestation; therefore, in female patients with 21-hydroxylase deficiency who have accumulation of androgen in their body there is virilization of the external genitalia due to this non-physiological state.

The development of the external genitalia of the female can be affected by the level of androgen, while the internal genitalia are not affected by androgen. The development of the internal genitalia, which are the uterus, fallopian tubes, and ovaries, is Mullerian-dependent, and in CAH patients no anti-Mullerian hormone (AMH), which is produced by the Sertoli cells, is present.

The change that can be seen in male CAH patients is small testes, due to a low level of gonadotropin that is suppressed by the high level of androgen.

Other enzyme defects in the same pathway give distinct pictures, summarised below by enzyme, genitalia, mineralocorticoid effect, typical features and gene: