New perspectives on congenital adrenal hyperplasia: current concepts in pathophysiology, fertility and therapeutic advances

Background CAH (Congenital Adrenal Hyperplasia) is a group of hereditary disorders of steroidogenesis, most commonly caused by 21-hydroxylase deficiency. The disease leads to abnormal cortisol and/or aldosterone synthesis, as well as excessive androgen production. The clinical manifestations are varied and depend on the type and severity of the enzyme deficiency. Pathomechanism An impairment of the adrenal cortex hormone biosynthesis pathway underlies CAH. The enzyme deficiency causes an increase in ACTH (Adrenocorticotropic Hormone) level, leading to compensatory adrenal hypertrophy and overproduction of androgen precursors. This results in masculinisation of the genitalia in girls, precocious virilisation in boys and water and electrolyte disturbances. Fertility Endocrine disorders and steroid treatment may exert an adverse effect on the fertility of CAH patients. Impaired ovulation is observed in women and reduced quality of semen in men, often due to the presence of TARTs (Testicular Adrenal Rest Tumours). However, with appropriately managed treatment, it is possible to preserve or restore reproductive function. Treatment Substitution of glucocorticoids (hydrocortisone) and mineralocorticoids remains the mainstay of treatment. Prenatal treatment with dexamethasone remains controversial and is only available under certain conditions. New therapeutic directions includes continuous subcutaneous infusion of hydrocortisone, modifies-release preparations of hydrocortisone, selective ACTH receptor modulators, androgen synthesis inhibitors (e.g. abiraterone), gene therapies and drugs modifying the activity of steroidogenesis enzymes.