Congenital Disorders of Synthesis
Hereditary pathology is frequently represented by congenital adrenal hyperplasia (CAH).
The underlying mechanism is a genetic defect in enzymes, most commonly 21-hydroxylase deficiency. This blocks cortisol production. The body attempts to compensate for the deficit: negative feedback decreases, and the pituitary gland secretes excess adrenocorticotropic hormone (ACTH). This leads to adrenal cortex hyperplasia.
Cortisol precursors (such as 17-OH-progesterone) accumulate and are shunted toward androgen synthesis. Excess male sex hormones cause:
- in males — precocious puberty;
- in females — virilization (masculinization);
- in adult females (with partial deficiency) — menstrual cycle irregularities.
Primary Insufficiency
Primary hypofunction (Addison's disease) occurs when the cortical cells are damaged by tuberculosis or autoimmune processes.
Consequently, corticosteroid levels drop, prompting the pituitary gland to produce more ACTH and related peptides. Among these is melanocyte-stimulating hormone, which causes the characteristic hyperpigmentation of the skin and mucous membranes ("bronze skin disease").
Typical symptoms:
- low blood pressure (hypotension);
- decreased blood sodium levels (hyponatremia);
- severe muscle weakness and weight loss;
- poor tolerance to stressful situations.
Secondary Insufficiency and Withdrawal Syndrome
This form is typically iatrogenic and associated with long-term glucocorticoid treatment.
Exogenous drugs suppress the secretion of endogenous ACTH. Without stimulation, cortical cells gradually atrophy. If the medication is stopped abruptly, the patient's own adrenal glands cannot produce the required volume of hormones, leading to acute adrenal insufficiency (withdrawal syndrome).
Signs of a crisis:
- blood pressure drop leading to circulatory collapse and loss of consciousness;
- loss of sodium and chlorides in the urine, leading to severe dehydration;
- hypoglycemia (low blood sugar) and depletion of glycogen stores in muscles and the liver.
ACTH Mechanism of Action
Corticotropin regulates steroid synthesis via a complex intracellular cascade:
- Binding to a membrane receptor and activating the Gs protein.
- Triggering adenylate cyclase and generating the secondary messenger — cAMP.
- Activating protein kinase A.
- Releasing cholesterol from esters via cholesterol esterase.
- Transporting cholesterol into mitochondria by the StAR protein.
- Conversion to pregnenolone via the action of the desmolase enzyme complex.