Congenital synthesis disorders
Hereditary pathology is frequently represented by congenital adrenal hyperplasia (CAH).
The underlying cause is a genetic enzyme defect, most commonly a shortage of 21-hydroxylase. This blocks the production of cortisol. The body attempts to compensate for the deficiency: negative feedback decreases, and the pituitary gland secretes excess corticotropin (ACTH). This leads to hyperplasia of the adrenal cortex.
Cortisol precursors (e.g., 17-OH-progesterone) accumulate and are redirected toward androgen synthesis. Excess male sex hormones cause:
- in boys — precocious puberty;
- in girls — development of male features (virilization);
- in adult women (with partial deficiency) — menstrual irregularities.
Primary insufficiency
Primary hypofunction (Addison's disease) occurs when the cortical cells are damaged by tuberculosis or an autoimmune process.
Consequently, corticosteroid levels drop, prompting the pituitary gland to produce more ACTH and related peptides. Among them is melanocyte-stimulating hormone, which causes characteristic hyperpigmentation of the skin and mucous membranes ("bronze skin disease").
Typical symptoms:
- low blood pressure (hypotension);
- drop in blood sodium levels (hyponatremia);
- severe muscle weakness and weight loss;
- poor tolerance to stressful situations.
Secondary insufficiency and withdrawal syndrome
This form is usually iatrogenic in nature and associated with long-term glucocorticoid treatment.
Exogenous drugs suppress the secretion of endogenous ACTH. Without stimulation, the cortical cells gradually atrophy. If the medications are abruptly discontinued, the native adrenal glands will be unable to produce the required volume of hormones, leading to acute adrenal insufficiency (withdrawal syndrome).
Signs of crisis:
- drop in blood pressure down to collapse and loss of consciousness;
- loss of sodium and chlorides in urine, leading to severe dehydration;
- hypoglycemia (low blood sugar) and depletion of glycogen stores in muscles and liver.
Mechanism of ACTH action
Corticotropin controls steroid synthesis through a complex intracellular cascade:
- Binding to the membrane receptor and activation of the Gs protein.
- Triggering adenylate cyclase and generating the secondary messenger — cAMP.
- Activation of protein kinase A.
- Release of cholesterol from esters via cholesterol esterase.
- Transport of cholesterol into mitochondria by the StAR protein.
- Conversion to pregnenolone involving the desmolase enzyme.
Briefly: answers to topical questions
Which enzymes, besides 21-hydroxylase, can lead to congenital adrenal hyperplasia when hereditarily deficient?
In addition to 21-hydroxylase, hereditary 11β-hydroxylase deficiency can lead to congenital adrenal hyperplasia. This enzyme defect blocks the synthesis pathway of cortisol and aldosterone. The reduction in cortisol synthesis eliminates negative feedback, causing the pituitary gland to compensatorily produce excess ACTH. As a result, steroidogenesis precursors accumulate and are shunted into the androgen synthesis pathway, causing virilization.
In which histological zones of the adrenal cortex are aldosterone, cortisol, and androgens synthesized?
Aldosterone, cortisol, and androgens are synthesized in three distinct morphofunctional zones of the adrenal cortex.
- Aldosterone — synthesized in the zona glomerulosa of the cortex (belongs to mineralocorticoids).
- Cortisol — produced in the zona fasciculata (belongs to glucocorticoids).
- Androgens — formed in the zona reticularis (main representatives are dehydroepiandrosterone and its sulfate).
How exactly is the dexamethasone suppression test performed for the differential diagnosis of Cushing's syndrome and Cushing's disease?
Differential diagnosis is performed by administering dexamethasone followed by evaluating changes in urinary 17-ketosteroid concentrations. The high-dose dexamethasone suppression test involves taking 2 mg of the drug every 6 hours for 3 days (total dose 24 mg).
| Abnormal | Mechanism | Result (17-ketosteroids) |
|---|---|---|
| Cushing's disease | The pituitary gland retains sensitivity to inhibition by glucocorticoids | Decrease (positive test) |
| Cushing's syndrome | The adrenal tumor secretes hormones autonomously | No change (negative test) |
Which peptides and hormones are formed from pro-opiomelanocortin (POMC) along with ACTH?
According to the sources, derivatives formed from pro-opiomelanocortin (POMC) include: ACTH, α-melanocyte-stimulating hormone, and γ-melanocyte-stimulating hormone. These POMC derivatives act as endogenous antipyretics; their mechanism is described as the modulation of neuronal activity in the septal region and other brain areas transmitting signals to the thermoregulatory center. In Addison's disease, increased pigmentation of the skin and mucous membranes is associated with elevated production of corticotropin and other POMC derivatives, particularly melanocyte-stimulating hormone.
Class and exam questions
Why does the skin darken in Addison's disease?
Due to cortisol deficiency, the pituitary gland intensely produces ACTH and other pro-opiomelanocortin derivatives. Melanocyte-stimulating hormone is released alongside them, which enhances pigmentation.
Why is abrupt discontinuation of corticosteroids dangerous?
The native adrenal cortex is atrophied and does not produce cortisol. An acute crisis occurs with sodium loss, dehydration, hypoglycemia, and risk of vascular collapse.
How to distinguish Cushing's disease from a hormone-secreting tumor?
The dexamethasone suppression test helps. In Cushing's disease, it suppresses ACTH production, and steroid levels decrease. An autonomous tumor, however, continues to function, and hormone levels will not change.
What else to study on this topic
- Stages of cortisol synthesis (from cholesterol to 11-deoxycortisol)
- Effect of cortisol on gluconeogenesis
- Functions of aldosterone and mineralocorticoid metabolism
- Adrenal androgen metabolism (17-ketosteroids)
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