What do the three causes have in common?
Each of these causes is one gland producing too much of one hormone. Three hormones are involved: aldosterone, catecholamines and cortisol, and each raises blood pressure by a different route. For each cause the useful questions are the same: how often is it found, which patients are at higher risk, and how does the excess hormone raise blood pressure?
How does too much aldosterone raise pressure?
The commonest endocrine cause is primary aldosteronism, also called primary hyperaldosteronism. In it, aldosterone is produced in amounts that the renin–angiotensin system no longer restrains. Normally that system switches aldosterone off when volume is adequate; in the disease the gland keeps producing it regardless.
Aldosterone acts on the mineralocorticoid receptor in the distal nephron, where it reclaims sodium and secretes potassium. Sodium uptake there leaves a negative charge in the tubular lumen, which pulls potassium out into the urine. Reabsorbed sodium takes water with it, so excess aldosterone expands the circulating volume and raises blood pressure. The potassium lost in the urine can produce hypokalemia.
Aldosterone also acts directly on the heart and blood vessels, where it promotes inflammation and fibrosis. So cardiovascular damage is not only a result of the high pressure, and this direct action explains why cardiovascular harm outlasts the pressure itself.
Who is more likely to have primary aldosteronism, and why does it matter to find it?
Because aldosterone reaches the heart and vessels directly, finding the condition matters, and it is easy to miss. Among patients with mild to moderate hypertension without hypokalemia, the prevalence of primary hyperaldosteronism is about 3%. Potassium is often normal, and certain groups are worth monitoring because the prevalence is higher in them. These are the settings where pressure is hard to control or where the picture points to hormone excess:
- resistant hypertension, where the prevalence is about 20%
- diuretic-induced hypokalemia
- spontaneous hypokalemia
- a family history of early-onset hypertension and stroke
- concomitant hypertension and adrenal incidentalomas
- concomitant hypertension and sleep apnea
Patients with primary aldosteronism have a higher risk of cardiovascular events than patients with essential hypertension matched for blood pressure level. A proposed link is the direct action of aldosterone on heart and vessels described above. Studies show that early diagnosis reverses the excessive cardiovascular morbidity. The higher cardiovascular risk and its reversal with early diagnosis underline the importance of early diagnosis.
How does a pheochromocytoma raise pressure?
The second hormone comes from a different gland and acts on vessels and heart through receptors rather than on the kidney. A pheochromocytoma is a tumour of the chromaffin cells of the adrenal medulla. It releases catecholamines, mainly adrenaline and noradrenaline. The release may be continuous or in bursts; in the literature noradrenaline tends to be released continuously and adrenaline in bursts.
Catecholamines raise blood pressure in two ways. They cause vasoconstriction through alpha receptors, which raises vascular resistance. They also increase heart rate and contractility through beta-1 receptors, so cardiac output rises.
The release is often paroxysmal rather than steady, and blood pressure follows hormone release. That is why the classic picture is episodic, with headaches, palpitations and profuse sweating, rather than a uniformly high reading. Between the attacks the reading may be lower.
Pheochromocytoma is uncommon among hypertensive patients, with a prevalence of about 0.2%. About 15% of patients with pheochromocytoma are normotensive, so normal blood pressure does not exclude the tumour. A tumour that secretes mainly dopamine or little hormone, or chronically high noradrenaline that may downregulate receptors, may give a milder picture.
How does too much cortisol raise pressure?
The third hormone works through several routes, one of which borrows the receptor of aldosterone. Hypercortisolism means excess cortisol, as in Cushing syndrome, and it is a common cause of secondary hypertension. About 80% of adults with hypercortisolism manifest hypertension, and half of children do.
Cortisol raises blood pressure through several mechanisms acting together:
- Mineralocorticoid receptor. Cortisol can occupy the mineralocorticoid receptor and mimic aldosterone, retaining sodium. The receptor binds cortisol with an affinity similar to that of aldosterone, and cortisol is far more abundant. In the kidney, the enzyme 11β-hydroxysteroid dehydrogenase type 2 turns cortisol into inactive cortisone and so keeps it off the receptor. Whenever cortisol overwhelms this enzyme, it acts like aldosterone.
- Angiotensinogen. Cortisol increases the liver’s production of angiotensinogen, the substrate of the renin–angiotensin system, so the system runs at a higher level.
- Cardiac output. Cortisol raises cardiac output through a direct glucocorticoid effect.
- Prostaglandins. Cortisol reduces the production of vasodilator prostaglandins by inhibiting phospholipase A. With fewer vasodilators, the vessels stay more constricted.
Hypertension can outlast the treatment of the hormone excess: after treatment of hypercortisolism in Cushing syndrome, about 30% of patients have persistent hypertension. Prolonged cortisol excess is thought to cause vascular remodelling and fibrosis, which may explain why the pressure persists after cure, and children may be prone to remodelling.
If each hormone drives pressure by its own route, how is each excess removed or blocked?