ALDOSTERONE - steroid hormone, mineralocorticoid hormone
Many important physiological functions of vertebrates are controlled by steroid hormones. Aldosterone is a steroid hormone secreted by the adrenal glands and a component of the renin-angiotensin-aldosterone system, involved in sodium and potassium homeostasis and in the maintenance of blood pressure. Aldosterone serves as the principal regulator of the salt and water balance of the body and thus is also categorized as a mineralocorticoid. It has effects on the metabolism of fats, carbohydrates, and proteins.
Aldosterone is a mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex that influences water and salt regulation in the body. Aldosterone is created from cholesterol within the zona glomerulosa of the adrenal glands. Aldosterone's primary function is to act on the late distal tubule and collecting duct of nephrons in the kidney, favoring sodium and water reabsorption and potassium excretion while also contributing to acid-base balance. To execute these tasks, it influences epithelial sodium channels, sodium-potassium exchange pumps, hydrogen ion ATPases, and bicarbonate-chloride antiporters. Cholesterol interacts sequentially with the enzymes 3-beta-hydroxysteroid dehydrogenase, 21-alpha-hydroxylase, 11-beta-hydroxylase, and steroid 18-hydroxylase (also called aldosterone synthase) to produce 11-beta, 21-dihydroxy-3, 20-dioxopregn-4-en-18-al (aldosterone). These enzymes also function in the production of other steroid hormones from cholesterol in the adrenal glands, including glucocorticoids (corticosterone and cortisol) and androgen hormones (estrone, estradiol, and dihydrotestosterone).
Mineralocorticoids (Aldosterone): Source and Control of Secretion
Like glucocorticoids, mineralocorticoids are a mixture of steroid hormones from the adrenal cortex.
Aldosterone secretion is controlled by four negative feedback mechanisms that operate through the kidney. These mechanisms help maintain homeostasis by regulating blood pressure, osmotic pressure, and blood levels of sodium and potassium.
In the most influential of these mechanisms, aldosterone secretion increases when the kidney secretes renin in response to low blood pressure, high osmotic pressure, or adverse changes in sodium concentrations. Aldosterone increases sodium and water reabsorption and retention by the kidneys, causing an increase in blood pressure and adjustments to osmotic pressure and sodium concentrations. Conversely, high blood pressure, low osmotic pressure, and the opposite changes in sodium concentration can suppress renin secretion and aldosterone production.
Aldosterone secretion is regulated secondarily by the effects of blood levels of sodium and potassium on the adrenal cortex, by a hormone (atrial natriuretic factor) secreted by the heart when blood volume is high, and by a hormone (ACTH) secreted by the anterior pituitary gland during stress. In each case, the adjustment in aldosterone secretion helps maintain proper blood pressure, osmotic pressure, and blood levels of sodium and potassium.
Age changes and aldosterone
Though aldosterone secretion decreases with aging, blood levels remain steady under ideal body conditions because the decline in secretion is accompanied by a compensatory decrease in elimination. However, aging is accompanied by a decrease in the ability to raise aldosterone secretion and blood levels when needed, leading to a decrease in aldosterone reserve capacity.
These changes are not due to age changes in the adrenal cortex, which largely retains the ability to increase aldosterone levels when needed. The age-related decrease in aldosterone reserve capacity is due primarily to the declining ability of the kidneys to secrete renin when needed. Aging is also accompanied by a declining ability to increase aldosterone secretion during stress. There is an age-related decrease in kidney sensitivity to aldosterone.
Because of the interrelationships between aldosterone secretion and kidney functioning, there is age-related decrease in the ability to maintain normal conditions when faced with adverse conditions such as low blood pressure, dehydration, and disease. Body conditions that are likely to become abnormal include blood pressure; osmotic pressure; concentrations of sodium and potassium; and acid/base balance.
Aldosterone secretion is stimulated by the following mechanism: decreased plasma volume and renal perfusion lead to increased renin secretion, which converts angiotensinogen into angiotensin I. Angiotensinogen is an α2-globulin derived from the liver, present in serum. Angiotensin I is converted in the lung to angiotensin II. Finally, angiotensin II stimulates aldosterone synthesis. Aldosterone acts at the distal and collecting tubules of the nephron to stimulate sodium reabsorption and potassium and hydrogen ion excretion.
On the other hand, elevated plasma potassium concentrations can directly stimulate adrenal aldosterone production. Under physiological conditions, pituitary adrenocorticotropic hormone (ACTH) is not a major factor in regulating aldosterone secretion. Physiologically, plasma aldosterone levels vary with body position (ortho- or clinostatism) and salt intake. Aldosterone concentration also follows a circadian rhythm that is similar to that of cortisol, but less pronounced. Thus, the hormone level peaks in the early morning hours.
The biological action of aldosterone is to increase the retention of sodium and water and to increase the excretion of potassium by the kidneys (and to a lesser extent by the skin and intestines). It acts by binding to and activating a receptor in the cytoplasm of the renal tubular cells. The activated receptor then stimulates the production of ion channels in the renal tubular cells, thereby increasing sodium reabsorption into the blood and increasing potassium excretion into the urine.
The effects of aldosterone secretion are mediated by genomic and nongenomic mechanisms. The genomic effects are linked to the binding of aldosterone to intracellular receptors with consequent transcriptions of genes involved in the regulation of vascular tone and in hydro-electrolyte balance; nongenomic effects are due to the direct binding of aldosterone to specific membrane receptors in heart, vessels, and kidney tissues. Aldosterone excess is caused by renin-independent production due to primary aldosteronism (PA) or hyperactivation of the renin-angiotensin-aldosterone system (RAAS) as in heart failure (HF) in the context of secondary aldosteronism. In both cases, fluid and sodium retention result in volume expansion, vasoconstriction, and consequent potassium depletion that are related to the development of hypertension. Moreover, aldosterone induces oxidative stress and decreased nitric oxide bioavailability, leading to reduced vascular compliance, accentuated by aldosterone-mediated vascular fibrosis. Mineralocorticoid receptors (MRs) are present in coronary artery smooth muscle cells. Hypersecretion of aldosterone is associated with vascular and cardiac remodeling, myocardial fibrosis, endothelial dysfunction with consequent increased risk of cardiovascular events and cardiovascular mortality.
The synthesis and release of aldosterone is controlled by:
- the renin-angiotensin-aldosterone system (the main regulatory factor);- plasma potassium concentration (an increased level stimulates aldosterone secretion);
- ACTH;
- blood pressure.
Aldosterone increases blood pressure by:
- stimulating water and sodium reabsorption in the distal renal tubules;
- increasing circulating blood volume.
Aldosterone's clinical significance
Chronic hyperproduction and secretion of aldosterone causes hypertension, with aldosterone determination being one of the important laboratory tests used in the differential diagnosis of hypertension.
Aldosterone measurement is useful in investigating primary aldosteronism (e.g. adrenal adenoma/carcinoma, adrenocortical hyperplasia) and secondary aldosteronism (renovascular disease, salt depletion, potassium overload, heart failure with ascites, pregnancy, Bartter syndrome).
Pathways in the biosynthesis of steroid hormones
The major pathway involved in the biosynthesis of steroid hormones is the renin-angiotensin system. The renin-angiotensin system is a physiological system that regulates blood pressure.
Renin is an enzyme secreted into the blood from specialized cells that encircle the arterioles at the entrance to the glomeruli of the kidneys (the renal capillary networks that are the filtration units of the kidney). The renin-secreting cells, which compose the juxtaglomerular apparatus, are sensitive to changes in blood flow and blood pressure. The primary stimulus for increased renin secretion is decreased blood flow to the kidneys, which may be caused by loss of sodium and water (as a result of diarrhea, persistent vomiting, or excessive perspiration) or by narrowing of a renal artery. Renin catalyzes the conversion of a plasma protein called angiotensinogen into a decapeptide (consisting of 10 amino acids) called angiotensin I. An enzyme in the serum called angiotensin-converting enzyme (ACE) then converts angiotensin I into an octapeptide (consisting of eight amino acids) called angiotensin II. Angiotensin II acts via receptors in the adrenal glands to stimulate the secretion of aldosterone, which stimulates salt and water reabsorption by the kidneys, and the constriction of small arteries (arterioles), which causes an increase in blood pressure. Angiotensin II further constricts blood vessels through its inhibitory actions on the reuptake into nerve terminals of the hormone norepinephrine.
Aldosterone levels in clinical laboratory
- can vary based on age and other factors.
Normal Range: The normal range for aldosterone levels varies by age:
0-6 days: 5.0 - 102.0 ng/dL
1-3 weeks: 6.0 - 179.0 ng/dL
1-11 months: 7.0 - 99.0 ng/dL
1-2 years: 7.0 - 93.0 ng/dL
3-10 years: 4.0 - 44.0 ng/dL
11-14 years: 4.0 - 31.0 ng/dL
15 years and older: ≤31.0 ng/dL.
Clinical Significance: Elevated aldosterone levels can indicate conditions like primary aldosteronism, which is often caused by a benign tumor on the adrenal glands. This condition can lead to hypernatremia (high sodium levels) and hypokalemia (low potassium levels).
Measurement: Aldosterone levels are typically measured in nanograms per deciliter (ng/dL) and are influenced by factors such as sodium intake, potassium levels, and other medical conditions.
Serum aldosterone measurement is useful both for detecting primary or secondary hyperaldosteronism and for evaluating patients suspected of having secondary hypertension. For the differential diagnosis between these two conditions, plasma renin should be tested simultaneously and the aldosterone/renin ratio calculated; thus, renin is low in primary hyperaldosteronism and high in secondary hyperaldosteronism.
Low serum aldosterone (hypoaldosteronism) may result from primary adrenal insufficiency (Addison's disease). Less common cause include hereditary defects in aldosterone biosynthesis, such as 21-hydroxylase deficiency, the salt-wasting form of adrenogenital syndrome. When hypoaldosteronism is the result of a primary defect in adrenal steroid biosynthesis, plasma renin levels are elevated.
Aldosterone deficiency can also occur in association with chronic kidney disease, especially tubulointerstitial disease and diabetic nephropathy. Most patients have low renin levels, a condition called hyporeninemic hypoaldosteronism.
Regardless of the cause, hypoaldosteronism causes hyperkalemia.
Aldosterone's importance in development
During fetal development, aldosterone plays a role in maternal volume expansion necessary to accommodate fetal perfusion and may also increase the expression of placental growth factors.
Congenital issues of concern related to aldosterone synthesis include autosomal recessive deficiencies in the enzymes responsible for adrenal hormone production. Congenital adrenal hyperplasia (CAH) can take many forms, depending on which enzyme is deficient. The three main enzymes that affect aldosterone are 21-hydroxylase, 11-beta-hydroxylase, and aldosterone synthase. A deficiency of any of these enzymes will halt aldosterone production. The production of aldosterone occurs in an interconnected pathway that produces mineralocorticoids, glucocorticoids, and androgens. The inability for aldosterone production to proceed leads to a buildup of intermediary products and cholesterol to be funneled down the glucocorticoid and androgen hormone production pathways instead. Depending on the severity of the enzyme deficiency, this can result in hyponatremia, hyperkalemia (due to the inability to exchange sodium for potassium in the nephron), and hypovolemia (low sodium causes a decrease in extracellular fluid). In aldosterone synthase deficiency, many of the functional losses are mitigated by the continued production of corticosterone, which acts similarly to aldosterone. The shunting of cholesterol towards the 17-alpha-hydroxylase pathway (androgen hormone production pathway) can result in virilization and ambiguous genitalia in females. Conversely, in the case of 17-alpha-hydroxylase deficiency, cholesterol is shunted towards mineralocorticoid production while glucocorticoid and androgen production is impaired, causing ambiguous genitalia in genetic males and lack of secondary sexual development in genetic females.
Organ Systems Involved
The organs involved in the production, utilization, and regulation of aldosterone are the adrenal glands, kidneys, and lungs, due to the pulmonary conversion of angiotensin 1 to angiotensin 2 in the renin-angiotensin-aldosterone system.
Function
When a stimulus such as low blood pressure or low serum sodium triggers the RAAS, first renin is secreted from the renal juxtaglomerular cells, then angiotensinogen is cleaved into angiotensin I. Angiotensin-converting enzyme (ACE) from the lungs then converts angiotensin I to angiotensin II, which in turn stimulates the production of aldosterone.
Aldosterone is a mineralocorticoid steroid hormone that modulates activity directly and indirectly in the aldosterone-sensitive distal nephron which includes the late distal convoluted tubule, the connecting tubule, and the collecting duct system. Because this region is so distal, aldosterone affects the final stages of electrolyte and water absorption within the nephron before the tubule contents are excreted in the urine. This only accounts for about 5-10% of total sodium reabsorption.
Depending on the specific physiologic parameters, aldosterone may:
- increase sodium reabsorption
- increase water retention
- increase potassium excretion
- increase acid (H+) excretion
- increase bicarbonate (HCO3-) excretion and chloride reabsorption
Although predominantly known for its activity in the kidney, aldosterone may act at mineralocorticoid receptors in other tissues as well such as the gastrointestinal tract, respiratory epithelium, myocardium, and vascular smooth muscle.
Mechanism
As with all steroid hormones, aldosterone passes through cell membranes to bind to cytoplasmic receptors which translocate to the nucleus to influence mRNA transcription and subsequently protein synthesis. The mineralocorticoid receptor (MR) may have higher or lower affinity for aldosterone, depending on whether or not it is phosphorylated. In the phosphorylated state, MR has lower affinity for aldosterone, therefore phosphorylation of MR in a given cell inhibits aldosterone activity.
Within the principal cells of the late distal tubule and collecting ducts, MR is largely in a non-phosphorylated state. In principal cells, aldosterone increases the expression of sodium channels and sodium-potassium ATPase in the cell membrane. The sodium channels are on the luminal side of the principal cells and allow sodium to passively diffuse into the principal cells due to the transepithelial potential difference of -50 mV. This gradient is maintained by the sodium-potassium ATPase on the basolateral side, which uses ATP to actively transport sodium into the blood and potassium into the cell. Meanwhile, potassium channels on the luminal side of the cell that allow passive diffusion out of the cell into the lumen of the kidney whenever a sodium ion enters the cell. The net effect of this process is sodium absorption from the lumen, which allows for water absorption, assuming ADH is present to make the cells permeable to water. This directly results in an increase in osmolality within the blood, causing water to flow down its concentration gradient.
Within intercalated cells, MR is often in a phosphorylated state, therefore the dephosphorylation of MR in the presence of angiotensin II enables intercalated cells to be responsive to aldosterone. This conditional response of intercalated cells results in seemingly paradoxical effects of aldosterone dependent upon whether or not angiotensin II is present.
In alpha-intercalated cells (A-intercalated, acid-secretory), aldosterone increases the expression of apical hydrogen ATPases to stimulate hydrogen ion (proton) excretion into the lumen. Additionally, the sodium resorption from adjacent principal cells creates a more negatively charged lumen space which further encourages acid secretion from the intercalated cells to compensate.
Within the non-A intercalated cells (beta-intercalated, and non-A non-B intercalated cells), aldosterone increases the activity of apical bicarbonate-chloride exchangers, which reabsorb chloride from the lumen into the cell and excrete bicarbonate from the cell into the lumen.
Aldosterone-related Testing
The most common test to assess disturbances of the aldosterone pathway is the aldosterone: renin ratio. This determines whether there is an isolated aldosterone problem or there is a disturbance within renin-angiotensin system. If an aldosterone problem is suspected, and the results show no elevation in either aldosterone or renin, then congenital adrenal hyperplasia is suspected. If both aldosterone and renin are increased, and their ratio is less than 10, then the differential includes renovascular hypertension. If the renin value is normal, the aldosterone level is elevated, and the ratio is greater than 30, the differential includes Conn syndrome. This can be confirmed with a salt suppression test, an MRI of the adrenal glands, and adrenal vein sampling.
Aldosterone's Clinical Significance
Aldosterone is clinically significant for two reasons. An increase or decrease in aldosterone can cause disease and medications affecting its function alter blood pressure. Changes in the concentration of aldosterone, either too much (Conn syndrome and renovascular hypertension) or too little (certain types of Addison's disease and congenital adrenal hyperplasia), can result in disastrous effects on the body.
Hyperaldosteronism is caused by either a primary tumor within the adrenal gland (Conn syndrome) or via renovascular hypertension. A primary tumor within the adrenal gland causes an uncontrolled production and release of aldosterone. Renovascular hypertension increases aldosterone through two primary mechanisms: fibromuscular dysplasia (usually in young females) and atherosclerosis (usually in older individuals). Both decreased perfusion to the afferent arterioles of the kidney causes the renin-angiotensin system to be activated. This causes uncontrolled hypertension and hypokalemia.
Contraction alkalosis is a side effect of increased absorption of water via aldosterone and ADH pathways during a volume-depleted state. The body senses a low mean arterial blood pressure when the ECF is low. Therefore the renin-angiotensin system is activated. This causes an increase in water absorption as well as activation of aldosterone. Aldosterone causes sodium to be absorbed and potassium to be excreted into the lumen by principal cells. In alpha intercalated cells, located in the late distal tubule and collecting duct, hydrogen ions and potassium ions are exchanged. Hydrogen is excreted into the lumen, and the potassium is absorbed. This mechanism prevents the body from losing too much potassium, which causes a relative depletion of hydrogen ions in the blood causing an alkalotic state.
