Aldosterone

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.

Aldosterone is involved in blood volume and pressure control through regulation of sodium and potassium homeostasis. It affects blood pressure by regulating the sodium gradient in the nephron to either increase or decrease the water reabsorbed to contribute to the volume of the extracellular fluid (ECF). This, however, is not to be confused with the effect of anti-diuretic hormone (ADH), also referred to as vasopressin. ADH is often released simultaneously with aldosterone in order to support water reabsorption to the ECF by mobilizing aquaporin channels to the apical (lumen-facing) membrane of principal cells in the collecting tubule. Overall, aldosterone is a key player in the multi-factorial regulation of salt, potassium, blood pressure, and acid-base balance.

Aldosterone is synthesized in the body from corticosterone, a steroid derived from cholesterol. Production of aldosterone (in adult humans, about 20–200 micrograms per day) in the zona glomerulosa of the adrenal cortex, is regulated by the renin-angiotensin system. 

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;

- secreting potassium into the urine;

- 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.

Inappropriate aldosterone secretion results in hypertension, muscle pain and cramps, tetany, paralysis, polyuria, proteinuria, and ultimately renal failure. Primary hyperaldosteronism is commonly caused by adrenal adenoma, unilateral or bilateral hyperplasia, and much less commonly by glucocorticoid-suppressible familial 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.

Addison’s disease is characterized by a hypo-functioning adrenal gland. However, depending on the cause of Addison’s disease, the regulation of aldosterone may be unaffected. Aldosterone is only affected by Addison’s disease when the adrenal gland undergoes destruction, for example, in autoimmune-mediated destruction. Aldosterone is controlled by the renin-angiotensin system, while the rest of the adrenal glands' hormone production is controlled by adrenocorticotropic hormone (ACTH). Therefore, in cases of Addison’s disease caused by pituitary dysfunction, adrenal insufficiency will exist, but with appropriate aldosterone levels. This is due to the fact that the renin-angiotensin system remains intact.

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.

Antidiuretic Hormone/ADH/Vasopressin/Arginine Vasopressin

Antidiuretic Hormone (ADH): Physiology, Pathophysiology, Diagnostic Evaluation, and Clinical Implications

AntiDiuretic Hormone (ADH) is a neuropeptide secreted from the hypothalamus in response to hypovolemia and elevated plasma osmolality. 

ADH, also known as vasopressin or arginine vasopressin, plays a critical role in regulating water balance, blood pressure, and vascular resistance. It is essential for maintaining homeostasis and is involved in various pathophysiological conditions, including cardiovascular diseases and diabetes insipidus. Understanding the function of vasopressin is vital for developing therapeutic strategies targeting these conditions.

Neurohypophisars: ADH/Vasopressin

ADH is a peptide hormone pivotal in maintaining fluid, electrolyte, and blood pressure homeostasis. ADH is synthesized by the supraoptic and paraventricular nuclei in the hypothalamus and transported to the posterior pituitary gland (is stored in the pituitary gland). ADH release: the neurohypophysis release ADH, in response to changes in blood osmolality and blood volume. Hence, it is secreted by the posterior pituitary in response to hyperosmolarity and hypovolemia, ADH promoting therefore water reabsorption in the kidneys and causing vasoconstriction. ADH acts on the kidneys to increase water reabsorption, reducing urine output and helping to maintain fluid balance and blood pressure. ADH's major action is on the distal or collecting tubules of the kidney where it promotes reabsorption of solute free water. Its tightly regulated mechanism ensures the preservation of effective arterial blood volume and osmotic equilibrium. ADH secretion is stimulated by an increase in plasma osmolality via osmoreceptors and by a decrease in plasma volume via volume receptors. The hormone's action is primarily mediated through the V2 receptors in renal principal cells, facilitating aquaporin-2 insertion and passive water transport, and through V1 receptors in vascular smooth muscle that increase peripheral resistance. Clinically, disorders of ADH secretion or response manifest in three primary conditions: syndrome of inappropriate ADH secretion (SIADH), central diabetes insipidus (CDI), and nephrogenic diabetes insipidus. Diagnostic evaluation involves serum and urine osmolality, electrolyte panels, water deprivation testing, and response to desmopressin. Understanding the physiological and pathological aspects of ADH is essential for diagnosing and managing a wide spectrum of endocrine, renal, and hematologic conditions.       

Antidiuretic Hormone (ADH) Test, Plasma

This test is useful for the differential diagnosis of patients with water balance disorders, including diabetes insipidus in conjunction with osmolality and hydration status.

The assessment of circulating ADH levels is challenging because it is released in a pulsatile pattern and is rapidly cleared from plasma. Measurement of ADH is further complicated by the high ex vivo instability of the peptide.

Mixed forms of diabetes insipidus (DI) can exist, and both central and peripheral DI may be incomplete, complicating the interpretation of results.

Additional Information about ADH in Pathology

Diabetes insipidus (DI) is a rare disorder of water homeostasis characterized by the excretion of abnormally large volumes of hypotonic urine due to the inability to appropriately concentrate urine in response to volume and osmolar stimuli. The primary causes of DI are decreased ADH production (central DI) or decreased renal response to ADH (nephrogenic DI); both of which lead to hypotonic polyuria which is usually accompanied by polydipsia. Along with these etiologies, the differential diagnosis of hypotonic polyuria includes primary polydipsia. In primary polydipsia, there is no initial compromise in ADH secretion or renal action and instead, excessive fluid intake leads to a drop in plasma osmolality and a suppression of ADH synthesis. Primary polydipsia can be caused by an abnormality in the thirst center (dipsogenic polydipsia) or, more commonly, as the result of one of a number of psychiatric disorders (psychogenic polydipsia).

Historically, the primary diagnostic test for the evaluation of polyuria-polydipsia syndrome has been the standard water deprivation test. In healthy subjects, water deprivation causes the plasma osmolality to rise, leading to the release of ADH into the circulation. In this test, insufficient ADH secretion or effect is revealed by insufficient concentration capacity of the kidneys on osmotic stimulation, which is achieved by a prolonged period of thirsting and followed by assessment of the response to exogenous ADH administration (Desmopressin). 

The two major clinical syndromes of antidiuretic hormone secretion are neurogenic diabetes insipidus (DI), an ADH deficiency disorder, and the syndrome of inappropriate ADH secretion (SIADH), a disorder of excess ADH synthesis. The tests used for the differential diagnosis of DI and SIADH, are: serum sodium, plasma osmolality, urine osmolality, U/P osmol ratio, urine output. 

Laboratory tests and examinations (DI versus SIADH)

DI is the chronic excretion of very high volumes of hypo-osmotic urine due to ADH deficiency. Polyuria triggers the thirst mechanism resulting in increased polydipsia. If water intake is inadequate, dehydration occurs. DI can be categorized as neurogenic and nephrogenic. In neurogenic DI, ADH secretion by the pituitary or hypothalamus is decreased. ADH deficiency can be partial or complete, depending on the degree of disturbance to the hypothalamus or pituitary. In nephrogenic DI, ADH production and secretion are adequate and appropriate, but the kidneys do not respond to the hormone because of damage to the renal tubules.

Plasma osmolality, urine osmolality and serum sodium are the principal laboratory tests used to diagnose ADH abnormalities. Polyuria increases plasma osmolality to >295 mmol/L and serum sodium to >145 meq/L. Urine osmolality is <300 mmol/L. In partial neurogenic DI, urine osmolality may range between 300 and 800 mmol/L.

Diabetes insipidus can be confirmed with an overnight water deprivation test. This test should be done if a baseline serum osmolality is <295 mosmol. Fluid intake is restricted for 12 to 18 hours and the body weight, urine osmolality, volume and plasma osmolality are measured every 1-2 hours. The test should be discontinued if body weight falls by more than 3%. The objective is to obtain consecutive urine osmolality's which do not differ by more than 30 mosmol. 

One can also measure antidiuretic hormone levels at maximum dehydration, which helps differentiate neurogenic from nephrogenic DI. In neurogenic DI, ADH levels decrease as plasma osmolality increases. Conversely, in nephrogenic DI, ADH levels increase with increasing plasma osmolality.

SIADH is the clinical condition that results from inappropriate continued secretion of ADH in the presence of low serum osmolality. The low serum osmolality is due to the retention of water by the kidney in response to ADH. The low serum sodium concentration is due to the dilutional effect of water retention and to the loss of sodium in the urine. Initial symptoms include anorexia, nausea, vomiting, and headache. Cerebral symptoms begin to appear when serum sodium is less than 125 meq/L. Severe hyponatremia (sodium <110 meq/L) or rapidly developing hyponatremia can cause cerebral edema, which is expressed as irritability, confusion, disorientation, convulsions, hemiparesis, and coma.

The major causes of SIADH include neoplasia, pulmonary disorders, neurological disorders and certain drugs.

Laboratory test results that favor a diagnosis of SIADH include: serum sodium <120 meq/L, serum osmolality <280 mOsm, decreased BUN, decreased serum uric acid, urine osmolality >100 mOsm, and urine sodium >20 meq/L. Other diagnostic criteria include the absence of dehydration, edema, adrenal insufficiency, hypothyroidism or renal failure.

The Neurohypophysis: Endocrinology of Vasopressin and Oxytocin

The neurohypophysis consists of three parts: the supraoptic and paravetricular nuclei of the hypothalamus; the supraoptico-hypophyseal tract; and the posterior pituitary. The neurohypophysis is one component of a complex neurohumoral system coordinating physiological responses to changes in both the internal and external environment.

Two hormones made by the hypothalamus and posterior pituitary are vassopressin (AVP) and oxytocin (OT). These hormones have key roles in water balance and reproductive function.

The neurohypophysis is the structural foundation of a neuro-humoral system coordinating fluid balance and reproductive function through the action of the two peptide hormones, vasopressin and oxytocin. Vasopressin is the principle endocrine regulator of renal water excretion, facilitating adaptive physiological responses to maintain plasma volume and plasma osmolality.

Oxytocin is important in parturition and lactation. Data support a wider role for both peptides in the neuro-regulation of complex behaviour. Clinically, deficits in the production or action of vasopressin manifest as diabetes insipidus. An understanding of the physiology and pathophysiology of vasopressin is also critical in approaching the diagnosis and management of hyponatremia, the most common electrolyte disturbance in clinical practice.

                

Vasopressin receptors

There are three distinct AVP receptor (V-R) subtypes. All have seven transmembrane spanning domain, and all are G protein coupled. They are encoded by different genes and differ in tissue distribution, down-stream signal transduction and function. 

Vasopressin Receptor Subtypes:

- V1a: vascular smooth muscle, liver, platelets, CNS;

- V1b: pituitary corticotroph;

- V2: basolateral membrane of distal nephron.

Physiological effects of receptor subtypes:

- V1a: smooth muscle contraction, stimulation of glycogenolysis, enhanced platelet adhesion, neurotransmitter & neuromodulatory function;

- V1b: enhanced ACTH release;

- V2: increased synthesis & assembly of aquaporin-2.

Vasopressin and renal water handling

Although AVP has multiple actions, its principle physiological effect is in the regulation of water resorption in the distal nephron, the structure and transport processes of which allow the kidney to both concentrate and dilute urine in response to the prevailing circulating AVP concentration. Active transport of solute out of the thick ascending loop of Henle generates an osmolar gradient in the renal interstitium, which increases from renal cortex to inner medulla, a gradient through which distal parts of the nephron pass end route to the collecting system. AVP stimulates the expression of a specific water channel protein (aquaporin) on the luminal surface of the interstitial cells lining the collecting duct.

The presence of aquaporin (AQP) in the wall of the distal nephron allows resorption of water from the duct lumen along an osmotic gradient, and excretion of concentrated urine; 13 different AQPs are important in humans, seven of which (AQP1-4, AQP6-8) are found in the kidney. AQPs act as passive pores for small substrates and are divided into 2 families: the water only channels; and the aquaglyceroporins that can conduct other small molecules such as glycerol and urea. Most substrates are neutral. However, this is not always the case. For example, AQP6 is a gated ion channel. AQPs are involved in a variety of cell processes: small molecule permeation; gas conduction and cell-cell interaction.

As with other membrane channels, specific structural arrangements within the primary, secondary, and tertiary structure convey the three functional characteristics of permeation, selectivity, and gating. The structure of AQPs involves 2 tandem repeats, each formed from 3 transmembrane domains, together with 2 highly conserved loops containing the signature motif asparagine-proline-alanine (NPA). All AQPs form homotetramers in the membrane, providing 4 functionally independent pores with an additional central pore formed between the 4 monomers. Water can pass through all the 4 independent channels of water-permeable AQPs. AQP1 is constitutively expressed in the apical and basolateral membranes of the proximal tubule and descending loop of Henle, where it facilitates isotonic fluid movement. Loss of function mutations of AQP1 in man lead to defective renal water conservation. AQP2 is expressed on the luminal surface of collecting duct cells and is the water channel responsible for AVP-dependent water transport from the lumen of the nephron into the collecting duct cells. V2-R activation in collecting duct cells produces a biphasic increase in expression of AQP2. Ligand-receptor binding triggers an intracellular phosphorylation cascade, ultimately resulting in phosphorylation of the nuclear transcription factor CREB and expression of c-Fos. In turn, these transcription factors stimulate AQP2 gene expression through CRE and AP-1 elements in the AQP2 gene promoter. In addition, AVP stimulates an immediate increase in AQP2 expression by accelerating trafficking and assembly of pre-synthesized protein into functional, homo-tetrameric water channels.

Maximum diuresis occurs at plasma AVP concentrations of 0.5 pmol/l or less. As AVP levels rise, there is a sigmoid relationship between plasma AVP concentration and urine osmolality, with maximum urine concentration achieved at plasma AVP concentrations of 3-4 pmol/L. Following persistent AVP secretion, antidiuresis may diminish. Down-regulation of both V2-R function and AQP2 expression may be responsible for this escape phenomenon.

Figure (on the left side) representing the relationship of plasma AVP concentration to urine osmolality. Shaded area represents range of normal; single line indicates representative individual. AVP has additional effects at other sites in the nephron: decreasing medullary blood flow; stimulating active urea transport in the distal collecting duct; and stimulating active sodium transport into the renal interstitium.  As a final outcome, there is generation and maintenance of a hypertonic medullary interstitium, and augment AVP-dependent water resorption.

Regulation of vasopressin release

Osmoregulation of Vasopressin

Plasma osmolality is the most important determinant of AVP secretion. The osmoregulatory systems for thirst and AVP secretion, and in turn the actions of AVP on renal water excretion, maintain plasma osmolality within narrow limits of 284 to 295 mOsmol/kg. The relationship between plasma osmolality and plasma AVP concentration has 3 characteristics.

- The osmotic threshold or 'set point' for AVP release

- The shape of the line describing changes in plasma AVP concentration with changing plasma osmolality

- The sensitivity of the osmoregulatory mechanism coupling plasma osmolality and AVP release.

There are situations where the normal relationship between plasma osmolality and AVP concentration breaks down:

- Rapid changes of plasma osmolality: rapid increases in plasma osmolality result in exaggerated AVP release;

- During the act of drinking: drinking rapidly suppresses AVP release, through afferent pathways originating in the oropharynx;

- Pregnancy: the osmotic threshold for AVP release is lowered in pregnancy.

Additional Mechanisms Regulating Vasopressin Release

A number of other stimuli influence AVP release independent of osmotic and hemodynamic status: 

- Nausea and emesis

- Unspecific stress

- Pain

- Manipulation of abdominal contents

- Immune-response mediators and inflammatory triggers

These stimuli contribute to high plasma AVP values observed in acute illness and after surgery.

Additional effects of vasopressin

Thirst

Renal free water clearance can be reduced to a minimum by the antidiuretic actions of vasopressin, but water loss is not completely eliminated, and insensible water loss from respiration and sweating is a continuous process. To maintain water homeostasis, water must also be consumed to replace the obligate urinary and insensible fluid losses. This is regulated by thirst. Thirst and drinking are key processes in the maintenance of fluid and electrolyte balance. Thirst perception and the regulation of water ingestion involve complex, integrated neural and neurohumoral pathways. Other centers are involved in thirst perception. There is a linear relationship between thirst and plasma osmolalities in the physiological range. The mean osmotic threshold for thirst perception is 281 mOsm/kg, similar to that for AVP release. Thirsty occurs when plasma osmolality rises above this threshold. As with osmoregulated AVP release, the characteristics of osmoregulated thirst remains consistent within an individual on related testing, despite wide inter-individual variation.

As with AVP release, there are also specific physiological situations in which the relationship between plasma osmolality and thirst breaks down.

- The act of drinking: reduces osmotically stimulated thirst.

- Extracellular volume depletion: this stimulates thirst through volume-sensitive cardiac afferents and the generation of circulating and intra-cerebral A-II, a powerful dipsogen.

- Pregnancy, the luteal phase of the menstrual cycle and super ovulation syndrome: these states reduce the osmolar threshold for thirst.

- Aging: both thirst appreciation and fluid intake can be blunted in the elderly.

The act of drinking reduces thirst perception before any change in plasma osmolality.

This effect is produced through three mechanisms: oropharyngeal sensory afferents; gastro-intestinal stretch-sensitive afferents; and peripheral osmoreceptors in the hepatic portal vein. As with AVP release, hypovolemia resets the relationship between plasma osmolality and thirst. A-II is one of the key mediators of this physiological response. Peripheral A-II generation can act on central osmoreceptors, to increase both thirst and AVP release. An independent, intra-cerebral A-II system is activated in parallel. A-II is a powerful central dipsogen.

Clinical problems secondary to defects in the hypothalamo-posterior pituitary axis

Defects in the production or action of AVP manifest as clinical problems in maintaining plasma sodium concentration and fluid balance, reflecting the key role of the hormone in these processes. A further group of related clinical conditions reflect primary defects in thirst. In some cases, the two may coincide, reflecting the close anatomical and functional relationship of both processes.

Diabetes Insipidus

Classification

Diabetes insipidus (DI) is characterized by production of dilute urine in excess of >50 ml/kg/24 hours in adults. DI arises through one of four mechanisms:

- Deficiency of AVP: central diabetes insipidus (CDI), also called Arginine Vasopressin Deficiency

- Inappropriate, excessive water drinking: primary polydipsia

- Renal resistance to the antidiuretic action of AVP: nephrogenic diabetes insipidus (NDI), also called Arginine Vasopressin Resistance

- Increased vasopressinase expression in pregnancy: gestational diabetes insipidus

Figure showing different forms of hypotonic polyurea

Central Diabetes Insipidus (CDI) (Arginine Vasopressin Deficiency)

CDI (also known as neurogenic or cranial DI) is the result of partial or complete lack of osmoregulated AVP secretion. Plasma AVP concentrations are inappropriately low with respect to prevailing plasma osmolalities. Presentation with CDI implies destruction or loss of function of more than 80% of vasopresinergic magnocellular neurons. Though persistent polyuria can lead to dehydration, most patients can maintain water balance through appropriate polydipsia if given free access to water.

Hypothalamic tumors (e.g., craniopharyngioma) or pituitary metastases (e.g., breast or bronchus) can present with CDI. However, primary pituitary tumors rarely cause CDI. In childhood, craniopharyngioma and germinoma/teratoma are a relatively common cause.

When obvious causes are not present, most cases of CDI will be "idiopathic". However, the possibility of an autoimmune process should be considered, as many idiopathic cases are considered to be autoimmune in origin. A well-recognized cause of autoimmune CDI is lymphocytic infundibulohypophysitis.

Primary Polydipsia (PP)

PP is a polyuric syndrome secondary to excess fluid intake. PP can be associated with organic structural brain lesions, e.g. sarcoidosis of the hypothalamus and craniopharyngioma. It can also be produced by drugs that cause a dry mouth or by any peripheral disorder causing an elevation of renin and/or angiotensin. However, mostly there is no identifiable pathologic etiology; in this circumstance the disorder is often associated with psychiatric syndromes. It also seems to be increasingly prevalent in health conscious people who voluntarily change their drinking habits with the aim to improve their well-being, in which case it is often called habitual polydipsia.

Nephrogenic Diabetes Insipidus (NDI)

NDI is due to renal resistance to the antidiuretic effects of AVP. Genetic variants of NDI usually present in infancy. In these forms, NDI can occur as a result of mutations in the V2 receptor and mutations of the aquaporin 2 water channels.

The development of NDI in an adult is less likely to reflect a genetic cause. Among causes of acquired NDI are hypokalemia, hypercalcemia, and release of bilateral urinary tract obstruction associated with downregulation of aquaporin 2 and decreased function of vasopressin. NDI secondary to lithium is characterized by dysregulated AQP2 expression and trafficking along the whole collecting duct as well as dysregulated expression of the amiloride-sensitive epithelial sodium channel (ENaC) in the cortical collecting duct.

Gestational Diabetes Insipidus

In normal pregnancy, physiologic adaptations include expansion of blood volume and decreased plasma osmolality and serum sodium. Thirst and increased fluid intake are commonly reported in pregnancy, but in some patients the increased thirst is driven by marked polyuria, which may point to the presence of diabetes insipidus. Two types of transient diabetes insipidus must be differentiated in pregnancy, both caused by the placental enzyme cysteine aminopeptidase, named oxytocinase, which enzymatically degrades oxytocin. Because of the close structural homology between AVP and oxytocin, this enzyme also metabolizes AVP. In the first type of pregnancy-associated DI, the activity of oxytocinase is abnormally elevated. This syndrome has been referred to as vasopressin resistant diabetes insipidus of pregnancy and has been reported to be associated with preeclampsia, acute fatty liver, and coagulopathies.

Figure showing the algorithm for the differential diagnosis for the diabetes insipidus.

In establishing the underlying mechanisms of central DI, once the diagnosis is confirmed, imaging of the hypothalamus, pituitary and surrounding structures with MRI is essential. If no mass lesion is identified, imaging should be repeated after 6-12 months so that slow growing germ cell tumors are not missed. Idiopathic and familial central DI are often associated with loss of the normal hyper-intense signal of the posterior pituitary on T1-weighted images. Signal intensity is correlated strongly with AVP content of the gland. 

Evidence of anterior pituitary dysfunction should be looked for in central DI, though it is relatively uncommon in the adult population. Interestingly, evidence of organ-specific autoimmune disease is relatively common in adult patients with isolated central DI, consistent with an autoimmune basis for the condition.

Human Chorionic Gonadotropin (HCG/hCG)

HCG/hCG/Human Chorionic Gonadotropin

HCG is a hormone that plays an important role in pregnancy, time at which its levels can vary widely. The hCG levels also vary between individuals. Outside a pregnancy, a high hCG level may be a sign of a health condition, such as cancer or liver disease, hence its importance for the clinical investigations.

HCG is a glycoprotein hormone that is normally found in the blood and urine only during pregnancy. It is secreted by the placenta. It is called "the pregnancy hormone", because of its unique role in supporting a pregnancy. During pregnancy, several hormones are involved in the proper functioning of the woman's body. HCG hormone supports the normal development of an egg in a woman's ovary, and stimulates the release of the egg during ovulation.

The early embryo tissue, which later forms part of the placenta, starts producing hCG. To maintain a pregnancy, hCG triggers the body to produce another hormone, progesterone. It can also help:

- promote the development of new blood vessels in the uterus;

- smooth the muscle cells in the middle layer of the uterine wall, which is important for maintaining pregnancy;

The hormone hCG is produced during pregnancy by cells formed in the placenta and nourishes the egg after it has been fertilized and attached to the wall of the uterus. In the first trimester of pregnancy, hCG ensures the maintenance of the corpus luteum and its secretion of estradiol and progesterone. HCG helps thicken the uterine lining to support a growing embryo and tells the body to stop menstruating. 

When does the body make hCG? 

All people have small amounts of hCG in their bodies (almost undetectable levels). The hCG levels rise fast (after conception) and continue to rise and then peak at around 10 weeks of pregnancy. After that, they gradually fall until childbirth. Once the placenta begins making hCG, it triggers the body to create more estrogen and progesteron. Together with hCG, these hormones help thicken the uterine lining and tell the body to stop menstruating (or release eggs). The correct balance of these three hormones sustains and supports the pregnancy.

A real "cocktail", made up of several chemical substances (hormones) is responsible for many less pleasant aspects of pregnancy, such as bloating, spotting, nausea and certain emotional states. Once the egg has met the sperm, the hormone hCG goes into action to amplify the production of estrogen and progesterone. At the same times, hCG suppresses the immune system, in order to support the development of the baby. 

People may be familiar with hCG because it is the hormone that pregnancy tests check for in the urine. A home test can first detect hCG levels that indicate pregnancy at about 1 to 2 weeks after conception. A doctor can also check for pregnancy by ordering a blood test to measure hCG levels. Testing the level of hCG in the blood can also help a doctor identify certain underlying health conditions, including some cancers, and check how effective cancer treatment is. HCG levels can first be detected by a blood test at about 11 days after conception and at about 12-14 days after conception by a urine test. Typically, the hCG levels will double every 72 hours. The level will reach its peak in the first 8-11 weeks, then decline and level off for the remainder of the pregnancy.

 

In rare cases, germ cell tumors or other cancers may cause the body to produce hCG. HCG can also be used as a treatment, to cause ovulation and to treat infertility in women. 

How is human chorionic gonadotropin produced?

After conception occurs, a fertilized egg travels through the fallopian tubes to the uterus. The fertilized egg (called an embryo) implants (attaches) into the wall of the uterus. This triggers the placenta to form. The placenta begins producing and releasing hCG into the blood and urine. HCG can be found in the pregnant's blood at around 11 days after conception. It takes slightly longer for hCG to appear on urine tests. 

HCG increases quickly (almost doubling every three days) for the first 8 to 10 weeks of pregnancy. Healthcare providers look at how quickly a person's hCG levels rise in early pregnancy to determine how the pregnancy and fetus are developing.

Clinical significance

Its rapid increase in serum levels immediately after conception makes HCG an excellent marker for early confirmation of pregnancy and monitoring its evolution.

Determination of serum HCG can be useful in anticipating the occurrence of spontaneous abortions, in diagnosing ectopic pregnancies or multiple pregnancies. 

The values of HCG increases in the first trimester of pregnancy and then gradually decreases towards the end of pregnancy. Significant, sudden decreases in HCG in a pregnant woman can be encountered in pregnancies that do not progress normally, in which case an immediate clinical examination is necessary. 

What level of hCG indicates pregnancy?

A urine hCG level as low as 6.3 to 12.5 U/l may be detectable by tests, indicating pregnancy. However, tests typically detect hCG levels closer to 20 to 50 U/l.

How quickly does hCG rise?

During pregnancy, hCG levels typically double every 24 hours during the first 2 months and peak at week 10.

What is a normal hCG level when not pregnant?

In people who are not pregnant, hCG levels are exceptionally low to undetectable. However, some experts approximate that hCG levels may increase in natal females with age, increases up to 14 U/l. Certain cancers may also cause increases in hCG levels.

HCG levels unrelated to pregnancy

Normal levels of hCG are typically undetectable in females who are not pregnant and in males.

Higher levels can sometimes point to an underlying health problem, such as:

- some cancers, including cancer of the liver, stomach, pancreas, lung, breast, or skin

- germ cell tumors of the ovary and testicles, which may be benign or malignant

- cirrhosis

- stomach ulcers

- inflammatory bowel disease

HCG as medication

Generic name: human chorionic gonadotropin (HCG) (injectable)
Drug class: Gonadotropins

Doctors sometimes prescribe hCG to combat the symptoms of conditions such as hypogonadism, in which the testes do not produce enough testosterone, sperm, or both.

What happens if missing a dose?

The doctor should be contacted if missing a dose of HCG.

What happens if overdosing?

Seeking emergency medical attention is what to do if thinking that too much of this medicine was used. An overdose of HCG is not expected to produce life-threatening symptoms, though.

What should I avoid?

The doctor's instructions should be followed about any restrictions on food, beverages, or activity while using HCG.

HCG side effects

Using HCG must be stopped and emergency medical help should be sought if having any of these signs of an allergic reaction: hives, difficulty breathing, swelling of the face/lips/tongue/throat.

The doctor must be called immediately if having any of these signs of a blood clot: pain, warmth, redness, numbness, or tingling in the arm or leg; confusion, extreme dizziness, or severe headache.

How is hCG used for fertility?

HCG injections can increase the chances of becoming pregnant when used with IVF (in-vitro fertilization) or IUI (intrauterine insemination). It works by inducing ovulation (when ovaries release an egg). If there is a history of infertility, monitoring hCG levels early in pregnancy can help the healthcare providers determine if a successful pregnancy has occurred.

Before using HCG as medication

This medication should not be used if the patient have ever had an allergic reaction to HCG, or if the patient has: 

- early puberty (also called precocious puberty); 

- a hormone-related cancer (such as prostate cancer);

- cancer or a tumour of the breast, ovary, or uterus;

- certain types of ovarian cysts;

- uncontrolled thyroid or adrenal dysfunction;

- a cancer or tumour of the hypothalamus or pituitary gland in the brain;

- vaginal bleeding without a known cause; or

- if the person is currently pregnant.

Before receiving HCG, the doctor must be called if the patient is allergic to this drugs or if the patient has: a thyroid or adrenal gland disorder, an ovarian cyst, unexplained vaginal bleeding, heart disease, kidney disease, epilepsy, migraines, or asthma.

If a patient is having any of these conditions, a dose adjustment may be needed and special tests, to safely use HCG.

Although HCG can help becoming pregnant, HCG should not be used if the patient is already pregnant. The patient should tell the doctor right away if becoming pregnant during treatment. The doctor should be told if the woman is breast-feeding a baby before using HCG.

Warnings

HCG is given as an injection under the skin or into a muscle. If using HCG at home, the doctor, nurse, or pharmacist will give the specific instructions on how and where to inject this medicine. One must not self-inject HCG if not fully understanding how to give the injection and properly dispose of used needles and syringes.

HCG can place the patient at higher risk for a blood clot. The doctor must be called if having any of these signs of a blood clot: pain, warmth, redness, numbness, or tingling in the arm or leg; confusion, extreme dizziness, or severe headache.

Some women using this medicine have developed a condition called ovarian hyperstimulation syndrome (OHSS), especially after the first treatment cycle. OHSS can be a life-threatening condition. The doctor must be called right away if having any symptoms of OHSS: severe pelvic pain, swelling of the hands or legs, stomach pain and swelling, shortness of breath, weight gain, diarrhea, nausea or vomiting, or if urinating less than normal.

HCG can cause early puberty in young boys. The doctor must be called if a boy using this medicine shows early signs of puberty, such as a deepened voice, pubic hair growth, and increased acne or sweating. 

Less serious side effects from HCG may include:

- headache;

- feeling restless or irritable;

- mild swelling or water weight gain;

- depression;

- feeling tired;

- breast tenderness or swelling; or

- pain, swelling, or irritation where the injection is given..

Using HCG can increase the woman's chances of having a multiple pregnancy (twins, triplets, quadruplets, etc). A multiple pregnancy is a high-risk pregnancy for the mother and for the babies. The doctor's instructions about any special care that may be needed should be followed during the pregnancy. 

How should HCG be used?

HCG must be used exactly as prescribed by the doctor. It must not be used in larger amounts or for longer than recommended. Directions on the prescription label should be followed.

Each disposable needle should only be used once. Used needles should be thrown away in a puncture-proof container (the pharmacist should be asked where getting one and how to dispose of the needles). This container should be kept out of the reach of children and pets.

To be sure HCG is helping the patient's condition, the doctor will need to check the subject on a regular basis. No scheduled appointments should be missed.

Some brands of HCG come in powder form with a separate liquid that one must mix together and draw into a syringe. Other brands are provided in single-dose prefilled syringes.

The medication should not be used if it has changed colours or if the liquid has any particles in it. In this case, the patient must call the doctor for a new prescription. Unmixed HCG should be stored at room temperature away from light, moisture, and heat. After mixing the HCG, it must be kept in the refrigerator until the patient is ready for the injection. Any mixed medicine that have not been used within 30 days after mixing should be thrown away.

What other drugs will affect HCG?

There may be other drugs that can interact with HCG. The doctor must be informed about all the prescription and over-the-counter medications that the patient uses. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. It is not advisable to start using a new medication without telling it to the doctor.

How do pregnancy tests work?

Pregnancy tests (like urine tests, which can be done at home), are designed to detect changes in the level of the hCG hormone using a scientific technique. HCG can be detected in either blood or urine. However, a blood test is more accurate, because it can detect smaller amounts of hCG. 

HCG is a large molecule, made up of two separate components: alpha hCG and beta hCG. A pregnancy test comes with antibodies to detect the alpha hCG part and the beta hCG part. So, if a home pregnancy test shows that one is pregnant, it means that the hCG hormone in the urine is sandwiched by the antibodies on the strip that have been smeared on, so this component of the test triggers the release of a colored substance, creating that dark line that indicates a positive pregnancy test result.

Even though home pregnancy tests detect the hCG hormone in the urine, to determine whether or not one is pregnant, such tests cannot actually tell you how much hCG is present. It is important to go to the gynecologist to confirm the result with other tests. The fetus is usually visible on a transvaginal ultrasound when the hCG values are above 1500 units. When the beta hCG value is above 4000 units, the fetus is also visible on an abdominal ultrasound.

How hCG levels are tested?

An at-home pregnancy test will be positive if hCG is detected in the urine. A urine hCG test is performed by either urinating on a chemical strip or placing a drop of urine on a chemical strip. At-home urine tests typically require higher hCG levels to return a positive result.

It should be kept in mind that a low hCG level doesn't diagnose anything. It's just a tool to detect potential issues. If the healthcare provider is concerned about the hCG level, the levels should be tested again in two or three days. Then, the results will be compared, in order to get a better picture of what's going on with the pregnancy.

hCG testing

Level of the hCG hormone can first be detected through a blood test, at about 11 days after conception, and through a urine test (pregnancy test), at about 12-14 days after conception.

Normally, hCG levels will double at every 48-72 hours. Its levels will reach a "peak" in the first 8-11 weeks of pregnancy, and then the level will begin to decrease and at some point, human chorionic gonadotropin will remain at the same level for the rest of the pregnancy.

hCG Levels

While getting further along in pregnancy and the hCG level gets higher, the time it takes to double can increase to about every 96 hours.

A normal pregnancy may have low hCG levels and result in a perfectly healthy baby. The results from an ultrasound after 5 - 6 weeks gestation are much more accurate than using hCG numbers.

An hCG level of less than 5 mIU/mL is considered negative for pregnancy, and anything above 25 mIU/mL is considered positive for pregnancy.

An hCG level between 6 and 24 mIU/mL is considered a grey area, and it's likely needed to be retested to see if the levels rise to confirm a pregnancy.

The hCG hormone is measured in milli-international units per milliliter (mIU/mL).

A transvaginal ultrasound should be able to show at least a gestational sac once the hCG levels have reached between 1,000 - 2,000 mIU/mL. Because levels can differentiate so much and conception dating can be wrong, a diagnosis should not be made by ultrasound findings until the hCG level has reached at least 2,000 mIU/mL.

A single reading is not enough information for most diagnoses. When there is a question regarding the health of the pregnancy, multiple testings of hCG done a couple of days apart give a more accurate assessment of the situation.

The hCG levels should not be used to date a pregnancy since these numbers can vary so widely.

There are two common types of hCG tests. A qualitative test detects if hCG is present in the blood. A quantitative test (or beta) measures the amount of hCG actually present in the blood.

Types of hCG Tests

There are two common types of hCG tests; these are different types of blood tests to detect hCG:

- A qualitative test detects whether human chorionic gonadotropin is present in the blood; it doesn't specify the amount, just that there is hCG;

- A quantitative (or beta-hCG) test measures the amount of human chorionic gonadotropin that is actually present in the blood; the results are in milli-international units of hCG per milliliter of blood (mIU/mL).

 A positive test referring to beta-hCG test means that the woman is pregnant, and a negative test referring to beta-hCG test means that there is no pregnancy. 

Should hCG levels be checked regularly? How often is hCG level tested in pregnancy?

It's not common for doctors to routinely check the hCG levels unless the patient is showing signs of a potential problem. HCG levels are typically not checked more than once or twice during pregnancy. 

Healthcare providers check hCG levels in the first trimester, but usually don't need to check again. The hCG level may be rechecked if there is bleeding, experiencing severe cramping, or having a history of miscarriage.

If initial hCG levels are lower than the average, hCG levels are to be tested again in a few days. Assessing hCG levels is done sequentially, testing several days apart and comparing levels. 

Some prenatal genetic tests use hCG levels to check for the possibility of a fetus having a congenital disorder. 

Total serum HCG: too low or too high values

Low hCG levels in pregnancy 

During pregnancy, low levels of hCG are not always a cause of concern. This finding may only indicate that there could be a health issue to investigate.

Other times, low hCG can point to a more serious problem. 

Low hCG can also indicate that the fetus is not growing appropriately. 

What do too low hCG levels mean?

A low or declining hCG level can mean many things and should be rechecked within 48-72 hours to see how the level is changing. A low level may indicate:

- an incorrect calculation of the due date (miscalculation of pregnancy dating, of last menstrual period);

- possible miscarriage (losing of pregnancy);

- blighted ovum/pregnancy (pregnancy with no embrion); 

- an ectopic pregnancy (extrauterine pregnancy).

If the hCG is low for the gestational age of the pregnancy, the healthcare provider will recheck the pregnant's hCG levels in two or three days or perform an ultrasound to get a better look at the uterus.

High hCG levels in pregnancy

As with low levels, high levels of hCG do not necessarily indicate a problem with a pregnancy. Some people simply have higher levels. 

If a woman has high hCG levels, it could point to twins or triplets, though only a scan can confirm this.

What do too high hCG levels mean?

A high level of the hCG hormone can mean many things and should be rechecked within 48-72 hours to evaluate changes in the level. A high level can mean:

- miscalculation of the pregnancy dating (miscalculation of last menstrual period);

- molar pregnancy (the placenta and the fetus do not develop correctly);

- multiple pregnancy (several fetuses; twins, triplets or more);

- abnormal growths on the uterus.

What are normal hCG levels by week in pregnancy?

Note that the following values represent Beta hCG reference values. 

Human chorionic gonadotropin is produced only during pregnancy, almost exclusively in the placenta. Levels of the hCG hormone, which is detected in the mother's blood and urine, increase dramatically in the first trimester and can contribute to nausea and vomiting associated with pregnancy. Here are the beta hCG values, depending on the week of pregnancy (gestational age: by convention, pregnancies are measured in weeks, starting with the first day of the woman's last menstruation).

HCG levels in pregnancy

hCG levels can vary widely from one pregnant person to another. A test measures hCG in units per liter (U/l).

Typical levels of hCG throughout pregnancy are: 

Week since last menstrual period        Standard hCG range (U/l)

4                                                           0-750

5                                                          200-7,000

6                                                          200-32,000

7                                                          3,000-160,000

8-12                                                    32,000-210,000

13-16                                                  9,000-210,000

16-29                                                  1,400-53,000

29-41                                                  940-60,000

During the first 8 weeks of pregnancy, concentrations of hCG in the blood and urine usually double every 24 hours. 

Levels of the hormone typically peak at around 10 weeks, decline until 1 week, then remain constant.

The chart shows how the hCG levels rise quickly and steadily in the first trimester before declining:

Weeks since last menstrual period                                                     hCG levels (mIU/mL)

3                                                                                                         5-50

4                                                                                                         5-426

5                                                                                                         18-7,340

6                                                                                                         1,080-56,500

7 to 8                                                                                                  7,650-229,000

9 to 12                                                                                                25,700-288,000

13 to 16                                                                                              13,300-254,000

17 to 24                                                                                              4,060-165,400

24 to 40                                                                                              3,640-117,000

non-pregnant                                                                                      55-200ng/ml

* These numbers are just a guideline - every woman's level of hCG can rise differently. It is not necessarily the level that matters, but rather the change in the level.

These numbers should be used as a guide only. The levels may rise differently in every woman. It's not the numbers that matters as much as how the number changes between different weeks. The healthcare provider will let the pregnant patient know if the hCG levels need to be checked again and what the test results mean for the pregnancy. An important point to remember is that healthy pregnancies may have lower than average hCG levels.

Non-pregnant women have hCG levels between 0 and 5 mIU/ml.

What Can Be Expected After a Pregnancy Loss?

Most women can expect their levels to return to a non-pregnant range at about 4 - 6 weeks after a pregnancy loss has occurred.

This can be differentiated by how the loss occurred (spontaneous miscarriage, abortion, natural delivery) and how high the levels were at the time of the loss.

Healthcare providers usually will continue to test hCG levels after a pregnancy loss to ensure they return back to <5.0.

Gestational trophoblastic disease

One medical concern about higher levels of hCG is that they may indicate gestational trophoblastic disease (GTD).

GTD can occur during or after pregnancy. It causes abnormal cells to grow in the uterus. Some can be cancerous, though most are benign. Treatment depends on the mass of cells and whether it is cancerous or benign.

To remove the mass, the doctor may recommend dilation and curettage, which involves sucking away the mass with a surgical vacuum and gently scraping away any remaining abnormal cells. Or, a doctor may recommend a hysterectomy to remove the uterus.

Summary HCG

HCG plays a key role in pregnancy, during which levels rise significantly. Especially high or low levels during pregnancy can indicate a problem, but this is not always the case.

In other people than pregnant women, high levels of hCG sometimes indicate an underlying health condition, possibly one that affects fertility.

If a woman gets a positive test result, she is most likely pregnant. False positives are extremely rare. However, there are some conditions that may cause a false positive, such as certain types of cancer and early miscarriage. Some antibodies may also interfere with test results.

Medications that contain hCG may interfere with hCG levels, as well. These medications are often used in fertility treatments, and the health care provider should advise the patient on how a test may be affected.

All other medications such as antibiotics, pain relievers, contraception or other hormone medications should not have any effect on a test that measures hCG.