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ArginineVasopressin Deficiency (Central Diabetes Insipidus)


John D. Carmichael

, MD, Keck School of Medicine of the University of Southern California

Reviewed/Revised Apr 2023
Topic Resources

Arginine vasopressin deficiency (central diabetes insipidus) results from a deficiency of vasopressin (antidiuretic hormone [ADH]) due to a hypothalamic-pituitary disorder. Polyuria and polydipsia develop. Diagnosis is by water deprivation test showing failure to maximally concentrate urine; vasopressin levels and response to exogenous vasopressin help distinguish argininevasopressin deficiency from argininevasopressin resistance (nephrogenic diabetes insipidus). Treatment is with desmopressin. Nonhormonal treatment includes use of diuretics (mainly thiazides) and vasopressin-releasing medications, such as chlorpropamide.

Pathophysiology of ArginineVasopressin Deficiency

Vasopressin acts primarily to promote water conservation by the kidneys by increasing the permeability of the distal tubular epithelium to water. At high concentrations, vasopressin also causes vasoconstriction. Like aldosterone, vasopressin plays an important role in maintaining fluid homeostasis Overview of Disorders of Fluid Volume Because sodium is the major osmotically active ion in the extracellular fluid (ECF), total body sodium content determines ECF volume. Deficiency or excess of total body sodium content causes... read more and vascular and cellular hydration. The main stimuli for vasopressin release are

  • Increased osmotic pressure of water in the body (sensed by osmoreceptors in the hypothalamus)

  • Volume depletion (sensed by vascular baroreceptors)

The posterior lobe of the pituitary is the primary site of vasopressin storage and release, but vasopressin is synthesized within the hypothalamus. Newly synthesized hormone can still be released into the circulation as long as the hypothalamic nuclei and part of the neurohypophyseal tract are intact. Only about 10% of neurosecretory neurons must remain intact to avoid argininevasopressin deficiency. The pathology of argininevasopressin deficiency thus always involves the supraoptic and paraventricular nuclei of the hypothalamus or a major portion of the pituitary stalk.

Arginine vasopressin deficiency may be

  • Complete (absence of vasopressin)

  • Partial (insufficient amounts of vasopressin)

Argininevasopressin deficiency also may be

  • Primary, in which there is a marked decrease in the hypothalamic nuclei of the neurohypophyseal system

  • Secondary (acquired)

Etiology of ArginineVasopressin Deficiency

Primary argininevasopressin deficiency

Genetic abnormalities of the vasopressin gene on chromosome 20 are responsible for autosomal dominant forms of primary argininevasopressin deficiency, but many cases are idiopathic.

Secondary argininevasopressin deficiency

Argininevasopressin deficiency may also be secondary (acquired), caused by various lesions, including hypophysectomy, cranial injuries (particularly basal skull fractures), suprasellar and intrasellar tumors (primary or metastatic), Langerhans cell histiocytosis Langerhans Cell Histiocytosis Langerhans cell histiocytosis (LCH) is a proliferation of dendritic mononuclear cells with infiltration into organs locally or diffusely. Most cases occur in children. Manifestations may include... read more Langerhans Cell Histiocytosis , lymphocytic hypophysitis, granulomas (sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis or tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Tuberculosis (TB) ), vascular lesions (aneurysm, thrombosis), and infections (encephalitis Encephalitis Encephalitis is inflammation of the parenchyma of the brain, resulting from direct viral invasion or occurring as a postinfectious immunologic complication caused by a hypersensitivity reaction... read more , meningitis Overview of Meningitis Meningitis is inflammation of the meninges and subarachnoid space. It may result from infections, other disorders, or reactions to drugs. Severity and acuity vary. Findings typically include... read more ).

Symptoms and Signs of ArginineVasopressin Deficiency

Onset of argininevasopressin deficiency may be insidious or abrupt, occurring at any age.

The only symptoms in primary argininevasopressin deficiency are polydipsia and polyuria. In secondary argininevasopressin deficiency, symptoms and signs of the associated lesions are also present.

Enormous quantities of fluid may be ingested, and large volumes (3 to 30 L/day) of very dilute urine (specific gravity usually < 1.005 and osmolality < 200 mOsm/kg [200 mmol/kg]) are excreted. Nocturia almost always occurs. Dehydration and hypovolemia may develop rapidly if urinary losses are not continuously replaced.

Diagnosis of ArginineVasopressin Deficiency

  • Water deprivation test

  • Sometimes vasopressin or copeptin levels

Argininevasopressin deficiency must be differentiated from other causes of polyuria, particularly primary polydipsia (see table ) and argininevasopressin resistance. All tests for argininevasopressin deficiency (and for argininevasopressin resistance) are based on the principle that increasing the plasma osmolality in normal people will lead to decreased excretion of urine with increased urine osmolality.


Common Causes of Polyuria



Vasopressin-sensitive polyuria

Decreased synthesis of vasopressin

Primary argininevasopressin deficiency, hereditary (usually autosomal dominant)

Acquired (secondary) argininevasopressin deficiency (causes outlined in text)

Primary diabetes insipidus, hereditary associated with diabetes mellitus, optic nerve atrophy, nerve deafness, and atonia of bladder and ureters (Wolfram syndrome)

Decreased release of vasopressin

Primary polydipsia (dipsogenic diabetes insipidus)

Vasopressin-resistant polyuria

Renal resistance to vasopressin

Osmotic diuresis

Poorly resorbed solutes (mannitol, sorbitol, urea)

The water deprivation test Water deprivation test Nephrogenic diabetes insipidus (NDI) is an inability to concentrate urine due to impaired renal tubule response to vasopressin (ADH), which leads to excretion of large amounts of dilute urine... read more is the simplest and most reliable method for diagnosing argininevasopressin deficiency but should be done only while the patient is under constant supervision. Serious dehydration may result. Additionally, if primary polydipsia is suspected, the patient must be observed to prevent surreptitious drinking.

The test is started in the morning by weighing the patient, obtaining venous blood to determine electrolyte concentrations and osmolality, and measuring urinary osmolality. Voided urine is collected hourly, and its specific gravity or, preferably, osmolality is measured. Dehydration is continued until orthostatic hypotension and postural tachycardia appear, 5% of the initial body weight has been lost, or the urinary concentration does not increase > 0.001 specific gravity or > 30 mOsm/L in sequentially voided specimens. Serum electrolytes and osmolality are again determined. Exogenous vasopressin is then given (5 units of aqueous vasopressin subcutaneously, 10 mcg desmopressin [DDAVP] intranasally, or 4 mcg IM or IV). Urine for specific gravity or osmolality measurement is collected one final time 60 minutes postinjection, and the test is terminated.

A normal response produces maximum urine osmolality after dehydration (often > 1.020 specific gravity or > 700 mOsm/kg [700 mmol/kg]), exceeding the plasma osmolality; osmolality does not increase more than an additional 5% after injection of vasopressin. Patients with argininevasopressin deficiency are generally unable to concentrate urine to greater than the plasma osmolality but are able to increase their urine osmolality by > 50 to > 100% after exogenous vasopressin administration. Patients with partial argininevasopressin deficiency are often able to concentrate urine to above the plasma osmolality but show a rise in urine osmolality of 15 to 50% after vasopressin administration. Patients with argininevasopressin resistance are unable to concentrate urine to greater than the plasma osmolality and show no additional response to vasopressin administration (see table ).

Measurement of circulating vasopressin or copeptin, the C-terminal peptide end of vasopressin, is the most direct method of diagnosing argininevasopressin deficiency; levels of vasopressin and copeptin at the end of the water deprivation test (before the vasopressin injection) are low in argininevasopressin deficiency and appropriately elevated in argininevasopressin resistance. However, vasopressin and copeptin levels are difficult to measure, and the tests are not routinely available. In addition, the physiologic response to water deprivation is so accurate that direct measurement of vasopressin or copeptin is unnecessary. Plasma vasopressin or copeptin levels are only diagnostic after either dehydration or infusion of hypertonic saline.

Pearls & Pitfalls

  • The water deprivation test should be done while the patient is under constant supervision because serious dehydration may occur.


Water Deprivation Test Results



Complete ArginineVasopressin Deficiency

Partial ArginineVasopressin Deficiency

Complete ArginineVasopressin Resistance

Partial ArginineVasopressin Resistance

Primary Polydipsia

Uosm after dehydration (step 1)

Very high (> 700–800 mOsm/kg [> 700–800 mmol/kg])

Very low (less than plasma osmolality)

Low (≥ 300 mOsm/kg [≥ 300 mmol/kg])

Very low (less than plasma osmolality)

Very low (less than plasma osmolality)

High (500–600 mOsm/kg [500–600 mmol/kg])

Uosm increase after vasopressin (step 2)

Minimal (< 5%)

50 to > 100%


< 50 mOsm/kg (<50>

Up to 45%

No change

Uosm = urine osmolality.

Primary polydipsia

Primary polydipsia (sometimes referred to as psychogenic polydipsia) may present a difficult problem in differential diagnosis. Patients may ingest and excrete up to 6 L of fluid/day and may have a mental health disorder. Unlike patients with argininevasopressin deficiency and argininevasopressin resistance, patients with primary polydipsia usually do not have nocturia, nor does their thirst wake them at night. Continued ingestion of large volumes of water in this situation can lead to life-threatening hyponatremia Hyponatremia Hyponatremia is decrease in serum sodium concentration < 136 mEq/L (< 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure... read more .

Patients with acute excessive water drinking are able to concentrate their urine during water deprivation. However, because chronic water intake diminishes medullary tonicity in the kidneys, patients with long-standing polydipsia are not able to concentrate their urine to maximal levels during water deprivation, a response similar to that of patients with partial argininevasopressin deficiency. However, unlike argininevasopressin deficiency, patients with primary polydipsia show no response to exogenous vasopressin after water deprivation. This response resembles that of argininevasopressin resistance, except that basal vasopressin levels are low compared with the elevated levels present in argininevasopressin resistance. After prolonged restriction of fluid intake to 2 L/day, normal concentrating ability returns within several weeks.

Treatment of ArginineVasopressin Deficiency

  • Hormonal medications, eg, desmopressin

  • Nonhormonal medications, eg, diuretics

Argininevasopressin deficiency can be treated with hormone replacement and treatment of any correctable cause. In the absence of appropriate management, permanent renal damage can result.

Restricting salt intake may also help because it reduces urine output by reducing solute load.

Hormonal medications

Desmopressin, a synthetic analog of vasopressin with minimal vasoconstrictive properties, has prolonged antidiuretic activity, lasting for 12 to 24 hours in most patients, and may be administered intranasally, orally, subcutaneously, or intravenously. Desmopressin is the aqueous preparation of choice for both adults and children. Intranasal administration is most common with a spray bottle that delivers 10 mcg of desmopressin in 0.1 mL of fluid. This preparation delivers a fixed quantity and can be given multiple times a day.

For each patient, the duration of action of a given dose must be established because variation among individuals is great. The duration of action can be established by following timed urine volumes and osmolality. The nightly dose is the lowest dose required to prevent nocturia. The morning and evening doses should be adjusted separately. The usual dosage range in individuals > 12 years is 10 to 40 mcg, with most requiring 10 mcg twice a day. For children age 3 months to 12 years, the usual dosage range is 2.5 to 10 mcg twice a day.

Overdosage can lead to fluid retention and decreased plasma osmolality, possibly resulting in seizures in small children. In such instances, furosemide can be given to induce diuresis. Headache may be a troublesome adverse effect but generally disappears if the dosage is reduced. Infrequently, desmopressin causes a slight increase in blood pressure. Absorption from the nasal mucosa may be erratic, especially when symptoms of an upper respiratory infection or allergic rhinitis occur.

Tablets are also available for outpatients. Choice of spray or tablet formulations depends on patient preference and other medical circumstances. Typically, intranasal preparations are not used immediately after intranasal surgeries but may be chosen if tablets do not control symptoms adequately. With oral desmopressin, dose equivalence with the intranasal formulation is unpredictable, so individual dose titration is needed. The initial dose is 0.1 mg orally 3 times a day, and the maintenance dose is usually 0.1 to 0.2 mg 3 times a day.

Parenteral routes of administration are generally reserved for inpatient use. When intranasal delivery of desmopressin is inappropriate, it may be administered subcutaneously using about one tenth of the intranasal dose. Aqueous vasopressin 1 to 2 mcg subcutaneously or IM can be given to provide an antidiuretic response that usually lasts up to 12 hours, with occasional longer effect. It is not easily obtained in outpatient pharmacies, thus, this medication has little use in long-term treatment but can be used in the initial therapy of unconscious patients and in patients with argininevasopressin deficiency who are undergoing surgery. Desmopressin may be used IV if a rapid effect is necessary (eg, for hypovolemia).

Pearls & Pitfalls

  • The duration of action of a given dose of desmopressin varies greatly among individuals and must be established for each patient.

Nonhormonal medications

At least 3 groups of nonhormonal medications are useful in reducing polyuria:

  • Diuretics, primarily thiazides

  • Vasopressin-releasing medications (eg, chlorpropamide, carbamazepine, clofibrate)

  • Prostaglandin inhibitors

These medications have been particularly useful in partial argininevasopressin deficiency and do not cause the adverse effects of exogenous vasopressin.

Thiazide diuretics paradoxically reduce urine volume in partial and complete argininevasopressin deficiency (and argininevasopressin resistance), primarily as a consequence of reducing extracellular fluid (ECF) volume and increasing proximal tubular resorption. Urine volumes may fall by 25 to 50% with 15 to 25 mg/kg of chlorothiazide.

Vasopressin-releasing medications can reduce or eliminate the need for vasopressin in some patients with partial central argininevasopressin deficiency. None is effective in argininevasopressin resistance. Chlorpropamide 3 to 5 mg/kg orally once or twice a day causes some release of vasopressin and also potentiates the action of vasopressin on the kidneys. Clofibrate 500 to 1000 mg orally twice a day or carbamazepine 100 to 400 mg orally twice a day is recommended for adults only. These medications may be used synergistically with a diuretic. However, significant hypoglycemia may result from chlorpropamide.

Prostaglandin inhibitors (eg, indomethacin 0.5 to 1.0 mg/kg orally 3 times a day, although most nonsteroidal anti-inflammatory drugs [NSAIDs] are effective) are modestly effective. They may reduce urine volume, but generally by no more than 10 to 25%, perhaps by decreasing renal blood flow and glomerular filtration rate (GFR). Together with indomethacin, restriction of sodium intake and a thiazide diuretic help further reduce urine volume in argininevasopressin resistance.

Key Points

  • Argininevasopressin deficiency is caused by a deficiency of vasopressin, which decreases the kidneys' ability to reabsorb water, resulting in massive polyuria (3 to 30 L/day).

  • The cause may be a primary genetic disorder or various tumors, infiltrative lesions, injuries, or infections that affect the hypothalamic-pituitary system.

  • Diagnose using a water deprivation test; patients cannot maximally concentrate urine following dehydration but can concentrate urine after receiving exogenous vasopressin.

  • Low vasopressin or copeptin levels are diagnostic, but vasopressin and copeptin levels are difficult to measure, and the tests are not routinely available.

  • Address any treatable causes and give desmopressin, a synthetic analog of vasopressin.

More Information

  • Working Group for Renaming Diabetes Insipidus, Arima H, Cheetham T, et al. Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus. Endocr J 69(11):1281-1284, 2022. doi:10.1507/endocrj.EJ20220831

Drugs Mentioned In This Article

Drug Name Select Trade
Arginine, Nutricia SHS L-Arginine, R-Gene
Pitressin, Vasostrict
DDAVP, Minirin, Nocdurna, Noctiva, Stimate
Delone , FUROSCIX, Lasix
Carbatrol, Epitol , Equetro, Tegretol, Tegretol -XR
Diuril, Sodium Diuril
Indocin, Indocin SR, TIVORBEX
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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