# 07 - 393 Disorders of the Neurohypophysis

### 393 Disorders of the Neurohypophysis

Diagnosis is based on demonstrating elevated serum free T4 levels, 
inappropriately normal or high TSH secretion, and MRI evidence of a 
pituitary adenoma. Elevated free glycoprotein hormone α subunits are 
seen in many patients.

It is important to exclude other causes of inappropriate TSH secre­
tion, such as resistance to thyroid hormone, an autosomal dominant 
disorder caused by mutations in the thyroid hormone β receptor 
(Chap. 394). The presence of a pituitary mass and elevated β subunit 
levels are suggestive of a TSH-secreting tumor. Dysalbuminemic 
hyperthyroxinemia syndromes, caused by mutations in serum thyroid 
hormone binding proteins, are also characterized by elevated thyroid 
hormone levels, but with normal rather than suppressed TSH levels. 
Moreover, free thyroid hormone levels are normal in these disorders, 
most of which are familial.
PART 12
Endocrinology and Metabolism
TREATMENT
TSH-Secreting Adenomas
The initial therapeutic approach is to remove or debulk the tumor 
mass surgically, usually using a transsphenoidal approach. Total 
resection is not often achieved as most of these adenomas are large 
and locally invasive. Normal circulating thyroid hormone levels 
are achieved in about two-thirds of patients after surgery. Thyroid 
ablation or antithyroid drugs (methimazole and propylthioura­
cil) can be used to reduce thyroid hormone levels. SRL treatment 
effectively normalizes TSH and α subunit hypersecretion, shrinks 
the tumor mass in 50% of patients, and improves visual fields in 
75% of patients; euthyroidism is restored in most patients. Because 
SRLs markedly suppress TSH, biochemical hypothyroidism often 
requires concomitant thyroid hormone replacement, which may 
also further control tumor growth.
■
■AGGRESSIVE ADENOMAS
Despite the rarity of malignant transformation and metastatic 
lesions, a subset of pituitary adenomas undergoes aggressive local 
growth and central nervous system invasion with high Ki67 levels 
(>4%). Silent corticotrope and somatotrope tumors, as well as pro­
lactinomas occurring in middle-aged men, are particularly prone to 
aggressive growth and recurrence. Patients with these tumors usually 
require an integrated management approach including repeat surger­
ies and irradiation. Temozolomide has also been used with variable 
responses.
■
■FURTHER READING
Coopmans EC et al: Multivariable prediction model for biochemical 
response to first-generation somatostatin receptor ligands in acro­
megaly. J Clin Endocrinol Metab 105:2964, 2020.
Elbelt U et al: Efficacy of temozolomide therapy in patients with 
aggressive pituitary adenomas and carcinomas: A German survey. 
J Clin Endocrinol Metab 105:e660, 2020.
Fleseriu M et al: Acromegaly: Pathogenesis, diagnosis, and manage­
ment. Lancet Diabetes Endocrinol 10:804, 2022.
Fleseriu M et al: An individualized approach to the management of 
Cushing disease. Nat Rev Endocrinol 19:581, 2023.
Hamblin R et al: Natural history of non-functioning pituitary micro­
adenomas: Results from the UK non-functioning pituitary adenoma 
consortium. Eur J Endocrinol 189:87, 2023.
Melmed S: Pituitary-tumor endocrinopathies. N Engl J Med 382:937, 
2020.
Neou M et al: Pangenomic classification of pituitary neuroendocrine 
tumors. Cancer Cell 37:123, 2020.
Petersenn S et al: Diagnosis and management of prolactin-secreting 
pituitary adenomas: A Pituitary Society international Consensus 
Statement. Nat Rev Endocrinol 19:722, 2023.
Samson SL et al: Maintenance of acromegaly control in patients 
switching from injectable somatostatin receptor ligands to oral 
octreotide. J Clin Endocrinol Metab 105:e3785, 2020.

Mirjam Christ-Crain, Mark Sherlock

Disorders of the 
Neurohypophysis
The posterior pituitary consists of the distal axons of the hypothalamic 
magnocellular neurons that make up the neurohypophysis. The peri­
karya (cell bodies) of these axons are located in paired paraventricular 
and supraoptic nuclei of the hypothalamus. Some of these neurons 
produce arginine vasopressin (AVP), also known as antidiuretic hor­
mone (ADH); others produce oxytocin. AVP acts on the renal tubules 
to reduce water loss by concentrating the urine. Oxytocin stimulates 
postpartum milk letdown in response to suckling, and also elicits 
socioemotional responses. A deficiency of AVP secretion or action 
causes a syndrome characterized by the production of large amounts 
of dilute urine. Excessive or inappropriate AVP production impairs 
urinary water excretion and predisposes to hyponatremia.
VASOPRESSIN
■
■SYNTHESIS AND SECRETION
AVP is a nonapeptide composed of a six-member disulfide ring and a 
tripeptide tail (Fig. 393-1). It is synthesized via a polypeptide precursor 
that includes AVP, neurophysin, and copeptin, all encoded by a single 
gene on chromosome 20. After preliminary processing and folding, 
the precursor is packaged in neurosecretory vesicles, where it is trans­
ported down the axon. It is further processed to AVP, neurophysin, 
and copeptin, and stored in neurosecretory vesicles in the posterior 
pituitary until it is released by exocytosis into peripheral blood.
In healthy individuals, AVP secretion is regulated primarily by the 
“effective” osmotic pressure, which is determined largely by the plasma 
concentration of sodium and its anions. This regulation is mediated by 
specialized cells in the anteromedial hypothalamus, known as osmo­
receptors. The osmoreceptors receive blood from small perforating 
branches of the anterior communicating artery. They are extremely 
sensitive to small changes in the plasma concentration of sodium and 
its anions but normally are insensitive to other naturally occurring 
plasma solutes such as urea and glucose. This osmoregulatory system 
includes inhibitory as well as stimulatory components that function in 
concert to create an osmotic threshold, or set point, control system. 
Below this osmotic threshold, plasma AVP is suppressed to levels 
that permit the development of a maximum water diuresis. Above the 
threshold, plasma AVP rises steeply in direct proportion to plasma 
osmolarity, quickly reaching levels sufficient to produce maximum 
antidiuresis. The absolute levels of plasma osmolarity/sodium at which 
minimally and maximally effective levels of plasma AVP occur differ 
from person to person, apparently due to genetic influences on the set 
and sensitivity of the system. However, the average threshold, or set 
point, for AVP release corresponds to a plasma osmolarity and sodium 
of ~275 mosmol/L and 135 meq/L, respectively; levels only 2–4% 
higher normally result in maximum antidiuresis.
AVP is also secreted in response to a decrease in blood pressure or by 
volume loss of >10–20%. These hemodynamic (baroregulated) influ­
ences are mediated by neuronal afferents that originate in transmural 
pressure receptors of the heart and large arteries and project via the 
vagus and glossopharyngeal nerves to the brainstem, which sends post­
synaptic projections to the hypothalamus. AVP secretion also can be 
stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, 
smoking, and possibly angiotensin. Emetic stimuli are extremely potent 
in comparison to osmotic stimuli; they typically elicit immediate, 50- to 
100-fold increases in plasma AVP even when the nausea is transient 
and not associated with vomiting or other symptoms. They act via the 
emetic center in the medulla and can be blocked completely by treat­
ment with antiemetics such as fluphenazine. There is no evidence that 
pain or other noxious stresses have any effect on AVP unless they elicit 
a vasovagal reaction and its associated nausea and hypotension.

DNA
Vasopressin
Neurophysin II
Copeptin
Oxytocin
Neurophysin I
FIGURE 393-1  Primary structure, production, and release of arginine vasopressin (AVP). AVP is a nonapeptide composed of a six-member disulfide ring and a tripeptide 
tail. It is synthesized via a polypeptide precursor that includes AVP, neurophysin, and copeptin, all encoded by a single gene on chromosome 20. The precursor hormone, 
pre-pro-vasopressin consists of three peptides: AVP, neurophysin 2, and copeptin.
■
■ACTION
The most important physiologic action of AVP is to reduce water 
excretion by promoting the concentration of urine. Other physiologic 
actions of AVP include stimulating ACTH and vasoconstriction. 
This antidiuretic effect is achieved primarily by increasing the hydroosmotic permeability of principal cells that line the distal tubule and 
medullary collecting ducts of the kidney (Fig. 393-2). In the absence 
of AVP, these cells are impermeable to water and reabsorb little, if 
any, of the relatively large volume of dilute filtrate that enters from the 
proximal nephron. In this condition, the rate of urine output can be as 
high as 0.2 mL/kg per min and the specific gravity and osmolarity as 
low as ~1.000 and 50 mOsmol/L, respectively. When AVP is secreted, 
it binds to V2 receptors on the basal surface of principal cells causing 
water channels composed of aquaporin-2 (AQ-2) to be inserted into 
the apical surface of the cell. These channels allow water to flow pas­
sively from the lumen through the cell down the osmotic gradient cre­
ated by the hypertonicity of the renal medulla. The magnitude of this 
antidiuretic effect varies in direct proportion to plasma AVP, the rate 
of solute excretion, and the level of hypertonicity in the renal medulla. 
The maximum antidiuresis achievable in healthy humans occurs at 
plasma AVP concentrations in the range of 1 to 3 pg/mL and results 
in a urine osmolarity as high as 1200 mOsmol/L. However, maximum 
concentrating capacity varies considerably depending on the level of 
hypertonicity in the renal medulla and that, in turn, is a function of the 
level and duration of AVP receptor 2 (AVPR2)–stimulated reabsorp­
tion of urea in the distal nephron. Hence, if basal AVP stimulation of 
AVPR2 is low (e.g., a high basal fluid intake in primary polydipsia), the 
rise in urine osmolarity that occurs immediately after an increase in 
AVP concentrations may be so blunted as to suggest a defect in antidi­
uretic function. This reduced concentrating capacity accounts for the 
shortcomings of the traditional indirect methods for the differential 
diagnosis of polyuric states (see below).
At high concentrations, AVP also causes contraction of smooth 
muscle in blood vessels in the skin and gastrointestinal tract, 
induces glycogenolysis in the liver, and potentiates ACTH release by 

Thirst
Brainstem
Osmoreceptor
Disorders of the Neurohypophysis
CHAPTER 393
Hypothalamus
Baroreceptor
Vagus
nerve
Posterior
pituitary
Luminal
membrane
AQ2 channel
Migration to the
luminal membrane
mRNA for
AQ2 channels
Pre-formed
AQ2 channels
ATP
cAMP
Basolateral
membrane
V2 receptor
AVP
FIGURE 393-2  Antidiuretic effect of arginine vasopressin (AVP) in the regulation 
of urine volume. In a typical 70-kg adult, the kidney filters ~180 L/d of plasma. Of 
this, ~144 L (80%) is reabsorbed isosmotically in the proximal tubule and another 8 
L (4–5%) is reabsorbed without solute in the descending limb of Henle’s loop. In the 
presence of AVP, solute-free water is reabsorbed osmotically through the principal 
cells of the collecting ducts, resulting in the excretion of a much smaller volume 
of concentrated urine. This antidiuretic effect is mediated via a G protein–coupled 
V2 receptor that increases intracellular cyclic AMP, thereby inducing translocation 
of aquaporin 2 (AQP 2) water channels into the apical membrane. The resultant 
increase in permeability permits an influx of water that diffuses out of the cell 
through AQP 3 and AQP 4 water channels on the basal-lateral surface. The net rate 
of flux across the cell is determined by the number of AQP 2 water channels in the 
apical membrane and the strength of the osmotic gradient between tubular fluid and 
the renal medulla.

NORMAL AVP AND THIRST RESPONSE TO 5% SALINE INFUSION

Plasma AVP (pg/mL)

PART 12
Endocrinology and Metabolism

LD

Plasma osmolality (mosm/kg)
FIGURE 393-3  The relationship of plasma osmolality to arginine vasopressin (AVP) secretion and thirst. VAS, visual analogue scale.
corticotropin-releasing factor. These effects are mediated by V1a or V1b 
receptors that are coupled to phospholipase C. They may also affect the 
sensitivity of the baroreceptor and influence sympathetic and parasym­
pathetic outflows to a variety of target organs, including the heart, the 
peripheral vasculature, and the kidneys.
■
■METABOLISM
AVP distributes rapidly into a space approximately equal to the extra­
cellular fluid volume. It is cleared irreversibly with a half-life (t1/2) of 
10–30 min. Most AVP clearance is due to degradation in the liver 
and kidneys. During pregnancy, the metabolic clearance of AVP is 
increased three- to fourfold due to placental production of an N-terminal 
peptidase (vasopressinase). Importantly, the synthetic vasopressin 
analogue desmopressin (DDAVP) is more resistant to N-terminal pep­
tidases, resulting in a longer half-life.
THIRST
Because AVP cannot reduce water loss below a certain minimum 
level obligated by urinary solute load and evaporation from skin and 
lungs, a mechanism for ensuring adequate water intake is essential for 
preventing dehydration. This vital function is performed by the thirst 
mechanism. Like AVP, thirst and fluid intake are regulated primarily 
by an osmostat that is localized in the anteromedial hypothalamus and 
detects very small changes in the plasma concentration of sodium and 
its anions. The thirst osmostat appears to be “set” about 3% higher 
than the AVP osmostat (Fig. 393-3). This relationship ensures that 
thirst, polydipsia, and dilution of body fluids do not occur until plasma 
osmolarity/sodium exceeds the defensive capacity of the antidiuretic 
mechanism. Defects in thirst result in hypodipsia/adipsia. The gas­
trointestinal tract also has a mechanism that detects fluid intake and 
inhibits thirst and AVP secretion before water is absorbed sufficiently 
to lower plasma osmolarity/sodium. However, the resultant inhibition 
of thirst and AVP is transient unless plasma osmolarity/sodium is 
reduced, and the role of this system in clinical disorders of water bal­
ance has not been determined.
OXYTOCIN
Oxytocin (OXT) is also a nonapeptide that differs from AVP at posi­
tions 3 and 8 (Fig. 393-1). However, it has relatively little antidiuretic 
effect and seems to act mainly on mammary ducts to facilitate milk 
letdown during nursing. It also may help initiate or facilitate labor by 
stimulating contraction of uterine smooth muscle, but it is not clear if 
this action is physiologic or necessary for normal delivery. In addition 
to its release from axonal terminals, OXT is dendritically released into 

Thirst (cm/VAS)

Plasma osmolality (mosm/kg)

the central extracellular space and directly projected to other brain 
regions, where it acts as a neurotransmitter. The central oxytocinergic 
system is key in regulating socioemotional functioning, including 
attachment and pair bonding, fear extinction, emotion recognition, 
and empathy.
DEFICIENCIES OF AVP SECRETION AND 
ACTION
■
■DIABETES INSIPIDUS (AVP DEFICIENCY AND AVP 
RESISTANCE)
Clinical Characteristics 
Deficiencies in AVP secretion or action 
result in the excretion of abnormally large volumes of dilute urine. 
The 24-h urine volume exceeds 40–50 mL/kg body weight and conse­
quently leads to polydipsia. Signs and symptoms of dehydration (and 
biochemical hypernatremia) are uncommon unless thirst and/or water 
intake are also impaired.
Etiology 
AVP deficiency and AVP resistance should be differenti­
ated from increased AVP metabolism in pregnancy and from primary 
polydipsia. Primary deficiency of AVP secretion was formerly called 
neurogenic, pituitary, cranial, or central diabetes insipidus but is now 
referred to as AVP deficiency. It can be caused by a variety of acquired, 
congenital, or genetic disorders but is often idiopathic (Table 393-1). 
The most common genetic form is transmitted in an autosomal domi­
nant mode and is caused by diverse mutations in the coding region 
of one allele of the AVP–neurophysin II (or AVP-NPII) gene. Renal 
insensitivity to the antidiuretic action of AVP leads to AVP resistance, 
which was formerly known as nephrogenic diabetes insipidus. It can be 
caused by a drug such as lithium, a disorder such as hypokalemia and 
hypercalcemia, or by a genetic mutation.
In pregnancy, increased metabolism of AVP may occur due to AVP 
degradation by an N-terminal aminopeptidase (vasopressinase) pro­
duced in the placenta. This is referred to as gestational AVP deficiency 
because the signs and symptoms manifest during pregnancy and usu­
ally remit several weeks after delivery.
These forms of AVP deficiency and AVP resistance should be dif­
ferentiated from excessive intake of fluids, which is commonly referred 
to as primary polydipsia. This disorder is common in patients with neu­
rodevelopmental or psychotic disorders, particularly chronic schizo­
phrenia. Outside the psychiatric setting, it is increasingly seen in the 
general population owing to the popularity of lifestyle programs and 
the belief that drinking large amounts of water is healthy and improves 
cognition (Table 393-1).

TABLE 393-1  Etiology of Polyuria–Polydipsia Syndromes
BASIC DEFECT
ACQUIRED CAUSES
HEREDITARY CAUSES
AVP Deficiency
Deficiency in AVP 
synthesis or secretion
• Trauma (surgery, deceleration injury)
• Neoplasia (craniopharyngioma, meningioma, germinoma, metastases)
• Vascular (cerebral or hypothalamic hemorrhage, infarction or ligation of anterior 
communicating artery aneurysm)
• Granulomatous (histiocytosis, sarcoidosis)
• Infectious (meningitis, encephalitis, tuberculosis)
• Inflammatory or autoimmune (lymphocytic infundibuloneurohypophysitis, IgG4 
neurohypophysitis)
• Drug or toxin exposure
• Osmoreceptor dysfunction (adipsic DI)
• Others (hydrocephalus, ventricular or suprasellar cyst, trauma, and degenerative diseases)
• Idiopathic
AVP Resistance
Reduced renal sensitivity 
to antidiuretic effect of 
physiologic AVP levels
• Drug exposure (lithium, demeclocycline, cisplatin, etc.)
• Hypercalcemia or hypokalemia
• Infiltrating lesions (sarcoidosis, amyloidosis, multiple myeloma, etc.)
• Vascular disorders (sickle cell anemia)
• Mechanical (polycystic kidney disease and urethral obstruction)
Primary Polydipsia
Excessive fluid intake at a 
diminished set point 
• Dipsogenica (idiopathic or similar lesions as with central DI)
• Psychosis intermittent hyponatremia–polydipsia (PIP) syndrome
• Compulsive water drinking
• Health enthusiasts
Gestational AVP Deficiency
Increased enzymatic 
metabolism of circulating 
AVP hormone
Pregnancy
NA
aDownward resetting of the thirst threshold.
Abbreviations: AVP, arginine vasopressin; AVPR, AVP receptor; DI, diabetes insipidus; NA, not applicable; PCSK1, proprotein convertase subtilisin/kexin type 1; WFS1, 
Wolfram syndrome 1.
Source: Reproduced with permission from M Christ-Crain et al: Diabetes insipidus. Nat Rev Dis Primers 5:54, 2019.
Pathophysiology 
In AVP deficiency and resistance, the defect in 
urine concentration increases the rate of water excretion and causes a 
small (1–2%) decrease in body water and a commensurate increase in 
plasma osmolarity/sodium, which stimulates thirst and a compensa­
tory increase in water intake. The severity of the defect in antidiuretic 
function varies significantly from patient to patient. In some patients, 
AVP deficiency is nearly complete and cannot be overcome by even an 
intense stimulus such as nausea or severe dehydration. In others, AVP 
deficiency is incomplete, and a modest stimulus such as a few hours 
of fluid deprivation, smoking, or a vasovagal reaction is sufficient to 
concentrate the urine. However, even in patients with a partial defect, 
the maximum level of urine osmolarity produced by these stimuli is 
usually less than normal partly because the prior deficiency in basal 
AVP stimulation temporarily diminishes renal concentrating capacity. 
Nevertheless, the underlying cause of the AVP deficiency/resistance 
can be determined by analyzing the relationship of urine osmolar­
ity to plasma AVP/copeptin and of plasma AVP/copeptin to plasma 
osmolarity/sodium.
The pathophysiology of primary polydipsia is the reverse of that 
in AVP deficiency or resistance. The increase in fluid intake reduces 
plasma osmolarity/sodium and leads to a physiologic decrease in 
AVP secretion. The resultant urinary dilution produces a compensa­
tory increase in urinary free-water excretion that usually offsets the 
increase in intake and stabilizes plasma osmolarity/sodium at a level 
below basal. Thus, hyponatremia is uncommon unless the polydipsia is 
very severe or the compensatory water diuresis is impaired (by another 
contributory factor that causes AVP release). In diagnostic tests, fluid 
deprivation or hypertonic saline infusion produces a normal rise in 
plasma AVP, but the resultant increase in urine concentration is usually 
subnormal because the capacity of the kidney to concentrate the urine 

• Autosomal dominant: AVP mutations
• Autosomal recessive, type a and b: 
AVP mutations
• Autosomal recessive, type c: WFS1 
mutations
• Autosomal recessive, type d: PCSK1 
Disorders of the Neurohypophysis
CHAPTER 393
mutations
• X-linked recessive: gene unknown
• X-linked: AVPR2 mutations
• Autosomal recessive or dominant: 
AQP2 mutations 
NA
is temporarily diminished by the prior lack of AVP stimulation. Thus, 
the maximum level of urine osmolarity achieved is often indistinguish­
able from that produced by fluid deprivation and/or administration 
of ADH in partial pituitary or partial nephrogenic diabetes insipidus. 
However, unlike AVP deficiency or resistance, the relationships of the 
rise in plasma AVP to the rise in plasma and urine osmolarity are both 
normal in primary polydipsia.
Differential Diagnosis 
If symptoms of polyuria, nocturia, and/or 
persistent thirst are present in the absence of glucosuria, the possibility 
of AVP deficiency or AVP resistance should be evaluated by collecting a 
24-h urine on unrestricted fluid intake. If the volume is >40–50 mL/kg 
per day and/or >3 L/d, further investigations are indicated. If sodium 
levels are below the normal reference range (<135 mmol/L), this sug­
gests primary polydipsia since these patients can drink themselves into 
hyponatremia. If sodium levels are above the normal reference range, 
the diagnosis of AVP deficiency or resistance is likely, and a test with 
desmopressin (2 μg) followed by a repeat measurement of urine osmo­
larity will determine if hypotonic polyuria is due to a AVP deficiency 
or AVP resistance. This is subcutaneous and should be done in hospital 
to allow reassessment of urinary osmolality. However, in most patients, 
sodium levels will be in the normal range, making further tests for dif­
ferential diagnosis necessary (Fig. 393-4).
The indirect water deprivation test was the gold standard for dif­
ferential diagnosis for many years. This test is based on indirect 
assessment of AVP activity by measurement of the urine concentra­
tion capacity during a prolonged period of dehydration and again 
after a subsequent injection of an exogenous synthetic AVP analogue, 
desmopressin. However, the published criteria for interpretation were 
based on post hoc data from a small number of patients with an overall

Suspected hypotonic polyuria
Confirm the presence of polyuria (>40–50 mL/kg/24 h)
GU evaluation 
Urine osmolality <800 mosm/kg
Measure serum sodium, plasma osmolality
Low serum sodium (<135 mmol/L)
PART 12
Endocrinology and Metabolism
Primary polydipsia
Normal serum sodium (136–146 mmol/L)
Baseline copeptin level
Water deprivation test
Urine osmolality
<300 mosm/kg
Copeptin
>21.4 pmol/L
Copeptin
<21.4 pmol/L
Urine osmolality
300–800 mosm/kg
Urine osmolality
>800 mosm/kg
Mild primary
polydipsia
Desmopressin test
Desmopressin test
Stimulated copeptin
>4.9 pmol/L
(at plasma sodium
>150 mmol/L)
<50% increase
>50% increase
>9% increase
<9% increase
Primary
polydipsia
Complete or partial
central DI
Nephrogenic
DI
Complete
central DI
Partial
central DI
Primary
polydipsia
FIGURE 393-4  Algorithm for differential diagnosis of polyuria polydipsia syndrome. If symptoms of polyuria, nocturia, and/or persistent thirst are present in the absence 
of glucosuria, the possibility of arginine vasopressin (AVP) deficiency or AVP resistance should be evaluated by collecting a 24-h urine on unrestricted fluid intake. If the 
volume is >50 mL/kg per day with a concomitant urinary osmolality <800 mOsm/kg, serum sodium and plasma osmolality should be measured. If sodium levels are below 
the normal reference range, it suggests primary polydipsia since these patients can drink themselves into hyponatremia. If sodium levels are above the normal reference 
range, the diagnosis of AVP deficiency or resistance can be made, and a test with desmopressin (2 μg) followed by a repeat measurement of urine osmolarity will determine 
if hypotonic polyuria is due to a AVP deficiency or AVP resistance. However, in most patients, sodium levels will be in the normal range, making further tests for differential 
diagnosis necessary. If copeptin measurement is available, a copeptin-based diagnostic algorithm is used. High baseline copeptin level of >21.4 pmol/L without prior water 
deprivation identifies AVP resistance. For the more difficult differential diagnosis of AVP deficiency and primary polydipsia, a copeptin level of >4.9 pmol/L at a high sodium 
level (≥150 mmol/L) after hypertonic saline infusion has an overall diagnostic accuracy of 97% to diagnose AVP deficiency. DI, diabetes insipidus; GU, genitourinary.
diagnostic accuracy of 70% and only 41% for patients with primary 
polydipsia. To overcome these limitations, direct measurement of AVP 
was proposed, but despite initial promising results, this method is not in 
routine clinical use, mainly because of technical limitations of the AVP 
assay. Copeptin is the C-terminal segment of the AVP prohormone and 
is an AVP surrogate that is very stable ex vivo (Fig. 393-1). Studies have 
shown that a high baseline copeptin level of >21.4 pmol/L, without 
prior water deprivation, unequivocally identifies AVP resistance. For 
the more difficult differential diagnosis of AVP deficiency and primary 
polydipsia, a copeptin level of >4.9 pmol/L at a high sodium level (≥150 
mmol/L) after hypertonic saline infusion has an overall diagnostic 
accuracy of 96.5%. Importantly, this test requires close monitoring of 
sodium levels. Copeptin levels after arginine infusion have also shown 
promising results in differentiating AVP deficiency from primary poly­
dipsia, but with a lower diagnostic accuracy. Currently, copeptin assays 
are commercially available in Europe, Australia, India, and Mexico, and 
tests are pending in several other countries.
Once AVP deficiency has been diagnosed, the underlying pathology 
must be identified by magnetic resonance imaging (MRI) of the sella 
and suprasellar regions. Also, assessment of the posterior pituitary and 
the pituitary stalk can be helpful in the differential diagnosis of AVP 
deficiency. The pituitary bright spot on MRI (a radiologic marker of 
neurosecretory vesicles containing AVP) is an area of hyperintensity 

Urinary volume <50 mL/kg/24 h
High serum sodium (>147 mmol/L)
Central or nephrogenic DI
Complete or partial
nephrogenic DI
Hypertonic saline test
Stimulated copeptin
<4.9 pmol/L
(at plasma sodium
>150 mmol/L)
seen in most healthy individuals, but may be lacking in patients with 
AVP deficiency. However, the absence of the pituitary bright spot is 
not sufficient to establish a diagnosis of AVP deficiency since it can 
be present in early stages of AVP deficiency or can be absent in elderly 
patients.
Treatment 
The signs and symptoms of uncomplicated AVP defi­
ciency can be eliminated by treatment with DDAVP, a synthetic ana­
logue of AVP. DDAVP acts selectively at V2 receptors to increase urine 
concentration and decrease urine flow in a dose-dependent manner. It 
is also more resistant to degradation than is AVP and has a three- to 
fourfold longer duration of action. The dose of DDAVP impacts on the 
duration of action (i.e., the higher the dose, the greater the duration of 
action). DDAVP can be given by IV or SC injection, nasal inhalation, 
or orally by means of a tablet or melt. The doses required to treat AVP 
deficiency vary depending on the patient and the route of administra­
tion. Among adults, doses usually range from 1–2 μg qd or bid by injec­
tion, 10–20 μg bid or tid by nasal spray, or 100–400 μg bid or tid orally. 
The onset of antidiuresis is rapid, ranging from as little as 15 min after 
injection to 60 min after oral administration. Hyponatremia is the most 
common complication of desmopressin therapy, with mild depres­
sion of plasma sodium concentration (131–134 mmol/L) reported 
in about a quarter of patients with intact thirst. In 15% of patients,

hyponatremia is more severe, with plasma sodium concentration of 
<130 mmol/L. Desmopressin escape, which involves intermittently 
delaying DDAVP for a number of hours to allow a transient aquaresis, 
reduces the risk of hyponatremia.
Treatment of primary polydipsia focuses on the reduction of exces­
sive fluid intake, optimally in a graded fashion to allow patients to 
slowly reduce fluids. Treatments to reduce mouth dryness (e.g., ice 
chips, hard candy to stimulate salivary flow) are also useful to reduce 
thirst. Pharmacologic therapies have been tried without consistent 
success. A recent study suggests that glucagon-like peptide 1 (GLP-1) 
analogues reduce fluid intake, urine output, and thirst perception. 
AVP resistance is difficult to treat. Patients typically do not respond to 
desmopressin treatment; however, some patients may respond to high 
doses if their resistance is only partial. Treatment with conventional 
doses of a thiazide diuretic and/or amiloride in conjunction with a lowsodium diet and coadministration of nonsteroidal anti-inflammatory 
drugs (NSAIDs) usually reduces the polyuria and polydipsia, but this 
combination is nephrotoxic, and careful monitoring of renal function 
is important. Drug-induced AVP resistance should be treated by dis­
continuation of the causative agent—most commonly lithium—where 
possible. Persistent lithium-induced AVP resistance can be treated 
by hydrochlorothiazide and amiloride. It important to be aware 
that plasma volume contraction produced by thiazide diuretics can 
decrease lithium excretion and predispose to lithium toxicity.
■
■HYPODIPSIC/ADIPSIC HYPERNATREMIA
An increase in plasma osmolarity/sodium above the normal range 
(hypertonic hypernatremia) can be due to a decrease in total body 
water or an increase in total body sodium. The former results from a 
failure to drink enough water to replace normal or increased urinary 
and insensible loss due either to water deprivation or a lack of thirst 
(hypodipsia/adipsia).
Clinical Characteristics 
Hypodipsic/adipsic hypernatremia is 
a rare syndrome characterized by chronic or recurrent hypertonic 
dehydration that most frequently coexists with AVP deficiency (adipsic 
diabetes insipidus or adipsic AVP deficiency). The hypernatremia var­
ies widely in severity and is often associated with signs of hypovolemia 
such as tachycardia, postural hypotension, azotemia, hyperuricemia, 
and hypokalemia due to secondary hyperaldosteronism. Muscle weak­
ness, pain, rhabdomyolysis, hyperglycemia, hyperlipidemia, thrombo­
embolic disease, acute renal failure, and obtundation can also occur.
Etiology 
Hypodipsia/adipsia is usually due to abnormalities of 
osmoreceptors in the anterior hypothalamus that regulate thirst. The 
defect can result from various congenital malformations of midline 
brain structures or may be acquired due to diseases such tumors (pri­
mary or secondary, and their associated surgery) or aneurysms of the 
anterior communicating artery, head trauma, granulomatous diseases 
such as sarcoidosis and histiocytosis, AIDS, and cytomegalovirus 
encephalitis. Adipsic hypernatremia without demonstrable hypotha­
lamic lesions has also been associated with autoantibodies directed 
against the subfornical organ.
Pathophysiology 
A deficiency in osmotically induced thirst 
results in a failure to drink enough water to replenish obligatory renal 
and extrarenal losses with resultant significant hypernatremia. Rarely, 
the regulation of AVP secretion is completely normal, suggesting that 
the lack of thirst is due to a defect in postosmoreceptor neural path­
ways to higher cognitive centers.
Differential Diagnosis 
Hypodipsic/adipsic hypernatremia with or 
without coexisting AVP deficiency usually can be distinguished from 
other causes of inadequate fluid intake (e.g., coma, paralysis, restraints, 
absence of fresh water) by the clinical history and setting as well as 
measurements of serum and urine osmolality. Previous episodes and/
or denial of thirst and failure to drink spontaneously when the patient 
is conscious, unrestrained, and hypernatremic are virtually diagnostic.
Treatment 
Hypodipsic hypernatremia can be corrected by admin­
istering water orally if the patient is alert and cooperative or by infusing 

TABLE 393-2  Approach to the Management of Water Balance for 
Patients with Adipsic Arginine Vasopressin (AVP) Deficiency
1.	 Replace AVP with sufficient vasopressin (DDAVP).
2.	 Monitor fluid input/output initially as an inpatient to achieve eunatremia.
3.	 Weigh and record patient’s eunatremic weight.
4.	 Recommend 1.5–2 L of fluid intake per day assuming urinary losses are less.
5.	 Weigh daily.
6.	 If below eunatremic weight, then replace with equivalent volume of fluid to 
restore eunatremic weight.
7.	 Recommend increased fluid intake in times of increased perspiration or 
Disorders of the Neurohypophysis
CHAPTER 393
ambient temperatures.
8.	 Regular plasma sodium measurements. 
hypotonic fluids (0.45% saline or 5% dextrose) if the patient is not. 
The amount of free water in liters required to correct the free water 
deficit should be estimated from body weight in kg and the serum 
sodium concentration in mmol/L. This amount plus an allowance for 
continuing insensible and urinary losses should be given over a 24- to 
48-h period with close monitoring of serum sodium to ensure that it 
does not correct too rapidly. Plasma urea/creatinine should be moni­
tored closely for signs of acute renal failure caused by rhabdomyolysis, 
hypovolemia, and hypotension. Once the patient has been rehydrated, 
an MRI of the brain and tests of anterior pituitary function should 
be performed to look for the cause and collateral defects in other 
hypothalamic functions. A long-term management plan to prevent or 
minimize recurrence of the fluid and electrolyte imbalance also should 
be developed. This should include a practical method to regulate fluid 
intake in accordance with variations in water balance as indicated by 
changes in body weight or serum sodium determined by home moni­
toring analyzers, if available. Another potential treatment approach is 
summarized in Table 393-2.
■
■INAPPROPRIATE ANTIDIURESIS (SEE IN MORE 
DETAIL CHAP. 56)
Clinical Characteristics 
Syndrome of inappropriate antidiuresis 
(SIAD) is produced when plasma levels of AVP are elevated at times 
when the physiologic secretion of AVP from the posterior pituitary 
would normally be osmotically suppressed. The clinical abnormality 
is a decrease in the osmotic pressure of body fluids, such that the hall­
mark of SIAD is hypoosmolality. If hyponatremia is severe or develops 
acutely, it can cause a variety of neurologic symptoms and signs, such 
as headache, confusion, anorexia, nausea, vomiting, coma, and con­
vulsions. If the hyponatremia develops gradually or exists for more 
than a few days, it may be apparently asymptomatic, but even mild 
hyponatremia is associated with an increased rate of falls and fractures, 
neurocognitive and neuromuscular symptoms, and increased morbid­
ity and mortality.
Etiology 
SIAD has many different etiologies, which are summa­
rized in Chap. 56.
Pathophysiology 
In SIAD, the failure to mount a water diuresis 
when intake exceeds urinary and insensible loss results in a slight 
expansion of total body water followed by a modest increase in urinary 
sodium excretion. As a result, expansion of extracellular volume is 
minimal, and clinically detectable edema does not develop. However, 
intracellular volume increases in proportion to the severity and rapid­
ity of the change in plasma sodium. In the brain, this cellular swelling 
causes an increase in pressure that triggers a variety of symptoms. After 
several days, the swelling and symptoms may subside due to inactiva­
tion of some intracellular solutes and resultant decrease in cellular 
volume.
Differential Diagnosis 
Evaluation of urine and serum osmo­
lality and sodium is the most useful investigation in establishing 
whether the diagnostic criteria for SIAD are met, alongside clinical 
assessment of volume status. Measurement of serum osmolality is 
important to exclude non-hypotonic causes of hyponatremia, such