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Table 25.3
Test Insulin-induced hypoglycemia Glucagon stimulation test Arginine
Contraindications History of seizures, coronary
Precautions Some patients may develop
Procedure Patient fasted from midnight for
Measurement Basal
Interpretation If adequate hypoglycemia
GH growth hormone, GHD growth hormone deciency, GHRH somatotropin releasing hormone, IGF insulin-like growth factor
Characteristics of the main GH stimulus tests
artery disease, pregnancy, or age
>55years
neuroglycopenic symptoms during
the test when glucose levels fall
and should eventually be
encouraged to report these
symptoms
8–10hours (water is allowed)
Discontinue all morning
medications
Weigh the patient
Administer insulin (standard dose:
0.05–0.1units/kg for non-diabetic
subjects with BMI <30kg/m
high dose: 0.15–0.3units/kg for
subjects with BMI ≥30kg/m
Blood is drawn to measure
glucose
During the test
Blood is drawn every 15minutes
to measure glucose levels
When hypoglycemia (<40mg/dL)
is reached, glucose and GH are
measured at 20, 25, 30, 35, 40, 60,
and 90minutes. When nished,
the patient can drink fruit juice
and eat to raise blood glucose
At the end of the test
Glucose levels should be >70mg/
dL
(<40mg/dL) is not achieved,
GHD cannot be diagnosed
A peak serum GH level <5ng/mL
at any time during the
hypoglycemic phase of the test is
diagnostic of GHD in the adult
2
and
2
)
Malnourished patients or
patients who did not eat
for more than 48hours
Fasting hyperglycemia
(glycemia >180mg/dL)
Patients could feel
nauseous during test
Possible late hypoglycemia
(at the end of the test,
patients should eat little
and slowly)
Make sure the patient has
been fasting for
8–10hours
Weigh the patient
Place the patient in the
supine position
Administer 1mg
intramuscular glucagon
(1.5mg if the patient has a
weight >90kg)
Measure serum GH and
glucose levels at 0, 30, 60,
90, 120, 150, 180, 210, and
240minutes
Peak serum GH levels tend
to appear between 120 and
180minutes
The GH peak <3ng/mL
and <1ng/mL in patients
with BMI <25kg/m
≥25kg/m2, respectively, at
any time during the test is
diagnostic of GHD in the
adult
2
and
Enhanced test
GHRH +arginine
Allergy to arginine Allergy to GHRH analogue
Nausea, vomiting,
headache and redness
Make sure the patient is
fasting from midnight for
8–10hours
Discontinue all morning
drugs
Weigh the patient
Administer arginine 0.5g/
kg (maximum 30g) as an
infusion for 30minutes
Basal
Dosage of GH and IGF-1
During the test
Serum GH levels are
measured at 30, 60, 90,
and 120minutes
The GH peak <0.4ng/mL
at any time during the test
is diagnostic of adult GHD
and arginine
Transient feeling of heat
and/or redness due to
GHRH
Nausea, headache, transient
hypotension
Make sure the patient is
fasting from midnight for
8–10hours (water is
allowed)
Discontinue all morning
drugs
Weigh the patient
Administer the GHRH
analogue (1μg/kg) as a
bolus and arginine
hydrochloride (30g)
simultaneously as an
infusion for 0–30minutes
Basal
Dosage of GH and IGF-1
levels
During the test
Serum GH levels are
measured at 30, 60, 90, and
120minutes
GH values must be
evaluated according to
BMI; serum GH levels
<11ng/mL, 8ng/mL, and
4ng/mL at any time during
testing in patients with BMI
≥30kg/m
and <25kg/m
are diagnostic of GHD in
adults
2
, 25–30kg/m2
2
, respectively,
tice but should be further investigated in the presence of the
following conditions:
• Severe short stature (<−3 SD)
• Stature <−1.5 SD relative to the familial genetic target
and growth velocity/year ≤−2 SD or ≤−1.5 SD after two
consecutive years
• Stature ≤−2 SD with a growth velocity/year <−1 SD relative to normal for age and sex, assessed at a distance of at
least 6months, or a reduction in stature of 0.5SD/year in
children older than 2years
• In the absence of short stature, growth velocity ≤−2 SD
over one year or ≤−1,5 SD over two years
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• Neuroradiologically demonstrated hypothalamicpituitary malformations/injuries
• Neonatal signs or symptoms of GHD
In children with short stature and suspected GHD, the
diagnosis is classically made when GH levels do not reach a
cutoff value after two pharmacological stimuli.
Increased GH in response to a single drug test excludes
the diagnosis of GH deciency. A second stimulus test must
conrm a positive response to a rst stimulus test. If the second test is also positive, the hormone deciency is conrmed,
which, associated with the clinical and auxological features,
allows the diagnosis of GH deciency.
Extemporaneous GH measurements cannot distinguish
healthy children from those with true GH deciency.
However, altered response to stimulus testing withnormal
auxologic and clinical ndings cannot be considered probative of GH deciency.
Determination of IGF-1 levels helps conrm possible GH
deciency. MRI of the pituitary gland can conrm the diagnostic hypothesis, highlighting any tumor lesions or structural defects.
An early diagnosis and an appropriate therapeutic
approach allow a signicant recovery of height growth and
the achievement of a nal height within the predictable target
based on the height of the parents (“genetic target”), thus
improving the patient’s quality of life.
Therapy is based on administering recombinant human
GH at a dosage of 0.2mg/kg/week, subcutaneously, divided
into daily evening administrations. A growth rate of up to
10cm/year should be observed with replacement therapy.
However, the extent of the result depends on the age at
which therapy begins. In some situations (onset of puberty,
decline in growth rate), it may be helpfulto modulate the
dosage by increasing the dose to a doubling. In any case, the
dosage should be modulated according to the clinical
response regarding stature growth.
Replacement therapy also effectively corrects growth def-
icit in girls with Turner syndrome or chronic renal failure.
In the case of pituitary deciency, any other tropin decits
should be corrected.
In children with GH insensitivity and GH receptor muta-
tion, IGF-1 replacement therapy overcomes the receptor
dysfunction.
GH Deciency inAdulthood
Diagnosing GHD in adults is difcult because its symptoms
are nonspecic.
Current guidelines recommend that the diagnosis of GHD
in adults be based on clinical criteria, medical history, and
biochemical conrmation of altered GH levels using appropriate stimulus testing.
Adult subjects mustalso have at least one of the following
conditions:
• Previous pituitary surgery
• Tumors or granulomas of the hypothalamic-pituitary
region
• Cranial irradiation
• Radiological evidence of a pituitary lesion
• Head trauma
• Diagnosis of GHD arising in childhood
• Reduced IGF-1 levels (rarer condition)
Stimulus testing is required to make the diagnosis. In par-
ticular, for diagnosing GHD in adults, the insulin-induced
hypoglycemia test is the gold standard, with the highest
sensitivity.
The GHRH + arginine test is now considered the alterna-
tive test of the rst choice.
The IGF-1 assay is not sufciently sensitive to be diag-
nostically valid; approximately 25% of adults with GHD
have normal IGF1 levels. Instead, it is used as an index of
therapeutic response.
Therapy is based on administering recombinant GH, ini-
tially at a dose of 0.15-0.3mg per day; the dosage should be
adjusted until IGF-1 levels reach normal levels according to
sex and age. Generally, women require a higher dose than
men. Long-term treatment with GH improves body composition, increasing lean body mass and reducing fat mass.
However, adults are more susceptible to side effects than
children, the most common of which are uid retention,
headaches, hypertension, and carpal tunnel syndrome.
Acromegaly
The diagnosis is made on average about 10years after the
onset of the rst symptoms because the physical changes
occurvery slowly.
Once the clinical suspicion of acromegaly is raised, the
diagnosis is conrmed by the nding of elevated basal GH
levels, IGF-1, and failure to suppress GH below 1ng/mL at
1 and 2hours after oral glucose load (75g).
In patients with acromegaly, GH secretion remains epi-
sodic but with increased peaks in number, duration, and
amplitude. In fact, in these patients, basal GH is always
measurable; to diagnose acromegaly, the repeated nding
of basal GH levels >5 ng/mL in several samples is
necessary.
The IGF-1 assay represents the most sensitive laboratory
test for diagnosing acromegaly because it is always increased
in these patients.
Subsequently, it is necessary to proceed to a localization
diagnosis by radiological investigations (computed tomography [CT] and magnetic resonance imaging [MRI]), which
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generally allow fordemonstrating the presence and extension of a pituitary adenoma. In such a case, it is necessary to
investigate hypothalamic-pituitary function by assaying the
other pituitary tropins (PRL, TSH, ACTH, LH, and FSH); for
example, an increase in PRL is observed in 25% of patients.
In rare cases, acromegaly is secondary to ectopic GH or
GHRH secretion by an extracranial tumor that must be
sought by appropriate instrumental investigations (chest
X-ray, abdominal ultrasound, etc.).
Since acromegaly is a systemic disease, once the diagnosis is made, a series of investigations should be performed to
dene the disease complications, especially those
cardiovascular.
Treatment of acromegaly can be surgical, radiotherapy, or
medical and has the following goals:
• Normalize the secretion of GH and IGF-1 (regression
and/or control of signs and symptoms of the disease);
• Remove the hypophyseal or extrahypophyseal tumor
(correction of campymetric decits);
• Maintain the integrity of normal function residual
pituitary;
• Prevent recurrence;
• Improve and prevent complications (cardiovascular,
respiratory, osteoarticular, and metabolic);
• Achieve a normal quality of life and life expectancy.
The disease’s mortality is related to GH and
IGF-1levels.
The criteria for biochemical remission of acromegaly are:
• Basal GH <2–2.5ng/mL
• GH after OGTT <1ng/mL
• Normal IGF-1 according to age and sex
Therefore, the main therapeutic goal is to ensure optimal
biochemical control.
Currently, surgical therapy represents the rst choice,
especially in pituitary microadenoma (i.e., with a diameter
<1cm). In this case, the results of neurosurgery are good,
with a cure rate of about 80%. In the presence of macroadenoma (a much more frequent occurrence), the efcacy of
neurosurgical therapy is more modest, with cure rates not
exceeding 40% of cases.
Medical therapy is particularly indicated after insufcient
neurosurgical intervention to maintain biochemical control
of the disease or, in the rst instance, in patients who refuse
surgery. In addition, medical therapy is also often prescribed
while awaiting surgery. Somatostatin analogsare the medical
therapy of choice. They have a marked inhibitory effect on
GH secretion, followed by a reduction in circulating IGF-1
levels.
Radiotherapy is currently the treatment of the third choice
due to the high incidence of complications and slow biochemical response (5–15 years). It is indicated in cases
where surgical therapy and/or medical therapy fail to control
tumor growth and normalize hormonal secretion.
Prolactin
Prolactin is a peptide hormone synthesized in lactotroph
cells constituting about 20% of the anterior pituitary gland.
PRL secretion is pulsatile and exhibits a circadian rhythm,
with the highest concentrations during sleep and the lowest
in the morning, about 2–3hours after waking up. Peak serum
PRL levels are observed between 4 and 6am. PRL has a halflife of about 50 minutes and is mainly metabolized in the
liver and, to a lesser extent, in the kidney.
Serum PRL levels transiently increase following exercise,
meals, sexual intercourse, minor surgery, general anesthesia,
acute myocardial infarction, and other forms of acute stress.
PRL represents a stress-related hormone. In addition, during
the last two trimesters of pregnancy and the rst months of
lactation, marked hyperplasia of lactotroph cells occurs transiently, with hypersecretion of PRL; the sucking reex
induces an increase in PRL that lasts 30–45minutes.
PRL is the only adenohypophysis hormone undergoing dopamine-mediated inhibitory neuroendocrine regulation. Thyrotropin-releasing hormone (TRH), vasoactive
intestinal peptide (VIP), estradiol, oxytocin, and vasopressin, on the other hand, stimulate PRL release.
The PRL exerts its action mainly at the breast level, stimulating breast tissue development and promoting lactation.
During pregnancy, in synergy with estrogen, progesterone,
and placental lactogen, PRL stimulates further development
of breast tissue aimed at milk production. After childbirth,
the milk production process begins with the sudden fall of
placental estrogen and progesterone, which antagonize the
effects of PRL on lactation. PRL, in fact, stimulates the synthesis of milk proteins (lactalbumin), lipids, and carbohydrates that are poured into the alveoli and mammary ducts.
Nipple sucking activates a nervous reex, which, by stimulating the secretion of oxytocin from the neurohypophysis
and PRL from the adenohypophysis, maintains the lactation
process. Prolactin also plays an essential role in reproductive
processes through direct and indirect mechanisms. In particular, it inhibits reproductive capacity indirectly by suppressing the synthesis and secretion of Gonadotropin-Releasing
Hormone (GnRH) at the hypothalamic level, followed by a
reduction in the secretion of gonadotropins and testosterone;
directly, by reducing the sensitivity of LH and FSH receptors
in the gonads. In this way, a state of anovulation (infertility)
contributes to maintaining lactation, preventing it from being
interrupted by a subsequent pregnancy. Prolactin also has a
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luteolytic effect, inducing a shortened or inadequate luteal
phase of the menstrual cycle.
PRL exerts its biological effects through interaction with
a receptor that belongs to the type 1 cytokine receptor family,
to which GH and IL-6 receptors also belong.
Hyperprolactinemia
The term hyperprolactinemia refers to increased circulating
PRL levels due to hormonal hypersecretion by the pituitary
gland, generally associated with reproductive problems in
both men and women. Hyperprolactinemia is found in physiological and pathological conditions (Table25.4); according
to the etiology, it can be classied into organic and functional. The most common cause of functional hyperprolactinemia is the intake of pharmacotherapeutic agents that
reduce hypothalamic dopamine secretion or its inhibitory
action on the pituitary gland (antipsychotics and antidepressants). Functional hyperprolactinemia is also common in
pregnancy and chronic renal insufciency due to reduced
peripheral PRL clearance, polycystic ovary syndrome due to
hyperestrogenism, or primary hypothyroidism due to
increased TRH secretion. Organic hyperprolactinemia is,
instead, due to lesions of the hypothalamic-pituitary region
that compromise dopamine synthesis, its transport through
portal vessels, or the response of lactotrophs elements;
among these, the most common causes are pituitary adenomas (prolactinoma and GH/PRL and ACTH/PRL-secreting
adenoma), hypothalamic tumors, and inltrative conditions
(sarcoidosis, craniopharyngioma, pituitary metastases, vascular malformations, empty saddle).
From a clinical point of view, the main manifestations of
hyperprolactinemia are amenorrhea, galactorrhea (inappropriate secretion of milk or a lactescent liquid from the breast),
and infertility in women and impotence, decreased libido,
and infertility in men. The onset of symptoms in men is gen-
Table 25.4 Causes of hyperprolactinemia
Physiological Pathological Pharmacological
Breastfeeding
Exercise
Pregnancy
Sexual
activity
Sleep
Stress
TRH thyrotropin releasing hormone
Pituitary
adenomas
Cirrhosis
Seizures
Chronic renal
failure
Primary
hypothyroidism
Lesions of the
pituitary stalk
Inltrative
diseases
Empty sella
Trauma
Hypothalamic
tumors
Histaminergic antagonists H
cimetidine
Drugs that block the dopamine
receptor: phenothiazines,
butyrophenones, thiaprides
Inhibitors of catecholamines:
reserpine
Serotonin reuptake inhibitors:
uoxetine
Inhibitors of dopamine
synthesis: α-methyldopa;
Opioid
Hormones: estrogen,
antiandrogens and TRH
2
:
erally later than in women because very high PRL values are
required. In the case of adenoma in both sexes, the symptoms
due to the expansive lesion (headache and visual impairment) can be observed.
Prolactinoma
Prolactinoma, a prolactin-secreting pituitary adenoma, is the
most frequent pituitary tumor, with a prevalence of 100 cases
per million population. Depending on the diameter of the
tumor, prolactinoma can be differentiate into microadenomas (<1cm in diameter), which generally do not invade the
parasellar regions, and macroadenomas (>1cm in diameter),
which can be locally invasive and compress adjacent structures. Generally, tumor size correlates with circulating PRL
levels. Microprolactinomas are quite frequent in females and
rare in males, with a male-to-female ratio of 1:20; this ratio
becomes 1:1 for macroprolactinomas.
Laboratory Investigations
Blood sampling for PRL levels measuring should be performed in the morning in a fasting patient who has been
awake for at least 2hours. Since PRL secretion is pulsatile, a
single determination is not sufcient to diagnose hyperprolactinemia; at least two blood samples should be taken
30–60 minutes apart, preferably using a needle cannula
because puncture of the vein can also induce an increase in
PRL secretion, or three samples taken on three different
days. The normal range of serum PRL levels in adults is
10–25ng/mL in women and 10–20ng/mL in men. In patients
with very high prolactinemia (>1000ng/mL), values may be
lower due to artifacts of the assay method; in these cases, the
sample should be diluted.
Diagnosis andTherapy
Hyperprolactinemia
The nding of serum PRL levels >25 ng/mL indicates
hyperprolactinemia.
The treatment of hyperprolactinemia depends on the etiology. However, regardless of the cause, it aims to normalize
PRL levels. Dopamine-agonist drugs are used in many forms
of hyperprolactinemia. In asymptomatic patients with hyperprolactinemia, treatment is not necessary.
Prolactinoma
Once physiologic and drug-induced hyperprolactinemia is
excluded, the diagnostic suspicion of prolactinoma is raised
for PRL values >100 ng/mL; PRL values >500 ng/mL
are diagnostic of macroprolactinoma. Once a condition of
hyperprolactinemia is identied, MRI or CT scan is necessary to dene the presence of a lesion compatible with a pituitary tumor.
The rst choice treatment in patients with a prolactinoma
is dopamine agonist therapy aimed at reducing tumor size
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and PRL levels. In patients with asymptomatic microprolactinoma no treatment is necessary; these patients should have
regular follow-ups with serial measurements of PRL levels
and MRI.Surgery is indicated in patients intolerant or unresponsive to long-term drug therapy.
Neurohypophysis
The neurohypophysis, or posterior pituitary gland, is an
extension of the hypothalamus, consisting of axon extensions whose cell bodies are located in the supraoptic and
paraventricular hypothalamic nuclei. The hypothalamicneurohypophyseal system secretes: vasopressin, also known
as antidiuretic hormone, and oxytocin.
Antidiuretic Hormone
Antidiuretic hormone (ADH), also known as vasopressin, is
a nonapeptide synthesized mainly by magnocellular neurons
of the supraoptic and paraventricular nuclei of the hypothalamus and in small amounts by some extra-hypothalamic tissues. Its primary function is maintaining hydroelectrolyte
balance through regulating renal reabsorption of water. In
particular, ADH has an antidiuretic effect by inducing an
increase in the hydro-osmotic permeability of the cells lining
the distal tube and medullary nephron collector ducts. In the
absence of ADH, these cells are impermeable to water, but
following the binding of the hormone to their receptors, they
express on their apical membrane pores for waterconsisting
of the protein aquaporin 2, which allows the reabsorption of
water followed by the urine concentration and the increase in
volemia, arterial pressure, and cardiac output. The magnitude of the antidiuretic effect is proportional to plasma ADH
concentrations. ADH also maintains electrolyte balance by
stimulating renal sodium reabsorption, mediated by ENaC
(epithelial sodium channel) luminal channels, further promoting water reabsorption.
ADH at high concentrations also exerts other actions. It
induces vascular wall smooth muscle contraction in the skin
and gastrointestinal tract, reduces lipolysis in adipose tissue,
stimulates glycogenolysis in the liver, and nally, acts synergistically with corticotropin-releasing hormone (CRH) for
the secretion of ACTH.All of these effects are mediated by
the interaction of ADH with its receptors.
The most critical factor that regulates the secretion of
ADH is the “effective” osmotic pressure of liquids whose
variations are detected by specialized hypothalamic cells
known as osmoreceptors. There is a regulatory threshold
below which ADH secretion is reduced, leading to the elimination of a large volume of very dilute urine (water diuresis)
and above which, instead, ADH levels increase in direct proportion to plasma osmolality, up to a reduction in urine ow
of 0.35mL/min. The threshold for ADH release usually cor-
responds to a plasma osmolality of 280mOsm/L and sodium
levels of 135mmol/L.The threshold value has interindividual variabilities, being genetically determined, and intraindividual variability, related to physiological factors such as
posture, pregnancy, menstrual cycle, and aging.
Although plasma hyperosmolality represents the primary
stimulus for ADH release, volemia and blood pressure reductions represent valuable inputs to its secretion. In particular,
ADH levels increase in response to a >10–20% reduction in
blood pressure and/or volemia. Finally, ADH secretion can
be inuenced by other variables such as nausea, vomiting,
smoking, acute hypoglycemia, and various drugs (diuretics,
morphine, carbamazepine, clonidine, etc.). Above all, nausea, even if transitory and not accompanied by vomiting, is a
powerful stimulant that can induce a 100–1000-fold increase
in circulating levels of ADH.
ADH exerts its effects through interaction with membrane
receptors, which can be of three types:
• V1aR: predominantly expressed onvascular smooth mus-
cle and responsible for a calcium-mediated vasoconstric-
tion mechanism
• V2R: expressed mainly on collector duct cells and, to a
lesser extent, at the endothelial level
• V1bR or V3R: mainly expressed on corticotropic cells of
the adenohypophysis, where it modulates ACTH release
via calcium signaling-mediated signal transduction
ADH has a half-life of about 10minutes and is mainly
eliminated renally and partly hepatically.
Oxytocin
Oxytocin is a nonapeptide whose primary biological function is stimulating milk secretion during lactation in response
to sucking. The sucking of the nipple activates the neurohormonal reex that stimulates the secretion of prolactin and
oxytocin; PRL stimulates the synthesis and secretion of milk
in the mammary ducts, while oxytocin promotes the contraction of the smooth muscles around the mammary glands,
increasing the ejection of milk and, in addition, stimulates
the secretion of PRL.Unlike PRL, oxytocin is sensitive to
physical or psychological stimulation related to breastfeeding and independent of the stimulus on the nipple.
Oxytocin also stimulates contractions of the uterine
smooth muscle, thus contributing to the onset of labor.
In males, no role of oxytocin is known.
Alterations in the neurohypophysis manifest as a hypo- or
hyperfunction state. The laboratory plays a crucial role in the
diagnosis of these disorders.
Diabetes Insipidus
Diabetes insipidus (DI) is a syndrome characterized by polyuria and polydipsia. DI reects reduced action or secretion of
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Table 25.5
Type of DI Defect Causes
PituitaryDI Reduced synthesis
Primitive
polydipsia
GestationalDI Increased
NephrogenicDI Partial or total loss of
ADH antidiuretic hormone
Types of diabetes insipidus (DI)
Acquired or genetic
and secretion of
ADH
Suppressed ADH
secretion due to
excessive uid intake
degradation of ADH
during pregnancy
renal sensitivity to
the antidiuretic
action of ADH
Inappropriate thirst
secondary to the reduction
of the set point of the
osmoregulatory
mechanisms (dipsogen)
Excessive thirst due to a
psychiatric (psychogenic)
disorder
Intake of large amounts of
uids for purported health
benets (iatrogenic)
Increased production of
placental N-terminal
aminopeptidases
Acquired or congenital
ADH; four different types are distinguished (Table 25.5),
described below.
Pituitary Diabetes Insipidus
The most common type is pituitary diabetes insipidus, also
known as hypothalamic, neurogenic, or central diabetes
insipidus, in which reduced ADH production and secretion
are usually related to agenesis or irreversible destruction of
the neurohypophysis that may be due to a variety of genetic
or acquired alterations. However, it is idiopathic in about
50% of cases (Table25.6). Reduced ADH secretion results in
renal free water reabsorption failure with the consequent
elimination of high amounts of poorly concentrated urine. As
a result, there is an increase in plasma osmolality, which
stimulates thirst for osmoreceptors, causing polydipsia.
Primary Polydipsia
Primary polydipsia is a clinical condition characterized by
an excessive and unmotivated introduction of uids (ingestion of more than 3liters of uids/day), usually water, resulting in polyuria. The picture is observed mainly in patients
with chronic psychiatric diseases, which is also dened as
psychogenic polydipsia. The increased intake of liquids
leads to a slight reduction in plasma osmolality, which determines a reduced secretion of ADH, leading to a reduction in
urinary osmolality and an increase in urine volume; this triggers a compensatory increase in water excretion that prevents hyperhydration.
Gestational Diabetes Insipidus
Gestational DI is also a consequence of reduced ADH levels
due to increased hormone degradation by an enzyme pro-
Table 25.6
Acquired
Head trauma
Neoplasms
- Primitive: craniopharyngioma, pituitary (suprasellar) adenoma,
-Metastatic: lung and breasts
- Hematological: lymphomas and leukemias
Granuloma
-Neurosarcoidosis
-Histiocytosis
-Disseminated xanthomas
Infections
-Meningitis
-Viral encephalitis
-Toxoplasmosis
Inammatory diseases
-Lymphocytic neurohypophysitis
-Granulomatosis with polyangiitis
-Lupus erythematosus
-Scleroderma
Vascular causes
-Sheehan syndrome
-Internal carotid aneurysm
-Coronary artery bypass grafting
-Hypoxic encephalopathy
Toxins
-Tetrodotoxin
-Snake venom
Congenital malformations
-Septo-optic dysplasia
-Craniofacial defects
-Holoprosencephaly
Idiopathic
Genetics
Autosomal dominant (gene ADH)
Autosomal recessive
-Type A (gene ADH)
-Type B (gene ADH)
-Type C (geneWFS-1)
X- linked recessive (Xq28)
Causes of pituitary diabetes insipidus
dysgerminoma, meningioma
duced by the placenta (N-terminal aminopeptidase).
Gestational DI typically develops in the third or fourth month
of pregnancy and resolves 4–6 weeks after delivery.
Generally, the changes are similar to those observed in pituitary DI.Plasma osmolality is usually in the normal range for
a pregnant woman, which is generally about 3–4% lower
than normal.
Nephrogenic Diabetes
It is caused by altered kidney sensitivity to the action of
ADH that may be genetic or acquired (Table25.7), resulting
in the inability to concentrate urine, polyuria, increased
plasma osmolality, and polydipsia. Plasma ADH concentration is normal or increased, according to plasma osmolality.
The severity of antidiuretic functiondefect is quite variable among patients with pituitary, gestational, and nephrogenic DI.In some individuals, the defect in ADH secretion or
action is so severe as to induce high urinary ow, up to
10–15liters per day.
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Table 25.7
Acquired
Drugs
-Lithium
-Demeclocycline
-Methoxyuorane
-Amphotericin B
-Aminoglycosides
-Cisplatin
-Rifampicin
-Foscarnet
Metabolic alterations
-Hypercalcemia, hypercalciuria
-Hypokalemia
Vascular causes
-Sickle cell anemia
-Ischemia (acute tubular necrosis)
Granulomas
-Neurosarcoidosis
Neoplasms
-Sarcoma
Inltrative diseases
-Amyloidosis
Pregnancy idiopathic
Genetics
Autosomal recessive (aquaporin-2)
Autosomal dominant (aquaporin-2)
X-linked recessive (ADH receptor 2 gene)
ADH antidiuretic hormone
Causes of nephrogenic diabetes insipidus
Inappropriate ADH Secretion Syndrome
Syndrome of Inappropriate Antidiuretic Hormone secretion
(SIADH) is a rare disorder characterized by inappropriately
elevated ADH levels associated with plasma hyperosmolarity
and urinary hyperosmolarity due to an altered osmoregulatory mechanism. SIADH represents a frequent cause of
hyponatremia (plasma sodium <135 mmol/L) in adults.
Inappropriate ADH secretion can be of neurohypophyseal or
ectopic origin. The latter represents the most frequent cause
of SIADH due to neoplastic pathologies. On the other hand,
the causes that can determine inappropriate secretion of
ADH by the neurohypophysis are numerous and include
infections, head traumas, vascular alterations, pulmonary
disorders, or drug intake. The latter can determine SIADH
by inducing an increase either in the release of ADH (morphine, carbamazepine, haloperidol, tricyclic antidepressants)
or in the receptor sensitivity to the hormone (nonsteroidal
anti-inammatory drugs, cyclophosphamide, chlorpropamide) (Table25.8).
Four types of altered osmoregulation have been described.
• Type a (40–70%): random secretion associated with
markedly increased ADH levels, independent of plasma
osmolarity. There is, therefore, a complete loss of the
osmoregulatory mechanism.
• Type b (20–40%): it is the classic picture of osmostat
reset (literally threshold reset) characterized by a reduc-
Table 25.8
Increased hypothalamic/pituitary secretion of ADH
Neurological/neuropsychic disorders
- Infections (meningitis, encephalitis, sarcoidosis, abscesses,
- Vascular causes (thrombosis, subarachnoid/subdural
-Psychosis
-Hydrocephalus
-Post-surgical causes
-Guillain-Barrè syndrome
Drugs
- Antidepressants (carbamazepine, tricyclic antidepressants,
-MDMA/ecstasy
-Cyclophosphamide
-Non-steroidal anti-inammatory drugs
Pulmonary disorders
- Tuberculosis, viral/bacterial pneumonia, asthma, atelectasis,
Ectopic production of ADH
Neoplasms
-Pulmonary microcytoma
-Nasopharyngeal tumors
-Gastrointestinal/pancreatic tumors
-Tumors of the genitourinary tract
-Mesothelioma
-Lymphomas, sarcomas
-Cyclophosphamide
-Chlorpropamide
Amplication of ADH effects at the receptor level
Drugs
-Cyclophosphamide
-Chlorpropamide
ADH antidiuretic hormone, MDMA methylenedioxymethamphetamine
(ecstasy)
Main causes of inappropriate ADH secretion syndrome
herpetic infections, AIDS)
hemorrhage, temporal arteritis)
phenothiazines, haloperidol, serotonin re-uptake inhibitors, etc.)
pneumothorax, HIV
tion in the osmolar threshold for ADH secretion. There is,
therefore, a defect affecting the inhibitory component of
the osmoregulation mechanism.
• Type c (10%): low plasma osmolarity does not inhibit
ADH secretion. Plasma ADH concentrations are, therefore, inappropriately high at low plasma osmolarity. There
is a normal relationship between plasma osmolality and
plasma ADH for physiological plasma osmolality values.
• Type d (<5%): it is characterized by normal osmoregulation (i.e., ADH secretion varies appropriately with plasma
osmolality), but urine is concentrated even when ADH
release is suppressed. The osmoregulatory mechanism of
ADH secretion thus is conserved, suggesting that different alterations cause inappropriate antidiuresis. A constitutively activating mutation of the ADH receptor has been
identied in some patients. There is no correlation
between the etiology and the type of alteration; any of the
four types described above can occur, regardless of the
cause of SIADH.
The increased secretion of ADH causes increased reab-
sorption of free water in the distal nephron, which, in turn,
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causes extracellular hypervolemia, increased levels of the
atrial natriuretic hormone, reduced plasma renin activity, and
increased urinary sodium excretion. This natriuresis serves
to balance hypervolemia but exacerbates hyponatremia. In
addition, hyponatremia induces increased intracellular volume in all organs, including the brain. If hyponatremia
develops slowly, patients do not have clear clinical manifestations; if, on the other hand, plasma sodium concentration
drops abruptly, patients develop severe neurological
manifestations.
Laboratory Investigations
The key laboratory tests for diagnosing neurohypophysis
disease are listed below.
24-Hour Urine Test
The 24-hour urinalysis assesses urine volume, osmolarity,
and specic gravity. Polyuria is the production of a volume
of urine >2.5L/day. Normal values of urine osmolarity are
300–800 mOsm/L. The normal specic gravity of urine is
1005–1020g/L.
Plasma ADH Assay
The values of the hormone must always be evaluated in relation to plasma and urinary osmolality because, in the normal
subject, they change according to the state of hydration. In
the presence of good hydration conditions, ADH values are
between 1.5 and 6pg/mL; with free uid intake, they suppress the assay method’s sensitivity to the lower limit. The
determination of ADH, however, is highly complex due to its
low molecular weight (~1 kDa), its very short half-life
(~20minutes), and its binding to platelets (>90%). In addition, samples are affected by high centrifugation rates, and
ADH levels are not very stable invitro.
Plasma Osmolality Assessment
Normal plasma osmolality values are between 285 and
295mOsm/L.
Water Deprivation Test
This test consists of water deprivation for an interval of
7–14hours during which the patient’s water balance is continuously monitored (hourly) through regular measurements
of body weight, plasma osmolality and/or natremia, urinary
volume, and osmolality. The test is discontinued in the presence of a weight loss greater than 5% or when a plasma
osmolality greater than or equal to 300mOsm/L is reached.
If uid deprivation does not result in urine concentration by
the end of the test, the patient has severe pituitary or nephrogenic DI. In such a case, to make a differential diagnosis,
desmopressin is administered at the end of the water deprivation test, and urine osmolality measurement is repeated every
hour for two hours; an increase (>300mOsm/L) is indicative
Table 25.9 Water deprivation test
Step 1. Dehydration phase
Objective Differential diagnosis of polyuria states
Principle Under physiological conditions, water deprivation
causes an increase in plasma osmolality; the plasma
hyperosmolality detected by hypothalamic
osmoreceptors leads to the release of ADH and,
consequently, the renalreabsorption of water
Procedure It is preferable to perform it in the morning to control
the patient
- Bladder emptying by urine collection (urinary
volume, osmolality and specic weight), blood
sampling (hemoglobin, hematocrit, sodium,
potassium, chlorine, protein and osmolality) and
body weight detection
- Absolute restriction of liquids between 8 and 16
- Hourly urine collection (urinary volume,
osmolality and specic weight), blood sampling
(osmolality) and body weight measurement
- The test should be stopped if thirst becomes
unbearable or if body weight has a reduction of
>5%
Interpretation Normal subject: water restriction causes diuresis
contraction, urine excretion with increasing
osmolality and specic gravity (osmolality
>800mOsm/L and urine specic gravity >1030)
Pituitary and severe nephrogenic diabetes insipidus
(DI): diuresis does not decrease, plasma osmolality
increases (>290mOsm/L) and urinary osmolality
remains low (<300mOsm/L)
Partial pituitary and nephrogenic DI or primary
polydipsia: normal plasma and urinary osmolality
Side effects Excessive dehydration with possible hypovolemia,
shock, and death. It is important to weigh the patient
because a reduction in body weight >5% indicates
severe dehydration and requires immediate
termination of the test
Step 2. Desmopressin test
Objective Differential diagnosis of pituitary and nephrogenic
DI
Principle Desmopressin is a synthetic analogue of ADH; it
binds to renal receptors and increases renal water
reabsorption
Procedure At the end of the water deprivation test, administer
desmopressin intramuscularly (1–2μg) and determine
the urinary osmolarity after 1 and 2hours
Interpretation Pituitary DI: urinary osmolality >300mOsm/L
Nephrogenic DI: urinary osmolality <300mOsm/L
ADH antidiuretic hormone
of severe pituitary DI, whereas the absence of change is
strongly suggestive of nephrogenic DI (Table25.9).
If the water deprivation test results in urine concentrations
before plasma osmolality and/or natremia exceed the upper
reference limits, in order to differentiate between primary
polydipsia, partial pituitary DI, and partial nephrogenic DI,
plasma ADH should be measured. Precisely, ADH concentration and plasma osmolality and/or natremia are measured,
and uid deprivation is continued while hypertonic saline
(3% sodium chloride) is infused at a rate of 0.05mL/kg/min.
During the infusion, plasma osmolality and/or natremia are
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measured every 30minutes; when the values rise above the
normal limit, usually 60–90minutes after the infusion, the
ADH assay is performed, and the test is terminated. The
results are interpreted using a nomogram depicting the relationship between plasma ADH values and plasma osmolality
and/or natremia or urinary osmolality. This method differentiates between primary polydipsia, partial pituitary DI, and
partial nephrogenic DI.
MRI oftheHypothalamic-Pituitary Region
MRI of the hypothalamic-pituitary region is an emerging
approach that eliminates the need for water deprivation and
provides a more straightforwardbut equally reliable way to
differentiate the three major types of DI, regardless of the
severity of the underlying defect. In most healthy adults and
children, the posterior pituitary gland emits a hyperintense
signal in T1-weighted mid-sagittal images. This bright spot
is almost always present in primary polydipsia, but it is
always absent or reduced in pituitary and nephrogenic
DI.Thus, according to this method, the three types of DI can
be differentiated in two steps. First, an assay of plasma ADH
levels and determination of urinary osmolality without the
restriction of uid intake is performed; if plasma ADH levels
are normal or high (>2pg/mL) and urinary osmolality is low
(<300 mOsm/L), the patient has nephrogenic DI. If ADH
levels are low or undetectable (<1pg/mL) and urinary osmolality is also low, an MRI of the brain may differentiate
between pituitary DI (no or small T1 signal) or primary
polydipsia (normal or enlarged T1 signal). In addition, MRI
may also indicate the etiology of both forms of DI.
Copeptin
Another proposed method to the differential DIdiagnosis is
the measurement of copeptin. This glycoprotein originates
from the pre-pro-hormone pre-provasopressin, consisting of
ADH, neurophysin II, and copeptin. Pre-provasopressin is
synthesized mainly in the paraventricular neurons of the
hypothalamus and, during axonal transport, undergoes cleavage followed by the release of the three molecules. The latter
are stored in the secretory granules of the neurohypophysis,
waiting to be secreted in response to pathophysiological
stimuli. The biological function of copeptin is still unclear,
although its importance in mediating the correct conformation of ADH has been hypothesized. Copeptin and ADH are
secreted in equimolar amounts. However, copeptin, compared to ADH, has a longer half-life, and greater preanalytical stability, resulting in superior analytical accuracy,
precision, and simplicity. The biological sample can be
stored for at least 7 days at room temperature and up to
14days at 4 °C.The assay is performed by immunometric
technique. The reference values of copeptin in the general
population are 1–14pmol/L.
Finally, another way to distinguish between the three
main types of DI is to closely monitor the effects of antidiuretic therapy on changes in water balance.
Once the diagnosis of the neurohypophysial disease has
been made, instrumental investigations can be helpful to
identify the underlyingcause. MRI can detect tumors, infections, hemorrhages, infarcts, and hydrocephalus. In case of
SIADHsuspicion, a chest X-ray may reveal any lesions.
Diagnosis andTherapy
Diabetes Insipidus
In the presence of frequent urination, enuresis (involuntary
emission of urine), nocturia (repeated need to urinate during
the night), and/or persistent thirst, a 24-hour urine test should
be performed; if the volume is >50cc/kg/day, corresponding
to a volume of 2.5L/day, the diagnosis of polyuria is established. After excluding the most common causes of polyuria
(antidiuretic drugs and metabolic causes such as diabetes
mellitus) through appropriate laboratory investigations, a
baseline copeptin measurement or the water deprivation test
is performed (Fig.25.3). In the case of the water deprivation
test, if uid deprivation does not lead to urine concentration
(urinary osmolality <300 mOsm/L), the patient has severe
pituitary or nephrogenic DI; to make a differential diagnosis,
desmopressin is administered. If uid deprivation results in
the production of concentrated urine, the patient may have
partial pituitary DI, partial nephrogenic DI, or primary polydipsia; to make the differential diagnosis, plasma ADH is
measured before and after infusion of hypertonic saline,
evaluating its values in relation to plasma osmolality/natremia and urinary osmolality (Fig.25.4).
Figure 25.5 shows Timper’s algorithm for differential
diagnosis of DI by determination of baseline copeptin levels
and/or after uid deprivation. It has been shown that copeptin
determination makes water deprivation testing unnecessary
in cases of nephrogenic DI, correctly identifying all patients
with reduced or absent peripheral sensitivity to ADH.In contrast, an 8-hour (overnight) uid deprivation resulting in a
copeptin value <2.6pmol/L is suggestive of complete central
DI.Finally, a baseline copeptin value <21.4 pmol/L in the
absence of water deprivation requires evaluation of the peptide response to an osmotic stimulus that induces an increase
in plasma sodium levels >147mmol/L, such as infusion of
3% hypertonic saline; following the stimulus, copeptin values <4.9 pmol/L are suggestive of partial central DI; conversely, values ≥4.9pmol/L indicate the presence of primary
polydipsia. The algorithm proposed by Timper represents an
evolution of the one proposed by Fenske (Fig.25.6), which
involves the calculation of the ratio of copeptin to serum
sodium concentrations during an appropriate osmotic stimulus (uid deprivation).
Ca++, serum calcium; K+, serum potassium; Na+, serum sodium; p-Osm, plasma osmolarity; u-Osm, urinary osmolarity.
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Endocrinopathy
Persistent
polyuria
*Lithium, cisplatin, ecc...
Post-operative NCH Interfering drugs Psychiatric
Obstructive nephro/
disease
patients
POLYURIA
(diuresis >50 cc/kg/day)
+
Measure Na
, p-Osm, u-Osm, Ca++, albumin, K+,
blood glucose, complete urine test
Hyperglycemia or glycosuria,
hypercalcemia, hyperkalemia
Consider causes of hypertonic
polyuria and plan specific
therapeutic interventions
Normal outcomes
Hypotonic urine or reduced
urinary specific gravity,
hypernatremia,
u-Osm/p-Osm <2
STOP
Baseline copeptin determination
and possible water
Polyuria resolution
STOP
deprivation test
Fig. 25.3 Diagnostic algorithm for the evaluation of polyuria. (Copyright EDISES 2021. Reproduced with permission)
Fig. 25.4 Algorithm for the
differential diagnosis of
Water deprivation test
diabetes insipidus by water
deprivation test. Na +
natremia, PO plasma
osmolality, UO urinary
osmolality, DI diabetes
PO >300 mOsm/L, Na
UO <300 mOsm/L
+
>145,
PO <300 mOsm/L, Na+ <145,
UO >300 mOsm/L
insipidus. (Copyright EDISES
2021. Reproduced with
permission)
Stop fluid deprivation,
desmopressin administration and
UO determination at 1 and 2 hours
Plasma ADH (pADH)
Infusion of hypertonic
UO <300 mOsm/L
Severe
nephrogenic DI
UO >300 mOsm/L
Severe
pituitaty DI
normal pADH vs.
+
PO/Na
and UO
Primary polydipsia
saline solution
Plasma ADH Nomogram
vs. PO/Na+ and UO
low pADH vs
PO/Na
Partial
pituitary DI
+
Low UO
vs. pADH
Partial
nephrogenic DI
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