2 HYPOTHALAMIC and PITUITARY DISORDERS, Part 2
Transcript of 2 HYPOTHALAMIC and PITUITARY DISORDERS, Part 2
Hypothalamic and
Pituitary Disorders
Part 2
Hypopituitarism: Clinical Manifestations
� If ACTH is Deficient ~
Secondary (Central) Hypoadrenalism:
Hypopituitarism: Clinical Manifestations
� If ACTH is Deficient ~
Secondary (Central) Hypoadrenalism:
• fatigue, weakness, weight loss, nausea,
vomiting, hypotension, shock
• if partial, may not have symptoms until
stressed by illness or surgery
Hypopituitarism: Clinical Manifestations
� If ACTH is Deficient ~
Secondary (Central) Hypoadrenalism:
• ↓ adrenal secretion of epinephrine
• adrenal aldosterone secretion is
relatively preserved unless ACTH is
totally absent (ACTH stimulation is
required for the initiation of
steroidogenesis, a small ACTH amount
is sufficient)
Hypopituitarism: Clinical Manifestations
� If ADH (AVP) is Deficient ~
Central (Cranial) Diabetes Insipidus (DI):
• polyuria (2-20 L/d), urinary frequency,
nocturia, enuresis, polydipsia
• it gets masked if ACTH and/or TSH are
deficient as well (free water clearance in
the kidney is dependent on a
background levels of cortisol and
T4/T3)
Hypopituitarism: Clinical Manifestations
� If ADH is Deficient ~
Cranial (Central) Diabetes Insipidus (DI):
• if fluid intake is inadequate: Symptoms
& Signs develop due to dehydration
(tachycardia, orthostatic hypotension,
dry mucous membranes and axilla,
oliguria) and due to ↑Na (lethargy,
irritability, weakness, fever, delirium,
seizures, focal deficits, coma)
Hypopituitarism
Laboratory Findings
Hypopituitarism: Lab Findings
� Fasting hypoglycemia (GH or ACTH
deficiency)
� Hyponatremia (hypothyroidism and/or
hypoadrenalism)
� Hypernatremia (in DI when fluid intake
is inadequate)
Hypopituitarism: Lab Findings � To evaluate the hypoadrenalism:
• ACTH is low or normal (8:00 am)
• Dehydroepiandrosterone (DHEA) is
often low
• An 8-9 am serum cortisol <3 mcg/dL
usually indicates adrenal insufficiency
but it may not be this low, and so what
to do? => => =>
Hypopituitarism: Lab Findings � To evaluate the hypoadrenalism:
• ACTH stimulation test (functional
atrophy of the adrenal cortex occurs
within two weeks of ACTH deficiency)
(synthetic ACTH1-24 would be given)
(natural ACTH peptide is composed of
39 amino acids)
• Random or stimulated serum cortisol
level of ≥ 20 mcg/dL rules out
hypoadrenalism
Hypopituitarism: Lab Findings
� To evaluate the hypothyroidism:
• Free T4 is low
• TSH is low, normal or very mildly
elevated
Hypopituitarism: Lab Findings
� To evaluate the hypogonadism:
• In males: low total testosterone with
low or normal serum FSH/LH
• In pre-menopausal women: if menses
are regular then it rules out
hypogonadism, otherwise there would
be low estradiol with low or normal
serum FSH/LH
Hypopituitarism: Lab Findings
� To evaluate the hypogonadism:
• In post-menopausal women: serum
LH and FSH would not be elevated as
expected (FSH normally > 30 IU/L
and LH > 20 IU/L)
Hypopituitarism: Lab Findings
� To evaluate the GH Deficiency (GHD) in
adults:
• Investigate only if GH replacement
therapy is being contemplated
• Diagnosis is difficult since normal GH
secretion is pulsatile and serum GH
levels are nearly undetectable for most
of the day
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• Also, adults (particularly men)
physiologically tend to produce less
GH when they are over age 50 or have
abdominal obesity
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• Therefore, it is often inferred by
symptoms in the presence of pituitary
destruction or other pituitary hormone
deficiencies
• GHD is present in 96% of patients with
≥3 pituitary hormone deficiencies and
a low serum IGF-1
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• Low IGF-1, but is not sensitive (about
50%) and not specific either in Adult
GHD
• Very low IGF-1 levels (<84 mcg/L) are
indicative of GHD in the absence of
conditions that lower it (eg,
malnutrition, prolonged fasting, oral
estrogen, hypothyroidism, uncontrolled
DM, liver failure)
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• GH <5 ng/ml w exercise (however, by
age 40, most normal adults have lost
their GH response to exercise)
• Provocative GH-stimulation testing to
help diagnose adult GHD has a
sensitivity of only 66%
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• Therefore, a therapeutic trial of GH
therapy should be considered for
symptomatic patients who have either
a serum IGF-1 <84 mcg/L or three
other pituitary hormone deficiencies
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• In the absence of those two conditions,
provocative GH-stimulation testing
may be indicated for the following
patients:
1) Young adult patients who have
completed GH therapy for
childhood GHD and have achieved
maximal linear growth
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
2) Patients who have a hypothalamic
or pituitary tumor or who have
received surgery or radiation
therapy to these areas
3) Patients who have had prior head
trauma, stroke, or encephalitis
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• Such testing usually entails measuring
serum GH following provocative
stimuli:
o =>
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
o Insulin Tolerance Test ‘ITT’
o Glucagon stimulation test
o Oral macimorelin (a GH
secretogogue) GH stimulation test
o L-arginine (may be combined with
GHRH)
o Oral clonidine (in children)
Hypopituitarism: Lab Findings
� To evaluate GHD in adults (continued):
• The glucagon stimulation test is a
practical alternative to traditional
provocative GH stimulation testing to
diagnose pathologic GH deficiency or
functional GH deficiency due to aging
or obesity
Hypopituitarism: Lab Findings
� To evaluate the DI:
Diabetes Insipidus (DI)
Diabetes Insipidus
It usually results from a decrease of 75%
or more in the
� secretion or
� action
of AVP (ADH)
Diabetes Insipidus
� A decrease in the secretion of AVP
1) Primary deficiency of AVP
secretion
2) Secondary deficiency of AVP
secretion
Diabetes Insipidus
� A decrease in the secretion of AVP
1) Primary deficiency of AVP
secretion ~ it is referred to
variously as central DI, cranial DI,
neurohypophyseal DI, neurogenic
DI, or pituitary DI
Diabetes Insipidus
1) Central DI (primary deficiency of AVP
secretion) ~ Causes:
• Congenital Malformations
• Genetic defect (example:
DIDMOAD or Wolfram syndrome)
• Acquired (head injury, (para)sellar
surgery, neoplasms, etc…)
• Idiopathic
• Gestational DI =>
Diabetes Insipidus
1) Central DI (primary deficiency of AVP
secretion) ~ Causes:
• Gestational DI: excessive placental
production and/or impaired
clearance of vasopressinase ~ it
occurs during pregnancy ‘last
trimester’ or postpartum; associated
with oligohydramnios, preeclampsia,
or hepatic dysfunction ~ also can be
called Vasopressinase-induced DI
Diabetes Insipidus
� A decrease in the secretion of AVP
2) Secondary deficiency of AVP
secretion: it results from excessive
intake of fluids => AVP secretion
inhibition ~ it is referred to as
primary polydipsia and can be
divided into 3 subcategories =>
Primary Polydipsia (PP)
� can be divided into 3 subcategories:
i. Dipsogenic DI
o characterized by inappropriate thirst
caused by a reduction in the set of
the osmoregulatory mechanism
o sometimes occurs in association
with multifocal diseases of the brain
such as neurosarcoid, tuberculous
meningitis, and multiple sclerosis
but is often idiopathic
Primary Polydipsia (PP)
� can be divided into 3 subcategories:
ii. Psychogenic polydipsia
o not associated with thirst
o the polydipsia is a feature of
obsessive compulsive disorder or
psychosis/schizophrenia
Primary Polydipsia (PP)
� can be divided into 3 subcategories:
iii. Iatrogenic results from
recommendations to increase fluid
intake for its presumed health
benefits
Diabetes Insipidus
It usually results from a decrease of 75%
or more in the
� secretion or
� action
of AVP (ADH)
Diabetes Insipidus
� A decrease in the action of AVP
1) Primary deficiency in the
antidiuretic action of AVP
2) Secondary deficiency in the
antidiuretic action of AVP
Diabetes Insipidus
� A decrease in the action of AVP
1) Primary deficiency in the
antidiuretic action of AVP~ it
results in nephrogenic DI~ causes:
� genetic defect
� metabolic abnormality
(hypercalcemia, hypokalemia,
hypercalciuria)
� poisoning (heavy metals)
Diabetes Insipidus
� A decrease in the action of AVP
1) Primary deficiency in the
antidiuretic action of AVP~ it
results in nephrogenic DI~ causes:
� kidney disease (polycysctic kidney
disease, sickle cell anemia,
infiltrative disease, pyelonephritis,
recovery from acute tubular
necrosis, urinary obstruction)
Diabetes Insipidus
� A decrease in the action of AVP
1) Primary deficiency in the
antidiuretic action of AVP~ it
results in nephrogenic DI~ causes:
� drug therapy (such as lithium,
cisplatin, amphotericin B,
rifampin, demeclocycline,
aminoglycosides)
� idiopathic
Diabetes Insipidus
� A decrease in the action of AVP
2) Secondary deficiency in the
antidiuretic action of AVP ~ it
results from polyuria itself ~it is
caused by washout of the
medullary concentration gradient
and/or suppression of aquaporin
function
Hypopituitarism: Lab Findings
� To evaluate the DI:
Hypopituitarism: Lab Findings
� To evaluate the DI:
• A urine volume <2 L/24 h w normal
urine creatinine (20-30 mg/kg/day) and
in the absence of hypernatremia rules
out DI
• Dilute urine (sg < 1.006; Urine
Osmolarity <300 mOsm/L)
• Hyperuricemia (↓ Urate tubular
clearance)
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• Plasma AVP is usually low (<1
pg/mL) in central DI (and primary
polydipsia)
• Whereas in Nephrogenic DI,
plasma AVP level is normal or
elevated (>1 pg/mL) while the
Urine Osmolarity is low (less than
300 mOsm/L)
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• However, plasma AVP assay is not
widely available because it is
difficult to interpret clinically given
the short half-life of circulating
AVP and its binding to platelets
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• A C-terminal fragment of pre-pro-
AVP called copeptin has no known
biologic function but has a much
longer half-life in the circulation,
which makes it a relatively stable
surrogate marker of AVP secretion
• The measurement of copeptin was
found to compare favorably with the
measurement of AVP
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• A single baseline measurement of
serum copeptin level greater than
21.4 pmol/L was found to
differentiate nephrogenic DI from
the other polyuric states (namely,
central DI and primary polydipsia)
with nearly 100% sensitivity and
specificity
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• The hypertonic saline infusion test
with copeptin measurement
(hypertonic saline-stimulated
copeptin measurement) can be used
to differentiate between central DI
and primary polydipsia
• The test involves a single iv infusion
of 3% saline over 3 hours =>
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• … => copeptin shall increase above
a specified cutoff in primary
polydipsia whereas it shall not
increase above the cutoff in central
DI (in nephrogenic DI it shall
remain high, pre- & post- infusion)
• The diagnostic accuracy of the test
is high (96.5% in one study)
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• Another test called ‘indirect water-
deprivation test’ can also
differentiate between Central DI,
Nephrogenic DI, and Primary
Polydipsia but with a moderate
diagnostic accuracy of 70-76.6%
• The test involves a 17-hour fast, …
=>
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• … => the collection of multiple
plasma and urine samples, and the
administration of desmopressin at
the end of the fast
� In severe (complete) DI (both
central and nephrogenic), U-
Osmo will remain low (i.e. <300
mOsm/L) at the end of the fast
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
� Whereas in Primary Polydipsia,
urine will typically become
maximally concentrated (i.e.,
>600 mOsm/L) at the end of the
fast
• Desmopressin is then given
(desmopressin challenge) to
distinguish between Central DI and
Nephrogenic DI =>
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
=> Central DI: ↑U-Osmo by >50%
with reduction in thirst and polyuria
=> Nephrogenic DI: Little or no
change in U-Osmo and no response
in thirst or polyuria
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• In primary polydipsia, the
desmopressin challenge causes no
significant reduction in polydipsia,
but it does reduce polyuria which
produces hyponatremia (this can be
severe and become fatal, and thus
the test requires close observation)
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• There are DI cases (central or
nephrogenic) where the defect is
partial (or mild, i.e. not complete or
not severe) and the water fast/
deprivation can yield a concentrated
urine but not to the maximum (i.e.
more than 300 but less than 600
mOsm/L)
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• Also, in some cases of primary
polydipsia (PP) the urine doesn’t
become maximally concentrated
with the water fast/deprivation
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• And those were the reasons behind
the moderate diagnostic accuracy of
the indirect water-deprivation test
even with the measurement of
copeptin levels, serum sodium
levels, or urine-to-plasma osmolality
ratios during the water deprivation
(as they did not improve the
accuracy)
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• Compared with the indirect water-
deprivation test, the hypertonic
saline infusion test with copeptin
measurement has shorter test times
and greater patient adherence but is
associated with more adverse effects
(such as vertigo and nausea) and
higher serum sodium levels
(requires closer monitoring and …
=>
Hypopituitarism: Lab Findings
� To evaluate the DI (continued):
• (and … => potentially becoming
problematic; for example, it could
induce congestive heart failure in
high-risk patients)
Hypopituitarism � To evaluate the DI (continued):
• Brain MRI can be helpful in
differentiating pituitary (central DI)
from primary polydipsia
Hypopituitarism � To evaluate the DI (continued):
• In healthy persons, the posterior
pituitary emits a hyperintense signal
visible in T1-weighted midsagittal
images
• This “bright spot” is almost always
present in patients with primary
polydipsia but is always absent or
abnormally small in patients with
central DI (even if it’s partial)
Hypopituitarism � To evaluate the DI (continued):
• The MRI is also useful in searching
for pathology responsible for central
DI or the dipsogenic form of
primary polydipsia
Hypopituitarism � To evaluate the DI (continued):
• The principal caveat is that MRI is
not reliable for differential diagnosis
of DI in patients with empty sella
because they typically lack a bright
spot even when their AVP secretion
and action are normal
Hypopituitarism � To evaluate the DI (continued):
• MRI also cannot be used to
differentiate central from
nephrogenic DI because many
patients with nephrogenic DI also
lack a posterior pituitary bright spot,
probably because they have an
abnormally high rate of AVP
secretion and turnover
Hypopituitarism
Treatment
Hypopituitarism: Treatment
� To treat the hypoadrenalism:
• Hydrocortisone tablets 15-35 mg/d in
2-3 divided doses
• Some patients feel better w prednisone
(3-7.5 mg/d in two divided doses)
• Higher doses during sickness and
surgery
Hypopituitarism: Treatment
� To treat the hypothyroidism:
• Levothyroxine (LT4) to keep FT4 in
the high-normal range
• Typical maintenance dose is about 1.6
mcg/kg/d
• TSH assessment is useless for
monitoring Rx
• LT4 should be given only after
assessing for cortisol deficiency or
already receiving GC
Hypopituitarism: Treatment
� To treat the hypogonadism in males:
• Testosterone Rx
• If fertility desired:
� HCG (equivalent to LH), and if
sperm counts remains low after 6-12
months => add FSH injections
� If pituitary intact => leuprolide
(GnRH analog) by intermittent
subcutaneous (sc) injection instead
Hypopituitarism: Treatment
� To treat the hypogonadism in males:
• If fertility desired (continued):
� Intracytoplasmic Sperm Injection
(ICSI )
� Clomiphene (a selective estrogen
receptor modulator ‘SERM’) can
sometimes work when pituitary is
intact
Hypopituitarism: Treatment
� To treat the hypogonadism in females:
• Estrogen/Progesterone Rx
• If fertility desired:
� Clomiphene citrate
� HCG & FSH injections
Hypopituitarism: Treatment
� To treat the GHD: