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The pituitary gland controls the function of multiple other glands
in the human body, including the thyroid, adrenals, ovaries and
testes. It regulates growth, lactation, uterine contractions
in labor as well as osmolality and intravascular fluid volume
v ia
resorption of water in the k idneys. It secretes eight
peptide hormones; six from the anterior lobe and two from the
posterior lobe (Table 1).
The Pituitary Gland
Assessment of Pituitary Function CARRIE R. MUH, MD, MS; NELSON M.
OYESIKU, MD, PhD, FACS Emory University Hospital, Department of
Neurological Surgery
Key words: pituitary gland, pituitary function,
hypothalamic-pituitary-adrenal (HPA) ax is, pituitary
dysfunction workup
194
Table 1 Summary of Pituitary Function. (Copied from Oyesiku
N: Assessment of Pituitary Function, Rengachary S, Ellenbogen
R (eds): Principles of Neurosurgery . New York,
Elsev ier Mosby, 2005)(30)
354
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The pituitary lies in the sella turcica, a concav ity in the
sphenoid bone. Its stalk, which contains the pituitary portal
veins and neuronal processes, passes through the diaphragma
sella, just above which pass the optic nerves (Figure
1). The cavernous sinuses form the lateral borders of the
sella, and contain w ithin them the internal carotid arteries,
cranial nerves III, IV and VI, and the ophthalmic and
max illary div isions of cranial nerve V.
Because of its diverse array of functions as well as the multiple
structures in close prox imity to the gland, tumors or
abnormalities of pituitary function can present in many
different ways. Disorders can lead to an excess or
def iciency of pituitary hormones, mass effect from tumors can
lead to compression of the pituitary stalk or ad jacent
structures,
and lesions may cause a blockage of the blood supply to the
gland. Therefore, a thoroughassessment of the pituitary
requires clinical examination for signs of hormonal abnormalities,
endocrine evaluation of pituitary and related target-organ
hormones, and ophthalmologic evaluation to assess for damage to the
ad jacent cranial nerves. These evaluations not only help
to def ine the pathology prior to treatment, but they can be
used to assess the effects of surgery, radiation or medical
treatment. Here, we w ill discuss details the endocrine
evaluations needed to determine pituitary function.
Anterior Pituitary Hormones Six hormones are produced in the
anterior pituitary by f ive distinct cell types.
Lactotroph cells make prolactin (PRL), somatotroph cells produce
growth hormone (GH), corticotrophs secrete adrenocorticotrophic
hormone (ACTH), thyrotrophs make thyroid-stimulating hormone (TSH),
and gonadotrophs produce follicle-stimulating
Assessment of Pituitary Function 195
Fig . 1 Anatomic relationships of the pituitary
gland. A coronal v iew through the sella turcica shows
the pituitary gland, its stalk and the relationship to
surrounding structures including the cavernous sinuses, carotid
arteries and cranial nerves II, III, IV, V1, V2 and
VI. (Figure from Oyesiku N: Assessment of Pituitary
Function, in Rengachary S, Ellenbogen R (eds) : Principles
of Neurosurgery . New York, Elsev ier Mosby,
2005, pp 559-591)(30)
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hormone (FSH) and luteinizing hormone (LH). The secretion of
these hormones is regulated by complex feedback controls from the
hypothalamus and target glands (Figure 2).
PRL release is largely determined by dopamine release from the
hypothalamus. Corticotropin-releasing factor (CRH),
thyrotropin-releasing factor (TRH) and gonadotropin-releasing
hormone (GnRH) are secreted by the hypothalamus to stimulate the
release of ACTH, TSH and the gonadotropins,
respectively . Both excitatory and inhibitory signals are
sent from the hypothalamus to the pituitary to control
hormone
production; for instance, growth hormone-releasing hormone
(GHRH) and somatostatinalternately increase and decrease growth
hormone secretion. Target gland hormones generally cause a
negative feedback loop, inhibiting further production of the
hormone that stimulated their release.
Prolactin The lactotrophs that secrete PRL are unique in that they
can proliferate during
adulthood. PRL production is inhibited by dopamine, also known
as prolactin-inhibiting factor (23). Dopamine travels along
the portal circulation from nerves that originate in the
hypothalamic arcuate nucleus. PRL production is stimulated by
sleep, vasoactive peptide (VIP), GnRH, peptide histidine methionine
(PHM), opiates and estrogen. Exogenous TRH leads to a rapid release
of PRL, though the normal physiologic role of this
interaction is unclear.
196 Neuro-oncology
Fig . 2 Hypothalamic control and feedback regulat
ion. The neural processes of the hypothalamic nuclei
terminate on the portal venous system in the median
eminence. The portal veins carry releasing and inhibiting
factors to the anterior lobe of the pituitary, where they regulate
the release of hormones. The production and secretion of
these hormones is inhibited by the hormonal products of the target
organs v ia negative feedback . The neural processes
of the hypothalamic neurons of the supraoptic and paraventricular
nuclei carry ADH and oxytocin which are released from nerve
terminals in the posterior pituitary . (Figure from Oyesiku
N: Assessment of Pituitary
Function, Rengachary S, Ellenbogen R (eds): Principles of
Neurosurgery . New York, Elsev ier Mosby,
2005)(30)
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PRL is secreted episodically, peak ing 13-14 times per day,
w ith an interpulse interval of about 90 minutes. Small
post-prandial rises can be seen, secondary to central stimulation
from the amino acids in food (9). During pregnancy, estrogen
stimulates lactotroph hyperplasia, leading to
hyperprolactinemia. The effects of PRL on the breasts are
blocked until after delivery, at which time PRL initiates
lactation. Within 4-6 months after delivery, basal PRL levels
return to normal (35).
Prolactin Deficiency Hypopituitarism leads to a decrease in PRL
release. A blunted PRL response in a TRH-
stimulation test, w ith a less than 2-fold increase over basal
levels, is ev idence of inadequate lactotroph reserve
which may occur w ith hypopituitarism. Insuff icient PRL
can lead to a failure of lactation. This may be an early
indication of peripartum pituitary necrosis, or Sheehan's
syndrome. Lymphocytic hypophysitis is an autoimmune disorder
which usually occurs during or immediately follow ing
pregnancy .
Transient hyperprolactinemia occurs during its active phase,
followed by hypopituitarism and hypoprolactinemia.
Prolactin Excess Multiple causes can lead to the over-stimulation
of prolactin release and elevated serum
PRL levels. Hyperprolactinemia may be due to: 1.
excess autonomous production, such as from a pituitary
prolactinoma; 2. decreased hypothalamic production
of dopamine or blockage of delivery of dopamine to the
pituitary, such as from a hypothalamic tumor, drugs that inhibit
dopamine production, interruption of the
portal venous system in the stalk from a pituitary tumor or
aneurysm, or follow ing pituitary
irradiation; 3. inhibition of dopamine activ ity on
lactotrophs, such as from phenothiazines that block the interaction
of dopamine from its receptors; or 4. over- stimulation
of PRL by estrogens or opiates. Non-hypothalamic-pituitary
causes may be responsible as well, including pregnancy, polycystic
ovarian syndrome or primary hypothyroidism. Physiologic,
transient hyperprolactinemia occurs w ith exercise, stress,
nipple stimulation, sexual intercourse, and breast-feeding.
Women w ith hyperprolactinemia generally present w ith
amenorrhea, galactorrhea, diminished libido and
infertility . Gonadal def iciency and decreased
estrogen secretion can
lead to osteoporosis. Hyperprolactinemia in men generally
manifests as decreasedlibido, impotence and decreased sperm count
leading to infertility .
Workup Laboratory tests for suspected hypo- or hyperprolactinemia
include serial
measurements of basal, resting serum PRL levels by
radioimmunoassay . Normal values are
gender-specif ic, and peak values occur during the late hours
of sleep (37). PRL is secreted episodically, so random levels
may be above or below normally-accepted limits. Because of
this variability, minimally elevated levels should be
conf irmed from several samples, or from a pooled
sample. In normal sub jects, serum PRL levels range from
5-20 ng/mL.
PRL def iciency of <2 ng/mL is generally associated
w ith severe hypopituitarism, though may be due to
PRL-lowering medications. A PRL level of more than 200
ng/mL
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is nearly diagnostic of a prolactinoma (33). Prolactinomas are
the most common type of hormone-secreting pituitary tumor,
comprising almost 30% of all pituitary tumors. Pregnancy must be
excluded, however, as PRL levels reach 100-250 ng/mL by the third
trimester (34).
An intermediate degree of PRL elevation, 20-200 ng/mL, can result
from a number of different conditions. Medications can
cause PRL levels of more than 100 ng/mL. Compression of the
pituitary stalk from a pituitary tumor rarely causes PRL to rise
above 100 ng/mL, but elevations to more than 200 ng/mL can
occur. This increase in PRL due to compression of the stalk is
known as the “stalk effect”. Stimulation of PRL secretion
w ith a TRH-stimulation test can suggest the presence of a
prolactinoma. In normal sub jects, intravenous (IV)
administration of 200-500 µg of TRH should lead to a 3 to 5- fold
increase in serum PRL level w ithin an hour. Patients
w ith a prolactinoma w ill often have a blunted response
of less than a 2-fold increase, due to their limited lactotroph
reserve.
Prolactin levels may be falsely low on laboratory testing due to
the “hook effect”. If the serum PRL level is extremely high,
the amount of PRL antigen may saturate the capture antibody in the
radioimmunoassay, leading to a falsely low PRL value. If a
prolactinoma is suspected, the PRL level should be tested again
w ith serial dilutions in order to determine the true PRL
level.
There is considerable heterogeneity in circulating PRL due to
posttranslational modif ication. 80-90% of PRL in serum
is monomeric, while 8-20% is dimeric, and 1-5% is polymeric
(41). Larger polymeric variants have decreased
bioactiv ity . Some patients w ith elevated
levels of basal PRL but normal reproductive function have
elevated
proportions of polymeric PRL that result in decreased PRL
bioactiv ity (41). Dynamic tests of PRL secretion, using TRH,
hypoglycemia, chlorpromazine, or L-dopa,
prov ide useful information about the mechanism of control of
PRL secretion but have a limited value in the differential
diagnosis of hyperprolactinemia. The patient's medical
history, physical examination, blood chemistries, thyroid function
tests and pregnancy test should be rev iewed to assess
for non-hypothalamic-pituitary causes.
Growth Hormone GH is required for normal human growth; it
plays little role in the f irst year of life, but
becomes very important during puberty . It is secreted in
bursts by the somatotroph cells,and its release is controlled by
GHRH and somatostatin which stimulate and inhibit its release,
respectively . GH, in turn, stimulates the liver's
production of somatomedin-C, also known as insulin-like growth
factor 1 (IGF-1). IGF-1 mediates many of the effects of GH,
including stimulating somatostatin release at the hypothalamus and
inhibiting GH release at the pituitary .
Sleep, stress, exercise and hypoglycemia increase the release of
GH, while obesity, hyperglycemia and excess glucocorticoids
decrease it. GH increases the uptake of amino acids into
tissue, and an increase in amino acids increases GH release in a
healthy indiv idual. GH and IGF-1 levels are
highest in children and young adults, then decrease w ith age
in normal sub jects. In normal sub jects, serum GH
levels are very low or undetectable for most of the
day . GH has a half life of 20-30 minutes and is secreted
in short pulses, w ith 2-7 peaks per day . Some of
these bursts are associated w ith meals, while
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others occur during the early stages of sleep. The half life
of IGF-1, on the other hand, is 2-18 hours, and serum levels are
relatively stable throughout the day .
GH def iciency in children leads to dwarf ism. In
adults, however, it is clinically silent. Because of its short half
life and the variations in GH levels throughout the day, serum GH
levels are not very useful in diagnosing GH
def iciency . Serum IGF-1 levels are more
useful; however these levels must be interpreted tak ing
age-related variations into account. The diagnosis of GH
def iciency, therefore, generally is accomplished using a
dynamic stimulation test. Dynamic stimulation tests include an
insulin tolerance test (ITT), a glucagon test, an arginine (ARG)
stimulation test, an L-Dopa test, or a combination of ARG and
GHRH. A subnormal rise in serum GH after one or more of
these tests can diagnose GH def iciency .
The insulin tolerance test is generally considered the
gold-standard for the biochemical diagnosis of GH def iciency,
as it is the most commonly used and well validated of these
dynamic studies. 0.15 units of insulin per kg body weight are
given as an IV bolus (32). The ITT is relatively
contraindicated in patients w ith epilepsy or vascular
disease, and a pre-test potassium level, cortisol level and EKG
should be performed prior to the test. The Growth Hormone
Research Society has def ined severe GH def iciency in
adults as a peak response to insulin-induced hypoglycemia of <3
µg/L (<9 mU/L) (2, 19). Normal indiv iduals should reach a
peak GH response of 7-15 ng/mL w ith this test.
A 2002 study determined the sensitiv ity and specif icity
of multiple diagnostic tests (7).
The ITT had 96% sensitiv ity and 92% specif icity using a
cut off of 5.1 ng/mL. This was followed closely by the ARG
plus GHRH test w ith 95% sensitiv ity and 91%
specif icity w ith a cut off of 4.1 ng/mL; the
latter test also scored a higher patient preference w ith
fewer side effects. Side effects of the ITT included sweating,
vasodilation, hunger, palpitations, dizziness and syncope; for
the ARG plus GHRH test, side effects included vasodilation,
paresthesias and nausea. Other dynamic tests, using ARG alone,
L-Dopa, or ARG plus L-Dopa, showed signif icant overlap
between healthy sub jects and GH def icient
sub jects, and adequate specif icity levels were
diff icult to achieve. This same study showed that
measurement of the IGF-1 level was less sensitive than any of the
dynamic
tests for diagnosing GH def iciency (7). IGF-1 levels are
also less useful in older patients,as normal GH and IGF-1 levels
decline w ith age. Other studies that can be used to diagnose
GH def iciency are the stimulation of GH
secretion w ith 20 minutes of brisk exercise, w ith GH
levels checked at 0, 20 and 40 minutes; or clonidine,
w ith GH levels checked at 0, 60 and 90 minutes. These
tests can stimulate GH levels to >7 ng/mL in normal
sub jects, but w ill be signif icantly lower in
those w ith GH def iciency .
Growth Hormone Excess An overproduction of GH results in excess
growth of soft tissue as well as bony
changes. Adults develop acromegaly while children affected
before epiphyseal closure w ill suffer gigantism. Signs
and symptoms of acromegaly include coarse facial features
w ith prognathism and malocclusion of the teeth, enlargement
of the paranasal sinuses w ith
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frontal bossing, deepening of the voice, organomegaly,
hyperhidrosis, acanthosis nigricans, enlargement of the hands and
feet leading to an increase in ring, glove and shoe size, and
headache. Insulin resistance can lead to diabetes
mellitus. Enlargement of the tongue can lead to sleep
apnea. Excess soft issue in the hands leads to a
“doughy ” handshake, and excess soft tissue in the feet can
lead to a noticeable increase in heel-pad thickness on
radiographs. Acromegalic patients may also suffer from
prox imal myopathy and weakness, osteoarthritis, carpal
tunnel syndrome, cardiomegaly and hypertension. Accelerated
atherosclerosis and metabolic changes lead to a shortened life
span, w ith death generally from cardiovascular,
cerebrovascular or respiratory events.
GH excess w ith acromegaly or gigantism is usually due to a
GH-secreting pituitary adenoma. The average acromegalic
patient has symptoms for eight to ten years before being diagnosed,
so these tumors are generally quite large on
presentation. Many of these lesions w ill compress the
optic apparatus and lead to a decrease in v isual acuity or
bitemporal hemianopia before the tumor is recognized.
Workup When acromegaly or gigantism are suspected, a thorough
endocrine evaluation
should include measurement of basal GH and IGF-1 levels as well as
test ing to assess for suppression of GH secretion w ith
hyperglycemia. Exercise and stress can stimulate GH
production, so serum GH levels should be obtained early in the
morning, before the patient arises from bed, or 2 hours after a
meal, when GH levels should be suppressed. There is some
heterogeneity in serum GH due to post-translational
modif ication and differential splicing (6, 13, 24). Two
main forms of GH are found in the circulation; the
22K form accounts for 90% of serum GH, while the 20K form makes up
5% (24). This heterogeneity may account for differences between
radioimmunoassay values and actual biological
activ ity . Although GH binding proteins ex ist
in circulation, it is unclear whether they affect GH activ ity
physiologically .
In healthy sub jects, basal GH levels are usually <5 ng/mL
while more than 90% of acromegalic patients have levels
>10 ng/mL. Levels vary w idely, however, so some
acromegalic patients have normal GH levels. In acromegalic
patients, the normal pulsatile GH secretory pattern is replaced by
a more consistent elevation throughout the day (4). Due to the
short half life and pulsatile secretion, random GH levels are
of
limited value and single determinations of GH correlate poorly
w ith severity of disease.Serum GH levels may be elevated in
other conditions as well, including uncontrolled diabetes mellitus,
malnutrition, renal failure, and during physical or emotional
stress (11).
To conf irm a diagnosis of acromegaly, a glucose suppression
test can be performed. In a normal glucose suppression test, GH
w ill suppress to <2 ng/mL after glucose loading, while in
an acromegalic patient, this suppression w ill fail to occur
(22).
Because serum levels of IGF-1 are more stable than those of GH,
measurement of IGF- 1 can be used to prov ide a reliable
indicator of the overall exposure of GH on the
body . IGF-1 is increased in nearly all patients
w ith acromegaly, even in those whose serum GH levels are
w ithin the range of normal. Normal levels of IGF-1 range
from 0.45-2.2 U/mL in women and from 0.34-2.0 U/mL in men
(11). IGF-1 is not directly affected by stress or
exercise, and it is bound to carrier proteins that regulate its
function and stabilize its levels. There are at least four
different IGF-binding proteins (IGFBPs), the
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levels of two of which can be measured to assist in the diagnosis
of acromegaly . The serum level of IGFBP-1 is correlated
inversely w ith the amount of GH, while the level of
IGFBP-3 w ill correlate directly w ith GH. IGF-1 is
also a reliable parameter for post- treatment follow-up of
acromegaly, since it reflects GH secretion over the prior 24 hours
(25).
Additional testing may be needed to conf irm the diagnosis of
excessive GH production. Thyrotropin releasing hormone (TRH)
stimulation does not cause a signif icant change in GH levels
in normal sub jects, but w ill lead to a 50% rise in GH
in untreated acromegalics. Though this f inding also
occurs in patients w ith liver disease, renal failure or
depression, it can be highly suggestive of acromegaly in the
correct clinical setting. This test may prov ide useful
therapeutic information as well, as patients who have a positive
response to TRH-stimulation may respond to bromocriptine
therapy . TRH-stimulation may also be used to identify
those patients who, despite a normal GH level after surgery, have
residual GH-secreting tumor and are therefore at risk of tumor
recurrence (12, 36).
An L-Dopa test may also be performed. Administration of oral
L-Dopa to a normal fasting sub ject w ill stimulate GH
secretion, while it w ill paradox ically lower GH levels
in a fasting patient w ith acromegaly
(8). Likew ise, Bromocriptine, a dopamine agonist that
binds D2 receptors, w ill raise GH levels in a normal
sub ject, but lower them in acromegalic patients. Other
dynamic tests include the arginine-stimulation test,
somatostatin-stimulation test, LH-releasing hormone stimulation
test, and insulin- induced hypoglycemia stimulation. Each of
these tests may also prov ide additional information in cases
of acromegaly .
As GH-producing pituitary lesions are often large at the time of
diagnosis, patients
should undergo formal v isual-f ield testing and
endocrine testing for hypopituitarism, in addition to an MRI
w ith thin cuts through the sella.
Those rare patients who have acromegaly, but no pituitary lesion on
MRI, should undergo a workup to f ind another site of a
GHRH-secreting tumor. GHRH levels can be useful in this
workup. Ectopic acromegaly, due to non-central nervous system
causes such as a pancreatic islet cell tumor or a bronchial
carcinoid, w ill result in a signif icantly
elevated level of circulating serum GHRH, whereas GHRH is barely
detectable in acromegaly due to a pituitary lesion (5).
Hypothalamic-Pituitary-Adrenal AxisCortisol is necessary for the
homeostatic biochemical and physiologic responses to stress, and
the hormone is essential for life. Cortisol secretion is
regulated by the hypothalamic-pituitary-adrenal (HPA)
ax is. Psychological and physical stress and signals from
the brain to produce the diurnal rhythm of plasma cortisol levels
stimulate the hypothalamus to secrete corticotrophin releasing
factor (CRH) which then stimulates pituitary ACTH
production. ACTH is produced by the corticotrophs while they
are producing pro-opiomelanocortin. The adrenal glands then
secrete cortisol in response to ACTH. This HPA ax is is
regulated by the balance between stimuli that encourage
secretion of CRH and ACTH, and the negative feedback inhibition
from cortisol on production of CRH and ACTH (Figure 3).
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Both ACTH and cortisol have pulsatile secretion patterns. In
a normal sub ject, ACTH peaks in the early morning, then
declines to a nadir around midnight (32). Circadian rhythms affect
ACTH secretion, so levels are affected by light and change in
time-zone. Physical trauma, surgery, fever, hypoglycemia and
other stressors lead to an increase in ACTH and cortisol
secretion. The half life of bioactive ACTH is only 4-8
minutes, while its immunoreactive half life is quite
variable.
Glucocorticoids increase gluconeogenesis and prevent glucose uptake
into peripheral tissues. With extended exposure to
glucocorticoids, lipolysis is enhanced and body fat
redistribution occurs. Glucocorticoids suppress inflammatory
responses, lower peripherallymphocyte counts and raise granulocyte
counts. They lead to an increase in osteoclasts and a decrease
in osteoblasts, and thereby diminish new bone
formation. Linear growth is suppressed in children. The
catabolic effects of glucocorticoids cause the destruction of
muscle proteins and lead to myopathy . Fibroblast
proliferation and function are inhibited, as are some extracellular
matrix proteins, leading to impaired wound healing. Glucocorticoids
can also have psychological and behav ioral effects, causing
altered mood, sleep and cognition.
Cortisol Deficiency Adrenocortical insuff iciency leads to
nausea and emesis, abdominal pain, anorex ia,
weight loss, generalized weakness, hypotension, hyponatremia, and
the inability to respond to stressful stimuli. Primary
adrenocortical insuff iciency, or Addison's disease,
202 Neuro-oncology
Fig . 3 Regulat ion of cortisol secretion . Th e
hypothalamus releases CRH to st imulate corticotrophs to produce
ACTH. This ACTH then stimulates the adrenal cortex to secrete
cortisol. A negative feedback loop occurs as cortisol inhibits
further CRH and ACTH release . (F igure from Oyesiku N:
Assessment of Pitu itary Function, Rengachary S, Ellenbogen R
(eds): Principles of Neurosurgery . New York,
Elsev ier Mosby, 2005)(30)
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is due to a disorder of the adrenal glands, while secondary
adrenocortical insuff iciency is due to a disorder of
the hypothalamic-pituitary ax is. Primary adrenal
disorders generally produce more severe and life-threatening
symptoms and may lead to hyponatremia, hyperkalemia and hypovolemia
due to lack of aldosterone secretion. Tuberculous infection was the
leading cause of Addison's disease in the past; however, today
it is more often due to autoimmune disease, adrenal hemorrhage from
severe stress, or surgical removal of the adrenal glands.
Secondary adrenocortical insuff iciency w ill occur
w ith pan-hypopituitarism. Isolated ACTH
insuff iciency is uncommon, though, as ACTH secretion is the
most resistant of the pituitary hormones to
loss. Prolonged exposure to exogenous glucocorticoids or to
the excessive endogenous production of glucocorticoids w ith
Cushing's syndrome, however, can lead to isolated ACTH
def iciency . This chronic hypercortisolism
w ill suppress hypothalamic CRH secretion and pituitary ACTH
secretion such that, even after the excess exposure to
glucocorticoids is eliminated, it may take 6-24 months before
the
HPA-ax is resumes normal function.
Workup Cortisol is a more stable hormone than ACTH, and cortisol
levels should be measured
in any evaluation of the HPA ax is. Basal levels should
be drawn between 8:00 and 9:00AM as production is highest at this
time. Random serum levels at other times of day are less
useful. Patients w ith severe adrenal insuff iciency
w ill often have a low 24 hour urine free-cortisol level as
well as a basal serum cortisol level of <100 nmol/L. A
basal level of >450 nmol/L demonstrates that the patient likely
has normal adrenal function (32).
Patients w ith moderate hypoadrenalism may have basal cortisol
levels in the low- normal range.
Medications may affect cortisol secretion or may interfere
w ith the radioimmunoassay used to measure cortisol
levels. Hydrocortisone and prednisolone w ill interfere
w ith the results, and should be stopped at least 24 hours
prior to testing (16). Oral estrogens may increase
cortisol levels for several weeks after administration, due to an
increase in the production of cortisol binding globulin. The
specif ic immunoassay used w ill affect the result as
well, as a w ide variation in results occurs w ith
different assays (10). The levels measured should therefore be
assessed in each patient's specif ic clinical context
rather
than rely ing on set cut-off points, and dynamic-stimulation
tests are needed to conf irmadrenal insuff iciency .
The adrenal cortex atrophies in the absence of ACTH stimulation, so
the response to
ACTH is suppressed in both primary and secondary adrenal
insuff iciency, The short ACTH stimulation test in jects
25 units (0.25 mg) of cosyntropin, synthetic short ACTH which
retains the biologic activ ity of ACTH, intravenously (IV) or
intramuscularly (IM), and measures plasma cortisol levels
immediately before, 30 minutes after and 60 minutes after
in jection. In normal sub jects, an increase in
cortisol of at least 7 µg/dL over the basal level, or a peak
cortisol of at least 20 µg/dL is expected. Patients w ith
chronic ACTH def iciency have a blunted response, while those
w ith primary adrenal insuff iciency generally have
no response to the cosyntropin.
Once a diagnosis of adrenal insuff iciency is conf irmed,
measurements of basal plasma ACTH levels and a CRH stimulation
tests are performed to determine the etiology of the
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disorder (16). In primary adrenal disease, diminished
cortisol production prov ides decreased negative feedback
inhibition on the pituitary corticotrophs, so basal ACTH levels
should be high. Conversely, in patients w ith pituitary
disease or those w ith prolonged glucocorticoid exposure,
basal ACTH levels are low and are unable to respond normally to CRH
stimulation.
The insulin tolerance test (ITT) and glucagon stimulation test
(GST) can be used to determine how the HPA ax is responds to
stress. The ITT, as discussed earlier, is considered by many
to be the 'gold-standard' for measuring both GH and ACTH
reserves (1, 29). A bolus of insulin, 0.15 units/kg, is given
IV, to induce hypoglycemia. A normal response is a cortisol
increase of 200 nmol/L, reaching a peak level of at least 500
nmol/L (32).
A glucagon-stimulation test is not as w idely used as the ITT,
but may be useful in those patients for whom an ITT would be
contraindicated. An IM in jection of 1 mg glucagon is
given, then ACTH and GH levels are measured six times, starting at
90 minutes
post-in jection and continuing every 30 minutes
thereafter. Normal cortisol response is delayed but
otherw ise similar to that for the ITT.
Cortisol Excess; Cushing's Syndrome Longstanding exposure to excess
cortisol leads to Cushing's syndrome. Multiple
processes can lead to this syndrome, and determining the exact
cause in a particular patient may be diff icult.
Generally, late evening plasma levels are elevated over the normal
values of f ive to 25 ng/mL and the usual diurnal variation in
levels is lost, leading to an elevated mean cortisol
level. This chronic hypercortisolemia suppresses
hypothalamic CRH and pituitary ACTH secretion, and the pituitary
corticotrophs atrophy .
Approx imately 75% of patients w ith Cushing's syndrome,
endogenous adrenocortical hyperfunction, have Cushing's disease,
excess ACTH secretion from a pituitary corticotroph
tumor. Many of these ACTH-secreting adenomas are microadenomas
which may not be v isible even on high quality sellar
MRI. Cushing's syndrome patients may also have an ectopic,
non-pituitary, source of excess ACTH production. This is most
often due to small cell lung carcinoma, but may also be
attributable to bronchial carcinoid, thymic carcinoid, pancreatic
carcinoid, pancreatic islet cell tumor,
pheochromocytoma, medullary thyroid carcinoma or another
neuroendocrine tumor.There are also rare CRH-secreting tumors,
generally bronchial carcinoids. Other patients w ith
Cushing's syndrome have adrenal tumors that secrete cortisol rather
than ACTH. These may be benign adenomas or malignant carcinomas,
and the syndrome can be clinically indistinguishable from that of
Cushing's disease or ectopic ACTH-secreting tumors. Therefore,
endocrine testing to determine the etiology of Cushing's syndrome
is very important.
Symptoms associated w ith Cushing's syndrome include central
weight gain, often accompanied by a buffalo hump; moon
facies, due to thickening of facial fat;
hypertension; hyperglycemia or diabetes
mellitus; hirsutism; acne; purple
striae; facial telangiectasias ; amenorrhea or
hypogonadism ; muscle wasting ; osteoporosis;
hyperpigmentation; and depression. Patients w ith
Cushing's syndrome lose the normal diurnal cortisol
variation. In Cushing's disease, the HPA ax is maintains
its homeostatic
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responses, but is altered to respond only to higher than normal
glucocorticoid levels. Cushing's syndrome from an ectopic
ACTH-secreting tumor, on the other hand, w ill exhibit
autonomous cortisol production and fail to demonstrate any feedback
inhibition. Cushing's disease is diagnosed if a patient has
1. increased basal cortisol levels, 2. relative resistance to
negative feedback from glucocorticoids, 3. ACTH response to
decreased cortisol, 4. ACTH response to CRH or vasopressin,
5. cortisol response to exogenous ACTH, and 6. a
pituitary source of the excess ACTH.
Workup When Cushing's syndrome is suspected, one must f irst
establish that there is indeed
excess secretion of cortisol. This may be accomplished
v ia tests that 1. directly or indirectly measure
cortisol production over 24 hours, such as v ia 24-hour urine
collection for free cortisol and 17-hydroxyglucocorticoid excretion
and 2. assess the presence of normal sensitiv ity of the
hypothalamic-pituitary-adrenal ax is to negative
feedback by glucocorticoids, for instance, by using a low-dose
glucocorticoid tests including the overnight test or the low-dose
portion of the 6-day dexamethasone suppression test.
Serum free cortisol f ilters into saliva and urine, and
cortisol urinary excretion products are elevated. 24 hour
urine free cortisol (UFC) is 20-90 µg in a normal sub ject,
but increases to >150 µg in Cushing's syndrome. Some of the
metabolites of cortisol, including 17-hydroxysteroids (17-OHCS),
and some of its precursors, including 17- ketosteroids and DHEAS,
are elevated as well. The saliva and urine free cortisol
levels are more accurate indicators of increased cortisol secretion
than is urinary 17-OHCS, as they
increase more rapidly after plasma cortisol exceeds the binding
capacity of transcortin. Salivary cortisol is easy to use in an
outpatient setting and allows for repeated sampling. An 11:00PM
salivary free cortisol >3.6 nmol/L is highly suggestive of
Cushing's syndrome.
Once it is determined that a patient has Cushing's syndrome, then
the next step is to determine the source of the excess hormone
production. The differential diagnosis includes
ACTH-dependent processes which lead to Cushing's syndrome by excess
ACTH secretion, and ACTH-independent processes which lead to the
syndrome by excess cortisol secretion. ACTH-dependent lesions
include ACTH-secreting pituitary tumors,
ectopic ACTH-secreting tumors such as small cell lung carcinoma,
diffuse corticotrophhyperplasia, and ectopic CRH secretion, while
ACTH-independent processes include cortisol-secreting primary
adrenal disease (Table 2).
Assessment of Pituitary Function 205
Table 2 Etiology of Cushing's Syndrome. (Copied from Oyesiku
N: Assessment of Pituitary Function, Rengachary S,
Ellenbogen R (eds): Principles of Neurosurgery . New
York, Elsev ier Mosby, 2005)(30)
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Normal ACTH is <10 pg/mL (2 pmol/L). Patients w ith
ACTH-dependent disease have excess cortisol due to excess ACTH, so
they w ill have plasma ACTH levels which are inappropriately
elevated for the level of cortisol present. Conversely, the
hypothalamic and pituitary portions of the HPA ax is are
relatively normal in primary adrenal disease, so hypercortisolemia
w ill suppress pituitary ACTH secretion in these patients, and
their serum ACTH levels w ill be undetectable or very
low . A simultaneous serum cortisol level must be drawn
to properly evaluate the plasma ACTH level.
Patients in whom ACTH-independent Cushing's syndrome is suspected
should undergo MRI or CT adrenal imaging. Nearly 100% of these
patients w ill have an adrenal tumor, most of which can be
v isualized radiographically . When ACTH- dependent
Cushing's syndrome is suspected, the differential is a bit
larger. Most ACTH- secreting pituitary and ectopic tumors are
very small and are not easily recognized on radiographic
imaging. Basic endocrinologic principles can assist in
mak ing the diagnosis. ACTH-secreting pituitary adenomas are
well-differentiated tumors that originate from
pituitary corticotrophs. They are therefore more likely to
respond to glucocorticoids and to CRH stimulation than are ectopic
ACTH-secreting tumors, which arise from tissues that are not
supposed to secrete ACTH, respond to glucocorticoids or contain
receptors for CRH. Therefore a dexamethasone suppression test
(DST) or CRH-stimulation test may be useful.
In the overnight DST, 0.5-1 mg of dexamethasone is given orally at
midnight, and serum cortisol is checked at 8:00AM the next morning,
while in the two day low-dose DST, 0.5 mg of dexamethasone is given
orally every 6 hours for 8 doses. In normal sub jects,
these doses are enough to suppress the HPA ax is, leading to
serum cortisol levels
<140 nmol (5 µg/dl), urinary 17-OHCS <6.9 µmol (2.5 mg) in 24
hours, and urinary free cortisol <55 nmol (20 µg) in 24
hours. Patients w ith Cushing's syndrome, on the other
hand, w ill not have this HPA ax is suppression.
The high dose DST gives patients 2 mg dexamethasone. Patients
w ith Cushing's disease w ill generally suppress their
levels to 50% of their baseline w ith this test, while
patients w ith ectopic ACTH tumors or adrenal tumors
w ill not have any signif icant suppression w ith
either the high or low dose tests.
The CRH or AVP suppression tests can also help differentiate
Cushing's disease from ectopic lesions. CRH and AVP are
physiologic secretagogues to which most
pituitary microadenomas w ill respond. In Cushing's
disease, either compound w illlead to a signif icant
increase in ACTH, while in cases of ectopic ACTH secretion, ACTH
levels w ill not respond.
The metyrapone test is a less common test that can also be used to
d istinguish between a pituitary and an ectopic ACTH
source. Metyrapone is a compound that inhibits cortisol
synthesis at several steps, including at the conversion of
11-deoxycortisol to cortisol. As plasma cortisol levels fall,
corticotrophs respond by increasing production of ACTH, which can
be measured v ia increased urinary 17-OHCS. For patients
w ith ectopic ACTH production, the hypothalamic and pituitary
ax is is chronically suppressed and is not reactivated
w ith metyrapone.
Another test which can help to differentiate between pituitary and
non-pituitary disease processes is the high dose 6 day
dexamethasone suppression test known as the Liddle test. In
this test, a patient undergoes 2 days of baseline urinary
17-hyrdroxysteroid
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measurements, then is given 2 days of low dose dexamethasone, 0.5
mg orally every 6 hours, lastly he is given 2 days of high dose
dexamethasone, 2 mg orally every 6 hours. Liddle f irst
observed in 1960 that the ma jority of patients w ith a
pituitary source of excess ACTH, Cushing's disease, had a more than
50% decrease in 17-OHCS excretion on the second day of high-dose
glucocorticoid administration, while this response was not seen in
patients w ith adrenal tumors (15).
Once Cushing's disease is suspected, the location of the tumor must
be established. When radiographic imaging does not demonstrate a
lesion, inferior petrosal sinus sampling (IPSS) can assist
w ith this. The petrosal sinuses drain the pituitary
gland. Bilateral catheters are placed v ia the femoral veins
and fed up the internal jugular veins to the inferior petrosal
sinuses. ACTH levels are measured in the peripheral
circulation and each sinus both before and after IV in jection
of CRH to stimulate ACTH secretion. Bilateral catheterization
allows for simultaneous sampling of the right and left sinuses so
that the ACTH concentrations can be compared. A gradient
between the sinuses can
lateralize the tumor w ithin the pituitary . As
spontaneous ACTH release is episodic in nature, CRH stimulation
helps to ensure secretion at the time of sampling. An inferior
petrosal sinus to peripheral blood (ISP:P) ratio >2.0 in basal
samples has up to 95% sensitiv ity and 100% specif icity,
while a peak IPS:P ratio >3.0 after CRH administration has been
reported to have 100% sensitiv ity and 100% specif icity
(14, 28, 38). An inter- sinus gradient >1.4 predicts the
location of the lesion in up to 75% of patients. Cavernous
sinus sampling is less commonly used, but can prov ide
slightly more accurate localization (Table 3).
Mild hyperprolactinemia is present in about one quarter of patients
w ith Cushing's disease. Some of these tumors contain
PRL-secreting cells (42). PRL levels can also be
Assessment of Pituitary Function 207
Table 3 Clinical Approach to Patients w ith Suspected
Cushing's Syndrome. (Copied from Oyesiku N: Assessment of
Pituitary Function, Rengachary S, Ellenbogen R
(eds): Principles of Neurosurgery . New York,
Elsev ier Mosby, 2005)(30)
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measured as part of the IPSS to assist in localizing the tumor.
Most patients undergo a combination of these tests. It is
important to establish that the
patient does indeed have Cushing's syndrome before proceeding
w ith tests to determine if the diagnosis is Cushing's disease
or an ectopic source. In sub jects w ithout
Cushing's syndrome, pituitary ACTH secretion is suppressed by
dexamethasone and responds to CRH. This can therefore be
erroneously attributed to Cushing's disease, causing a normal
patient to undergo unnecessary pituitary surgery .
Glycoprotein Hormones The glycoprotein pituitary hormones are
thyroid-stimulating hormone (TSH),
follicle-stimulating hormone (FSH), and luteinizing hormone
(LH). Each of these is composed of 2 glycopeptide
chains: an alpha chain and a unique beta chain. These
chains are synthesized indiv idually, and there is generally a
slight excess of the alpha chain which can be detected w ith
radioimmunoassay .
Pituitary-Thyroid Axis Hypothalamic secretion of TRH to the portal
venous complex regulates the production
and secretion of thyrox ine (T4) and triiodothyronine
(T3). When thyrotrophs sense TRH, they release TSH, which acts
on the thyroid gland to release T3 and T4. T3 and T4, in turn,
inhibit hypothalamic TRH release and pituitary TSH
release. Somatostatin, glucocorticoids and dopamine also
suppress both TRH release and the pituitary response to TRH.
Hypothyroidism Signs and symptoms of hypothyroidism include
fatigue, dry sk in, cold intolerance,
alopecia, and, in severe cases, myxedema coma. Most patients
w ith hypothyroidism have primary hypothyroidism due to a
disorder of the thyroid gland. Autoimmune Hashimoto's
thyroiditis, thyroid destruction after 131I therapy and surgery for
hyperthyroidism are the most common causes of this condition
. In primary hypothyroidism, absence of the feedback
inhibition of the thyroid hormones on the pituitary and
hypothalamus results in elevated TRH and TSH levels. When
patients are untreated, the increased TRH secretion stimulates
thyrotroph hyperplasia and may
lead to pituitary enlargement. As TRH also stimulates PRL
secretion, these patients may be misdiagnosed w ith a
PRL-secreting or TSH-secreting tumor. TSH def iciency causes
secondary hypothyroidism and results from pituitary or
hypothalamic disease. It frequently accompanies pan-pituitary
def iciency from a large pituitary adenoma or suprasellar
mass.
Workup The mean TSH concentration in euthyroid adults is 1.4-2.0
U/ml. These levels do not
differ signif icantly w ith gender or w ith age
between adolescence and about 60 years. TSH levels rise to a
peak between midnight and the early morning and drop to a nadir in
the late afternoon (26, 31). Increased TSH levels are seen in
hypothyroidism, TSH-secreting tumors, and w ith some drugs,
including iodine and dopamine antagonists. Decreased TSH
levels occur w ith hyperthyroidism, severe illnesses, chronic
renal failure, pan-
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hypopituitarism, pituitary tumors or hypophysitis, sarcoid,
hypothalamic tumors or trauma, or drugs such as glucocorticoids,
oral contraceptives or dopamine agonists.
In both primary and secondary hypothyroidism, the serum level of
free thyrox ine (free T4) is low . Free T4 can be
measured by direct radioimmunoassay from a serum sample or may be
estimated by the free thyrox ine index (FTI = total T4 x T3
resin uptake). Though it is generally reliable, the FTI can be
misleading in patients in whom prolonged illness causes a low FTI
despite clinical euthyroidism and normal serum levels of free T4.
When serum free T4 is low, measurement of plasma TSH can
distinguish primary from secondary hypothyroidism: an elevated
TSH is a sign of primary disease, while a low TSH is a sign of
secondary disease (Table 4). Non-thyroid illnesses, such as
hepatic failure or sepsis, can also alter TSH levels,
however.
A TRH stimulation test w ill further differentiate primary and
secondary hypothyroidism, and in secondary hypothyroidism may
distinguish between pituitary and hypothalamic
disorders. 200-500 µg TRH is given IV over 30 minutes, and
serum TSH levels are obtained at -5, 0, 15, 30 and 60
minutes. Patients w ith primary hypothyroidism w ill
have elevated basal TSH levels and w ill respond rapidly and
excessively to TRH stimulation. Patients w ith pituitary
lesions that damage the thyrotrophs w ill have no TSH response
to TRH, while patients w ith hypothalamic disorders w ill
have a delayed TSH response which peaks at 60 minutes. Normal
sub jects w ill have a serum TSH peak at 15 minutes after
stimulation as well as an increase of at least 6 µU/mL over their
basal value.
Hyperthyroidism Symptoms of hyperthyroidism include tremulousness,
anx iety, heat intolerance,
diarrhea and changes in mental status. The ma jority of
hyperthyroid patients have a circulating thyroid-stimulating
antibody, a thyroid adenoma, or thyroiditis. Hypersecretion of TSH
by a pituitary adenoma is quite rare, occurring in less than 1% of
hypothyroid patients. These TSH-secreting tumors may also
secrete GH or PRL. Since primary hyperthyroidism is relatively
common and TSH-secreting tumors are rare, many patients w ith
TSH-secreting pituitary adenomas are initially misdiagnosed and
receive ablative therapy of the thyroid gland. Thus, they may
no longer have hyperthyroidism when the pituitary tumor is
recognized, mak ing it more diff icult to
diagnose. Because of the common delay in diagnosis,
TSH-secreting pituitary adenomas are often large, invasive tumors
at the time that they are recognized.
Assessment of Pituitary Function 209
Table 4 Thyroid Screening Tests. (Copied from Oyesiku N:
Assessment of Pituitary Function, Rengachary S, Ellenbogen R
(eds):
Principles of Neurosurgery . New York, Elsev ier
Mosby, 2005)(30)
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Workup As w ith the evaluation of hypothyroidism, TSH levels
should be measured, but they
may not prov ide the full picture. Patients w ith
hyperthyroidism due to primary thyroid disease w ill have
elevated serum levels of free T4, w ith a low plasma
TSH. A TRH stimulation test may be useful in the assessment
of mild thyroid dysfunction and in the functional evaluation of the
hypothalamic-pituitary-thyroid ax is. Serum TSH levels
are measured at baseline and again after the administration of
TRH. A dose-response relationship between TRH and TSH levels
is observed (18). In primary hyperthyroidism, the excess
thyroid hormones w ill inhibit the pituitary thyrotrophs, so
the pituitary TSH response to TRH stimulation w ill be
suppressed.
Secondary hypothyroidism, from a pituitary or hypothalamic
disorder, w ill generally demonstrate low levels of
T4 in combination w ith lower than expected levels of
TSH. Serum TSH levels are not always useful, however, as they may
appear normal if the patient secretes a form of TSH which is
detectable on radioimmunoassay but biologically
inactive. In TSH-secreting tumors, the production of alpha and beta
subunits is imbalanced
such that excess alpha subunit is secreted, which produces a ratio
of serum alpha subunit to serum TSH of >1. In a patient
w ith hyperthyroidism, or a patient w ith a pituitary
tumor who has been prev iously treated for hyperthyroidism, an
elevated TSH level combined w ith an elevated ratio of
alpha-subunit to TSH, indicates a TSH- secreting pituitary
adenoma.
In patients who have had ablative thyroid treatments for
misdiagnosed TSH-secreting pituitary tumors, elevated plasma TSH
levels do not fully suppress when the patient is
given thyroid hormone, and the pituitary TSH response to TRH is
blunted.
Gonadotropins FSH and LH are produced and released by the
gonadotrophs of the adenohypophysis
to regulate ovarian and testicular function. In women, FSH
stimulates growth of the granulosa cells of the ovarian follicle
and controls their estrogen secretion. At the midpoint of the
menstrual cycle, the increasing level of estradiol stimulates a
surge of LH secretion, which then triggers ovulation. After
ovulation, LH supports the formation of the corpus
luteum. Exposure of the ovary to FSH is required for
expression of the LH
receptors. In men, LH is responsible for the production of
testosterone by Leydig cells inthe testes. The combined
effects of FSH and testosterone on the seminiferous tubule
stimulate sperm production.
FSH and LH secretion occur in a pulsatile fashion in response to
pulses of secretion of GnRH from the hypothalamus. GnRH
is also known as LH-releasing hormone (LHRH) because of its potent
stimulation of LH secretion. Levels of FSH and LH are
regulated by a balance of GnRH stimulation, negative feedback
regulation from the inhibin peptide secreted by the ovaries and the
testes, and the effect of the sex steroids on the pituitary and the
hypothalamus. Appropriate concentrations of FSH and LH are
required for normal sexual development and reproductive function in
both women and men. LH and FSH circulate in blood
predominantly in the monomeric form found in the
pituitary . FSH has a half life of 3-5 hours, so serum
levels are more stable than are those of LH, which has a half life
of 30-60 minutes.
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GnRH stimulates gonadotropin secretion from the pituitary for the
f irst few months of life, then the pituitary becomes
unresponsive to GnRH until puberty, when pulsatile secretion of FSH
and LH occur in response to pulses of GnRH. At menopause, when
gonadal failure occurs, the negative feedback prov ided by the
hormonal products of the gonads is eliminated so serum levels of
FSH and LH increase.
Gonadotropin Deficiency and Workup Hypogonadism presents in women
as amenorrhea and loss of libido associated w ith
uterine and vaginal atrophy . In men, low testosterone
results in loss of libido, impotence, decreased beard growth and
body hair, and testicular softening.
When hypogonadism is suspected, endocrine evaluation should include
measurement of plasma FSH, LH and sex hormones estradiol in women
and testosterone in men. FSH and LH are measured by
immunoassay . In men above the age of puberty, these
levels are w ithin a fairly narrow range. In women,
however, the pulsatile nature of LH and FSH,
and their marked fluctuation during the menstrual cycle, pregnancy
and menopause have to be considered in the interpretation of these
lab results. In adolescents and women, isolated and random FSH
and LH levels are of little diagnostic use alone, and must be
correlated w ith the results of simultaneous levels of
estradiol or testosterone and the results of dynamic testing.
Estradiol binds to sex-hormone binding globulin which w ill
have elevated levels in women who are tak ing oral
contraceptive pills or hormone replacement therapy .
Testosterone in men has a signif icant diurnal variation, and
should be assessed between 8:00am and 9:00am.
Primary hypogonadism is associated w ith low levels of sex
steroids and high levels of FSH and LH. This may be due
to primary ovarian failure such as w ith ovarian dysgenesis,
oophorectomy or premature ovarian failure, or primary testicular
failure such as w ith Klinefelter's syndrome or
orchiectomy . Decreased levels of FSH and LH may also be
found in hypothalamic disease including tumors such as
craniopharyngiomas or hypothalamic region meningiomas, germinomas,
gliomas or hamartomas, as well as other hypothalamic
inf iltrative or infectious pathology such as sarcoidosis,
eosinophilic granuloma, tuberculosis, fungal infections or
syphilis. Hypothalamic trauma, vascular disease and radiation
therapy can also be the cause.
If FSH and LH are inappropriately low and are associated w ith
a decreased level of estradiol or testosterone, then
hypogonadotropic hypogonadism can be diagnosed. This may be a
primary result of congenital causes, as w ith Kallman's
syndrome, in which GnRH def iciency is associated w ith
anosmia and defective development of the midline structures of the
brain. More commonly however, hypogonadotropic hypogonadism is
a secondary, acquired defect of GnRH production associated
w ith hypothalamic dysfunction, as occurs w ith
destruction of the pituitary gonadotrophs or interruption of
pituitary stalk function from a sellar mass or apoplexy, or from
surgery or radiation to treat a sellar tumor, or as a result
of stress, system ic disease, anorex ia nervosa or bulimia, or
sometimes seen in very athletic women.
GnRH stimulation testing is rarely used today, but at times may be
useful to determine the presence of adequate gonadotroph
reserve. If a detectable elevation of FSH and LH levels occurs
after GnRH administration, functional gonadotropic cells are still
present.
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This response to GnRH may require priming of the gonadotrophs
w ith repeated in jections of GnRH.
Gonadotropin Excess and Workup Elevated FSH and LH may be seen
w ith polycystic ovary syndrome, paraneoplastic
gonadotropin secretion, precocious puberty and
gonadotrope-secreting adenomas. Though FSH-secreting and
LH-secreting pituitary adenomas are rarely observed clinically,
approx imately 5% of pituitary adenomas have
immunohistochemical staining for the gonadotropins or their
subunits. Nearly all of these tumors are clinically
nonfunctioning pituitary macroadenomas that cause symptoms because
of their mass effect on sellar or parasellar structures, as there
is no characteristic hypersecretory endocrinopathy, as occurs
w ith other hormone secreting tumors. About 20% of these
tumors secrete the alpha-subunit rather than a complete
gonadotropin.
Precocious puberty is often associated w ith hypothalamic
hamartomas in children.
These tumors interrupt the normal suppression of pituitary
gonadotropin function by higher neural centers, leading to
pulsatile secretion of GnRH and, in turn, secretion of FSH and LH,
estrogen, and testosterone and premature sexual
development. Sustained, non-pulsatile exposure to GnRH
desensitizes the gonadotrophs to GnRH and inhibits FSH and LH
release. A long-acting analogue of GnRH is used to suppress
pituitary gonadotropin secretion and reverse sexual
development in children w ith idiopathic precocious puberty or
precocious puberty due to a hypothalamic hamartoma. Ectopic
production of gonadotropin, usually of human chorionic gonadotropin
which has LH- like activ ity, by germinomas, lung carcinomas
and other tumors may also lead to
precocious puberty .
Posterior Pituitary Hormones The neurohypophysis is the posterior
lobe of the pituitary . This lobe secretes
antidiuretic hormone (ADH) and oxytocin, which are produced by
hypothalamic neurons but are stored in secretory granules in the
nerve terminals of the neurohypophysis and are released from there
in response to various stimuli.
If the posterior pituitary is selectively damaged but the median
eminence and hypothalamus remain intact, these hormones can be
secreted from the median eminence.
Antidiuretic Hormone ADH conserves water by reducing the rate of
urine output. This antidiuretic effect is
achieved by promoting the reabsorption of solute-free water in the
distal collecting tubules of the k idney . Though
this hormone is also known as vasopressin, it has little to no
cardiac pressor effect in healthy humans. Through the action
of ADH, serum sodium concentrations and serum osmolality are
maintained w ithin a narrow range, despite large daily
variations in sodium intake and water loss. Derangements in
ADH secretion can lead to severe, life-threatening disturbances in
serum osmolality and volume.
Though multiple hypothalamic signals influence ADH secretion, the
primary stimuli for ADH release are an increase in plasma
osmolality or a decrease in plasma volume. Even a 2% increase in
plasma osmolality caused by an impermeable solute, such as NaCl,
causes shrinkage of hypothalamic osmoreceptor cells, stimulating
ADH release as well as
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thirst. This osmoregulatory mechanism is differentially
sensitive to various plasma solutes. Sodium and its anions,
which normally contribute >95% of the osmotic pressure in
plasma, are the most potent stimulators of ADH
release. Sugars, such as sucrose and mannitol, are nearly as
powerful. Decreased intravascular volume is also a potent
stimulator of ADH secretion. Small decreases in volume
activate stretch receptors in the left atrium which lead to ADH
release, while decreases in volume of about 10% stimulate ADH
release v ia baroreceptors in the carotid arteries and the
aortic arch (Figure 4).
Higher neural centers also influence ADH
levels. Beta-adrenergic and cholinergic agonists stimulate ADH
secretion, while alpha-adrenergic agonists and atropine inhibit
it. Psychological factors, pain, and stress can therefore
increase ADH release. Nausea is an instantaneous and extremely
potent stimulus for ADH secretion in humans. Other
stimuli for ADH release include hypoglycemia, angiotensin,
nicotine, morphine, and barbiturates, while inhibitors of ADH
release include alcohol, phenytoin, and narcotic antagonists.
Assessment of Pituitary Function 213
Fig . 4 Regulation of ADH secretion. The main
stimulators of ADH release by the posterior pituitary are an
increase in plasma osmolality or a decrease in intravascular
volume. Osmolality is detected by hypothalamic osmoreceptor
cells, while volume changes are detected by atrial stretch
receptors and carotid and aortic baroreceptors. (Figure from
Oyesiku N: Assessment of Pituitary
Function, Rengachary S, Ellenbogen R (eds):Principles of
Neurosurgery . New York, Elsev ier Mosby,
2005)(30)
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Deficient ADH; Diabetes Insipidus The typical clinical
manifestations of diabetes insipidus (DI) include polyuria,
polydipsia, excessive thirst and nocturia. Polyuria may be
def ined as the excretion of more than 2.5 L of urine per 24
hours on at least 2 consecutive days, prov ided that patients
are allowed free access to and drink water ad libitum. The
severity of diabetes insipidus varies w idely, w ith
urine volumes ranging up to 20 L per day . If access to
water is restricted, dehydration can rapidly become severe and
result in altered mentation, fever, hypotension, and death.
Central DI is def icient ADH secretion from the
neurohypophysis in response to normal osmotic
stimulation. This disorder is also known as hypothalamic DI,
cranial DI or neurogenic DI. These patients generally have
normal thirst sensation though they have insuff icient
circulating antidiuretic activ ity . Diabetes
insipidus secondary to renal tubular insensitiv ity to the
antidiuretic effect of ADH is usually called nephrogenic diabetes
insipidus. These patients generally have a normal of high
level of circulating
ADH. Primary polydipsia is a third mechanism leading to
diabetes insipidus. This is the ingestion of excessive volumes
of water, resulting in suppression of vasopressin release and
consequent polyuria.
Causes of central DI include sellar and parasellar tumors,
especially craniopharyngiomas, large non-functional pituitary
adenomas, germinomas, and metastatic tumors; hypothalamic
tumors or inf iltrative processes such as sarcoidosis and
histiocytosis-X ; pituitary or hypothalamic in jury
or surgery ; head trauma; subarachnoid hemorrhage
from ruptured intracranial aneurysms; and idiopathic
causes. DI is rarely a presenting feature in patients
w ith pituitary adenomas, but is more common in patients
w ith craniopharyngioma or hypothalamic lesions. DI from
head trauma or damage to the pituitary stalk or hypothalamus
generally presents w ith 24 hours of
in jury . In about 50% of cases of posttraumatic
diabetes insipidus, the condition resolves spontaneously
w ithin a few days. Permanent diabetes insipidus develops
in another 30-40% of these patients, and the remainder exhibit a
triphasic response to in jury . In this last group,
the onset of polyuria is abrupt but lasts only a few days. It
is followed by a period of anti- diuresis similar to SIADH that
lasts 2-14 days before permanent DI develops . This triple
response to in jury is believed to be attributable to release
of the stored ADH w ithin the neurohypophysis (27, 40).
Glucocorticoid def iciency or thyroid hormone def iciency
can lead to impairment of the k idney 's ability to
excrete a water load and to dilute urine
max imally . This impairment of anterior pituitary
function can therefore mask central DI, which becomes apparent only
when the hypopituitarism is treated.
Workup Patients w ith DI w ill demonstrate persistent
urine osmolality of less than 300
mOsm/kg H2O associated w ith urine specif ic
grav ity of 1.005 or less and plasma osmolality greater than
the normal 287 mOsm/kg H2O. To conf irm the diagnosis,
patients are tested to document that there is inadequate release of
ADH to an osmotic stimulus. The safest and most w idely
used test to raise plasma osmolality is the water deprivation
test. In this test, baseline body weight, urine and plasma
osmolality, and v ital signs are measured, then all oral
intake is stopped. Water deprivation begins the night
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before the test in patients w ith mild polyuria, and early on
the day of the test in patients w ith severe polyuria. It
is important that the test only be performed while the patient is
under constant superv ision, to prevent severe
dehydration. For patients w ith DI this test can be
dangerous. Hourly measurements of urine osmolality and weight
are obtained. Dehydration continues until either two sequential
urine osmolalities vary by <30 mOsm/kg H2O, more than 3% of body
weight is lost, or orthostatic hypotension and postural tachycardia
appear. Sub jects then receive 5 units of aqueous
vasopressin subcutaneously and a f inal urine osmolality is
measured 1 hour later. In normal sub jects, endogenous
ADH secretion concentrates the urine and preserves normal plasma
osmolality . Thus, urine osmolality normally exceeds 500
mOsm/kg H2O and plateaus, while plasma osmolality remains below 300
mOsm/kg H2O before vasopressin in jection, and urine
osmolality rises less than 5% after in jection. By
contrast, in patients w ith central DI, urine osmolality
plateaus at 300-500 mOsm/kg H2O, plasma osmolality may exceed 300
mOsm/kg H2O, and urine osmolality rises >9% after vasopressin
in jection.
This test not only establishes whether or not diabetes insipidus is
present, it also distinguishes central DI from other causes of
polyuria. In patients w ith polyuria from renal disease
or nephrogenic DI, the rise in urine osmolality w ith
dehydration is limited and does not increase after vasopressin
administration. In patients w ith primary
polydipsia, water deprivation is prolonged before urine osmolality
plateaus, and urine osmolality does not increase after the
in jection of vasopressin.
The measurement of plasma ADH concentration under basal conditions
can be used as an ad junct to the water deprivation test, but
this radioimmunoassay test is not routinely available and is rarely
affords diagnostic benef it.
Excess ADH; Syndrome of Inappropriate ADH Secretion The syndrome of
inappropriate antidiuretic hormone (SIADH) is the most common
cause of euvolemic hypo-osmolality . It is also the most
prevalent cause of hypo- osmolality of all etiologies encountered
in current clinical practice, occurring in 30-40% of all
hypo-osmolar patients (21). SIADH results from excess ADH
secretion, either from the hypothalamus or from an ectopic
source. This excess ADH stimulates excessive retention of
free water and leads to the inability to excrete dilute
urine. This results in hyponatremia and serum
hypotonicity . When a patient has hyponatremia and
low
serum osmolality, then continued ADH release, w ith the
osmolality of urine higher thanthat of plasma, is inappropriate.
The etiology of SIADH is diverse. Causes include ectopic
production of ADH by
tumors, classically oat cell carcinoma; by lung tissue during
inflammatory diseases such as tuberculosis; excessive
neuro-hypophyseal release of ADH caused by intracranial disorders,
including head trauma, subarachnoid hemorrhage, subdural hematoma,
pituitary apoplexy, pituitary stalk damage, intracranial surgery,
encephalitis, meningitis, intracranial abscess, or
hydrocephalus; Guillain-Barré syndrome; delirium
tremens; acute psychosis; or by drugs that stimulate ADH
release such as chlorpropamide, carbamazepine or tricyclic
antidepressants (20, 21).
The clinical features of SIADH include weight gain, weakness,
lethargy, and mental confusion. As serum sodium drops below
120 mEq/L seizures and coma can occur. Hypo-osmolality is
associated w ith a broad spectrum of neurologic
manifestations. In the
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most severe cases, death can result from respiratory arrest after
tentorial cerebral herniation and brainstem compression. This
process has been termed hyponatremic encephalopathy and primarily
reflects brain edema resulting from osmotic water shifts into the
brain due to decreased plasma osmolality (3, 17).
Signif icant symptoms generally do not occur until plasma
sodium concentration falls below 123 mEq/L, and the severity of
symptoms can be roughly correlated w ith the degree of
hypo-osmolality (3).
The period over which hypo-osmolality develops also greatly affects
the severity of symptoms. Rapid development of
hypo-osmolality w ill cause marked neurologic symptoms,
whereas gradual development over several days or weeks often
presents w ith only mild symptomatology despite profound
degrees of hypo-osmolality . If given suff icient
time, the brain can counteract osmotic swelling by excreting
intracellular solutes such as potassium and organic osmolytes, an
adaptive process known as volume regulation (17, 39). Rapid
development of hypo-osmolality may cause brain edema before
this adaptation can occur. Underly ing neurologic disease also
affects the level of hypo-osmolality at which CNS
symptoms appear. Moderate hypo-osmolality that would be of
little concern in an otherw ise healthy patient can cause
morbidity in a patient w ith an underly ing seizure
disorder. Non-neurologic metabolic disorders such as
hypox ia, hypercapnia, acidosis and hypercalcemia, can
similarly affect the level of serum osmolality at which CNS
symptoms occur.
Workup
Laboratory f indings in SIADH include hyponatremia, serum
hypotonicity, urine osmolality that exceeds that of plasma, and
elevated urinary sodium concentration. Plasma osmolality is
generally >275 mOsm/kg H2O, urine osmolality is >100 mOsm/kg
H2O w ith normal renal function, and urine sodium w ill
generally be greater than or equal to 20 mEq/L, though this may be
lower in patients who are chronically sodium depleted of
sodium. The SIADH patient w ill be euvolemic,
w ithout clinical signs of hypovolemia such as orthostatic
hypotension or tachycardia, or signs of hypervolemia such as
ascites. The diagnosis of SIADH is made when these features are
present and after adrenal, thyroid, renal, and hepatic dysfunction
and diuretic use have been excluded.
Measurement of a plasma ADH level that is inappropriately elevated
relative toplasma osmolality conf irms, but is not essential
for, the diagnosis. An abnormal water load test can also
conf irm SIADH. A patient is given a 20 ml/kg water bolus
and excretion and urine osmolality are measured. Inability to
excrete at least 90% of the water load w ithin 4 hours and/or
failure to dilute urine osmolality to <100 mOsm/hg H2O
demonstrate an abnormal test.
Once true hypo-osmolality is verif ied, the patient's
extra-cellular fluid volume status should be assessed by careful
clinical examination. If the patient has SIADH and is
truly euvolemic, then he w ill experience no
signif icant correction of osmolality w ith volume
expansion but w ill have improvement after fluid
restriction. If fluid retention is present, the treatment of
the underly ing disease should take precedence over the
correction of plasma osmolality . If hypovolemia is
present, the patient must be considered to have depletion-induced
hypo-osmolality, in which case volume repletion w ith isotonic
saline
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at a rate appropriate for the estimated volume depletion should be
immediately initiated. If diuretics have been used, the isotonic
saline should be supplemented w ith 30-40 mEq/L potassium even
if serum potassium concentrations are normal, because of the high
incidence of total body potassium depletion in these
patients.
Oxytocin Oxytocin stimulates uterine contractions at parturition
and facilitates nursing through
stimulating contraction of the myoepithelial cells in the lactating
mammary gland; it works to expel milk from the secretory
tissue of the breast to the nipple during suckling. There is no
signif icant clinical hypo- or hypersecretory syndrome, and
oxytocin is not routinely assayed in the assessment of pituitary
function.
Non-endocrine Studies In addition to the multiple endocrine studies
discussed above, any patient w ith
suspected pituitary disease should be evaluated for ophthalmologic
dysfunction as well. Because of the prox imity of the optic
structures to the pituitary gland, full v isual f ields
should be documented and any in jury to the optic nerves
should be assessed. Magnetic resonance imaging (MRI)
w ith gadolinium should also be obtained w ith thin cuts
through the sella in order to evaluate for any pituitary mass or
other lesion. The assistance of the neuro-ophthalmology and
neuro-radiology serv ices in addition to the endocrinology
serv ice w ill be invaluable in the assessment of these
patients.
In a Nutshell
• The pituitary secretes 8 peptide hormones: 6 from the
anterior lobe and 2 from the posterior lobe.
• A PRL level of <2 ng/mL is associated w ith severe
hypopituitarism; a PRL level of >200 ng/mL is nearly
diagnostic of prolactinoma.
• The insulin tolerance test is the gold-standard for the
biochemical diagnosis of GH def iciency ; IGF-1
levels are more accurate that GH levels in the diagnosis of
acromegaly .
• For a diagnosis of Cushing's disease, a patient must have an
increased basal cortisol level, resistance to negative feedback
from glucocorticoids, ACTH
response to decreased cortisol or to CRH, cortisol response to
exogenous ACTH,and a pituitary source of the excess ACTH. • SIADH
causes euvolemic hypo-osmolality, while DI leads to low urine
osmolality
w ith an elevated plasma osmolality .
Multiple Choice Questions 1. In acromegalic patients:
a. random GH levels are the easiest and most accurate diagnostic
test. b. a glucose suppression test w ill not suppress GH to
<2ng/mL as it w ill in normal
sub jects. c. basal GH levels are usually 2-8ng/mL. d. due to
its short half life, pulsatile secretion and w idely variable
daily levels, random
IGF-1 levels are not an accurate indicator of overall GH
levels.
Assessment of Pituitary Function
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2. A TRH stimulation test (200-500 µg IV TRH): a. w ill lead
to a 3-5 fold increase in PRL level in normal sub jects, and
can help
differentiate between primary and secondary hypothyroidism. b. does
not prov ide any information for prolactin level workup, but
w ill lead to a rapid
decrease in TSH levels in normal sub jects. c. w ill lead
to a rapid 2-6 fold decrease in PRL in normal sub jects, but
has no role to
play in a hypothyroid workup. d. w ill lead to a less than
2-fold increase in PRL in normal sub jects, and a rapid
increase in TSH levels in secondary hypothyroid patients. 3. Which
is false regarding DI?
a. Typical symptoms of DI include polyuria, polydipsia, excessive
thirst and nocturia. b. Patients w ith DI have urine
osmolality <300 mOsm/kg H2O, urine specif ic
grav ity
<1.005 and plasma osmolality >287 mOsm/kg H2O. c. The water
deprivation test is the safest and easiest test to diagnose DI as
it can be
given to the patient to complete on his own and does not require
medical superv ision.
d. In central DI, there is def icient ADH secretion in
response to normal osmotic stimulation; these patients often
have normal thirst but insuff icient circulating antidiuretic
activ ity .
4. Signs of SIADH include: a. low serum sodium, high serum
tonicity, low urine osmolality, low urine sodium and
tachycardia. b. high serum sodium, high serum tonicity, low urine
osmolality, low urine sodium
and bradycardia. c. low serum sodium, low serum tonicity, high
urine osmolality, high urine sodium
and euvolemia. d. high serum sodium, low serum tonicity, high urine
osmolality, high urine sodium
and orthostatic hypotension.
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