Assessment of Normal Pituitary
Testing for each of the primary hormones
secreted by the adenohypophysis can be complicated. Each of the six major
hormones requires basal and dynamic testing to portray accurately the
reserve potential of the adenohypophysis. Patients with hypopituitarism may
display no outward evidence of pituitary insufficiency, since a small amount
of tissue can sustain adequate function. However, impaired reserve capacity
can become apparent during periods of stress. The detection of inadequate
reserves requires provocative tests, as basal hormonal levels can be
misleading. It is not unusual to find that reserves are normal for several
pituitary hormones but marginal or absent for others. In practice, the
determination of thyroid and adrenal function is more important, since only
for these two glands is failure life-threatening. The failure or
insufficiency of gonadotropic, somatotropic, or lactotropic function might
or might not be pertinent to the health of the patient, depending on age,
sex, psychological needs, and other determinants. As more information
concerning the role of pituitary peptides becomes available, it becomes
increasingly possible to prevent systemic changes that can impair health
many decades later. For example, hyperprolactinemia, while known to affect
fertility, libido, and potency, also can produce osteopenia as a result of
estrogen or testosterone deficiency, and, if not corrected in young women or
men may ultimately cause osteoporosis later in life, The succeeding
paragraphs outline the basal and dynamic tests that should give an accurate
portrayal of the adequacy of the adenohypophysis. Table-1 gives the major
screening tests used to prove total hypophysectomy, and Table-2 lists normal
The endocrine evaluation of the somatotropes
centres on measuring serum levels of growth hormone both in the fasting
state and after the administration of stimulatory or inhibitory agents.
Until recently, growth hormone was thought to be necessary only for growth
in children. Current endocrine investigation now suggests that this hormone
may be important for adults as well, including for preservation of bone
density, normal body composition, and lipid levels. Growth hormone is
released in a pulsatile fashion by the adenohypophysis in response to
positive control from growth hormone-releasing hormone (GHRH) and negative
control from somatostatin, and serum levels are variable. A growth hormone
measurement taken at random in an individual with hypopituitarism may be
normal, so the reserve must be tested. In normal persons, the level of
growth hormone rises after insulininduced hypoglycaemia or after the
administration of GHRH, arginine, clonidine, propranolol, or dopamine
precursors (L-dopa) or agonists (apomorphine).
Insulin hypoglycaemia is the most commonly
used provocative test. After the intravenous administration of regular
insulin (0.1 to 0.15 U/kg), plasma glucose levels in normal individuals
usually fall to less than 40 mg/dl. A decline in glucose level by at least
50 percent below baseline associated with a growth hormone level greater
than 5 ng/ml indicates normal somatotropic function. Some normal subjects
demonstrate levels as high as 25 ng/ml. Any response indicates surviving
Arginine stimulates the release of
growth hormone through the alpha-adrenergic receptor mechanism and is more
effective in women than in men. After its infusion in normal individuals,
growth hormone levels generally rise to more than 5 ng/m!. Again, any
detectable level indicates the presence of surviving somatotropes.
Clonidine, propranolol, and L-dopa also
elicit a rise in human growth hormone. A level greater than 5 ng/ml
indicates normal somatotrope reserve, and any detectable level of human
growth hormone indicates surviving somatotropes.
Some of the tests
described above can cause nausea and hypotension and must be administered
under closely monitored conditions. The most commonly used test, insulin
hypoglycaemia, can be hazardous in hypopituitarism patients with inadequate
adrenal reserve. It should be avoided in elderly patients and in those with
vascular or cerebrovascular disease or a history of a convulsive disorder.
Insulin stimulation is the
best single test to verify total ablation or loss of somatotropes. The
absence of growth hormone in the serum following adequate stimulation by
insulin indicates that all somatotropic cells are dead or absent. Inadequate
levels of growth hormone represent a blunted response. Hepatic, renal, and
central nervous system diseases as well as cancer and poor nutrition also
can blunt the response to insulin.
cells make up most of the adenohypophysis. In most laboratories, 15 to 20
ng/ml is the upper limit and 5 ng/ml is the lower limit of the normal basal
serum prolactin level. Prolactin secretion is pulsatile during the day and
rises during sleep. In hypersecretory states associated with amenorrhea or
pituitary tumors, prolactin levels are usually above 30 ng/ml, but patients
without pituitary tumors can have levels as high as 100 ng/ml.
test employed most often in the past was the thyrotropin-releasing hormone
(TRH) stimulation test. TRH administration (200
µg intravenously) should
cause at least a twofold rise in prolactin levels within an hour; any rise
over 100 percent is considered normal. Failure to obtain a rise is almost
always abnormal. A blunted response with a low basal level usually indicates
inadequate lactotrope reserve. An elevated basal prolactin level
with a subnormal response to TRH is consistent with a prolactinsecreting
adenoma. However, because there is considerable overlap with other
etiologies, a blunted rise is not pathognomonic of a tumour. Therefore, this
test is no longer often used. After total hypophysectomy, no prolactin
should be detectable after stimulation with TRH.
A low level
of prolactin should be present in the hypopituitary state and can also be
seen in patients taking dopaminergic drugs such as L-dopa or bromocriptine.
High levels can be due to a number of factors, the most common being
pregnancy, breast feeding, hypothyroidism, or the ingestion of drugs such as
phenothiazines or high-dose estrogens.
of thyroid function generally indicate an adequate pituitary-thyroid axis.
Today, many factors can be measured, such as T3, T4, and free thyroxine. The
free T4 index is a good screening test for thyroid function because it takes
into account both T3 uptake and total T4 in the serum. Radioactive iodine
uptake should not be used as a screening test of thyroid function. Table-2 shows the physiologic levels of these factors.
When these factors are low, one must
measure serum thyroidstimulating hormone (TSH) directly to distinguish
primary from secondary hypothyroidism. However, a normal level of TSH is not
a satisfactory indication of adequate thyrotrope reserve. To measure TSH
reserve, TRH (200 µg) is administered intravenously. The adenohypophysis
generally is considered normal if TSH values rise to 6 to 20
blunted response indicates diminished reserve and, therefore, diminished
activity of the adenohypophysis, presumably with depopulation of thyrotropic cells. After total hypophysectomy, the administration of TRH
should result in no measurable level of TSH. A decreased response to TRH
stimulation also occurs in a variety of clinical settings, including
thyroid hormone or glucocorticoid therapy, hyperthyroidism, renal failure,
Adrenocorticotropic Hormone (ACTH)
secreted in pulsatile fashion and is highest at 8 A.M. and lowest at
midnight. Because ACTH is released episodically, serum cortisol levels vary
widely over the day, so a random measurement is rarely useful. The exception
is a morning serum cortisol level above 20 µg/dl,
which indicates intact hypothalamic-pituitaryadrenal function. Twenty-four
hour urine collections represent the integrated secretion of cortisol and
thus are more useful than random serum levels, particularly when there is
concern about possible overproduction of cortisol. The urinary free
cortisol level should be less than 100 µg per 24 h, and 17 -hydroxysteroids should be 3 to 8 mg per 24 h.
of circulating cortisol is evidence that some ACTH is being secreted from
the pituitary gland and thus indicates incomplete hypophysectomy. However,
levels may be undetectable despite the presence of a very few remaining
cells. ACTH reserve can be demonstrated using the metyrapone test or
insulininduced hypoglycaemia. Totally hypophysectomized patients produce no
rise in hormone levels in response to either of these provocative tests.
inhibits 11-,B-hydroxylase in the adrenal cortex, thus blocking the
conversion of 11 -deoxycortisol to cortisol. The attendant drop in serum
cortisol stimulates ACTH secretion by surviving
corticotropes. The release of ACTH stimulates the synthesis of 11-deoxycortisol,
the hormone proximal to the block, and the metabolites of this compound can
be measured in the urine. Hence, over a 1 - or 2-day period, measurable
amounts of urinary
17-hydroxycorticoids indicate production of ACTH by the pituitary gland. In
normal individuals, 24-h urinary 17-hydroxycorticoid levels measured after
metyrapone administration are usually two to three times higher than
baseline. The level is lower in hypophysectomized patients; if
hypophysectomy is complete, no 17hydroxycorticoids are found in the urine.
A quick test
involves administering metyrapone (2.0 to 3.0 g) at midnight and measuring
plasma 11-deoxycortisol and plasma cortisol levels at 8 A.M. In normal
subjects, the plasma cortisol value is usually less than 5.0
plasma 11-deoxycortisol is greater than 7.5 µg/dl. In completely
hypophysectomized patients, the plasma deoxycortisol level is negligible.
Insulin-induced hypoglycaemia is also an excellent method for achieving
maximal hypothalamic-pituitary-adrenal stimulation. Normal individuals will
show a rise in plasma cortisol to 20 µg/dl or higher when serum glucose is
lowered by 50 percent. This test is contraindicated in patients with
cardiovascular disease or a convulsive disorder.
levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH),
estradiol, and testosterone depict the status of the gonadotropic elements
of the hypophysis. Where plasma levels of these hormones are not measurable
or are low, stimulation with gonadotropin-releasing hormone (GnRH) can help
to determine the presence of adequate pituitary reserve, Administration
of GnRH should produce no detectable level of these hormones in patients
with total hypophysectomy, and low levels when reserves are low. Any
detectable level of FSH or LH indicates some remaining gonadotropic cells.
High levels of the pituitary hormones and
low levels of the end-organ hormones testosterone or estradiol indicate
end-organ failure, The best example of this is menopause, when estradiol is
low and FSH and LH rise. When the levels of both pituitary and end-organ
hormones are high, a rare pituitary adenoma secreting bioactive
gonadotropins or a pituitary hormone resistance state may be present.
under tonic inhibition by the hypothalamus and thus is unique among
pituitary hormones, Dopamine is the hypothalamic agent primarily implicated
in the inhibition of prolactin, Sectioning of the pituitary stalk and
administration of a variety of substances can override tonic inhibition,
thus causing secretion of prolactin by the adenohypophysis, In addition, a
number of substances act directly on lactotropes or the hypothalamus to
negate the influence of dopaminergic inhibition.
prolactin-stimulating factors are not yet known, but there can be some rise
in prolactin in response to high-dose estrogen and TRH, Estrogen acts
directly at the level of the pituitary lactotrope to stimulate the
synthesis and release of prolactin. In normal subjects, the administration
of either high-dose estrogen or TRH causes a prompt two- to threefold rise
of the prolactin level. The administration of serotonin or its precursors (e.g.
5-hydroxytryptophan or L-tryptophan) also increases prolactin levels.
Agents like γ-aminobutyric acid, the phenothiazines, metoclopramide, opiate
agonists, and intravenous cimetidine cause the prolactin level to rise to
various degrees, whereas serotonin blockers, L-dopa,
and other dopaminergic agents can reduce the level of prolactin.
Men and women
with large prolactin-secreting tumors present no major diagnostic problem
because a positive magnetic resonance imaging (MRI) scan and an elevated
level of prolactin together are diagnostic, especially if the prolactin
level is greater than 200 to 300 ng/ml. Lower levels may be found with other
central nervous system tumors or non-neoplastic lesions that functionally
sever the pituitary stalk, thereby interrupting the flow of inhibitory
dopamine, or with other lesions such as mixed prolactin and growth
Hyperprolactinemia in women usually presents with one or more of the
following: oligoamenorrhea, galactorrhea, infertility, and androgen excess
(acne or hirsutism). The diagnosis of a microadenoma generally demands
great experience and judgment, since endocrine and radiologic tests can be
misleading, Prolactinomas are common in men (60 percent of all adenomas),
but usually they are not found until they are large, since systemic
complaints often are ignored for many years. Men may not seek early
attention despite loss of libido and potency, headache, or fatigue. Only
when visual loss or disturbing endocrine symptoms are present do they seek medical
attention, by which time the opportunity for early endocrine diagnosis is
patients have mild rises of prolactin and growth hormone levels and report
not only amenorrhea and galactorrhea but also fatigue, weakness, and slight
swelling of the hands and feet. Their tumour may demonstrate both prolactin
and growth hormone secreting cells. Tumour removal is followed by a return
to well-being and resumption of normal menstrual function. These tumors can
be termed clinically active dual-secretory adenomas or silent somatotroph
The single most useful endocrine
is determination of the basal serum prolactin level. In most laboratories,
the normal level ranges from 5 to 20 ng/ml. Minimal elevations must be
confirmed by taking several fasting samples on different days in patients
who have taken no medication during the previous week.
elevated level is confirmed, primary hypothyroidism and pregnancy must be
excluded with a TSH level and pregnancy test, since both conditions can
elevate prolactin values. Profound primary hypothyroidism can be associated
with thyrotrope hyperplasia, causing the appearance of an enlarged
pituitary on MRI scan, which may be mistaken for a prolactinoma. The
pituitary regresses with thyroid replacement therapy in this disorder. When
an elevated prolactin level is confirmed but radiologic verification is
absent, great care must be exercised in making decisions regarding therapy.
the serum prolactin level, the more likely it is that a tumour is present.
When the level is much lower than 100 ng/ml, the likelihood of finding an
identifiable tumour drops by as much as 50 percent. With levels as high as
350 ng/ml, a tumour is almost always found.
The size of
the prolactin-secreting tumour also is related to the level of serum
prolactin, but with wide variations. Microadenomas can secrete levels as
high as 550 ng/ml, whereas larger tumors (i.e., with a diameter of 2 cm or
greater) can secrete levels lower than 100 ng/ml. One must keep in mind that
prolactin levels as high as 150 to 200 ng/ml can be caused by partial or
total functional pituitary stalk sectioning resulting from some other
process or tumour. Thus, a small craniopharyngioma, a null cell tumour, an
oncocytoma, or a vascular, granulomatous, or other type of lesion can
account for hyperprolactinemia. In such cases, the hyperprolactinemia can
revert to normal with bromocriptine therapy while the non secretory lesion
grows to invasive size. In view of this possibility, it is necessary to
ensure after operation that a presumed prolactinoma in fact contains
prolactin granules as demonstrated by immunocytochemistry.
stimulation tests (TRH, chlorpromazine, metoclopramide) and suppression
tests (L-dopa, nomifensine) have historically been used to provide ancillary
aid in arriving at a diagnosis. In a pragmatic sense, none of
these endocrine tests is totally reliable for the diagnosis of a
prolactin-secreting adenoma, and they are now rarely used. The criteria
mentioned above apply to both sexes, as there is no consistent difference
between normal serum prolactin levels in men and nonpregnant women.
Hypothyroidism, pregnancy, and medications used for psychiatric illnesses,
as well as chronic disease of the liver and renal failure must be excluded,
as these entities also can be associated with hyperprolactinemia. In
addition, serum prolactin levels are sometimes elevated in hypoglycaemia,
during stress, and in the postpartum period. Acromegaly can be associated
with modest elevations in prolactin levels, sometimes as high as 150 to 200
ng/ml. Hyperprolactinemia also can accompany Cushing's disease. Since some
commonly used drugs enhance prolactin secretion, especially psychotropic
drugs, high doses of estrogens, and some antihypertensives, a complete
drug history is mandatory.
of a prolactin-secreting microadenoma returns prolactin levels to normal
within a day or two. If the level is lower than 10
ng/ml, the surgeon can feel confident of prolonged remission if not
outright cure. When the level of prolactin is normal, ovulation and
menstruation return in at least 75 percent of women, and galactorrhea
ceases. These findings are evidence of total remission, although recurrence
is still possible. Failure of prolactin to fall to normal levels usually is
caused by incomplete tumour removal. However, it also can result from injury
to the pituitary stalk. If the surgeon suspects a retained fragment of
in the first few weeks after operation in a straightforward case, early
re-exploration is warranted.
evidence of late recurrence is much more sensitive. Thus, if menses and
ovulation again begin to fail and if galactorrhea resumes, endocrine
verification must be undertaken quickly.
thought to have acromegaly on clinical grounds must undergo verification by
endocrine testing and MRI scanning. The differential diagnosis must exclude
individuals with a genetically determined physiognomy similar to that of the
acromegalic but who do not have the disease. All individuals with true
acromegaly harbour a growth-hormone-secreting adenoma or, more rarely, an
ectopic tumour producing growth-hormone-releasing hormone (GHRH).
The level of
growth hormone is governed by the interplay of GHRH, a 41-amino-acid peptide
characterized in 1983, and somatostatin, an inhibitory l4-amino-acid
peptide. The balance between these two peptides is regulated by neighbouring
hypothalamic neurons. Other substances that can stimulate growth hormone
release are enkephalin, glucagon, a melanocyte-stimulating hormone,
vasopressin, diazepam, and estrogens. Variations during the day are quite
striking. High levels of growth hormone are found during the first few hours
of sleep, with smaller rises occurring during the day. For many hours no
secretion is evident. The ventromedial and infundibular nuclei of the
hypothalamus are involved with the pulsatile nature of the secretion.
of growth hormone release is mediated through alpha-adrenergic and
dopaminergic mechanisms. Therefore, in normal individuals, the growth
hormone level increases after the administration of norepinephrine, L-dopa,
clonidine, and apomorphine. In addition, behavioural conditions that
stimulate alphaadrenergic mechanisms, such as stress, hypoglycaemia, and
exercise, also enhance the secretion .of growth hormone. The limbic system
participates in growth hormone release through serotonergic mechanisms.
Thus, the administration of serotonin precursors such as L-tryptophan or
5-hydroxytryptophan also causes growth hormone release.
mechanisms inhibit the secretion of growth hormone. Therefore, isoproterenol blocks secretion, whereas
propranolol, its antagonist,
enhances secretion to a certain extent in response to glucagon,
vasopressin, and L-dopa. Growth hormone release also is inhibited by the
administration of glucocorticoids and in patients who are obese or have
elevated levels of free fatty acids.
The somatomedins mediate the stimulation
of cell growth by growth hormone. Two somatomedins have been
identified, and their secretion by the liver depends largely on the level of
growth hormone. Somatomedin C, now called insulin-like growth factor-1 (IGF-1),
possesses properties similar to those of insulin, and its level is increased
acromegaly is suspected, endocrine diagnosis depends on the demonstration of
(1) an elevated level of human growth hormone that fails to decrease to
less than 2 ng/ml during a glucose tolerance test and (2) an elevated level
of IGF-1. It must be remembered, however, that normal adolescents sometimes
do not demonstrate growth hormone suppression with glucose and have higher
levels of IGF-1 than adults. Almost all acromegalies have levels of growth
hormone greater than 10 ng/ml, but a few have levels between 4 and 10 ng/ml.
fails to suppress the hypersecretion of growth hormone in acromegalics.
Therefore, endocrinologists rely on the oral glucose tolerance test as the
best screening and diagnostic test for acromegaly. If the elevated basal
level of growth hormone fails to fall below 2 ng/ml during the test, it is
safe to conclude that the patient has acromegaly. In many patients with
untreated acromegaly, but not in normal individuals, TRH stimulates the
release of growth hormone. Surgical cure of acromegaly should eliminate this
The level of
IGF-1 is always elevated in active acromegaly and therefore is an excellent
screening marker. Normal levels are 0.34 to 1.97 lU/ml in males and 0.45 to
2.2 lU/ml in females. Higher levels confirm acromegaly. The clinical
disturbances of acromegaly are related more closely to the level of IGF-1
than to the level of growth hormone.
patients do not display normal regulatory responses to certain agents, and
often their growth hormone response is described as "paradoxical." For
example, in 10 to 20 percent of patients, glucose ingestion does not cause
the fall in growth hormone levels seen in normal individuals, but rather
causes a paradoxical rise. L-Dopa increases growth hormone values in normal
subjects, but in most acromegalics it induces a fall. Similarly, the
dopaminergic agonist bromocriptine, while increasing growth hormone levels
in normal individuals, causes a decrease in some acromegalies. This finding
is the basis of bromocriptine therapy for acromegaly. TRH does not affect
the growth hormone level in normal subjects, but increases it in 70 to 80
percent of acromegalies. The serotonergic agonist L-tryptophan, while
increasing human growth hormone values in normal subjects, causes no change
in patients with acromegaly. Taken together, these factors help to clarify
the diagnosis in doubtful cases. They are especially helpful in adolescents
and in patients thought to have gigantism.
the endocrine diagnosis of acromegaly rests on the failure of glucose
loading to suppress the level of growth hormone to less than 2 ng/ml, and
the presence of elevated levels of IGF-1. The other dynamic tests described
are reserved for equivocal cases.
patients after operation, radiotherapy, or pharmacologic treatment demands
the same testing. If the glucosesuppressed growth hormone level is less
than 2 ng/ml and the IGF-1 level is normalized, clinical remission is almost
certain in all spheres save those in which permanent changes have already
taken place. Thus, bone changes and cardiac disease rarely reverse, but
should not progress. Absolute cure of acromegaly is accompanied by a full
return of normal dynamics, that is, the mean value of growth hormone on four
to six determinations during the day would not be higher than 2 to 4 ng/ml;
oral glucose would suppress growth hormone levels to below 2 ng/ml; and IGF-1
levels would return to normal. Use of the term "cure" or "remission" when
resting levels of growth hormone are greater than 4 ng/ml and are not
suppressed to less than 2 ng/ml with glucose loading, or when the IGF-1
level is not normal, is misleading and inaccurate.
also can be detected by these examinations. The first indications of
recurrence may be a rise in IGF-1 level or the return of a paradoxical
response of growth hormone to glucose intake. It is necessary to remember
that any therapy that results in apparent normalization of growth hormone
levels may be accompanied by continued or later growth of the tumour.
Consequently, even when the results of endocrine testing are normal, if the
patient reports a return of symptoms, every effort should be made to detect
a possible recurrence so that appropriate therapy can be instituted as soon
disease can be defined as hypersecretion of cortisol caused by an
abnormality of the pituitary gland. The lesion most commonly responsible for
the disease is an adenoma. More rarely, pituitary hyperplasia is the cause.
Hypercortisolemia also can be caused by a number of different systemic
lesions, such as ectopic tumors that produce ACTH and adrenal cortical
lesions that produce cortisol. The general syndrome caused by excess
cortisol is, by convention, called Cushing's syndrome. The term Cushing's
disease is used for parasellar etiologies.
diagnostic problem thus is twofold: (1) to verify hypercortisolemia, and
(2) to identify the primary cause of the hypercortisolemia.
Corticotropin-releasing hormone (CRH) is produced in neurons in the anterior
median eminence of the hypothalamus and regulates normal ACTH secretion by
the pituitary gland. ACTH secretion has a diurnal rhythm, which is
regulated by the central nervous system. The highest levels are found early
in the morning, with spiking later during the day, especially in
midafternoon. The diurnal rhythm of cortisol secretion must be taken into
account when resting or sporadic sampling of plasma is undertaken. The
secretion of ACTH is dependent on serotonergic mechanisms and can be
blocked by serotonin-blocking agents. Many forms of stress, including
hypoglycaemia, also increase the production of ACTH through mechanisms
mediated by the hypothalamus. Negative feedback on ACTH secretion is due
primarily to the action of plasma cortisol, which exerts its effect directly
on the pituitary gland and probably also on the hypothalamus.
stimulation of the adrenal gland by ACTH causes the secretion of cortisol
and other adrenal hormones. Because of similarities in structure between
ACTH and melanocyte-stimulating hormone, ACTH possesses some melanocytic-stimulating
activity as well.
Demonstration of Hypercortisolemia
tests can be used to determine whether cortisol secretion is within the
normal range. Plasma cortisol levels vary widely and are therefore rarely
useful as a screening test. A 24-h urine collection can be tested for free
cortisol and 17-hydroxycorticosteroids. Elevated levels of either raises
the suspicion of Cushing's syndrome. An amount of free cortisol above 100
per 24 h or of 17-hydroxycorticosteroids above 12 mg per 24 h suggests
hypersecretion of cortisol.
individuals, the administration of a small quantity of a glucocorticoid such
as dexamethasone, which does not crossreact in the cortisol assays, lowers
the level of cortisol in plasma or I7-hydroxysteroids and free cortisol in
the urine. When Cushing's syndrome is caused by a pituitary disorder, the
hypothalamic "set point" for dexamethasone inhibition of ACTH secretion is
believed to be raised, thus requiring a higher dose of dexamethasone to
suppress ACTH and cortisol secretion. When an excess of cortisol is
suspected, a quick overnight test (the 1 mg overnight dexamethasone
suppression test) is carried out as follows. At 11 P.M., 1 mg of
dexamethasone is given by mouth. The following morning (8 A.M.), serum
cortisol is determined again. If the cortisol level is less than 5
Cushing's syndrome can be eliminated as a possibility, with a
false-negative rate of less than 3 percent.
The 1 mg
overnight dexamethasone test is the best screening test for Cushing's
syndrome. An abnormal test result does not establish the diagnosis, however,
because there are many causes for a false-positive result (failure to
suppress cortisol). An abnormal test result indicates the need for
additional testing, since stress, psychiatric illnesses, estrogen therapy,
phenytoin and other medications, as well as failure to do the test
properly, can all cause abnormal results. If Cushing's syndrome is
suspected, a low dose of oral dexamethasone (0.5 mg four times a day for 2
days) is then given. In normal individuals, the urinary free cortisol and
17hydroxysteroid values fall over a 24-h period to less than 20 mg and 4
mg, respectively. In patients with Cushing's syndrome, levels of plasma
cortisol and urinary steroids fail to suppress.
low-dose dexamethasone test gives an abnormal result, the patient is given a
2-day high-dose dexamethasone test. This requires the administration of four
2-mg doses daily for 2 days. The 17-hydroxycorticosteroids should be reduced
by more than 64 percent and the urine free cortisol by more than 90 percent
to signify suppressibility. On some occasions, more than 8 mg of
dexamethasone are necessary to suppress pituitary-based Cushing's syndrome.
A high-dose overnight test has been used in which 8 mg of dexamethasone is
given at midnight, and plasma cortisol is measured at 8 A.M. and compared
with the level obtained the previous morning. Recently, an intravenous
high-dose dexamethasone suppression test has been described in which 1 mg/h
of dexamethasone is administered intravenously for 7 h. A fall in cortisol
of at least 7 µg/dl is consistent with suppression.
In all of
these forms of dexamethasone testing, the presence of suppression is
consistent with a pituitary source of Cushing's syndrome. Adrenal and
ectopic Cushing's tumors have traditionally been considered nonsuppressible.
It has been increasingly recognized, however, that some ectopic
ACTH-producing tumors can exhibit suppression with dexamethasone.
demonstration of abnormal cortisol dynamics has been said to be valuable in
making the diagnosis of Cushing's syndrome. In normal individuals, serum
cortisol is highest at 8 A.M. and, despite pulses of secretion during the
day, is lowest between 6 P.M. and midnight. This fluctuation (termed the
diurnal rhythm) is lost in Cushing's syndrome, where the midnight level
might be 8 µg/dl or higher (normal is <8
re-establishment of a normal diurnal pattern is a reliable demonstration of
remission of the disease. However, some patients with Cushing's syndrome
have plasma cortisol levels that can overlap the normal range at all times of the
day, so testing for loss of diurnal rhythm is not always reliable.
Cushing's disease is accompanied by hypersecretion of ACTH, the levels of
ACTH in plasma are often normal or only slightly elevated. ACTH levels in
normal individuals vary from 50 to 100 pg/ml; in Cushing's disease, they can
range from 50 to 250 pg/ml.
There is now
a sensitive, specific, and rapid method for detection of ACTH levels by immunoradiometric assay. When ACTH levels are undetectable or extremely low
in a patient with Cushing's syndrome, the diagnosis is ACTH-independent or
adrenal Cushing's syndrome. If the ACTH levels are in the normal to mildly
elevated range, the patient may have pituitary or ectopic Cushing's
syndrome. When the ACTH levels are extremely high (thousands of picograms
per millilitre), the patient has ectopic Cushing's syndrome.
of Cushing's syndrome may be difficult in several
situations. Cortisol hypersecretion can be sporadic in Cushing's disease
(called periodic or cyclic Cushing's syndrome), necessitating long-term
repeated testing. A false-positive diagnosis of Cushing's disease is
observed sometimes in alcoholics (alcoholic pseudo-Cushing's disease). More
important, depressed patients can exhibit hypercortisolemia that does not
suppress with dexamethasone and, to a certain extent, may appear to be "cushingoid"
when in fact they are simply obese. These individuals may show loss of
diurnal variation and increased cortisol levels during the day. They can be
distinguished from patients with Cushing's disease by their lack of true
clinical signs of excessive cortisol and their response to insulin-induced
hypoglycaemia. Patients with Cushing's disease have no noticeable increases
in plasma cortisol during periods of hypoglycemic stress, whereas depressed
or normal individuals demonstrate the usual rise in cortisol levels. More
recently, the CRH test has been used to distinguish depressed patients with
hypercortisolemia from patients who have depression associated with
Cushing's syndrome. In depression, there is a blunted response of ACTH to
the injection of 1 µg/kg ovine CRH, whereas patients with Cushing's disease
exhibit a normal to exaggerated response. Unfortunately, this test is not
always definitive because of some overlap between groups.
Cushing's disease is associated with hypercortisolemia, loss of the
diurnal rhythm of cortisol secretion, and normal to slightly raised levels
of ACTH in plasma. It is important for an experienced diagnostician to
exclude the many causes of false-positive test results. The definitive
diagnosis is based on the failure of low-dose dexamethasone (0.5 mg orally,
four times a day for 2 days) to suppress the level of cortisol, whereas high
doses (2.0 mg orally, four times a day for 2 days) are successful in
Diagnosis-Site of Hormone Excess
A number of tumors can secrete ACTH,
including small cell carcinoma of the lung, some bronchial adenomas,
medullary carcinoma of the thyroid, pancreatic carcinoma, and carcinoid
cases the production of ACTH usually is autonomous and fails to respond to
increasing doses of dexamethasone or to a CRH test. There is, however,
increasing recognition of a subset of ectopic ACTH-producing tumors that
result in a clinical and biochemical pattern identical to that seen in
pituitary Cushing's syndrome. A major advance in addressing this problem is
the bilateral inferior petrosal sinus catheterization procedure. In this
radiologic procedure, catheters are placed bilaterally in the femoral veins
and threaded up into the inferior petrosal veins just outside the pituitary
gland. Blood is then sampled simultaneously from each side and from a
peripheral (hand) vein and assayed for ACTH. If the pituitary/peripheral
ACTH ratio is ≥2, the Cushing's syndrome
has been localized to the
pituitary. If the ratio is <1.5, the patient has ectopic (or adrenal)
Cushing's syndrome. Localization of the ectopic ACTH tumour, which is
often small, requires CT scanning or other imaging techniques in other
organs. When head scans are negative in a patient with pituitary Cushing's
syndrome, it also is possible to use bilateral inferior petrosal sinus
catheterization to predict the side of the tumour's location; if the
side-to-side ACTH ratio is > 1.4, the tumour is more likely to be on the side
with the higher level.
Hypercortisolemia also can be caused by adrenal lesions such as independent
adenomas and adrenal carcinoma. These lesions are independent of ACTH, and
thus hypercortisolemia is resistant to the administration of dexamethasone
(no suppression) or of CRH (no elevation). Also, resting ACTH levels in
these diseases are usually low or undetectable.
diagnosis of Cushing's disease can be difficult, but is being done with
increasing frequency today because of heightened awareness on the part of
physicians. Early cases can lack the classic stigmata, and
hypercortisolemia may be marginal. Classic features often help to identify
true Cushing's disease and differentiate the various causes of the syndrome.
Cushing's disease is commonest in young to middle-aged women and has a slow
progression. In early cases, abnormal menstrual cycles, abnormal striae,
spontaneous bruising, androgen excess and hypertension may be absent. The
classic ectopic ACTH syndrome, on the other hand, is found typically in
older men who smoke to excess. Recent weight loss, anaemia, low serum
potassium levels, and severe hypertension are prominent. Adrenal adenomas
are relatively slowly progressive; cortisol excess is mild, and very often
androgen features are minimal. Adrenal carcinoma has a rapid onset with
very high levels of adrenocorticoid hormones. Adrenal carcinomas and
adenomas that produce cortisol cause atrophy of the contralateral adrenal.
Consequently, asymmetry of the adrenals should warn against the diagnosis
of a pituitary adenoma.
It is well to
remember that the accuracy of endocrine testing for Cushing's disease is not
absolute, but is in the range of 90 percent. Consequently, in the absence of
confirmation by MRI or another imaging modality, errors will be made, and
this must be stressed to the patient and family in the context of
discussions surrounding operation.
postoperative evaluation is limited to measuring serum cortisol levels and
24-h urine free cortisol values while the patient is receiving
dexamethasone. All patients require replacement therapy of adrenal cortisol
hormones because the normal corticotropes have been suppressed by the
chronically elevated cortisol levels. Following the removal of the adenoma,
it is necessary to use dexamethasone in the early postoperative period to
confirm the adequacy of the operative procedure. Dexamethasone does not
cross-react significantly with the serum cortisol testing procedure. Several
days after operation, when the patient is on maintenance or slightly higher
doses of dexamethasone, the plasma cortisol level and 24-h urine free cortisol
value should be determined, If the plasma cortisol level is less than 5
µg/dl and the urine value is low,
one can have some confidence that the procedure was successful and that
satisfactory removal of the tumour has been accomplished. True remission, as
measured by endocrine testing as opposed to clinical examination, demands
the following: (1) normal or low serum cortisol levels; (2) return of the
diurnal rhythm; (3) normal 24-h urinary output of free cortisol and
17-hydroxysteroids; (4) normal dexamethasone suppressibility.
criteria are met, especially if clinical remission has occurred as well,
one's confidence of total removal can be high. As time goes on, the need for
replacement therapy lessens as normal endogenous cortisol secretion returns
(within 6 to 12 months in most cases). At this time, formal testing should
detect normal cortisol dynamics and basal levels.
adenomas that secrete thyroid-stimulating hormone are unusual and account
for less than 1 percent of all adenomas. Diagnosis requires
judicious interpretation of serum TSH levels. These can range from 1.6 to 480
µU /ml in the presence of clinical
hyperthyroidism. In approximately 30 percent of these cases, TSH levels are
lower than 10 µU/ml.
TSH-secreting adenomas commonly release excessive quantities of the alpha
subunit of this glycoprotein hormone. In terms of molarity, the alpha
subunit exceeds the TSH beta subunit, the other half of the molecule. The
ratio of the alpha subunit to TSH is greater than 1.
individuals, TRH stimulation causes a rise in TSH. In patients with
TSH-secreting pituitary adenomas, the response to TRH is negligible, with
few exceptions. This blunting of the response is not seen exclusively in
TSH-secreting adenomas, but helps in making the diagnosis. Thyroid hormone
generally suppresses TSH secretion in normal persons, However, the
administration of thyroid hormone may fail to suppress TSH and the free
alpha subunit when the tumour is a TSH-secreting adenoma.
Gonadotropin-Secreting Pituitary Adenomas
gonadotropin-secreting pituitary adenomas usually produce FSH and/or LH. One
recent problem in diagnosis has been the sensitivity of the radioimmunoassay
for FSH and LH, Other problems involve the high serum concentration of
gonadotropins normally observed in menopause. Since these tumors have few
systemic effects, they rarely are diagnosed until headache and loss of
vision have been reported. Three types of tumour have been recorded:
LH-secreting, FSH-secreting, and FSH- and LH-secreting, Many difficulties
arise in making the diagnosis, as other factors such as testicular failure
may be the cause of elevated levels of FSH or LH. Thus, serum testosterone
concentrations must be obtained to verify the diagnosis.
Subunit-Secreting Pituitary Adenomas
glycoprotein hormones are composed of alpha and beta subunits. The alpha
subunit is the same for all of these hormones. The beta subunit is unique to
each hormone and confers biological and immunologic specificity. Some
pituitary adenomas have been associated solely with the production of the
alpha subunit. This entity must be considered, especially in patients with
large, apparently non secreting tumors. The serum alpha-subunit level can
be measured directly by radioimmunoassay. For further confirmation, immunocytochemical staining of the tissue should be carried out to
demonstrate the presence of the alpha subunit alone in the secretory
granules. The importance of this test is that serum alphasubunit levels may
then be useful as a tumour marker to be followed postoperatively.