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sulinemia can partially activate IGF-I receptors.16 GH an overnight fast, and the patient is given a 100-gram oral
stimulates the production of IGF-I from the liver and, as glucose load. GH is measured at time zero and at 60 and
a result, IGF-I becomes a biologic amplifier of GH levels. 120 minutes after glucose ingestion. Following oral glu-
IGFs are complexed to specific serum binding proteins cose loading, GH levels are undetectable in normal indi-
that have been shown to affect the actions of IGFs in viduals; however, in patients with acromegaly, GH levels
multifaceted ways.17 IGF-binding protein III (IGFBP-III) fail to suppress and may even paradoxically rise.
is perhaps the best studied member of the IGFBP family. Testing patients for suspected GH deficiency is more
The levels of IGFBP III are positively correlated with complicated. There are several strategies to stimulate
IGF-I levels and, as a result, GH levels.18 Because of this GH, and new protocols are currently evolving.24 Once
relationship, IGF-I has been used in the clinical evalua- considered the gold standard, insulin-induced hypo-
tion of both GH deficiency and excess.19 glycemia is being replaced by less uncomfortable testing
schemes. Combination infusions of GHRH and the
Testing amino acid L-arginine or an infusion of L-arginine cou-
pled with oral L-DOPA are the most widely used. If GH
As noted above, a single, random measurement of GH is levels rise above 3–5 ng/mL, it is unlikely that the patient
rarely diagnostic. The current testing paradigms for GH is GH deficient24; however, a lower threshold may be
are soundly based on the dynamic physiology of the GH adopted because of improved sensitivity of the newer
axis. For example, circulating levels of IGF-I and, per- two-site GH assays.25 On the other hand, several studies
haps, IGFBP-III reasonably integrate the peaks of GH have shown that provocative GH testing may not be nec-
secretion, and elevated levels of both are consistent with essary in patients with low IGF-1 levels and otherwise
a sustained excess of GH.20 Other conditions, however, documented panhypopituitarism.26
notably hepatomas, can be associated with high levels of
IGF-I, and levels of IGFBP-III may be inappropriately
normal in some people with active acromegaly.21
Conversely, low IGF-I levels may reflect inadequate pro- Acromegaly results from pathologic or autonomous GH
duction of GH; however, low IGF levels are also seen in excess and, in the vast majority of patients, is a result of
patients with poorly controlled diabetes, malnutrition, or a pituitary tumor. There have been isolated case reports
other chronic illnesses.22 of tumors causing acromegaly as a result of the ectopic
Definitive testing for determining the autonomous pro- production of GHRH,27 and, although exceedingly inter-
duction of GH relies upon the normal suppressibility of esting or instructive, the ectopic production of GHRH or
GH by oral glucose loading.23 This test is performed after GH (one case) remains rare.28 If a GH-producing tumor
occurs before epiphyseal closure, the patient develops
gigantism and may grow to an impressive height; other-
wise, the patient develops classical, but insidious,
CASE STUDY 19-1 features of bony and soft tissue overgrowth.29 These
features include progressive enlargement of the hands
A 48-year-old man seeks care for evaluation of mus-
and feet as well as growth of facial bones, including the
cle weakness, headaches, and excessive sweating. He
mandible and bones of the skull. In advanced cases, the
has poorly controlled hypertension and, on question-
patient may develop significant gaps between their teeth.
ing, admits to noticing a gradual increase in both
Diffuse (not longitudinal if the condition occurred fol-
glove and shoe size, as well as a reduction in libido.
lowing puberty) overgrowth of the ends of long bones or
A review of older photographs of the man docu-
the spine can produce a debilitating form of arthritis.
ments coarsening of facial features, progressive prog-
Because GH is an insulin antagonist, glucose intolerance
nathism, and broadening of the nose. Acromegaly is
or overt diabetes can occur. Hypertension; accelerated
atherosclerosis; and proximal muscle weakness, result-
ing from acquired myopathy, may be seen late in the ill-
ness. Sleep apnea is common. Organomegaly, especially
1. What screening tests are available? IGF1 , OGGT thyromegaly, is common, but hyperthroidism is exceed-
ingly rare unless the tumor cosecretes TSH. GH excess is
2. What is the definitive test for autonomous growth
also a hypermetabolic condition and, as a result, acrome-
hormone production? IGF1 and OGGT
galic patients may complain of excessive sweating or heat
3. Because the patient complains of reduced libido, intolerance. The features of acromegaly slowly develop
hypogonadism is suspected. What evaluation is over time, and the patient (or their family) may be obliv-
appropriate? LH and testorone ious that changes in physiognomy have occurred. In
these cases, the patient’s complaints may center on the

secretion, and increases in TRH (as seen in primary hy- may present with reduced libido or complaints of erec-
pothyroidism) elevate prolactin levels.43 Estrogens also tile dysfunction. The reason(s) for the varied presenta-
directly stimulate lactotropes to synthesize prolactin. tions of a prolactinoma are somewhat obscure but likely
Pathologic stimulation of the neural suckling reflex is relate to the dramatic, noticeable alteration in menses or
the likely explanation of hyperprolactinemia associated the abrupt onset of a breast discharge in younger
with chest wall injuries. Hyperprolactinemia may also be women. By contrast, the decline in reproductive func-
seen in renal failure and polycystic ovary syndrome. tion in older patients may be overlooked as an inex-
Physiologic stressors, such as exercise and seizures, also orable consequence of “aging.” One recently recognized
elevate prolactin. The feedback effector for prolactin is complication of prolactin-induced hypogonadism is
unknown. Although the primary regulation of prolactin osteoporosis.45
secretions is tonic inhibition (e.g., dopamine), it is also
regulated by several hormones, including gonadotropin- Other Causes of Hyperprolactinemia
releasing hormone, thyrotropin-releasing hormone and
There are many physiologic, pharmacologic, and patho-
vasoactive intestinal polypeptide. Stimulation of breasts,
logic causes of hyperprolactinemia, and a common error
as in nursing, causes the release of prolactin secreting hor-
by clinicians is to ascribe any elevation in prolactin to a
mones from the hypothalamus through a spinal reflex act.
“prolactinoma.” Generally, substantial elevations in pro-
As mentioned, the physiologic effect of prolactin is
lactation. The usual consequence of prolactin excess is lactin (150 ng/mL) indicate prolactinoma, and the de-
hypogonadism, either by suppression of gonadotropin gree of elevation in prolactin is correlated with tumor
secretion from the pituitary or by inhibition of go- size.46 Modest elevations in prolactin (25–100 ng/mL)
nadotropin action at the gonad.44 The suppression of may be seen with pituitary stalk interruption, use of
dopaminergic antagonist medications, or other medical
ovulation seen in lactating postpartum mothers is related
conditions such as primary thyroidal failure, renal fail-
to this phenomenon.
ure, or polycystic ovary syndrome. Breast or genital stim-
ulation may also modestly elevate prolactin. Significant
Prolactinoma hyperprolactinemia is also encountered during preg-
nancy. Under most circumstances, the principal form of
A prolactinoma is a pituitary tumor that directly secretes
prolactin is a 23-kD peptide; however, a 150-kD form
prolactin, and it represents the most common type of
may also be secreted. This larger prolactin molecule has
functional pituitary tumor. The clinical presentation of
a markedly reduced biologic potency and does not share
a patient with a prolactinoma depends on the age and
the reproductive consequences of the 23-kD variety. If
gender of the patient and the size of the tumor.
the 150-kD form of prolactin predominates, this is called
Premenopausal women most frequently complain of
macroprolactinemia, and the clinical consequences are
menstrual irregularity/amenorrhea, infertility, or galact-
unclear but most patients are relatively asymptomatic.47
orrhea; men or postmenopausal women generally pres-
The prevalence of macroprolactinemia has been esti-
ent with symptoms of a pituitary mass, such as
mated at 10%–22% of hyperprolactinemic samples48 and
headaches or visual complaints. Occasionally, a man
can be excluded by precipitating serum samples with
polyethylene glycol prior to measuring prolactin.
Clinical Evaluation of Hyperprolactinemia
A 23-year-old woman has experienced recent onset
A careful history and physical examination are usually
of a spontaneous, bilateral breast discharge and grad-
sufficient to exclude most common, nonendocrine causes
ual cessation of menses. She reports normal growth
of hyperprolactinemia. It is essential to obtain TSH and
and development and has never been pregnant.
free T4 (or total thyroxine and T3 resin uptake) to elimi-
nate primary hypothyroidism as a cause for the elevated
Questions She might be pregnant
prolactin. If a pituitary tumor is suspected, a careful as-
1. What conditions could be causing her symptoms? sessment of other anterior pituitary function (basal corti-
sol, LH, FSH, and gender-specific gonadal steroid [either
2. What medical conditions (other than a prolactin-
estradiol or testosterone]) and an evaluation of sellar
oma) are associated with hyperprolactinemia?
anatomy with a high-resolution MRI should be obtained.
3. Which medications raise prolactin? Dopaminigic antagonist
prolactin blocker should be dopamine
Management of Prolactinoma
4. How would your thinking change if she had
galactorrhea but normal levels of prolactin? The therapeutic goals are correction of symptoms that
result from local invasion or extension of the tumor by

reducing tumor mass, restoration of normal gonadal

function and fertility, prevention of osteoporosis, and
preservation of normal anterior and posterior pituitary A 60-year-old man presented with intractable
function. The different therapeutic options include headaches. MRI was requested to evaluate this
simple observation, surgery, radiotherapy, or medical complaint, and a 2.5-cm pituitary tumor was discov-
management with dopamine agonists.42 However, the ered. In retrospect, he noted an unexplained 20-kg
management of prolactinoma also depends on the size of weight loss, cold intolerance, fatigue, and loss of
the tumor (macroadenomas [tumor size 10 mm] are sexual desire.
less likely to be “cured” than are microadenomas [tumor
size 10 mm])49 and the preferences of the patient. Questions
Dopamine agonists are the most commonly used
therapy for microprolactinomas. Tumor shrinkage is 1. How would you approach the evaluation of his
noted in more than 90% of patients treated with anterior pituitary function?
bromocriptine mesylate (Parlodel) or the new 2. What additional testing may be required to con-
dopamine agonist, cabergoline (Dostinex). Both drugs firm a loss in anterior pituitary function?
also shrink prolactin-secreting macroadenomas.50 A re-
sumption of menses and restoration of fertility is also
frequently seen during medical therapy. The adverse ef-
fects of bromocriptine include orthostatic hypotension,
dizziness, and nausea. The gastrointestinal adverse ef-
fects of bromocriptine can be ameliorated through in- may be a loss of only a single pituitary hormone, which is
travaginal administration, and its efficacy is otherwise referred to as a monotropic hormone deficiency. The loss of
uncompromised.51 Cabergoline has fewer adverse ef- a tropic hormone (ACTH, TSH, LH, and FSH) is reflected
fects and may be administered biweekly because of its in function cessation of the affected endocrine gland. Loss
longer duration of action. By virtue of its ability to in- of the direct effectors (GH and prolactin) may not be
teract with the 5-hydroxytryptamine (5-HT)2B seroton- readily apparent. This section concentrates on the causes
ergic receptor, cabergoline has been linked to the de- of hypopituitarism and certain subtleties involved in the
velopment of valvular heart disease,52 although the therapy of panhypopituitarism; more detailed descrip-
doses of cabergoline required to elicit the risk valvular tions of various hormone deficiency states are covered in
damage are in vast excess to the doses used in the man- other chapters.
agement of prolactinomas. Either agent should be dis- The laboratory diagnosis of hypopituitarism is rela-
continued during pregnancy unless tumor regrowth has tively straightforward. In contrast to the primary failure
been documented. of an endocrine gland that is accompanied by dramatic
Neurosurgery is not a primary mode of prolactinoma increases in circulating levels of the corresponding
management. The indications for neurosurgical interven- pituitary tropic hormone, secondary failure (hypopitu-
tion include pituitary tumor apoplexy (hemorrhage), itarism) is associated with low or normal levels of tropic
acute visual loss due to macroadenoma, cystic prolactin- hormone. In primary hypothyroidism, for example, the
oma, or intolerance to medical therapy. Surgical cure circulating levels of thyroxine are low and TSH levels
rates are inversely proportional to tumor size and the de- may exceed 200 U/mL (normal, 0.4–5.0). As a result of
gree of prolactin elevation. External beam radiotherapy is pituitary failure in hypothyroidism, TSH levels are inap-
generally reserved for high surgical risk patients with lo- propriately low and typically less than 1.0 U/mL.
cally aggressive macroadenomas who are unable to toler- There are several important issues in distinguishing
ate dopamine agonists. between primary and secondary hormone deficiency
states. To differentiate between primary and secondary
Idiopathic Galactorrhea deficiencies, both tropic and target hormone levels
should be measured when there is any suspicion of pitu-
Lactation occurring in women with normal prolactin lev- itary failure or as part of the routine evaluation of go-
els is defined as idiopathic galactorrhea. This condition is nadal or adrenal function. If one secondary deficiency is
usually seen in women who have been pregnant several documented, it is essential to search for other deficiency
times and has no pathologic implication. states and the cause for pituitary failure. For example,
failure to recognize secondary hypoadrenalism may have
catastrophic consequences if the patient is treated with
The failure of either the pituitary or hypothalamus results thyroxine. Similarly, initially overlooking a pituitary or
in the loss of anterior pituitary function. Complete loss of hypothalamic lesion could preclude early diagnosis and
function is termed panhypopituitarism; however, there treatment of a potentially aggressive tumor.

TABLE 19-4 CAUSES OF HYPOPITUITARISM lactate in the puerperium. Infiltrative diseases, such as
hemachromatosis, sarcoidosis, or histiocytosis, can also
1. Pituitary tumors
affect pituitary function. Fungal infections, tuberculosis,
2. Parapituitary/hypothalmic tumors and syphilis can involve the pituitary or hypothalamus
3. Trauma and may cause impairment of function. Lymphocytic hy-
4. Radiation therapy/surgery pophysitis, an autoimmune disease of the pituitary, may
only affect a single cell type in the pituitary, resulting in a
5. Infarction
monotropic hormone deficiency, or can involve all cell
6. Infection types, yielding total loss of function. Severe head trauma
7. Infiltrative disease may shear the pituitary stalk or may interrupt the portal
8. Immunologic circulation. Similarly, surgery involving the pituitary may
compromise the stalk and/or blood supply to the pituitary
9. Familial
or may iatrogenically diminish the mass of functioning
10. Idiopathic pituitary tissue. Panhypopituitarism can result from
radiotherapy used to treat a primary pituitary tumor or a
pituitary that was inadvertently included in the radiation
Etiology of Hypopituitarism port; loss of function, however, may be gradual and may
occur over several years. There have been rare instances
The many causes of hypopituitarism are listed in Table of familial panhypopituitarism or monotropic hormone
19-4. Direct effects of pituitary tumors, or the sequelae of deficiencies. In Kallmann’s syndrome, for example, GnRH
treatment of tumors, are the most common causes of is deficient and the patient presents with secondary hy-
pituitary failure. Pituitary tumors may cause panhypopi- pogonadism. Last, there may not be an apparent identi-
tuitarism by compressing or replacing normal tissue or fied cause for the loss of pituitary function, and the
interrupting the flow of hypothalamic hormones by de- patient is classified as having idiopathic hypopituitarism,
stroying the pituitary stalk. Large, nonsecretory pituitary although one recent case report emphasized the need to
tumors (chromophobe adenomas or null cell tumors) or continue the search for a cause.54
macroprolactinomas are most commonly associated with
this phenomenon. Parasellar tumors (meningiomas and Treatment of Panhypopituitarism
gliomas), metastatic tumors (breast and lung), and hypo-
In the average patient, replacement therapy for panhy-
thalamic tumors (craniopharyngiomas or dysgermino-
popituitarism is the same as for primary target organ fail-
mas) can also cause hypopituitarism through similar
ure. Patients are treated with thyroxine, glucocorticoids,
mechanisms. Hemorrhage into a pituitary tumor (pitu-
and gender-specific sex steroids. It is less clear about GH
itary tumor apoplexy) is rare; however, when it occurs,
replacement in adults, and additional studies are needed
it frequently causes complete pituitary failure.53
to clarify this issue.55,56 Replacement becomes more
Postpartum ischemic necrosis of the pituitary following a
complicated in panhypopituitary patients who desire fer-
complicated delivery (Sheehan’s syndrome) typically
tility. Pulsatile GnRH infusions have induced puberty
presents as profound, unresponsive shock or as failure to
and restored fertility in patients with Kallmann’s syn-
drome, and gonadotropin preparations have restored
ovulation/spermatogenesis in people with gonadotropin
CASE STUDY 19-4 deficiency.57

An 18-year-old woman was admitted to the neuro- POSTERIOR PITUITARY HORMONES

logic intensive care unit following a severe closed
The posterior pituitary is an extension of the forebrain
head injury. Her course stabilized after 24 hours, but
and represents the storage region for vasopressin (also
the nursing staff noticed a dramatic increase in the
called antidiuretic hormone [ADH]) and oxytocin. Both of
patient’s urine output, which exceeded 1000 mL/h.
these small peptide hormones are synthesized in the
supraoptic and paraventricular nuclei of the hypothala-
mus and transported to the neurohypophysis via their
1. What caused her increased urine production? axons in the hypothalamoneurohypophysial tract. This
tract transits the median eminence of the hypothalamus
2. How could you prove your suspicions?
and continues into the posterior pituitary through the pi-
3. Could she have other possible endocrinologic tuitary stalk. The synthesis of each of these hormones is
problems? tightly linked to the production of neurophysin, a larger
protein whose function is poorly understood. Both hor-