DISORDERS OF THE

ANTERIOR PITUITARY
AND HYPOTHALAMUS

Melanie C. Dionaldo, MD
IM- Pulmonary
 ANTERIOR PITUITARY
"master gland"
it orchestrates the complex regulatory
functions of multiple other endocrine
glands
produces six major hormones
(1) prolactin (PRL), (2) growth hormone (GH),
(3) adrenocorticotropin hormone (ACTH), (4)
luteinizing hormone (LH), (5) follicle-
stimulating hormone (FSH), and (6) thyroid-
stimulating hormone (TSH)
 Pituitary hormones are secreted
in a pulsatile manner
Each of these pituitary hormones
elicits specific responses in
peripheral target tissues.
hormonal products of these
peripheral glands, in turn, exert
feedback control at the level of the
hypothalamus and pituitary to
modulate pituitary function.
 ANATOMY

pituitary gland weighs ~600 mg

located within the sella turcica
ventral to the diaphragma sella
comprises anatomically and
functionally distinct anterior and
posterior lobes.
 The sella is contiguous to
vascular and neurologic
structures, including the
cavernous sinuses, cranial
nerves, and optic chiasm.
expanding intrasellar pathologic
processes may have significant
central mass effects in addition to
their endocrinologic impact.
 Blood supply of the pituitary
gland is derived from the superior
and inferior hypophyseal arteries.
hypothalamic-pituitary portal
plexus provides the major blood
source for the anterior pituitary.
posterior pituitary is supplied by
the inferior hypophyseal arteries.
 PITUITARY DEVELOPMENT

develop from Rathke's pouch

The transcription factor Pit-1
determines cell-specific
expression of GH, PRL, and TSH
in somatotropes, lactotropes, and
thyrotropes
 Hypothalamic and Anterior
Pituitary Insufficiency

Hypopituitarism
results from impaired
production of one or more of the
anterior pituitary trophic
hormones.
 Reduced pituitary function can
result from inherited disorders;
more commonly, it is acquired
and reflects the mass effects of
tumors or the consequences of
inflammation or vascular
damage.
 Etiology of Hypopituitarism

1. Development/structural
Transcription factor defect
Pituitary dysplasia/aplasia
Congenital CNS mass, encephalocele
Primary empty sella
Congenital hypothalamic disorders
(septo-optic dysplasia, Prader-Willi
syndrome, Laurence-Moon-Biedl
syndrome, Kallmann syndrome)
 Etiology of Hypopituitarism

2. Infiltrative/inflammatory
Lymphocytic hypophysitis
Hemochromatosis
Sarcoidosis
Histiocytosis X
Granulomatous hypophysitis
 Etiology of Hypopituitarism
3. Vascular
Pituitary apoplexy
Pregnancy-related (infarction with diabetes;
postpartum necrosis)
Sickle cell disease
Arteritis
4. Infections
Fungal (histoplasmosis)
Parasitic (toxoplasmosis)
Tuberculosis
Pneumocystis carinii
 Etiology of Hypopituitarism
5. Traumatic
Surgical resection, Radiation damage, Head injuries
6. Neoplastic
Pituitary adenoma
Parasellar mass (meningioma, germinoma,
ependymoma, glioma)
Rathke's cyst
Craniopharyngioma
Hypothalamic hamartoma, gangliocytoma
Pituitary metastases (breast, lung, colon carcinoma)
Lymphoma and leukemia
Meningioma
 Presentation and Diagnosis

The clinical manifestations of

hypopituitarism depend on which
hormones are lost and the extent of
the hormone deficiency.

GH deficiency causes growth

disorders in children and leads to
abnormal body composition in adults
 Gonadotropin deficiency causes
menstrual disorders and infertility in
women and decreased sexual
function, infertility, and loss of
secondary sexual characteristics in
men.
TSH and ACTH deficiency usually
develop later in the course of pituitary
failure.
 TSH deficiency causes growth
retardation in children and features of
hypothyroidism in children and in
adults.
The secondary form of adrenal
insufficiency caused by ACTH
deficiency leads to hypocortisolism
with relative preservation of
mineralocorticoid production.
PRL deficiency causes failure of
lactation.
 When lesions involve the posterior
pituitary, polyuria and polydipsia
reflect loss of vasopressin secretion.
Epidemiologic studies have
documented an increased mortality
rate in patients with longstanding
pituitary damage, primarily from
increased cardiovascular and
cerebrovascular disease.
 Laboratory Investigation
Biochemical diagnosis of
pituitary insufficiency is made
by demonstrating low levels of
trophic hormones in the setting
of low target hormone levels.
 For example, low free thyroxine
in the setting of a low or
inappropriately normal TSH
level suggests secondary
hypothyroidism.
a low testosterone level without

elevation of gonadotropins
suggests hypogonadotropic
hypogonadism.
 Provocative tests may be required
to assess pituitary reserve
GH responses to insulin-induced
hypoglycemia, arginine, L-dopa,
growth hormonereleasing
hormone (GHRH), or growth
hormonereleasing peptides
(GHRPs) can be used to assess GH
reserve.
 Corticotropin-releasing hormone
(CRH) administration induces
ACTH release, and administration
of synthetic ACTH (cortrosyn)
evokes adrenal cortisol release as
an indirect indicator of pituitary
ACTH reserve.
 ACTH reserve is most reliably
assessed during insulin-induced
hypoglycemia.
test should be performed cautiously
in patients with suspected adrenal
insufficiency because of enhanced
susceptibility to hypoglycemia and
hypotension.
Insulin-induced hypoglycemia is
contraindicated in patients with
active coronary artery disease or
seizure disorders.
 Treatment
Hormone replacement therapy, including
glucocorticoids, thyroid hormone, sex
steroids, growth hormone, and
vasopressin, is usually safe.
homeostasis.
Patients in need of glucocorticoid
replacement require careful dose
adjustments during stressful events such
as acute illness, dental procedures,
trauma, and acute hospitalization.
 Pituitary Tumors
Pituitary adenomas
are the most common cause of
pituitary hormone hypersecretion
and hyposecretion syndromes in
adults.
account for ~15% of all intracranial

neoplasms.
 At autopsy, up to one-quarter of
all pituitary glands harbor an
unsuspected microadenoma
(<10 mm diameter).
pituitary imaging detects small

clinically inapparent pituitary

lesions in at least 10% of
individuals.
 Pathogenesis
benign neoplasms that arise
from one of the five anterior
pituitary cell types.
Hormonally active tumors are
characterized by autonomous
hormone secretion with
diminished responsiveness to
physiologic inhibitory
pathways.
 Small hormone-secreting adenomas
may cause significant clinical
perturbations,
whereas larger adenomas that

produce less hormone may be

clinically silent and remain
undiagnosed (if no central
compressive effects occur).
one-third of all adenomas are
clinically nonfunctioning.
 Almost all pituitary adenomas are
monoclonal in origin, implying
the acquisition of one or more
somatic mutations that confer a
selective growth advantage.
Several etiologic genetic events
have been implicated in the
development of pituitary tumors
Genetic Syndromes Associated
with Pituitary Tumors
1. Multiple endocrine neoplasia (MEN)
1
is an autosomal dominant syndrome
characterized primarily by a genetic
predisposition to parathyroid, pancreatic
islet, and pituitary adenomas.
caused by inactivating germline
mutations in MENIN, a constitutively
expressed tumor-suppressor gene located
on chromosome 11q13.
 Loss of heterozygosity, or a somatic
mutation of the remaining normal
MENIN allele, leads to
tumorigenesis.
half of affected patients develop

prolactinomas; acromegaly and

Cushing's syndrome are less
commonly encountered.
 2. Carney syndrome
is characterized by spotty skin
pigmentation, myxomas, and
endocrine tumors including
testicular, adrenal, and pituitary
adenomas.
Acromegaly occurs in about 20% of
patients. A subset of patients have
mutations in the R1 regulatory
subunit of protein kinase A
(PRKAR1A)..
 3. McCune-Albright syndrome
consists of polyostotic fibrous dysplasia,
pigmented skin patches, and a variety of
endocrine disorders, including GH-
secreting pituitary tumors, adrenal
adenomas, and autonomous ovarian
function).
Hormonal hypersecretion is the result of
constitutive cyclic AMP production
caused by inactivation of the GTPase
activity of Gs .
 4. Familial acromegaly
is a rare disorder in which family
members may manifest either
acromegaly or gigantism.
The disorder is associated with LOH

at a chromosome 11q13 locus

distinct from that of MENIN.
 Other Sellar Masses
Craniopharyngiomas
Sella chordomas
Meningiomas
Histiocytosis X
Pituitary metastases
Hypothalamic hamartomas and
gangliocytomas
Hypothalamic gliomas and optic gliomas
Brain germ-cell tumors
 Metabolic Effects of
Hypothalamic Lesions
Lesions involving the anterior and
preoptic hypothalamic regions
cause paradoxical
vasoconstriction, tachycardia,
and hyperthermia.
Acute hyperthermia is usually
due to a hemorrhagic insult, but
poikilothermia may also occur.
 Central disorders of
thermoregulation result from
posterior hypothalamic damage.
The periodic hypothermia
syndrome comprises episodic
attacks of rectal temperatures
<30C, sweating, vasodilation,
vomiting, and bradycardia.
 Damage to the ventromedial
hypothalamic nuclei by
craniopharyngiomas, hypothalamic
trauma, or inflammatory disorders
may be associated with hyperphagia
and obesity.
This region appears to contain an
energy-satiety center where
melanocortin receptors are influenced
by leptin, insulin, POMC products,
and gastrointestinal peptides.
 Polydipsia and hypodipsia are associated
with damage to central osmoreceptors
located in preoptic nuclei.
Slow-growing hypothalamic lesions can
cause increased somnolence and disturbed
sleep cycles as well as obesity,
hypothermia, and emotional outbursts.
Lesions of the central hypothalamus may
stimulate sympathetic neurons, leading to
elevated serum catecholamine and cortisol
levels.
These patients are predisposed to cardiac
arrhythmias, hypertension, and gastric
erosion.
 Evaluation
Local Mass Effects
Clinical manifestations of sellar
lesions vary, depending on the
anatomic location of the mass and
direction of its extension.
The dorsal sellar diaphragm
presents the least resistance to soft
tissue expansion from the sella
 pituitary adenomas frequently
extend in a suprasellar
direction.
Bony invasion may occur as

well.
 Headaches are common features of
small intrasellar tumors
Suprasellar extension can lead to
visual loss by several mechanisms,
the most common being compression
of the optic chiasm, but direct
invasion of the optic nerves or
obstruction of CSF flow leading to
secondary visual disturbances also
occurs
Features of Sellar Mass Lesions

Impacted Structure Clinical Impact

Pituitary Hypogonadism
Hypothyroidism
Growth failure and adult
hyposomatotropism
Hypoadrenalism
Optic chiasm Loss of red perception
Bitemporal hemianopia
Superior or bitemporal field
defect
Scotoma
Blindness
Hypothalamus Temperature dysregulation
Appetite and thirst disorders
Obesity, Diabetes insipidus,
Sleep disorders, Behavioral
dysfunction
Sleep disorders, Autonomic
dysfunction

Cavernous sinus Opthalmoplegia with or without

ptosis or diplopia, Facial
numbness
Frontal lobe Personality disorder, anosmia

Brain Headache, Hydrocephalus,

Psychosis,
Dementia, Laughing seizures
 MRI
Sagittal and coronal T1-weighted MRI
imaging, before and after administration
of gadolinium, allow precise
visualization of the pituitary gland with
clear delineation of the hypothalamus,
pituitary stalk, pituitary tissue and
surrounding suprasellar cisterns,
cavernous sinuses, sphenoid sinus, and
optic chiasm.
Pituitary gland height ranges from 6 mm
in children to 8 mm in adults
 during pregnancy and puberty, the
height may reach 1012 mm.
The upper aspect of the adult
pituitary is flat or slightly concave
in adolescent and pregnant
individuals, this surface may be
convex, reflecting physiologic
pituitary enlargement. The stalk
should be midline and vertical.
CT scan is indicated to define the
extent of bony erosion or the
presence of calcification.
 Adenoma density is usually lower
than that of surrounding normal tissue
on T1-weighted imaging, and the
signal intensity increases with T2-
weighted images.
The high phospholipid content of the
posterior pituitary results in a
"pituitary bright spot."
Sellar masses are commonly
encountered as incidental findings on
MRI
 Ophthalmologic Evaluation
Because optic tracts may be contiguous
to an expanding pituitary mass,
reproducible visual field assessment that
uses perimetry techniques should be
performed on all patients with sellar
mass lesions that abut the optic chiasm.
Bitemporal hemianopia or superior
bitemporal defects are classically
observed, reflecting the location of these
tracts within the inferior and posterior
part of the chiasm.
 Homonymous cuts reflect
postchiasmal and monocular field
cuts prechiasmal lesions.
Loss of red perception is an early

sign of optic tract pressure.

Early diagnosis reduces the risk of
blindness, scotomas, or other visual
disturbances.
 Laboratory Investigation
The presenting clinical features of
functional pituitary adenomas (e.g.,
acromegaly, prolactinomas, or Cushing's
syndrome) should guide the laboratory
studies.
for a sellar mass with no obvious clinical
features of hormone excess, laboratory
studies are geared towards determining
the nature of the tumor and assessing the
possible presence of hypopituitarism.
 When a pituitary adenoma is suspected
based on MRI, initial hormonal
evaluation usually includes (1) basal
PRL; (2) insulin-like growth factor (IGF) I;
(3) 24-h urinary free cortisol (UFC) and/or
overnight oral dexamethasone (1 mg)
suppression test; (4) subunit, FSH, and
LH; and (5) thyroid function tests.
a menstrual history, testosterone and 8
A.M. cortisol levels, and thyroid function
tests usually identify patients with
pituitary hormone deficiencies that
require hormone replacement before
further testing or surgery.
Screening Tests for Functional
Pituitary Adenomas
Test Comments

Acro- Serum IGF-I IGF-I Interpret relative to

age- and gender-
megaly matched controls

Oral glucose tolerance Normal subjects

test with GH obtained should suppress
at 0, 30, and 60 min growth hormone to <1
g/L
Prolac- Serum PRL Exclude medications
MRI of the sella
tinoma should be ordered if
prolactin is elevated

Cushing's -24-h urinary free -Ensure urine

cortisol collection is total
disease - Dexamethasone (1 and accurate
mg) at 11 P.M. and -Normal subjects

fasting plasma suppress to <5 g/dL

cortisol measured at
8 A.M. -Distinguishes
- ACTH assay adrenal adenoma
(ACTH suppressed)
from ectopic ACTH
or Cushing's
disease (ACTH
normal or elevated)
 Histologic Evaluation
Immunohistochemical staining of
pituitary tumor specimens obtained at
transsphenoidal surgery confirms
clinical and laboratory studies and
provides a histologic diagnosis when
hormone studies are equivocal and in
cases of clinically nonfunctioning
tumors.
ultrastructural assessment by electron
microscopy is required for diagnosis.
Hypothalamic, Pituitary, and Other
Sellar Masses: Treatment
Transsphenoidal Surgery
desired surgical approach for
pituitary tumors, except for the rare
invasive suprasellar mass
surrounding the frontal or middle
fossa, the optic nerves, or invading
posteriorly behind the clivus
 Radiation
used either as a primary therapy for
pituitary or parasellar masses or, more
commonly, as an adjunct to surgery or
medical therapy
a total of <50 Gy (5000 rad) is given as
180-cGy (180-rad) fractions split over
about 6 weeks
The role of radiation therapy in pituitary
tumor management depends on multiple
factors including the nature of the tumor,
age of the patient, and the availability of
surgical and radiation expertise.
 radiation therapy is usually reserved for
postsurgical management.
As an adjuvant to surgery, radiation is
used to treat residual tumor and in an
attempt to prevent regrowth. Irradiation
offers the only effective means for
ablating significant postoperative
residual nonfunctioning tumor tissue.
PRL-, GH-, and sometimes ACTH-
secreting tumor tissues are amenable to
medical therapy.
 Medical
Medical therapy for pituitary tumors is
highly specific and depends on tumor
type.
For prolactinomas, dopamine agonists
are the treatment of choice.
For acromegaly and TSH-secreting
tumors, somatostatin analogues and,
occasionally, dopamine agonists are
indicated.
ACTH-secreting tumors and
nonfunctioning tumors are generally not
responsive to medications and require
surgery and/or irradiation.
 HYPERPROLACTINEMIA
most common pituitary hormone
hypersecretion syndrome in both men and
women.
PRL-secreting pituitary adenomas
(prolactinomas) are the most common
cause of PRL levels >100 g/L.
Less pronounced PRL elevation can also be
seen with microprolactinomas but is more
commonly caused by drugs, pituitary stalk
compression, hypothyroidism, or renal
failure .
 Presentation and Diagnosis
Amenorrhea, galactorrhea, and
infertility are the hallmarks of
hyperprolactinemia in women.
If hyperprolactinemia develops
prior to menarche, primary
amenorrhea results.
More commonly,
hyperprolactinemia develops later
in life and leads to oligomenorrhea
and, ultimately, to amenorrhea.
 In men with hyperprolactinemia,
diminished libido, infertility, or visual loss
(from optic nerve compression) are the
usual presenting symptoms. Gonadotropin
suppression leads to reduced testosterone,
impotence, and oligospermia.
If the disorder is longstanding, secondary
effects of hypogonadism are evident,
including osteopenia, reduced muscle
mass, and decreased beard growth.
The diagnosis of idiopathic
hyperprolactinemia is made by exclusion of
known causes of hyperprolactinemia in the
setting of a normal pituitary MRI.
 Laboratory Investigation
Basal, fasting morning PRL levels
(normally <20 g/L) should be
measured to assess hypersecretion.
Because hormone secretion is

pulsatile , it may be necessary to

measure levels on several different
occasions when clinical suspicion is
high.
 Treatment
depends on the cause of elevated
PRL levels. Regardless of the
etiology, however, treatment should
be aimed at normalizing PRL levels
to alleviate suppressive effects on
gonadal function, halt galactorrhea,
and preserve bone mineral density.
 ACROMEGALY
Etiology
GH hypersecretion is usually the result of a
somatotrope adenoma but may rarely be caused
by extrapituitary lesions.
In addition to more common GH-secreting
somatotrope adenomas, mixed
mammosomatotrope tumors and acidophilic
stem-cell adenomas secrete both GH and PRL.
In patients with acidophilic stem-cell
adenomas, features of hyperprolactinemia
(hypogonadism and galactorrhea) predominate
over the less clinically evident signs of
acromegaly.
 Presentation and Diagnosis
Protean manifestations of GH and IGF-I
hypersecretion are indolent and often are
not clinically diagnosed for 10 years or
more.
Acral bony overgrowth results in frontal
bossing, increased hand and foot size,
mandibular enlargement with
prognathism, and widened space
between the lower incisor teeth.
In children and adolescents, initiation of
GH hypersecretion prior to epiphyseal
long bone closure is associated with
development of pituitary gigantism.
 Treatment
Surgery
Somastostatin analogues

GH Receptor anatagonists

Dopamine Agonists

Radiation
Cushing's Syndrome (ACTH-
Producing Adenoma)
Etiology and Prevalence
Pituitary corticotrope adenomas account
for 70% of patients with endogenous
causes of Cushing's syndrome.
Iatrogenic hypercortisolism is the most
common cause of cushingoid features.
ACTH-producing adenomas account for
about 1015% of all pituitary tumors.
Cushing's disease is 510 times more
common in women than in men.
 Presentation and Diagnosis
The diagnosis of Cushing's

syndrome presents two great

challenges:
(1) to distinguish patients with
pathologic cortisol excess from those
with physiologic or other disturbances
of cortisol production; and
(2) to determine the etiology of cortisol

excess.
 Typical features of chronic cortisol
excess include thin, fragile skin, central
obesity, hypertension, plethoric moon
facies, purple striae and easy
bruisability, glucose intolerance or
diabetes mellitus, gonadal dysfunction,
osteoporosis, proximal muscle weakness,
signs of hyperandrogenism (acne,
hirsutism), and psychological
disturbances (depression, mania, and
psychoses) (Table 333-11).
 Laboratory Investigation
The diagnosis of Cushing's syndrome is based
on laboratory documentation of endogenous
hypercortisolism.
Measurements of 24-h urine free cortisol (UFC)
is a precise and cost-effective screening test.
Alternatively, the failure to suppress plasma
cortisol after an overnight 1-mg dexamethasone
suppression test can be used to identify patients
with hypercortisolism.
As nadir levels of cortisol occur at night,
elevated midnight samples of cortisol are
suggestive of Cushing's syndrome.
 Treatment
Selective transsphenoidal resection is
the treatment of choice for Cushing's
syndrome
Ketoconazole, an imidazole derivative
antimycotic agent, inhibits several
P450 enzymes and effectively lowers
cortisol in most patients with Cushing's
disease when administered twice daily
(6001200 mg/d).
Metyrapone , Mitotane