MEDICINE (Dr.

QUISUMBING)

ANT. PITUITARY TUMOR SYNDROMES

26 FEBRUARY 2018

MRI:
HYPOTHALAMIC, PITUITARY AND OTHER SELLAR MASSES
» Pituitary gland height ranges from 6 mm in children to 8 mm
EVALUATION OF SELLAR MASSES: in adults; during pregnancy and puberty, the height may
Local Mass Effects: reach 10–12 mm.
§ The dorsal sellar diaphragm presents the least resistance to » The upper aspect of the adult pituitary is flat or slightly con-
soft tissue expansion from the sella; consequently, pituitary cave, but in adolescent and pregnant individuals, this surface
adenomas frequently extend in a suprasellar direction. may be convex, reflecting physiologic pituitary enlargement.
§ Bony invasion may occur as well. » Anterior pituitary gland soft tissue consistency is slightly
§ Headaches are common features of small intrasellar tumors, heterogeneous on MRI, and signal intensity resembles that of
even with no demonstrable suprasellar extension. brain matter on T1-weighted imaging.
o headache severity correlates poorly with adenoma
size or extension.
§ Suprasellar extension à visual loss by several mechanisms,
the most common being compression of the optic chiasm
§ Pituitary stalk compression by a hormonally active or inactive
intrasellar mass may compress the portal vessels, disrupting
pituitary access to hypothalamic hormones and dopamine;
this results in early hyper- prolactinemia and later concurrent
loss of other pituitary hormones.
o This “stalk section” phenomenon may also be
caused by trauma, whiplash injury with posterior
clinoid stalk compression, or skull base fractures.
o Lateral mass invasion may impinge on the
cavernous sinus and compress its neural contents,
leading to cranial nerve III, IV, and VI palsies as well
as effects on the ophthalmic and maxillary branches
of the fifth cranial nerve
§ Patients may present with diplopia, ptosis, ophthalmoplegia,
and decreased facial sensation, depending on the extent of
neural damage.
§ Extension into the sphenoid sinus indicates that the pituitary » Adenoma density is usually lower than that of surrounding
mass has eroded through the sellar floor. normal tissue on T1-weighted imaging, and the signal
§ Rare symptoms: intensity increases with T2-weighted images.
o Invasion of the palate roof and cause » high phospholipid content of the posterior pituitary results in
nasopharyngeal obstruction, infection, and CSF a “pituitary bright spot.”
leakage » Sellar masses are encountered commonly as incidental
o Temporal and frontal lobe involvement àuncinate findings on MRI, and most of them are pituitary adenomas
seizures, personality disorders, and anosmia (incidentalomas).
§ Direct hypothalamic encroachment àprecocious puberty or » When larger masses (>1 cm) are encountered, they should
hypogonadism, diabetes insipidus, sleep disturbances, also be distinguished from nonadenomatous lesions.
dysthermia, and appetite disorders. » Meningiomas often are associated with bony hyperostosis;
craniopharyngiomas may be calcified and are usually
hypodense, whereas gliomas are hyperdense on T2-weighted
images.

OPHTHALMOPLAGIC EVALUATION
» Bitemporal hemianopia, often more pronounced superiorly, is
observed classically
» Occasionally, homonymous hemianopia occurs from
postchiasmal compression or monocular temporal field loss
from prechiasmal compression.
» Invasion of the cavernous sinus can produce diplopia from
ocular motor nerve palsy.
» Early diagnosis reduces the risk of optic atrophy, vision loss,
or eye misalignment.
LABORATORY INVESTIGATION
» 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 toward 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:
o basal prolactin (PRL)
o insulin-like growth factor (IGF) I

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 o 24-h urinary free cortisol (UFC) and/or overnight Side Effects:
oral dexamethasone (1 mg) suppression test ü Tumor size, the degree of invasiveness, and experience of the
o α subunit, follicle-stimulating hormone (FSH), and surgeon largely determine the incidence of surgical
luteinizing hormone (LH) complications.
o thyroid function tests. ü Operative mortality rate is about 1%.
HISTOLOGIC EVALUATION ü Transient diabetes insipidus and hypopituitarism occur in up
» Immunohistochemical staining of pituitary tumor specimens to 20% of patients.
obtained at transsphenoidal surgery confirms clinical and ü Permanent diabetes insipidus, cranial nerve damage, nasal
laboratory studies and provides a histologic diagnosis when septal perforation, or visual disturbances may be encountered
hormone studies are equivocal and in cases of clinically in up to 10% of patients.
nonfunctioning tumors. ü CSF leaks occur in 4% of patients.
HYPOTHALAMIC, PITUITARY AND OTHER SELLA ü Less common complications include carotid artery injury, loss
TREATMENT
MASSES of vision, hypothalamic damage, and meningitis.
Overview: ü Permanent side effects are rare after surgery for
§ Most pituitary tumors are benign and slow-growing microadenomas.
§ Clinical features result from local mass effects and hormonal
hyper- or hyposecretion syndromes caused directly by the RADIATION:
adenoma or occurring as a consequence of treatment. § used either as a primary therapy for pituitary or parasellar
§ The goals of pituitary tumor treatment include: masses or, more commonly, as an adjunct to surgery or
o normalization of excess pituitary secretion medical therapy.
o amelioration of symptoms and signs of hormonal § A major determinant of accurate irradiation is reproduction of
hypersecretion syndromes the patient’s head position during multiple visits and
o shrinkage or ablation of large tumor masses with maintenance of absolute head immobility.
relief of adjacent structure compression. § A total of <50 Gy (5000 rad) is given as 180-cGy (180-rad)
TRANSSPHENOIDAL SURGERY: fractions divided over about 6 weeks.
§ the desired surgical approach for pituitary tumors, except for § The role of radiation therapy in pituitary tumor management
the rare invasive suprasellar mass surrounding the frontal or depends on multiple factors, including the nature of the
middle fossa or the optic nerves or invading posteriorly behind tumor, the age of the patient, and the availability of surgical
the clivus. and radiation expertise.
§ This also avoids the cranial invasion and manipulation of brain § radiation therapy is usually reserved for postsurgical
tissue required by subfrontal surgical approaches. management
§ Individual surgical experience is a major determinant of § Adjuvant to surgery, radiation is used to treat residual tumor
outcome efficacy with these techniques. and in an attempt to prevent regrowth.
§ Surgical decompression and resection are required for an § Irradiation offers the only means for potentially ablating
expanding pituitary mass accompanied by persistent significant postoperative residual nonfunctioning tumor
headache, progressive visual field defects, cranial nerve tissue.
palsies, hydrocephalus, and, occasionally, intrapituitary § PRL- and growth hormone (GH)- secreting tumor tissues are
hemorrhage and apoplexy. amenable to medical therapy.
o normal pituitary tissue should be manipulated or Side Effects:
resected only when critical for effective mass ü Short term: transient nausea and weakness.
dissection ü Alopecia and loss of taste and smell may be more long-
§ This sometimes is used for pituitary tissue biopsy to establish lasting.
a histologic diagnosis. ü head and neck or pituitary-directed irradiation àFailure of
§ Preoperative mass effects, including visual field defects and pituitary hormone synthesis
compromised pituitary function, may be reversed by surgery, ü >50% loss of GH, adrenocorticotropin hormone (ACTH),
particularly when the deficits are not long-standing. thyroid-stimulating hormone (TSH), and/or gonadotropin
secretion within 10 years, usually due to hypothalamic
damage
ü Optic nerve damage with impaired vision due to optic neuritis
is reported in about 2% of patients who undergo pituitary
irradiation.
ü use of stereotactic radiotherapy may reduce damage to
adjacent structures
MEDICAL
§ For prolactinomas àdopamine agonists are the treatment of
choice.
§ For acromegaly àsomatostatin analogues and GH receptor
antagonists are indicated.
§ For TSH-secreting tumors àsomatostatin 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.

SELLAR MASSES
» Sellar masses other than pituitary adenomas may arise from
brain, hypothalamic, or pituitary tissues.

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 o Normal pituitary tissue may be visible on MRI,
SELLAR MASSES
distinguishing chordomas from aggressive pituitary
HYPOTHALAMIC LESIONS: adenomas.
z MENINGOMAS
Lesions/ its location Effects o from nonfunctioning pituitary adenomas.
anterior and preoptic paradoxical vasoconstriction, o typically enhance on MRI and may show evidence of
hypothalamic regions tachycardia, and hyperthermia calcification or bony erosion.
hemorrhagic insult Acute hyperthermia and also o may cause compressive symptoms.
poikilothermia z HISTIOCYTOSIS X
posterior hypothalamic damage Central disorders of o includes a variety of syndromes associated with foci of
thermoregulation eosinophilic granulomas.
Damage to the ventromedial hyperphagia and obesity o Diabetes insipidus, exophthalmos, and punched-out lytic
hypothalamic nuclei by bone lesions (Hand-Schüller-Christian disease) are
craniopharyngiomas, associated with granulomatous lesions visible on MRI, as
hypothalamic trauma, or well as a characteristic axillary skin rash.
inflammatory disorders z PITUITARY METASTASES
damage to central Polydipsia and hypodipsia o occur in ~3% of cancer patients.
osmoreceptors located in o Bloodborne metastatic deposits are found almost
preoptic nuclei exclusively in the posterior pituitary
Slow-growing hypothalamic increased somnolence and o diabetes insipidus can be a presenting feature of lung,
lesions disturbed sleep cycles as well as gastrointestinal, breast, and other pituitary metastases
obesity, hypothermia, and o about 50% of the pituitary metastases originate from
emotional outbursts breast cancer
Lesions of the central stimulate sympathetic neurons, z HYPOTHALAMIC HAMARTOMAS AND GANGLIOCYTOMAS
hypothalamus leading to elevated serum o may arise from astrocytes, oligodendrocytes, and
catecholamine and cortisol levels. neurons with varying degrees of differentiation
o may overexpress hypothalamic neuropeptides, including
§ The periodic hypothermia syndrome is characterized by episodic gonadotropin-releasing hormone (GnRH), growth
attacks of rectal temperatures <30°C (86°F), sweating, vasodilation, hormone–releasing hormone (GHRH), and corticotropin-
vomiting, and bradycardia releasing hormone (CRH).
» GnRH-producing tumors àchildren present
z CRANIOPHARYNGOMA with precocious puberty, psychomotor delay,
o benign, suprasellar cystic masses that present with and laughing-associated seizures
headaches, visual field deficits, and variable degrees of » Pallister-Hall syndrome- a craniofacial
hypopituitarism abnormalities; imperforate anus; cardiac, renal,
o derived from Rathke’s pouch and arise near the pituitary and lung disorders; and pituitary failure
stalk, commonly extending into the suprasellar cistern. • caused by mutations in the carboxy
o are often large, cystic, and locally invasive. terminus of the GLI3 gene
o >50% present before age 20, usually with signs of o Histologic evidence of hypothalamic neurons in tissue
increased intracranial pressure, including headache, resected at transsphenoidal surgery may be the first
vomiting, papilledema, and hydrocephalus. indication of a primary hypothalamic lesion.
o Associated symptoms include visual field abnormalities, z HYPOTHALAMIC GLIOMAS AND OPTIC GLIOMAS
personality changes and cognitive deterioration, cranial o occur mainly in childhood and usually present with visual
nerve damage, sleep difficulties, and weight gain. loss.
o 90%- hypopituitarism, 10% diabetes insipidus, about o Adults have more aggressive tumors; about a third are
50% preset with growth retardation associated with neurofibromatosis.
o MRI is generally superior to CT for evaluating cystic z BRAIN GERM CELL TUMORS
structure and tissue components of craniopharyngiomas. o may arise within the sellar region.
o CT is useful to define calcifications and evaluate invasion o They include dysgerminomas, which frequently are
into surrounding bony structures and sinuses. associated with diabetes insipidus and visual loss.
o Treatment: a transcranial or transsphenoidal surgical o Germinomas, embryonal carcinomas, teratomas, and
resection followed by postoperative radiation of residual choriocarcinomas may arise in the parasellar region and
tumor. produce hCG.
» Surgery alone is curative in less than half of » present with precocious puberty, diabetes
patients insipidus, visual field defects, and thirst
• The goal of surgery is to remove as disorders.
much tumor as possible without
risking complications associated PITUITARY ADENOMAS AND HYPERSECRETION SYNDROMES
with efforts to remove firmly ü Pituitary adenomas are the most common cause of pituitary
adherent or inaccessible tissue. hormone hypersecretion and hyposecretion syndromes in
z RATHKE’S CYST adults.
o Developmental failure of Rathke’s pouch obliteration ü They account for ~15% of all intracranial neoplasms
o which are small (<5 mm) cysts entrapped by squamous
epithelium and are found in about 20% of individuals at
autopsy.
PITUITARY ADENOMAS AND HYPERSECRETION SYNDROMES
o 1/3 third present in adulthood with compressive PATHOGENESIS:
symptoms, diabetes insipidus, and hyperprolactinemia » are benign neoplasms that arise from one of the five anterior
due to stalk compression pituitary cell types.
o Diagnosis: suggested preoperatively by visualizing the » The clinical and biochemical phenotypes of pituitary
cyst wall on MRI, which distinguishes these lesions from adenomas depend on the cell type from which they are
craniopharyngiomas. Cyst contents range from CSF-like derived.
fluid to mucoid material. » may arise from a single polysecreting cell type or include cells
z SELLA CHORDOMAS with mixed function within the same tumor.
o A present with bony clival erosion, local invasiveness,
and, on occasion, calcification.
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 » Hormonally active tumors are characterized by autonomous
hormone secretion with diminished feedback responsiveness
to physiologic inhibitory pathways.
» Hormone production does not always correlate with tumor
size. z McCune-Albright syndrome
o Small hormone-secreting adenomas à significant o consists of polyostotic fibrous dysplasia, pigmented skin
clinical perturbations, whereas larger adenomas patches, and a variety of endocrine disorders, including
àproduce less hormone may be clinically silent and acromegaly, adrenal adenomas, and autonomous ovarian
remain undiagnosed function.
» 1/3 of all adenomas are clinically nonfunctioning and produce z Familial acromegaly
no distinct clinical hypersecretory syndrome. o is a rare disorder in which family members may manifest
o Most of them arise from gonadotrope cells and may either acromegaly or gigantism
secrete small amounts of α- and β-glycoprotein o germline mutations in the AIP gene,
hormone subunits
» True pituitary carcinomas with documented extracranial HYPERROLACTINEMIA
metastases are exceedingly rare ETIOLOGY:
» Almost all pituitary adenomas are monoclonal in origin » the most common pituitary hormone hypersecretion
» A subset (~35%) of GH-secreting pituitary tumors contains syndrome in both men and women.
sporadic mutations in Gsα (Arg 201 → Cys or His; Gln 227 → » PRL-secreting pituitary adenomas (prolactinomas) are the
Arg). most common cause of PRL levels >200 μg/L
o elevation of cyclic AMP, Pit-1 induction, and
activation of cyclic AMP response element binding
protein (CREB), thereby promoting somatotrope cell
proliferation and GH secretion.
» Characteristic loss of heterozygosity (LOH) in various
chromosomes has been documented in large or invasive
macroadenomas
» A growth factor promotion of pituitary tumor proliferation is
evident:
o Basic fibroblast growth factor (bFGF) is abundant in » Pregnancy and lactation are the important physiologic causes
the pituitary and stimulates pituitary cell of hyperprolactinemia.
mitogenesis, whereas epithelial growth factor (EGF) » Sleep-associated hyperprolactinemia reverts to normal within
receptor signaling induces both hormone synthesis an hour of awakening.
and cell proliferation. » Nipple stimulation and sexual orgasm also may increase PRL.
o Other factors: loss of negative-feedback inhibition » Chest wall stimulation or trauma invoke the reflex suckling arc
and estrogen-mediated or paracrine angiogenesis with resultant hyperprolactinemia
and activated oncogenes, including RAS and
pituitary tumor transforming gene (PTTG), or
inactivation of growth suppressor genes, including
MEG3.

PITUITARY ADENOMAS AND HYPERSECRETION SYNDROMES

GENETIC SYNDROMES ASSOCIATED WITH PITUITARY TUMORS:
z Multiple endocrine neoplasia (MEN) 1
o is an autosomal dominant syndrome characterized
primarily by a genetic predisposition to parathyroid,
pancreatic islet, and pituitary adenomas
o caused by inactivating germline mutations in MENIN
o about 50% affected patients develop prolactinomas;
acromegaly and Cushing’s syndrome are less commonly
encountered.
z Carney’s Syndrome
o characterized by spotty skin pigmentation, myxomas,
and endocrine tumors, including testicular, adrenal, and
pituitary adenomas.
o Acromegaly occurs in about 20% of these patients.
o A subset of patients has mutations in the R1α regulatory
subunit of protein kinase A (PRKAR1A).
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 GALACTORRHEA
» the inappropriate discharge of milk-containing fluid from the
breast, is considered abnormal if it persists longer than 6
months after childbirth or discontinuation of breast-feeding.
» Postpartum galactorrhea associated with amenorrhea is a self-
limiting disorder usually associated with moderately elevated
PRL levels.
» Chronic renal failure elevates PRL by decreasing peripheral » In both men and women, galactorrhea may vary in color and
clearance. consistency (transparent, milky, or bloody) and arise either
» Primary hypothyroidism is associated with mild unilaterally or bilaterally
hyperprolactinemia, probably because of compensatory TRH » Mammography or ultrasound is indicated for bloody
secretion. discharges which may be caused by breast cancer.
» Galactorrhea is commonly associated with hyperprolactinemia
caused by any of the conditions
» Acromegaly is associated with galactorrhea in about one-third
of patients.
» Treatment of galactorrhea usually involves managing the
underlying disorder (e.g., replacing T4 for hypothyroidism,
discontinuing a medication, treating prolactinoma).
GALACTORRHEA
LABORATORY INVESTIGATION:
ü Basal, fasting morning PRL levels (normally <20 μg/L) should
be measured to assess hypersecretion

TREATMENT HYPERPROLACTINEMIA
§ depends on the cause of elevated PRL levels
§ Regardless of the etiology, however, treatment should be aimed at:
o normalizing PRL levels to alleviate suppressive effects on
gonadal function
o halt galactorrhea
o preserve bone mineral density
§ Dopamine agonists are effective for most causes of
hyperprolactinemia
§ Hyperprolactinemia usually resolves after adequate thyroid
» Antipsychotics and antidepressants are a relatively common hormone replacement in hypothyroid patients or after renal
cause of mild hyperprolactinemia. transplantation in patients undergoing dialysis.
» Most patients receiving risperidone have elevated prolactin § Resection of hypothalamic or sellar mass lesions can reverse
levels, sometimes exceeding 200 μg/L. hyperprolactinemia caused by stalk compression and reduced
» Methyldopa inhibits dopamine synthesis, and verapamil blocks dopamine tone.
dopamine release, also leading to hyperprolactinemia. o with irreversible hypothalamic damage, no treatment
» Hormonal agents that induce PRL include estrogens and may be warranted
thyrotropin-releasing hormone (TRH).

HYPERROLACTINEMIA PROLACTINOMA
PRESENTATION AND DIAGNOSIS: ETIOLOGY AND PREVALENCE:
o Amenorrhea, galactorrhea, and infertility are the hallmarks of ü Microadenomas are classified as <1 cm in diameter and
hyperprolactinemia in women usually do not invade the parasellar region.
» If hyperprolactinemia develops before menarche à ü Macroadenomas are >1 cm in diameter and may be locally
primary amenorrhea results invasive and impinge on adjacent structures.
» commonly, hyperprolactinemia develops later in life and ü The female-to-male ratio for microprolactinomas is 20:1,
leads to oligomenorrhea and ultimately to amenorrhea whereas the sex ratio is near 1:1 for macroadenomas.
o If hyperprolactinemia is sustained, vertebral bone mineral ü Tumor size generally correlates directly with PRL
density can be reduced compared with age-matched controls, concentrations; values >250μg/L usually are associated with
particularly when it is associated with pronounced macroadenomas
hypoestrogenemia. ü Men tend to present with larger tumors than women, possibly
o Galactorrhea is present in up to 80% of hyperprolactinemic because the features of male hypogonadism are less readily
women. evident.
o In men with hyperprolactinemia, diminished libido, infertility,
PROLACTINOMA
and visual loss (from optic nerve compression) are the usual
presenting symptoms. PRESENTATION AND DIAGNOSIS:
o Gonadotropin suppression leads to: § Women:
» reduced testosterone o Amenorrhea
» impotence o Infertility
» oligospermia o Galactorrhea
o True galactorrhea is uncommon in men with § If the tumor extends outside the sella, visual field defects or other
hyperprolactinemia mass effects may be seen.
o Diagnosis of idiopathic hyperprolactinemia is made by § Men:
exclusion of known causes of hyperprolactinemia in the o Impotence
setting of a normal pituitary MRI. o loss of libido
o infertility
o signs of central nervous system (CNS) compression,
including headaches and visual defects.
§ A diagnosis of prolactinoma is likely with a PRL level >200 μg/L.
§ PRL levels <100 μg/L may be caused by microadenomas
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§ MRI should be performed in all patients with hyperprolactinemia TREATMENT SURGERY
§ Indications for surgical adenoma debulking include:
TREATMENT HYPERPROLACTINOMA o dopamine resistance or intolerance
ü For asymptomatic and fertility is not desired à No treatment may o the presence of an invasive macroadenoma with
be needed compromised vision that fails to improve after drug
ü For symptomatic microadenomas àtherapeutic goals include TREATMENT PREGNANCY
reduction of tumor size, restoration of menses and fertility, and § pituitary gland increases in size during pregnancy, reflecting
resolution of galactorrhea the stimulatory effects of estrogen and perhaps other growth
ü A normalized PRL level does not ensure reduced tumor size. factors on pituitary vascularity and lactotrope cell
ü For macroadenomas, formal visual field testing should be hyperplasia.
performed before initiating dopamine agonists. § Bromocriptine has been used for more than 30 years to
restore fertility in women with hyperprolactinemia, without
MEDICAL TREATMENT HYPERPROLACTINOMA evidence of teratogenic effects.
§ Oral dopamine agonists (cabergoline and bromocriptine) are the § When pregnancy is confirmed, bromocriptine should be
mainstay of therapy for patients with micro- or discontinued and PRL levels followed serially, especially if
macroprolactinomas. headaches or visual symptoms occur.
o Dopamine agonists suppress PRL secretion and synthesis § For women harboring macroadenomas, regular visual field
as well as lactotrope cell proliferation testing is recommended.
o Patients who have achieved normoprolactinemia and § Surgical decompression may be indicated if vision is
significant reduction of tumor mass, the dopamine threatened
agonist may be withdrawn after 2 years. § cabergoline is long-acting with a high D2- receptor affinity, it
z CABERGOLINE- long-acting dopamine agonist with high D2 is not recommended for use in women when fertility is desired.
receptor affinity.
o The drug effectively suppresses PRL for >14 days after a
single oral dose and induces prolactinoma shrinkage in
most patients
o Cabergoline (0.5–1.0 mg twice weekly) achieves:
§ normoprolactinemia and resumption of normal
gonadal function in ~80% of patients with
microadenomas;
§ galactorrhea improves or resolves in 90% of
patients.
§ normalizes PRL and shrinks ~70% of
macroprolactinomas
o mass effect symptoms, improve dramatically within days
after cabergoline initiation;
o improvement of sexual function requires several weeks of
treatment
o Cabergoline also may be effective in patients resistant to
bromocriptine.
o Adverse effects and drug intolerance are encountered ACROMEGALY
less commonly than with bromocriptine. ETIOLOGY:
z BROMOCRIPTINE- ergot alkaloid bromocriptine mesylate is a
ü GH hypersecretion is usually the result of a somatotrope adenoma
dopamine receptor agonist that suppresses prolactin secretion but may rarely be caused by extrapituitary lesions
o it is short-acting and is preferred when pregnancy is
desired
o Therapy is initiated by administering a low bromocriptine
dose (0.625–1.25 mg) at bedtime with a snack, followed
by gradually increasing the dose.
o Most patients are controlled with a daily dose of ≤7.5 mg
(2.5 mg tid).

MEDICAL TREATMENT SIDE EFFECTS

§ Side effects of dopamine agonists include;
o constipation
o nasal stuffiness
o dry mouth
o nightmares
o insomnia
o vertigo
⇒ decreasing the dose usually alleviates these problems.
o Nausea, vomiting, and postural hypotension with
faintness may occur in ~25% of patients after the
initial dose.
§ fewer side effects are reported with cabergoline
§ Intravaginal administration of bromocriptine is often ü mixed mammosomatotrope tumors and acidophilic stem-cell
efficacious in patients with intractable gastrointestinal side adenomas secrete both GH and PRL
effects. ü acidophilic stem-cell adenomas, features of hyperprolactinemia
§ Auditory hallucinations, delusions, and mood swings have (hypogonadism and galactorrhea) predominate over the less
been reported in up to 5% of patients àdue to the dopamine clinically evident signs of acromegaly
agonist properties or to the lysergic acid derivative of the ü excess GHRH production may cause acromegaly, presenting:
compounds o with classic features of acromegaly
§ Patients with Parkinson’s disease who receive at least 3 mg of o elevated GH levels
cabergoline à risk for development of cardiac valve o pituitary enlargement on MRI
regurgitation o pathologic characteristics of pituitary hyperplasia

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 ü The most common cause of GHRH-mediated acromegaly is a chest § Somatostatin analogues may be required while awaiting the full
or abdominal carcinoid tumor. benefits of radiotherapy.

ACROMEGALY SURGERY ACROMEGALY

§ Transsphenoidal surgical resection by an experienced surgeon is
PRESENTATION AND DIAGNOSIS:
the preferred primary treatment for both microadenomas
§ Protean manifestations of GH and IGF-I hypersecretion are indolent
(remission rate ~70%) and macroadenomas (<50% in remission).
and often are not clinically diagnosed for 10 years or more.
§ GH levels return to normal within an hour, and IGF-I levels are
o Acral bony overgrowth results in frontal bossing,
normalized within 3–4 days.
increased hand and foot size, mandibular enlargement
§ In ~10% of patients, acromegaly may recur several years after
with prognathism, and widened space between the lower
apparently successful surgery; hypopituitarism develops in up to
incisor teeth.
15% of patients after surgery.
o In children and adolescents, initiation of GH
hypersecretion before epiphyseal long bone closure is
associated with development of pituitary gigantism
o Soft tissue swelling results in increased heel pad
thickness, increased shoe or glove size, ring tightening,
characteristic coarse facial features, and a large fleshy
nose.
o Other commonly encountered clinical features include
hyperhidrosis, a deep and hollow-sounding voice, oily
skin, arthropathy, kyphosis, carpal tunnel syndrome,
proximal muscle weakness and fatigue, acanthosis
nigricans, and skin tags.
o Generalized visceromegaly occurs, including
cardiomegaly, macroglossia, and thyroid gland
enlargement.
§ The most significant clinical impact of GH excess occurs with
respect to the cardiovascular system
§ 60%- Upper airway obstruction with sleep apnea
§ 25%- Diabetes mellitus and most patients are intolerant of a
glucose load
§ Acromegaly is associated with an increased risk of colon polyps and
mortality from colonic malignancy; polyps are diagnosed in up to
one-third of patients.
ACROMEGALY SOMATOSTATIN ANALOGUES
§ Somatostatin analogues exert their therapeutic effects through
SSTR2 and SSTR5 receptors
§ Octreotide acetate
o is an eight-amino- acid synthetic somatostatin analogue
o relatively resistant to plasma degradation
o 2-h serum half-life; administered by subcutaneous
injection
§ octreotide and lanreotide- long-acting somatostatin; preferred
medical treatment for patients with acromegaly.
§ Most patients report symptomatic improvement, including
amelioration of headache, perspiration, obstructive apnea, and
cardiac failure.
z SIDE EFFECTS:
ACROMEGALY ü Somatostatin analogues are well tolerated in most patients.
LABORATORY INVESTIGATION: ü Adverse effects are short-lived and mostly relate to drug-
§ Age-matched serum IGF-I levels are elevated in acromegaly induced suppression of gastrointestinal motility and secretion.
o IGF-I level provides a useful laboratory screening ü Octreotide suppresses postprandial gallbladder contractility
measure when clinical features raise the possibility of and delays gallbladder emptying; up to 30% of patients
acromegaly. develop long-term echogenic sludge or asymptomatic
§ A single random GH level is not useful for the diagnosis or exclusion cholesterol gallstones.
of acromegaly and does not correlate with disease severity
§ The diagnosis of acromegaly is confirmed by demonstrating the ACROMEGALY GH- RECEPTOR ANTAGONIST
failure of GH suppression to <0.4 μg/L within 1–2 h of an oral § Pegvisomant antagonizes endogenous GH action by blocking
glucose load (75 g). peripheral GH binding to its receptor.
§ 20%- paradoxical GH rise after glucose § Consequently, serum IGF-I levels are suppressed, reducing the
§ 25%- elevated PRL deleterious effects of excess endogenous GH.
§ Thyroid function, gonadotropins, and sex steroids may be § Side effects include reversible liver enzyme elevation,
attenuated because of tumor mass effects. lipodystrophy, and injection site pain.

TREATMENT ACROMEGALY ACROMEGALY DOPAMINE AGONISTS

§ The goal of treatment is to control GH and IGF-I hypersecretion, § Bromocriptine and cabergoline may modestly suppress GH
ablate or arrest tumor growth, ameliorate comorbidities, restore secretion in some patients.
mortality rates to normal, and preserve pituitary function. § Very high doses of bromocriptine (≥20 mg/d) or cabergoline (0.5
§ Surgical resection of GH-secreting adenomas is the initial treatment mg/d) are usually required to achieve modest GH therapeutic
for most patients efficacy.
§ Somatostatin analogues are used as adjuvant treatment for
preoperative shrinkage of large invasive macroadenomas,
immediate relief of debilitating symptoms, and reduction of GH ACROMEGALY RADIATION
hypersecretion
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§ External radiation therapy or high-energy stereotactic techniques § Rapid development of features of hypercortisolism associated with
are used as adjuvant therapy for acromegaly. skin hyperpigmentation and severe myopathy suggests an ectopic
§ An advantage of radiation is that patient compliance with long-term tumor source of ACTH.
treatment is not required. o Hypertension, hypokalemic alkalosis, glucose
intolerance, and edema are also more pronounced in
SUMMARY TREATMENT FOR ACROMEGALY these patients.
Ö In summary, surgery is the preferred primary treatment for o Serum potassium levels <3.3 mmol/L are evident in ~70%
GHsecreting micr oadenomas of patients with ectopic ACTH secretion but are seen in
Ö The high frequency of GH hypersecretion after macroadenoma <10% of patients with pituitary-dependent Cushing’s
resection usually necessitates adjuvant or primary medical therapy syndrome.
for these larger tumors.
Ö Patients unable to receive or respond to unimodal medical CUSHING’S SYNDROME (ACTH- PRODUCING ADENOMA)
treatment may benefit from combined treatments, or can be
LABORAORY INVESTIGATION:
offered radiation.
§ The diagnosis of Cushing’s syndrome is based on laboratory
documentation of endogenous hypercortisolism.
CUSHING’S SYNDROME (ACTH- PRODUCING ADENOMA) § Measurement of 24-h urine free cortisol (UFC) is a precise and cost-
ETIOLOGY AND PREVALENCE: effective screening test.
§ Pituitary corticotrope adenomas account for 70% of patients with § Alternatively, the failure to suppress plasma cortisol after an
endogenous causes of Cushing’s syndrome. overnight 1-mg dexamethasone suppression test can be used to
§ Iatrogenic hypercortisolism is the most common cause of identify patients with hypercortisolism
cushingoid features o nadir levels of cortisol occur at night, elevated midnight
§ Other causes: serum or salivary samples of cortisol are suggestive of
o ectopic tumor ACTH production Cushing’s syndrome
o cortisol-producing adrenal adenomas o Basal plasma ACTH levels often distinguish patients with
o adrenal carcinoma ACTH-independent (adrenal or exogenous glucocorticoid)
o adrenal hyperplasia from those with ACTH-dependent (pituitary, ectopic
§ Cushing’s disease is 5–10 times more common in women than in ACTH) Cushing’s syndrome.
men. » Mean basal ACTH levels are about eightfold
§ These pituitary adenomas exhibit unrestrained ACTH secretion, higher in patients with ectopic ACTH
with resultant hypercortisolemia. secretion than in those with pituitary ACTH-
secreting adenomas.
CUSHING’S SYNDROME (ACTH- PRODUCING ADENOMA) § Dynamic testing based on differential sensitivity to glucocorticoid
feedback or ACTH stimulation in response to CRH or cortisol
PRESENTATION AND DIAGNOSIS:
reduction is used to distinguish ectopic from pituitary sources of
§ The diagnosis of Cushing’s syndrome presents two great
excess ACTH
challenges:
o circulating CRH levels are elevated, reflecting ectopic
1. to distinguish patients with pathologic cortisol excess from
tumor- derived secretion of CRH and often ACTH
those with physiologic or other disturbances of cortisol
§ Most ACTH-secreting pituitary tumors are <5 mm in diameter, and
production
about half are undetectable by sensitive MRI.
2. to determine the etiology of pathologic cortisol excess.

§ Hematopoietic features of hypercortisolism:

o Leukocytosis
o Lymphopenia
o Eosinopenia
§ Certain features make pathologic causes of hypercortisolism more
likely;
o central redistribution of fat
o thin skin with striae and bruising
o proximal muscle weakness
§ The primary cause of death is cardiovascular disease, but life-
threatening infections and risk of suicide are also increased.

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 CUSHING’S SYNDROME (ACTH- PRODUCING ADENOMA) NONFUNCTIONING AND GONADOTROPIN PRODUCING PIT. ADENOMAS
INFERIOR PETROSAL VENOUS SAMPLING: ETIOLOGY AND PREVALENCE:
§ detects small (<2 mm) § include those that secrete little or no pituitary hormones as well as
§ peak petrosal:peripheral ACTH ratios ≥3 confirm the presence of a tumors that produce too little hormone to result in recognizable
pituitary ACTH-secreting tumor clinical features.
§ the sensitivity of this test is >95% § They are the most common type of pituitary adenoma and are
§ procedure should not be performed in patients with hypertension, usually macroadenomas at the time of diagnosis because clinical
in patients with known cerebrovascular disease, or in the presence features are not apparent until tumor mass effects occur.
of a well-visualized pituitary adenoma on MRI. § most clinically nonfunctioning adenomas originate from
gonadotrope cells.
TREATMENT CUSHING’S SYNDROME § These tumors typically produce small amounts of intact
§ Selective transsphenoidal resection is the treatment of choice for gonadotropins (usually FSH) as well as uncombined α, LH β, and
Cushing’s disease FSH β subunits àelevated α and FSH β subunits
o remission rate for this procedure is ~80% for
microadenomas but <50% for macroadenomas. NONFUNCTIONING AND GONADOTROPIN PRODUCING PIT. ADENOMAS
o After successful tumor resection, most patients PRESENTATION AND DIAGNOSIS:
experience a postoperative period of symptomatic ACTH § often present with optic chiasm pressure and other symptoms of
deficiency that may last up to 12 months. local expansion
» requires low-dose cortisol replacement, as § Adenoma compression of the pituitary stalk or surrounding
patients experience both steroid withdrawal pituitary tissue à attenuated LH and features of hypogonadism.
symptoms and have a suppressed § PRL levels are usually slightly increased, also because of stalk
hypothalamic-pituitary-adrenal axis. compression.
§ Pasireotide (600 or 900 ug/day subcutaneously), a somatostatin § It is important to distinguish this circumstance from true
analog with high affinity for SST5 > SST2 receptors, has been prolactinomas, as nonfunctioning tumors do not shrink in response
approved for treating patients with ACTH-secreting pituitary to treatment with dopamine agonists.
tumors when surgery is not an option or has been unsuccessful.
§ Ketoconazole, an imidazole derivative antimycotic agent, inhibits NONFUNCTIONING AND GONADOTROPIN PRODUCING PIT. ADENOMAS
several P450 enzymes and effectively lowers cortisol in most
LABORATORY INVESTIGATION:
patients with Cushing’s disease when administered twice daily
§ laboratory testing in clinically nonfunctioning tumors is to classify
(600–1200 mg/d).
the type of the tumor, identify hormonal markers of tumor activity,
o Elevated hepatic transaminases, gynecomastia,
and detect possible hypopituitarism.
impotence, gastrointestinal upset, and edema are
§ 10- 15%- Free α subunit levels may be elevated
common side effects.
§ In men, gonadotropin-secreting tumors may be diagnosed because
§ Mifepristone (300–1200 mg/d), a glucocorticoid receptor
of slightly increased gonadotropins (FSH > LH) in the setting of a
antagonist, blocks peripheral cortisol action and is approved to
pituitary mass.
treat hyperglycemia in Cushing’s disease.
§ Testosterone levels are usually low despite the normal or increased
§ Metyrapone (2–4 g/d) inhibits 11β-hydroxylase activity and
LH level, perhaps reflecting reduced LH bioactivity or the loss of
normalizes plasma cortisol in up to 75% of patients.
normal LH pulsatility.
o Side effects include nausea and vomiting, rash, and
§ GnRH testing, however, is not helpful for making the diagnosis
exacerbation of acne or hirsutism.
§ If PRL levels are <100 μg/L in a patient harboring a pituitary mass,
§ Mitotane suppresses cortisol hypersecretion
a nonfunctioning adenoma causing pituitary stalk compression
§ Etomidate- for overt cases
should be considered.
§ The use of steroidogenic inhibitors has decreased the need for
bilateral adrenalectomy.
TREATMENT NONFUNCTIONING AND GONADOTROPIN
§ Adrenalectomy in the setting of residual corticotrope adenoma
PRODUCING PIT. ADENOMAS
tissue predisposes to the development of Nelson’s syndrome
§ Asymptomatic and with no threat to vision à regular MRI and
o a disorder characterized by rapid pituitary tumor
visual field testing without immediate intervention
enlargement and increased pigmentation secondary to
§ Macroadenomas àtranssphenoidal surgery is indicated to reduce
high ACTH 2273 levels.
tumor size and relieve mass effects
o Prophylactic radiation therapy may be indicated to
prevent the development of Nelson’s syndrome

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 TSH- SECRETING ADENOMAS
CLINICAL PRESENTATION:
§ TSH-producing macroadenomas are very rare but are often large
and locally invasive when they occur.
§ Patients usually present with:
o thyroid goiter and hyperthyroidismàreflecting
overproduction of TSH.
§ Diagnosis is based on demonstrating:
o elevated serum free T4 levels
o inappropriately normal or high TSH secretion
o MRI evidence of a pituitary adenoma.
o Elevated uncombined α subunits are seen in many
patients.
§ The presence of a pituitary mass and elevated β subunit levels are
suggestive of a TSH-secreting tumor.
§ Dysalbuminemic hyperthyroxinemia syndromes, caused by
mutations in serum thyroid hormone binding proteins, are also
characterized by elevated thyroid hormone levels, but with normal
rather than suppressed TSH levels.

TREATMENT TSG- SECRETING ADENOMAS

§ The initial therapeutic approach is to remove or debulk the tumor
mass surgically, usually using a transsphenoidal approach.
§ Thyroid ablation or antithyroid drugs (methimazole and
propylthiouracil) can be used to reduce thyroid hormone levels.
§ Somatostatin analogue treatment effectively:
o normalizes TSH and α subunit hypersecretion
o shrinks the tumor mass in 50% of patients
o improves visual fields in 75% of patients;
o euthyroidism is restored in most patients.

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