Transcript Pituitary Disorders - Endocrinology

Anterior Pituitary Masses
and Hyperprolactinemia
Thomas Repas DO FACP CDE
UW Hospital and Clinics Department of Medicine
Section of Endocrinology, Diabetes & Metabolism
H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792
Thursday October 13, 2005
Objectives
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Causes of Pituitary Masses
Evaluation of a Pituitary Incidentaloma
Management of Pituitary Neoplasia
Abnormal Anterior Pituitary Function Associated
with Pituitary Masses
• Hyperprolactinemia and Prolactinomas
• Causes
• Management
I will not discuss in detail…
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Management of Cushing’s Disease
Management of Acromegaly
Management of Hypopituitarism
Evaluation and Management of Posterior Pituitary
Disorders and Diabetes Insipidus
Normal Pituitary Anatomy
Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987
Normal Pituitary Anatomy
Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987
Development of Human Anterior
Pituitary
Cohen and Radovick, Endocrine Reviews 23: 431-442, 2002
Anterior Pituitary Function
Hormone
Stimulators
Corticotroph
Gonadotroph
Thyrotroph
Lactotroph
Somatotroph
POMC, ACTH
FSH, LH
TSH
Prolactin
GH
TRH
Estrogen,
TRH
GHRH, GHS
T3, T4,
Dopamine,
Somatostati
n, GH
Dopamine
Somatostatin,
IGF-1,
Activins
Thyroid
Breast and
other
tissues
Liver, bone and
other
tissues
CRH, AVP, gp130
cytokines
Inhibitors
Glucocorticoids
Target
Gland
Adrenals
Trophic
Effects
Steroid
production
GnRH,
Estrogen
Sex steroids,
inhibin
Ovary, Testes
Sex Steroid,
Follicular
growth,
Germ Cell
maturation
T4 synthesis
and
secretion
Adapted from: William’s Textbook of Endocrinology, 10th ed., Figure 8-4, pg 180.
Milk
Productio
n
IGF-1
production,
Growth
induction,
Insulin
antagonis
m
Etiology of Pituitary
Masses
Etiology of Pituitary-Hypothalamic
Lesions
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Non-Functioning Pituitary Adenomas
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Endocrine active pituitary adenomas
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Prolactinoma
Somatotropinoma
Corticotropinoma
Thyrotropinoma
Other mixed endocrine active adenomas
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Malignant pituitary tumors: Functional and non-functional pituitary carcinoma
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Metastases in the pituitary (breast, lung, stomach, kidney)
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Pituitary cysts: Rathke's cleft cyst, Mucocoeles, Others
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Empty sella syndrome
Etiology of Pituitary-Hypothalamic
Lesions (continued)
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Developmental abnormalities: Craniopharyngioma (occasionally intrasellar location),
Germinoma, Others
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Primary Tumors of the central nervous system: Perisellar meningioma, Optic
glioma, Others
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Vascular tumors: Hemangioblastoma, Others
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Malignant systemic diseases: Hodgkin's disease, Non-Hodgkin lymphoma, Leukemic
infiltration, Histiocystosis X, Eosinophilic granuloma, Giant cell granuloma (tumor)
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Granulomatous diseases: Neurosarcoidosis, Wegner's granulomatosis, Tuberculosis,
Syphilis
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Vascular aneurysms (intrasellar location)
Pituitary Adenoma
Sellar Masses
Pituitary Adenoma
Snyder, P. UpToDate
Craniopharyngioma
Sellar Masses
Pituitary Adenoma
Snyder, P. UpToDate
Lymphocytic Hypophysitis
Infiltrative Disorders: Sarcoidosis
From EndoText: http://www.endotext.com/neuroendo/neuroendo4/neuroendoframe4.htm
Evaluation of a Pituitary
Incidentaloma
Evaluation of an Incidental
Pituitary Mass
• Radiologic Evaluation
• Clinical Evaluation
• Hormonal Evaluation
Radiologic Evaluation: MRI
• Preferred imaging study for the pituitary
• Better visualization of soft tissues and vascular
structures than CT
• No exposure to ionizing radiation
• Images are generated based upon the magnetic
properties of the hydrogen atoms
• T1-weighted images produce high–signal intensity
images of fat. Structures such as fatty marrow and
orbital fat show up as bright images.
• T2-weighted images produce high-intensity signals of
structures with high water content, such as
cerebrospinal fluid and cystic lesions
Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm
Radiologic Evaluation: CT
• Better at visualizing bony structures and calcifications
within soft tissues
• Better at determining diagnosis of tumors with calcification,
such as germinomas, craniopharyngiomas, and
meningiomas
• May be useful when MRI is contraindicated, such as in
patients with pacemakers or metallic implants in the brain
or eyes
• Disadvantages include:
– less optimal soft tissue imaging compared to MRI
– use of intravenous contrast media
– exposure to radiation
Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm
Craniopharyngioma on CT
Kruskal, J. UpToDate
Clinical Evaluation
• All patients with macroadenomas
should have formal visual field testing
• In addition to radiographic and
hormonal evaluation, patients should be
asked and examined for any clinical
signs suspicious for pituitary
hyperfunction or hypofunction
Hormonal Evaluation
• May include of both basal hormone
measurement and dynamic stimulation
testing.
• All pituitary masses should have screening
basal hormone measurements, including:
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Prolactin
TSH, FT4
ACTH, AM cortisol, midnight salivary cortisol
LH, FSH, estradiol or testosterone
Insulin-like growth factor-1 (IGF-1)
Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm
Hormonal Evaluation
(continued)
Dynamic stimulation/suppression testing may be
useful in select cases to further evaluate pituitary
reserve and/or for pituitary hyperfunction
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Dexamethasone suppression testing
Oral glucose GH suppression test
GHRH, L-dopa, arginine
CRH stimulation
Metyrapone
TRH stimulation
GnRH stimulation
Insulin-induced hypoglycemia
Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm
Management of
Pituitary Tumors
Management of Pituitary
Neoplasia
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Observation
Pharmacotherapy
Surgery
Radiation Therapy
Pituitary Incidentaloma
< 10 mm
> 10 mm
Evaluate for:
Evaluate for
Hormonal
Hypersecretion
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Hormonal Hypersecretion
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Hormonal Hyposecretion
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Normal
Hormonal or Visual
Abnormalities
Observe
Treatment
Visual Changes/defects
No Abnormalities
Observe
Observation and Follow-up
• If less than 20 mm and no neurologic or hormonal
abnormalities:
– Monitor for adenoma size, visual changes, and
hormonal hypersecretion in 6 and 12 months, then
annually for a few years
• Lesions less than 10 mm and proven to have no
hormonal hypersecretion:
– Lesions 2 to 4 mm: no further testing required
– Lesions 5 to 9 mm: MRI can be done once or twice
over the subsequent two years; if the lesion is stable in
this period, the frequency can be decreased
Peter J Snyder MD, “Pituitary incidentaloma” UpToDate November 25, 2003
Pharmacotherapy
• Most useful in prolactinomas, alone or
with other intervention.
• May be used in certain other functioning
tumors as adjunctive therapy along with
surgical and/or radiotherapy
Pharmacotherapy
Which pharmacologic option to choose depends on
type of tumor:
• Dopamine agonists: bromocriptine, cabergoline- most
useful for prolactinomas, less useful for GH secreting
adenomas
• Somatostatin analog (Octreotide, Octreotide
LAR)- most useful for acromegaly
• Pegvisomant (GH receptor blocker)- useful in
acromegaly refractory to somatostatin analogues
• Other: ketoconazole, metyrapone, mitotane- for
Cushings disease- use limited by side effects, expense
and lack of efficacy
Pituitary Surgery
• Transsphenoidal approach:
used for 95% of pituitary
tumors
• Endonasal submucosal
transseptal approach
• Septal Pushover/Direct
Sphenoidotomy
• Endoscopic approach
Indications for Surgery
• Surgery is the first-line treatment of
symptomatic pituitary adenomas.
• Useful when medical or radiotherapy fails
• Surgery provides prompt relief from excess
hormone secretion and mass effect.
• Indicated in pituitary apoplexy with
compressive symptoms
Outcome of Transsphenoidal
Surgery
Tumor
Remission (%)
Recurrence at 10
years (%)
Non-functioning
adenoma
Not applicable*
16
GH adenoma
Microadenoma
88
1.3
Macroadenoma
PRL adenoma
Microadenoma
Macroadenoma
ACTH adenoma
Microadenoma
Macroadenoma
65
87
13
56
91
65
*Visual improvement occurs in 87% of those with preoperative visual loss.
John A. Jane, Jr., MD Edward R. Laws, Jr., MD, SURGICAL MANAGEMENT OF PITUITARY ADENOMAS
Chapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm
12 (Adults), 42
(Pediatric)
Complications of
Transsphenoidal Surgery
Outcome Measure
Mortality
Incidence (%)
<0.5
Major complication (CSF leak,
1.5
Minor complication (sinus
6.5
meningitis, ischemic stroke,
intracranial hemorrhage,
vascular injury, visual loss)
disease, septal perforations,
epistaxis, wound infections and
hematomas)
John A. Jane, Jr., MD Edward R. Laws, Jr., MD, SURGICAL MANAGEMENT OF PITUITARY ADENOMAS
Chapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm
Radiation Therapy
• Reserved for patients with larger tumors
and/or persistent hormonal
hyperfunction despite surgical
intervention
– Conventional radiotherapy
– Gamma knife radiosurgery
Conventional Radiotherapy
• Response is slow, may take 5 to 10 years for
full effect
• Successful in up to 80% of acromegalics and
55-60% of Cushing’s disease
• High rate of hypopituitarism: up to 60%
• Other complications: optic nerve damage,
seizures, radionecrosis of brain tissue
Basic and Clinical Endocrinology, 6th ed. Chapter 5 Hypothalamus and Pituitary, 100-162.
Gamma Knife Radiosurgery
• Stereotactic CT guided cobalt 60 gamma
radiation to narrowly focused area
• Long term data not yet available but suggest
up to a 70% response rate for acromegaly
and up to 70% for Cushing’s in some centers
• Complication rate likely lower, but still high
rate of hypopituitarism (~55%)
Basic and Clinical Endocrinology, 6th ed. Chapter 5 Hypothalamus and Pituitary, 100-162.
Abnormal Pituitary Function
Associated with Pituitary
Tumors
Disorders of Pituitary Function
• Hypopituitarism
– Central hypoadrenalism, hypogonadism,
hypothyroidism or GH deficiency
– Panhypopituitarism
• Hypersecretion of Pituitary Hormones
– Hyperprolactinemia
– Acromegaly
– Cushing’s Disease
Acromegaly
http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm
Wright, V. UpToDate
Clinical Findings of Acromegaly
Symptoms and signs at
presentation
Overall prevalence (%)
Facial change, acral enlargement, and soft-tissue
swelling
100
Excessive sweating
83
Acroparesthesiae/ carpal tunnel syndrome
68
Tiredness and lethargy
53
Headaches
53
Oligo- or amenorrhea, infertility
55*
Erectile dysfunction and/or decreased libido
42#
Arthropathy
37
Impaired glucose tolerance/ diabetes
37
Goiter
35
Ear, nose throat and dental problems
32
Congestive cardiac failure/ arrythmia
25
Hypertension
23
Visual field defects
17
* percentage of female patients
# percentage of male patients
http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm
Complications of Acromegaly
Cardiovascular
• Ischemic heart disease
• Cardiomyopathy
• Congestive heart failure
• Arrhythmias
• Hypertension
Respiratory
• Kyphosis
• Obstructive sleep apnea
Metabolic
• Diabetes mellitus/IGT
• Hyperlipidemia
http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm
Neurologic
•Carpal Tunnel syndrome
•Stroke
Neoplastic
•Colorectal
•(Breast and prostate - uncertain)
Musculoskeletal
•Degenerative arthropathy
•Calcific discopathy, pyrophosphate
arthropathy
Acromegaly: Causes of Death
• Cardiovascular- 38 to 62 percent
• Respiratory- 0 to 25 percent
• Malignancy- 9 to 25 percent
Diagnosis of Acromegaly
• Random GH – not useful
• Insulin like growth factor 1 (IGF-1) –
best for screening
• Oral glucose GH suppression testing –
gold standard to confirm diagnosis
Cushing’s Disease
William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996
Cushing’s Syndrome vs. Cushing’s
Disease
• Cushing’s syndrome is a syndrome
due to excess cortisol from pituitary,
adrenal or other sources (exogenous
glucocorticoids, ectopic ACTH, etc.)
• Cushing’s disease is hypercortisolism
due to excess pituitary secretion of
ACTH (about 70% of cases of
endogenous Cushing’s syndrome)
Cushing’s Syndrome
• Moon facies
• Facial plethora
• Supraclavicular
fat pads
• Buffalo hump
• Truncal obesity
• Weight gain
• Purple striae
•Proximal muscle
weakness
•Easy bruising
•Hirsutism
•Hypertension
•Osteopenia
•Diabetes mellitus/IGT
• Impaired immune
function/poor wound
healing
Central Obesity in Cushing’s
Disease
William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996
Progressive Obesity of Cushing’s
Disease
Age 6
Age 7
Age 8
Age 9
William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996
Age 11
Buffalo Hump in Cushing’s
Disease
Orth, D. UpToDate
Striae in Cushing’s Disease
Orth, D. UpToDate
Proximal Muscle Wasting in
Cushing’s Syndrome
William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996
Diagnosis of Cushing’s Syndrome
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ACTH, AM cortisol
24 hour urine cortisol
Dexamethasone suppression testing
Midnight salivary cortisol
Dexamethasone Suppression Test
http://www.endotext.com/neuroendo/neuroendo7/neuroendoframe7.htm
Circadian Studies of Serum Cortisol
Levels
http://www.endotext.com/neuroendo/neuroendo7/neuroendoframe7.htm
Hyperprolactinemia
and Prolactinomas
Prolactin
• Human prolactin is a 198 amino acid
polypeptide
• Primary function is to enhance breast
development during pregnancy and to induce
lactation
• Prolactin also binds to specific receptors in
the gonads, lymphoid cells, and liver
• Secretion is pulsatile; it increases with sleep,
stress, pregnancy, and chest wall stimulation
or trauma
Prolactin
• Secretion of prolactin is under tonic
inhibitory control by dopamine, which acts
via D2-type receptors located on lactotrophs
• Prolactin production can be stimulated by
the hypothalamic peptides, thyrotropinreleasing hormone (TRH) and vasoactive
intestinal peptide (VIP)
Clinical Features of
Hyperprolactinemia/Prolactinoma
• Women may present with oligomenorrhea,
amenorrhea, galactorrhea or infertility
• Men often have less symptoms than women
(sexual dysfunction, visual problems, or
headache) and are diagnosed later
• In both sexes, tumor mass effects may cause
visual-field defects or headache
Causes of Hyperprolactinemia
• Hypothalamic Dopamine Deficiency
– Diseases of the hypothalamus( including tumors, arterio-venous
malformations, and inflammatory processes
– Drugs (e.g. alpha-methyldopa and reserpine)
• Defective Transport Mechanisms
– Section of the pituitary stalk
– Pituitary or stalk tumors
Causes of Hyperprolactinemia
(continued)
• Lactotroph Insensitivity to Dopamine
– Dopamine-receptor-blocking agents: phenothiazines (e.g.
chlorpromazine), butyrophenones (haloperidol), and
benzamides (metoclopramide, sulpiride, and domperidone)
• Stimulation of Lactotrophs
– Hypothyroidism- increased TRH production (acts as a PRF)
– Estrogens: stimulate lactotrophs
– Injury to the chest wall: abnormal stimulation of the reflex
associated with the rise in prolactin that is seen normally in
lactating women during suckling
REMEMBER: Not all
hyperprolactinemia is due to
a prolactinoma
Am J Obstet Gynecol 1972; 113:14; N Engl J Med 1977; 296:589; Clin Ther 200; 22:1085; Clin Endocrinol 1976; 5:273;
J Clin Endocrinol Metab 1976; 42:1148; J Clin Endocrinoll Metab 42: 181; J Clin Endocrinol Metab 1982; 54:869; Br Med J 1976; 1:1186;
JAMA 1976; 235:2316; Am J Cardiol 1983; 51:1466; J Clin Endocrinol Metab 1985; 60:144.
Work up of Patient with
Hyperprolactinemia
• In females, pregnancy must always be ruled out
• Get a TSH- hypothyroidism is another common cause of
elevated prolactin:
• Obtain detailed drug history- rule out medication effects
• Rule out other common causes including:
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Nonfasting sample
Nipple stimulation or sex
Excessive exercise
History of chest wall surgery or trauma
Renal failure
Cirrhosis
• If no cause determined or tumor suspected, consider MRI,
especially if high prolactin levels (> 100 ng/mL)
http://www.emedicine.com/Med/topic1915.htm
Prolactinomas
• Most common of functional pituitary adenomas
• 25-30% of all pituitary adenomas
• Some growth hormone (GH)–producing tumors
also co-secrete PRL
• Of women with prolactinomas- 90% present with
microprolactinomas
• Of men with prolactinomas- up to 60% present
with macroprolactinomas
http://www.emedicine.com/Med/topic1915.htm
Treatment
• Pharmacotherapy
• Surgical resection
• Radiotherapy
Pharmacotherapy of Prolactinomas
• Dopamine agonists are treatment of
choice for most prolactinomas
• Choices include Bromocriptine,
Pergolide and Cabergoline
• Side effects include: postural
hypotension, dizziness, nasal stuffiness,
GI side effects.
Dopamine Agonist Therapy
Webster, J et al. N Engl J Med 1994; 331:904.
Long-term Effects of Bromocriptine
Therapy
J Clin Endocrinol Metab 50:1026 1033
Success Rate of Bromocriptine in
Amenorrhea
• After 1 month of treatment,
one woman in four will
return to normal menstrual
cycling;
• In 2 months, this number
will increase to six out of 10
• After 10 months, eight out of
10 women will be
menstruating normally
• Of the remaining 20%, most
are hypogonadal due to
pituitary surgery or
irradiation
http://www.endotext.com/neuroendo/neuroendo6/neuroendoframe6.htm
Decrease in Size of Prolactinoma
after Bromocriptine
Abrahamson, M. UpToDate
Dopamine Agonists
• Bromocriptine- start low dose at 1.25- 2.5 mg day
at night before increasing to 2.5 – 10 mg per day
in divided doses. Take with food to reduce side
effects.
• Cabergoline- more effective and with less side
effects than Bromocriptine but also more
expensive- given once or twice a week with a
starting dose of 0.25 mg 2 x week
Titrate these based on prolactin levels and
tolerability
Conclusion
• Pituitary microadenomas are common, not all are of
clinical concern
• ALL pituitary tumors require evaluation of hormonal
status
• Follow up and monitoring will depend on size and other
features of tumor
• Dopamine agonists are the treatment of choice for most
prolactinomas
• Surgical intervention is initial TOC for large tumors and
other hyperfunctional tumors (GH, ACTH secreting)
• Not every patient with hyperprolactinemia has a
prolactinoma!!!