Clinical features of CS
Box 18.2 Clinical features of Cushing’s syndrome Features that best distinguish Cushing’s syndrome • Facial appearance: moon facie and plethoric complexion • Spontaneous ecchymoses
• Violaceous striae: >1 cm on abdomen, thighs and axillae • Proximal muscle weakness
• In children, weight gain with decreased growth velocity
• Early bone fractures, especially atraumatic rib or vertebral fractures Clinical features less specifi c for Cushing’s syndrome
• Fatigue • Hypertension
• Impaired glucose tolerance, diabetes mellitus • Osteopenia, osteoporosis
• Susceptibility to infections
• Mood disturbance — depression, irritability, insomnia, psychosis • Menstrual disturbance
• Low libido and impotence
• Weight gain — truncal obesity, buffalo hump, supraclavicular fat pads • Acne
• Hirsutism
• Polycystic ovarian syndrome
Box 18.1 Causes of endogenous Cushing’s syndrome ACTH-dependent
• Pituitary adenoma (Cushing’s disease): 70–80%
• Ectopic ACTH syndrome: 10%
• Ectopic CRH secretion: <1%
ACTH-independent • Adrenal adenoma: 10–20%
• Adrenal carcinoma: <5%
• Nodular (macro or micro) hyperplasia: 1%
• Carney’s complex • McCune–Albright syndrome
• Aberrant adrenal receptor expression (e.g., GIP, LH, 5-HT4)
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CHAPTER 18
Cushing’s disease
118Investigations
Step 1. Conduct screening tests
Consider screening patients who have multiple and progressive
‘high-discriminatory’ features consistent with Cushing’s syndrome, particu-larly with an early onset (Box 18.2). In addition, patients with an adrenal adenoma >1 cm should be screened.
2 Note: All screening tests can give false-positive results with pseudo-Cushing’s disease.
Outpatient screening tests (Fig. 18.1).
24-hour urinary free cortisol (UFC) • At least two measurements
• Upper limit of normal for costisol is assay dependent (e.g., antibody-based
> chromatography-based).
2 Caveats: 1) Some medications can interfere with the cortisol assays (e.g., fenofi brate, carbamazepine and digoxin can give false-positive results on HPLC-based assays), and 2) reduced glomerular fi ltration rates (GFR)
<60 mL/min may lead to false-negative results.
Overnight dexamethasone suppression test (DST)
• Administration of 1 mg dexamethasone (DEX) at 11–12 P.M., followed by a serum cortisol measurement the following morning (between 7 and 9 A.M.). A longer, low-dose dexamethasone suppression test (2 mg/day for 48 hours) is a comparable screening test.
• Normal: Serum cortisol < 1.8 mcg/dL (with a sensitive cortisol assay) 2 Caveats : The following interfering conditions should be excluded:
d dexamethasone absorption, hepatic enzyme inducers (e.g., phenytoin, carbamazepine, and rifampin), and i (cortisol-binding globulin (CBG) (from oral contraceptive pills, which should be discontinued 6 weeks before testing or pregnancy). A morning dexamethasone level can be drawn to exclude rapid metabolism in specifi c cases.
Midnight salivary cortisol • At least two measurements
2 Caveats: Patients must have a normal sleep–wake cycle.
Step 2. Establish the cause ACTH
A basal A.M. ACTH level should be measured to distinguish between ACTH-dependent vs. ACTH-independent Cushing’s syndrome.
• ACTH >10 pmol/mL indicate an ACTH-dependent etiology • ACTH levels are generally higher in ectopic patients, although 1/3
are within the normal range.
• ACTH values <10 pmol/mL indicate an ACTH-independent tumor.
• Equivocal ACTH values require additional testing.
18-Draznin-Chap18.indd 118 3/31/2011 9:37:47 PM
INVESTIGATIONS 119
Step 3. Localize the tumor Pituitary imaging
80% of corticotrope adenomas are microadenomas, but MRI localizes these tumors in only 7 50% of cases (with 1.5 Tesla MRI technology).
2 Because 7 10% of the normal population has a microadenoma (mostly
<5 mm), patients with very small tumors or undetectable adenomas on Diagnose
CS
Determine CS Etiology
Locate
& Treat
Exclude med effect Adequate collection?
Repeat Screening
ACTH Central/Peripheral Basal Gradient >2
+CRH >3
Suggest ACTH
-independent
Suggest ACTH
-dependent
Indeterminant
Low High-Normal/↑
Reassess periodically (e.g., q 6 months) if clinically indicated
Indeterminant (discordant)
Positive (Concordant)
Exclude Pseudo-Cushing’s
A.M. Plasma ACTH Level
Indeterminant
MRI 8 mg DST Consider
CRH Stim.
Adrenal Imaging
Adrenal Tumor Resection
Pituitary/TSS Evaluate/Tx
for Ectopic CS + –
+Suppression +MRI (>5mm)
–Suppression –MRI IPSS
Consider DEX-CRH Testing Negative (Concordant) + Signs and Symptoms
of Cushing’s Screening Tests
UFC 1 mg DST MN Salivary Cortisol
Fig 18.1 Algorithm for diagnosis of Cushing’s syndrome. Adapted and Reprinted with permission from Liu H, Crapo L (2005). Update on the diagnosis of Cushing syndrome. The Endocrinologist 15(3):165–179.
18-Draznin-Chap18.indd 119 3/31/2011 9:37:47 PM
CHAPTER 18
Cushing’s disease
120MRI should undergo an inferior petrosal sinus sampling (IPSS) for defi ni-tive diagnosis of Cushing’s disease.
Inferior petrosal sinus sampling (Fig 18.2)
2 IPSS is the single best test to distinguish Cushing’s disease from ectopic CS, with a sensitivity and specifi city of >95%. Comparatively, the 8 mg DST and CRH stimulation tests are inferior diagnostic tests.
• Bilateral IPSS involves the measurement of ACTH centrally and peripherally, in the basal state and following stimulation with CRH (100 mcg IV). A basal central-to-peripheral ACTH ratio of >2:1 (or >3:1 stimulated, 5-15 minutes after CRH injection) is diagnostic of CD.
• Ideally, IPSS should be performed only in experienced centers.
Abdominal CT
This is indicated for a suspected adrenal source.
t f e L t
h g i
R Pituitary
Adenoma
Catheter
Inferior petrosal sinus High jugular vein Low jugular vein
Left inferior petrosal sinus Right inferior petrosal sinus Simultaneous peripheral vein
Plasma ACTH (ng/L) After IV CRH 100 mg 0 min
14 16 17
477 23 19
280 28 25
123 54 32 5 min 10 min 15 min
Fig. 18.2 Inferior petrosal sinus sampling (IPSS). Simultaneous bilateral inferior petrosal sinus and peripheral vein sampling for ACTH. The ratio of >3 between the left central and peripheral vein confi rms a diagnosis of Cushing’s disease.
Right Basal Gradient 71
ACTH stimulated (+CRH) gradient = 1.7 Left Basal Gradient 71
ACTH stimulated (+CRH) gradient = 3.8
Reprinted with permission from Besser M, Thorner GM (1994). Clinical Endocrinology , 2nd ed. New York: Elsevier.
18-Draznin-Chap18.indd 120 3/31/2011 9:37:47 PM
INVESTIGATIONS 121
Abdominal and chest CT/MRI
These are indicated for suspected ectopic ACTH tumors and identify 7 75%
of tumors. Detection may be augmented by the complimentary use of func-tional studies, such as an octreotide scan or a positron emission tomography (PET) scan.
Additional tests
• Serum potassium: Hypokalemia is found in >95% of patients with ectopic, ACTH tumors but only 10% of patients with CD. Confounding issues for hypokalemia, such as diuretic use must be excluded.
• High-dose dexamethasone suppression test ( b see Pituitary function testing, p. 92).
• Corticotropin-releasing hormone test ( b see Pituitary function testing, p. 92).
• Assess other pituitary hormones : Hypercortisolism suppresses the thyroidal, gonadal and GH axes.
• Assess and treat hypercortisolemia-associated co-morbidities: impaired glucose tolerance, diabetes, hypertension, dyslipidemia and low bone mineral density
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CHAPTER 18
Cushing’s disease
122Treatment
Transsphenoidal surgery (TSS) b Also see Transsphenoidal surgery (p. 140).
This is the fi rst-line therapy in most Cushing’s disease cases. Selective hypophysectomy is curative in up to 80–90% of microadenomas, and 750%
of macroadenomas.
A post-operative cortisol level of <2 mcg/dL is reassuring for short-term remission, although long-short-term studies indicate a recurrence rate for Cushing’s disease of approximately 15-20% at 5 years.
Medical therapies (see Table 18.1 )
To date, there are no effective tumor-directed therapies for Cushing’s disease. Most of the adrenal-directed therapies are ineffective at normaliz-ing hypercortisolemia and have poor side-effect profi les. As such, medical therapies are generally used as a temporizing measure (e.g., preoperatively or during the latency period after radiation therapy).
Pituitary radiotherapy (see p. 147)
Radiation therapy is usually third-line treatment following incomplete sur-gical resection and inadequate medical therapies.
Control of hypersecretion is frequently delayed (e.g., fractionated radia-tion therapy controls hypercortisolemia in 750–60% of patients within 3–5 years).
Adrenalectomy
In ACTH-dependent Cushing’s, bilateral adrenalectomy is the treatment of last resort, but may be indicated for patients with severe persistent hypercortisolism and/or an unlocalizable ectopic ACTH tumor.
Nelson’s syndrome is caused by an enlargement of a pituitary adenoma (often aggressively), and may occur in up to 30% of Cushing’s disease patients who have undergone a bilateral adrenalectomy. These tumors are associated with a marked increase in ACTH levels, hyperpigmentation and mass effects. Monitoring should be performed annually with a basal ACTH measurement and pituitary MRI (as indicated for signs and symptoms of mass effects or a markedly elevated ACTH level). Transsphenoidal surgery and radiation therapy are the main treatment options.
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TREATMENT 123
Table 18.1 Drug treatments for Cushing’s syndrome
Drug Dose Action Side effects
Metyrapone 1–4 g/day (usually given in 4 divided doses)
11B-hydroxylase inhibitor
Nausea, i androgenic and mineralcorticoid precursors lead to hirsutism and hypertension Neutropenia.
Ketoconazole 200–400 mg tid fi rst line in children.
Avoid if taking H2 antagonists as acid is required to metabolize active compound
Direct inhibitor of P450 enzymes at several different sites
Abnormalities of liver function (usually reversible).
Gynecomastia
Mitotane (o-p- DDD)
4–12 g/day (begin at 0.5–1 g/day and gradually increase dose)
Inhibits steroido-genesis at the side-chain cleavage, 11- and 18-hydroxylase and 3B-hydroxy-steroid dehydrogenase.
Adrenolytic
Nausea & vomit-ing, Cerebellar disturbance, Somnolence, Hyper-cholesterolemia.
May increase clearance of steroids. May be teratogenic. Avoid if fertility desired.
RU486 (mifopristone)
400–1000 mg/
day
Glucocorticoid Antagonists
Amenorrhea Hypokalemia (antagonizes progesterone and androgen receptors)
Etomidate
0.03 mg/kg IV, followed by infusion of 0.1 mg/kg/h
Inhibits side-chain cleavage and 11B-hydroxylase
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CHAPTER 18
Cushing’s disease
124Follow-up
• After a successful transsphenoidal tumor resection, periodic assessment of basal and stimulated cortisol levels are indicated to monitor for recovery from central adrenal insuffi ciency (which is typically prolonged [>1 year]).
• Monitor periodically for disease recurrence, particularly in patients at high risk for CD recurrence (i.e., non-suppressed post-op cortisol levels, rapid glucocorticoid taper, macroadenomas and/or failed intraoperative adenoma detection).
• ACTH-secreting macroadenoma are generally not cured with TSS and require subsequent radiation therapy ± medical therapies. In addition,
“silent” ACTH adenomas are among the most aggressive tumors with 730% recurrence rates.
Further reading
Biller BK, Grossman AB, Stewart PM, Melmed S, et al. (2008). Treatment of adrenocorticotropin-dependent Cushing’s syndome: a concensus statement J Clin Endocrinol Metab 93:2454–2462.
Ilias I, Torpy DJ, Pacak K, Mullen N, et al. (2005). Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institute of Health. J Clin Endocrinol Metab 91(2):371–377.
Nieman LK (2002). Medical therapy of Cushing’s disease. Pituitary 5:77–82.
Nieman LK, Biller BM, Findling JW, Newell-Price J, et al. (2008). The diagnosis of Cushing’s syn-drome. An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540.
Patil CG, Prevedello DM, Shivanand P, Vance ML et al. (2008). Late recurrences of Cushing’s disease after initial successful transphenoidal surgery. 93:358–362.
18-Draznin-Chap18.indd 124 3/31/2011 9:37:47 PM
CLINICAL FEATURES 125
Gonadotropinomas
Epidemiology
Gonadotropinomas are the most common non-functioning pituitary tumors and account for 740–50% of all pituitary macroadenomas. They are most commonly diagnosed in middle-aged men.
Pathology
• Gonadotropinomas synthesize but generally do not effi ciently secrete intact glycoprotein hormones (FSH, LH) or their free (A or B) subunits.
• Null cell tumors are defi ned by the absence of immunoreactive hormone expression and likely represent poorly differentiated gonadotrope cells.
Clinical features
Mass effects • Headache
• Visual fi eld defects (uni- or bitemporal quadrantanopia or hemianopia) • Ophthalmoplegia (III, IV and VI cranial nerve palsies)
• Vision loss (optic nerve atrophy) • Cerebrospinal fl uid rhinorrhea (rarely)
• Hypopituitarism. At diagnosis, > 50% of patients are growth hormone and/or gonadotrope defi cient. Adrenal and thyroid insuffi ciencies are less common (<30%).
Hormone effects
Rarely, gonadotropinomas can present with hormone hypersecretory syn-dromes, such as ovarian hyperstimulation syndrome, testicular enlarge-ment or precocious puberty.
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CHAPTER 19
Gonadotropinomas
126Investigations
• Pituitary imaging: Usually presents as a macroadenoma on MRI/CT • Visual fi elds assessment: Vision fi eld defects are observed in 760–70% of
patients.
• PRL: Mild hyperprolactinemia is common due to stalk compression.
0 Pituitary function: Gonadotropinomas rarely present with elevated serum FSH, LH, and/or A-subunit levels, but may be confused with pri-mary gonadal failure and or the postmenopausal state. Headaches, visual fi eld disturbances and hypopituitarism are distinguishing features of a large gonadotropinoma.
Management
Surgery
Transsphenoidal resection is the preferred therapy in most cases.
Radiotherapy
Radiation therapy is indicated for invasive or recurrent tumors, after initial surgical resection, or for patients who are deemed poor surgical candidates.
• Conventional fractionated or stereotactic radiotherapies are effective at controlling tumor growth in (>80–90% of cases).
• XRT carries a long-term risk of hypopituitarism (750% at 5–10 years with conventional XRT).
Medical treatment
Medical therapies, such as dopamine agonists, somatostatin analogs and GnRH agonist/antagonists are ineffective for gonadotropinomas.
• Hormone replacement therapy is required for any hypopituitarism ( b see p. 98).
Follow-up and prognosis
• Surgical gross-total resection rates for gonadotropinomas are 760–70%, with experienced neurosurgeons.
• Risk of tumor recurrence and growth are estimated at 75–10% at 5 years following gross-total resection of gonadotropinomas, and 20–50% at 10 years with subtotal resection.
• Most patients with gonadotropinomas lack a detectable serum hormone marker (e.g., FSH/LH), so must be followed clinically and radiographically (with MRIs).
• For patients with asymptomatic/residual tumors or microadenomas, a watchful waiting approach with annual imaging is recommended Consideration should be given to repeat TSS, or XRT, for evidence of signifi cant interval tumor growth.
19-Draznin-Chap19.indd 126 3/31/2011 2:46:25 PM
FOLLOW-UP AND PROGNOSIS 127
Further reading
Chaidarun SS, Klibanski A (2002). Gonadotropinomas. Semin Reprod Med 20:339–348.
Dekkers OM, Pereira AM, Romijn JA (2008). Treatment and follow-up of clinically nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 93:3717–3726.
Jaffe CA (2006). Clinically non-functioning pituitary adenomas. Pituitary 9:317–322.
19-Draznin-Chap19.indd 127 3/31/2011 2:46:25 PM
CHAPTER 20
Thyrotropinomas
128Thyrotropinomas
Epidemiology
• Less than 2% of pituitary adenomas are thyrotropinomas (TSH-secreting).
• Female predominance-10:1, 5 : 4 .
• Thyrotropinomas are frequently misdiagnosed and treated as primary hyperthyroidism.
Clinical features
• Hyperthyroidism ( b see p. 17)
• Most thyrotropinomas are macroadenomas at the time of diagnosis and present with mass effects, including headaches (20%), vision defects (25%) and hypopituitarism (50%).
• Goiter is common at presentation.
Differential diagnosis of elevated free T 4 /T 3 and non-suppressed TSH
• TSH-secreting tumor • Thyroid hormone resistance
• Inherited abnormalities of thyroid-binding globulin proteins
Investigations
• Elevated Free T 4 and T 3 levels with an inappropriately normal or elevated TSH level
• Elevated glycoprotein hormone A-subunit/TSH molar ratio • PRL and/or GH may be elevated in mixed tumors (725%).
• Elevated sex hormone binding globulins (hyperthyroid effect) • Failed suppression of TSH with T 3 (80–100 mcg x 8–10 days) with
TSH-secreting tumor • Pituitary imaging MRI
Management
Surgery
• First-line therapy, with >80% cure rates for microadenomas and 750%
cure rates for macroadenomas
20-Draznin-Chap20.indd 128 3/31/2011 2:47:40 PM
MANAGEMENT 129
Medical therapies Somatostatin analogs
b See Medical therapies for pituitary tumors (p. 144).
• Somatostatin analogs, including octreotide LAR and lanreotide, are second-line therapy after failed or incomplete surgical resection.
• Normalizes TSH secretion in >80% of patients and decreases tumor size in 740–50% of patients.
Antithyroid medications
• Short-term use only, for preoperative normalization of thyroid hormone levels. Long-standing use has potential adverse effects of tumor growth.
• B-blockers as needed for symptomatic hyperthyroidism.
Radiotherapy
Radiation therapy is used as adjuvant therapy following incomplete surgical resection or inadequate medical response.
Further reading
Beck-Peccoz P, Persani L (2008). Thyrotropinomas. Endocrinol Metab Clin North Am 37:123–134.
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CHAPTER 21
Craniopharyngiomas & Rathke’s cleft cysts
130130