Further reading Asa SL, Ezzat S (2002). The pathogenesis of pituitary tumors. Nat Rev Cance r 2:836 \200\223849. Karavitaki N, Collison K, Halliday J, Byrne JV, Price P, Cudlip S, Wass JA (2007). What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol 67:93 8 \200\223943. Molitch ME (2009). Pituitary tumors: pituitary incidentaloma. Best Pract Res Clin Endocrino l Metab 23:667 \200\223675. Dekkers OM, Pereira AM & Romijin JA (2008). Treatment and follow-up of clinically nonfuncti oning pituitary macroadenomas. J Clin Endocrinol Metab 93:3717 \200\2233726. 15-Draznin-Chap15.indd 103 4/1/2011 4:40:01 PM CHAPTER 16 Prolactinomas 104 Prolactinomas Epidemiology \200 Prolactinomas account for 735 \200\22340% of pituitary tumors and are t he most common functioning tumor \200 Female-predominance 10:1, 5 :4 \200 Microadenomas ar e more common in females, whereas macroadenomas are more common in males at the time of presentation. Etiology/pathogenesis See Box 16.1 for causes of hyperprolactinemia. Prolactinomas are the most common pituitary tumor in MEN-1, occur in 20% of cases, and may be more aggressive than sporadic prolactinomas. Clinical features Hyperprolactinemia effects (microadenomas and macroadenomas) \200 Galactorrhea (up to 90% of women, <10% of men) \200 Hyperprolactinemia inhibits GnRH release, leading to hypogonadotropic hypogonadism. Women present with menstrual disturbance \200\224amenorrhea, oligomenorrhea, reduced libido and infertility. Men present with loss of libido, erectile dysfunction and in fertility. Gynecomastia is uncommon. Hyperprolactinemia is associated with a long-term risk of d bone mineral density. Hyperprolactinemia was an adverse effect on libido, independent from hypogonadism. Mass effects (macroadenomas only) . \200 Headaches \200 Visual \201 eld defects (uni- or bitemporal \201 eld defects) \200 Hypopituitarism \200 Cranial nerve palsies from cavernous sinus invasion \200 Rarely, CSF leak or meningitis from tumor invasion of the sphenoid bone 16-Draznin-Chap16.indd 104 3/31/2011 4:56:42 PM CLINICAL FEATURES 105 Box 16.1 Causes of hyperprolactinemia Physiological \200 Pregnancy \200 Sexual intercourse \200 Nipple stimulation, sucklin g \200 Physical and/or psychological stressors Pituitary tumors \200 Prolactinomas \200 Mixed GH/PRL tumor \200 Macroadenoma-related stalk compression Parasellar causes \200 Hypothalamic disease \200\224 stalk compression (craniopharyngioma, meningioma, germinoma, glioma) In \201 ltration \200\224 sarcoidosis, Langerhans \200\231 cell histiocytosis \200 Pitu itary Stalk section \200\224traumatic head injury, neurosurgery \200 Empty sella syndrome Drug treatment \200 Dopamine receptor antagonists (metoclopramide, domperidone) \200 N euroleptics (phenothiazines, butyrophenones, thioxanthenes, risperidone, molindone, olanzapine) Antidepressants (tricyclics, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors) Antihypertensive drugs \200\224verapamil, methyldopa, reserpine. \200 Opiates and cocaine \200 Estrogens Metabolic \200 Primary hypothyroidism \200\224TRH increases PRL \200 Chronic renal failure \200\224reduced PRL clearance \200 Severe liver disease \200\224dis ordered hypothalamic regulation Other \200 Chest wall lesions \200\224zoster, burns, trau ma (stimulation of suckling re \202 ex) Idiopathic hyperprolactinemia \200 Macroprolactin (Ig6: PRL complex) 16-Draznin-Chap16.indd 105 3/31/2011 4:56:42 PM CHAPTER 16 Prolactinomas 106 Investigations Serum PRL \200 Normative PRL levels differ by gender and are slightly higher in females (e.g., 20 \200\22325 ng/mL in females, and 15 \200\22320 ng/mL in males). A slightly elevated PRL may represent a stress response or a pulsed secretion and should be con \201 rmed with additional PRL measurements. Serum PRL levels >100 \200\223150 ng/mL are suggestive of pituitary prolactinomas, whereas lower PRL levels are generally more consistent with non-tumoral etiologies (e.g., medicatio ns, renal insuf \201 ciency, stalk effect) or very small prolactinomas. PRL levels generally trend with adenoma size. 2 Exclude GH co-secretion with a prolactinoma (20 \200\22325% of tumors) as clinically indicated. Issue with PRL measurements Hook effect This is a lab artifact of a two-site immunoassay is which very high PRL levels (most commonly from giant [>4 cm] prolactinomas) saturate both the capture and the detectio n antibodies and prevent \200\234sandwich \200\235 complex formation. The PRL levels are s puriously normal or only slightly elevated. 2 PRL assays of large tumors, and suspected pro lactinomas, should be performed as a 1:100 \200\2231000 diluted serum sample. Hyperprolactinemia and drugs Antipsychotics and antidepressants are among the most common m edi- cations that cause hyperprolactinemia (dopamine agonists are contrain- dicated with ps ychiatric diseases). For cases of medication-induced hyperprolactinemia that are complicate d by hypogonadotropic hypo- gonadism, consideration could be given, under the guidance of a psych- iatrist or a mental health professional, to a trial of an alternate psychiatric med ication that is not associated with hyperprolactinemia. Alternatively, the hypogonadism cou ld be treated with sex steroid replacement. Idiopathic hyperprolactinemia Hyperprolactinemia of unclear etiology is designated idiopath ic but is likely due to an undetected microprolactinoma on imaging or to hypothalamic dysre gulation. PRL normalizes in 71/3 of idiopathic cases. 16-Draznin-Chap16.indd 106 3/31/2011 4:56:43 PM TREATMENT 107 Treatment Aims of therapy Microprolactinomas \200 Restoration of normal gonadal function and libido \200 Relief f rom galactorrhea Macroprolactinomas \200 Reduction in tumor size and prevention of tumor growth \200 Clinical improvement in signs and symptoms of tumor mass effects (e.g., headaches, vision impairment or hypopituitarism) Restoration of normal gonadal function and libido Drug therapy \200\224dopamine agonists Dopamine agonist (DA) treatment ( b see Dopamine ago nists, p. 144) is \201 rst-line medical therapy for patients with prolactinomas and norma lizes prolactin levels, and signi \201 cantly decreases tumor size in >90% of cases. Dopam ine agonist resistance is uncommon (see Box 16.2) \200 Cabergoline (Dostinex) is the pref erred therapy because of its greater ef \201 cacy at normalizing PRL levels and decreasing tumor size than bromocriptine. In addition, cabergoline is better tolerated and requires l ess frequent dosing (twice weekly). Bromocriptine (Parlodel) is recommended for women seeking fertility, because of the greater safety data in pregnancy. Monitoring : Adjust DA agonist every 1 \200\2232 months as needed to maintain PRL in the no rmative range. Repeat MRI at 76 \200\22312 months, particularly with macroadenomas, to ensu re that the tumor size decreases with the PRL levels. PRL normalization generally precedes a decreased tumor size by several weeks to months. Sex steroids Estrogen/progesterone replacement (in females) or testosterone therapy (in mal es), rather than dopamine agonist therapy, may be appropriate Box 16.2 Dopamine agonist resistance \200 General de \201 nition: failure to normalize p rolactin and/or failure to decrease tumor size by <50%. More commonly, drug non-compliance or drug intolerance lead to an erroneous diagnosis of DA resistance. \200 Prevalence: resistance is observed in 711% and 5 \200\22310% of cabergoline- treated patients, respectively. Etiology: reduced tumor D 2 receptors concentration \200 Treatment options: switch dopami ne agonists, increase dose as tolerated, surgery, fertility treatment, sex steroid replacement or radiation therapy (for macroprolactinomas) 16-Draznin-Chap16.indd 107 3/31/2011 4:56:43 PM CHAPTER 16 Prolactinomas 108 for patients with idiopathic hyperprolactinemia or microprolactinomas in whom fertility, ga lactorrhea and/or decreased libido are not of concerns. Surgery b See Transsphenoidal surgery (p. 140). Transsphenoidal surgery is second-line therapy and is indicated for patients who are resist ant to, or intolerant of, dopamine agonists. In add- ition, prolactinoma patients who have severe or vision-threatening apo- plexy that is unresponsive to initial medical management are also potential surgical candidates. The surgical success rates vary by the tumor size, the neurosurgery expertise and previous treatment, but range between 73.3 10.7% for microadenomas and 38.0 21.3% for macroade nomas (in large surgical series). Radiotherapy b See Radiation therapy for pituitary tumors (p. 147). Radiation therapy is generally indicated for patients with residual or recurrent prolactinomas after failed medical and surgical approaches. Long-term management (see Box 16.3) Pituitary Society Guidelines support attempted DA dose reduction or dis- continuation if, after 72 years of medical therapy, the PRL level remains normal and the MRI shows a marked tumor reduction. PRL should then be closely monitored for recurrence, which is usually observed in the \201 rst several months after drug withdrawal. The best predictor of reoccurrence is the presence of residual tumor on MRI. In cases of DA re-initiation or long-term use, patients should be maintained on the lowest possible DA dose that achieves the desired treatment goals. Box 16.3 Cabergoline and cardiac valvulopathy \200 Cabergoline, but not bromocriptine is a 5-hydroxytryptamine 2B receptor agonist. High doses of cabergoline (e.g., 3 mg/day for (cid:2)6 months in Parkinson \200\231s patients) have been associated with valvular heart disease (aortic, mit ral, and tricuspid regurgitations) via a 5-HT2B off-target effect. The risk of cardiac valvulopathy appears to be low in prolactinoma patients on standard doses of cabergoline ((cid:3)2 mg/week). \200 For patients requiring higher cabergoline doses, annual clinical cardiac exams are warranted, and consideration should be given to periodic echocardiograms. 16-Draznin-Chap16.indd 108 3/31/2011 4:56:43 PM MANAGEMENT OF PROLACTINOMAS IN PREGNANCY 109 Management of prolactinomas in pregnancy b See Prolactinoma in pregnancy (p. 354). Further reading Casaneuva FF, Molitch ME, Schlechte JA, Abs R, et al. (2006). Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol 6 5(2):265 \200\223273. Cheung D, Heaney A (2009). Dopamine agonists and valvular heart disease. Curr Opin Endocrin ol Diabetes Obes 16:316 \200\223320. Colao A (2009). The prolactinoma. Best Pract Res Clin Endocrinol Metab 23:575 \200\223596. Molitch ME (1992). Pathologic hyperprolactinemia. Endocrinol Metabo Clin North Am 21:877 \200\223910. Molitch ME (2008). Drugs and prolactin. Pituitary 11:209 \200\223218. Klibanski A (2010). Prolactinomas. N Engl J Med 362:1219 \200\22326. 16-Draznin-Chap16.indd 109 3/31/2011 4:56:43 PM CHAPTER 17 Acromegaly 110 Acromegaly De \201 nition Acromegaly is the clinical condition resulting from prolonged exposure to e xcessive GH/IGF-1 levels in adults. Epidemiology Estimated annual incidence is 3 \200\2234 cases/million population. There is e qual sex distribution. Acromegaly has an insidious onset which often results in a delayed d iagnosis (77 \200\22310 years). Etiologies of acromegaly \200 Pituitary adenoma (95% of cases) Rare causes of GH excess \200 GHRH secretion \200\224hypothalamic tumor (gangliocytoma) \200 Ectopic GHRH \200 \224carcinoid tumors (e.g., pancreas, lung), pheochromocytoma and medullary thyroid cancer Ectopic GH secretion \200\224pancreatic islet cell tumor and lymphoma Pathophysiology \200 Constitutively-active mutations of the A-subunit of the stimulatory G protein are seen in 730 \200\22340% of densely granulated GH tumors. \200 Familial syndro mes: MEN-1, Carney complex, and McCune \200\223Albright syndrome can manifest with GH tumors in 710% of cases. \200 Isolated familial somatotropi nomas are associated with aryl hydrocarbon receptor interacting protein (AIP gene) mutations in 710 \200\22315% of cases. Clinical features The clinical features arise from the somatic and metabolic effects of pro - longed excess GH/IGF-1 exposure. Symptoms \200 Hyperhidrosis (i Sweating) \200 Headaches \200\224independent of tumor ef fect 17-Draznin-Chap17.indd 110 4/1/2011 4:42:21 PM CLINICAL FEATURES 111 Fatigue \200 Arthralgias \200 Increased ring or shoe size \200 Carpal tunnel syndrome \200 Muscle weakness and myopathy Signs \200 Facial appearance: coarse, acral features, frontal bossing, enlarged nose, deep nasolabial furrows, prognathism, jaw malocclusion and i interdental spacing Deep voice: laryngeal thickening \200 Macroglossia \200 Musculoskeletal changes: enlarg ement of hands and feet, large joint and axial arthropathy, osteopenia/osteoporosis Goiter and other visceromegaly: liver, spleen, kidney, prostate \200 Skin changes: oily s kin, acanthosis nigricans, skin tags Complications \200 Hypertension \200 Insulin resistance: impaired glucose tolerance and diabetes mellitus \200 Sleep apnea: 1/3 central and 2/3 obstructive \200 Kyphosis and vertebral fractures (attributable to hypogonadism) \200 Hypertriglyceridemia \200 Cardi ovascular diseases: cardiomyopathy, arrhythmias, valvular heart disease and congestive heart failure Colonic polyps and colon cancer: slightly i risk Mass effects of tumor \200 Visual \201 eld defects \200 Hypopituitarism 17-Draznin-Chap17.indd 111 4/1/2011 4:42:21 PM CHAPTER 17 Acromegaly 112 Investigations Insulin-like growth factor-1 (IGF-1) IGF-1 is the single best screening test for acromegaly (Fig. 17.1). IGF-1 has a long half-life (18 \200\22320 hours), re \202 ects integrated GH secretion, and cor- relates with clinical features of acromegaly. It is important to use a ge- and gender-based normative ranges for IGF-1. 2 Etiologies for false negative (low) IGF- 1 levels include: malnutrition, hypothyroidism, poorly controlled type I diabetes mellitus (DM), and chronic liver disease. +Signs and Symptoms of Acromegaly IGF-1 (age and gender matched) Elevated Equivocal Abn. OGTT MRI \200\223 Tumor + Evaluate for Ectopic Source GHRH Level Chest/Abd CT Surgery \200\223 Periodic Follow-up IGF-1 Elevated Residual Tumor Somatostatin Analog \200\223 IGF-1 Elevated Residual Tumor Large Tumor Periodic Follow-up \200\223 + Long- Term Rx Pegvisomant XRT Fig. 17.1 Algorithm for the evaluation and management of acromegaly. 17-Draznin-Chap17.indd 112 4/1/2011 4:42:21 PM INVESTIGATIONS 113 Oral glucose tolerance test (OGTT) OGTT is a con \201 rmatory test for acromegaly and is i ndicated for an equivo- cal IGF-1 level (on screening), or after transsphenoidal surgery to assess for disease control. An abnormal test is de \201 ned by a failure to suppress GH t o <1 mcg/dL (in response to a 75 g oral glucose load), as assessed by GH measurements every 30 minutes over a 2-hour period. Lower cutoffs (<0.30 mcg/dL) are recommended for ultrasen sitive GH assays. 2 Etiologies for false positive results (failure to suppress GH) include: chronic renal and liver failure, malnutrition, anorexia, uncontrolled dia- betes mellitus, heroin addiction, estrogen use, pregnancy and adolescence (due to high pubertal GH surges) . Random GH This is generally not useful for the diagnosis of acromegaly, but a low ran- dom GH level (<0.40 mcg/dL with an ultrasensitive assay), in conjunction with a normal IGF-1 le vel, excludes the diagnosis. MRI MRI usually demonstrates a pituitary tumor (>95%), of which 80% are macroadenomas. Pituitary function testing Serum PRL may be elevated from stalk effect or GH/PRL tumors \200\231 co- secretion. In case of macroadenomas, assess other anterior pituitary hormones (e.g., free T4, cortisol, testosterone or estradiol) to exclude hypopituitarism. GHRH In cases where a pituitary tumor is not identi \201 ed, a serum GHRH level and chest and abdomen imaging are recommend to identify a potential extrapituitary source of GH exces s. Comorbidities Evaluate and treat potential comorbid conditions, including: impaired glu- co se intolerance/diabetes, dyslipidemia, sleep apnea, cardiac disease (base- line EKG and ech ocardiogram) and colonic polyps (colonoscopy). 17-Draznin-Chap17.indd 113 4/1/2011 4:42:22 PM CHAPTER 17 Acromegaly 114 Management Transsphenoidal surgery See Transsphenoidal surgery (p. 140). This is \201 rst-line thera py in most U.S. neurosurgery centers. Cure rates are generally 80 \200\22390% for microaden omas and 40 \200\22360% for macroadenomas. Role of preoperative somatostatin analog treatment There is limited evidence to recommend p reoperative treatment to improve surgical outcomes or postoperative complications, although treatment can be considered for large, invasive tumors (if anticipated sur- gical delays), or for signi \201 cant GH-related co-morbidities such as congest- ive heart failure or se vere OSA. Criteria for cure De \201 ned as \200 Absence of clinical signs and symptoms of GH excess \200 Normaliza tion of IGF-1 levels \200 GH nadir following OGTT to <1 mcg/dL (or <0.30 mcg/dL with an ultrasensitive GH assay) \200 Failed OGTT, with normal IGF-1, is a potential marker of re currence risk. 730% discordance rates between the IGF-1 and the OGTT results have been observed in acromegalics: \200\223 High GH/normal IGF-1 is more common in young estrogen- suf \201 cient females and somatostatin-treated patients. \200\223 Normal GH/high IGF-1 is more common in older patients and radiation-treated patients. Medical therapies Somatostatin analogs b See Somatostatin analogs (p. 145). \200 Somatostatin analogs are t he \201 rst-line medical therapy after failed or incomplete surgical resection. They may be used as primary therapy in patients who are not surgical candidates. Ef \201 cacy \200 Normalizes IGF-1 levals in 750 \200\22360% /of patients. \200 More e f \201 cacious with densely-granulated GH tumors than the sparsely-granulated GH sub-type. Constrains tumor growth (>90%) and decreases tumor size (mild to moderately) in 750% of patients. GH receptor antagonists (pegvisomant) b see Pegvisomant (p . 146). \200 Indicated for somatostatin non-responders or intolerance \200 Normalizes o f IGF-1 levels in >90% of patients \200 IGF-1 levels are used exausively to monitor thera py (not GH). 17-Draznin-Chap17.indd 114 4/1/2011 4:42:22 PM MORTALITY DATA 115 Dopamine agonists b See Dopamine agonists (p. 144). \200 Therapy is generally ineffective at normalizing IGF-1 levels, but may be useful for GH/PRL co-secretors. Only cabergoline is effective (not bromocriptine), but requires signi \201 cantly higher doses than those used for prolactinomas ((cid:2)3 mg/ week). Radiotherapy b Also see Technique (p. 147). Generally this is third-line therapy after failed surgery and medical approaches, although radiation therapy can be used to decrease the need for lifelong medications. Normalization of GH hypersecretion may take several years (e.g., 5 \200\22310 years) with c onventional radiotherapy, although it is likely faster with smaller tumors stereotactic radiosurgery. \200 Adjunctive medical treatment (e.g., somatostatin analogs or pegvisomant) is usually required during the latency period after XRT. \200 Prevention of tumor growth precedes control of GH hypersecretion by several months to years. Mortality data A recent meta-analysis found an overall 772% increase in all-cause mortal- i ty in patients with acromegaly compared with the general population. \200 Historically, m ajor causes of mortality in acromegalic patients include cardiovascular diseases, respiratory diseases and malignancies. A greater awareness of acromegaly, newer medications and improved treatment strategies, over the past decade, have resulted in earlier diagnosis, be tter outcomes and decreased mortality rates. Further reading Alexopoulou O, Bex M, Abs R, Tsoen R, et al. (2008). Divergence between gro wth hormone and insulin-like growth factor-1 concentrations in the follow-up of acromegaly. J Clin Endocrinol Metab 93:1324 \200\2231330. Dekkers OM, Biermasz AM, Pereira AM, Romijn JA, et al. (2008). Mortality in acromegaly: a m eta- analysis. J Clin Endocrinol Metab 93:61 \200\22367. Melmed S (2006). Medical progress: acromegaly. N Engl J Med 355:2558 \200\2232573. Melmed S, Colao A, Barkan M, Molitch M, et al. (2009). Guidelines for acromegaly management : an update. J Clin Endocrinol Metab 94:1509 \200\2231517. Verloes A, Stevenaert A, Teh BT, Petrossians P, et al. (1999). Familial acromegaly: case re port and review of the literature. Pituitary 1:273 \200\223277. 17-Draznin-Chap17.indd 115 4/1/2011 4:42:22 PM CHAPTER 18 Cushing \200\231s disease 116 Cushing \200\231s disease De \201 nition Cushing \200\231s syndrome (CS) is a disease complex that results from chro nic hypercortisolemia of any cause. Cushing \200\231s disease (CD) is hypercortisolemia from an ACTH-secreting pituitary tumor chronic. Untreated hypercortisolemia leads to a 73 to 5-fold increased mortality rate. Epidemiology \200 Annual incidence of CD is approximately 2 \200\2234/million population \200 Female prevalence (3 \200\22315:1, 5:4 ) \200 Age at diagnosis-20 \200\22340 years X Subclinical CS may be more common than clinically-Apparent CS, although this is still a controversial area regarding de \201 nition, diagnosis and optimal management. Differential diagnosis \200 Iatrogenic etiologies (e.g., oral, inhaled or topical steroid s) are the most common cause of CS Pseudo-Cushing \200\231s disease , de \201 ned as non-tumorous activation of the HPA axis from multiple potential stressors, including: psychiatric disorders (i.e., severe depressio n, anxiety disorder, obsessive-compulsive disorder), uncontrolled diabetes, alcoholism and severe obesity. Glucocorticoid resistance syndrome Etiologies of CS The majority of endogenous Cushing \200\231s syndrome is due to ACTH-secre ting pituitary adenomas (Cushing \200\231s disease). 18-Draznin-Chap18.indd 116 3/31/2011 9:37:46 PM CLINICAL FEATURES OF CS 117 Box 18.1 Causes of endogenous Cushing \200\231s syndrome ACTH-dependent \200 Pituitary adenoma (Cushing \200\231s disease): 70 \200\22380% \200 Ectopic ACTH syndrome: 10% \200 Ectopic CRH secretion: <1% ACTH-independent \200 Adrena l adenoma: 10 \200\22320% \200 Adrenal carcinoma: <5% \200 Nodular (macro or micro) hyp erplasia: 1% Carney \200\231s complex \200 McCune \200\223Albright syndrome \200 Aberrant adrenal re ceptor expression (e.g., GIP, LH, 5-HT4) Clinical features of CS Box 18.2 Clinical features of Cushing \200\231s syndrome Features that best distinguish Cushing \200\231s syndrome \200 Facial appearance: moon fa cie and plethoric complexion \200 Spontaneous ecchymoses \200 Violaceous striae: >1 cm on abdomen, thighs and axillae \200 Proximal muscle weakness \200 In children, weight g ain with decreased growth velocity \200 Early bone fractures, especially atraumatic rib o r vertebral fractures Clinical features less speci \201 c for Cushing \200\231s syndrome \200 Fatigue \200 Hypertension \200 Impaired glucose tolerance, diabetes mellitus \200 Osteopenia, osteoporosis \200 Susceptibility to infections \200 Mood disturbance \200\224 depression, irritability, insomnia, psychosis \200 Menstrual disturbance \200 Low libido and impotence \200 Weight gain \200\224 truncal obesity, buffalo hump, supra clavicular fat pads \200 Acne \200 Hirsutism \200 Polycystic ovarian syndrome 18-Draznin-Chap18.indd 117 3/31/2011 9:37:46 PM CHAPTER 18 Cushing \200\231s disease 118 Investigations Step 1. Conduct screening tests Consider screening patients who have multiple and progressi ve \200\230high-discriminatory \200\231 features consistent with Cushing \200\231s syndrom e, particu- larly with an early onset (Box 18.2). In addition, patients with an adrenal ade noma >1 cm should be screened. 2 Note: All screening tests can give false-positive results with pseudo- Cushing \200\231s disease. Outpatient screening tests (Fig. 18.1). 24-hour urinary free cortisol (UFC) \200 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., feno \201 bra te, carbamazepine and digoxin can give false-positive results on HPLC-based assays), and 2) reduced glomerular \201 ltration rates (GFR) <60 mL/min may lead to false-negative resul ts. Overnight dexamethasone suppression test (DST) \200 Administration of 1 mg dexamethasone (DEX) at 11 \200\22312 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 . \200 Normal: Serum cortisol < 1.8 mcg/dL (with a sensitive cortisol assay) 2 Caveats : The following interfering conditions should be excluded: d dexamethasone absorption, hepati c enzyme inducers (e.g., phenytoin, carbamazepine, and rifampin), and i (cortisol-binding g lobulin (CBG) (from oral contraceptive pills, which should be discontinued 6 weeks before t esting or pregnancy). A morning dexamethasone level can be drawn to exclude rapid metabolis m in speci \201 c cases. Midnight salivary cortisol \200 At least two measurements 2 Caveats: Patients must have a normal sleep \200\223wake 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 \200\231s syndrome. \200 ACTH >10 pmo l/mL indicate an ACTH-dependent etiology \200 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. \200 Equivocal ACTH values re quire additional testing. 18-Draznin-Chap18.indd 118 3/31/2011 9:37:47 PM INVESTIGATIONS 119 + Signs and Symptoms of Cushing \200\231s Diagnose CS Exclude med effect Adequate collection? Repeat Screening Reassess periodically (e.g., q 6 months) if clinically indicated Screening Tests UFC 1 mg DST MN Salivary Cortisol Indeterminant (discordant) Positive (Concordant) Negative (Concordant) Consider DEX-CRH Testing Exclude Pseudo- Cushing \200\231s Determine CS Etiology A.M. Plasma ACTH Level High-Normal/ \206\221 Indeterminant Low Suggest ACTH- independent Suggest ACTH- dependent Consider CRH Stim. Adrenal Imaging MRI 8 mg DST Indeterminant \200\223Suppression \200\223MRI +Suppression +MRI (>5mm) IPSS ACTH Central/Peripheral Basal Gradient >2 +CRH >3 Locate & Treat + \200\223 Adrenal Tumor Resection Pituitary/TSS Evaluate/Tx for Ectopic CS Fig 18.1 Algorithm for diagnosis of Cushing \200\231s syndrome. Adapted and Reprinted with permission from Liu H, Crapo L (2005). Update on the diagnosis of Cushing syndrome. The End ocrinologist 15(3):165 \200\223179. 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 ver y small tumors or undetectable adenomas on 18-Draznin-Chap18.indd 119 3/31/2011 9:37:47 PM CHAPTER 18 Cushing \200\231s disease 120 MRI should undergo an inferior petrosal sinus sampling (IPSS) for de \201 ni- tive diagnos is of Cushing \200\231s disease. Inferior petrosal sinus sampling (Fig 18.2) 2 IPSS is the single best test to distinguish C ushing \200\231s disease from ectopic CS, with a sensitivity and speci \201 city of >95%. Comparatively, the 8 mg DST and CRH stimulation tests are inferior diagnostic tests. \200 Bilateral IPSS involves the measurement of ACTH centrally and peripherally, in the basal state and following stimulation with CRH (100 mcg IV). A basal c entral-to-peripheral ACTH ratio of >2:1 (or >3:1 stimulated, 5-15 minutes after CRH injecti on) is diagnostic of CD. Ideally, IPSS should be performed only in experienced centers. Abdominal CT This is indicat ed for a suspected adrenal source. Pituitary thgiR tfeL Adenoma Inferior petrosal sinus High jugular vein Low jugular vein Catheter Plasma ACTH (ng/L) After IV CRH 100 mg 5 min 10 min 15 min 0 min 123 280 477 Left inferior petrosal sinus 14 54 28 23 Right inferior petrosal sinus 16 32 25 19 Simultanous peripheral vein 17 Fig. 18.2 Inferior petrosal sinus sampling (IPSS). Simultanous bilateral inferior petrosal sinus and peripheral vein sampling for ACTH. The ratio of >3 between the left central and p eripheral vein con \201 rms a diagnosis of Cushing \200\231s 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 identi fy 7 75% of tumors. Detection may be augmented by the complimentary use of func- tional stu dies, such as an octreotide scan or a positron emission tomography (PET) scan. Additional tests \200 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. \200 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 18-Draznin-Chap18.indd 121 3/31/2011 9:37:47 PM CHAPTER 18 Cushing \200\231s disease 122 Treatment Transsphenoidal surgery (TSS) b Also see Transsphenoidal surgery (p. 140). This is the \201 rst-line therapy in most Cushing \200\231s disease cases. Selective hypo physectomy is curative in up to 80 \200\22390% of microadenomas, and 750% of macroadenomas. A post-operative cortisol level of <2 mcg/dL is reassuring for short- term remission, altho ugh long-term studies indicate a recurrence rate for Cushing \200\231s disease of approxima tely 15-20% at 5 years. Medical therapies (see Table 18.1 ) To date, there are no effective tumor-directed therapie s for Cushing \200\231s disease. Most of the adrenal-directed therapies are ineffective at normaliz- ing hypercortisolemia and have poor side-effect pro \201 les. As such, medical t herapies are generally used as a temporizing measure (e.g., preoperatively or during the la tency period after radiation therapy). Pituitary radiotherapy (see p. 147) Radiation therapy is usually third-line treatment follo wing incomplete sur- gical resection and inadequate medical therapies. Control of hypersecretion is frequently delayed (e.g., fractionated radia- tion therapy con trols hypercortisolemia in 750 \200\22360% of patients within 3 \200\2235 years). Adrenalectomy In ACTH-dependent Cushing \200\231s, 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 \200\231s syndrome is caused by an enlargement of a pituitary adenoma (often aggress ively), and may occur in up to 30% of Cushing \200\231s disease patients who have undergone a bilateral adrenalectomy. These tumors are associated with a marked increase in ACTH leve ls, hyperpigmentation and mass effects. Monitoring should be performed annually with a basa l ACTH measurement and pituitary MRI (as indicated for signs and symptoms of mass effects o r a markedly elevated ACTH level). Transsphenoidal surgery and radiation therapy are the ma in treatment options. 18-Draznin-Chap18.indd 122 3/31/2011 9:37:47 PM TREATMENT 123 Table 18.1 Drug treatments for Cushing \200\231s syndrome Drug Dose Action Side effects Nausea, i androgenic and mineralcorticoid precursors lead to hirsutism and hypertension Neu tropenia. 11B- hydroxylase inhibitor Metyrapone 1 \200\2234 g/day (usually given in 4 divided doses) Ketoconazole 200 \200\223400 mg tid \201 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 \200\22312 g/day (begin at 0.5 \200\2231 g/day and gradually increase dose) Inhibits steroido- genesis at the side-chain cleavage, 11- and 18-hydroxylase and 3B-hydrox y- steroid dehydrogenase. Adrenolytic Nausea & vomit- ing, Cerebellar disturbance, Somnolence, Hyper- cholesterolemia. May increa se clearance of steroids. May be teratogenic. Avoid if fertility desired. RU486 (mifopristone) 400 \200\2231000 mg/ day Glucocorticoid Antagonists Amenorrhea Hypokalemia (antagonizes progesterone and androgen receptors) 0.03 mg/kg IV, followed by infusion of 0.1 mg/kg/h Inhibits side- chain cleavage and 11B- hydroxylase Etomidate 18-Draznin-Chap18.indd 123 3/31/2011 9:37:47 PM CHAPTER 18 Cushing \200\231s disease 124 Follow-up \200 After a successful transsphenoidal tumor resection, periodic assessment of basal and stimulated cortisol levels are indicated to monitor for recovery fr om central adrenal insuf \201 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 glucoco rticoid taper, macroadenomas and/or failed intraoperative adenoma detection). ACTH-secreting macroadenoma are generally not cured with TSS and require subsequent radiati on therapy medical therapies. In addition, \200\234silent \200\235 ACTH adenomas are am ong the most aggressive tumors with 730% recurrence rates. Further reading Biller BK, Grossman AB, Stewart PM, Melmed S, et al. (2008). Treatment of a drenocorticotropin- dependent Cushing \200\231s syndome: a concensus statement J Clin Endoc rinol Metab 93:2454 \200\2232462. Ilias I, Torpy DJ, Pacak K, Mullen N, et al. (2005). Cushing \200\231s syndrome due to ecto pic corticotropin secretion: twenty years \200\231 experience at the National Institute of Health. J Clin Endocrinol Metab 91(2):371 \200\223377. Nieman LK (2002). Medical therapy of Cushing \200\231s disease. Pituitary 5:77 \200\22382. Nieman LK, Biller BM, Findling JW, Newell-Price J, et al. (2008). The diagnosis of Cushing \200\231s syn- drome. An Endocrine Society clinical practice guideline. J Clin Endocrinol M etab 93:1526 \200\2231540. Patil CG, Prevedello DM, Shivanand P, Vance ML et al. (2008). Late recurrences of Cushing \200\231s disease after initial successful transphenoidal surgery. 93:358 \200\223362. 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 acco unt for 740 \200\22350% of all pituitary macroadenomas. They are most commonly diagnosed in middle-aged men. Pathology \200 Gonadotropinomas synthesize but generally do not ef \201 ciently secrete intact glycoprotein hormones (FSH, LH) or their free (A or B) subunits. Null cell tumors are de \201 ned by the absence of immunoreactive hormone expression and l ikely represent poorly differentiated gonadotrope cells. Clinical features Mass effects \200 Headache \200 Visual \201 eld defects (uni- or bitemporal quadranta nopia or hemianopia) \200 Ophthalmoplegia (III, IV and VI cranial nerve palsies) \200 V ision loss (optic nerve atrophy) \200 Cerebrospinal \202 uid rhinorrhea (rarely) \200 Hypopituitarism. At diagnosis, > 50% of patients are growth hormone and/or gonadotrope de \201 cient. Adrenal and thyroid insuf \201 ciencies are less common (<30%). Hormone effects Rarely, gonadotropinomas can present with hormone hypersecretory syn- drome s, such as ovarian hyperstimulation syndrome, testicular enlarge- ment or precocious pubert y. 19-Draznin-Chap19.indd 125 3/31/2011 2:46:25 PM CHAPTER 19 Gonadotropinomas 126 Investigations \200 Pituitary imaging: Usually presents as a macroadenoma on MRI/CT \200 Visual \201 elds assessment: Vision \201 eld defects are observed in 760 \200\22370% of patients. PRL: Mild hyperprolactinemia is common due to stalk compression. 0 Pituitary function: Gona dotropinomas rarely present with elevated serum FSH, LH, and/or A-subunit levels, but may b e confused with pri- mary gonadal failure and or the postmenopausal state. Headaches, visua l \201 eld disturbances and hypopituitarism are distinguishing features of a large gonado tropinoma. 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 \200\22390% of cases). XRT carries a long-term risk of hypopituitarism (750% at 5 \200\22310 years with conventional XRT). Medical treatment Medical therapies, such as dopamine agonists, somatostatin analogs and Gn RH agonist/antagonists are ineffective for gonadotropinomas. Hormone replacement therapy is required for any hypopituitarism ( b see p. 98). Follow-up and prognosis \200 Surgical gross-total resection rates for gonadotropinomas ar e 760 \200\22370%, with experienced neurosurgeons. Risk of tumor recurrence and growth are estimated at 75 \200\22310% at 5 years following gr oss-total resection of gonadotropinomas, and 20 \200\22350% at 10 years with subtotal resec tion. Most patients with gonadotropinomas lack a detectable serum hormone marker (e.g., FSH/LH), so must be followed clinically and radiographically (with MR Is). For patients with asymptomatic/residual tumors or microadenomas, a watchful waiting approac h with annual imaging is recommended Consideration should be given to repeat TSS, or XRT, f or evidence of signi \201 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 \200\223348. Dekkers OM, Pereira AM, Romijn JA (2008). Treatment and follow-up of clinically nonfunction ing pituitary macroadenoma. J Clin Endocrinol Metab 93:3717 \200\2233726. Jaffe CA (2006). Clinically non-functioning pituitary adenomas. Pituitary 9:317 \200\223322 . 19-Draznin-Chap19.indd 127 3/31/2011 2:46:25 PM CHAPTER 20 Thyrotropinomas 128 Thyrotropinomas Epidemiology \200 Less than 2% of pituitary adenomas are thyrotropinomas (TSH- secreting). Female predominance-10:1, 5 : 4 . \200 Thyrotropinomas are frequently misdiagnosed and tr eated as primary hyperthyroidism.