1 1 0 0 P i t u i t a r y 15 \200\22325 (i in pregnancy) Lactotropes (prolactin) PRL Thyrotropin- releasing hormone (TRH) and estrogen Dopamine Breast Lactation g l a n d Gonadotropes (luteinizing hormone and follicle- stimulating hormone) FSH/LH 10 \200\22315 Gonadotropin- releasing hormone (GnRH) Estrogen- late follicular phase of menstrual cycle Estrogen Progesterone Testosterone (on FSH) Inhibin Gonads Sex steroids production. Folliculogenesis and ovulation ( 5) Spermatogenesis ( 4) Thyroid h ormone production a n a t o m y Thyrotropes (thyroid- stimulating hormone) TSH 5 \200\22310 TRH T 4 , T 3 , Somatostatin Thyroid Corticotropes (adrenocorticotropin) ACTH 15 \200\22320 Corticotropin- releasing hormone (CRH) Cortisol Adrenal gland Glucocorticoid and DHEA production a n d p h y s i o l o g y 3 / 3 1 / 2 0 1 1 3 : 1 9 : 1 7 P M POSTERIOR GLAND PHYSIOLOGY 85 Posterior gland physiology The posterior pituitary gland secretes antidiuretic hormone and oxytocin, which are synthesized in the hypothalamic neurons of the supraoptic and paraventr icular nuclei. Antidiuretic hormone (ADH) ADH is a nonapeptide that is released in response to hyperosmoti c and hypovolemic stimuli. ADH acts on V2 renal collecting tubule receptors to mediate free water retention, and acts on V1 blood vessel receptors, at higher concentrations, to cause vasoconstriction. ADH also acts synergis- tically with corticotropin-releasing hormone (CR H) to augment ACTH release. Oxytocin In women, oxytocin facilitates uterine contraction, during parturition, and milk l et-down in the post-partum period. In men, oxytocin has no known function but may aid in se minal vesicle contractions. Further reading Aron DC, Findling JW, Tyrrell JB (2007). Hypothalamus and pituitary gland. In Gardner DG, Shoback D (Eds.), Greenspan \200\231s Basic and Clinical Endocrinology , 8th ed, New York: McGraw Hill, pp. 101 \200\223140. 10-Draznin-Chap10.indd 85 3/31/2011 3:19:17 PM CHAPTER 11 Imaging 86 Imaging Background High-resolution, contrast-enhanced, thin-cut (3mm) magnetic resonance imaging (M RI) provides the optimal evaluation of the sellar and parasellar regions. Coronal and sagittal T 1 -weighted images, before and after gadolinium administration, are recommended. T 2 -weighted imaging is usually unneces- sary, but may assist in the diagnosi s of cystic lesions. In addition, axial imaging may be helpful to de \201 ne lateral exten sion with large tumors. Computed tomography (CT) scans are most useful for patient with contra-indications to MRIs. In addition, they may demonstrate boney destruction and calci \201 cation with some tumor s (e.g., meningiomas and craniopharyngiomas). MRI appearances See Figure 11.1 . The size, shape and signal characteristics of the pituitary gland vary with age, gender and physiological status. Non-contrasted T 1 images of the anterior pituitary gland are isoint ense with cerebral white matter, whereas the posterior pituitary gland appears hyperintense (as a bright spot), in most normal subjects. Following contrast administration, the pituitary gland and stalk enhance, because they are below the blood \200\223brain barrier. 2 There is signi \201 cant overlap in the imaging characteristics of adenomas, and other pituitary diseases such as craniopha ryngiomas, in \202 ammatory/ in \201 ltrative lesions and cysts. 11-Draznin-Chap11.indd 86 3/31/2011 2:39:03 PM PITUITARY ADENOMAS 87 Fig. 11.1 Normal and abnormal pituitary MRI images. A. Normal coronal, post- contrast T 1 i mage showing optic chiasm (OC). B. Normal saggital image showing pituitary stalk (PS) and O C. C. Pituitary macroadenoma with evidence of pituitary gland (PG) compression, left cavern ous sinus invasion, and encroachment of carotid artery (CA). D. Rathke \200\231s cleft cyst \200\224bright T 1 image consistent with mucinous, proteinaceous or blood products. Pituitary adenomas See Figure 11.1 . Microadenomas are best appreciated on contrast-enhanced, T 1 weighted, coronal MRI images. They appear as hypointense signals, and often with associated pituitary gland asymmetry and stalk deviation (contralateral to the tumor). Macroadenomas are characterized radiographically by their size and extrasellar extension. I mportant considerations include the proximity of the adenoma to the optic chiasm and any ra diological evidence for cavern- ous sinus invasion. Macroadenomas are frequently heterogeno us appear- ing and may undergo spontaneous necrotic and/or hemorrhagic changes. On T 1 -wei ghted images: \200 Low-intensity areas indicate necrotic or cystic changes. \200 High-i ntensity signals indicate hemorrhage (particularly after the acute phase, days 1-2). The normal pituitary gland enhances more avidly with contrast than tumors, so is commonly seen as an enhanced signal that is peripherally located. 11-Draznin-Chap11.indd 87 3/31/2011 2:39:03 PM CHAPTER 11 Imaging 88 Craniopharyngioma/Rathke \200\231s cleft cyst Craniopharyngiomas are typically suprasellar in location. They vary in content from cystic to mixed solid/cystic (most commonly) to pred om- inantly solid. Imaging characteristics vary with the tumor composition. Calci \201 cat ions are a distinguishing feature of adamantinomatous craniophar- yngiomas, and are best de tected by CT scans. Rathke \200\231s cleft cysts (RCC) are typically intrasellar, but may extend into the supra sellar space. MRI images vary by cyst content from hypointense (with serous \202 uid), to hyperintense (with mucinous, proteinaceous or blood products) on T 1 -weighted images. Further reading Naidich MJ, Russell EJ (1999). Current approaches to imaging of the sellar region and pituitary. Endocrinol Metab Clin North Am 28:45 \200\22379. 11-Draznin-Chap11.indd 88 3/31/2011 2:39:06 PM THYROTROPES 89 Pituitary function testing Background \200 Pituitary function is best assessed with basal concentrations of the pituitary hormones and their corresponding target gland hormones. \200 Pituitary hormone de \201 ciency is established by a low target hormone level in the setting of a low, or an inappropriately normal pituitary hormone level. In equivocal cases, stimulation tests are used to assess the pituitary hormone reserve (e.g., Insulin tolerance test for GH de \201 ciency). Pituitary hormone excess (or less commonly, resistance to target organ hormone) is established by a high target hormone level in the setting of an inappropr iately normal or a high pituitary hormone level. In equivocal cases, suppression tests are used to assess for a hyper-secretory state. (e.g., OGTT for acromegaly). Lactotropes Basal testing Lactotrope function is best assessed by a fasting PRL level. Dynamic testing None is used. Thyrotropes Basal testing Thyrotrope function is best assessed with concomitant TSH and cir culat- ing thyroid hormone levels (free T 4 and less commonly, T 3 ). Dynamic testing None is used; TRH is not commercially available in the United States. 12-Draznin-Chap12.indd 89 4/1/2011 6:01:34 PM CHAPTER 12 Pituitary function testing 90 Gonadotropes Basal testing Gonadotrope function is best assessed with concomitant gonadotro pin (FSH and LH) and sex steroid levels: estradiol (in females) and testoster- one (in male s). In premenopausal females, because the gonadotropin levels differ signi \201 - cantly acros s the menstrual cycle, hormone testing should be performed in the early follicular phase (d ays 1 \200\2235 after the onset of menses), when the LH and FSH levels are approximately eq ual. In males, testosterone levels are best assessed in the early morning (7 \200\2239 A.M.), which corresponds to normal peak levels. Dynamic testing Gonadotropin-releasing hormone (GnHR) testing is most commonly used to asse ss pubertal disorders, particularly precocious puberty. 12-Draznin-Chap12.indd 90 4/1/2011 6:01:34 PM CORTICOTROPES 91 Corticotropes Basal testing Basal cortisol levels have a broad normal range: 3 \200\22318 m cg/dL. Random A.M. cortisol levels <3 mcg/dL indicate adrenal insuf \201 ciency, whereas l evels >18 mcg/dL exclude adrenal insuf \201 ciency. A stimulation test is indi- cated for equivocal cortisol values to exclude adrenal insuf \201 ciency. Midnight salivary or serum cortisol levels, which correspond to the normal nadir level, are used as screening tests for cortisol excess (Cushing \200\231s syndrome). Stimulation testing Insulin tolerance test (ITT) and metyrapone tests are the gold standard s for assessing corticotrope de \201 ciency. The ITT is based on the physiological stressor of insulin-induced hypogly- cemia on CRH \200\223ACTH \200\223cortisol activation (and GH release) and assesses the complete hypotha lamic \200\223pituitary \200\223adrenal (HPA) axis. Test protocol: Insulin bolus (0.1-0.15 units/kg IV). Goal glucose <40 mg/dL. Normal serum cortisol >18 mcg/dL ITT has the disadvantages of being labor intensive, requiring close monitoring and having a number of important contraindications. Contraindications to ITT \200 Abnormal ECG \200 Ischemic heart disease \200 Seizures \200 Elderly Metyrapone test protocol : Metyrapone (30 mg/kg) is given at 11 \200\22312 P.M., and 11-dex ocycortisol (DOC), ACTH and cortisol are measured the next morning. Normal response: 11-DOC >7 mcg/dL, ACTH >50 pg/mL and cortisol < 5 mcg/dL. 2 Metyrapone must be obtained by written request from Novartis in the U.S. Cosyntropin stimulation test : The Synacthen test is performed with synthetic ACTH (amino acids 1 \200\22324) which stimulates the adrenal glands See Box 12.1. 2 Importantly, the Cosyntropin test is unreliable for assessing adrenal dysfunction attribu table to acute CRH/ACTH de \201 ciencies (within several weeks). CRH test for Cushing \200\231s disease Administration of 100 mcg of CRH (IV) leads to an ex aggerated rise in cortisol (20%, above basal at 30/45 minutes (mean)) and ACTH (35% above b asal at 15/30 minutes (mean)) in patients with Cushing \200\231s disease. The test sensitivity and speci \201 city are 91% and 88%, respectively. 12-Draznin-Chap12.indd 91 4/1/2011 6:01:35 PM CHAPTER 12 Pituitary function testing 92 Box 12.1 Cosyntropin stimulation test \200 The test can be done at any time of the day. \200 Prednisone and hydrocortisone, but not dexamethasone, interfere with the cortisol assay. Synacthen is administered 250 mcg IV, and cortisol is measured at 0, 30 and 60 minutes. A normal post-stimulation cortisol level should increase to >18 mcg/dL. \200 Controversy still exists regarding the utility of the low-dose (1 mcg) ACTH test, although this test is limited by the lack of a commercially- available preparation. In addition, a number of stu dies showed comparable test performance characteristics between the high-dose (250 mcg) and the low-dose ACTH tests. Suppression tests for Cushing \200\231s syndrome \200 1 mg dexamethasone suppression test : 1 mg dexamethasone is given between 11 and 12 P.M., and a serum cortisol is drawn the fol lowing morning (8 A.M.). \200 Interpretation: cortisol <1.8 mcg/dL (with a sensitive cort isol assay) excludes Cushing \200\231s syndrome 8 mg dexamethasone suppression test is used to distinguish ectopic Cushing \200\231s from C ushing \200\231s disease. 8 mg dexamethasone is given at 11 \200\22312 P.M., and a random c ortisol is drawn the following morning. \200 Interpretation: A (cid:2) 50% decreases in b asal cortisol level is suggestive of CD, although 20% of ectopic ACTH tumors (particularly bronchia Carcinoids) may suppress to this degree. DEX-CRH test is used to distinguish pseudo-Cushing \200\231s disease from Cushing \200\231s disease: Dexamethasone (0.5 mg q6h x 8 doses) starting at 12 noon, followed by CRH adminis tration (1 mcg/kg) at 8 A.M. (2 hours after the \201 nal dexamethasone dose). \200 Norm al cortisol suppression will be observed in pseudo-Cushing \200\231s disease: cortisol <1.4 mcg/dL (5-15 minutes after CRH), but not in Cushing \200\231s disease. Test sensitivity an d speci \201 city are 98% and 70%, respectively. 12-Draznin-Chap12.indd 92 4/1/2011 6:01:35 PM SOMATOTROPES 93 Somatotropes Basal testing Insulin-like growth factor-1 (IGF-1) represents integrated GH se cretion and varies signi \201 cantly with age and gender. 2 IGF-1 is generally not a good indicator for GH de \201 ciency in adults >40 years of age. Random growth hormone levels are generally not useful unless very low (excludes acromegaly) or very elevated [(suggestive of acromegaly) and excludes growth hormone de \201 ciency ( GHD)]. Patients with (cid:2)3 pituitary hormone de \201 ciencies, and a low IGF-1 level, have a > 95% probability of GHD and can generally forego GH stimulation testing. Suppression test for acromegaly Oral glucose (75 g) is given after an overnight fast, follo wed by serial GH measurements every 30 minutes \227 2 hours. Normal response is GH <1 mcg/ dL (with RIA) and <0.30 mcg/dL (with ultrasensitive GH assays). Stimulation tests for growth hormone de \201 ciency The insulin tolerance test is the gold standard for GHD testing, although it has limited use because of the disadvantages stated above. GHRH plus arginine (Semorelin) is the second-best provocative test for GH de \201 - ciency, but is no longer commercially available in the U.S. \200 Glucagon and arginine , although suboptimal GH secretagogues, are now commonly used to assess GHD. Glucagon test protocol: Glucagon-1 mg IM is given, followed by serial GH measurements q 30 minutes for 3 hours . \200 Normal response: GH level >3 mcg/dL (usin g an ultrasensitive assay). Test sensitivity and speci \201 city are >95%. Arginine test protocol: Arginine 0.5g/kg (max 30 g) in 100 mL normal saline is infused IV over 30 minutes, followed by serial GH measurements q 30 minute s for 2 hours. \200 Normal response: GH level >0.4 mcg/dL. Test sensitivity is 87% and speci \201 city is 91%. Further reading Gasco V, Corneli G, Rovere S, Croce C, et al. (2008). Diagnosis of adult GH de \201 ciency. Pituitary 11:121 \200\223128. Kola B, Grossman AB. (2008). Dynamic testin g in Cushing \200\231s syndrome. Pituitary 11:155 \200\223162. 12-Draznin-Chap12.indd 93 4/1/2011 6:01:35 PM CHAPTER 13 Hypopituitarism 94 Hypopituitarism De \201 nition Hypopituitarism is de \201 ned as the partial or complete de \201 ciency of one or more pituitary hormones from hypothalamic or pituitary gland diseases. Etiologies of hypopituitarism 2 Pituitary tumors and/or their treatments account for 775% o f cases (in adults) \200 Radiotherapy \200\224hypothalamus, pituitary, skull base tumors \200 Pituitary infarction/hemorrhage \200 In \201 ltrative diseases \200\224sarcoidosi s, lymphocytic hypophysitis hemochromatosis, Langerhans \200\231 cell histiocytosis, metastases. Infection \200\224tuberculosis, pituitary abscess, meningitis \200 Traumatic brain injury \200 Isolated hypothalamic releasing hormone de \201 ciency \200\224e.g., Kallmann \200 \231s syndrome is congenital GnRH de \201 ciency + anosmia Parasellar tumors \200\224craniopharyngiomas, meningiomas, chordomas, gliomas, schwanomas Congenital pituitary transcription factor mutations: POU1F1 gene mutations (GH, PRL, and TSH de \201 ciencies). PROP1 gene mutations (GH, PRL, TSH, FSH/LH ACTH de \201 ciencies). Isolated ACTH de \201 ciency (very rare) 13-Draznin-Chap13.indd 94 3/31/2011 4:55:27 PM FEATURES 95 Features The clinical features of hypopituitarism depend on the severity of the hor- mone d e \201 ciency (from partial to complete) and the rate of development (from acute to chroni c) (see Table 13.1 ). 2 The loss of anterior pituitary hormone function, from pituitary dis eases and/or their treatments, generally follows a predictable order: GH 8 GnRH > ACTH 8 TSH >PRL ADH de \201 ciency is very rare with pituitary adenomas. \200 The clinical features of h ypopituitarism are generally similar to those of target gland insuf \201 ciency. A notable exception is the lack of pigmentation a nd hyperkalemia in secondary adrenal insuf \201 ciency vs. primary adrenal insuf \201 cie ncy. Houssay phenomenon is de \201 ned as the improvement of diabetes mellitus in patients with hypopituitarism due to a reduction in counterregulatory hormones (GH and cortisol). Apoplexy Apoplexy is the clinical syndrome of sudden headache, visual impairment, ophthalmo plegia, and/or altered mental status caused by hemorrhage or infarction of the pituitary gl and. It occurs in 710 \200\22315% of pituitary adenomas. Subclinical apoplexy is more commo n than clinically-apparent disease. Treatment Surgical decompression is indicated for patients with severe neuro- ophthalamolog ic signs, such as severely reduced visual acuity or a deteri- orating level of consciousnes s. Secondary adrenal insuf \201 ciency complicates up to 70% of apoplectic patients, and i s a major cause of morbidity and mortality in untreated cases. Stress-dose glucocorticoids (50 \200\223100 mg IV hydrocortisone q 6 \200\2238 hours) are i ndicated for patients with proven or presumptive adrenal insuf \201 ciency (i.e., hemodyna mic instability). Panhypopituitarism is common and should be evaluated and managed expectan tly after an acute apoplectic event. Empty sella syndrome (ESS) ESS is de \201 ned as a sella that is partially or completely \201 lled with CSF. \200 Primary ESS is most often due to arachnoid herniation through a congenital diaphragmatic defect. Hyperprolactinemia occurs in 710% of cases, but hypopituit arism is uncommon. Secondary ESS is due to a pituitary tumor and/or its treatment (e.g., apoplexy, surgery or radiotherapy). Hypopituitarism is common with this condition. Traumatic brain injury (TBI) TBIs associated with subarachnoid hemorrhage and skull-based f ractures have a high incidence of hypopituitarism. In addition, patients with moder- ate-to -severe head traumas are also at increased risk for hypopituitarism. The most common de \201 ciencies are GH and gonadotropins (10 \200\22315% of cases), and these are best assess ed at 6 \200\22312 months, post-TBI. 13-Draznin-Chap13.indd 95 3/31/2011 4:55:27 PM CHAPTER 13 Hypopituitarism 96 Table 13.1 Clinical features of pituitary hormone de \201 ciencies Hormone de \201 ciency GH ld IGF-1 Clinical features In children: short stature, decreased somatic maturation (e.g., bones and muscles) In adults: altered body composition (e.g., increased central adiposity/fat mass and reduced lean body mass), fatigue, reduced exercise capacity, impaired psychological well- being, r educed bone mineral density, pro-atherogenic lipid pro \201 le (i cardiovascular risk) In children: delayed puberty LH/FSH ld T and E In women: anovulatory cycles, oligo- or amenorrhea, vaginal dryness/atrophy, dyspareunia, h ot \202 ashes and breast atrophy In men: reduced libido, erectile dysfunction, testicular atrophy and decreased muscle mass and strength In both sexes: infertility, decreased bone mineral density and decreased body hair ACTH ld cortisol dDHEA-S Features as in Addison \200\231s disease, except lack of hyperpigmentation and hyperkalemia ( b p. 196) Acute: fatigue, anorexia, weight loss, nausea, vomiting, abdominal pain, hypog lycemia and circulatory collapse Chronic: fatigue, weight loss, decreased axillary/pubic ha ir, decreased libido, myalgias and arthralgias TSH ld T4/T3 Fatigue, dry skin, cold intolerance, constipation, weight gain, irregular menses (women), h air loss, brittle nails, bradycardia and normocytic anemia PRL Failure of lactation 13-Draznin-Chap13.indd 96 3/31/2011 4:55:27 PM TREATMENT 97 Investigations Basal levels Basal concentrations of the anterior pituitary hormones and their target organ hormones should be measured. Pituitary hormone de \201 ciencies are characterized by low levels of target hormones in the setting of low or inappropriately normal pituitary hormone levels. \200 TSH and free T 4 \200 ACTH and A.M.Cortisol \200 PRL \200 LH, FSH, A. M. testosterone (4 ), estradiol (5 ) \200 GH, IGF-1 Dynamic pituitary hormone testing This testing is done to assess for GHD and adrenal insuf \201 ciency (b see p. 92). Posterior pituitary function \200 Serum sodium, serum osmolality, urine osmolality and 24 -hour urinary volume A formal water deprivation test should be performed in cases of suspected diabetes insipidus. Treatment Hypopituitarism treatment involves management of the underlying eti- ology, and h ormone replacement as indicated ( b see p. 99) Further reading Marinis L, Bonadonna AB, Maira G, Giustina A (2005). Extensive clinical exp erience. Primary empty sella. J Clin Endocrinol Metab 90:5471 \200\2235477. Popovic V, Aimaretti G, Casanueva FF, Ghigo E (2005). Hypopituitarism following traumatic b rain injury. Growth Hormone IGF Res 15:177 \200\223184. Toogood AA, Stewart PM (2008). Hypopituitarism: clinical features, diagnosis and management . Endocrinol Metab Clin North Am 37:235 \200\223261. Rajasekaran S, Vanderpump M, Baldeweg WD, Narendra R, et al. (2011). UK guidelines for the management of pituitary apoplexy. Clinic Endo 74:9 \200\22320. 13-Draznin-Chap13.indd 97 3/31/2011 4:55:27 PM CHAPTER 14 Anterior pituitary hormone replacement 98 Anterior pituitary hormone replacement Background Anterior pituitary hormone de \201 ciencies are usually repleted with the tar- get hormones. Exceptions are GH replacement in adults, and gonadotro- pin replacement for f ertility treatment. Glucocorticoid replacement See Table 14.1 . \200 Patients with ACTH de \201 ciency need only glucocorticoid replacement, as mineralcorticoid secretion, via the renin \200\223angio tension \200\223aldosterone axis, is still intact. Prednisone and hydrocortisone are the most commonly used medications. Dexamethasone is generally avoided in secondary adrenal de \201 ciency because of its long half-life (36 hours), and non-physiological pro \201 le. The goal for replacement is the lowest possible glucocorticoid dose that eliminates clinica l features of glucocorticoid de \201 ciency (see Table 13.1), and also avoids clinical sig ns and symptoms of glucocorticoid excess (e.g., Cushingoid features, weight gain, hypertens ion, dyslipidemia, impaired glucose tolerance and decreased bone mineral density). 1 Patients with concomitant thyroid hormone de \201 ciency should initiate glucocorticoid replacement \201 rst, because T 4 accelerates cortisol metabo- lism and may precipitate a n adrenal crisis. Safety and stress-dose steroids Patients with adrenal insuf \201 ciency should be encourag ed to carry appro- priate medical identi \201 cation and should also be instructed in the indica- tions for increased glucocorticoid dosing, as follows: \200 Mild disease without fever: no change in glucocorticoid replacement \200 Febrile illness: double or triple the replacement dose for the duration of fever. \200\2343 x 3 \200\235 day rule Vomiting or diarrhea: parenteral therapy and seek medical assistance \200 Minor surgery ( e.g., under local anesthetic, arthroscopy, dental procedure): 25 mg hydrocortisone at the time of the procedure, then usual replacement dose. Moderate surgical stress (e.g., cholecystectomy, joint replacement): 50 \200\22375 mg hydrocortisone QD \227 2 days, then usual replacement dose \200 Severe illness/major operation: parenteral therapy (IV) hydrocortisone 50 \200\223100 mg q6 \200 \2238h \227 2 \200\2233 days, with subsequent taper to maintenance glucocorticoid dose 14-Draznin-Chap14.indd 98 4/1/2011 4:34:32 PM GROWTH HORMONE REPLACEMENT 99 Table 14.1 Pituitary hormone replacement regimens Hormone or drug Dosage Hydrocortisone or 15 \200\22325 mg/day (in 2 \200\2233 divided doses)10 \200\22315 mg on waking, 5 mg at earl y afternoon Prednisone 5 \200\2237.5 mg on waking L-thyroxine (T 4 ) GH 1.6 mcg/kg/day replacement dose Age <30 years 400 \200\223500 mcg/day Age 30 \200\22359 years 300 mcg/day Age >60 years 100 \200\223200 mcg/day Estrogen/progesterone/testosterone dDAVP Formulation dependant Intranasal spray (10 mcg BID) or oral tablets (100 mcg BID) are stand ard starting doses Growth hormone replacement X GH replacement has been approved for use in adult since 1996, but is still somewhat controversial regarding the cost \200\223bene \201 t ratio relative to other medical therapies for GHD-related comorbidities. GH therapy is most likely to bene \201 t those patients who have severe clinical and biochemical manifestations of GH de \201 ciency. Treatment and Monitoring \200 Start with a low, age-appropriate GH dose, and titrate acco rding to clinical response, IGF-1 levels and side effects. Goal: IGF-1 in the upper half of the normal range for age and gender \200 Annual lipid le vel, fasting blood sugar, DEXA scans (every 1 \200\2232 years) \200 Reversible, dose-depe ndent side effects: peripheral edema, headaches hypertension, arthralgias, carpal tunnel sy ndrome, impaired glucose tolerance or diabetes 2 In general, premenopausal women and women taking oral estrogens require higher GH doses t han do males, because estrogen antagonizes GH at the liver. 1 GH increases the conversion o f T 4 to T 3 , so GH replacement may decrease free T 4 levels. In addition, GH increases co rtisol metabo- lism to cortisone, so GH replacement may unmask subclinical adrenal insuf \201 ciency. 14-Draznin-Chap14.indd 99 4/1/2011 4:34:32 PM CHAPTER 14 Anterior pituitary hormone replacement 100 Thyroid hormone replacement This is as discussed in the section on primary hypothyroidism ( b p. 58). Monitoring In central hypothyroidism, unlike in primary hypothyroidism, the TSH level canno t be used to assess the adequacy of thyroid hormone replacement, and instead the free T 4 l evel is used exclusively for monitoring. \200 The free T 4 level should be maintained in the upper half or third of the normal range. Sex hormone replacement \200 b See Hormone replacement therapy in females (p. 268). \200 b Androgen replacement therapy in males (p. 296). \200 b Fertility treatment in males a nd females (p. 324 \200\223325). Further reading Auernhammer CJ, Vlotides G (2007). Anterior pituitary hormone replacement t herapy \200\224a clinical review. Pituitary 10:1 \200\22315. Crown A, Lightman S (2005). Why is the management of glucocorticoid de \201 ciency still c ontrover- sial: a review of the literature. Clin Endocrinol 63:483 \200\223492. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, et al. (2006). Evaluation and treatment of adult growth hormone de \201 ciency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 91:1621 \200\2231634. 14-Draznin-Chap14.indd 100 4/1/2011 4:34:32 PM CLASSIFICATION 101 Pituitary tumor basics Epidemiology \200 Pituitary adenomas are the most common pituitary disease in adults ( Box 15.1 ). Approximately 10% of the population harbors incidental adenomas, most commonly microadenomas (<5 mm). Clinically-apparent pituitary disease occurs in an estimated 71:10,000 people/year. Pituitary carcinomas are very rare (<0.1% of tumors), and but most commonly involve ACTH and PRL-secreting tumors. Classi \201 cation Size \200 Microadenoma <1 cm \200 Macroadenoma >1 cm Box 15.1 Lesions of the sellar turcica and parasellar regions Pituitary adenomas (>90% of sellar lesions) \200 Prolactinoma \200 Gonadotropinoma \200 Null cell adenoma \200 GH-secreting adenoma \200 ACTH-secreting adenoma \200 TS Homa Granulomatous, infectious, in \202 ammatory lesions \200 Abscess \200 Sarcoidosis \200 Tuberculosis \200 Histiocytosis X \200 Granulomatous disease \200 Lymphocytic h ypophysitis Cell rest tumors \200 Rathke \200\231s cleft cyst \200 Craniopharyngioma \200 Chordom a/chondrosarcoma \200 Epidermoid cyst Metastatic tumors Vascular aneurysms Benign lesions \200 Meningiomas \200 Gangiocytoma \200 Hypothalamic hamartoma \200 Schwannoma Miscellaneous \200 Empty sella syndrome \200 Arachnoid cyst \200 Gliomas, Germ cell t umor \200 Lymphoma 15-Draznin-Chap15.indd 101 4/1/2011 4:40:01 PM CHAPTER 15 Pituitary tumor basics 102 Functional status This is de \201 ned by clinical and biochemical evidence of hormone exce ss. Tumor Types and Distribution \200 Nonfunctioning adenomas (bonadotropinoma/null cell aden oma) 30 \200\22335% \200 Prolactinoma: 35 \200\22340% \200 Growth hormone adenoma (acro megaly): 10 \200\22315% \200 ACTH adenoma (Cushing \200\231s disease): 10 \200\22315% \200 TSH adenoma: <2% Mass effects Common with macroadenomas and include the following: \200 Headache \200 Vi sual \201 eld defects (uni- or bitemporal quadrantanopia or hemianopia) \200 Hypopituit arism \200 Ophthalmoplegia/cranial nerve palsies (CN III, IV and VI) \200 Vision loss ( optic nerve atrophy) \200 CSF rhinorrhea (rarely from inferior tumor extension) Pathophysiology \200 Adenomas are monoclonally-derived tumors, and they are categorized b y their hormone expression, as determined by clinical/biochemical features and immunohistoc hemical staining (on surgically-resected pathology specimens). The most important oncogene involved in sporadic pituitary adenomas tumorgenesis is gsp- wh ich encodes a constitutively-active mutation in the A-subunit of the stimulatory G protein. This mutation occurs in 740% of GH tumors. Various other mutations, including: growth factor receptors (FGFR4), tumor suppressor genes (ZAC, MEG3, menin, GADD45G), oncogenes (PTTG), cell signaling pathways (BMP-4), and cell c ycle regulators (p53, p27, p16, p18, cyclin D/E), have been detected in pituitary adenomas but do not account for most mutations. In addition, RAS mutations occur in rare pituitary c arcinomas. Inheritable diseases associated with pituitary tumors are uncommon (<5%) and include MEN-1, McCune \200\223 Albright syndrome, Carney \200\231s complex and familial somatotropinoma syndromes. PRL- and GH-secreting tumors are the most common tumor types. Investigations \200 For microadenomas, evaluate clinically and biochemically for hormone excess. Check basal PRL TSH, free T4, FSH, LH, testosterone (in males), estradiol (in femal es) and IGF-1 levels. Screen for Cushing \200\231s disease if clinically indicated (see , b p. 118). For macroadenomas, assess for hormone excess and de \201 ciencies. \200 Conduct formal v isual \201 eld tests for patients with subjective vision loss and with tumors that abut the optic chiasm. 15-Draznin-Chap15.indd 102 4/1/2011 4:40:01 PM MANAGEMENT AND NATURAL HISTORY 103 Management and natural history Adenomas with excess hormone secretion (of any size) and non - functioning macroadenomas associated with mass effects require treatment. \200 Medical therapy, with dopamine agonists, is \201 rst-line therapy for prolactinomas (micro- or macroadenomas). Transsphenoidal resection is indicated for all other functioning and non-functioning tumor types. For patients without speci \201 c indications for treatment, periodic MRI surveillance is recommended. Approximately 10% of incidentally-detected microadenomas and 730 \200\22350% of macroadenom as will signi \201 cantly enlarge, without treatment, over a 8 year period. Pituitary Tumor Evaluate Pituitary Hormones Nonfunctioning Hyper-functioning Prolactinoma All Others <1 cm >1 cm TSS DA agonist Mass Effects (HA, Vision \224 Hypopituitarsim) h t w o r G ? No Yes Reassess Periodically TSS Fig. 15.1 Algorithm for pituitary tumor evaluation. * Reassessment period varies by tumor s ize and clinical status, but generally includes annual MRIs, particularly for macroadenomas . Transsphenoidal surgery (TSS) is recommended for continued macroadenoma growth, before th e development of adverse mass effects. 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)