Thomas Repas DO FACP CDE UW Hospital and Clinics Department of Medicine

1. Anterior Pituitary Masses and Hyperprolactinemia Thomas Repas DO FACP CDE UW Hospital and Clinics Department of Medicine Section of Endocrinology, Diabetes & Metabolism H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792 Thursday October 13, 2005

2. Objectives • Causes of Pituitary Masses • Evaluation of a Pituitary Incidentaloma • Management of Pituitary Neoplasia • Abnormal Anterior Pituitary Function Associated with Pituitary Masses • Hyperprolactinemia and Prolactinomas • Causes • Management

3. I will not discuss in detail… • Management of Cushing’s Disease • Management of Acromegaly • Management of Hypopituitarism • Evaluation and Management of Posterior Pituitary Disorders and Diabetes Insipidus

4. Normal Pituitary Anatomy Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987

5. Normal Pituitary Anatomy Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987

6. Development of Human Anterior Pituitary Cohen and Radovick, Endocrine Reviews 23: 431-442, 2002

7. Anterior Pituitary Function Adapted from: William’s Textbook of Endocrinology, 10th ed., Figure 8-4, pg 180.

8. Etiology of Pituitary Masses

9. Etiology of Pituitary-Hypothalamic Lesions • Non-Functioning Pituitary Adenomas • Endocrine active pituitary adenomas • Prolactinoma • Somatotropinoma • Corticotropinoma • Thyrotropinoma • Other mixed endocrine active adenomas • Malignant pituitary tumors:Functional and non-functional pituitary carcinoma • Metastases in the pituitary (breast, lung, stomach, kidney) • Pituitary cysts:Rathke's cleft cyst, Mucocoeles, Others • Empty sella syndrome

10. Etiology of Pituitary-Hypothalamic Lesions (continued) • Developmental abnormalities:Craniopharyngioma (occasionally intrasellar location), Germinoma, Others • Primary Tumors of the central nervous system: Perisellar meningioma, Optic glioma, Others • Vascular tumors:Hemangioblastoma, Others • Malignant systemic diseases:Hodgkin's disease, Non-Hodgkin lymphoma, Leukemic infiltration, Histiocystosis X, Eosinophilic granuloma, Giant cell granuloma (tumor) • Granulomatous diseases: Neurosarcoidosis, Wegner's granulomatosis, Tuberculosis, Syphilis • Vascular aneurysms (intrasellar location)

11. Pituitary Adenoma

12. Sellar Masses Pituitary Adenoma Craniopharyngioma Snyder, P. UpToDate

13. Sellar Masses Lymphocytic Hypophysitis Pituitary Adenoma Snyder, P. UpToDate

14. Infiltrative Disorders: Sarcoidosis From EndoText: http://www.endotext.com/neuroendo/neuroendo4/neuroendoframe4.htm

15. Evaluation of a Pituitary Incidentaloma

16. Evaluation of an Incidental Pituitary Mass • Radiologic Evaluation • Clinical Evaluation • Hormonal Evaluation

17. Radiologic Evaluation: MRI • Preferred imaging study for the pituitary • Better visualization of soft tissues and vascular structures than CT • No exposure to ionizing radiation • Images are generated based upon the magnetic properties of the hydrogen atoms • T1-weighted images produce high–signal intensity images of fat. Structures such as fatty marrow and orbital fat show up as bright images. • T2-weighted images produce high-intensity signals of structures with high water content, such as cerebrospinal fluid and cystic lesions Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

18. Radiologic Evaluation: CT • Better at visualizing bony structures and calcifications within soft tissues • Better at determining diagnosis of tumors with calcification, such as germinomas, craniopharyngiomas, and meningiomas • May be useful when MRI is contraindicated, such as in patients with pacemakers or metallic implants in the brain or eyes • Disadvantages include: • less optimal soft tissue imaging compared to MRI • use of intravenous contrast media • exposure to radiation Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

19. Craniopharyngioma on CT Kruskal, J. UpToDate

20. Clinical Evaluation • All patients with macroadenomas should have formal visual field testing • In addition to radiographic and hormonal evaluation, patients should be asked and examined for any clinical signs suspicious for pituitary hyperfunction or hypofunction

21. Hormonal Evaluation • Mayinclude of both basal hormone measurement and dynamic stimulation testing. • All pituitary masses should have screening basal hormone measurements, including: • Prolactin • TSH, FT4 • ACTH, AM cortisol, midnight salivary cortisol • LH, FSH, estradiol or testosterone • Insulin-like growth factor-1 (IGF-1) Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

22. Hormonal Evaluation (continued) Dynamic stimulation/suppression testing may be useful in select cases to further evaluate pituitary reserve and/or for pituitary hyperfunction • Dexamethasone suppression testing • Oral glucose GH suppression test • GHRH, L-dopa, arginine • CRH stimulation • Metyrapone • TRH stimulation • GnRH stimulation • Insulin-induced hypoglycemia Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

23. Management of Pituitary Tumors

24. Management of Pituitary Neoplasia • Observation • Pharmacotherapy • Surgery • Radiation Therapy

25. Pituitary Incidentaloma < 10 mm > 10 mm • Evaluate for: • Hormonal Hypersecretion • Hormonal Hyposecretion • Visual Changes/defects Evaluate for Hormonal Hypersecretion Hormonal or Visual Abnormalities Normal No Abnormalities Observe Treatment Observe

26. Observation and Follow-up • If less than 20 mm and no neurologic or hormonal abnormalities: • Monitor for adenoma size, visual changes, and hormonal hypersecretion in 6 and 12 months, then annually for a few years • Lesions less than 10 mm and proven to have no hormonal hypersecretion: • Lesions 2 to 4 mm: no further testing required • Lesions 5 to 9 mm: MRI can be done once or twice over the subsequent two years; if the lesion is stable in this period, the frequency can be decreased Peter J Snyder MD, “Pituitary incidentaloma” UpToDate November 25, 2003

27. Pharmacotherapy • Most useful in prolactinomas, alone or with other intervention. • May be used in certain other functioning tumors as adjunctive therapy along with surgical and/or radiotherapy

28. Pharmacotherapy Which pharmacologic option to choose depends on type of tumor: • Dopamine agonists:bromocriptine, cabergoline- most useful for prolactinomas, less useful for GH secreting adenomas • Somatostatin analog (Octreotide, Octreotide LAR)-most useful for acromegaly • Pegvisomant (GH receptor blocker)-useful in acromegaly refractory to somatostatin analogues • Other: ketoconazole, metyrapone, mitotane-for Cushings disease- use limited by side effects, expense and lack of efficacy

29. Pituitary Surgery • Transsphenoidal approach: used for 95% of pituitary tumors • Endonasal submucosal transseptal approach • Septal Pushover/Direct Sphenoidotomy • Endoscopic approach

31. Indications for Surgery • Surgery is the first-line treatment of symptomatic pituitary adenomas. • Useful when medical or radiotherapy fails • Surgery provides prompt relief from excess hormone secretion and mass effect. • Indicated in pituitary apoplexy with compressive symptoms

32. Outcome of Transsphenoidal Surgery John A. Jane, Jr., MD Edward R. Laws, Jr., MD,SURGICAL MANAGEMENT OF PITUITARY ADENOMASChapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm

33. Complications of Transsphenoidal Surgery John A. Jane, Jr., MD Edward R. Laws, Jr., MD,SURGICAL MANAGEMENT OF PITUITARY ADENOMASChapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm

34. Radiation Therapy • Reserved for patients with larger tumors and/or persistent hormonal hyperfunction despite surgical intervention • Conventional radiotherapy • Gamma knife radiosurgery

35. Conventional Radiotherapy • Response is slow, may take 5 to 10 years for full effect • Successful in up to 80% of acromegalics and 55-60% of Cushing’s disease • High rate of hypopituitarism: up to 60% • Other complications: optic nerve damage, seizures, radionecrosis of brain tissue Basic and Clinical Endocrinology, 6th ed. Chapter 5 Hypothalamus and Pituitary, 100-162.

36. Gamma Knife Radiosurgery • Stereotactic CT guided cobalt 60 gamma radiation to narrowly focused area • Long term data not yet available but suggest up to a 70% response rate for acromegaly and up to 70% for Cushing’s in some centers • Complication rate likely lower, but still high rate of hypopituitarism (~55%) Basic and Clinical Endocrinology, 6th ed. Chapter 5 Hypothalamus and Pituitary, 100-162.

37. Abnormal Pituitary Function Associated with Pituitary Tumors

38. Disorders of Pituitary Function • Hypopituitarism • Central hypoadrenalism, hypogonadism, hypothyroidism or GH deficiency • Panhypopituitarism • Hypersecretion of Pituitary Hormones • Hyperprolactinemia • Acromegaly • Cushing’s Disease

39. Acromegaly http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm

40. Wright, V. UpToDate

41. Clinical Findings of Acromegaly http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm

42. Complications of Acromegaly • Neurologic • Carpal Tunnel syndrome • Stroke • Neoplastic • Colorectal • (Breast and prostate - uncertain) • Musculoskeletal • Degenerative arthropathy • Calcific discopathy, pyrophosphate arthropathy Cardiovascular • Ischemic heart disease • Cardiomyopathy • Congestive heart failure • Arrhythmias • Hypertension Respiratory • Kyphosis • Obstructive sleep apnea Metabolic • Diabetes mellitus/IGT • Hyperlipidemia http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm

43. Acromegaly: Causes of Death • Cardiovascular- 38 to 62 percent • Respiratory- 0 to 25 percent • Malignancy- 9 to 25 percent

44. Diagnosis of Acromegaly • Random GH – not useful • Insulin like growth factor 1 (IGF-1) – best for screening • Oral glucose GH suppression testing – gold standard to confirm diagnosis

45. Cushing’s Disease William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

46. Cushing’s Syndrome vs. Cushing’s Disease • Cushing’s syndrome is a syndrome due to excess cortisol from pituitary, adrenal or other sources (exogenous glucocorticoids, ectopic ACTH, etc.) • Cushing’s disease is hypercortisolism due to excess pituitary secretion of ACTH (about 70% of cases of endogenous Cushing’s syndrome)

47. Cushing’s Syndrome • Proximal muscle weakness • Easy bruising • Hirsutism • Hypertension • Osteopenia • Diabetes mellitus/IGT • Impaired immune function/poor wound healing • Moon facies • Facial plethora • Supraclavicular fat pads • Buffalo hump • Truncal obesity • Weight gain • Purple striae

48. Central Obesity in Cushing’s Disease William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

49. Progressive Obesity of Cushing’s Disease Age 6 Age 7 Age 8 Age 9 Age 11 William’s Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

50. Buffalo Hump in Cushing’s Disease Orth, D. UpToDate