Anterior Pituitary Masses and Hyperprolactinemia

Thomas Repas DO FACP CDE

UW Hospital and Clinics Department of Medicine Section of Endocrinology, Diabetes & Metabolism H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792

Thursday October 13, 2005

Objectives
Causes of Pituitary Masses Evaluation of a Pituitary Incidentaloma Management of Pituitary Neoplasia Abnormal Anterior Pituitary Function Associated with Pituitary Masses
Causes Management

Hyperprolactinemia and Prolactinomas

I will not discuss in detail

Management of Cushings Disease Management of Acromegaly Management of Hypopituitarism Evaluation and Management of Posterior Pituitary Disorders and Diabetes Insipidus

Normal Pituitary Anatomy

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

Normal Pituitary Anatomy

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

Development of Human Anterior Pituitary

Cohen and Radovick, Endocrine Reviews 23: 431-442, 2002

Anterior Pituitary Function

Corticotroph
Hormone Stimulators POMC, ACTH CRH, AVP, gp130 cytokines Glucocorticoids

Gonadotroph
FSH, LH GnRH, Estrogen Sex steroids, inhibin

Thyrotroph
TSH TRH

Lactotroph
Prolactin Estrogen, TRH Dopamine

Somatotroph
GH GHRH, GHS

Inhibitors

T3, T4, Dopamine, Somatostati n, GH Thyroid

Somatostatin, IGF-1, Activins Liver, bone and other tissues IGF-1 production, Growth induction, Insulin antagonis m

Target Gland Trophic Effects

Adrenals

Ovary, Testes

Breast and other tissues Milk Productio n

Steroid production

Sex Steroid, Follicular growth, Germ Cell maturation

T4 synthesis and secretion

Adapted from: Williams Textbook of Endocrinology, 10th ed., Figure 8 -4, pg 180.

Etiology of Pituitary Masses

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

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)

Pituitary Adenoma

Sellar Masses

Pituitary Adenoma
Snyder, P. UpToDate

Craniopharyngioma

Sellar Masses

Pituitary Adenoma

Lymphocytic Hypophysitis

Snyder, P. UpToDate

Infiltrative Disorders: Sarcoidosis

From EndoText: http://www.endotext.com/neuroendo/neuroendo4/neuroendoframe4.htm

Evaluation of a Pituitary Incidentaloma

Evaluation of an Incidental Pituitary Mass

Radiologic Evaluation Clinical Evaluation Hormonal Evaluation

Radiologic Evaluation: MRI

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

Radiologic Evaluation: CT
Better at visualizing bony structures and calcifications within soft tissues Better at determining diagnosis of tumors with calcification, such as germinomas, craniopharyngiomas, and meningiomas May be useful when MRI is contraindicated, such as in patients with pacemakers or metallic implants in the brain or eyes Disadvantages include:
less optimal soft tissue imaging compared to MRI use of intravenous contrast media exposure to radiation

Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

Craniopharyngioma on CT

Kruskal, J. UpToDate

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

Hormonal Evaluation
May include of both basal hormone measurement and dynamic stimulation testing. All pituitary masses should have screening basal hormone measurements, including:
Prolactin TSH, FT4 ACTH, AM cortisol, midnight salivary cortisol LH, FSH, estradiol or testosterone Insulin-like growth factor-1 (IGF-1)

Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

Hormonal Evaluation

(continued)

Dynamic stimulation/suppression testing may be useful in select cases to further evaluate pituitary reserve and/or for pituitary hyperfunction
Dexamethasone suppression testing Oral glucose GH suppression test GHRH, L-dopa, arginine CRH stimulation Metyrapone TRH stimulation GnRH stimulation Insulin-induced hypoglycemia

Mulinda, J. Pituitary Macroadenomas, 9/19/05. http://www.emedicine.com/med/topic1379.htm

Management of Pituitary Tumors

Management of Pituitary Neoplasia

Observation Pharmacotherapy Surgery Radiation Therapy

Pituitary Incidentaloma

< 10 mm

> 10 mm

Evaluate for: Evaluate for Hormonal Hypersecretion

Hormonal Hypersecretion

Hormonal Hyposecretion
Visual Changes/defects

Normal

Hormonal or Visual Abnormalities

No Abnormalities

Observe

Treatment

Observe

Observation and Follow-up

If less than 20 mm and no neurologic or hormonal abnormalities:
Monitor for adenoma size, visual changes, and hormonal hypersecretion in 6 and 12 months, then annually for a few years

Lesions less than 10 mm and proven to have no hormonal hypersecretion:

Lesions 2 to 4 mm: no further testing required Lesions 5 to 9 mm: MRI can be done once or twice over the subsequent two years; if the lesion is stable in this period, the frequency can be decreased
Peter J Snyder MD, Pituitary incidentaloma UpToDate November 25, 2003

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

Pharmacotherapy
Which pharmacologic option to choose depends on type of tumor: Dopamine agonists: bromocriptine, cabergoline- most
useful for prolactinomas, less useful for GH secreting adenomas

Somatostatin analog (Octreotide, Octreotide LAR)- most useful for acromegaly Pegvisomant (GH receptor blocker)- useful in
acromegaly refractory to somatostatin analogues

Other: ketoconazole, metyrapone, mitotane- for

Cushings disease- use limited by side effects, expense and lack of efficacy

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

Indications for Surgery

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

Outcome of Transsphenoidal Surgery

Tumor
Non-functioning adenoma GH adenoma Microadenoma Macroadenoma PRL adenoma Microadenoma Macroadenoma ACTH adenoma Microadenoma Macroadenoma

Remission (%)
Not applicable* 88 65 87 56 91 65

Recurrence at 10 years (%)

16 1.3

13

12 (Adults), 42 (Pediatric)

*Visual improvement occurs in 87% of those with preoperative visual loss.

John A. Jane, Jr., MD Edward R. Laws, Jr., MD, SURGICAL MANAGEMENT OF PITUITARY ADENOMAS Chapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm

Complications of Transsphenoidal Surgery

Outcome Measure
Mortality Major complication (CSF leak,
meningitis, ischemic stroke, intracranial hemorrhage, vascular injury, visual loss)

Incidence (%)
<0.5 1.5

Minor complication (sinus

6.5

disease, septal perforations, epistaxis, wound infections and hematomas)

John A. Jane, Jr., MD Edward R. Laws, Jr., MD, SURGICAL MANAGEMENT OF PITUITARY ADENOMAS Chapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm

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

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

Gamma Knife Radiosurgery

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

Abnormal Pituitary Function Associated with Pituitary Tumors

Disorders of Pituitary Function

Hypopituitarism
Central hypoadrenalism, hypogonadism, hypothyroidism or GH deficiency Panhypopituitarism

Hypersecretion of Pituitary Hormones

Hyperprolactinemia Acromegaly Cushings Disease

Acromegaly

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

Wright, V. UpToDate

Clinical Findings of Acromegaly

Symptoms and signs at presentation
Facial change, acral enlargement, and soft-tissue swelling Excessive sweating Acroparesthesiae/ carpal tunnel syndrome Tiredness and lethargy Headaches Oligo- or amenorrhea, infertility Erectile dysfunction and/or decreased libido Arthropathy Impaired glucose tolerance/ diabetes Goiter Ear, nose throat and dental problems Congestive cardiac failure/ arrythmia Hypertension Visual field defects
* percentage of female patients # percentage of male patients http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm

Overall prevalence (%)

100 83 68 53 53 55* 42# 37 37 35 32 25 23 17

Complications of Acromegaly
Cardiovascular Ischemic heart disease Cardiomyopathy Congestive heart failure Arrhythmias Hypertension Respiratory Kyphosis Obstructive sleep apnea Metabolic Diabetes mellitus/IGT Hyperlipidemia
http://www.endotext.com/neuroendo/neuroendo5e/neuroendoframe5e.htm

Neurologic Carpal Tunnel syndrome Stroke Neoplastic Colorectal (Breast and prostate - uncertain) Musculoskeletal Degenerative arthropathy Calcific discopathy, pyrophosphate arthropathy

Acromegaly: Causes of Death

Cardiovascular- 38 to 62 percent Respiratory- 0 to 25 percent Malignancy- 9 to 25 percent

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

Cushings Disease

Williams Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

Cushings Syndrome vs. Cushings Disease

Cushings syndrome is a syndrome due to excess cortisol from pituitary, adrenal or other sources (exogenous glucocorticoids, ectopic ACTH, etc.) Cushings disease is hypercortisolism due to excess pituitary secretion of ACTH (about 70% of cases of endogenous Cushings syndrome)

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

Central Obesity in Cushings Disease

Williams Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

Progressive Obesity of Cushings Disease

Age 6

Age 7

Age 8

Age 9

Age 11

Williams Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

Buffalo Hump in Cushings Disease

Orth, D. UpToDate

Striae in Cushings Disease

Orth, D. UpToDate

Proximal Muscle Wasting in Cushings Syndrome

Williams Textbook of Endocrinology. 8th Ed. Foster, DW, Wilson, JD (Eds), WB Saunders, Philadelphia, 1996

Diagnosis of Cushings Syndrome

ACTH, AM cortisol 24 hour urine cortisol Dexamethasone suppression testing Midnight salivary cortisol

Dexamethasone Suppression Test

http://www.endotext.com/neuroendo/neuroendo7/neuroendoframe7.htm

Circadian Studies of Serum Cortisol Levels

http://www.endotext.com/neuroendo/neuroendo7/neuroendoframe7.htm

Hyperprolactinemia and Prolactinomas

Prolactin
Human prolactin is a 198 amino acid polypeptide Primary function is to enhance breast development during pregnancy and to induce lactation Prolactin also binds to specific receptors in the gonads, lymphoid cells, and liver Secretion is pulsatile; it increases with sleep, stress, pregnancy, and chest wall stimulation or trauma

Prolactin
Secretion of prolactin is under tonic inhibitory control by dopamine, which acts via D2-type receptors located on lactotrophs
Prolactin production can be stimulated by the hypothalamic peptides, thyrotropinreleasing hormone (TRH) and vasoactive intestinal peptide (VIP)

Clinical Features of Hyperprolactinemia/Prolactinoma

Women may present with oligomenorrhea, amenorrhea, galactorrhea or infertility Men often have less symptoms than women (sexual dysfunction, visual problems, or headache) and are diagnosed later In both sexes, tumor mass effects may cause visual-field defects or headache

Causes of Hyperprolactinemia
Hypothalamic Dopamine Deficiency
Diseases of the hypothalamus( including tumors, arterio-venous malformations, and inflammatory processes Drugs (e.g. alpha-methyldopa and reserpine)

Defective Transport Mechanisms

Section of the pituitary stalk Pituitary or stalk tumors

Causes of Hyperprolactinemia
(continued)

Lactotroph Insensitivity to Dopamine

Dopamine-receptor-blocking agents: phenothiazines (e.g. chlorpromazine), butyrophenones (haloperidol), and benzamides (metoclopramide, sulpiride, and domperidone)

Stimulation of Lactotrophs
Hypothyroidism- increased TRH production (acts as a PRF) Estrogens: stimulate lactotrophs Injury to the chest wall: abnormal stimulation of the reflex associated with the rise in prolactin that is seen normally in lactating women during suckling

REMEMBER: Not all hyperprolactinemia is due to a prolactinoma

Am J Obstet Gynecol 1972; 113:14; N Engl J Med 1977; 296:589; Clin Ther 200; 22:1085; Clin Endocrinol 1976; 5:273; J Clin Endocrinol Metab 1976; 42:1148; J Clin Endocrinoll Metab 42: 181; J Clin Endocrinol Metab 1982; 54:869; Br Med J 1976; 1:1186; JAMA 1976; 235:2316; Am J Cardiol 1983; 51:1466; J Clin Endocrinol Metab 1985; 60:144.

Work up of Patient with Hyperprolactinemia

In females, pregnancy must always be ruled out Get a TSH- hypothyroidism is another common cause of elevated prolactin: Obtain detailed drug history- rule out medication effects Rule out other common causes including:
Nonfasting sample Nipple stimulation or sex Excessive exercise History of chest wall surgery or trauma Renal failure Cirrhosis

If no cause determined or tumor suspected, consider MRI, especially if high prolactin levels (> 100 ng/mL)
http://www.emedicine.com/Med/topic1915.htm

Prolactinomas
Most common of functional pituitary adenomas 25-30% of all pituitary adenomas Some growth hormone (GH)producing tumors also co-secrete PRL Of women with prolactinomas- 90% present with microprolactinomas Of men with prolactinomas- up to 60% present with macroprolactinomas

http://www.emedicine.com/Med/topic1915.htm

Treatment
Pharmacotherapy Surgical resection Radiotherapy

Pharmacotherapy of Prolactinomas
Dopamine agonists are treatment of choice for most prolactinomas Choices include Bromocriptine, Pergolide and Cabergoline Side effects include: postural hypotension, dizziness, nasal stuffiness, GI side effects.

Dopamine Agonist Therapy

Webster, J et al. N Engl J Med 1994; 331:904.

Long-term Effects of Bromocriptine Therapy

J Clin Endocrinol Metab 50:1026 1033

Success Rate of Bromocriptine in Amenorrhea

After 1 month of treatment, one woman in four will return to normal menstrual cycling; In 2 months, this number will increase to six out of 10 After 10 months, eight out of 10 women will be menstruating normally Of the remaining 20%, most are hypogonadal due to pituitary surgery or irradiation

http://www.endotext.com/neuroendo/neuroendo6/neuroendoframe6.htm

Decrease in Size of Prolactinoma after Bromocriptine

Abrahamson, M. UpToDate

Dopamine Agonists
Bromocriptine- start low dose at 1.25- 2.5 mg day at night before increasing to 2.5 10 mg per day in divided doses. Take with food to reduce side effects. Cabergoline- more effective and with less side effects than Bromocriptine but also more expensive- given once or twice a week with a starting dose of 0.25 mg 2 x week
Titrate these based on prolactin levels and tolerability

Conclusion
Pituitary microadenomas are common, not all are of clinical concern ALL pituitary tumors require evaluation of hormonal status Follow up and monitoring will depend on size and other features of tumor Dopamine agonists are the treatment of choice for most prolactinomas Surgical intervention is initial TOC for large tumors and other hyperfunctional tumors (GH, ACTH secreting) Not every patient with hyperprolactinemia has a prolactinoma!!!