Thomas Repas DO FACP CDEThomas Repas DO FACP CDEUW Hospital and Clinics Department of Medicine UW Hospital and Clinics Department of Medicine

Section of Endocrinology, Diabetes & Metabolism Section of Endocrinology, Diabetes & Metabolism

H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792 H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792

Thursday October 13, 2005Thursday October 13, 2005

Anterior Pituitary Masses Anterior Pituitary Masses and Hyperprolactinemiaand Hyperprolactinemia

ObjectivesObjectives

• 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

I will not discuss in detail…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

Normal Pituitary AnatomyNormal Pituitary Anatomy

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

Normal Pituitary AnatomyNormal Pituitary Anatomy

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

Development of Human Anterior Development of Human Anterior PituitaryPituitary

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

Anterior Pituitary FunctionAnterior Pituitary Function

Corticotroph Gonadotroph Thyrotroph Lactotroph Somatotroph

Hormone POMC, ACTH FSH, LH TSH Prolactin GH

Stimulators CRH, AVP, gp-130

cytokines

GnRH, Estrogen

TRH Estrogen, TRH

GHRH, GHS

Inhibitors Glucocorticoids   Sex steroids, inhibin

T3, T4, Dopamine,

Somatostatin, GH

Dopamine Somatostatin, IGF-1,

Activins

Target Gland

Adrenals Ovary, Testes Thyroid Breast and other

tissues

Liver, bone and other

tissues

Trophic Effects

Steroid production

   Sex Steroid, Follicular growth,

Germ Cell maturation

T4 synthesis and

secretion

Milk Productio

n

IGF-1 production,

Growth induction,

Insulin antagonis

m

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

Etiology of Pituitary Etiology of Pituitary MassesMasses

Etiology of Pituitary-Hypothalamic Etiology of Pituitary-Hypothalamic LesionsLesions

• 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 Etiology of Pituitary-Hypothalamic Lesions Lesions (continued)(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 AdenomaPituitary Adenoma

Sellar MassesSellar Masses

Pituitary AdenomaPituitary Adenoma CraniopharyngiomaCraniopharyngioma

Snyder, P. UpToDate

Sellar MassesSellar Masses

Pituitary AdenomaPituitary Adenoma Lymphocytic HypophysitisLymphocytic Hypophysitis

Snyder, P. UpToDate

Infiltrative Disorders: SarcoidosisInfiltrative Disorders: Sarcoidosis

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

Evaluation of a Pituitary Evaluation of a Pituitary IncidentalomaIncidentaloma

Evaluation of an Incidental Evaluation of an Incidental Pituitary MassPituitary Mass

• Radiologic Evaluation

• Clinical Evaluation

• Hormonal Evaluation

Radiologic Evaluation: MRIRadiologic 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

Radiologic Evaluation: CTRadiologic 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 CTCraniopharyngioma on CT

Kruskal, J. UpToDate

Clinical EvaluationClinical 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 EvaluationHormonal 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 Hormonal Evaluation (continued)(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 Management of Pituitary TumorsPituitary Tumors

Management of Pituitary Management of Pituitary NeoplasiaNeoplasia

• Observation

• Pharmacotherapy

• Surgery

• Radiation Therapy

Pituitary IncidentalomaPituitary IncidentalomaPituitary IncidentalomaPituitary Incidentaloma

< 10 mm< 10 mm >> 10 mm 10 mm

Evaluate for Evaluate for Hormonal Hormonal

HypersecretionHypersecretion

Evaluate for: Evaluate for:

• Hormonal HypersecretionHormonal Hypersecretion

• Hormonal HyposecretionHormonal Hyposecretion

• Visual Changes/defectsVisual Changes/defects

Hormonal or Visual Hormonal or Visual Abnormalities Abnormalities NormalNormal No AbnormalitiesNo Abnormalities

ObserveObserve ObserveObserveTreatmentTreatment

Observation and Follow-upObservation 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

PharmacotherapyPharmacotherapy

• 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

PharmacotherapyPharmacotherapy

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 SurgeryPituitary 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 Outcome of Transsphenoidal SurgerySurgery

Tumor Remission (%)  Recurrence at 10 years (%)

Non-functioning Non-functioning adenomaadenoma  

Not applicable*  16

GH adenomaGH adenoma Microadenoma

88 1.3

Macroadenoma  65    

PRL adenomaPRL adenoma Microadenoma 

87  13

Macroadenoma  56     

ACTH adenomaACTH adenoma Microadenoma 

91  12 (Adults), 42 (Pediatric)

Macroadenoma  65     *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 ADENOMASChapter 13. http://www.endotext.com/neuroendo/neuroendo13/neuroendoframe13.htm

Complications of Complications of Transsphenoidal SurgeryTranssphenoidal Surgery

Outcome Measure Outcome Measure  Incidence (%)Incidence (%)

Mortality Mortality  <0.5

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

1.5

Minor complicationMinor complication (sinus disease, septal perforations, epistaxis, wound infections and hematomas) 

6.5

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

Radiation TherapyRadiation Therapy

• Reserved for patients with larger tumors and/or persistent hormonal hyperfunction despite surgical intervention

– Conventional radiotherapy– Gamma knife radiosurgery

Conventional RadiotherapyConventional 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.

Gamma Knife RadiosurgeryGamma 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.

Abnormal Pituitary Function Abnormal Pituitary Function Associated with Pituitary Associated with Pituitary

TumorsTumors

Disorders of Pituitary FunctionDisorders of Pituitary Function

• Hypopituitarism– Central hypoadrenalism, hypogonadism,

hypothyroidism or GH deficiency – Panhypopituitarism

• Hypersecretion of Pituitary Hormones– Hyperprolactinemia– Acromegaly– Cushing’s Disease

AcromegalyAcromegaly

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

Wright, V. UpToDate

Clinical Findings of AcromegalyClinical Findings of Acromegaly

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

Symptoms and signs at presentation 

Overall prevalence (%)

Facial change, acral enlargement, and soft-tissue swelling

100

Excessive sweating 83

Acroparesthesiae/ carpal tunnel syndrome 68

Tiredness and lethargy 53

Headaches 53

Oligo- or amenorrhea, infertility 55*

Erectile dysfunction and/or decreased libido 42#

Arthropathy 37

Impaired glucose tolerance/ diabetes 37

Goiter 35

Ear, nose throat and dental problems 32

Congestive cardiac failure/ arrythmia 25

Hypertension 23

Visual field defects 17

* percentage of female patients# percentage of male patients

Complications of AcromegalyComplications of Acromegaly

Cardiovascular • Ischemic heart disease• Cardiomyopathy • Congestive heart failure• Arrhythmias• Hypertension

Respiratory• Kyphosis• Obstructive sleep apnea

Metabolic• Diabetes mellitus/IGT• Hyperlipidemia

NeurologicNeurologic•Carpal Tunnel syndrome•Stroke

Neoplastic Neoplastic •Colorectal •(Breast and prostate - uncertain)

MusculoskeletalMusculoskeletal •Degenerative arthropathy •Calcific discopathy, pyrophosphate arthropathy

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

Acromegaly: Causes of Death

• Cardiovascular- 38 to 62 percentCardiovascular- 38 to 62 percent

• Respiratory- 0 to 25 percentRespiratory- 0 to 25 percent

• Malignancy- 9 to 25 percentMalignancy- 9 to 25 percent

Diagnosis of AcromegalyDiagnosis 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

Cushing’s DiseaseCushing’s Disease

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

Cushing’s Syndrome vs. Cushing’s Cushing’s Syndrome vs. Cushing’s DiseaseDisease

• Cushing’s syndromeCushing’s syndrome is a syndrome due to excess cortisol from pituitary, adrenal or other sources (exogenous glucocorticoids, ectopic ACTH, etc.)

• Cushing’s diseaseCushing’s disease is hypercortisolism due to excess pituitary secretion of ACTH (about 70% of cases of endogenous Cushing’s syndrome)

Cushing’s SyndromeCushing’s 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 Cushing’s Disease

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

Progressive Obesity of Cushing’s Disease

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

Age 6Age 6 Age 7 Age 7 Age 8 Age 8 Age 9Age 9 Age 11Age 11

Buffalo Hump in Cushing’s Disease

Orth, D. UpToDate

Striae in Cushing’s DiseaseStriae in Cushing’s Disease

Orth, D. UpToDate

Proximal Muscle Wasting in Proximal Muscle Wasting in Cushing’s SyndromeCushing’s Syndrome

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

Diagnosis of Cushing’s SyndromeDiagnosis of Cushing’s Syndrome

• ACTH, AM cortisol

• 24 hour urine cortisol

• Dexamethasone suppression testing

• Midnight salivary cortisol

Dexamethasone Suppression TestDexamethasone Suppression Test

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

Circadian Studies of Serum Cortisol Circadian Studies of Serum Cortisol LevelsLevels

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

Hyperprolactinemia Hyperprolactinemia and Prolactinomasand Prolactinomas

ProlactinProlactin

• 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

ProlactinProlactin

• 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, thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP)

Clinical Features of Clinical Features of Hyperprolactinemia/ProlactinomaHyperprolactinemia/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 HyperprolactinemiaCauses 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 Causes of Hyperprolactinemia (continued)(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:REMEMBER: Not all Not all hyperprolactinemia is due to hyperprolactinemia is due to

a prolactinomaa prolactinoma

REMEMBER:REMEMBER: Not all Not all hyperprolactinemia is due to hyperprolactinemia is due to

a prolactinomaa 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; 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; 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.JAMA 1976; 235:2316; Am J Cardiol 1983; 51:1466; J Clin Endocrinol Metab 1985; 60:144.

Work up of Patient with Work up of Patient with HyperprolactinemiaHyperprolactinemia

• 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

ProlactinomasProlactinomas

• 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 TherapyDopamine Agonist Therapy

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

Long-term Effects of Bromocriptine Long-term Effects of Bromocriptine TherapyTherapy

J Clin Endocrinol Metab 50:1026 1033

Success Rate of Bromocriptine in Success Rate of Bromocriptine in AmenorrheaAmenorrhea

• 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 Decrease in Size of Prolactinoma after Bromocriptine after Bromocriptine

Abrahamson, M. UpToDate

Dopamine AgonistsDopamine 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

ConclusionConclusion

• 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!!!