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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.

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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

  • 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 anatomy
Normal Pituitary Anatomy

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

normal pituitary anatomy1
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
Development of Human Anterior Pituitary

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

anterior pituitary function
Anterior Pituitary Function

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

etiology of pituitary hypothalamic lesions
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
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)
sellar masses
Sellar Masses

Pituitary Adenoma


Snyder, P. UpToDate

sellar masses1
Sellar Masses

Lymphocytic Hypophysitis

Pituitary Adenoma

Snyder, P. UpToDate

infiltrative disorders sarcoidosis
Infiltrative Disorders: Sarcoidosis

From EndoText:

evaluation of an incidental pituitary mass
Evaluation of an Incidental Pituitary Mass
  • Radiologic Evaluation
  • Clinical Evaluation
  • Hormonal Evaluation
radiologic evaluation mri
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.

radiologic evaluation ct
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.

craniopharyngioma on ct
Craniopharyngioma on CT

Kruskal, J. UpToDate

clinical evaluation
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
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.

hormonal evaluation continued
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.

management of pituitary neoplasia
Management of Pituitary Neoplasia
  • Observation
  • Pharmacotherapy
  • Surgery
  • Radiation Therapy
pituitary incidentaloma
Pituitary Incidentaloma

< 10 mm

> 10 mm

  • Evaluate for:
  • Hormonal Hypersecretion
  • Hormonal Hyposecretion
  • Visual Changes/defects

Evaluate for Hormonal Hypersecretion

Hormonal or Visual Abnormalities


No Abnormalities




observation and follow up
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

  • 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

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


complications of transsphenoidal surgery
Complications of Transsphenoidal Surgery


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

gamma knife radiosurgery
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.

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

clinical findings of acromegaly
Clinical Findings of Acromegaly

complications of acromegaly
Complications of Acromegaly
  • Neurologic
    • Carpal Tunnel syndrome
    • Stroke
  • Neoplastic
    • Colorectal
    • (Breast and prostate - uncertain)
  • Musculoskeletal
    • Degenerative arthropathy
    • Calcific discopathy, pyrophosphate arthropathy


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


  • Kyphosis
  • Obstructive sleep apnea


    • Diabetes mellitus/IGT
    • Hyperlipidemia

acromegaly causes of death
Acromegaly: Causes of Death
  • Cardiovascular- 38 to 62 percent
  • Respiratory- 0 to 25 percent
  • Malignancy- 9 to 25 percent
diagnosis of acromegaly
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
cushing s disease
Cushing’s Disease

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

cushing s syndrome vs cushing s disease
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)
cushing s syndrome
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
central obesity in cushing s disease
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
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

proximal muscle wasting in cushing s syndrome
Proximal Muscle Wasting in Cushing’s Syndrome

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

diagnosis of cushing s syndrome
Diagnosis of Cushing’s Syndrome
  • ACTH, AM cortisol
  • 24 hour urine cortisol
  • Dexamethasone suppression testing
  • Midnight salivary cortisol
dexamethasone suppression test
Dexamethasone Suppression Test

circadian studies of serum cortisol levels
Circadian Studies of Serum Cortisol Levels

  • 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
  • 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 hyperprolactinemia prolactinoma
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
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
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

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
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)

  • 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

  • Pharmacotherapy
  • Surgical resection
  • Radiotherapy
pharmacotherapy of prolactinomas
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
Dopamine Agonist Therapy

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

long term effects of bromocriptine therapy
Long-term Effects of Bromocriptine Therapy

J Clin Endocrinol Metab 50:1026 1033

success rate of bromocriptine in amenorrhea
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

dopamine agonists
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

  • 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!!!