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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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slide1

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
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
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

Craniopharyngioma

Snyder, P. UpToDate

sellar masses1
Sellar Masses

Lymphocytic Hypophysitis

Pituitary Adenoma

Snyder, P. UpToDate

infiltrative disorders sarcoidosis
Infiltrative Disorders: Sarcoidosis

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

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. http://www.emedicine.com/med/topic1379.htm

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. http://www.emedicine.com/med/topic1379.htm

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. http://www.emedicine.com/med/topic1379.htm

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. http://www.emedicine.com/med/topic1379.htm

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

Normal

No Abnormalities

Observe

Treatment

Observe

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

pharmacotherapy
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
pharmacotherapy1
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
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

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 transsphenoidal surgery
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

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
acromegaly
Acromegaly

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

clinical findings of acromegaly
Clinical Findings of Acromegaly

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

complications of acromegaly
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

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

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

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

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

prolactin
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
prolactin1
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, 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
slide64

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)

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

prolactinomas
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
Treatment
  • 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

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

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

conclusion
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!!!