Washington manual of endocrinology 3rd ed subspeciality consult

THE WASHINGTON MANUAL™Associate Professor of Medicine Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine St.. Clutter, MD Associate Profess

THE WASHINGTON MANUAL™

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

William E Clutter, MD

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Series Editors

Katherine E Henderson, MD

Assistant Professor of Clinical Medicine

Division of Medical Education

Washington University School of Medicine

Barnes-Jewish Hospital

St Louis, Missouri

Thomas M De Fer, MD

Professor of Medicine

Division of Medical Education

Washington University School of Medicine

St Louis, Missouri

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The Washington manual endocrinology subspecialty consult – 3rd ed / editors, Thomas J Baranski, William E Clutter, Janet B McGill.

p ; cm – (Washington manual subspecialty consult series)

Includes bibliographical references and index.

ISBN 978-1-4511-1407-2 (alk paper)

I Baranski, Thomas J.II Clutter, William E.III McGill, Janet B IV Washington University (Saint Louis, Mo.) School of Medicine V Title: Endocrinology subspecialty consult.VI Series: Washington manual subspecialty consult series.

[DNLM: 1 Endocrine System Diseases–Handbooks 2 Metabolic Diseases–Handbooks WK 39]

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Contributing Authors

Ana Maria Arbelaez, MD

Assistant Professor of Pediatrics

Division of Pediatric Endocrinology and Diabetes

Washington University School of Medicine

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Carlos Bernal-Mizrachi, MD

Assistant Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Kim Carmichael, MD

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Sara Chowdhury, MD

Clinical Fellow

Division of Endocrinology, Metabolism, and Lipid Research

Washington University School of Medicine

St Louis, Missouri

Roberto Civitelli, MD

Sydney M and Stella H Schoenberg Professor of Medicine

Professor of Orthopaedic Surgery and of Cell Biology and Physiology

Director, Bone and Mineral Diseases

Division of Endocrinology, Metabolism, and Lipid Research

Washington University School of Medicine

St Louis, Missouri

William E Clutter, MD

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid Research

Washington University School of Medicine

St Louis, Missouri

Philip E Cryer, MD

Irene E and Michael M Karl Professor of Endocrinology and Metabolism in Medicine

Division of Endocrinology, Metabolism, and Lipid Research

Washington University School of Medicine

St Louis, Missouri

Kathryn Diemer, MD

Assistant Professor of Medicine

Division of Bone and Mineral Diseases

Washington University School of Medicine

St Louis, Missouri

Judit Dunai, MD

Associate Professor of Medicine, Cell Biology, and Physiology

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Stephen J Giddings, MD, PhD

Associate Professor of Medicine

St Louis VA Medical Center

Washington University School of Medicine

St Louis, Missouri

Anne C Goldberg, MD, FACP, FAHA

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

Associate Professor of Pediatrics

Division of Pediatric Endocrinology and Diabetes

Washington University School of Medicine

St Louis, Missouri

Associate Professor of Medicine

Division of Geriatrics and Nutritional Science

Washington University School of Medicine

St Louis, Missouri

Amy E Riek, MD

Associate Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Dwight A Towler, MD, PhD

Lang Professor of Medicine

Division of Endocrinology, Metabolism, and Lipid ResearchWashington University School of Medicine

St Louis, Missouri

Clinical Fellow

Division of Endocrinology, Metabolism, and Lipid Research

Washington University School of Medicine

St Louis, Missouri

Michael P Whyte, MD

Professor of Medicine, Pediatrics, and Genetics

Division of Bone and Mineral Diseases

Washington University School of Medicine

Medical-Scientific Director, Center for Metabolic Bone Disease and Molecular

Research, Shriners Hospitals for Children, St Louis

St Louis, Missouri

Kevin Yarasheski, PhD

Professor of Medicine, Cell Biology, and Physiology, and Physical Therapy

Division of Endocrinology, Metabolism, and Lipid Research

Washington University School of Medicine

St Louis, Missouri

Washington Manual Subspecialty Series addresses this challenge by concisely and

practically providing current scientific information for clinicians to aid them in thediagnosis, investigation, and treatment of common medical conditions

I want to personally thank the authors, which include house officers, fellows, andattendings at Washington University School of Medicine and Barnes JewishHospital Their commitment to patient care and education is unsurpassed, and theirefforts and skill in compiling this manual are evident in the quality of the finalproduct In particular, I would like to acknowledge our editors, Drs Thomas J.Baranski, William E Clutter, and Janet B McGill, and the series editors, Drs.Katherine Henderson and Tom De Fer, who have worked tirelessly to produceanother outstanding edition of this manual I would also like to thank Dr MelvinBlanchard, Chief of the Division of Medical Education in the Department at ofMedicine at Washington University School of Medicine, for his advice andguidance I believe this Subspecialty Manual will meet its desired goal of providingpractical knowledge that can be directly applied at the bedside and in outpatientsettings to improve patient care

Victoria J Fraser, MD

Dr J William Campbell ProfessorInterim Chairman of MedicineCo-Director of the Infectious Disease DivisionWashington University School of Medicine

to serve as a comprehensive review of the field of endocrinology Rather, it focuses

on practical approaches to endocrine disorders commonly seen in consultation, withemphasis on key components of evaluation and treatment

Several changes in content were made with the third edition All chapters havebeen updated to provide the latest information on the pathophysiology and treatment

of endocrine disorders A new chapter has been added that covers InpatientManagement of Diabetes Drug dosing information was reviewed and updated ineach chapter Clinical pearls are highlighted in boldfaced text within the chapters

We are indebted to the remarkable efforts of the fellows and attending physicianswho contributed to the current edition of this manual and worked enthusiastically toprovide high-quality, contemporary, concise chapters

TJB WEC JBM

Prajesh M Joshi and Julie Silverstein

5 Syndrome of Inappropriate Antidiuretic Hormone

Scott Goodwin and Thomas J Baranski

PART II THYROID DISORDERS

6 Evaluation of Thyroid Function

PART III ADRENAL DISORDERS

10 Adrenal Incidentaloma

Shunzhong Bao and Simon J Fisher

11 Adrenal Insufficiency

Zhiyu Wang and Kim Carmichael

12 Adult Congenital Adrenal Hyperplasia

Judit Dunai and Kim Carmichael

Prajesh M Joshi and Simon J Fisher

PART IV GONADAL DISORDERS

Shunzhong Bao and Stephen J Giddings

20 Polycystic Ovary Syndrome

Nadia Khoury and Janet B McGill

PART V DISORDERS OF BONE AND MINERAL METABOLISM

24 Vitamin D Deficiency

Amy E Riek, Ana Maria Arbelaez, and Carlos Bernal-Mizrachi

25 Osteoporosis

Amy E Riek, Kathryn Diemer, and Roberto Civitelli

26 Paget’s Disease of Bone

Scott Goodwin and Michael P Whyte

PART VI DISORDERS OF FUEL METABOLISM

27 Standards of Care for Diabetes Mellitus

Prajesh M Joshi and Janet B McGill

28 Diabetes Mellitus Type 1

Judit Dunai and Janet B McGill

29 Diabetes Mellitus Type 2

Zhiyu Wang and Janet B McGill

30 Inpatient Management of Diabetes

David A Rometo and Garry Tobin

Mariko Johnson and Anne C Goldberg

PART VII NEOPLASMS

34 Multiple Endocrine Neoplasia Syndromes

Shunzhong Bao and Thomas J Baranski

35 Carcinoid Syndrome

Judit Dunai and Thomas J Baranski

36 Polyendocrine Syndromes

Prajesh M Joshi, Kavita Juneja, and Janet B McGill

37 Endocrine Disorders in HIV/AIDS

Scott Goodwin, Paul Hruz, and Kevin Yarasheski

1 Pituitary Adenomas

Zhiyu Wang and Julie Silverstein

GENERAL PRINCIPLES

Pituitary adenomas are benign neoplasms arising in the adenohypophysial cells Pituitary tumors constitute 10% of intracranial tumors

The most frequent primary pituitary tumors are pituitary adenomas

Pituitary adenomas occur in 10% to 15% of the general population1 and areusually benign

Most pituitary adenomas are sporadic, but some arise as a component of geneticsyndromes

Pituitary carcinomas are rare.2

Classification

According to the tumor size, pituitary adenomas are classified as microadenomas (<10 mm in greatest diameter) or macroadenomas (≥10 mm in greatest diameter) Depending on the cell of origin, they can be hormone-producing, or functionally

inactive (Table 1-1).3

Etiology

Pituitary adenomas arise as a result of monoclonal pituitary cell proliferation.Several different mutations have been associated with pituitary adenomas.4

Activating gsp mutations are present in 40% of GH-secreting adenomas These are

point mutations of the G protein alpha subunit (Gs alpha) gene, which activate Gsalpha protein and increase cyclic adenosine monophosphate (cAMP) levels,leading to GH hypersecretion and cell proliferation

H-ras gene mutations have been identified in metastatic pituitary carcinomas

Pituitary tumor transforming gene (PTTG) is abundant in all pituitary tumor types,especially prolactinomas

A truncated form of FGFR-4 is immunodetected in about a third of prolactinomas

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by combined tumorformation or hyperfunction of pancreatic islets, anterior pituitary, and parathyroidglands.

Carney’s complex is characterized by pituitary adenomas, cardiac myxomas,schwannomas, and thyroid adenomas with spotty skin pigmentation

Hypothalamic factors may promote and maintain growth of transformed pituitaryadenomatous cells There is emerging data that dysregulation of cell-cycle controlproteins, and loss of reticulin network play a role in pituitary tumor formation.4

TABLE 1-1 FUNCTIONAL CLASSIFICATION OF PITUITARY ADENOMAS

DIAGNOSIS

Clinical Presentation

The clinical presentation of pituitary adenomas depends on whether or not thetumor is hormonally functional or nonfunctional and on whether or not there ismass effect or hemorrhage

The diagnosis is sometimes made when a pituitary tumor is found incidentally onimaging studies performed for other reasons.5

Hormonal Hypersecretion

Prolactinomas (see Chapter 2, Prolactinoma)

Hyperprolactinemia causes hypogonadism in men and premenopausal women.Men present with decreased libido and impotence Women often present withabnormal menses or infertility and galactorrhea.6 There is often a delay in thediagnosis in postmenopausal women due to lack of clinical manifestations

Somatotroph adenomas (see Chapter 3, Acromegaly)

Acromegaly is growth hormone oversecretion occurring in the postpubertal phase

of life Gigantism is growth hormone excess that occurs before fusion of the

epiphyseal growth plates in children or adolescents Acromegaly is characterized

by skeletal overgrowth and soft tissue enlargement Acromegalic patients have anincrease in mortality related to associated cardiovascular, respiratory,gastrointestinal, and metabolic disorders.7 The onset of acromegaly is insidiousand often results in a delay in diagnosis

Corticotroph adenomas (see Chapter 14, Cushing’s Syndrome)

ACTH–secreting tumors cause Cushing’s disease.8 The classic symptoms andsigns of hypercortisolism are not always present and are often not specific.Obesity (predominantly central fat distribution), hypertension, glucose intolerance

or diabetes, hirsutism, and gonadal dysfunction are common Hypercortisolismproduces skin thinning, easy bruising, abdominal striae, and proximal muscleweakness (inability to climb stairs or rise from a deep chair) Psychiatricabnormalities occur in 50% of patients (depression, lethargy, paranoia, andpsychosis) Long-standing Cushing’s disease can cause osteoporosis and asepticnecrosis of the femoral and humeral heads Patients may present with poor woundhealing and frequent superficial fungal infections

Thyrotroph adenomas

Hyperthyroidism due to a TSH-secreting pituitary adenoma is very rare.9

Thyrotroph adenomas usually present as large macroadenomas, and >60% arelocally invasive

Gonadotroph adenomas

Gonadotroph adenomas are usually macroadenomas and present with visualdisturbances, symptoms of hypopituitarism or headache.10 Most are clinicallynonfunctioning

Hormonal Hyposecretion (Hypopituitarism)

Hypopituitarism can be a result of any hypothalamic or pituitary lesion.11

Gonadotrophs are most commonly affected Patients present with hypogonadismwith low or inappropriately normal FSH and/or LH levels (secondaryhypogonadism)

Corticotrophs and thyrotrophs are most resistant to mass effects and the last to losefunction TSH or ACTH deficiency usually indicates panhypopituitarism ACTHdeficiency causes secondary adrenal insufficiency TSH deficiency causessecondary hypothyroidism

GH deficiency is often present when two or more other hormones are deficient Prolactin deficiency is rare and occurs when the anterior pituitary is completelydestroyed, as in apoplexy

Mass Effect

Local effects are closely related to the size and location of the adenoma

Headaches are common and may not correlate with the size of the adenoma

Visual defects are also common

Upward compression and pressure on the optic chiasm may result in bitemporalhemianopsia, loss of red perception, scotomas, and blindness

Lateral invasion may impinge on the cavernous sinus, leading to lesions of theIII, IV, VI, and V1 cranial nerves, causing diplopia, ptosis, ophthalmoplegia,and facial numbness

Direct hypothalamic involvement may cause several endocrine disorders such as: Diabetes insipidus (see Chapter 4, Diabetes Insipidus)

Appetite/behavioral disorders (obesity, hyperphagia, anorexia, adipsia, andcompulsive drinking)

Sleep and temperature dysregulation

Cerebrospinal fluid rhinorrhea, caused by inferior extension of the adenoma, is avery rare presentation

Uncinate seizures, personality disorders, and anosmia can occur if temporal andfrontal brain lobes are invaded by the expanding parasellar mass

collapse, and coma Acute adrenal insufficiency may also occur Patients mayexperience long-term pituitary insufficiency.

Pituitary imaging reveals intraadenomal hemorrhage and stalk deviation

Differential Diagnosis

For a list of common sellar and parasellar masses, see Table 1-2

Sellar/parasellar cysts

Craniopharyngiomas are the most common and are calcified, cystic,

suprasellar tumors arising from embryonic squamous cell rests of Rathke’scleft Craniopharyngiomas have a bimodal peak of incidence, occurring

predominantly in children between the ages of 5 and 10 years; a second peakoccurs in late middle age.13 Craniopharyngiomas are slow growing Large

craniopharyngiomas can obstruct CSF flow and cause increased intracranialpressure Children present with headache, vomiting, visual field deficits, andgrowth failure Adults may present with neurologic symptoms, anterior pituitaryhormone deficits, and DI

Rathke’s cleft cysts are benign, noncalcified lesions that mimic hormonally

inactive adenomas or craniopharyngiomas They have a particularly low

recurrence rate after partial excision

Pituitary granulomas

Sarcoidosis of the hypothalamic-pituitary region occurs in most patients with

CNS involvement and can cause hypopituitarism with or without symptoms of

an intrasellar mass Sarcoidosis has a predilection for the hypothalamus,

posterior pituitary, and cranial nerves.14 The most common hormonal

abnormalities are hypogonadotropic hypogonadism, mild hyperprolactinemia,and DI

Langerhans’ cell histiocytosis (LCH)

Langerhans’ histiocytosis is characterized by infiltration of dendtritic cells(Langerhans’ cells).15 It can be unifocal or multifocal and affect multiplesites, such as bone, skin, lung, pituitary, hypothalamus, liver, and spleen LCH occurs more often in children and is almost always associated withdiabetes insipidus Anterior pituitary dysfunction occurs in 20% ofpatients.16

Hand–Schüller–Christian (HSC) disease includes the triad of DI,exophthalmos, and lytic bone disease Other features of the disease includeaxillary skin rash and a history of recurrent pneumothorax Children canpresent with growth retardation and anterior pituitary hormone deficits

MRI may reveal a thickened pituitary stalk or a diminished posterior pituitarybright spot, and possibly bone lesions.

Hypophysitis is characterized by either focal or diffuse infiltration of the pituitary

by inflammatory cells.17

Lymphocytic hypophysitis affects mostly women in late pregnancy or during

the postpartum period Other autoimmune diseases (autoimmune thyroiditis)may also be present The diagnosis is confirmed by histology or resolution ofthe mass over time Partial recovery of pituitary function and resolution of thesellar mass can occur spontaneously or with use of corticosteroids and

hormone replacement

Granulomatous hypophysitis is not usually associated with pregnancy.

Pituitary histology shows features of chronic inflammation and granulomas

Pituitary hyperplasia usually presents as generalized enlargement of the

pituitary.18 Pituitary hyperplasia may be caused by:

Lactotroph hyperplasia during pregnancy

Thyrotroph hyperplasia secondary to long-standing primary hypothyroidism Gonadotroph hyperplasia in long-standing primary hypogonadism

Very rarely, somatotroph hyperplasia in ectopic secretion of growth releasing hormone (GHRH)

hormone-TABLE 1-2 COMMON SELLAR AND PARASELLAR MASSES

Pituitary metastases most commonly arise from breast carcinomas (women) and

lung carcinomas A rapidly enlarging mass is highly suggestive of a metastaticlesion.19

Pituitary carcinomas are rare.19 They may produce GH, ACTH, or prolactin, orthey may be clinically nonfunctioning The diagnosis can only be established whenthe lesion metastasizes

generally >250 ng/mL in macroprolactinomas.6

Hyperprolactinemia between 20 and 200 ng/mL can be due tomicroprolactinomas, stalk compression from a sellar masse, medicationinduced hyperprolactinemia, or due to the “hook effect” (see Chapter 2,Prolactinoma)

An elevated ACTH level in the setting of biochemically confirmed Cushing’ssyndrome suggests either a pituitary source (Cushing’s disease) or ectopicACTH syndrome A high-dose dexamethasone suppression test and/orinferior petrosal sinus sampling (IPSS) can be used to differentiate betweenthe two (see Chapter 14, Cushing’s Syndrome)

TSH-secreting adenomas

Elevated thyroid hormone levels in the setting of an elevated orinappropriately normal TSH suggests the diagnosis.9 An elevated pituitaryglycoprotein hormone alpha-subunit (α-GSU) may be present

Similar laboratory values may be seen in the presence of circulatingantibodies against TSH Therefore, a methodologic interference in themeasurement of TSH must be ruled out Dynamic testing, such as T3suppression and TRH stimulation can be used to differentiate a TSH-secreting adenoma from thyroid hormone resistance syndromes

Gonadotroph adenomas

Most non-functioning pituitary adenomas arise from gonadotroph cells

Although circulating LH and FSH levels may be elevated in a minority ofpatients, this is rarely clinically significant

Hypopituitarism

Corticotropin deficiency (secondary adrenal insufficiency)

ACTH deficiency produces hypotension, shock, nausea, vomiting, fatigue, andhyponatremia (see Chapter 11, Adrenal Insufficiency).

Dynamic testing to evaluate the HPA axis can be done with a cosyntropinstimulation test or insulin-induced hypoglycemia

Cosyntropin stimulation test may be normal in recent-onset corticotropindeficiency, because it takes time for adrenals to atrophy after acutedisruption of ACTH secretion

Thyrotropin deficiency (secondary hypothyroidism)

A low serum free T4 in the setting of an inappropriately low/normal TSHsuggests secondary hypothyroidism.20

A free T4 level should be used as the follow-up test for secondaryhypothyroidism

Gonadotropin deficiency (secondary hypogonadism)

May be secondary to hyperprolactinemia

Normal menses in premenopausal women not on birth control suggests anintact pituitary-gonadal axis In female patients with abnormal menses, serumLH/FSH, prolactin, and estradiol levels should be checked

Low serum testosterone in the setting of an inappropriately low or normal LH

in males suggests the diagnosis

hypopituitarism or visual abnormalities is not necessary unless the patient hasrelated symptoms or signs.

Asymptomatic non-functioning incidentalomas may be followed up by periodicMRI for tumor growth Tumor growth without treatment occurs in about 10% ofmicroadenomas and 24% of macroadenomas.5

Imaging Studies

Pituitary MRI: MRI with a focus on the pituitary (contiguous sections detect

lesions of 1 to 3 mm) is the best imaging study to visualize pituitary tumors.22 MRIdetects tumor effects on soft tissue structures, cavernous sinus or optic chiasm,sphenoid sinus, and hypothalamus T1-weighted sections in the coronal andsagittal plane distinguish most pituitary masses Pituitary adenomas usually take

up less gadolinium than the normal pituitary tissue but more than the CNS weighted images are important for diagnosing high-signal hemorrhage Teenagegirls exhibit increasing gland convexity during their menstrual cycle Duringpregnancy, the gland should normally not exceed 12 mm A thickened stalk mayindicate the presence of hypophysitis, a granuloma, or an atypical chordoma

Pituitary CT allows better visualization of bony structures, including the sellar

floor and clinoid bones Calcifications associated with craniopharyngiomas,which may not be visible on MRI, can be seen on CT

Progressive compressive features including visual compromise,

hypopituitarism, or other CNS dysfunctions

Hemorrhage especially with sudden visual field compromise

Patients who are intolerant or resistant to medical therapy

The transsphenoidal microsurgical approach is the procedure of choice for >90%

of pituitary tumors The adenoma is selectively removed Normal pituitary tissue

is identified and preserved if possible

Major complications:

CSF leakage, DI, and SIADH are the most common transient complications Iatrogenic hypopituitarism, permanent DI, or SIADH

Local damage

Radiotherapy

Pituitary irradiation is usually reserved for large tumors with incomplete resection

or for patients who have a contraindication for surgery

Gamma knife delivers high-dose radiation to the tumor while sparing surroundingtissue as compared to conventional radiation They have similar long-termefficacy

Major complications include hypopituitarism (develops in up to 80% of patientsafter 10 years), optic nerve damage, and brain necrosis It is unclear whether ornot the risk of cancer is increased

Medical Therapy

Dopamine agonists are usually the first line therapy for prolactinomas of all sizes.

They decrease hyperprolactinemia due to any cause and decrease the size andsecretion of most prolactinomas.6

Bromocriptine and cabergoline are both commonly used Cabergoline is morepotent, better tolerated, and longer-acting as compared to bromocriptine

Dopamine agonists can be added in combination with somatostatin analogs

(SSAs) for acromegaly therapy

SSAs, including octreotide (Sandostatin) and lanreotide (Somatuline) bind to

somatostatin receptor subtypes (SSTRs) and act as inhibitors to a number ofendocrine cells.23

SSAs are the mainstay of medical therapy for acromegaly and TSH-secretingpituitary adenomas

The growth hormone receptor antagonist (Pegvisomant) inhibits peripheral GHaction It is highly effective in reducing IGF-1 levels in acromegaly

Temozolomide is an oral chemotherapeutic agent that has been used in thetreatment of aggressive pituitary tumors.24

Ketoconazole and metyrapone may be used to inhibit cortisol synthesis inCushing’s disease.8 Occasionally mitotane is used to achieve biochemical control

MONITORING/FOLLOW-UP

Postsurgical patients should be evaluated for complete tumor resection and

hormone dysfunction in 4 to 6 weeks.

Follow-up after pituitary irradiation is essential, because the response to therapymay be delayed and the incidence of hypopituitarism increases with time

Follow-up MRI may not be necessary in patients with normal posttherapy pituitaryfunction, but should be done in patients with persistent or recurrent disease

REFERENCES

1 Daly AF, Tichomirowa MA, Beckers A The epidemiology and genetics of

pituitary adenomas Best Pract Res Clin Endocrinol Metab 2009;23(5):543–554.

2 Scheithauer BW, Gaffey TA, Lloyd RV, et al Pathobiology of pituitary adenomas

and carcinomas Neurosurgery 2006;59(2):341–353.

3 Saeger W, Lüdecke DK, Buchfelder M, et al Pathohistological classification ofpituitary tumors: 10 years of experience with the German Pituitary Tumor

Registry Eur J Endocrinol 2007;156(2):203–216.

4 Dworakowska D, Grossman AB The pathophysiology of pituitary adenomas Best Pract Res Clin Endocrinol Metab 2009;23(5):525–541.

5 Molitch ME Pituitary tumours: Pituitary incidentalomas Best Pract Res Clin Endocrinol Metab 2009;23(5):667–675.

6 Klibanski A Clinical practice Prolactinomas N Engl J Med

2010;362(13):1219–1226

7 Molitch ME Clinical manifestations of acromegaly Endocrinol Metab Clin North Am 1992;21(3):597–614.

8 Nieman L, Biller B, Finding J, et al The diagnosis of Cushing’s syndrome: An

endocrine society clinical practice guideline J Clin Endocrinol Metab

2008;93:1526–1540

9 Beck-Peccoz P, Persani L, Mannavola D, et al Pituitary tumours: TSH-secreting

adenomas Best Pract Res Clin Endocrinol Metab 2009;23(5):597–606.

10 Greenman Y, Stern N Non-functioning pituitary adenomas Best Pract Res Clin Endocrinol Metab 2009;23(5):625–638.

11 Arafah BM Reversible hypopituitarism in patients with large nonfunctioning

pituitary adenomas J Clin Endocrinol Metab 1986;62(6):1173–1179.

12 Turgut M, Ozsunar Y, Başak S, et al Pituitary apoplexy: An overview of 186

cases published during the last century Acta Neurochir (Wien) 2010;152(5):749–

761

13 Garnett MR, Puget S, Grill J, et al Craniopharyngioma Orphanet J Rare Dis

2007;2: 18

14 Bell NH Endocrine complications of sarcoidosis Endocrinol Metab Clin North Am 1991; 20(3):645–654.

15 Kaltsas GA, Powles TB, Evanson J, et al Hypothalamo-pituitary abnormalities

in adult patients with langerhans cell histiocytosis: Clinical, endocrinological,

and radiological features and response to treatment J Clin Endocrinol Metab

2000;85(4):1370–1376

16 Carpinteri R, Patelli I, Casanueva FF, et al Pituitary tumours: Inflammatory and

granulomatous expansive lesions of the pituitary Best Pract Res Clin Endocrinol Metab 2009;23(5): 639–650.

17 Honegger J, Fahlbusch R, Bornemann A, et al Lymphocytic and granulomatous

hypophysitis: Experience with nine cases Neurosurgery 1997;40(4):713–722;

21 Clemmons DR The diagnosis and treatment of growth hormone deficiency in

adults Curr Opin Endocrinol Diabetes Obes 2010;17(4):377–383.

22 Melmed S, Kleinberg D Anterior pituitary In: Kronenberg HM, Melmed S,

Polonsky KS, eds Williams Textbook of Endocrinology, 11th ed Philadelphia,

PA: Saunders/Elsevier, 2008: 155–261

23 Fleseriu M, Delashaw JB Jr, Cook DM Acromegaly: A review of current

medical therapy and new drugs on the horizon Neurosurg Focus 2010;29(4):E15.

24 Raverot G, Sturm N, de Fraipont F, et al Temozolomide treatment in aggressive

pituitary tumors and pituitary carcinomas: A French multicenter experience J Clin Endocrinol Metab 2010;95(10):4592–4599.

2 Prolactinoma

Mariko Johnson and Julie Silverstein

Microprolactinomas are tumors <10 mm in greatest diameter.

Macroprolactinomas are tumors ≥10 mm in greatest diameter.

Based on local invasion

Microprolactinomas by definition are confined to the pituitary

Macroprolactinomas can invade local structures such as the cavernous and

sphenoid sinuses and compress the optic chiasm

Based on metastatic spread

Most prolactinomas are benign and confined to the pituitary

Malignant prolactinomas are extremely rare and are defined by the presence ofmetastases to the bone, lymph nodes, lung, liver, or spinal cord

Epidemiology

Prolactinomas are the most common secretory pituitary tumors with an estimatedprevalence of 100 per million population.1 Large autopsy series have foundpituitary microadenomas in 10% of individuals.2 Prolactinomas account for 40%

of pituitary adenomas.3

Microprolactinomas occur more often in women with a female:male ratio of 20:1.4

Macroprolactinomas occur with similar frequency in men and women.4

Associated Conditions

Prolactinoma is the most frequent pituitary tumor occurring in the multipleendocrine neoplasia syndrome.

Prolactinomas may also secrete other hormones The most frequent mixed tumorsare growth hormone (GH)/prolactin-secreting adenomas

DIAGNOSIS

Clinical Presentation

Prolactinomas cause symptoms on the basis of hormonal secretion and mass effect Symptoms due to hyperprolactinemia can include galactorrhea and symptoms ofhypogonadism Galactorrhea occurs via direct action of prolactin on the

estrogenized breast Hypogonadism occurs due to inhibitory effects of prolactin

on gonadotropin secretion or via direct compression of gonadotrophs

Therefore, hypogonadism can occur with tumors of any size and may be

reversible if prolactin levels are controlled

Symptoms due to mass effect include headache and visual field defects

Ophthalmoplegia and rhinorrhea are signs of more advanced disease

Headaches are caused by the expanding tumor Visual field defects are caused

by compression of the optic chiasm Ophthalmoplegia may occur when tumorsexpand laterally and invade the cavernous sinus Rhinorrhea may occur if thetumor invades the sphenoid or ethmoid sinuses or after rapid drug-inducedtumor shrinkage Hypothyroidism and adrenal insufficiency occur via directcompression of thyrotrophs or corticotrophs by a macroprolactinoma Unlikehypogonadism, if these hormonal deficiencies are present as a result of a

macroprolactinoma, they are generally not reversible

The clinical presentation of prolactinomas can vary based on the gender and age ofthe patient

Premenopausal women may present with galactorrhea and/or hypogonadism(infertility, oligomenorrhea, or amenorrhea) Women who are amenorrheic forlong periods are at risk for osteopenia and osteoporosis and are less likely topresent with galactorrhea

Postmenopausal women rarely present early in the course of disease since

menses are no longer present and galactorrhea is rarely present due to lowestrogen levels Hyperprolactinemia is often not recognized in postmenopausalpatients until a prolactinoma has become sufficiently large to produce

symptoms of mass effect such as headache or visual field defects

Men present with secondary hypogonadism and symptoms of decreased libido,

impotence, infertility, loss of body hair, or gynecomastia More subtle

manifestations include decreased cognitive function and energy, and loss ofmuscle and bone mass Men almost never have galactorrhea

The clinical presentation of prolactinomas can vary based on the size of the tumor Symptoms of mass effect generally only occur in the presence of a

macroadenoma

History

The history should focus on symptoms of hormonal overproduction and mass effect

It should also seek to define possible alternate causes for hyperprolactinemia.Symptoms or history of hypothyroidism, adrenal insufficiency, renal disease, orcirrhosis should be sought Current medications should be carefully reviewed Anyfamily history of pituitary tumors or syndromes of endocrine neoplasia should benoted

Physical Examination

The physical examination should evaluate for bitemporal visual field defects,galactorrhea (in premenopausal females), as well as for signs of hypothyroidism orhypogonadism

Diagnostic Criteria

The first requirement for a diagnosis of prolactinoma is a persistently

elevated prolactin level The likelihood of prolactinoma can be roughly

estimated based on the degree of elevation in the prolactin.5

Levels above normal but <100 ng/mL: possible prolactinoma

Levels 100 to 200 ng/mL: likely prolactinoma

Levels >200 ng/mL: usually diagnostic of prolactinoma

Alternate causes of mild to moderate prolactin elevations should be consideredand if possible excluded (see Section on Differential Diagnosis)

Once persistent hyperprolactinemia is established and alternate causes excluded, apituitary protocol brain MRI should be performed to define tumor size andanatomy Microprolactinomas may be too small to be seen on MRI

TABLE 2-1 DIFFERENTIAL DIAGNOSIS OF HYPERPROLACTINEMIA: MNEMONIC HIGH PROLACTIN

Differential Diagnosis

Many factors other than a prolactinoma can lead to hyperprolactinemia and adifferential diagnosis can be remembered using the mnemonic HIGHPROLACTIN (Table 2-1).14

of the hypothalamus, infiltrative diseases, disruption of the hypothalamic-pituitarystalk in head trauma, or non-functioning pituitary macroadenomas

Hypothyroidism

Most patients with hypothyroidism have normal prolactin levels Rarely, patientswith hypothyroidism present with elevated prolactin values Thyroid hormonereplacement typically restores normal prolactin values

Chest wall injury

Chest wall injuries, irritating lesions (e.g., herpes zoster), and spinal cord injuriescan activate neural reflexes similar to nipple stimulation and increase prolactinlevels

TABLE 2-2 MEDICATIONS THAT MAY CAUSE HYPERPROLACTINEMIA

Renal or hepatic failure

Elevations in prolactin levels may be seen in renal or hepatic failure due todecreased prolactin clearance

Macroprolactinemia (“Big Prolactin”)

Prolactin can circulate as a monomer or in aggregates (usually bound to IgG).Monomeric hyperprolactinemia leads to classical symptoms and signs such as

menstrual disturbance and galactorrhea In contrast, the presence of circulatingprolactin aggregates (macroprolactinemia) is felt to be a benign variant.7 In long-term follow-up of such patients, few had initial symptoms and none had symptomprogression.7 Macroprolactinemia can be distinguished from monomerichyperprolactinemia by polyethylene glycol precipitation Some, but not all,laboratories routinely test for macroprolactinemia.

Diagnostic Testing

Laboratories

Laboratory testing begins with a serum prolactin level

If the serum prolactin is elevated, a serum TSH, a comprehensive metabolic panel,and a pregnancy test (in premenopausal females) may be ordered to begin to ruleout secondary causes

A prolactin with serial dilutions should be measured in all patients with a pituitarymacroadenoma who have a mild to moderate prolactin elevation to exclude theHook effect

Distinguishing a prolactinoma from a nonfunctioning pituitary macroadenoma is

of utmost importance because prolactinomas are best treated medically,

whereas nonfunctioning tumors require surgery

An immunoradiometric assay is frequently used for measurement of serum

prolactin levels Falsely low values can occur when a large amount of prolactinsaturates the antibodies This is known as the Hook effect

Mild to moderate prolactin elevations (<200 ng/mL) in the setting of a pituitarymacroadenoma may be due to stalk compression but may also be due to theHook effect This artifact can be excluded by performing an additional

prolactin determination on diluted serum If the diluted specimen yields a valuethat is the same or higher, the diagnosis of macroprolactinoma can be made Screening for hypopituitarism should be considered in all patients withmacroprolactinomas

Imaging

MRI with gadolinium enhancement provides the best anatomic detail of the

hypothalamic-pituitary area

Visual field testing should be obtained in patients with tumors that are adjacent to

or compressing the optic chiasm

All macroprolactinomas require treatment whether or not compressive

symptoms are present

Not all microprolactinomas require treatment and should be treated only when

symptoms caused by hyperprolactinemia or rapidly increasing prolactin levelsindicative of an enlarging tumor are present As such, microprolactinomas inpostmenopausal women rarely require treatment

Prolactinomas are unique among pituitary tumors in that first-line treatment is

medical, not surgical.

The mainstays of management for prolactinomas are the dopamine agonists

bromocriptine and cabergoline.

Most patients will respond to therapy within weeks of initiation, as evidenced bysymptoms and prolactin levels The majority of patients will also have a >25%decrease in the size of the adenoma.3

A normal prolactin level should be the target of therapy for macroprolactinomas Restoration of gonadal function and relief from symptoms should be the goal oftherapy for microprolactinomas, and achieving a normal prolactin level may not

Cabergoline

Cabergoline is a nonergot D2 receptor agonist with a long half-life, and can be given

orally at 0.25 to 1 mg twice a week A large comparator study of cabergoline andbromocriptine demonstrated the superiority of cabergoline over bromocriptine inboth efficacy and tolerability.9 Cabergoline leads to a greater reduction in prolactinsecretion, decrease in tumor size, and improvement in gonadal function thanbromocriptine Side effects are much less frequent and less severe than withbromocriptine Recent studies have shown that cabergoline can cause valvularfibrosis at the higher doses used for treatment of Parkinson’s disease.10 Forhyperprolactinemic disorders, a considerably lower dose of cabergoline is used Atthese lower doses, there appears to be minimal risk of valvular abnormalities thoughlarge randomized studies have not yet been performed and the true risk remains to bedefined.10

Other dopamine agonists

Quinagolide is not yet approved for use in the United States

Surgical Management

Pituitary surgery is reserved for patients who are refractory to or intolerant ofdopamine agonists, have persistent visual field deficits despite medical therapy, orhave other neurologic signs in the context of a cystic macroadenoma or pituitaryapoplexy.3 Pituitary surgery aimed at debulking the tumor to reduce the risk ofpotential expansion is indicated for women with macroprolactinomas desiringpregnancy Trans-sphenoidal surgery by an experienced neurosurgeon can be offered

to patients with microadenomas who do not wish to receive lifelong medicaltherapy

Radiotherapy

Radiotherapy is not a primary therapy for prolactinomas Its use is limited to patientswith macroprolactinomas that are refractory to medical treatment and surgery or inthe rare case of a malignant prolactinoma.3

SPECIAL CONSIDERATIONS

Pregnancy

During pregnancy, the normal pituitary increases in size, owing to markedlactotroph hyperplasia due to the effect of estrogen on prolactin synthesis Therisk of tumor expansion is small (<3%) for microprolactinomas but significant(30%) for macroprolactinomas.11

Patients with prolactinomas wishing to become pregnant should be referred to

No increase in adverse fetal events has been demonstrated with use of eitherbromocriptine or cabergoline.12 , 13 However, experience with cabergoline inpregnancy is more limited than bromocriptine, making bromocriptine the drug ofchoice in pregnancy.

In women with microprolactinomas desiring fertility, bromocriptine should betitrated to normalize prolactin levels and restore regular menses Barriercontraception should be recommended until menstrual cycles become regular sothat a pregnancy test can be performed immediately if a cycle is missed Oncepregnancy is confirmed, bromocriptine should be discontinued in order to limitfetal exposure to the drug

In women with macroprolactinomas, control of tumor size should ideally beattained prior to conception because of the growth potential of these tumors duringpregnancy These patients should be pretreated with bromocriptine for a sufficientperiod to cause substantial tumor shrinkage in addition to regular menses Onlythen should contraception be discontinued If the tumor does not shrink sufficiently

in size, prepregnancy transsphenoidal surgical debulking can be considered Oncepregnancy is achieved, bromocriptine should be discontinued followed by closesurveillance for symptoms of tumor enlargement

Monitoring prolactin levels in pregnant patients is of no benefit, as levels do notalways rise during pregnancy and may not rise with tumor enlargement Visualfield testing and imaging is reserved for patients with symptoms of tumorenlargement Reinstitution of bromocriptine therapy at the lowest effective doseduring pregnancy is the treatment of choice for patients with symptomatic tumorenlargement Transsphenoidal surgery or delivery (if pregnancy is far enoughadvanced) should be performed if there is no response to bromocriptine andvision is progressively worsening

Visual field testing and MRI evaluation should be repeated at regular intervals if avisual field defect was present at diagnosis

Several recent studies demonstrate that cabergoline or bromocriptine can betapered safely in a subset of patients but the rate of remission has been variable

between studies.11

Tapering of dopamine agonists can be considered when the prolactin level hasbeen normal for at least 3 years and the size of the tumor has decreasedsignificantly.3 These patients require close follow-up to monitor for recurrence ofhyperprolactinemia and tumor growth

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