Health Questions and Answers

Pituitary Gland

Summarize the general functions of the pituitary gland.
The pituitary gland is the “master gland” of the endocrine system. It is involved in many body functions, including growth and development, metabolism, and reproduction. These functions are regulated by the secretion of hormones that interact at specific target organ sites.

Describe the anterior pituitary gland.
The anterior pituitary or adenopypophysis, which composes 80% of the entire gland, is derived embryologically from Rathke’s pouch and is oral ectoderm in origin. Anterior pituitary hormones are synthesized in the pituitary by specific cell types and are regulated by hypothalamic and target organ factors.

List the six major hormones secreted by the anterior pituitary.

  • Somatotropin (growth hormone [GH])
  • Prolactin
  • Corticotropin (ACTH)
  • Thyrotropin (thyroid-stimulating hormone [TSH])
  • Luteinizing hormone (LH)
  • Follicle-stimulating hormone (FSH)

Describe the posterior pituitary. What hormones does it secrete?
The posterior pituitary or neurohypophysis is an extension of the floor of the third ventricle and originates from cells of the central nervous system. Posterior pituitary hormones included arginine vasopressin (AVP, antidiuretic hormone) and oxytocin. These hormones are synthesized in the cell bodies of hypothalmic neurons and stored in the axons that terminate in the posterior pituitary.



Describe the general approach to evaluating a patient with pituitary disease.
It is important to take a good history and ask specific questions related to hormonal hyper- or hypofunction. Think specifically about assessing anterior and posterior pituitary function.

In particular, what should be evaluated in patients with pituitary tumors?
Questions should identify clinical problems associated with pituitary tumors, which include hormonal abnormalities and mass effects. Mass effects can include neurologic symptoms and impaired anterior pituitary function. It is rare to have posterior pituitary dysfunction as a consequence of a pituitary tumor, but it can be seen in patients with pituitary trauma or disorders of the pituitary stalk. Headache and disruption of cranial nerve function (cranial nerves II, III, IV, and VI) are the most common neurologic symptoms. Pituitary tumors that compress the optic nerves or optic chiasm are typically associated with visual field deficits (bitemporal hemianopsia) or visual loss.
KEY POINTS: MECHANISMS BY WHICH PITUITARY TUMORS CAUSE PROBLEMS

  • Mass effect: tumors apply pressure to surrounding structures causing functional disruption that may lead to: headaches, visual disturbance/visual field defects, cranial nerve dysfunction and, anterior pituitary hormone deficiencies
  • Endocrine hyperfunction: due to excessive secretion of a particular anterior pituitary hormone by the tumor.

What factors should be the focus of the physical exam?
On physical exam it is important to perform a full neurologic exam with visual field testing by confrontation and to look for clinical evidence of hormonal hyperfunction (e.g., enlarged hands and feet, skin tags, and facial features of acromegaly) or hypofunction (e.g., loss of body hair in hypogonadal men or delayed deep tendon reflexes as a sign of hypothyroidism).

What causes acromegaly?
Acromegaly is caused by a tumor of the GH-secreting cell.

How does acromegaly present clinically?
If the tumor occurs in childhood before the closure of the epiphyses, the effect is known as gigantism. Patients frequently present late in the disease with large tumors (macroadenomas in 85%) due to the very slow development of the clinical features. It often goes unrecognized by the patient, his or her family, and the primary care provider because the physical changes occur so slowly. Such patients can present with soft tissue hypertrophy; headache; arthritis/carpal tunnel syndrome; increased size of hands, head, and feet; organomegaly, including cardiomegaly with congestive heart failure; and obstructive sleep apnea.

What physical exam findings are suggestive of acromegaly?
Physical exam findings include soft tissue characteristics (large doughy hands), frontal bossing, widening spaces in teeth, skin tags, organomegaly, large body size, signs of hyperprolactinemia, hypogonadism, and visual field deficits.

How is acromegaly diagnosed?
Diagnosis is based on clinical features, laboratory evaluation, and magnetic resonance imaging (MRI) of the pituitary. Diagnostic lab abnormalities include elevated GH with failure to suppress with oral glucose administration and an elevated IGF-1 (somatomedin-C). Patients may also have insulin resistance/DM, hyperprolactinemia due to stalk compression, hypogonadism, and hypercalciuria/nephrolithiasis. They are at higher risk of colon polyps/cancer and have increased mortality rates.

Explain the goal for treatment of acromegaly.
The goal of treatment is to normalize anterior pituitary function and GH secretion. Mortality rates return to baseline levels if the GH is normalized (normal GH, normal IGF-1, and normal GH suppression [< 1 μg/L] following oral glucose).

How can this goal be achieved?
Transsphenoidal surgical resection is typically the treatment of choice. Medical treatment is often required because many tumors are too large at presentation to be completely excised by surgery. In such cases, somatostatin analogs are indicated for medical therapy to control GH secretion. GH cells have somatostatin receptors and treatment with somatostatin analogs (octreotide), have been shown to decrease GH levels and induce tumor shrinkage. A new GH receptor antagonist, pegvisomant, has also been approved for medical therapy. Although less effective, dopamine agonists such as bromocriptine or cabergoline can also be tried to control GH levels. Finally, radiation therapy can be offered to patients who fail surgical and medical interventions.

Prolactinomas are the most common type of pituitary tumor. In general, how do they present?
The clinical picture of hyperprolactinemia is variable, depending on age, sex, duration of hyperprolactinemia, and tumor size. Hypogonadism is common and due to prolactin inhibition of gonadotropin-releasing hormone neurons and leads to suppression of the hypothalamic-pituitary-gonadal axis. Women of reproductive age present earlier with amenorrhea and galactorrhea. Men and postmenopausal women usually present later in the disease course with mass effect such as headache and visual deficits.

List the clinical features of hyperprolactinemia.

  1. Galactorrhea Amenorrhea/menstrual irregularities
  2. Infertility Hirsutism
  3. Gynecomastia and erectile dysfunction in men
  4. Growth arrest/delayed puberty
  5. Mass lesions/visual field defects (primarily in men and postmenopausal women)
  6.  Osteopenia (due to hypogonadism)

What is the differential diagnosis of hyperprolactinemia?

  • Pregnancy (normal physiologic cause of hyperprolactinemia)
  • Neurogenic disorder (chest wall lesion, suckling; do not measure prolactin after a breast exam.)
  • Drugs: dopamine depletion or antagonists (usually psychoactive medications)
  • Cirrhosis Primary hypothyroidism (thyrotropin-releasing hormone [TRH] also stimulates prolactin secretion)
  • Ectopic production (ovarian tumors)
  • Pituitary tumors/prolactinomas
  • Idiopathic disease

What are the treatment options for hyperprolactinemia?
Treatment obviously depends on the etiology. When due to a medication, it is obviously best to stop the offending agent if possible. Medical therapy with dopamine agonists is the treatment of choice for prolactinomas. Oral contraceptives can be used to restore normal menstrual cycles and protect against bone loss in female patients who have mild elevations in prolactin in the absence of a visible pituitary tumor. Surgery is not typically the treatment of choice for prolactinomas due to a high recurrence rate (especially for macroadenomas) but can be considered in invasive tumors or tumors resistant to medication. Radiation can always be considered in patients who fail other modalities.

How do dopamine agonists work?
Dopamine agonists have been shown to inhibit prolactin secretion and cause tumor shrinkage. Examples include bromocriptine, pergolide, and the newer, more potent agent, cabergoline. All must be started at low doses and titrated upward very slowly to avoid side effects. The most common side effects include nausea, vomiting, and orthostatic hypotension. Cabergoline appears to be the best tolerated but most expensive option.

What is the “stalk effect”?
Large non-prolactin-secreting tumors compress the pituitary stalk, thus interrupting the tonic inhibitory effect of dopamine (or prolactin-inhibiting factor) on the pituitary. The result is elevation of prolactin levels up to 200 ng/mL.

What is pituitary apoplexy?
Pituitary apoplexy is defined as sudden headache, visual change, ophthalmoplegia, and altered mental status caused by the acute hemorrhage or infarction of the pituitary gland. Most cases are due to pituitary hemorrhage of a previously undiagnosed pituitary adenoma (65%). Patient presentation may range from asymptomatic to symptoms of severe retro-orbital headache, visual defects, meningeal signs, altered sensorium, seizure, or coma depending on the extent of the lesion. Clinical symptoms and signs plus CT scan or MRI of the pituitary aid in the diagnosis. This condition can be life-threatening if unrecognized.

How is pituitary apoplexy treated?
Treatment consists of stress doses of steroids (for cerebral edema and presumed adrenal insufficiency) and/or neurosurgical decompression. Hormonal deficiencies following apoplexy are the rule, and panhypopituitarism is common. Hypogonadism occurs in nearly 100%, GH deficiency in 88%, hyperprolactinemia in 67%, adrenal insufficiency in 66%, hypothyroidism in 42%, and diabetes insipidus in 3%.

What is a thyrotropinoma?
As the name suggests, it is a tumor of the TSH-producing cell. This rare tumor occurs in approximately one in a million people. It produces a clinical syndrome of hyperthyroidism that is indistinguishable from other more common causes (e.g., Graves’ disease, toxic nodular goiter). It is differentiated from primary hyperthyroidism by an inappropriately normal or elevated TSH in the setting of elevated thyroid hormone levels. Since TSH is secreted as a dimer peptide comprised of the TSH beta and alpha subunits, alpha subunit levels are typically elevated. Patients have an elevated molar ratio of alpha-SU/TSH > 1.

How is a thyrotropinoma diagnosed?
Pituitary MRI typically demonstrates a tumor. If not, since these tumors display somatostatin receptors, octreotide scanning may be helpful for tumor localization.

What causes hypopituitarism?
It is possible to have an isolated hormonal deficiency or complete anterior pituitary hormonal dysfunction (panhypopituitarism). Causes of hypopituitarism include:

  • Mass lesions from tumors (pituitary adenoma, craniopharyngiomas, metastatic lesions)
  • Iatrogenic causes (pituitary surgery, radiation)
  • Infiltrative disease (hemochromatosis, lymphoma, sarcoid, histiocytosis X)
  • Pituitary infarction (Sheehan syndrome, after coronary artery bypass grafting, trauma)
  • Pituitary apoplexy
  • Genetic disease (transcription factor mutations)
  • Empty sella syndrome (typically secondary)
  • Hypothalamic dysfunction (mass lesions, infiltrative diseases, radiation, trauma, infection)
  • Autoimmune lymphocytic hypophysitis
  • Miscellaneous (abscess/infection; aneurysm)

How do patients with hypopituitarism present?
Patients present with signs and symptoms of hormonal deficiency. Evaluation is aimed at documenting deficiency and may include stimulation testing (i.e., adrenal insufficiency, GH deficiency).

How is hypopituitarism treated?
Treatment consists of correcting the hormonal deficiency. Patients with adrenal insufficiency need to be educated about stress-dose steroids for acute illness, and all patients should wear medical alert jewelry.

What is diabetes insipidus (DI)? How is it treated?
DI is characterized by an inability to concentrate urine due to insufficient arginine vasopressin (AVP, antidiuretic hormone) release or activity. Large amounts of dilute urine are excreted in the setting of hyperosmolality and hypernatremia.

What are the two types of DI?

  1. Central (neurogenic) DI, which is due to impaired or inadequate secretion of AVP from the posterior pituitary, and nephrogenic DI, which is due to resistance to AVP. Central DI can be partial or complete and is typically an acquired condition related to trauma or infiltrative disease of the hypothalamus/posterior pituitary.
  2. Nephrogenic DI can be acquired due to hypercalcemia, hypokalemia, drug-induced (lithium), or congenital.

How do patients with DI present?
Patients present with polyuria (typically large volumes with osmolality < 200 mOsm/kg), polydipsia, and hypernatremia if the patients do not have an intact thirst mechanism or do not drink water. Diagnosis is confirmed by performing a water deprivation test.

How is DI treated?
Treatment depends on diagnosis. Central DI is typically treated with AVP replacement in the form of dDAVP (desmopressin), a synthetic AVP agonist. There are no good therapies for nephrogenic DI, but treatment is usually aimed at volume contraction using thiazide diuretics, salt depletion or prostaglandin synthesis inhibitors. These agents decrease renal blood flow by volume contraction and decrease urine output by reducing glomerular filtration rates.

References
USEFUL WEB SITES
The Endocrine Society: www.endo-society.org
Uptodate Reference: www.uptodate.com
Endotxt.org (Web-based source of information about endocrine diseases directed to physicians)
American Association of Clinical Endocrinologists: www.aace.com
Pituitary Society: www.pituitarysociety.org

BIBLIOGRAPHY

  • Melmed S, et al: Consensus guidelines for acromegaly management. JCEM 87(9):4054-4058, 2002.
  • Braverman LE, Utiger RD (eds): Werner and Ingbars’ Thyroid. A Fundamental and Clinical Text. Philadelphia, Lippincott Williams & Wilkins, 2000.
  • Larson PR, et al: Williams Textbook of Endocrinology, 10th ed. Philadelphia, W.B. Saunders, 2003.
  • Pickett CA: Diagnosis and management of pituitary tumors: Recent advances. Prim Care Clin Office Pract 30:765-789, 2003.
  • Wierman ME (ed): Diseases of the Pituitary: Diagnosis and Treatment. Totowa, NJ, Humana Press, 1997.

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