Pituitary Tumors

Background

Pierre Marie, a French neurologist (Salpetriere Hospital, Paris) was the first to describe a disease that involved the pituitary gland. In 1886, he studied 2 patients with clinical findings of what he termed acromegaly and postulated that the pituitary gland was involved in the pathogenesis.

Pituitary tumors are common neoplasms, and recognition of their presentation is critical since a favorable therapeutic outcome is dependent on early identification of the lesion.

The history of pituitary tumor biology is rich. A recent DNA examination from the teeth of an Irish patient with gigantism (7 ft, 7 in in height), who lived from 1761 to 1783 and was housed at the Hunterian Museum in London, revealed the same mutation in the AIP gene (c.910 C- T mutation) present in 4 families with pituitary tumors from Northern Ireland. This patient shared common haplotypes with the recent families studied. The skull of the index patient was actually examined by Harvey Cushing and Sir Arthur Keith in 1909 and found to have an enlarged pituitary fossa. Current technologic advances in genetics, as demonstrated by Chahal et al, permit a fascinating insight into the causes of human diseases spanning probably over 57 generations.^[1]

Pituitary tumors are common neoplasms, and recognition of their presentation is critical since a favorable therapeutic outcome is dependent on early identification of the lesion.

Villwock et al noted that pituitary tumors constitute 10-15% of all diagnosed intracranial tumors, 90% of which are adenomas. In a study of pituitary tumor diagnoses and procedures from 1993 to 2011, they found that pituitary tumor diagnoses and resections have grown significantly over the past 20 years and that transsphenoidal surgical resection has increased, while transfrontal resections have decreased.^[2]

• References

Pathophysiology

Multiple oncogene abnormalities may be involved in pituitary tumorigenesis. G-protein abnormalities, ras gene mutations, p53 gene deletions, mutations, and rearrangements, and the association of pituitary tumors with the syndrome of multiple endocrine neoplasia have been described and are involved in the development of adenomas in the pituitary gland. The pituitary tumor transforming gene-1 (PTTG-1) is a newly discovered oncogene that serves as a marker of malignancy grades in several endocrine malignancies; this gene is known to regulate the cellular mitosis process and forced expression of this gene induces tumor formation in nude mice. PTTG-1 is overexpressed in pituitary tumors.^[3]

Recent work suggests that pituitary tumorigenesis is more heterogenous than formerly thought.^[4] Nonfunctioning adenomas are associated with hypermethylation of p16 prolactinomas, and corticotropin-secreting tumors express galectin-3 (Gal-3), a gene involved in cell growth and apoptosis. Inhibition of Gal-3 may serve as a molecular therapeutic target. Mutations of the aryl hydrocarbon-interacting protein gene (AIP) may be present in some cases of familial gigantism and acromegaly, as well as other pituitary tumor types.^{[5, 6]}

Most of these tumors are benign, but certain factors involved in the genesis of the tumor may determine its rate of growth and aggressiveness. For instance, the presence of p53 correlates with more aggressive tumor behavior.

Clinical manifestations are due to the local effect of the mass and distant endocrine manifestations that can affect a variety of organ systems. These effects are due to lack or excess of a given stimulating hormone on the target organ. Pituitary adenomas, with a few exceptions, are not under the control of hypothalamic releasing factors.

An explanation for the development of bitemporal visual-field defects in association with pituitary tumors has been a subject of renewed interest. In a recent study, comparative pressure gradients were measured between nasal crossing and temporal uncrossed fibers. Two 30-gauge needles connected to separate pressure transducers and a digital pressure monitor were introduced into the chiasm of donated cadaveric specimens. A pediatric Foley catheter was placed into the pituitary fossa and gradually inflated to simulate the effect of a pituitary mass. Pressure was consistently higher in the central aspect of the chiasm than in lateral chiasm.^[7] New engineering models of chiasmal compression (finite element modeling) may be developed in the future, taking into account the geometry of the nasal crossing fibers and the increased mechanical pressure; theoretically, this could provide the possibility of measuring the degree of chiasmal compression in each patient based on MRI anatomic findings.^[8]

Classification of pituitary tumors

Based on size, pituitary tumors can be divided into microadenomas (< 1 cm diameter) and macroadenomas (>1 cm diameter). They also can be classified on the basis of staining characteristics, as chromophobic and chromophilic tumors. The latter can be further subdivided using hematoxylin and eosin stains (ie, eosinophilic or basophilic).^[9]

However, this classification has proven to be of no clinical value and now has been replaced by a more functional classification that involves electromicroscopy and immunohistochemistry. These techniques have identified hormonal production in many chromophobe adenomas, enabling pathologists to identify hormones that are produced by eosinophilic tumors. They also have demonstrated that many tumors produce more than one hormone. The mutated form of p53, a tumor suppressor, also can be determined histologically. The presence of this mutated gene suggests a tumor with rapid growth.

The endocrinologic morbidity that is associated with pituitary tumors is dependent on the specific underproduction or overproduction of a hormone or hormones associated with the tumor.

Hormonal deficiencies - Clinical effects

Growth hormone deficiency

• Adults - Increased rate of cardiovascular disease, obesity, reduced muscle strength and exercise capacity, and increased cholesterol
• Infants - Hypoglycemia
• Children - Decreased height and growth rate

Gonadotrophin deficiency

• Men - Diminished libido and impotence; testes shrink in size, but spermatogenesis generally preserved
• Women - Diminished libido and dyspareunia; breast atrophy in chronic deficiency
• Children - Delayed or frank absence of puberty
• Adolescent girls - Present similarly to adult women

Thyrotropin deficiency - Malaise, weight gain, lack of energy, cold intolerance, and constipation

Corticotrophin deficiency

• Unlike primary adrenal insufficiency, mineralocorticoid function (which is dependent on the angiotensin-renin axis) not affected; deficiency limited to glucocorticoids and adrenal androgens
• Initially, symptoms nonspecific (eg, weight loss, lack of energy, malaise); severe adrenal insufficiency may present as a medical emergency

Panhypopituitarism - Refers to deficiency of several anterior pituitary hormones; may occur in a slowly progressive fashion (eg, pituitary adenomas)

Hormonal overproduction - Clinical effects

Prolactin

• Hypogonadism, if hyperprolactinemia sustained
• Women - Amenorrhea, galactorrhea, and infertility
• Men - Decreased libido, impotence, and rarely galactorrhea

Growth hormone

• Children and adolescents - May result in pituitary gigantism
• Adults - Acromegaly

  • Changes in the size of the hand and feet, coarseness of the face, frontal bossing, and prognathism result. Further changes in the voice, and hirsutism, confirm the diagnosis.
  • Acromegaly frequently results in glucose intolerance, with 20% of patients progressing to diabetes mellitus.
  • Respiratory difficulty and sleep apnea are fairly common.
  • Cardiac complications result from acromegalic cardiomyopathy.
  • Although patients have a bulky appearance, they are generally weak as a result of associated myopathy.
  • Carpal tunnel syndrome is seen frequently.
  • Lumbar canal stenosis can present with a syndrome resembling amyotrophic lateral sclerosis.
  • Acromegaly may be associated with colonic polyps, although an increased colon cancer incidence has not been shown definitively.

   

  

   

Cushing disease^{[6, 10]}

• Weight gain, centripetal obesity, moon facies, violet striae, easy bruisability, proximal myopathy, and psychiatric changes
• Other possible effects - Arterial hypertension, diabetes, cataracts, glaucoma, and osteoporosis

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Epidemiology

Frequency

United States

Pituitary tumors represent anywhere between 10% and 15% of all intracranial tumors.

Incidental pituitary tumors are found in approximately 10% of autopsies.

The incidence of acromegaly is approximately 3 per million. Acromegaly has no sex predilection.

International

The incidence of pituitary tumors is probably the same worldwide.

Mortality/Morbidity

Mortality rate related to pituitary tumors is low. Advances in medical and surgical management of these lesions and the availability of hormonal replacement therapies have contributed to successful management.

Pituitary apoplexy can be a lethal complication.

Morbidity associated with macroadenomas may include permanent visual loss, ophthalmoplegia, and other neurological complications.

Tumor recurrence is also a possibility.

CNS metastases and, rarely, distant metastases occur with pituitary tumors.

Endocrine abnormalities are amenable to correction. However, damage in many organ systems as a result of long-standing uncorrected deficiencies may be irreversible.

Sex

Symptomatic prolactinomas are found more frequently in women. Cushing disease also is more frequent in women (female-to-male ratio 3:1).

Age

Most pituitary tumors occur in young adults, but they may be seen in adolescents and elderly persons. Acromegaly usually is seen in the fourth and fifth decades of life.

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History

See the list below:

• The presentation of a pituitary macroadenoma relates to its mass effect and pressure on surrounding structures.
• Fifty to sixty percent present with visual symptoms due to compression of optic nerve structures.
• Nonspecific headache can be seen.
• Lateral extension can result in compression of the cavernous sinuses and may cause ophthalmoplegia, diplopia, and/or ptosis. Talkad et al recently reported an isolated, painful, postganglionic Horner syndrome as the initial sign of lateral extension of a large prolactinoma.^[11]
• Extension into the sphenoid sinuses can cause spontaneous cerebrospinal fluid (CSF) rhinorrhea.
• In addition to visual symptoms, endocrine dysfunction, as described in Pathophysiology, can result.

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Physical

Macroadenomas can compress optic nerve structures. The optic chiasm is the most frequently affected structure, and bitemporal field defects are the most common findings.

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This is a characteristic bitemporal hemianopic visual field defect.

See the list below:

• Neuro-ophthalmologic examination

  • Visual acuity can be decreased in one or both eyes.
  • Pupillary light reaction can be abnormal.
  • Color vision can be affected. Bitemporal hemiachromatopsia to red may be localized to the optic chiasm. This can be tested easily at bedside.
  • Visual fields
    • The hallmark abnormality associated with chiasmal compression is a bitemporal superior quadrantanopsia.
    • Larger lesions may be associated with a bitemporal hemianopsia.
    • Since the optic chiasm is usually adjacent to the tuberculum sellae, chiasmal compression is seen commonly.
    • Less frequently, the chiasm may be anterior or posterior to the tuberculum sellae (ie, prefixed or postfixed chiasm). Thus, the pattern of visual field defect can be variable. Any form of temporal field defect, even if monocular, can result from chiasmal compression.
    • The anterior chiasmal syndrome is not caused often by pituitary adenomas. However, bitemporal scotomata and, infrequently, homonymous defects due to optic tract compression may be seen

      View Image

      This visual field was plotted using a Goldman perimeter (ie, kinetic perimetry). It was obtained from a patient who reported visual loss and had a nor....

   

  

   
• Ophthalmoscopic examination

  • Optic atrophy is seen frequently. It is generally a horizontal-oriented atrophy (ie, bow-tie) that corresponds to the topographic localization of the nasal retina within the optic nerve. Dropout of the nerve fiber layer in the nasal retina also may be noted.
  • Papilledema is exceptional, seen only in patients with pituitary apoplexy.
  • Less frequent optic atrophy with increased cup-to-disk ratio resembling glaucomatous optic atrophy can occur.

   

  

   
• These abnormalities may be present in isolation or in association with physical changes associated with endocrine dysfunction.

  • Prolactinomas
    • In females, galactorrhea may be present on clinical examination. Women undergoing an infertility evaluation may be found to have a prolactinoma.
    • In males, galactorrhea is infrequent; testicles may be decreased in size and may be soft to palpation.
  • Acromegaly
    • A multitude of clinical signs can be appreciated by comparing the current facial appearance with prior photographs.
    • These changes include large hands and feet (with thick fingers and toes) and coarse facial features with frontal bossing. Women may appear masculinized. Other findings might include prognathism, carpal tunnel syndrome, and voice quality changes.
  • Cushing disease: Findings are prominent and include obesity, centripetal fat deposition, proximal myopathy, moon facies, buffalo hump, posterior subcapsular cataracts, arterial hypertension, bruises, and skin striae.
  • Hypopituitarism
    • Chronic hypopituitarism results in hypotension, generalized weakness, hypothermia, malaise, and depression.
    • Acute sudden hypopituitarism (ie, pituitary apoplexy) is associated with shock, coma, and death.

   

  

   

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Causes

See Pathophysiology.

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Laboratory Studies

See the list below:

• Pituitary mass

  • Visual fields and ophthalmologic evaluation are critical in defining the presence of a chiasmal syndrome.
  • Neuroimaging would be appropriate (see Imaging Studies).

   

  

   
• Prolactinomas

  • Serum prolactin levels should be measured in any patient with a suspected sellar or suprasellar mass. If elevated, investigate the possibility of pharmacologic and other factors prior to ordering extensive neuroimaging studies.
  • Generally, a single elevated prolactin level may confirm the diagnosis. Minor elevations may be somewhat difficult to interpret, since breast manipulation can elevate the serum level. The first level obtained serves as a baseline and guides the course of dopamine-agonist therapy.
  • Serum prolactin level >200 mcg/L in a patient with a macroadenoma greater than 10 mm in size is diagnostic of a prolactinoma. Levels below that range in a macroadenoma suggest hyperprolactinemia secondary to hypothalamic compression.

   

  

   
• Growth hormone abnormalities

  • Growth hormone (GH) levels are elevated in acromegaly but can fluctuate significantly.
  • Intravenous (IV) GH levels every 5 minutes for 24 hours may show consistent elevation of GH. This is not a practical diagnostic method, but does indicate that a single GH value is not sufficient to make a diagnosis.
  • Serum insulinlike growth factor 1 (IGF-1) level is the best endocrinologic test for acromegaly. IGF-1 reflects GH concentration in the last 24 hours. Technical factors may limit its usefulness in some laboratories.
  • Oral glucose tolerance test is the definitive test for the diagnosis of acromegaly; a positive result is the failure of GH to decrease to < 1 mcg/L after ingesting 50-100 g of glucose.
    • Thyrotrophin-releasing hormone (TRH), 200 mcg, can be given to increase the test's accuracy. A GH level > 5 mcg/L suggests acromegaly.
    • Failure to decrease the GH concentration to < 2 mcg/L after a glucose load and after TRH stimulation is highly suggestive of acromegaly.

   

  

   
• Cushing disease and Cushing syndrome

  • Twenty-four hour urine is collected for free cortisol. Usually 2 baseline values are obtained.
  • Dexamethasone suppression test: The physiological basis of this test is a decrease in adrenocorticotropic hormone (ACTH) secretion by the pituitary because of exogenous glucocorticoid administration. One mg of dexamethasone is administered. Serum cortisol level is measured the next morning; it should be < 138 nmol/L (ie, < 5 mcg/dL).
  • Standard low-dose dexamethasone: Two-day baseline serum and urine cortisol levels are determined. The patient is then given 4 doses of 0.5 mg of dexamethasone at 6-hour intervals. Normal suppression is a serum cortisol level of < 138 nmol/L or a urine level of less than 55 nmol/L.
  • If cortisol levels are increased abnormally, corticotrophin-releasing factor (CRF) in a dose of 100 mcg can be given to differentiate between Cushing disease and other causes of hypercortisolism (ie, Cushing syndrome). With pituitary adenomas, cortisol secretion is increased over the baseline.
  • High-dose dexamethasone suppression confirms diagnosis of a pituitary adenoma. It suppresses the pituitary gland even in the presence of an adenoma. If cortisol levels remain unchanged, the cause of increased cortisol is not a pituitary adenoma.
  • Metyrapone test: Metyrapone inhibits synthesis of cortisol. Patients with pituitary tumors remain responsive to low levels of cortisol, prompted by metyrapone administration, with increased secretion of cortisol precursors (ie, 11-deoxycortisol).
  • Serum levels of ACTH: The serum concentration of ACTH is higher than normal (>5.5 pmol/L at 9 am and >2.2 pmol/L at midnight).
  • At times, venous sampling of ACTH from the petrosal sinuses by means of cerebral venography may be valuable when making the diagnosis is difficult.
  • Baseline petrosal sinus levels of CRF distinguish patients with Cushing disease from those with ectopic ACTH secretion.

   

  

   
• Glycoprotein hormones -Thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone

  • Pituitary adenomas that are associated with thyroid-stimulating hormone (TSH) hypersecretion are uncommon. These patients have increased T3 and T4 levels, hyperthyroidism, and goiter with inappropriately high levels of TSH.
  • Increased follicle-stimulating hormone (FSH) levels may be apparent in the histologic examination of a pituitary adenoma in patients without apparent preoperative endocrine abnormalities and in some patients with hypogonadism.
  • Increased luteinizing hormone (LH) levels also may be seen in patients with hypogonadism. The secreted hormone is not intact LH, and serum testosterone levels are not increased.
  • Free alpha and beta subunits of FSH are secreted by pituitary tumors that are thought to be inactive. A high percentage of these tumors have a paradoxical release of FSH subunits in response to TRH stimulation (200 mcg). Rarely, these tumors are associated with precocious puberty or resumption of bleeding in a postmenopausal woman.
  • The initial screening endocrine tests should include levels of prolactin, IGF-1, LH, FSH, TRH and alpha subunit, cortisol, and T4; men should have testosterone level checked.

   

  

   
• Pituitary apoplexy: CSF may be xanthochromic, with crenated RBCs and high protein level.

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Imaging Studies

MRI of the brain and sellar region with multiplanar thin sections is of critical importance. This provides axial, coronal, and sagittal sections of the sellar contents. Generally, the relationship between the lesion and the optic chiasm and visual pathways is recognized easily. Pregadolinium and postgadolinium images are recommended to ensure that primarily isointense lesions do not escape detection. See the images below.

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This contrast-enhanced coronal MRI was obtained in a patient who complained of visual loss.

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Coronal T1 precontrast MRI A (left panel), B postcontrast (middle panel) and T2 (right panel) showing a sellar mass causing obvious left and upward di....

View Image

Axial, sagittal, and coronal MRI of the sellae in a patient with a severe headache, normal neuro-ophthalmologic examination, and no evidence of endocr....

In a study by Paterno and Fahlbusch of patients who underwent transsphenoidal pituitary adenoma surgery, intraoperative high-field magnetic resonance imaging (iMRI) was used for immediate intraoperative quality control to evaluate extent of tumor removal during the surgical procedure. Use of iMRI allowed resections to be extended in cases in which tumor remnants could be documented as suspicious after total resection. According to the authors, incomplete removal of resectable pituitary adenomas could be avoided in many cases by identifying the location of the tumor remnants. In cases in which it is not possible to achieve complete resection of an adenoma, further treatment can be planned earlier, without having to wait 2-3 months after surgery for conventional postoperative MRI scans to be performed.^[12]

CT scan of the brain with sellar images may be sufficiently specific and can detect tumor calcifications. However, the detail is generally inferior to that of MRI. However, in many cases CT and MRI imaging data can be complementary and thus on a case-by-case basis both imaging studies may be indicated.^[13]

Cerebral angiography is not performed routinely in the workup of sellar mass lesions. It generally is performed when vascular lesions are suspected.

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Other Tests

See the list below:

• A final diagnosis generally is not made until the lesion is resected.
• If a granulomatous or infectious process is the primary concern, other systemic and neurological testing may be required.

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Procedures

See the list below:

• Visual field testing
• Petrosal sinus venous sampling for ACTH- or TSH-producing adenomas in selective cases

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Histologic Findings

The role of pathologic examination of pituitary tumors is critical. Routinely perform standard histologic examination, electromicroscopy, and immunohistochemistry for these lesions. Findings then are correlated with clinical and imaging results. The histologic characteristics of these lesions are discussed in Pathophysiology. At times, the differentiation of hyperplasia from adenoma may be difficult. Other nonpituitary mass lesions may be identified easily by pathologic examination.

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Medical Care

See the list below:

• Prolactinomas: The majority of these lesions respond to dopamine receptor agonists. Improvement in visual field abnormalities, resolution of symptoms associated with hyperprolactinemia, and visible diminution of the actual mass can result with treatment.
• Acromegaly: Somatostatin analogues (octreotide) can be helpful in the treatment of increased postoperative levels of GH. In some cases, the tumor may shrink modestly. Gallstones are a frequent complication of somatostatin-analogue therapy. Dopamine agonists also have been used.
• Replacement therapy for decreased or absent hormones should be instituted as needed.
• All hormone-based treatment should be directed by a consulting endocrinologist.

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Surgical Care

Pituitary surgery has undergone quite an evolution since the days of Harvey Cushing’s research and his pioneering development of the sublabial and transcranial methods of accessing the sella. Besides the transsphenoidal/translabial approaches, an endoscopic transnasal approach has become an additional an increasingly favored option with a wider surgical field. For intrasellar tumors the transsphenoidal or endonasal endoscopic techniques show similar results but for larger extrasellar tumors the endonasal approach may be preferred.^[14]

• Transsphenoidal surgery

  • Transsphenoidal microscopic surgery is the most frequent surgical approach for the resection of pituitary tumors. With larger lesions, a transfrontal approach may become necessary to decompress the visual pathways.
  • Minimally invasive endoscopic surgery using a 4-mm endoscope through a nostril is a possibility in selective cases. A 2013 review examined the transnasal endoscopy approach for resection of giant adenomas with profound mass effect. In 54 cases, the lesions had the greatest diameters, measuring 4 cm; roughly 80% of them had visual-field defects. Near-total resection was achieved in 67% of cases, demonstrating efficacy of the approach in larger tumors. The endonasal approach was concluded to be effective, not only in tumor removal, but had limited complication rates. CSF leak, residual tumor, postoperative diabetes insipidus, and apoplexy in residual adenoma were listed as complications.
  • Open low-field intraoperative MRI monitoring for transsphenoidal surgical resection is gaining acceptance to monitor the precise extent of tumor resection.
  • Null cell tumors and gonadotrophinomas are best treated with transsphenoidal surgery.
  • The main complication after transsphenoidal surgery (from the endocrine standpoint) is hypopituitarism.
  • Low- and high-field intraoperative monitoring is used to minimize resectable tumor.^[15]

   

  

   
• Prolactinomas

  • Microprolactinomas: Transsphenoidal resection of the tumor offers a chance for a cure without the need for long-standing dopamine agonist therapy; however, many patients choose dopaminergic therapy.
  • Macroadenomas that secrete prolactin are best treated with dopamine agonists.

   

  

   
• Acromegaly

  • Transsphenoidal surgery decreases GH levels to less than 5 mcg/L in 60% of cases.
  • Normal pulsatile secretion of GH is not always regained, and 20% of patients continue to have increased GH levels in response to TRH.
  • Radiotherapy is an alternative, although GH levels may not decrease for 2-4 years.
  • Elevated GH levels may be treated with somatostatin analogues and dopamine agonists, if tolerated.

   

  

   
• Cushing disease

  • Transsphenoidal tumor resection is the first line of treatment in patients with basophilic adenomas of the pituitary gland. It is curative in 80% of cases.
  • Pituitary irradiation is required in the remaining cases to prevent the development of Nelson syndrome.
  • In children, pituitary irradiation and adrenalectomy are highly effective.
  • Immediate postoperative biochemical remission of Cushing syndrome, evidenced by cortisol levels less than 2 micrograms/dL, was associated with sustained postoperative remission lasting 68.4 months. MRI evidence of a microadenoma was also a predictor of successful tumor resection via a transsphenoidal microsurgical approach.

   

  

   

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Consultations

See the list below:

• The treatment team should consist of any or all of the following specialists: ophthalmologist or neuro-ophthalmologist, neuroradiologist, endocrinologist, gynecologist, neurosurgeon, neuropathologist, and radiation medicine specialist.
• Different specialists may be involved as indicated by the patient's specific symptoms.

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Diet

See the list below:

• Dietary factors are important in patients with acromegaly or Cushing disease.
• Patients with hypothyroidism, hypoadrenalism, or hypopituitarism have specific dietary needs.

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Activity

See the list below:

• Activities of daily living (ADLs) generally are not restricted in these patients.
• Exercise tolerance may be limited in some cases.

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Medication Summary

All hormone-related therapy should be initiated and directed by a consulting endocrinologist. The specific disorders are treated as follows:

Pituitary disorders associated with hormonal excess

Prolactinomas - Dopamine agonists (eg, bromocriptine, cabergoline)

Acromegaly - Octreotide (somatostatin analogue), dopamine agonists

Syndromes associated with hormonal deficiency and hypopituitarism

Hypothyroidism - Synthroid

Adrenocorticosteroid deficiency - Cortisol

Male hypogonadism - Testosterone

Female hypogonadism - Estrogen/progesterone

Growth hormone deficiency - GH replacement may be needed, more often in children than in adults

Many patients who have undergone surgery may experience posterior pituitary hypofunction with resultant diabetes insipidus and may require transnasal arginine vasopressin (DDAVP).

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Octreotide (Sandostatin)

• Dosing, Interactions, etc.

Clinical Context:  Hypothalamic polypeptide that inhibits production of GH. Acts primarily on somatostatin receptor subtypes II and V. Has multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.

More effective than dopamine agonists in acromegaly.

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Class Summary

These agents are used to treat disorders associated with acromegaly. Recent work suggests the use of pegvisomant; however, no definite guideline indication has been determined.^[16]

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Bromocriptine (Parlodel)

• Dosing, Interactions, etc.

Clinical Context:  Ergot alkaloid derivative with dopaminergic properties. Inhibits prolactin secretion.

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Cabergoline (Quinazoline, Dostinex)

• Dosing, Interactions, etc.

Clinical Context:  Formerly CV205-502. Long-acting dopamine receptor agonist with high affinity for D2 receptors. Prolactin secretion by anterior pituitary predominates under hypothalamic inhibitory control exerted through dopamine.

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Pergolide (Permax)

Clinical Context:  Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

Potent dopamine receptor agonist at both D1 and D2 receptor sites. Approximately 10-1000 times more potent than bromocriptine on mg per mg basis. Inhibits secretion of prolactin; causes transient rise in serum concentrations of GH and decrease in serum concentrations of LH.

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Class Summary

Dopamine receptors in the hypothalamus exert an inhibitory action on some pituitary cells, particularly those producing prolactin and, to a lesser extent, GH.

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Hydrocortisone (Cortef, Solu-Cortef, Hydrocort)

• Dosing, Interactions, etc.

Clinical Context:  DOC because of mineralocorticoid activity and glucocorticoid effects.

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Class Summary

These agents are used in the management of adrenocortical insufficiency.

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Levothyroxine (Synthroid, Levoxyl, Levothroid)

• Dosing, Interactions, etc.

Clinical Context:  DOC. Rapidly inhibits the release of thyroid hormones via a direct effect on the thyroid gland and inhibits the synthesis of thyroid hormones. Iodide also appears to attenuate cAMP-mediated effects of thyrotropin. In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.

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Class Summary

These agents are used as supplemental therapy in hypothyroidism.

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Estrogens (Premarin)

• Dosing, Interactions, etc.

Clinical Context:  Contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. Mixture of sodium estrone sulfate and sodium equilin sulfate. Contains as concomitant components, sodium sulfate conjugates, 17-alpha-dihydroequilenin, 17-alpha-estradiol, and 17-beta-dihydroequilenin.

Restores estrogen levels to concentrations that induce negative feedback at gonadotrophic regulatory centers, which, in turn, reduces release of gonadotropins from pituitary. Increases synthesis of DNA, RNA, and many proteins in target tissues.

Important in developing and maintaining female reproductive system and secondary sex characteristics; promotes growth and development of vagina, uterus, fallopian tubes, and breasts. Affects release of pituitary gonadotropins; causes capillary dilatation, fluid retention, and protein anabolism; increases water content of cervical mucus; and inhibits ovulation. Predominantly produced by the ovaries.

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Class Summary

These agents are used in the treatment of hypoestrogenism.

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Testosterone (Depo-Testosterone, Andro-LA, Delatest)

• Dosing, Interactions, etc.

Clinical Context:  Promotes and maintains secondary sex characteristics in androgen-deficient males.

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Class Summary

These agents are used in the treatment of male hypogonadism.

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Human growth hormone (Genotropin, Humatrope, Nutropin)

• Dosing, Interactions, etc.

Clinical Context:  Stimulates growth of linear bone, skeletal muscle, and organs. Stimulates erythropoietin, which increases red blood cell mass.

Currently widely available in SC injection form. Adjust dose gradually based on clinical and biochemical responses assessed at monthly intervals, including body weight, waist circumference, serum IGF-1, IGFBP-3, serum glucose, lipids, thyroid function, and whole body dual-energy x-ray absorptiometry. In children, assess response based on height and growth velocity. Continue treatment until final height or epiphysial closure or both have been recorded.

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Class Summary

These agents are used in the replacement of endogenous growth hormone in patients with adult growth hormone deficiency.

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Desmopressin (DDAVP, Stimate)

• Dosing, Interactions, etc.

Clinical Context:  Synthetic analogue of hypothalamic/posterior pituitary hormone 8-arginine vasopressin (antidiuretic hormone [ADH]). Has no effect on V1 receptors, which are responsible for vasopressin-induced vasoconstriction. Instead, acts on V2 receptors at renal tubuli, increasing cellular permeability of collecting ducts, which are responsible for antidiuretic effect. Effect is prevention of nocturnal diuresis and elevated BP in the mornings, resulting in reabsorption of water by kidneys. Formulated as a tab and a nasal spray. Tab is more convenient to administer.

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Class Summary

These agents are used in the treatment of diabetes insipidus.

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Further Outpatient Care

See the list below:

• Adjustment of hormonal therapy is necessary following transsphenoidal resection of the adenoma. This may be accomplished in the weeks following surgery by the consulting endocrinologist.

  • Assess the need for replacement of cortisol 4 weeks after the resection. This is done by measuring the cortisol levels following an IV injection of 250 mcg of tetracosactin. Cortisol levels greater than 500 nmol/L indicate sufficient endogenous steroid production.
  • Low thyroid levels are an indication for replacement. The same is true for low testosterone levels in symptomatic males and low estrogen/progesterone levels in females.

   

  

   
• Periodic neuro-ophthalmologist follow-up is essential, particularly when residual tumor is present. Visual fields and fundus photographs should be obtained before and immediately after tumor resection. These parameters provide a baseline for follow-up examinations.
• Radiation therapy (RT) is often necessary for managing local mass effects of large macroadenomas. The indications for RT at this time are controversial. In a recent study, Alameda et al followed 51 patients with pituitary tumor who underwent surgery; 22 with complete macroscopic resections, judged by imaging, were tumor-free 3-6 years postoperatively. Twenty-seven patients with residual tumors after surgical resection were treated with RT. Fourteen residual tumors decreased in size, 11 remained stable, 1 increased in size, and 1 patient was lost to follow-up. RT is a useful treatment alternative among patients with residual tumors after surgery. Fractionated stereotactic radiotherapy (FSR) was found to be safe and effective by Colin et al in 110 consecutive patients. Moreover, it may reduce the possibility of postradiation optic neuropathy.
• The use of Gamma knife radiation to treat residual tumor has been the subject of reviews, which have found it effective, particularly in acromegaly and Cushing syndrome. The risk of postradiation optic neuropathy averaged less than 5%.

• References

Further Inpatient Care

Care of patients is primarily on an outpatient basis. Only patients who are undergoing surgery are inpatients. Additionally, a small percentage of patients with pituitary apoplexy present with a clinical picture similar to that of subarachnoid hemorrhage.

Transsphenoidal surgery

• Careful hormonal control of these patients under the direction of an endocrinologist is essential.
• A syndrome of inappropriate antidiuretic hormone secretion (SIADH) may be seen transiently, followed by diabetes insipidus.
• Postoperative hypoadrenalism is a possibility that requires careful monitoring.
• Hormonal levels should be assessed and replacements provided when appropriate.
• In most cases, CSF rhinorrhea should be diagnosed and addressed promptly.
• In most cases, transsphenoidal hypophysectomy involves low risk and has a good prognosis.

Pituitary apoplexy

• As its name indicates, the apoplectic onset of hemorrhage within a pituitary adenoma may lead to hypothalamic, chiasmal, cavernous sinus, and brainstem compression.
• Meningeal irritation results from blood in the subarachnoid space. On occasion, the degree of subarachnoid hemorrhage is significant, and a spinal tap may show evidence of acute or subacute bleeding. The acute panhypopituitarism is associated with shock and hypothalamic-brainstem compression, which could lead to coma and even death.
• Headache, vomiting, visual loss, blindness, ophthalmoplegia, and altered consciousness may be present. In a series involving 62 patients, Semple et al found headache was the most common symptom in 87% of their cases, visual loss occurred in 56% of the patients, ophthalmoplegia in 45%, and altered level of consciousness in 13%. Hypopituitarism was present in 73% of patients and diabetes insipidus in 8%.^[17]
• In most cases, surgical intervention is required with excellent results. Candidates for emergency surgery include patients with rapidly deteriorating vision, altered mental status, and hypothalamic compression. Pituitary apoplexy may be fatal in a few instances. Conservative treatment is an option in stable cases, particularly if they are prolactinomas.
• Factors leading to hemorrhage within a pituitary adenoma identified by Biousse et al include the following: reduced blood flow to the gland, sudden increment of blood flow, stimulation of the gland by endocrine mechanisms, anticoagulation, and trauma.^[18] An upper respiratory tract infection with frequent coughing and sneezing also may trigger an apoplectic event. The best method to make the diagnosis of pituitary apoplexy is cerebral imaging. MRI preferentially but CT scan is an acceptable option if MRI is not available.

• References

Inpatient & Outpatient Medications

Initial hormonal deficiencies may improve over time. Therefore, frequent endocrine re-evaluation is necessary.

Perform preradiation and postradiation endocrinologic and neuro-ophthalmologic evaluations. A postoperative cerebral imaging study is important to determine the possibility of residual tumor. If residual tumor is present, serial imaging is required.

Adverse radiation effects on the hypothalamus, pituitary, and visual pathways require close monitoring.

• References

Transfer

Pituitary apoplexy

• Patients with a diagnosis of pituitary apoplexy should be transferred immediately to a tertiary care center intensive care unit.
• IV fluids and IV steroid replacement should be initiated.
• Urgent decompression surgery is indicated.

Patients with other pituitary lesions are investigated as outpatients and admitted for transsphenoidal resection.

Inferior petrosal sinus corticotrophin levels also can be obtained on an outpatient basis.

• References

Complications

Treatment of pituitary tumors, particularly those resected via a transsphenoidal approach, has an excellent outcome with successful decompression of the visual pathways, cavernous sinus, and hypothalamus.

The possibility of significant loss of olfactory function following endoscopic transphenoidal pituitary surgery has been recently recognized as a frequent finding. A study by Rotenberg et al found damage to olfactory tissues to be a result of raising the vascularized septal flap that incorporates tissue rich in olfactory nerve receptors. Patients should be warned about this possibility prior to surgery. No suggestions for alternative olfactory receptor-sparing techniques were reviewed.^[19]

Transfrontal resections are associated with more complications.

In cases handled by a skilled surgeon, surgical complications are minimal but can include any of the following:

• Incomplete resection of large adenomas
• Transient or permanent diabetes insipidus
• CSF rhinorrhea
• Monohormonal or polyhormonal deficiencies
• Residual permanent visual field defects

Empty sella syndrome: An empty sella may occur after transsphenoidal surgery and is generally benign. Generally, herniation of the chiasm inside the sella typically does not cause visual field defects.

Radiation toxicity may occur as a rare complication in the treatment of pituitary adenomas, resulting in hypothalamic and chiasmal necrosis.

• References

Prognosis

See the list below:

• Prolactin-secreting microadenomas

  • Surgical resection is curative.
  • Dopamine agonists provide symptom control.

   

  

   
• Prolactin-secreting macroadenomas: Dopamine agonists provide symptom control.
• Acromegaly

  • Surgical resection is curative in 60% of patients.
  • Octreotide therapy controls symptoms. In some instances, the use of PPAR-gamma ligands such as rosiglitazone or retinoic acid may be potential therapeutic options in the management of persistent or recurrent corticotropin-producing adenomas.^[10]

   

  

   
• Cushing disease: Surgical resection is curative. Rarely, invasive tumors produce metastatic deposits within the neuraxis via CSF pathways.
• Rarely, distant metastases may occur.

• References

Patient Education

The successful management of pituitary adenomas requires a highly motivated and compliant patient.

Hormone-replacement therapy is demanding, and a noncompliant patient is at risk for complications due to misuse of these agents.

Interaction of a team of specialists is required to manage these lesions. One of the specialists should serve as team leader and coordinate the patient's care.

Prompt reporting of new symptoms is important in addition to routine follow-up visits.

If the patient has no new symptoms or problems beyond about 5 years after beginning treatment, follow-up visits can be less frequent.

The frequency of follow-up visits depends on the presence of residual tumor, visual deficit, hormonal needs, history of radiation therapy, or other complicating circumstances.

Visual prognosis is excellent with transsphenoidal surgery. Ninety-five percent of patients studied by Gnanalingham et al experienced visual improvement.^[20] The extent of the visual field recovery is mainly dependent on the preoperative visual field defect. These authors also found that visual recovery may occur in a rapid fashion (3-6 mo) but may also take place slowly over several months and even a few years.

• References