Pituitary Tumors: Diagnosis and Management

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Chapter 40 Pituitary Tumors

Diagnosis and Management

Clinical Pearls

Pituitary tumors present in various ways as a result of excess or deficient secretion of pituitary hormones or extrinsic compression on the pituitary stalk or adjacent structures. Approximately 75% of pituitary adenomas are functioning tumors; of these, half are prolactinomas, less than 25% secrete growth hormone (GH), and the rest secrete adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), or thyroid-stimulating hormone (TSH).

Functioning tumors often present with symptoms due to hormone hypersecretion, and nonfunctioning tumors generally present with symptoms due to mass effect.

Transsphenoidal adenomectomy (TSA) is the first line of treatment for nonfunctioning tumors. Medical therapy is the first line of treatment for prolactinomas. Other functioning adenomas generally require surgical resection, medical treatment, or radiation therapy. Surgery through the microscopic, extended transsphenoidal, or endoscopic route is safe and effective in experienced hands. Craniotomy may be required for a tumor extending beyond the sellar region.

Patients with functioning pituitary adenomas require long-term follow-up to assess clinical and laboratory parameters. This is best done at a center that can provide a neurosurgeon, an endocrinologist, a radiation oncologist, and an ophthalmologist. Pituitary hormones should be regularly followed in all these patients; patients with residual tumor after treatment should be monitored with magnetic resonance imaging (MRI) scans, and patients with optic nerve compression require periodic formal visual field testing.

The Pituitary Gland

The pituitary gland regulates the function of numerous other glands, including the thyroid, adrenals, ovaries, and testes. It controls linear growth, lactation, and uterine contractions in labor, and it manages osmolality and intravascular fluid volume via resorption of water in the kidneys. It secretes eight peptide hormones, six from the anterior lobe and two from the posterior lobe (Table 40.1).

The pituitary lies in the sella turcica, a saddle-shaped concavity in the sphenoid bone. Its stalk, which contains the pituitary portal veins and neuronal processes, passes through the diaphragma sella, just above which pass the optic nerves (Fig. 40.1). The cavernous venous sinuses form the lateral borders of the sella, and contain within them the internal carotid arteries, cranial nerves III, IV, and VI, and the ophthalmic and maxillary divisions of cranial nerve V.

In the anterior lobe of the pituitary gland, known as the adenohypophysis, five distinct types of cells produce and secrete six different hormones. Lactotroph cells make prolactin (PRL), somatotroph cells produce growth hormone (GH), corticotrophs secrete adrenocorticotropic hormone (ACTH), thyrotrophs make thyroid-stimulating hormone (TSH), and gonadotrophs produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The secretion of these hormones is regulated by the hypothalamus and by inhibitory feedback control by target organ hormone products (Figs. 40.2 and 40.3).

The posterior lobe of the pituitary, the neurohypophysis, secretes antidiuretic hormone (ADH) and oxytocin, which are produced by hypothalamic neurons and released directly from nerve terminals in the posterior pituitary.

The hypothalamus secretes releasing factors to stimulate the production of pituitary hormones. Corticotropin-releasing factor (CRH), thyrotropin-releasing factor (TRH), and gonadotropin-releasing hormone (GnRH) positively regulate the production of ACTH, TSH, and the gonadotropins, LH and FSH. GH secretion is more complicated in that it receives both positive and negative hypothalamic manipulation, via GH-releasing hormone (GHRH) and somatostatin, respectively. Prolactin secretion is primarily inhibited by the hypothalamic release of dopamine, also known as prolactin-inhibiting factor. Some of these hypothalamic factors influence the production of more than one anterior pituitary hormone. For instance, TRH, which primarily stimulates TSH production, also has a positive effect on prolactin release.

Pituitary adenomas are composed of adenohypophyseal cells, which constitute 10% to 15% of primary intracranial tumors. Among pituitary tumors, the majority are functioning, or hormone-secreting, tumors, while approximately 30% are classified as nonfunctioning adenomas.

Symptoms and signs of disorders affecting the pituitary reflect the function and anatomy of the gland. Because of its diverse array of functions as well as the multiple structures in close proximity to the gland, pituitary tumors present in various ways due to excess or deficient secretion of pituitary hormones or extrinsic compression on the pituitary stalk or adjacent structures.

Epidemiology

Pituitary adenomas have an annual incidence of 25 per 1 million people and account for nearly 10% of all surgically resected brain tumors, with nonfunctioning adenomas and prolactinomas being the most common pituitary tumors.1,2 Many of these tumors are subclinical and may never present during a patient’s lifetime; autopsy studies show an 11% to 27% incidence of occult microadenomas.36 Pituitary tumors are the third most common primary intracranial neoplasm, behind glioma and meningioma,7 and are more common among African Americans, in whom they account for more than 20% of central nervous system neoplasms.8

Microadenomas are most often found in women of childbearing age. Though studies in the 1970s appeared to demonstrate a higher incidence of adenomas among women than men, it is unclear if there is actually a higher prevalence among women or if the effect of a tumor on pituitary function and, therefore, reproduction leads to a higher rate of detection. Autopsy studies show no sex predominance.2 Men with pituitary tumors more often present with macroadenomas in their fifth and sixth decades of life.3

Nonfunctioning Pituitary Adenomas

Nonfunctioning adenomas account for 30% of pituitary tumors.12 The term nonfunctioning reflects the fact that these tumors do not cause clinical hormone hypersecretion and so do not cause hypersecretory syndromes.13 These tumors are heterogeneous with multiple histopathological cell types. Though they do not cause signs of clinical hormone hypersecretion, histopathological evidence of hormone expression is evident in more than 40%.

Pathological specimens of null cell adenomas do not express hormones, but oncocytomas may show focal immunostaining for anterior pituitary hormones and produce hormones in vitro. Silent gonadotropes morphologically resemble glycopeptide-secreting tumors and stain positive for FSH, LH, or the common α-subunit. Silent somatotropes stain positive for GH and silent corticotrophs stain positive for ACTH on pathological specimen, but these tumors do not cause the clinical manifestations of acromegaly or hypercortisolemia, respectively.

Presentation

Nonfunctioning adenomas are benign lesions that are typically large upon presentation and manifest with symptoms of mass effect.14 Pressure on the pituitary gland can lead to decreased pituitary function, and nearly one third of these patients have hypopituitarism.15 Gonadotropins are generally the first hormones affected, then GH, followed by TSH and ACTH. Hormone dysfunction may lead to amenorrhea or hypogonadism and decreased libido, or to hypothyroidism with weight gain, depression, fatigue, and mental slowing. These changes develop insidiously as the tumor grows, so the patient may be unaware until the lesion is large.

Parasellar structures may be compressed. Superior enlargement effaces the optic chiasm, causing visual loss. Compression on the inferonasal fibers that decussate at the anterior and inferior aspect of the chiasm leads to superior temporal quadrantanopia, then bitemporal hemianopia. An adenoma may grow laterally into the cavernous sinus, leading to extraocular muscle palsies or deficits to the sympathetic nerves and cranial nerves III, IV, or VI, leading to mydriasis, ptosis, facial pain, or infrequently, diplopia. Headache due to pressure on the dura may occur as well. Once a large tumor has extended out of the sella, it can cause pressure on the temporal or frontal lobes and, rarely, hydrocephalus via obstruction of cerebrospinal fluid (CSF) pathways. Occasionally, large adenomas become suddenly apparent after hemorrhage or infarction known as pituitary apoplexy. Pituitary lesions may be discovered incidentally during evaluations for other conditions such as trauma.

Diagnosis

Patients with a pituitary mass should undergo a complete neurological and endocrinological evaluation including a detailed history and physical examination to assess for signs or symptoms of hypersecretory syndromes such as Cushing’s disease, hyperprolactinemia, or acromegaly. Endocrinological testing is needed to determine hormonal function. Laboratory studies include prolactin, FSH, LH, GH, insulin-like growth factor 1 (IGF-1), ACTH, cortisol, TSH, thyroxine, estradiol, and testosterone. A mildly elevated prolactin level does not exclude a nonfunctioning tumor as any sellar mass can compress the stalk, interrupting dopaminergic inhibition of PRL and leading to mild hyperprolactinemia up to 150 µg/mL known as the stalk effect.

Neuro-ophthalmological examination, including visual field testing and visual acuity, is necessary before and after treatment to document deficits and monitor changes.

Plain radiographs may demonstrate an enlarged, round sella, and the sellar floor may appear doubled due to a thinned, asymmetrically worn lamina dura. High-resolution magnetic resonance imaging (MRI) with cuts through the sellar region is essential for surgical planning, as it will show the precise size and location of the lesion as well as its relationship with the chiasm, cavernous sinus, and other surrounding structures (Fig. 40.4), and a computed tomography (CT) scan will demonstrate the sphenoid sinus anatomy.

The differential diagnosis of a nonfunctioning pituitary adenoma includes multiple other lesions, including functioning pituitary tumors, which can be differentiated by laboratory results. A Rathke’s cleft cyst may appear similar to a cystic pituitary adenoma. A tuberculum sellae meningioma may compress the chiasm, but it will generally not cause enlargement of the sella. A craniopharyngioma is more often a suprasellar lesion. Metastasis to the sella will often cause diabetes insipidus or extraocular muscle palsies, which are rarely seen in patients with pituitary adenomas. An internal carotid artery aneurysm may fill the sella; however, a flow void will be visible on MRI. A sarcoid granuloma or a tuberculoma is quite rare.

Treatment Options

Surgery

The first line of treatment for a nonfunctioning pituitary adenoma is transsphenoidal resection of the tumor, which provides immediate relief of mass effect and has a low rate of complications.1619 This surgery is generally done as an elective procedure. An extended transsphenoidal approach may be needed when the tumor has reached beyond the sella and a transcranial approach or combined transsphenoidal-transcranial approach may be considered if there is significant supratentorial tumor extension.20,21

The goals of surgery are to eliminate mass effect from the pituitary and surrounding structures, to preserve or restore pituitary and visual function, to resect enough of the lesion to prevent recurrence, and to obtain tissue for histopathological analysis.22

Hermann Schloffer performed the first transsphenoidal resection of a pituitary tumor in 1907 and Harvey Cushing popularized it in the two decades afterward.23,24 Neurosurgeons have been trying to perfect the transsphenoidal adenomectomy (TSA) since. The standard methods in use today involve either an endonasal or sublabial approach to the sella.

Endonasal Transsphenoidal Approach

In the endonasal transsphenoidal approach, the patient’s head is placed in a Mayfield cranial fixation clamp. The body is placed supine with the neck somewhat extended and the head turned slightly toward the right to face the surgeon, permitting a good view through the nares (Fig. 40.5).

In a direct endonasal approach, the surgeon enters directly into the sphenoid sinus though the ostium. In the microscopic unilateral transseptal approach, a small incision is made in the right nostril mucosa and a submucosal plane is developed along the septum until the anterior wall of the sphenoid sinus is identified. A speculum is inserted and the septum is subluxed and deviated.

The operating microscope is brought into the field and the sphenoid sinus is opened with an osteotome and Kerrison rongeur. The opening is enlarged to allow visualization of the lateral portion of the sella. Some surgeons then obtain fluoroscopic or image-guided confirmation of the sella’s position; however, direct visualization is generally sufficient.

An osteotome and up-biting Kerrison rongeur are used to open the sellar floor. The dura is revealed and a midline vertical incision is made with a No. 11 blade. Up-angled scissors are used to enlarge the dural opening and expose the adenoma. The tumor may be debulked intracapsularly, or an extracapsular plane may be developed along the tumor’s pseudocapsule. The tumor is extracted piecemeal using ring curets, pituitary rongeurs, gentle suction, and irrigation. Adenoma removal can involve significant bleeding, making adequate suction imperative, as the bleeding often ceases only when the tumor is removed.

After tumor resection, the sellar floor may be repaired with DuraForm, fascia, fat from the patient’s abdomen, bone, cartilage, or prosthesis. The sphenoid sinus may be packed with DuraForm, DuraSeal, or fat. The speculum is removed, the septum returned to midline, and the mucosa is sutured shut at the inside edge of the naris with absorbable suture. The patient will have copious mucosal secretions postoperatively, so a nasal trumpet may be placed in the nares overnight.

If a spinal fluid leak occurs through the diaphragm, then a sealant such as DuraSeal or Tisseel can be used to seal the leak and reconstruct the floor of the sella with bone, cartilage, or prosthesis, with or without a free fat graft from the abdomen. A few days of lumbar drainage of CSF may be used as well.

Endoscopy

The endoscope may be used in place of the microscope. When performing an endoscopic TSA, the patient is positioned in a manner similar to that used for the standard microscopic approach. A 4-mm or 2.7-mm endoscope is used to visualize the sphenoethmoid recess. The bilateral sphenoid ostia are entered and widened using a mushroom punch. The posterior nasal septum is incised and resected using a microdébrider and straight through-cutting instruments. The anterior wall of the sphenoid sinus is resected using straight through-cutting instruments and Kerrison punches.

The lesion is removed in the same manner as with the microscopic approach. The endoscope provides a wide field of view and angled scopes permit enhanced inspection of the walls of the sella, as well as the suprasellar, retrosellar, and parasellar regions to search for residual tumor. Three-dimensional endoscopes have been introduced recently and permit a more realistic, nondistorted view of the regional anatomy than do the conventional two-dimensional endoscopes (Fig. 40.6).

After the lesion is removed, DuraForm is placed over the sella. Gelfoam is used to pack the sphenoid sinus, and NasoPore is laid over the bilateral sphenoethmoid recesses. If a CSF leak is present, a mucosal septal flap may be used to assist in closure. A speculum is not needed with this approach.25,26

Outcomes

Following operative decompression, vision generally improves and endocrine function recovers to a lesser extent, and surgical resection generally halts progressive loss of hormonal function. After TSA, visual field defects will improve in 70% to 89% of patients,30,31 will not change significantly in 7%, and will worsen in less than 4% of patients.32

Approximately 30% of patients with nonfunctioning adenomas have some degree of hypopituitarism prior to surgery.33 In one quarter of these patients, preoperative pituitary deficiencies will improve after surgery, although 10% of patients have some postoperative worsening of hormone function.8 Oral hormone replacement is generally sufficient for those patients whose pituitary deficiencies worsen or do not improve.

Complications from transsphenoidal surgery include intracranial hemorrhage, carotid artery injury, ischemic stroke, visual impairment, CSF leak, nasal septal perforation, and epistaxis. The risk of stroke or death is less than 1%, the risk of visual loss is less than 2%, and the risk of CSF rhinorrhea is less than 4%.34

After transsphenoidal removal of an adenoma, hormone levels must be closely followed because the patient is at risk for hypopituitarism. Morning cortisol levels are checked for several days, and patients with hypocortisolemia are treated with steroid replacement as needed.

Diabetes insipidus (DI) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are common but transient postoperative complications after transsphenoidal surgery. Nearly 18% of patients will develop DI, though this is often temporary.34 It is imperative to closely monitor fluid balance, serum sodium levels, and urine specific gravity. In a small number of patients, hyponatremia can occur a week or more after the surgery.

Following resection of a giant macroadenoma, when it is likely that some residual tumor may remain, a rare but potentially fatal complication is postoperative apoplexy. This complication must be closely monitored for. In one study of 134 surgically resected giant adenomas, four patients had fatal postoperative pituitary apoplexy.35

The mortality rate for patients undergoing transsphenoidal surgery is very low, approximately 0.5%. Among giant macroadenomas, the mortality rate is approximately 1%. After successful surgical resection, 10% to 20% of tumors are reported to recur within 6 years.30,31 At 10-year follow-up, more than 80% of patients who underwent transsphenoidal resection of a nonfunctioning pituitary adenoma are alive and disease free.8

Radiation Therapy

Radiation therapy may be used in patients with recurrent or residual tumor, or in patients who cannot tolerate surgery. Radiotherapy controls tumor growth in 80% to 98% of nonfunctioning tumors.36

Conventional radiotherapy calls for fractionated doses of 1.6 to 2 Gy four or five times per week for 5 to 6 weeks, for a maximum dose of 45 to 50 Gy.9 Tumors respond slowly, with benefits delayed for a year or more.

Stereotactic radiosurgery (SRS) uses only a single session to deliver focused radiation to the lesion with less radiation to surrounding structures. Several forms of SRS are available, including Gamma Knife surgery (GKS), linear accelerator (linac) radiation, and CyberKnife surgery. There is also fractionated stereotactic radiotherapy and proton beam therapy. SRS is generally able to use a higher radiation dose per fraction than is conventional radiation, and usually results in earlier endocrine control. It is not risk-free, however.

The major concern from SRS is radiation damage to the visual pathways, but this can be decreased by limiting the radiation dose to the optic chiasm to less than 10 Gy.37,38 Patients with adenomas closer than 2 to 5 mm to the optic chiasm or larger than 30 mm in diameter are generally not candidates for SRS, though they may undergo fractionated stereotactic radiotherapy or conventional radiation.39 The neuronal and vascular structures in the cavernous sinus are less radiosensitive, so an ablative dose may be administered to tumors with lateral invasion or impingement on the cranial nerves. This allows SRS to function as an adjuvant to surgical resection in patients with tumors that have invaded the cavernous sinus.

As with conventional radiotherapy, hormone deficiencies are the most common side effect with an incidence of 13% to 56%.4043 The risks of radiation-induced second neoplasm and neuropsychiatric changes are lower with SRS than with conventional radiotherapy. Other side effects are rare. Long-term risk for radiation necrosis is approximately 0.2%. Optic neuropathy occurs in 1.7%, vascular changes in 6.3%, neuropsychological changes in 0.7%, and radiation-induced secondary malignancies in 0.8%.44 All forms of radiation therapy have delayed benefit, though SRS induces remission more rapidly than does fractionated radiotherapy.42,45

Functioning Pituitary Adenomas

Functioning pituitary adenomas secrete excessive quantities of a physiologically active pituitary hormone. They present with clinical syndromes caused by their hormone overproduction.

The majority of pituitary tumors are functioning adenomas. Of these, PRL-secreting tumors, or prolactinomas, account for 40% to 60%, while GH-secreting tumors make up 15% to 25%.47 Corticotropin-secreting adenomas represent about 5% of functioning adenomas, and gonadotropin- and thyrotropin-secreting tumors account for less than 1%. Neurohypophyseal tumors are very rare.

Prolactinoma

Prolactin Physiology

Lactotrophs secrete prolactin and are unique in that normal cells can proliferate during adulthood. PRL interacts with receptors in the gonads and acts on breast tissue to initiate and maintain lactation. Hypothalamic moderation of PRL secretion occurs by the release of dopamine into the portal circulation from nerve processes that originate in the arcuate nucleus of the hypothalamus (Fig. 40.8). PRL release is increased by TRH, vasoactive intestinal peptide (VIP), GnRH, peptide histidine methionine, opiates, and estrogen. Pharmacological doses of TRH lead to a rapid release of PRL; however, the physiological role of TRH in PRL production is unclear.

PRL is secreted episodically, with 13 to 14 peaks per day and an interpulse interval of approximately 90 minutes. Small postprandial rises occur secondary to central stimulation from the amino acids in food. Physiological hyperprolactinemia occurs following exercise, psychological and physical stress, sexual intercourse, nipple stimulation, or postpartum breastfeeding, and peak levels occur during the late hours of sleep.

During pregnancy, estrogen stimulates lactotroph hyperplasia and hyperprolactinemia but blocks the action of PRL on the breast, inhibiting lactation until after delivery. Within 4 to 6 months after delivery, basal PRL levels return to normal.

Evaluation

Laboratory testing in patients with suspected hyperprolactinemia includes serial measurements of basal, resting serum PRL levels by radioimmunoassay. Because of the variability in PRL levels over the course of a day, minimally elevated levels should be confirmed with several samples or from a pooled sample.

Normal PRL levels are approximately 5 to 20 ng/mL in men and 5 to 25 ng/mL in nonpregnant women. Any sellar mass can compress the pituitary stalk and interrupt dopaminergic inhibition of PRL. This leads to a “stalk effect,” which results in mildly elevated PRL levels, generally 20 to 150 ng/mL, but should not be confused with a true prolactinoma. Serum PRL levels tend to correlate with the size of the prolactinoma, so that microadenomas generally lead to serum prolactin levels of 100 to 250 ng/mL, and macroadenomas may lead to a serum PRL well above 200 ng/mL. Invasive adenomas or giant adenomas may cause a serum PRL to be several thousand to 100,000 ng/mL.50,52,53 A PRL level more than 200 ng/mL is nearly pathognomonic for a prolactinoma. In patients with amenorrhea, however, pregnancy must also be excluded, as it is associated with PRL levels of 100 to 250 ng/mL by the third trimester. A PRL level of less than 2 ng/mL is generally associated with hypopituitarism, though this may be due to PRL-lowering medications.

One must be suspicious of the “hook effect,” if prolactin values are very low in the presence of a suspected giant prolactinoma.54,55 If the serum PRL level is extremely high, the amount of prolactin-antigen may saturate the antibodies in the radioimmunoassay, failing to form the antigen plus two-antibody “sandwich” complexes required for accurate measurement, and thus leading to a falsely low value (Fig. 40.9). If a prolactinoma is suspected, the PRL level should be tested with serial dilutions to determine an accurate PRL value.52,56

Stimulation of PRL secretion during the TRH-stimulation test suggests the presence of a prolactinoma, but is not diagnostic for this condition. In normal subjects intravenous administration of 200 to 500 µg of TRH stimulates a three- to fivefold rise in serum prolactin levels within an hour. Patients with a prolactinoma, however, usually have a blunted response of less than a twofold increase owing to their limited lactotroph reserve.

Hyperprolactinemia per se is not diagnostic of a prolactinoma, as there are multiple physiological and pathological conditions that can elevate serum PRL. Pregnancy, of course, must be assessed in female patients with hyperprolactinemia. Hyperprolactinemia may also be due to diminished hypothalamic production of dopamine or an interruption of dopamine delivery to the pituitary; interruption of the portal venous system by a sellar tumor or aneurysm compressing the pituitary stalk; previous pituitary irradiation, or the empty sella syndrome; end-stage renal disease, which decreases renal clearance of PRL; and chronic hypothyroidism, which spurs increased TRH secretion stimulating PRL release. Other causes include chest wall or breast lesions, hypoglycemia, hepatic cirrhosis, seizures, polycystic ovary syndrome, or an ectopic site of PRL secretion. Hyperprolactinemia may also occur in up to 40% of patients with acromegaly and has been reported in Cushing’s disease.

Dopamine inhibits PRL secretion, so any drug that decreases dopamine levels will increase serum PRL. These drugs include many antidepressants, such as tricyclics, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors, as well as methyldopa, reserpine, and verapamil.57 Other medications such as phenothiazines and metoclopramide block dopamine receptors, indirectly leading to increased PRL levels.57

When other causes of hyperprolactinemia have been ruled out, an MRI with and without contrast, with thin cuts through the sella, should be obtained to confirm the presence of a prolactinoma.

Medical Treatment

Dopamine agonists are the treatment of choice for prolactinoma.58 These agents can normalize PRL levels within hours to days, shrink tumors, restore reproductive and sexual function, and allow patients to avoid the potential risks of surgery.

Current dopamine agonists, including bromocriptine, cabergoline, and pergolide, are synthetic derivatives of ergot alkaloids.59 Bromocriptine is begun orally once daily and increased over several weeks to multiple daily doses. It decreases tumor volume in approximately 85% of patients, and reduces PRL levels to normal in nearly 90%.50 Bromocriptine works very rapidly, often leading to a decrease in PRL within 1 to 2 hours. More than 10% of tumors are not sensitive to bromocriptine,60 and 5% to 10% of patients are intolerant of its gastrointestinal side effects, though intravaginal administration may lessen these symptoms.61

Cabergoline is more expensive than bromocriptine, but may be better tolerated, and is administered once or twice weekly.58 It normalizes PRL levels in up to 84% of patients.62 Studies of cabergoline in women of childbearing age are limited, but bromocriptine has been extensively studied and appears safe in pregnancy. Therefore, if pregnancy is desired, bromocriptine should be used,63 then discontinued during pregnancy unless symptomatic tumor enlargement occurs.

Medical treatment is generally continued chronically as cessation of either drug may result in recurrent hyperprolactinemia and tumor re-expansion.64 After initiation of medical therapy, MRI and visual examination should be repeated, and serum PRL levels should be monitored at least annually.65,66

One must be cautious with prolonged use of cabergoline and other ergot-derived dopamine agonists, as they may lead to an increased risk of pleural and pericardial fibrosing serositis and valvular heart disease when used in large doses, as they are in patients with Parkinson’s disease.6769 Patients with prolactinoma receive significantly smaller doses of the drug than do patients receiving the drugs for parkinsonism, and it is unknown if the risk of symptomatic valvular heart disease exists at these low doses. Studies of echocardiograms in patients receiving cabergoline for hyperprolactinemia have reported conflicting results.7074 There does not appear to be any statistical increase in incidence of clinically relevant or symptomatic cardiac regurgitation in patients treated with cabergoline. We recommend echocardiographic evaluation of patients who are receiving long-term, high-dose cabergoline.

Surgery

The effectiveness and safety of medical therapy have limited the need for surgery in most patients with prolactinoma. If a patient fails to respond to or is unable to tolerate the side effects of medical treatment, then surgery is recommended, as medication may be more effective after surgical debulking.75,76 Surgery is also suggested for patients who develop CSF leak while undergoing medical therapy or patients who have a dissociated response to drugs in which their prolactin level falls but the tumor does not shrink. TSA, as described previously, is the surgery of choice.34,77 An extended transsphenoidal approach may be needed if the tumor is beyond the sella, and craniotomy should be considered if there is significant extension.20,78

The higher the PRL level, the lower the chance of surgical cure. Patients with microprolactinomas and serum PRL level below 200 ng/mL have a greater than 90% chance of cure with TSA when performed by experienced pituitary surgeons at high-volume centers, and morbidity and mortality risks are less than 1%.34,75 However, patients with a preoperative PRL level above 200 ng/mL with large, invasive prolactinomas have a less than 41% surgical cure rate.76 In patients with giant or invasive prolactinomas, pretreatment with a dopamine agonist may improve the success of surgery; however, long-term pharmacotherapy can alter the tumor’s consistency and make surgery more challenging.79

Radiation Therapy

Radiation therapy is an option for patients who have failed surgery or medical therapy.80,81 Though there is a risk of hypopituitarism or damage to the optic nerves, radiation therapy is generally considered safe and effective. Radiotherapy may be combined with medical or surgical management and may be delivered as conventional external beam radiotherapy or SRS.

Conventional radiotherapy regimens use approximately 4500 cGy in 25 to 30 fractions.82 Tumor growth is controlled in 83% to 100% of patients, and reduction in tumor mass is achieved in 36% to 45% of patients.83 SRS may provide more rapid endocrine control while permitting the delivery of radiation in a single session with less exposure to surrounding normal tissue.

Dopamine agonists may provide a radioprotective effect on tumors, and preferably should be discontinued during radiosurgery.80 In a study of 164 patients with prolactinoma who underwent primary treatment with Gamma Knife, tumor growth was controlled in all but two patients, and biochemical cure was attained in more than half.81

Growth Hormone–Secreting Adenomas

Growth Hormone Physiology

GH is required for normal human growth; it plays little role in the first year of life, but becomes very important during puberty. GH is required for normal linear growth and is secreted in pulses by the somatotroph cells. Its release is controlled by GHRH and somatostatin, which stimulate and inhibit release, respectively (Fig. 40.10). GH, in turn, stimulates the liver’s production of somatomedin-C, also known as insulin-like growth factor 1 (IGF-1). IGF-1 inhibits GH secretion at the hypothalamus, where it stimulates somatostatin release, and at the pituitary, where it suppresses GHRH-induced GH secretion.

Sleep, stress, exercise, and hypoglycemia increase the release of GH, while obesity, hyperglycemia, and excess glucocorticoids decrease it. GH is anabolic and increases the uptake of amino acids into tissue; conversely, a rise in amino acids increases GH release in a healthy individual. GH and IGF-1 levels are highest in children and young adults, then decrease with age in normal subjects. In normal subjects, serum GH levels are very low or undetectable for most of the day. GH has a half-life of 20 to 30 minutes and is secreted in short pulses, with two to seven peaks per day, leading to significant fluctuations in levels during the day. Some of these bursts are associated with meals, while others occur during the early stages of sleep. The half-life of IGF-1, on the other hand, is 2 to 18 hours, and serum levels are relatively stable. IGF-1 measurements therefore provide a more reliable indication of the exposure of the body to GH than do GH measurements.

Growth Hormone Excess: Acromegaly

Excess GH secretion, which results in excess growth of the soft tissues, bony changes, and multiple biochemical changes, produces the syndromes of acromegaly in adults and gigantism in children who are affected before epiphyseal closure. Characteristics of acromegaly include coarse facial features with prognathism and malocclusion of the teeth, enlargement of the paranasal sinuses with frontal bossing, deepening of the voice, organomegaly, hyperhidrosis, acanthosis nigricans, enlargement of the hands and feet leading to an increase in ring, glove, and shoe size, and headache8486 (Fig. 40.11). Insulin resistance can lead to diabetes mellitus. Tongue enlargement produces obstructive sleep apnea. Accumulation of excess soft tissue in the hands results in a wet, doughy handshake and in the feet it produces increased heel-pad thickness on radiographs. Patients with acromegaly also suffer from headache, proximal myopathy, osteoarthritis, carpal tunnel syndrome, cardiomegaly, and hypertension. Metabolic derangements lead to accelerated atherosclerosis and a shortened life expectancy as a result of cardiovascular, cerebrovascular, and respiratory causes. There is also a higher risk of developing other neoplasms, especially colon cancer.1,87 With appropriate reduction of GH levels, however, mortality risk decreases and can normalize.88

The average annual incidence of acromegaly is approximately 3.3 per million.88 Ninety-eight percent of patients with acromegaly harbor a GH-secreting pituitary adenoma.89 From 20% to 50% of these tumors also secrete PRL or other pituitary hormones.90 Rarely, acromegaly is the result of ectopic GH-producing tumors such as bronchial carcinoid or pancreatic islet cell tumors, a hypothalamic GHRH-releasing tumor, exogenous administration of GH for antiaging treatments, or familial syndromes such as multiple endocrine neoplasia I, McCune-Albright syndrome, or Carney complex.89

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