HYPOTHALAMIC, PITUITARY, AND OTHER SELLAR MASSES
EVALUATION OF SELLAR MASSES
Clinical manifestations of sellar lesions vary, depending on the anatomic location of the mass and the direction of its extension (Table 403-1). The dorsal sellar diaphragm presents the least resistance to soft tissue expansion from the sella; consequently, pituitary adenomas frequently extend in a suprasellar direction. Bony invasion may occur as well.
TABLE 403-1Features of Sellar Mass Lesionsa ||Download (.pdf) TABLE 403-1 Features of Sellar Mass Lesionsa
|Impacted Structure ||Clinical Impact |
|Pituitary || |
Growth failure and adult hyposomatotropism
|Optic chiasm || |
Loss of red perception
Superior or bitemporal field defect
|Hypothalamus || |
Appetite and thirst disorders
|Cavernous sinus || |
Ophthalmoplegia with or without ptosis or diplopia
|Frontal lobe || |
|Brain || |
Headaches are common features of small intrasellar tumors, even with no demonstrable suprasellar extension. Because of the confined nature of the pituitary, small changes in intrasellar pressure stretch the dural plate; however, headache severity correlates poorly with adenoma size or extension.
Suprasellar extension can lead to visual loss by several mechanisms, the most common being compression of the optic chiasm, but rarely, direct invasion of the optic nerves or obstruction of cerebrospinal fluid (CSF) flow leading to secondary visual disturbances can occur. Pituitary stalk compression by a hormonally active or inactive intrasellar mass may compress the portal vessels, disrupting pituitary access to hypothalamic hormones and dopamine; this results in early hyperprolactinemia and later concurrent loss of other pituitary hormones. This “stalk section” phenomenon may also be caused by trauma, whiplash injury with posterior clinoid stalk compression, or skull base fractures. Lateral mass invasion may impinge on the cavernous sinus and compress its neural contents, leading to cranial nerve III, IV, and VI palsies as well as effects on the ophthalmic and maxillary branches of the fifth cranial nerve (Chap. 455). Patients may present with diplopia, ptosis, ophthalmoplegia, and decreased facial sensation, depending on the extent of neural damage. Extension into the sphenoid sinus indicates that the pituitary mass has eroded through the sellar floor. Aggressive tumors rarely invade the palate roof and cause nasopharyngeal obstruction, infection, and CSF leakage. Temporal and frontal lobe involvement may rarely lead to uncinate seizures, personality disorders, and anosmia. Direct hypothalamic encroachment by an invasive pituitary mass may cause important metabolic sequelae, including precocious puberty or hypogonadism, diabetes insipidus, sleep disturbances, dysthermia, and appetite disorders.
Magnetic Resonance Imaging
Sagittal and coronal T1-weighted magnetic resonance imaging (MRI) before and after administration of gadolinium allows precise visualization of the pituitary gland with clear delineation of the hypothalamus, pituitary stalk, pituitary tissue and surrounding suprasellar cisterns, cavernous sinuses, sphenoid sinus, and optic chiasm. Pituitary gland height ranges from 6 mm in children to 8 mm in adults; during pregnancy and puberty, the height may reach 10–12 mm. The upper aspect of the adult pituitary is flat or slightly concave, but in adolescent and pregnant individuals, this surface may be convex, reflecting physiologic pituitary enlargement. The stalk should be midline and vertical. Computed tomography (CT) scan is reserved to define the extent of bony erosion or the presence of calcification.
Anterior pituitary gland soft tissue consistency is slightly heterogeneous on MRI, and signal intensity resembles that of brain matter on T1-weighted imaging (Fig. 403-1). Adenoma density is usually lower than that of surrounding normal tissue on T1-weighted imaging, and the signal intensity increases with T2-weighted images. The high phospholipid content of the posterior pituitary results in a “pituitary bright spot.”
Pituitary adenoma. Coronal T1-weighted postcontrast magnetic resonance image shows a homogeneously enhancing mass (arrowheads) in the sella turcica and suprasellar region compatible with a pituitary adenoma; the small arrows outline the carotid arteries.
Sellar masses are encountered commonly as incidental findings on MRI, and most of them are pituitary adenomas (incidentalomas). In the absence of hormone hypersecretion, these small intrasellar lesions can be monitored safely with MRI, which is performed annually and then less often if there is no evidence of further growth. Resection should be considered for incidentally discovered larger macroadenomas, because about one-third become invasive or cause local pressure effects. If hormone hypersecretion is evident, specific therapies are indicated as described below. When larger masses (>1 cm) are encountered, they should also be distinguished from nonadenomatous lesions. Meningiomas often are associated with bony hyperostosis; craniopharyngiomas may be calcified and are usually hypodense, whereas gliomas are hyperdense on T2-weighted images.
Because optic tracts may be contiguous to an expanding pituitary mass, reproducible visual field assessment using perimetry techniques should be performed on all patients with sellar mass lesions that impinge the optic chiasm (Chap. 39). Bitemporal hemianopia, often more pronounced superiorly, is observed classically. It occurs because nasal ganglion cell fibers, which cross in the optic chiasm, are especially vulnerable to compression of the ventral optic chiasm. Occasionally, homonymous hemianopia occurs from postchiasmal compression or monocular temporal field loss from prechiasmal compression. Invasion of the cavernous sinus can produce diplopia from ocular motor nerve palsy. Early diagnosis reduces the risk of optic atrophy, vision loss, or eye misalignment.
The presenting clinical features of functional pituitary adenomas (e.g., acromegaly, prolactinomas, or Cushing’s syndrome) should guide the laboratory studies (Table 403-2). However, for a sellar mass with no obvious clinical features of hormone excess, laboratory studies are geared toward determining the nature of the tumor and assessing the possible presence of hypopituitarism. When a pituitary adenoma is suspected based on MRI, initial hormonal evaluation usually includes (1) basal prolactin (PRL); (2) insulin-like growth factor (IGF) I; (3) 24-h urinary free cortisol (UFC) and/or overnight oral dexamethasone (1 mg) suppression test; (4) α subunit, follicle-stimulating hormone (FSH), and luteinizing hormone (LH); and (5) thyroid function tests. Additional hormonal evaluation may be indicated based on the results of these tests. Pending more detailed assessment of hypopituitarism, a menstrual history, measurement of testosterone and 8 A.M. cortisol levels, and thyroid function tests usually identify patients with pituitary hormone deficiencies that require hormone replacement before further testing or surgery.
TABLE 403-2Screening Tests for Functional Pituitary Adenomas ||Download (.pdf) TABLE 403-2 Screening Tests for Functional Pituitary Adenomas
| ||Test ||Comments |
|Acromegaly || |
Oral glucose tolerance test with GH obtained at 0, 30, and 60 min
Interpret IGF-I relative to age- and sex-matched controls
Normal subjects should suppress growth hormone to <1 g/L
|Prolactinoma ||Serum PRL || |
MRI of the sella should be ordered if PRL is elevated
|Cushing’s disease || |
24-h urinary free cortisol
Dexamethasone (1 mg) at 11 p.m. and fasting plasma cortisol measured at 8 a.m.
Ensure urine collection is total and accurate
Normal subjects suppress to <5 g/dL
Distinguishes adrenal adenoma (ACTH suppressed) from ectopic ACTH or Cushing’s disease (ACTH normal or elevated)
Immunohistochemical staining of pituitary tumor specimens obtained at transsphenoidal surgery confirms clinical and laboratory studies and provides a histologic diagnosis when hormone studies are equivocal and in cases of clinically nonfunctioning tumors. Occasionally, ultrastructural assessment by electron microscopy is required for diagnosis.
TREATMENT Hypothalamic, Pituitary, and Other Sellar Masses OVERVIEW
Successful management of sellar masses requires accurate diagnosis as well as selection of optimal therapeutic modalities. Most pituitary tumors are benign and slow-growing. Clinical features result from local mass effects and hormonal hyper- or hyposecretion syndromes caused directly by the adenoma or occurring as a consequence of treatment. Thus, lifelong management and follow-up are necessary for these patients.
MRI with gadolinium enhancement for pituitary visualization, new advances in transsphenoidal surgery and in stereotactic radiotherapy (including gamma-knife radiotherapy), and novel therapeutic agents have improved pituitary tumor management. The goals of pituitary tumor treatment include normalization of excess pituitary secretion, amelioration of symptoms and signs of hormonal hypersecretion syndromes, and shrinkage or ablation of large tumor masses with relief of adjacent structure compression. Residual anterior pituitary function should be preserved during treatment and sometimes can be restored by removing the tumor mass. Ideally, adenoma recurrence should be prevented. TRANSSPHENOIDAL SURGERY
Transsphenoidal rather than transfrontal resection is the desired surgical approach for pituitary tumors, except for the rare invasive suprasellar mass surrounding the frontal or middle fossa or the optic nerves or invading posteriorly behind the clivus. Intraoperative microscopy facilitates visual distinction between adenomatous and normal pituitary tissue as well as microdissection of small tumors that may not be visible by MRI(Fig. 403-2). Transsphenoidal surgery also avoids the cranial invasion and manipulation of brain tissue required by subfrontal surgical approaches. Endoscopic techniques with three-dimensional intraoperative localization have also improved visualization and access to tumor tissue. Individual surgical experience is a major determinant of outcome efficacy with these techniques.
In addition to correction of hormonal hypersecretion, pituitary surgery is indicated for mass lesions that impinge on surrounding structures. Surgical decompression and resection are required for an expanding pituitary mass accompanied by persistent headache, progressive visual field defects, cranial nerve palsies, hydrocephalus, and, occasionally, intrapituitary hemorrhage and apoplexy. Transsphenoidal surgery sometimes is used for pituitary tissue biopsy to establish a histologic diagnosis.Whenever possible, the pituitary mass lesion should be selectively excised; normal pituitary tissue should be manipulated or resected only when critical for effective mass dissection. Nonselective hemihypophysectomy or total hypophysectomy may be indicated if no hypersecreting mass lesion is clearly discernible, multifocal lesions are present, or the remaining nontumorous pituitary tissue is obviously necrotic. This strategy, however, increases the likelihood of hypopituitarism and the need for lifelong hormone replacement.
Preoperative mass effects, including visual field defects and compromised pituitary function, may be reversed by surgery, particularly when the deficits are not long-standing. For large and invasive tumors, it is necessary to determine the optimal balance between maximal tumor resection and preservation of anterior pituitary function, especially for preserving growth and reproductive function in younger patients. Similarly, tumor invasion outside the sella is rarely amenable to surgical cure; the surgeon must judge the risk-versus-benefit ratio of extensive tumor resection. Side Effects
Tumor size, the degree of invasiveness, and experience of the surgeon largely determine the incidence of surgical complications. Operative mortality rate is about 1%. Transient diabetes insipidus and hypopituitarism occur in up to 20% of patients. Permanent diabetes insipidus, cranial nerve damage, nasal septal perforation, or visual disturbances may be encountered in up to 10% of patients. CSF leaks occur in 4% of patients. Less common complications include carotid artery injury, loss of vision, hypothalamic damage, and meningitis. Permanent side effects are rare after surgery for microadenomas. RADIATION
Radiation is used either as a primary therapy for pituitary or parasellar masses or, more commonly, as an adjunct to surgery or medical therapy. Focused megavoltage irradiation is achieved by precise MRI localization, using a high-voltage linear accelerator and accurate isocentric rotational arcing. A major determinant of accurate irradiation is reproduction of the patient’s head position during multiple visits and maintenance of absolute head immobility. A total of <50 Gy (5000 rad) is given as 180-cGy (180-rad) fractions divided over about 6 weeks. Stereotactic radiosurgery delivers a large single high-energy dose from a cobalt-60 source (gamma knife), linear accelerator, or cyclotron. Long-term effects of gamma-knife surgery are unclear but appear to be similar to those encountered with conventional radiation. Proton beam therapy is available in some centers and provides concentrated radiation doses within a localized region.
The role of radiation therapy in pituitary tumor management depends on multiple factors, including the nature of the tumor, the age of the patient, and the availability of surgical and radiation expertise. Because of its relatively slow onset of action, radiation therapy is usually reserved for postsurgical management. As an adjuvant to surgery, radiation is used to treat residual tumor and in an attempt to prevent regrowth. Irradiation offers the only means for potentially ablating significant postoperative residual nonfunctioning tumor tissue. In contrast, PRL- and growth hormone (GH)-secreting tumor tissues are amenable to medical therapy. Side Effects
In the short term, radiation may cause transient nausea and weakness. Alopecia and loss of taste and smell may be more long-lasting. Failure of pituitary hormone synthesis is common in patients who have undergone head and neck or pituitary-directed irradiation. More than 50% of patients develop loss of GH, adrenocorticotropin hormone (ACTH), thyroid-stimulating hormone (TSH), and/or gonadotropin secretion within 10 years, usually due to hypothalamic damage. Lifelong follow-up with testing of anterior pituitary hormone reserve is therefore required after radiation treatment. Optic nerve damage with impaired vision due to optic neuritis is reported in about 2% of patients who undergo pituitary irradiation. Cranial nerve damage is uncommon now that radiation doses are ≤2 Gy (200 rad) at any one treatment session and the maximum dose is <50 Gy (5000 rad). The use of stereotactic radiotherapy may reduce damage to adjacent structures. Radiotherapy for pituitary tumors has been associated with adverse mortality rates, mainly from cerebrovascular disease. The cumulative risk of developing a secondary tumor after conventional radiation is 1.3% after 10 years and 1.9% after 20 years. MEDICAL
Medical therapy for pituitary tumors is highly specific and depends on tumor type. For prolactinomas, dopamine agonists are the treatment of choice. For acromegaly, somatostatin analogues and GH receptor antagonists are indicated. For TSH-secreting tumors, somatostatin analogues and occasionally dopamine agonists are indicated. ACTH-secreting tumors and nonfunctioning tumors are generally not responsive to medications and require surgery and/or irradiation.
Transsphenoidal resection of pituitary mass via the endonasal approach. (Adapted from R Fahlbusch: Endocrinol Metab Clin 21:669, 1992.)
Sellar masses other than pituitary adenomas may arise from brain, hypothalamic, or pituitary tissues. Each exhibit features related to the lesion location but also unique to the specific etiology.
Lesions involving the anterior and preoptic hypothalamic regions cause paradoxical vasoconstriction, tachycardia, and hyperthermia. Acute hyperthermia usually is due to a hemorrhagic insult, but poikilothermia may also occur. Central disorders of thermoregulation result from posterior hypothalamic damage. The periodic hypothermia syndrome is characterized by episodic attacks of rectal temperatures <30°C (86°F), sweating, vasodilation, vomiting, and bradycardia (Chap. 478e). Damage to the ventromedial hypothalamic nuclei by craniopharyngiomas, hypothalamic trauma, or inflammatory disorders may be associated with hyperphagia and obesity. This region appears to contain an energy-satiety center where melanocortin receptors are influenced by leptin, insulin, pro-opiomelanocortin (POMC) products, and gastrointestinal peptides (Chap. 415e). Polydipsia and hypodipsia are associated with damage to central osmoreceptors located in preoptic nuclei (Chap. 404). Slow-growing hypothalamic lesions can cause increased somnolence and disturbed sleep cycles as well as obesity, hypothermia, and emotional outbursts. Lesions of the central hypothalamus may stimulate sympathetic neurons, leading to elevated serum catecholamine and cortisol levels. These patients are predisposed to cardiac arrhythmias, hypertension, and gastric erosions.
Craniopharyngiomas are benign, suprasellar cystic masses that present with headaches, visual field deficits, and variable degrees of hypopituitarism. They are derived from Rathke’s pouch and arise near the pituitary stalk, commonly extending into the suprasellar cistern. Craniopharyngiomas are often large, cystic, and locally invasive. Many are partially calcified, exhibiting a characteristic appearance on skull x-ray and CT images. More than half of all patients present before age 20, usually with signs of increased intracranial pressure, including headache, vomiting, papilledema, and hydrocephalus. Associated symptoms include visual field abnormalities, personality changes and cognitive deterioration, cranial nerve damage, sleep difficulties, and weight gain. Hypopituitarism can be documented in about 90%, and diabetes insipidus occurs in about 10% of patients. About half of affected children present with growth retardation. MRI is generally superior to CT for evaluating cystic structure and tissue components of craniopharyngiomas. CT is useful to define calcifications and evaluate invasion into surrounding bony structures and sinuses.
Treatment usually involves transcranial or transsphenoidal surgical resection followed by postoperative radiation of residual tumor. Surgery alone is curative in less than half of patients because of recurrences due to adherence to vital structures or because of small tumor deposits in the hypothalamus or brain parenchyma. The goal of surgery is to remove as much tumor as possible without risking complications associated with efforts to remove firmly adherent or inaccessible tissue. In the absence of radiotherapy, about 75% of craniopharyngiomas recur, and 10-year survival is less than 50%. In patients with incomplete resection, radiotherapy improves 10-year survival to 70–90% but is associated with increased risk of secondary malignancies. Most patients require lifelong pituitary hormone replacement.
Developmental failure of Rathke’s pouch obliteration may lead to Rathke’s cysts, which are small (<5 mm) cysts entrapped by squamous epithelium and are found in about 20% of individuals at autopsy. Although Rathke’s cleft cysts do not usually grow and are often diagnosed incidentally, about a third present in adulthood with compressive symptoms, diabetes insipidus, and hyperprolactinemia due to stalk compression. Rarely, hydrocephalus develops. The diagnosis is suggested preoperatively by visualizing the cyst wall on MRI, which distinguishes these lesions from craniopharyngiomas. Cyst contents range from CSF-like fluid to mucoid material. Arachnoid cysts are rare and generate an MRI image that is isointense with CSF.
Sella chordomas usually present with bony clival erosion, local invasiveness, and, on occasion, calcification. Normal pituitary tissue may be visible on MRI, distinguishing chordomas from aggressive pituitary adenomas. Mucinous material may be obtained by fine-needle aspiration.
Meningiomas arising in the sellar region may be difficult to distinguish from nonfunctioning pituitary adenomas. Meningiomas typically enhance on MRI and may show evidence of calcification or bony erosion. Meningiomas may cause compressive symptoms.
Histiocytosis X includes a variety of syndromes associated with foci of eosinophilic granulomas. Diabetes insipidus, exophthalmos, and punched-out lytic bone lesions (Hand-Schüller-Christian disease) are associated with granulomatous lesions visible on MRI, as well as a characteristic axillary skin rash. Rarely, the pituitary stalk may be involved.
Pituitary metastases occur in ~3% of cancer patients. Bloodborne metastatic deposits are found almost exclusively in the posterior pituitary. Accordingly, diabetes insipidus can be a presenting feature of lung, gastrointestinal, breast, and other pituitary metastases. About half of pituitary metastases originate from breast cancer; about 25% of patients with metastatic breast cancer have such deposits. Rarely, pituitary stalk involvement results in anterior pituitary insufficiency. The MRI diagnosis of a metastatic lesion may be difficult to distinguish from an aggressive pituitary adenoma; the diagnosis may require histologic examination of excised tumor tissue. Primary or metastatic lymphoma, leukemias, and plasmacytomas also occur within the sella.
Hypothalamic hamartomas and gangliocytomas may arise from astrocytes, oligodendrocytes, and neurons with varying degrees of differentiation. These tumors may overexpress hypothalamic neuropeptides, including gonadotropin-releasing hormone (GnRH), growth hormone–releasing hormone (GHRH), and corticotropin-releasing hormone (CRH). With GnRH-producing tumors, children present with precocious puberty, psychomotor delay, and laughing-associated seizures. Medical treatment of GnRH-producing hamartomas with long-acting GnRH analogues effectively suppresses gonadotropin secretion and controls premature pubertal development. Rarely, hamartomas also are associated with craniofacial abnormalities; imperforate anus; cardiac, renal, and lung disorders; and pituitary failure as features of Pallister-Hall syndrome, which is caused by mutations in the carboxy terminus of the GLI3 gene. Hypothalamic hamartomas are often contiguous with the pituitary, and preoperative MRI diagnosis may not be possible. Histologic evidence of hypothalamic neurons in tissue resected at transsphenoidal surgery may be the first indication of a primary hypothalamic lesion.
Hypothalamic gliomas and optic gliomas occur mainly in childhood and usually present with visual loss. Adults have more aggressive tumors; about a third are associated with neurofibromatosis.
Brain germ cell tumors may arise within the sellar region. They include dysgerminomas, which frequently are associated with diabetes insipidus and visual loss. They rarely metastasize. Germinomas, embryonal carcinomas, teratomas, and choriocarcinomas may arise in the parasellar region and produce hCG. These germ cell tumors present with precocious puberty, diabetes insipidus, visual field defects, and thirst disorders. Many patients are GH-deficient with short stature.
PITUITARY ADENOMAS AND HYPERSECRETION SYNDROMES
Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and hyposecretion syndromes in adults. They account for ~15% of all intracranial neoplasms and have been identified with a population prevalence of ~80/100,000. At autopsy, up to one-quarter of all pituitary glands harbor an unsuspected microadenoma (<10 mm diameter). Similarly, pituitary imaging detects small clinically inapparent pituitary lesions in at least 10% of individuals.
Pituitary adenomas are benign neoplasms that arise from one of the five anterior pituitary cell types. The clinical and biochemical phenotypes of pituitary adenomas depend on the cell type from which they are derived. Thus, tumors arising from lactotrope (PRL), somatotrope (GH), corticotrope (ACTH), thyrotrope (TSH), or gonadotrope (LH, FSH) cells hypersecrete their respective hormones (Table 403-3). Plurihormonal tumors express various combinations of GH, PRL, TSH, ACTH, or the glycoprotein hormone α or β subunits. They may be diagnosed by careful immunocytochemistry or may manifest as clinical syndromes that combine features of these hormonal hypersecretory syndromes. Morphologically, these tumors may arise from a single polysecreting cell type or include cells with mixed function within the same tumor.
Hormonally active tumors are characterized by autonomous hormone secretion with diminished feedback responsiveness to physiologic inhibitory pathways. Hormone production does not always correlate with tumor size. Small hormone-secreting adenomas may cause significant clinical perturbations, whereas larger adenomas that produce less hormone may be clinically silent and remain undiagnosed (if no central compressive effects occur). About one-third of all adenomas are clinically nonfunctioning and produce no distinct clinical hypersecretory syndrome. Most of them arise from gonadotrope cells and may secrete small amounts of α- and β-glycoprotein hormone subunits or, very rarely, intact circulating gonadotropins. True pituitary carcinomas with documented extracranial metastases are exceedingly rare.
Almost all pituitary adenomas are monoclonal in origin, implying the acquisition of one or more somatic mutations that confer a selective growth advantage. Consistent with their clonal origin, complete surgical resection of small pituitary adenomas usually cures hormone hypersecretion. Nevertheless, hypothalamic hormones such as GHRH and CRH also enhance mitotic activity of their respective pituitary target cells in addition to their role in pituitary hormone regulation. Thus, patients who harbor rare abdominal or chest tumors that elaborate ectopic GHRH or CRH may present with somatotrope or corticotrope hyperplasia with GH or ACTH hypersecretion.
Several etiologic genetic events have been implicated in the development of pituitary tumors. The pathogenesis of sporadic forms of acromegaly has been particularly informative as a model of tumorigenesis. GHRH, after binding to its G protein–coupled somatotrope receptor, uses cyclic adenosine monophosphate (AMP) as a second messenger to stimulate GH secretion and somatotrope proliferation. A subset (~35%) of GH-secreting pituitary tumors contains sporadic mutations in Gsα (Arg 201 → Cys or His; Gln 227 → Arg). These mutations attenuate intrinsic GTPase activity, resulting in constitutive elevation of cyclic AMP, Pit-1 induction, and activation of cyclic AMP response element binding protein (CREB), thereby promoting somatotrope cell proliferation and GH secretion.
Characteristic loss of heterozygosity (LOH) in various chromosomes has been documented in large or invasive macroadenomas, suggesting the presence of putative tumor suppressor genes at these loci in up to 20% of sporadic pituitary tumors, including GH-, PRL-, and ACTH-producing adenomas and some nonfunctioning tumors. Lineage-specific cell cycle disruptions with elevated levels of CDK inhibitors are present in most of these adenomas.
Compelling evidence also favors growth factor promotion of pituitary tumor proliferation. Basic fibroblast growth factor (bFGF) is abundant in the pituitary and stimulates pituitary cell mitogenesis, whereas epithelial growth factor (EGF) receptor signaling induces both hormone synthesis and cell proliferation. Other factors involved in initiation and promotion of pituitary tumors include loss of negative-feedback inhibition (as seen with primary hypothyroidism or hypogonadism) and estrogen-mediated or paracrine angiogenesis. Growth characteristics and neoplastic behavior also may be influenced by several activated oncogenes, including RAS and pituitary tumor transforming gene (PTTG), or inactivation of growth suppressor genes, including MEG3.
Genetic Syndromes Associated with Pituitary Tumors
Several familial syndromes are associated with pituitary tumors, and the genetic mechanisms for some of them have been unraveled (Table 403-4).
Multiple endocrine neoplasia (MEN) 1 is an autosomal dominant syndrome characterized primarily by a genetic predisposition to parathyroid, pancreatic islet, and pituitary adenomas (Chap. 408). MEN1 is caused by inactivating germline mutations in MENIN, a constitutively expressed tumor-suppressor gene located on chromosome 11q13. Loss of heterozygosity or a somatic mutation of the remaining normal MENIN allele leads to tumorigenesis. About half of affected patients develop prolactinomas; acromegaly and Cushing’s syndrome are less commonly encountered.
Carney’s syndrome is characterized by spotty skin pigmentation, myxomas, and endocrine tumors, including testicular, adrenal, and pituitary adenomas. Acromegaly occurs in about 20% of these patients. A subset of patients have mutations in the R1α regulatory subunit of protein kinase A (PRKAR1A).
McCune-Albright syndrome consists of polyostotic fibrous dysplasia, pigmented skin patches, and a variety of endocrine disorders, including acromegaly, adrenal adenomas, and autonomous ovarian function (Chap. 426e). Hormonal hypersecretion results from constitutive cyclic AMP production caused by inactivation of the GTPase activity of Gsα. The Gsα mutations occur postzygotically, leading to a mosaic pattern of mutant expression.
Familial acromegaly is a rare disorder in which family members may manifest either acromegaly or gigantism. A subset of families with a predisposition for familial pituitary tumors, especially acromegaly, have been found to harbor germline mutations in the AIP gene, which encodes the aryl hydrocarbon receptor interacting protein.
TABLE 403-3Classification of Pituitary Adenomasa ||Download (.pdf) TABLE 403-3 Classification of Pituitary Adenomasa
|Adenoma Cell Origin ||Hormone Product ||Clinical Syndrome |
|Lactotrope ||PRL ||Hypogonadism, galactorrhea |
|Gonadotrope ||FSH, LH, subunits ||Silent or hypogonadism |
|Somatotrope ||GH ||Acromegaly/gigantism |
|Corticotrope ||ACTH ||Cushing’s disease |
|Mixed growth hormone and prolactin cell ||GH, PRL ||Acromegaly, hypogonadism, galactorrhea |
|Other plurihormonal cell ||Any ||Mixed |
|Acidophil stem cell ||PRL, GH ||Hypogonadism, galactorrhea, acromegaly |
|Mammosomatotrope ||PRL, GH ||Hypogonadism, galactorrhea, acromegaly |
|Thyrotrope ||TSH ||Thyrotoxicosis |
|Null cell ||None ||Pituitary failure |
|Oncocytoma ||None ||Pituitary failure |
TABLE 403-4Familial Pituitary Tumor Syndromes ||Download (.pdf) TABLE 403-4 Familial Pituitary Tumor Syndromes
| ||Gene Mutated ||Clinical Features |
|Multiple endocrine neoplasia 1 (MEN 1) || |
Pancreatic neuroendocrine tumors
Pituitary adenomas (40%)
|Multiple endocrine neoplasia 4 (MEN 4) || |
|Carney complex || |
Pituitary hyperplasia andadenomas (10%)
|Familial pituitary adenomas || |
|Acromegaly/gigantism (~15% of afflicted families) |
Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. PRL-secreting pituitary adenomas (prolactinomas) are the most common cause of PRL levels >200 μg/L (see below). Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly caused by drugs, pituitary stalk compression, hypothyroidism, or renal failure (Table 403-5).
Pregnancy and lactation are the important physiologic causes of hyperprolactinemia. Sleep-associated hyperprolactinemia reverts to normal within an hour of awakening. Nipple stimulation and sexual orgasm also may increase PRL. Chest wall stimulation or trauma (including chest surgery and herpes zoster) invoke the reflex suckling arc with resultant hyperprolactinemia. Chronic renal failure elevates PRL by decreasing peripheral clearance. Primary hypothyroidism is associated with mild hyperprolactinemia, probably because of compensatory TRH secretion.
TABLE 403-5Etiology of Hyperprolactinemia ||Download (.pdf) TABLE 403-5 Etiology of Hyperprolactinemia
I. Physiologic hypersecretion
Chest wall stimulation
II. Hypothalamic–pituitary stalk damage
Suprasellar pituitary mass
Adenoma with stalk
Pituitary stalk section
III. Pituitary hypersecretion
IV. Systemic disorders
Chronic renal failure
V. Drug-induced hypersecretion
Dopamine receptor blockers
Atypical antipsychotics: risperidone
Phenothiazines: chlorpromazine, perphenazine
Dopamine synthesis inhibitors
Serotonin reuptake inhibitors
Calcium channel blockers
Lesions of the hypothalamic-pituitary region that disrupt hypothalamic dopamine synthesis, portal vessel delivery, or lactotrope responses are associated with hyperprolactinemia. Thus, hypothalamic tumors, cysts, infiltrative disorders, and radiation-induced damage cause elevated PRL levels, usually in the range of 30–100 μg/L. Plurihormonal adenomas (including GH and ACTH tumors) may hypersecrete PRL directly. Pituitary masses, including clinically nonfunctioning pituitary tumors, may compress the pituitary stalk to cause hyperprolactinemia.
Drug-induced inhibition or disruption of dopaminergic receptor function is a common cause of hyperprolactinemia (Table 403-5). Thus, antipsychotics and antidepressants are a relatively common cause of mild hyperprolactinemia. Most patients receiving risperidone have elevated prolactin levels, sometimes exceeding 200 μg/L. Methyldopa inhibits dopamine synthesis, and verapamil blocks dopamine release, also leading to hyperprolactinemia. Hormonal agents that induce PRL include estrogens and thyrotropin-releasing hormone (TRH).
Presentation and Diagnosis
Amenorrhea, galactorrhea, and infertility are the hallmarks of hyperprolactinemia in women. If hyperprolactinemia develops before menarche, primary amenorrhea results. More commonly, hyperprolactinemia develops later in life and leads to oligomenorrhea and ultimately to amenorrhea. If hyperprolactinemia is sustained, vertebral bone mineral density can be reduced compared with age-matched controls, particularly when it is associated with pronounced hypoestrogenemia. Galactorrhea is present in up to 80% of hyperprolactinemic women. Although usually bilateral and spontaneous, it may be unilateral or expressed only manually. Patients also may complain of decreased libido, weight gain, and mild hirsutism.
In men with hyperprolactinemia, diminished libido, infertility, and visual loss (from optic nerve compression) are the usual presenting symptoms. Gonadotropin suppression leads to reduced testosterone, impotence, and oligospermia. True galactorrhea is uncommon in men with hyperprolactinemia. If the disorder is long-standing, secondary effects of hypogonadism are evident, including osteopenia, reduced muscle mass, and decreased beard growth.
The diagnosis of idiopathic hyperprolactinemia is made by exclusion of known causes of hyperprolactinemia in the setting of a normal pituitary MRI. Some of these patients may harbor small microadenomas below visible MRI sensitivity (~2 mm).
Galactorrhea, the inappropriate discharge of milk-containing fluid from the breast, is considered abnormal if it persists longer than 6 months after childbirth or discontinuation of breast-feeding. Postpartum galactorrhea associated with amenorrhea is a self-limiting disorder usually associated with moderately elevated PRL levels. Galactorrhea may occur spontaneously, or it may be elicited by nipple pressure. In both men and women, galactorrhea may vary in color and consistency (transparent, milky, or bloody) and arise either unilaterally or bilaterally. Mammography or ultrasound is indicated for bloody discharges (particularly from a single nipple), which may be caused by breast cancer. Galactorrhea is commonly associated with hyperprolactinemia caused by any of the conditions listed in Table 403-5. Acromegaly is associated with galactorrhea in about one-third of patients. Treatment of galactorrhea usually involves managing the underlying disorder (e.g., replacing T4 for hypothyroidism, discontinuing a medication, treating prolactinoma).
Basal, fasting morning PRL levels (normally <20 μg/L) should be measured to assess hypersecretion. Both false-positive and false-negative results may be encountered. In patients with markedly elevated PRL levels (>1000 μg/L), reported results may be falsely lowered because of assay artifacts; sample dilution is required to measure these high values accurately. Falsely elevated values may be caused by aggregated forms of circulating PRL, which are usually biologically inactive (macroprolactinemia). Hypothyroidism should be excluded by measuring TSH and T4 levels.
Treatment of hyperprolactinemia depends on the cause of elevated PRL levels. Regardless of the etiology, however, treatment should be aimed at normalizing PRL levels to alleviate suppressive effects on gonadal function, halt galactorrhea, and preserve bone mineral density. Dopamine agonists are effective for most causes of hyperprolactinemia (see the treatment section for prolactinoma, below) regardless of the underlying cause.
If the patient is taking a medication known to cause hyperprolactinemia, the drug should be withdrawn, if possible. For psychiatric patients who require neuroleptic agents, supervised dose titration or the addition of a dopamine agonist can help restore normoprolactinemia and alleviate reproductive symptoms. However, dopamine agonists may worsen the underlying psychiatric condition, especially at high doses. Hyperprolactinemia usually resolves after adequate thyroid hormone replacement in hypothyroid patients or after renal transplantation in patients undergoing dialysis. Resection of hypothalamic or sellar mass lesions can reverse hyperprolactinemia caused by stalk compression and reduced dopamine tone. Granulomatous infiltrates occasionally respond to glucocorticoid administration. In patients with irreversible hypothalamic damage, no treatment may be warranted. In up to 30% of patients with hyperprolactinemia—usually without a visible pituitary microadenoma—the condition may resolve spontaneously.
Tumors arising from lactotrope cells account for about half of all functioning pituitary tumors, with a population prevalence of ~10/100,000 in men and ~30/100,000 in women. Mixed tumors that secrete combinations of GH and PRL, ACTH and PRL, and rarely TSH and PRL are also seen. These plurihormonal tumors are usually recognized by immunohistochemistry, sometimes without apparent clinical manifestations from the production of additional hormones. Microadenomas are classified as <1 cm in diameter and usually do not invade the parasellar region. Macroadenomas are >1 cm in diameter and may be locally invasive and impinge on adjacent structures. The female-to-male ratio for microprolactinomas is 20:1, whereas the sex ratio is near 1:1 for macroadenomas. Tumor size generally correlates directly with PRL concentrations; values >250 μg/L usually are associated with macroadenomas. Men tend to present with larger tumors than women, possibly because the features of male hypogonadism are less readily evident. PRL levels remain stable in most patients, reflecting the slow growth of these tumors. About 5% of microadenomas progress in the long term to macroadenomas.
Presentation and Diagnosis
Women usually present with amenorrhea, infertility, and galactorrhea. If the tumor extends outside the sella, visual field defects or other mass effects may be seen. Men often present with impotence, loss of libido, infertility, or signs of central nervous system (CNS) compression, including headaches and visual defects. Assuming that physiologic and medication-induced causes of hyperprolactinemia are excluded (Table 403-5), the diagnosis of prolactinoma is likely with a PRL level >200 μg/L. PRL levels <100 μg/L may be caused by microadenomas, other sellar lesions that decrease dopamine inhibition, or nonneoplastic causes of hyperprolactinemia. For this reason, an MRI should be performed in all patients with hyperprolactinemia. It is important to remember that hyperprolactinemia caused secondarily by the mass effects of nonlactotrope lesions is also corrected by treatment with dopamine agonists despite failure to shrink the underlying mass. Consequently, PRL suppression by dopamine agonists does not necessarily indicate that the underlying lesion is a prolactinoma.
Because microadenomas rarely progress to become macroadenomas, no treatment may be needed if patients are asymptomatic and fertility is not desired; these patients should be monitored by regular serial PRL measurements and MRI scans.For symptomatic microadenomas, therapeutic goals include control of hyperprolactinemia, reduction of tumor size, restoration of menses and fertility, and resolution of galactorrhea. Dopamine agonist doses should be titrated to achieve maximal PRL suppression and restoration of reproductive function (Fig. 403-3). A normalized PRL level does not ensure reduced tumor size. However, tumor shrinkage usually is not seen in those who do not respond with lowered PRL levels. For macroadenomas, formal visual field testing should be performed before initiating dopamine agonists. MRI and visual fields should be assessed at 6- to 12-month intervals until the mass shrinks and annually thereafter until maximum size reduction has occurred. MEDICAL
Oral dopamine agonists (cabergoline and bromocriptine) are the mainstay of therapy for patients with micro- or macroprolactinomas. Dopamine agonists suppress PRL secretion and synthesis as well as lactotrope cell proliferation. In patients with microadenomas who have achieved normoprolactinemia and significant reduction of tumor mass, the dopamine agonist may be withdrawn after 2 years. These patients should be monitored carefully for evidence of prolactinoma recurrence. About 20% of patients (especially males) are resistant to dopaminergic treatment; these adenomas may exhibit decreased D2 dopamine receptor numbers or a postreceptor defect. D2 receptor gene mutations in the pituitary have not been reported. Cabergoline
An ergoline derivative, cabergoline is a long-acting dopamine agonist with high D2 receptor affinity. The drug effectively suppresses PRL for >14 days after a single oral dose and induces prolactinoma shrinkage in most patients. Cabergoline (0.5–1.0 mg twice weekly) achieves normoprolactinemia and resumption of normal gonadal function in ~80% of patients with microadenomas; galactorrhea improves or resolves in 90% of patients. Cabergoline normalizes PRL and shrinks ~70% of macroprolactinomas. Mass effect symptoms, including headaches and visual disorders, usually improve dramatically within days after cabergoline initiation; improvement of sexual function requires several weeks of treatment but may occur before complete normalization of prolactin levels. After initial control of PRL levels has been achieved, cabergoline should be reduced to the lowest effective maintenance dose. In ~5% of treated patients harboring a microadenoma, hyperprolactinemia may resolve and not recur when dopamine agonists are discontinued after long-term treatment. Cabergoline also may be effective in patients resistant to bromocriptine. Adverse effects and drug intolerance are encountered less commonly than with bromocriptine. BROMOCRIPTINE
The ergot alkaloid bromocriptine mesylate is a dopamine receptor agonist that suppresses prolactin secretion. Because it is short-acting, the drug is preferred when pregnancy is desired. In microadenomas, bromocriptine rapidly lowers serum prolactin levels to normal in up to 70% of patients, decreases tumor size, and restores gonadal function. In patients with macroadenomas, prolactin levels are also normalized in 70% of patients, and tumor mass shrinkage (≥50%) is achieved in most patients.
Therapy is initiated by administering a low bromocriptine dose (0.625–1.25 mg) at bedtime with a snack, followed by gradually increasing the dose. Most patients are controlled with a daily dose of ≤7.5 mg (2.5 mg tid). SIDE EFFECTS
Side effects of dopamine agonists include constipation, nasal stuffiness, dry mouth, nightmares, insomnia, and vertigo; decreasing the dose usually alleviates these problems. Nausea, vomiting, and postural hypotension with faintness may occur in ~25% of patients after the initial dose. These symptoms may persist in some patients. In general, fewer side effects are reported with cabergoline. For the approximately 15% of patients who are intolerant of oral bromocriptine, cabergoline may be better tolerated. Intravaginal administration of bromocriptine is often efficacious in patients with intractable gastrointestinal side effects. Auditory hallucinations, delusions, and mood swings have been reported in up to 5% of patients and may be due to the dopamine agonist properties or to the lysergic acid derivative of the compounds. Rare reports of leukopenia, thrombocytopenia, pleural fibrosis, cardiac arrhythmias, and hepatitis have been described. Patients with Parkinson’s disease who receive at least 3 mg of cabergoline daily have been reported to be at risk for development of cardiac valve regurgitation. Studies analyzing over 500 prolactinoma patients receiving recommended doses of cabergoline (up to 2 mg weekly) have shown no evidence for an increased incidence of valvular disorders. Nevertheless, because no controlled prospective studies in pituitary tumor patients are available, it is prudent to perform echocardiograms before initiating standard-dose cabergoline therapy. Surgery
Indications for surgical adenoma debulking include dopamine resistance or intolerance and the presence of an invasive macroadenoma with compromised vision that fails to improve after drug treatment. Initial PRL normalization is achieved in about 70% of microprolactinomas after surgical resection, but only 30% of macroadenomas can be resected successfully. Follow-up studies have shown that hyperprolactinemia recurs in up to 20% of patients within the first year after surgery; long-term recurrence rates exceed 50% for macroadenomas. Radiotherapy for prolactinomas is reserved for patients with aggressive tumors that do not respond to maximally tolerated dopamine agonists and/or surgery. PREGNANCY
The pituitary increases in size during pregnancy, reflecting the stimulatory effects of estrogen and perhaps other growth factors on pituitary vascularity and lactotrope cell hyperplasia. About 5% of microadenomas significantly increase in size, but 15–30% of macroadenomas grow during pregnancy. Bromocriptine has been used for more than 30 years to restore fertility in women with hyperprolactinemia, without evidence of teratogenic effects. Nonetheless, most authorities recommend strategies to minimize fetal exposure to the drug. For women taking bromocriptine who desire pregnancy, mechanical contraception should be used through three regular menstrual cycles to allow for conception timing. When pregnancy is confirmed, bromocriptine should be discontinued and PRL levels followed serially, especially if headaches or visual symptoms occur. For women harboring macroadenomas, regular visual field testing is recommended, and the drug should be reinstituted if tumor growth is apparent. Although pituitary MRI may be safe during pregnancy, this procedure should be reserved for symptomatic patients with severe headache and/or visual field defects. Surgical decompression may be indicated if vision is threatened. Although comprehensive data support the efficacy and relative safety of bromocriptine-facilitated fertility, patients should be advised of potential unknown deleterious effects and the risk of tumor growth during pregnancy. Because cabergoline is long-acting with a high D2-receptor affinity, it is not recommended for use in women when fertility is desired.
Management of prolactinoma. MRI, magnetic resonance imaging; PRL, prolactin.
GH hypersecretion is usually the result of a somatotrope adenoma but may rarely be caused by extrapituitary lesions (Table 403-6). In addition to the more common GH-secreting somatotrope adenomas, mixed mammosomatotrope tumors and acidophilic stem-cell adenomas secrete both GH and PRL. In patients with acidophilic stem-cell adenomas, features of hyperprolactinemia (hypogonadism and galactorrhea) predominate over the less clinically evident signs of acromegaly. Occasionally, mixed plurihormonal tumors are encountered that also secrete ACTH, the glycoprotein hormone α subunit, or TSH in addition to GH. Patients with partially empty sellas may present with GH hypersecretion due to a small GH-secreting adenoma within the compressed rim of pituitary tissue; some of these may reflect the spontaneous necrosis of tumors that were previously larger. GH-secreting tumors rarely arise from ectopic pituitary tissue remnants in the nasopharynx or midline sinuses.
There are case reports of ectopic GH secretion by tumors of pancreatic, ovarian, lung, or hematopoietic origin. Rarely, excess GHRH production may cause acromegaly because of chronic stimulation of somatotropes. These patients present with classic features of acromegaly, elevated GH levels, pituitary enlargement on MRI, and pathologic characteristics of pituitary hyperplasia. The most common cause of GHRH-mediated acromegaly is a chest or abdominal carcinoid tumor. Although these tumors usually express positive GHRH immunoreactivity, clinical features of acromegaly are evident in only a minority of patients with carcinoid disease. Excessive GHRH also may be elaborated by hypothalamic tumors, usually choristomas or neuromas.
TABLE 403-6Causes of Acromegaly ||Download (.pdf) TABLE 403-6 Causes of Acromegaly
| ||Prevalence, % |
|Excess Growth Hormone Secretion |
Densely or sparsely granulated GH cell adenoma
Mixed GH cell and PRL cell adenoma
Mammosomatotrope cell adenoma
GH cell carcinoma or metastases
Multiple endocrine neoplasia 1 (GH cell adenoma)
Ectopic sphenoid or parapharyngeal sinus pituitary adenoma
Pancreatic islet cell tumor
|Excess Growth Hormone–Releasing Hormone Secretion |
Hypothalamic hamartoma, choristoma, ganglioneuroma
Bronchial carcinoid, pancreatic islet cell tumor, small cell lung cancer, adrenal adenoma, medullary thyroid carcinoma, pheochromocytoma
Presentation and Diagnosis
Protean manifestations of GH and IGF-I hypersecretion are indolent and often are not clinically diagnosed for 10 years or more. Acral bony overgrowth results in frontal bossing, increased hand and foot size, mandibular enlargement with prognathism, and widened space between the lower incisor teeth. In children and adolescents, initiation of GH hypersecretion before epiphyseal long bone closure is associated with development of pituitary gigantism (Fig. 403-4). Soft tissue swelling results in increased heel pad thickness, increased shoe or glove size, ring tightening, characteristic coarse facial features, and a large fleshy nose. Other commonly encountered clinical features include hyperhidrosis, a deep and hollow-sounding voice, oily skin, arthropathy, kyphosis, carpal tunnel syndrome, proximal muscle weakness and fatigue, acanthosis nigricans, and skin tags. Generalized visceromegaly occurs, including cardiomegaly, macroglossia, and thyroid gland enlargement.
Features of acromegaly/gigantism. A 22-year-old man with gigantism due to excess growth hormone is shown to the left of his identical twin. The increased height and prognathism (A) and enlarged hand (B) and foot (C) of the affected twin are apparent. Their clinical features began to diverge at the age of approximately 13 years. (Reproduced from R Gagel, IE McCutcheon: N Engl J Med 324:524, 1999; with permission.)
The most significant clinical impact of GH excess occurs with respect to the cardiovascular system. Coronary heart disease, cardiomyopathy with arrhythmias, left ventricular hypertrophy, decreased diastolic function, and hypertension ultimately occur in most patients if untreated. Upper airway obstruction with sleep apnea occurs in more than 60% of patients and is associated with both soft tissue laryngeal airway obstruction and central sleep dysfunction. Diabetes mellitus develops in 25% of patients with acromegaly, and most patients are intolerant of a glucose load (as GH counteracts the action of insulin). Acromegaly is associated with an increased risk of colon polyps and mortality from colonic malignancy; polyps are diagnosed in up to one-third of patients. Overall mortality is increased about threefold and is due primarily to cardiovascular and cerebrovascular disorders and respiratory disease. Unless GH levels are controlled, survival is reduced by an average of10 years compared with an age-matched control population.
Age-matched serum IGF-I levels are elevated in acromegaly. Consequently, an IGF-I level provides a useful laboratory screening measure when clinical features raise the possibility of acromegaly. Due to the pulsatility of GH secretion, measurement of a single random GH level is not useful for the diagnosis or exclusion of acromegaly and does not correlate with disease severity. The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to <0.4 μg/L within 1–2 h of an oral glucose load (75 g). When newer ultrasensitive GH assays are used, normal nadir GH levels are even lower (<0.05 μg/L). About 20% of patients exhibit a paradoxical GH rise after glucose. PRL should be measured, as it is elevated in ~25% of patients with acromegaly. Thyroid function, gonadotropins, and sex steroids may be attenuated because of tumor mass effects. Because most patients will undergo surgery with glucocorticoid coverage, tests of ACTH reserve in asymptomatic patients are more efficiently deferred until after surgery.
The goal of treatment is to control GH and IGF-I hypersecretion, ablate or arrest tumor growth, ameliorate comorbidities, restore mortality rates to normal, and preserve pituitary function.
Surgical resection of GH-secreting adenomas is the initial treatment for most patients (Fig. 403-5). Somatostatin analogues are used as adjuvant treatment for preoperative shrinkage of large invasive macroadenomas, immediate relief of debilitating symptoms, and reduction of GH hypersecretion; in frail patients experiencing morbidity; and in patients who decline surgery or, when surgery fails, to achieve biochemical control. Irradiation or repeat surgery may be required for patients who cannot tolerate or do not respond to adjunctive medical therapy. The high rate of late hypopituitarism and the slow rate (5–15 years) of biochemical response are the main disadvantages of radiotherapy. Irradiation is also relatively ineffective in normalizing IGF-I levels. Stereotactic ablation of GH-secreting adenomas by gamma-knife radiotherapy is promising, but initial reports suggest that long-term results and side effects are similar to those observed with conventional radiation. Somatostatin analogues may be required while awaiting the full benefits of radiotherapy. Systemic co-morbid sequelae of acromegaly, including cardiovascular disease, diabetes, and arthritis, should be managed aggressively. Mandibular surgical repair may be indicated. SURGERY
Transsphenoidal surgical resection by an experienced surgeon is the preferred primary treatment for both microadenomas (remission rate ~70%) and macroadenomas (<50% in remission). Soft tissue swelling improves immediately after tumor resection. GH levels return to normal within an hour, and IGF-I levels are normalized within 3–4 days. In ~10% of patients, acromegaly may recur several years after apparently successful surgery; hypopituitarism develops in up to 15% of patients after surgery. SOMATOSTATIN ANALOGUES
Somatostatin analogues exert their therapeutic effects through SSTR2 and SSTR5 receptors, both of which are expressed by GH-secreting tumors. Octreotide acetate is an eight-amino-acid synthetic somatostatin analogue. In contrast to native somatostatin, the analogue is relatively resistant to plasma degradation. It has a 2-h serum half-life and possesses fortyfold greater potency than native somatostatin to suppress GH. Octreotide is administered by subcutaneous injection, beginning with 50 μg tid; the dose can be increased gradually up to 1500 μg/d. Fewer than 10% of patients do not respond to the analogue. Octreotide suppresses integrated GH levels and normalizes IGF-I levels in ~60% of treated patients.
The long-acting somatostatin depot formulations, octreotide and lanreotide, are the preferred medical treatment for patients with acromegaly. Sandostatin-LAR is a sustained-release, long-acting formulation of octreotide incorporated into microspheres that sustain drug levels for several weeks after intramuscular injection. GH suppression occurs for as long as 6 weeks after a 30-mg intramuscular injection; long-term monthly treatment sustains GH and IGF-I suppression and also reduces pituitary tumor size in ~50% of patients. Lanreotide autogel, a slow-release depot somatostatin preparation, is a cyclic somatostatin octapeptide analogue that suppresses GH and IGF-I hypersecretion after a 60-mg subcutaneous injection. Long-term (4–6 weeks) administration controls GH hypersecretion in about two-thirds of treated patients and improves patient compliance because of the long interval required between drug injections. Rapid relief of headache and soft tissue swelling occurs in ~75% of patients within days to weeks of somatostatin analogue initiation. Most patients report symptomatic improvement, including amelioration of headache, perspiration, obstructive apnea, and cardiac failure. Side Effects
Somatostatin analogues are well tolerated in most patients. Adverse effects are short-lived and mostly relate to drug-induced suppression of gastrointestinal motility and secretion. Transient nausea, abdominal discomfort, fat malabsorption, diarrhea, and flatulence occur in one-third of patients, and these symptoms usually remit within 2 weeks. Octreotide suppresses postprandial gallbladder contractility and delays gallbladder emptying; up to 30% of patients develop long-term echogenic sludge or asymptomatic cholesterol gallstones. Other side effects include mild glucose intolerance due to transient insulin suppression, asymptomatic bradycardia, hypothyroxinemia, and local injection site discomfort. GH RECEPTOR ANTAGONIST
Pegvisomant antagonizes endogenous GH action by blocking peripheral GH binding to its receptor. Consequently, serum IGF-I levels are suppressed, reducing the deleterious effects of excess endogenous GH. Pegvisomant is administered by daily subcutaneous injection (10–20 mg) and normalizes IGF-I in ~70% of patients. GH levels, however, remain elevated as the drug does not target the pituitary adenoma. Side effects include reversible liver enzyme elevation, lipodystrophy, and injection site pain. Tumor size should be monitored by MRI.
Combined treatment with monthly somatostatin analogues and weekly or biweekly pegvisomant injections has been used effectively in resistant patients. DOPAMINE AGONISTS
Bromocriptine and cabergoline may modestly suppress GH secretion in some patients. Very high doses of bromocriptine (≥20 mg/d) or cabergoline (0.5 mg/d) are usually required to achieve modest GH therapeutic efficacy. Combined treatment with octreotide and cabergoline may induce additive biochemical control compared with either drug alone. RADIATION
External radiation therapy or high-energy stereotactic techniques are used as adjuvant therapy for acromegaly. An advantage of radiation is that patient compliance with long-term treatment is not required. Tumor mass is reduced, and GH levels are attenuated over time. However, 50% of patients require at least 8 years for GH levels to be suppressed to <5 μg/L; this level of GH reduction is achieved in about 90% of patients after 18 years but represents suboptimal GH suppression. Patients may require interim medical therapy for several years before attaining maximal radiation benefits. Most patients also experience hypothalamic-pituitary damage, leading to gonadotropin, ACTH, and/or TSH deficiency within 10 years of therapy.
In summary, surgery is the preferred primary treatment for GH-secreting microadenomas (Fig. 403-5). The high frequency of GH hypersecretion after macroadenoma resection usually necessitates adjuvant or primary medical therapy for these larger tumors. Patients unable to receive or respond to unimodal medical treatment may benefit from combined treatments, or can be offered radiation.
Management of acromegaly. GH, growth hormone; CNS, central nervous system; IGF, insulin-like growth factor. (Adapted fromS Melmed et al: J Clin Endocrinol Metab 94:1509–1517, 2009; © The Endocrine Society.)
CUSHING’S SYNDROME (ACTH-PRODUCING ADENOMA)
Pituitary corticotrope adenomas account for 70% of patients with endogenous causes of Cushing’s syndrome. However, it should be emphasized that iatrogenic hypercortisolism is the most common cause of cushingoid features. Ectopic tumor ACTH production, cortisol-producing adrenal adenomas, adrenal carcinoma, and adrenal hyperplasia account for the other causes; rarely, ectopic tumor CRH production is encountered.
ACTH-producing adenomas account for about 10–15% of all pituitary tumors. Because the clinical features of Cushing’s syndrome often lead to early diagnosis, most ACTH-producing pituitary tumors are relatively small microadenomas. However, macroadenomas also are seen and some ACTH-expressing adenomas are clinically silent. Cushing’s disease is 5–10 times more common in women than in men. These pituitary adenomas exhibit unrestrained ACTH secretion, with resultant hypercortisolemia. However, they retain partial suppressibility in the presence of high doses of administered glucocorticoids, providing the basis for dynamic testing to distinguish pituitary from nonpituitary causes of Cushing’s syndrome.
Presentation and Diagnosis
The diagnosis of Cushing’s syndrome presents two great challenges: (1) to distinguish patients with pathologic cortisol excess from those with physiologic or other disturbances of cortisol production and (2) to determine the etiology of pathologic cortisol excess.
Typical features of chronic cortisol excess include thin skin, central obesity, hypertension, plethoric moon facies, purple striae and easy bruisability, glucose intolerance or diabetes mellitus, gonadal dysfunction, osteoporosis, proximal muscle weakness, signs of hyperandrogenism (acne, hirsutism), and psychological disturbances (depression, mania, and psychoses) (Table 403-7). Hematopoietic features of hypercortisolism include leukocytosis, lymphopenia, and eosinopenia. Immune suppression includes delayed hypersensitivity and infection propensity. These protean yet commonly encountered manifestations of hypercortisolism make it challenging to decide which patients mandate formal laboratory evaluation. Certain features make pathologic causes of hypercortisolism more likely; they include characteristic central redistribution of fat, thin skin with striae and bruising, and proximal muscle weakness. In children and young females, early osteoporosis may be particularly prominent. The primary cause of death is cardiovascular disease, but life-threatening infections and risk of suicide are also increased.
Rapid development of features of hypercortisolism associated with skin hyperpigmentation and severe myopathy suggests an ectopic tumor source of ACTH. Hypertension, hypokalemic alkalosis, glucose intolerance, and edema are also more pronounced in these patients. Serum potassium levels <3.3 mmol/L are evident in ~70% of patients with ectopic ACTH secretion but are seen in <10% of patients with pituitary-dependent Cushing’s syndrome.
TABLE 403-7Clinical Features of Cushing’s Syndrome (All Ages) ||Download (.pdf) TABLE 403-7 Clinical Features of Cushing’s Syndrome (All Ages)
|Symptoms/Signs ||Frequency, % |
|Obesity or weight gain (>115% ideal body weight) ||80 |
|Thin skin ||80 |
|Moon facies ||75 |
|Hypertension ||75 |
|Purple skin striae ||65 |
|Hirsutism ||65 |
|Menstrual disorders (usually amenorrhea) ||60 |
|Plethora ||60 |
|Abnormal glucose tolerance ||55 |
|Impotence ||55 |
|Proximal muscle weakness ||50 |
|Truncal obesity ||50 |
|Acne ||45 |
|Bruising ||45 |
|Mental changes ||45 |
|Osteoporosis ||40 |
|Edema of lower extremities ||30 |
|Hyperpigmentation ||20 |
|Hypokalemic alkalosis ||15 |
|Diabetes mellitus ||15 |
The diagnosis of Cushing’s syndrome is based on laboratory documentation of endogenous hypercortisolism. Measurement of 24-h urine free cortisol (UFC) is a precise and cost-effective screening test. Alternatively, the failure to suppress plasma cortisol after an overnight 1-mg dexamethasone suppression test can be used to identify patients with hypercortisolism. As nadir levels of cortisol occur at night, elevated midnight serum or salivary samples of cortisol are suggestive of Cushing’s syndrome. Basal plasma ACTH levels often distinguish patients with ACTH-independent (adrenal or exogenous glucocorticoid) from those with ACTH-dependent (pituitary, ectopic ACTH) Cushing’s syndrome. Mean basal ACTH levels are about eightfold higher in patients with ectopic ACTH secretion than in those with pituitary ACTH-secreting adenomas. However, extensive overlap of ACTH levels in these two disorders precludes using ACTH measurements to make the distinction. Preferably, dynamic testing based on differential sensitivity to glucocorticoid feedback or ACTH stimulation in response to CRH or cortisol reduction is used to distinguish ectopic from pituitary sources of excess ACTH (Table 403-8). Very rarely, circulating CRH levels are elevated, reflecting ectopic tumor-derived secretion of CRH and often ACTH. For further discussion of dynamic testing for Cushing’s syndrome, see Chap. 406.
Most ACTH-secreting pituitary tumors are <5 mm in diameter, and about half are undetectable by sensitive MRI. The high prevalence of incidental pituitary microadenomas diminishes the ability to distinguish ACTH-secreting pituitary tumors accurately from nonsecreting incidentalomas.
Inferior Petrosal Venous Sampling
Because pituitary MRI with gadolinium enhancement is insufficiently sensitive to detect small (<2 mm) pituitary ACTH-secreting adenomas, bilateral inferior petrosal sinus ACTH sampling before and after CRH administration may be required to distinguish these lesions from ectopic ACTH-secreting tumors that may have similar clinical and biochemical characteristics. Simultaneous assessment of ACTH in each inferior petrosal vein and in the diagnosis of peripheral circulation provides a strategy for confirming and localizing pituitary ACTH production. Sampling is performed at baseline and 2, 5, and 10 min after intravenous bovine CRH (1 μg/kg) injection. An increased ratio (>2) of inferior petrosal:peripheral vein ACTH confirms pituitary Cushing’s syndrome. After CRH injection, peak petrosal:peripheral ACTH ratios ≥3 confirm the presence of a pituitary ACTH-secreting tumor. The sensitivity of this test is >95%, with very rare false-positive results. False-negative results may be encountered in patients with aberrant venous drainage. Petrosal sinus catheterizations are technically difficult, and about 0.05% of patients develop neurovascular complications. The procedure should not be performed in patients with hypertension, in patients with known cerebrovascular disease, or in the presence of a well-visualized pituitary adenoma on MRI.
TREATMENT Cushing’s Syndrome
Selective transsphenoidal resection is the treatment of choice for Cushing’s disease (Fig. 403-6). The remission rate for this procedure is ~80% for microadenomas but <50% for macroadenomas. However, surgery is rarely successful when the adenoma is not visible on MRI. After successful tumor resection, most patients experience a postoperative period of symptomatic ACTH deficiency that may last up to 12 months. This usually requires low-dose cortisol replacement, as patients experience both steroid withdrawal symptoms and have a suppressed hypothalamic-pituitary-adrenal axis. Biochemical recurrence occurs in approximately 5% of patients in whom surgery was initially successful.
When initial surgery is unsuccessful, repeat surgery is sometimes indicated, particularly when a pituitary source for ACTH is well documented. In older patients, in whom issues of growth and fertility are less important, hemi- or total hypophysectomy may be necessary if a discrete pituitary adenoma is not recognized. Pituitary irradiation may be used after unsuccessful surgery, but it cures only about 15% of patients. Because the effects of radiation are slow and only partially effective in adults, steroidogenic inhibitors are used in combination with pituitary irradiation to block adrenal effects of persistently high ACTH levels.
Pasireotide (600 or 900 ug/day subcutaneously), a somatostatin analog with high affinity for SST5 > SST2 receptors, has been approved for treating patients with ACTH-secreting pituitary tumors when surgery is not an option or has been unsuccessful. In clinical trials, the drug lowered plasma ACTH levels, normalized 24-h urinary free cortisol levels in about 25% of patients, and resulted in up to 40% mean pituitary tumor shrinkage. Side effects include development of hyperglycemia and diabetes in about 70% of patients, likely due to suppressed pancreatic secretion of insulin and incretins. Because patients with hypercortisolism are insulin-resistant, hyperglycemia should be rigorously managed. Other side effects are similar to those encountered for somatostatin analogs and include transient abdominal discomfort, diarrhea, nausea, and gallstones (20% of patients). The drug requires consistent long-term administration.
Ketoconazole, an imidazole derivative antimycotic agent, inhibits several P450 enzymes and effectively lowers cortisol in most patients with Cushing’s disease when administered twice daily (600–1200 mg/d). Elevated hepatic transaminases, gynecomastia, impotence, gastrointestinal upset, and edema are common side effects.
Mifepristone (300–1200 mg/d), a glucocorticoid receptor antagonist, blocks peripheral cortisol action and is approved to treat hyperglycemia in Cushing’s disease. Because the drug does not target the pituitary tumor, both ACTH and cortisol levels remain elevated, thus obviating a reliable circulating biomarker. Side effects are largely due to general antagonism of other steroid hormones and include hypokalemia, endometrial hyperplasia, hypoadrenalism, and hypertension.
Metyrapone (2–4 g/d) inhibits 11β-hydroxylase activity and normalizes plasma cortisol in up to 75% of patients. Side effects include nausea and vomiting, rash, and exacerbation of acne or hirsutism. Mitotane (o,p ‘-DDD; 3–6 g/d orally in four divided doses) suppresses cortisol hypersecretion by inhibiting 11β-hydroxylase and cholesterol side-chain cleavage enzymes and by destroying adrenocortical cells. Side effects of mitotane include gastrointestinal symptoms, dizziness, gynecomastia, hyperlipidemia, skin rash, and hepatic enzyme elevation. It also may lead to hypoaldosteronism. Other agents include aminoglutethimide (250 mg tid), trilostane (200–1000 mg/d), cyproheptadine (24 mg/d), and IV etomidate (0.3 mg/kg per hour). Glucocorticoid insufficiency is a potential side effect of agents used to block steroidogenesis.
The use of steroidogenic inhibitors has decreased the need for bilateral adrenalectomy. Surgical removal of both adrenal glands corrects hypercortisolism but may be associated with significant morbidity rates and necessitates permanent glucocorticoid and mineralocorticoid replacement. Adrenalectomy in the setting of residual corticotrope adenoma tissue predisposes to the development of Nelson’s syndrome, a disorder characterized by rapid pituitary tumor enlargement and increased pigmentation secondary to high ACTH levels. Prophylactic radiation therapy may be indicated to prevent the development of Nelson’s syndrome after adrenalectomy.
Management of Cushing’s syndrome. ACTH, adrenocorticotropin hormone; MRI, magnetic resonance imaging. *, Not usually required.
TABLE 403-8Differential Diagnosis of ACTH-Dependent Cushing’s Syndromea ||Download (.pdf) TABLE 403-8 Differential Diagnosis of ACTH-Dependent Cushing’s Syndromea
| ||ACTH-Secreting Pituitary Tumor ||Ectopic ACTH Secretion |
|Etiology || |
Pituitary corticotrope adenoma
Bronchial, abdominal carcinoid
Small cell lung cancer
|Sex ||F > M ||M > F |
|Clinical features ||Slow onset || |
|Serum potassium <3.3μg/L ||<10% ||75% |
|24-h urinary free cortisol (UFC) ||High ||High |
|Basal ACTH level ||Inappropriately high ||Very high |
1 mg overnight
Low-dose (0.5 mg q6h)
|Cortisol >5 μg/dL ||Cortisol >5 μg/dL |
| High-dose (2 mg q6h) ||Cortisol <5 μg/dL ||Cortisol >5 μg/dL |
|UFC >80% suppressed || |
|Inferior petrosal sinus sampling (IPSS) || || |
|>2 ||<2 |
|>3 ||<3 |
NONFUNCTIONING AND GONADOTROPIN-PRODUCING PITUITARY ADENOMAS
Nonfunctioning pituitary adenomas include those that secrete little or no pituitary hormones as well as tumors that produce too little hormone to result in recognizable clinical features. They are the most common type of pituitary adenoma and are usually macroadenomas at the time of diagnosis because clinical features are not apparent until tumor mass effects occur. Based on immunohistochemistry, most clinically nonfunctioning adenomas can be shown to originate from gonadotrope cells. These tumors typically produce small amounts of intact gonadotropins (usually FSH) as well as uncombined α, LH β, and FSH β subunits. Tumor secretion may lead to elevated α and FSH β subunits and, rarely, to increased LH β subunit levels. Some adenomas express α subunits without FSH or LH. TRH administration often induces an atypical increase of tumor-derived gonadotropins or subunits.
Presentation and Diagnosis
Clinically nonfunctioning tumors often present with optic chiasm pressure and other symptoms of local expansion or may be incidentally discovered on an MRI performed for another indication (incidentaloma). Rarely, menstrual disturbances or ovarian hyperstimulation occur in women with large tumors that produce FSH and LH. More commonly, adenoma compression of the pituitary stalk or surrounding pituitary tissue leads to attenuated LH and features of hypogonadism. PRL levels are usually slightly increased, also because of stalk compression. It is important to distinguish this circumstance from true prolactinomas, as nonfunctioning tumors do not shrink in response to treatment with dopamine agonists.
The goal of laboratory testing in clinically nonfunctioning tumors is to classify the type of the tumor, identify hormonal markers of tumor activity, and detect possible hypopituitarism. Free α subunit levels may be elevated in 10–15% of patients with nonfunctioning tumors. In female patients, peri- or postmenopausal basal FSH concentrations are difficult to distinguish from tumor-derived FSH elevation. Premenopausal women have cycling FSH levels, also preventing clear-cut diagnostic distinction from tumor-derived FSH. In men, gonadotropin-secreting tumors may be diagnosed because of slightly increased gonadotropins (FSH > LH) in the setting of a pituitary mass. Testosterone levels are usually low despite the normal or increased LH level, perhaps reflecting reduced LH bioactivity or the loss of normal LH pulsatility. Because this pattern of hormone test results is also seen in primary gonadal failure and, to some extent, with aging (Chap. 411), the finding of increased gonadotropins alone is insufficient for the diagnosis of a gonadotropin-secreting tumor. In the majority of patients with gonadotrope adenomas, TRH administration stimulates LH β subunit secretion; this response is not seen in normal individuals. GnRH testing, however, is not helpful for making the diagnosis. For nonfunctioning and gonadotropin-secreting tumors, the diagnosis usually rests on immunohistochemical analyses of surgically resected tumor tissue, as the mass effects of these tumors usually necessitate resection.
Although acromegaly or Cushing’s syndrome usually presents with unique clinical features, clinically inapparent (silent) somatotrope or corticotrope adenomas may only be diagnosed by immunostaining of resected tumor tissue. If PRL levels are <100 μg/L in a patient harboring a pituitary mass, a nonfunctioning adenoma causing pituitary stalk compression should be considered.
TREATMENT Nonfunctioning and Gonadotropin-Producing Pituitary Adenomas
Asymptomatic small nonfunctioning microadenomas adenomas with no threat to vision may be followed with regular MRI and visual field testing without immediate intervention. However, for macroadenomas, transsphenoidal surgery is indicated to reduce tumor size and relieve mass effects (Fig. 403-7). Although it is not usually possible to remove all adenoma tissue surgically, vision improves in 70% of patients with preoperative visual field defects. Preexisting hypopituitarism that results from tumor mass effects may improve or resolve completely. Beginning about 6 months postoperatively, MRI scans should be performed yearly to detect tumor regrowth. Within 5–6 years after successful surgical resection, ~15% of nonfunctioning tumors recur. When substantial tumor remains after transsphenoidal surgery, adjuvant radiotherapy may be indicated to prevent tumor regrowth. Radiotherapy may be deferred if no postoperative residual mass is evident. Nonfunctioning pituitary tumors respond poorly to dopamine agonist treatment and somatostatin analogues are largely ineffective for shrinking these tumors. The selective GnRH antagonist Nal-Glu GnRH suppresses FSH hypersecretion but has no effect on adenoma size.
Management of a nonfunctioning pituitary mass. MRI, magnetic resonance imaging.
TSH-producing macroadenomas are very rare but are often large and locally invasive when they occur. Patients usually present with thyroid goiter and hyperthyroidism, reflecting overproduction of TSH. Diagnosis is based on demonstrating elevated serum free T4 levels, inappropriately normal or high TSH secretion, and MRI evidence of a pituitary adenoma. Elevated uncombined α subunits are seen in many patients.
It is important to exclude other causes of inappropriate TSH secretion, such as resistance to thyroid hormone, an autosomal dominant disorder caused by mutations in the thyroid hormone β receptor (Chap. 405). The presence of a pituitary mass and elevated β subunit levels are suggestive of a TSH-secreting tumor. Dysalbuminemic hyperthyroxinemia syndromes, caused by mutations in serum thyroid hormone binding proteins, are also characterized by elevated thyroid hormone levels, but with normal rather than suppressed TSH levels. Moreover, free thyroid hormone levels are normal in these disorders, most of which are familial.
TREATMENT TSH-Secreting Adenomas
The initial therapeutic approach is to remove or debulk the tumor mass surgically, usually using a transsphenoidal approach. Total resection is not often achieved as most of these adenomas are large and locally invasive. Normal circulating thyroid hormone levels are achieved in about two-thirds of patients after surgery. Thyroid ablation or antithyroid drugs (methimazole and propylthiouracil) can be used to reduce thyroid hormone levels. Somatostatin analogue treatment effectively normalizes TSH and α subunit hypersecretion, shrinks the tumor mass in 50% of patients, and improves visual fields in 75% of patients; euthyroidism is restored in most patients. Because somatostatin analogues markedly suppress TSH, biochemical hypothyroidism often requires concomitant thyroid hormone replacement, which may also further control tumor growth.