Figure 46.1. Pituitary Anatomy. (A), P = pituitary gland; S = sphenoid sinus; A = carotid artery; 3, 4, 6, cranial nerves III, IV, and VI; V1,V2, branches 1 and 2 of cranial nerve V. (B) MRI of normal pituitary gland. SOURCES: (A) Reprinted from Naidich MJ and Russell EJ. Current Approaches to Imaging of the Sellar Region and Pituitary. Endocrinol Metab Clin North Am. 1999;28(1):45–79, with permission from Elsevier. (B) Reprinted with permission from Vance ML. Hypopituitarism. N Engl J Med. 1994; 330(23):1651–1662. © 1994 Massachusetts Medical Society. All rights reserved.

    The pituitary gland is divided into an anterior and a posterior portion. The anterior pituitary, also known as the adenohypophysis, is composed of five distinct cell types, each of which secretes a distinct hormone. The anterior pituitary forms part of a tightly coordinated system of hypothalamic-pituitary-target organ axes, in which hormonal signals from the hypothalamus stimulate or inhibit secretion of anterior pituitary hormones, which in turn act on specific organs as follows.

    Hypothalamic neurons produce gonadotropin-releasing hormone (GnRH), which stimulates pituitary production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and these signal the ovaries to secrete estrogen and progesterone or the testes to secrete testosterone. Hypothalamic corticotropin-releasing hormone (CRH) induces pituitary adrenocorticotropic hormone (ACTH) production, which regulates adrenal cortisol synthesis. Thyrotropin-releasing hormone (TRH) stimulates thyroid-stimulating hormone (TSH), which in turn regulates thyroid hormone production. Hypothalamic growth hormone releasing hormone (GHRH) is responsible for pituitary growth hormone (GH) production, which leads to insulin-like growth factor-1 (IGF-1) production in the liver. While most hypothalamic hormones have a stimulatory effect on the anterior pituitary, somatostatin plays an inhibitory role; it inhibits the secretion of GH and TSH. Finally, prolactin secretion is tonically inhibited by hypothalamic dopamine (Figure 46.2).

    The hypothalamic-pituitary-target gland axes tend to function as negative-feedback systems in which hormones secreted by target organs suppress hypothalamic and/or pituitary activity. A hormone deficiency can be primary, caused by target gland failure, or secondary or tertiary, caused by failure of the pituitary or hypothalamus, respectively, to stimulate the target gland.

    The posterior pituitary, also known as the neurohypophysis, is the site of storage and secretion of vasopressin (AVP) and oxytocin, which are both synthesized in neurons in the hypothalamus.

PITUITARY LESIONS

Pituitary lesions can be of multiple etiologies and thus have a broad differential diagnosis. Tumors of several types can involve the pituitary gland. Benign tumors of anterior pituitary cell origin are known as adenomas. Very rarely, these can become carcinomas. Other tumors that can affect the pituitary gland include craniopharyngiomas, Rathke’s cleft cysts, and germinomas. Malignancies from multiple primary sites, including hematologic malignancies, can metastasize to the pituitary. Last, granulomatous, infectious, infiltrative, and inflammatory processes such as sarcoidosis, eosinophilic granulomatosis, tuberculosis, mycosis, abscesses, hemochromatosis, and lymphocytic hypophysitis can all cause pituitary lesions (box 46.1).

Box 46.1 DIFFERENTIAL DIAGNOSIS OF SELLAR/PARASELLAR LESIONS

PITUITARY ADENOMAS

By far the most common pituitary lesion is the pituitary adenoma, with a prevalence of approximately 1 in 1000 to 1 in 10,000 individuals. In formulating a clinical approach to the diagnosis and management of a patient with a pituitary adenoma, two major factors need to be considered: mass effects and effects on pituitary function.

    Mass effects are neurological and hormonal abnormalities that develop secondary to the intracranial space occupied by the lesion or to its proximity to important anatomical structures. Patients who develop mass effects from a pituitary lesion may complain of headaches. Temporal visual field deficits may develop as a result of compression of the optic chiasm.

    Ocular nerve palsies and diplopia can occur if cranial nerves III, IV, or VI, which travel in the cavernous sinus, are compressed; facial numbness and pain can result if cranial nerve V is affected (Figure 46.1). Additionally, the presence of a pituitary mass can distort regional anatomy sufficiently to decrease hormone production by adjacent cells. This can lead to various degrees of hypopituitarism. Hyperprolactinemia can result from compression of the pituitary stalk, as this interrupts inhibitory dopamine signaling.

    The second important consideration when evaluating a patient with a pituitary lesion is its effect on pituitary hormone production. Adenomas can be nonfunctioning (15% of all adenomas), or they can secrete one or more pituitary hormones in excess. The most common type of hyperfunctioning lesions (60%) are lactotroph adenomas, which produce prolactin. GH-secreting adenomas (15%) result in the disease known as acromegaly, and 6% of adenomas secrete ACTH, resulting in Cushing disease. Adenomas that secrete bioactive LH, FSH, or TSH are very rare.

    At the same time, as mentioned above, whether an adenoma is hyperfunctioning or nonfunctioning, it can cause pituitary hypofunction by compression of nearby normal anterior pituitary cells. Indeed, a pituitary tumor could cause impaired secretion of all hormones except for the one that it secretes in excess. The clinical manifestations and differential diagnosis of hypopituitarism are addressed in detail below.

Prolactinomas

Clinical Presentation

    The most common symptoms of high prolactin levels, or hyperprolactinemia, in premenopausal women are menstrual abnormalities (oligomenorrhea or amenorrhea) and anovulation. Galactorrhea occurs in about 50–80% of women. In men, hyperprolactinemia can cause decreased libido, impotence, and infertility; galactorrhea is less common. The reproductive abnormalities seen in both sexes are thought to be secondary to a direct suppressive effect of prolactin on hypothalamic gonadotropin-releasing hormone (GnRH) production; this inhibits gonadotropin (LH and FSH) release, and consequently impairs gametogenesis and gonadal steroidogenesis. Prolonged estrogen and androgen deficiency also leads to decreased bone density. The clinical presentation of a prolactinoma may also include symptoms from mass effect, including headache and visual field cuts, especially in men, who generally present with larger tumors.

Differential Diagnosis of Hyperprolactinemia

    Prolactinomas are not the only cause of hyperprolactinemia (box 46.2). As previously stated, prolactin secretion is under tonic inhibitory control by dopamine, and any process that interferes with hypothalamic dopamine secretion or its delivery to the pituitary gland can result in hyperprolactinemia. There are also factors that stimulate prolactin release, including stress, exercise, sleep, chest wall stimulation (via afferent neural pathways), TRH, serotonin, estrogen, and others.

Box 46.2 CAUSES OF HYPERPROLACTINEMIA

    There are physiological states of hyperprolactinemia, such as pregnancy and lactation. During pregnancy, rising estrogen levels stimulate prolactin, which can increase 10- to 20-fold. The stimulus of suckling maintains high prolactin levels during lactation. There are also multiple pharmacologic agents that elevate prolactin. The majority of these are dopamine antagonists, such as the antipsychotic agents (risperidone, haloperidol) and metoclopramide. Last, there are pathophysiological states that result in hyperprolactinemia. Pituitary stalk compression secondary to tumors or infiltrative diseases interferes with dopamine inhibition of prolactin. Primary hypothyroidism results in elevation of TRH, which stimulates both TSH and prolactin (and in such cases, treatment of hypothyroidism should normalize prolactin). Chronic renal failure causes hyperprolactinemia secondary to decreased clearance of the hormone. Finally, prolactinomas are a major cause of prolactin elevation; occasionally, adenomas co-secrete prolactin with other anterior pituitary hormones.

Diagnosis

    A patient who presents with symptoms of hyperprolactinemia can be evaluated with a random measurement of serum prolactin. If the prolactin level is mildly elevated the measurement should be repeated, given the various physiological factors (listed above) that can transiently elevate prolactin. If the level remains high, further evaluation should include a detailed history of recent medication use, a pregnancy test (if the patient is female), and thyroid and renal function tests. If no secondary cause of hyperprolactinemia is identified, the patient should be evaluated for the presence of a pituitary mass by gadolinium-enhanced magnetic resonance imaging (MRI).

    Pituitary adenomas are classified as a microadenoma if they are <10 mm in size and as macroadenomas if they ≥10 mm in size. In general, in the case of prolactinomas, the magnitude of prolactin elevation correlates well with radiographic estimates of tumor size. Macroadenomas are generally associated with prolactin levels >200–250 µg/L. Therefore, a mild prolactin elevation in the presence of a macroadenoma should raise suspicion that the tumor is not in fact prolactin-secreting, but is causing hyperprolactinemia secondary to compression of the pituitary stalk. In such cases, treatment with dopamine agonists will lower prolactin levels but will not cause a decrease in tumor size (see below).

Management

    The indications for treatment of a prolactin-secreting adenoma depend on the size of the tumor, the presence of hypogonadism, menstrual irregularities, bothersome symptoms such as galactorrhea, and the patient’s desire for fertility.

    The presence of a macroadenoma is an absolute indication for therapy, as there is significant potential for tumor expansion (Figure 46.3). Patients with macroadenomas that extend beyond the sella turcica should undergo visual field testing and evaluation of anterior pituitary function. The goals of treatment are to normalize prolactin levels and achieve remission of symptoms, reduce tumor size, and prevent disease progression.

    On the other hand, most microadenomas do not increase in size over time. Therefore, these patients require treatment only if they desire fertility, have amenorrhea, hypogonadism, or troublesome galactorrhea, or if the adenoma enlarges. Patients with microadenomas without these indications for treatment can be followed with periodic prolactin measurements and MRI if their clinical symptoms progress (Figure 46.3). Women can also safely be treated with oral contraceptives or estrogen/progesterone replacement to prevent bone loss.

    The first line of treatment for prolactin-secreting tumors is a dopamine agonist, of which two are approved for this indication in the United States: bromocriptine and cabergoline. Both medications effectively lower serum prolactin levels, restore gonadal function, and reduce tumor size. Cabergoline is the preferred choice as it is more efficacious than bromocriptine, is usually better tolerated, and can be administered once or twice weekly rather than daily. Both bromocriptine and cabergoline are usually started at low doses and titrated until prolactin levels normalize. Side effects include nausea, headache, and dizziness. In women attempting to conceive, because of more extensive safety data, bromocriptine is generally preferred. The medication should be discontinued when pregnancy is achieved.

    Dopamine agonists may not be necessary indefinitely; when dopamine agonist therapy is discontinued, 20–25% of patients remain normoprolactinemic. Therefore, after 2 years of therapy and if there has been tumor shrinkage on imaging, it is reasonable to taper the dopamine agonist therapy while monitoring prolactin levels to determine if permanent remission of hyperprolactinemia has occurred.

    It is worth noting that the ergot-derived dopamine agonists, pergolide and cabergoline, have recently been associated with increased risk of cardiac valve regurgitation in patients treated with these medications for Parkinson disease. However, the doses used for the treatment of Parkinson disease are much higher than those used for hyperprolactinemia, and there is no evidence that valvulopathy occurs at the lower cumulative doses used for this indication. A possible mechanism for the valvular disease associated with these drugs is the activation of cardiac serotonin receptor subtype 5-HT_2B; valvulopathies associated with carcinoid syndrome and fenfluramine also occur through this mechanism.

    In addition to dopamine agonists, treatment options for prolactinomas include surgery and external radiation. Transsphenoidal removal of a prolactinoma is indicated when a macroadenoma does not respond to medical therapy or when there is tumor growth despite medical treatment. If a substantial amount of tumor remains after surgical excision, external radiation may occasionally be necessary.

Acromegaly

Clinical Presentation

    Acromegaly is rare, with an incidence of approximately three cases per 1 million persons per year. The vast majority of cases are caused by pituitary GH–secreting adenomas. The clinical manifestations of acromegaly are varied. Accelerated growth and gigantism occur only if the disease develops in adolescence before epiphyseal plates are closed. In adults the most common clinical features are coarsening of facial features, such as frontal bone bossing and jaw prognathism, and soft-tissue swelling that can lead to increases in ring, shoe, or hat size. Patients also frequently complain of increased sweating, and premenopausal women may note menstrual irregularities. Arthralgias and osteoarthritis are a source of significant functional disability. Metabolic complications include hyperglycemia and hyperlipidemia. Cardiac abnormalities such as arrhythmias, hypertension, valvular disease, and heart failure, as well sleep apnea secondary to airway soft-tissue swelling, may develop (box 46.3). Additionally, acromegaly is associated with an increased risk of certain tumors, such as colonic polyps.

Box 46.3 CLINICAL FEATURES OF ACROMEGALY IN ADULTS

    More than 75% of patients with acromegaly have a macroadenoma at diagnosis, and if that is the case they may additionally present with symptoms of mass effect, such as headaches, visual field defects, and pituitary hormone deficiencies. About 25% of GH adenomas co-secrete prolactin, and in these instances galactorrhea may be present.

Diagnosis

    Under normal physiological conditions GH is released in a pulsatile fashion, which results in considerable variation in circulating levels. A random serum GH level is therefore not an accurate indicator of GH excess. GH induces the synthesis of IGF-1 from tissues such as the liver. Circulating IGF-1 concentrations reflect peripheral GH levels, but unlike GH, IGF-1 has a long half-life and can be reliably measured at any time of day. As a result, measurement of serum IGF-1 is the best screening test for acromegaly. IGF-1 levels should be compared against age- and gender-matched normative data.

    If IGF-1 levels are elevated, the diagnosis of acromegaly can then be confirmed by documenting failure of suppression of GH secretion. This is best accomplished by performing a 75g oral glucose tolerance test, during which GH levels are obtained. The most widely used diagnostic criterion is a GH level 2 hours after glucose ingestion of >1 µg/L Conventionally, both an elevated IGF-1 level and failure of GH suppression are required for a diagnosis of acromegaly (table 46.1). In clinical practice, however, GH suppression testing is not always necessary if the clinical picture is highly suggestive, IGF-1 levels are elevated, and a pituitary mass is present.

NOTES: ACTH, corticotrophin; FSH, follicle-stimulating hormone; IGF-1, insulin-like growth Factor-1; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; T₄, thyroxine.

    Indeed, the evaluation of a patient with suspected acromegaly should also include a gadolinium-enhanced pituitary MRI to establish the presence and dimensions of a pituitary tumor, as well as its proximity to the optic chiasm. In addition, given the significant number of patients who present with macroadenomas, these patients should undergo evaluation of other pituitary hormones to rule out hypopituitarism. This should include measurement of morning serum cortisol, TSH and free T₄, testosterone levels in men, and a menstrual history in premenopausal women. Because many adenomas co-secrete growth hormone and prolactin, the latter should also be measured.

Management

    The goals of treatment for acromegaly are to control GH and IGF-1 levels (GH <1 µg/L after oral glucose tolerance, and IGF-1 levels in the normal range for age and gender) as well as to reduce tumor size and mass effects and improve comorbid conditions, including restoration or preservation of pituitary function. Patients with acromegaly have increased risk of premature mortality, and epidemiologic studies suggest that normalizing GH and IGF-1 levels helps to reduce complications and normalize mortality rates. During treatment for acromegaly it is important to continue monitoring for associated morbidities including pituitary insufficiency, cardiovascular dysfunction, sleep apnea, hyperglycemia, musculoskeletal diseases, and colonic polyps.

    Transsphenoidal surgery is the treatment of choice for acromegaly in most patients. This is the only treatment with potential for definitive cure. Surgery reduces tumor size and relieves complications from mass effect. Surgical outcomes depend on several factors. Certain tumor characteristics such as size, presence of extrasellar growth, and dural invasion are associated with lower rates of cure. Individual surgical expertise is another major determinant of outcome. Postoperatively, IGF-1 and nadir glucose-suppressed GH levels should be measured to determine the success of the procedure. In one series, after 12 months of postoperative follow-up, about 70% of patients had normal IGF-1 levels, and about 60% had nadir glucose-suppressed GH levels <1 µg/L.

    When surgery fails to normalize the biochemical parameters, or when patients refuse or have a contraindication to surgery, medical therapy should be initiated. The first line of treatment in such cases is a somatostatin analogue (octreotide or lanreotide). These drugs suppress pituitary GH secretion and block the synthesis of IGF-1 in the liver. They are administered subcutaneously or intramuscularly, have long-acting forms that can be injected monthly, and are generally well tolerated, although gastrointestinal side effects such as nausea, vomiting, and diarrhea are common, and risk of gallstone formation and hyperglycemia is increased. When used as adjunctive therapy postoperatively, somatostatin analogues normalize IGF-1 levels in about 60% of patients and result in symptomatic improvement and decreased soft-tissue swelling in about 80%, but tumor size is reduced in only about 30% of cases. GH and IGF-1 assessment should be performed a few months after initiation of treatment to establish dose adequacy.

    When surgery and somatostatin analogues both fail to normalize biochemical parameters, another available drug is pegvisomant, a GH receptor antagonist. Importantly, because the drug acts peripherally but does not affect the pituitary secretion of GH, it does not lower GH or reduce tumor size; therefore, patients on pegvisomant should be monitored biochemically with IGF-1 levels and radiographically for tumor growth. Pegvisomant is administered subcutaneously on a daily basis and normalizes IGF-1 levels in over 85% of cases.

    Somatotroph adenomas express dopamine receptors, and dopamine agonists have been used in the management of acromegaly, but they are not as effective as other agents. Radiation therapy is generally reserved as a last resort for patients who have undergone surgery and subsequently were resistant to or intolerant of medical treatment. Radiotherapy slows tumor growth and can effectively normalize biochemical parameters, but its effects are delayed, and hypopituitarism is a common adverse effect.

Cushing Disease

Pituitary adenomas of corticotroph origin secrete ACTH, which in turn causes excess adrenal production of cortisol and results in Cushing disease. Note that Cushing disease refers specifically to an ACTH-producing pituitary adenoma, whereas Cushing syndrome refers to the clinical manifestations of cortisol excess of any etiology. Clinical features of Cushing syndrome include fatigue, weight gain, hirsutism, proximal muscle weakness, hypertension, hyperglycemia, and hypokalemia, as well as loss of bone mineral density. Patients with Cushing syndrome have a characteristic physical appearance with facial plethora, moon-shaped facies, and supraclavicular and dorsocervical fat pads, and they may have wide purple striae or ecchymoses. The etiologies of endogenous Cushing syndrome include adrenal cortisol-secreting tumors and ectopic ACTH production, for example from small cell lung cancer, in addition to ACTH-producing pituitary adenomas, which are the most common cause.

    Screening for Cushing syndrome can be done by 24-hour urinary free cortisol measurement, dexamethasone suppression testing (1 mg given overnight or 2 mg given over 48 hours, followed by morning serum cortisol measurement), or late-night salivary cortisol (two independent measurements). If the result of one of these tests is abnormal, it should be confirmed by performing another test. If values are elevated on both tests, further evaluation is required to determine the etiology of the disease. ACTH levels can be used to establish if the cause of excess cortisol is ACTH-dependent, in which ACTH levels are elevated or inappropriately normal as is seen in pituitary or ectopic ACTH production, versus ACTH-independent in which ACTH levels are low as seen in adrenal cortical tumors. If ACTH levels are elevated or normal, follow-up testing with high-dose (8 mg) dexamethasone suppression can be used to distinguish between a pituitary source, in which case cortisol should suppress, or an ectopic source, which will not respond to dexamethasone. If the results suggest a pituitary source, the pituitary gland should be imaged. Most clinicians favor proceeding at this point with catheterization and sampling of the inferior petrosal sinus veins to establish a central-to-peripheral gradient, as well as trying to lateralize the source of ACTH hypersecretion.

    If sampling results are consistent with Cushing disease, transsphenoidal surgery is the treatment of choice. To improve the medical status of critically ill patients, often in preparation for surgery—or if the ACTH source is undetermined or the culprit tumor cannot be resected—medical therapies may help to control hypercortisolism in Cushing syndrome. Medications that inhibit adrenal steroidogenesis (and the diagnosis and management of Cushing syndrome) are reviewed in chapter 49 on adrenal gland disorders. A selective glucocorticoid receptor antagonist, mifepristone, was approved in 2012 for the treatment of hyperglycemia in Cushing syndrome in those who have failed surgery or are not surgical candidates. Medications that suppress ACTH secretion, including dopamine agonists (cabergoline) and somatostatin receptor agonists (octreotide or pasireotide) are used, but are variably effective clinically—theoretically because some but not all ACTH-secreting adenomas and ectopic tumors have dopamine and/or somatostatin receptors.

TSH AND GONADOTROPIN PRODUCING PITUITARY ADENOMAS

Pituitary tumors that secrete biologically active LH or FSH are rare. Tumors of gonadotropic origin may also secrete gonadotropin subunits or proteins without functional activity. In fact, many adenomas considered nonfunctional are actually gonadotropic in origin. The diagnosis of gonadotroph adenoma can be difficult to make, because tumors that secrete gonadotropins or gonadotropin subunits usually do not result in a specific clinical syndrome. When they become sufficiently large, like all other pituitary tumors, gonadotroph adenomas can cause mass effects. Patients suspected of having gonadotropin-secreting adenomas should undergo pituitary MRI as well as testing of pituitary function. Transsphenoidal surgery is the treatment of choice.

    Adenomas that secrete TSH are exceedingly rare. Clinically, these tumors present with hyperthyroidism. They are usually large at the time of diagnosis, and as a result are usually also associated with mass effects. This diagnosis should be suspected in patients with elevated serum T₄ and T₃ levels but with an inappropriately normal or elevated TSH concentration (rather than suppressed TSH values, as would be expected in primary hyperthyroidism). The primary treatment for TSH-producing adenomas is transsphenoidal excision. In cases of residual tumor or contraindications to surgery, somatostatin analogues are an alternative therapeutic option.

GENETIC SYNDROMES ASSOCIATED WITH PITUITARY TUMORS

Some genetic syndromes are associated with the formation of pituitary tumors or hypopituitarism. The familial isolated pituitary adenomas (FIPA) syndrome is an autosomal dominant disorder characterized clinically by presentation at an early age, most commonly with GH or PRL-producing tumors, which are often large and invasive. A subset of FIPA families have germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene; in others the genetic basis remains unknown. Mutations in the transcription factors PROP-1 and PIT-1 cause combined pituitary hormone deficiencies. In contrast to these syndromes associated with pituitary defects exclusively, multiple endocrine neoplasia type 1 (MEN 1) is characterized by tumors in multiple endocrine glands, including pituitary adenomas but also parathyroid adenomas, pancreatic and gastrointestinal neuroendocrine tumors, and, less frequently, other endocrine tumors. MEN 1 is an autosomal dominant disorder that results from a mutation in the gene that encodes menin, a tumor suppressor protein. Anterior pituitary tumors develop in approximately 65% of patients with MEN 1.

    The MEN 2 syndromes (MEN 2A, MEN 2B, and familial medullary thyroid cancer) are autosomal dominant and caused by germline mutations in the RET proto-oncogene. In contrast to the MEN 1 syndrome, the MEN 2 syndromes do not involve the pituitary gland. The MEN 2 syndromes are all characterized by medullary thyroid cancer (MTC), which is fully penetrant in all affected individuals. MEN 2B is also associated with pheochromocytoma, mucosal and intestinal neuromas, and marfanoid habitus; MEN 2A is associated with MTC, pheochromocytoma, and parathyroid tumors.

Hypopituitarism

Hypopituitarism is characterized by decreased secretion of one or more anterior pituitary hormones, which include GH, ACTH, TSH, FSH, LH, and prolactin. Deficiencies may be partial or complete. Panhypopituitarism refers to a deficiency of all pituitary hormones.

Differential Diagnosis

    A pituitary hormone deficiency may result from intrinsic pituitary disease or from a derangement in the pituitary stalk or hypothalamus that results in a deficiency in the hypothalamic hormones that stimulate pituitary function. The causes of acquired hypopituitarism are myriad (box 46.4), and the most common are described below.

    Mass lesions in or near the hypothalamus or pituitary gland can cause partial or complete hypopituitarism. By far the most common such lesions are pituitary adenomas, which may be functioning or nonfunctioning. As has been previously reviewed, a mass lesion causes hormone insufficiencies either by mechanical compression or by impairment of blood flow to adjacent pituitary tissue or by interference with the delivery of hypothalamic regulating factors through the hypothalamic-hypophyseal portal system (Figure 46.4). Excision or shrinkage of the tumor may result in restoration of pituitary function, although if pituitary tissue has been destroyed this is unlikely, and lifelong hormone-replacement therapy will be required.

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