Symptoms of pituitary hormone excess or deficiency, headache, or visual disturbance lead the clinician to consider a hypothalamic-pituitary disorder. In this setting, accurate neuroradiologic assessment of the hypothalamus and pituitary is essential in confirming the existence and defining the extent of hypothalamic-pituitary lesions. However, the diagnosis of such lesions should be based on both endocrine and radiologic criteria, because variability of pituitary anatomy in the normal population may lead to false-positive interpretations. Furthermore, patients with pituitary microadenomas may have normal neuroradiologic studies. Imaging studies must be interpreted in light of the fact that 10% to 20% of the general population harbor nonfunctional and asymptomatic pituitary microadenomas.
Magnetic Resonance Imaging
MRI is the current procedure of choice for imaging the hypothalamus and pituitary. It has superseded the use of computed tomography (CT) because it allows better definition of normal structures and has better resolution in defining tumors. Arteriography is rarely utilized at present except in patients with intrasellar or parasellar aneurysms.
Imaging is performed in sagittal and coronal planes at 1.5 to 2 mm intervals. This allows clear definition of hypothalamic and pituitary anatomy and can accurately visualize lesions as small as 3 to 5 mm. The use of the heavy-metal contrast agent gadolinium allows even more precise differentiation of small pituitary adenomas from normal anterior pituitary tissue and other adjacent structures as shown in Figure 4–15.
Upper panel: A: The coronal magnetic resonance (MR) image shows a large nonfunctioning pituitary adenoma (arrows) with pronounced suprasellar extension and chiasmal compression. B: A sagittal MR image of another large pituitary adenoma shows spontaneous hemorrhage within the suprasellar portion of the adenoma (arrows).
(Photographs courtesy of David Norman, MD. Reproduced, with permission, from West J Med. 1995;162:342, 350.)
Lower panel: Gadolinium-enhanced MR images are shown of the pituitary gland. A and B: Coronal and sagittal images show the normal, uniformly enhancing pituitary stalk and pituitary gland. C: A pituitary microadenoma appears as a low-intensity lesion in the inferior aspect of the right lobe of the gland (arrow). D: The pituitary microadenoma appears as a low-intensity lesion between the left lobe of the pituitary and the left cavernous sinus (arrow).
(Photographs courtesy of David Norman, MD.)
The normal anterior pituitary is 5 to 7 mm in height and approximately 10 mm in its lateral dimensions. The superior margin is flat or concave but may be upwardly convex with a height of 10 to 12 mm in healthy menstruating young women. The floor of the sella turcica is formed by the bony roof of the sphenoid sinus, and its lateral margins are formed by the dural membranes of the cavernous sinuses, which contain the carotid arteries and the third, fourth, and sixth cranial nerves. The posterior pituitary appears on MRI as a high-signal-intensity structure, the “posterior pituitary bright spot,” which is absent in patients with diabetes insipidus. The pituitary stalk, which is normally in the midline, is 2 to 3 mm in diameter and 5 to 7 mm in length. The pituitary stalk joins the inferior hypothalamus below the third ventricle and posterior to the optic chiasm. All of these normal structures are readily visualized with MRI; the normal pituitary and the pituitary stalk show increased signal intensity with gadolinium.
These lesions, which range from 2 to 10 mm in diameter, appear as low-signal-intensity lesions on MRI and do not usually enhance with gadolinium. Adenomas less than 5 mm in diameter may not be visualized and do not usually alter the normal pituitary contour. Lesions greater than 5 mm in diameter create a unilateral convex superior gland margin and usually cause deviation of the pituitary stalk toward the side opposite the adenoma.
MRI scans must be interpreted with caution, because minor abnormalities occur in 10% of patients who have had incidental high-resolution scans but no clinical pituitary disease. These abnormalities may represent the clinically insignificant pituitary abnormalities that occur in 10% to 20% of the general population, and they may also be due to small intrapituitary cysts, which usually occur in the pars intermedia. Artifacts within the sella turcica associated with the bones of the skull base may also result in misinterpretation of imaging studies. Finally, many patients with pituitary microadenomas have normal high-resolution MRI scans. Therefore, despite increased accuracy of neuroradiologic diagnosis, the presence or absence of a small pituitary tumor and the decision concerning its treatment must be based on the entire clinical picture.
Pituitary adenomas greater than 10 mm in diameter are readily visualized with MRI scans, and the scan also defines the adjacent structures and degree of extension of the lesion. Thus, larger tumors show compression of the normal pituitary and distortion of the pituitary stalk. Adenomas larger than 1.5 cm frequently have suprasellar extension, and MRI scans show compression and upward displacement of the optic chiasm. Less commonly, there is lateral extension and invasion of the cavernous sinus.
High-resolution MRI scanning is also a valuable tool in the diagnosis of empty sella syndrome, hypothalamic tumors, and other parasellar lesions.
Pituitary and Hypothalamic Disorders
Hypothalamic-pituitary lesions present with a variety of manifestations, including pituitary hormone hypersecretion and hyposecretion, sellar enlargement, and visual loss. The approach to evaluation should be designed to ensure early diagnosis at a stage when the lesions are amenable to therapy.
Etiology and Early Manifestations
In adults, the most common cause of hypothalamic-pituitary dysfunction is a pituitary adenoma, of which the great majority are hypersecreting. Thus, the earliest symptoms of such tumors are due to endocrinologic abnormalities—hypogonadism is the most frequent manifestation—and these precede sellar enlargement and local manifestations such as headache and visual loss, which are late manifestations seen only in patients with larger tumors or suprasellar extension.
In children, pituitary adenomas are uncommon; the most frequent structural lesions causing hypothalamic-pituitary dysfunction are craniopharyngiomas and other hypothalamic tumors. These also usually manifest as endocrine disturbances (low GH levels, delayed puberty, diabetes insipidus) prior to the development of headache, visual loss, or other central nervous system symptoms.
Common and Later Manifestations
PRL is the hormone most commonly secreted in excess amounts by pituitary adenomas, and it is usually elevated in patients with hypothalamic disorders and pituitary stalk compression as well. Thus, PRL measurement is essential in evaluating patients with suspected pituitary disorders and should be performed in patients presenting with galactorrhea, gonadal dysfunction, secondary gonadotropin deficiency, or enlargement of the sella turcica. Hypersecretion of GH or ACTH leads to the more characteristic syndromes of acromegaly and Cushing disease (see discussion later).
Although panhypopituitarism is a classic manifestation of pituitary adenomas, it is present in less than 20% of patients in current large series because of earlier diagnosis of these lesions.
The earliest clinical manifestation of a pituitary adenoma in adults is hypogonadism secondary to elevated levels of PRL, GH, or ACTH and cortisol. The hypogonadism in these patients is due to interference with the secretion of GnRH rather than to destruction of anterior pituitary tissue. Thus, patients with hypogonadism should first be screened with FSH and LH measurements to exclude primary gonadal failure (elevated FSH or LH) and those with hypogonadotropic hypogonadism should have serum PRL levels measured and be examined for clinical evidence of GH or ACTH and cortisol excess.
In children, short stature is the most frequent clinical presentation of hypothalamic-pituitary dysfunction; in these patients, GH deficiency should be considered (see Chapter 6).
TSH or ACTH deficiency is relatively unusual and, if present, usually indicates panhypopituitarism. Thus, patients with secondary hypothyroidism or hypoadrenalism should undergo a complete assessment of pituitary function and neuroradiologic studies, because panhypopituitarism and large pituitary tumors are common in this setting. PRL measurement is again essential, because prolactinomas are the most frequent pituitary tumors in adults.
Patients may present with enlargement of the sella turcica, which may be noted on radiographs performed for head trauma or on sinus series. These patients usually have either a pituitary adenoma or empty sella syndrome. Other less common causes include craniopharyngioma, lymphocytic hypophysitis, and carotid artery aneurysm. Evaluation should include clinical assessment of pituitary dysfunction and measurements of PRL and thyroid and adrenal function. Pituitary function is usually normal in the empty sella syndrome; this diagnosis can be confirmed by MRI. Patients with clinical or laboratory evidence of pituitary dysfunction usually have a pituitary adenoma.
Patients presenting with bitemporal hemianopsia or unexplained visual field defects or visual loss should be considered to have a pituitary or hypothalamic disorder until proven otherwise. The initial steps in diagnosis should be neuro-ophthalmologic evaluation and neuroradiologic studies with MRI, which will reveal the tumor if one is present. These patients should also have PRL measurements and be assessed for anterior pituitary insufficiency, which is especially common with large pituitary adenomas.
In addition to causing visual field defects, large pituitary lesions may extend laterally into the cavernous sinus, compromising the function of the third, fourth, or sixth cranial nerve, leading to diplopia.
Diabetes insipidus is a common manifestation of hypothalamic lesions and metastases to the pituitary, but is rare in primary pituitary lesions. Diagnostic evaluation is described in Chapter 5. In addition, all patients should undergo radiologic evaluation and assessment of anterior pituitary function.
Empty sella syndrome occurs when the subarachnoid space extends into the sella turcica, partially filling it with cerebrospinal fluid. This process causes remodeling and enlargement of the sella turcica and flattening of the pituitary gland.
Primary empty sella syndrome resulting from congenital incompetence of the diaphragma sellae (Figure 4–16) is common, with an incidence in autopsy series ranging from 5% to 23%. It is the most frequent cause of enlarged sella turcica. An empty sella is also commonly seen after pituitary surgery or radiation therapy and may also occur following postpartum pituitary infarction (Sheehan syndrome). In addition, both PRL-secreting and GH-secreting pituitary adenomas may undergo subclinical hemorrhagic infarction and cause contraction of the overlying suprasellar cistern downward into the sella. Therefore, the presence of an empty sella does not exclude the possibility of a coexisting pituitary tumor.
Representation of the normal relationship of the meninges to the pituitary gland (left) and the findings in the empty sella (right) as the arachnoid membrane herniates through the incompetent diaphragma sellae.
(Reproduced, with permission, from Jordan RM, Kendall JW, Kerber CW. The primary empty sella syndrome: analysis of the clinical characteristics, radiographic features, pituitary function, and cerebrospinal fluid adenohypophysial hormone concentrations. Am J Med. 1977;62:569).
Most patients are middle-aged obese women. Many have systemic hypertension; benign intracranial hypertension may also occur. Although 48% of patients complain of headache, this feature may have only initiated the evaluation (ie, skull x-rays), and its relationship to the empty sella is probably coincidental. Serious clinical manifestations are uncommon. Spontaneous cerebrospinal fluid rhinorrhea and visual field impairment may occur rarely.
Tests of anterior pituitary function are almost always normal, although some patients have hyperprolactinemia. Endocrine function studies should be performed to exclude pituitary hormone insufficiency or a hypersecretory pituitary microadenoma.
The diagnosis of empty sella syndrome can be readily confirmed by MRI, which demonstrates the herniation of the diaphragma sellae and the presence of cerebrospinal fluid in the sella turcica.
Hypothalamic dysfunction is most often caused by tumors, of which craniopharyngioma is the most common in children, adolescents, and young adults. In older adults, primary central nervous system tumors and those arising from hypothalamic (epidermoid and dermoid tumors) and pineal structures (pinealomas) are more common. Other causes of hypothalamic-pituitary dysfunction are discussed below in the section on hypopituitarism.
Craniopharyngiomas are thought to originate from metaplasia of remnant epithelial cell rests in Rathke pouch and the craniopharyngeal duct during development. The differential diagnosis includes Rathke cleft cysts and arachnoid cysts. Rathke cleft cysts are a common incidental finding within the pituitary, but may present with symptoms similar to craniopharyngiomas. Although Rathke cleft cysts and craniopharyngiomas are both thought to arise from Rathke pouch during development, craniopharyngiomas tend to be more aggressive and are more likely to recur after resection.
The initial symptoms of craniopharyngioma in children and adolescents are predominantly endocrinologic; however, these manifestations are frequently unrecognized, and at diagnosis more than 80% of patients have hypothalamic-pituitary endocrine deficiencies. These endocrine abnormalities may precede presenting symptoms by months or years; GH deficiency is most common, with about 50% of patients having growth retardation and approximately 70% decreased GH responses to stimulation at diagnosis. Gonadotropin deficiency leading to absent or arrested puberty is usual in older children and adolescents; TSH and ACTH deficiencies are less common, and diabetes insipidus is present in about 15%.
Symptoms leading to the diagnosis are frequently neurologic and due to the mass effect of the expanding tumor. Symptoms of increased intracranial pressure such as headache and vomiting are present in about 40% of patients; decreased visual acuity or visual field defects are the presenting symptoms in another 35%. MRI confirms the tumor in virtually all patients; in 95%, the tumor is suprasellar.
In adults, craniopharyngiomas have similar presentations; that is, the diagnosis is usually reached as a result of investigation of complaints of headache or visual loss. However, endocrine manifestations—especially hypogonadism, diabetes insipidus, or other deficiencies of anterior pituitary hormones—usually precede these late manifestations. MRI readily demonstrates the tumors, which in adults are almost always both intrasellar and suprasellar. The appearance is typically of a heterogeneous, cystic mass that enhances with contrast. Calcifications may also be present.
Other hypothalamic or pineal tumors and primary central nervous system tumors involving the hypothalamus have variable presentations in both children and adults. Thus, presentation is with headache, visual loss, symptoms of increased intracranial pressure, growth failure, various degrees of hypopituitarism, or diabetes insipidus. Endocrine deficiencies usually precede neurologic manifestations. Hypothalamic tumors in childhood may present with precocious puberty.
Other Manifestations of Hypothalamic Dysfunction
Lesions in the hypothalamus can cause many other abnormalities, including disorders of consciousness, behavior, thirst, appetite, and temperature regulation. These abnormalities are usually accompanied by hypopituitarism and diabetes insipidus.
Somnolence can occur with hypothalamic lesions, as can a variety of changes in emotional behavior. Decreased or absent thirst may occur and predispose these patients to dehydration. When diminished thirst accompanies diabetes insipidus, fluid balance is difficult to control. Hypothalamic dysfunction may also cause increased thirst, leading to polydipsia and polyuria that may mimic diabetes insipidus. Obesity is common in patients with hypothalamic tumors because of hyperphagia, decreased satiety, and decreased activity. Frohlich syndrome, or adiposogenital dystrophy, is characterized by obesity, growth retardation, and delayed development of sexual organs. Anorexia and weight loss are unusual manifestations of these tumors.
Temperature regulation can also be disordered in these patients. Sustained or, less commonly, paroxysmal hyperthermia can occur following acute injury due to trauma, hemorrhage, or craniotomy. This problem usually lasts less than 2 weeks. Poikilothermia, the inability to adjust to changes in ambient temperature, can occur in patients with bilateral hypothalamic lesions. These patients most frequently exhibit hypothermia but can also develop hyperthermia during hot weather. A few patients manifest sustained hypothermia due to anterior hypothalamic lesions.
Patients with suspected hypothalamic tumors should undergo MRI to determine the extent and nature of the tumor. Complete assessment of anterior pituitary function is necessary in these patients, because deficiencies are present in the great majority (see section on Hypopituitarism below), and the evaluation will establish the requirements for replacement therapy. PRL levels should also be determined, because most hypothalamic lesions cause hyperprolactinemia either by hypothalamic injury or by damage to the pituitary stalk.
Treatment depends on the type of tumor. Because complete resection of craniopharyngioma is usually not feasible, this tumor is best managed by limited neurosurgical removal of accessible tumor and decompression of cysts, followed by radiotherapy. Patients treated by this method have a recurrence rate of approximately 20%; with surgery alone, the recurrence rate approximates 80%.
Other hypothalamic tumors are usually not completely resectable; however, biopsy is indicated to arrive at a histologic diagnosis.
Hypopituitarism is manifested by diminished or absent secretion of one or more pituitary hormones. The development of signs and symptoms is often slow and insidious, depending on the rate of onset and the magnitude of hypothalamic-pituitary damage—factors that are influenced by the underlying pathogenesis. Hypopituitarism is either a primary event caused by destruction of the anterior pituitary gland or a secondary phenomenon resulting from deficiency of hypothalamic stimulatory factors normally acting on the pituitary. In general, acquired loss of anterior pituitary function follows the sequence of GH, LH/FSH, TSH, ACTH, and PRL. Treatment and prognosis depend on the extent of hypofunction, the underlying cause, and the location of the lesion in the hypothalamic-pituitary axis.
The etiologic considerations in hypopituitarism are diverse. As shown below, a helpful mnemonic device is the phrase “nine Is”: invasive, infarction, infiltrative, injury, immunologic, iatrogenic, infectious, idiopathic, and isolated. Most of these lesions may cause pituitary or hypothalamic failure (or both). Establishing the precise cause of hypopituitarism is helpful in determining treatment and prognosis.
Space-occupying lesions cause hypopituitarism by destroying the pituitary gland or hypothalamic nuclei or by disrupting the hypothalamic-hypophysial portal venous system. Large pituitary adenomas cause hypopituitarism by these mechanisms, and pituitary function may improve after their removal. Small pituitary tumors—microadenomas (<10 mm in diameter)—characteristically seen in the hypersecretory states (excess PRL, GH, ACTH) do not directly cause pituitary insufficiency. Craniopharyngioma, the most common tumor of the hypothalamic-pituitary region in children, frequently impairs pituitary function by its compressive effects. Primary central nervous system tumors, including meningioma, chordoma, optic glioma, epidermoid tumors, and dermoid tumors, may decrease hypothalamic-pituitary secretion by their mass effects. Metastatic lesions to this area are common (especially breast carcinoma) but rarely result in clinically obvious hypopituitarism. Anatomic malformations such as basal encephalocele and parasellar aneurysms cause hypothalamic-pituitary dysfunction and may enlarge the sella turcica and mimic pituitary tumors.
Ischemic damage to the pituitary has long been recognized as a cause of hypopituitarism. In 1914, Simmonds reported pituitary necrosis in a woman with severe puerperal sepsis and in 1937 Sheehan published his classic description of its occurrence following postpartum hemorrhage and vascular collapse. The mechanism for the ischemia in such cases is not certain. Hypotension along with vasospasm of the hypophysial arteries is currently believed to compromise arterial perfusion of the anterior pituitary. During pregnancy, the pituitary gland may be more sensitive to hypoxemia because of its increased metabolic needs or more susceptible to the prothrombotic effects of the hyperestrogenic state. Some investigators have noted that the hypopituitarism does not always correlate with the degree of hemorrhage but that there is good correlation between the pituitary lesion and severe disturbances of the clotting mechanism (as in patients with placenta previa). Ischemic pituitary necrosis has also been reported to occur with greater frequency in patients with diabetes mellitus.
The extent of pituitary damage determines the rapidity of onset as well as the magnitude of pituitary hypofunction. The gland has a great secretory reserve, and more than 75% must be destroyed before clinical manifestations are evident. The initial clinical feature in postpartum necrosis may be failure to lactate after parturition; failure to resume normal menstrual periods is another clue to the diagnosis. However, the clinical features of hypopituitarism are often subtle, and years may pass before pituitary insufficiency is recognized following an ischemic insult.
Spontaneous hemorrhagic infarction of a pituitary tumor (pituitary apoplexy) frequently results in partial or total pituitary insufficiency. Pituitary apoplexy is often a fulminant clinical syndrome manifested by severe headache, visual impairment, ophthalmoplegias, meningismus, and an altered level of consciousness. Pituitary apoplexy is usually associated with a pituitary tumor; it may also be related to diabetes mellitus, radiotherapy, or open heart surgery. Acute pituitary failure with hypotension may result, and rapid mental deterioration, coma, and death may ensue. Emergency treatment with corticosteroids (see Chapter 24) and transsphenoidal decompression of the intrasellar contents may be lifesaving and may prevent permanent visual loss. Most patients who have survived pituitary apoplexy have developed multiple adenohypophysial deficits, but infarction of the tumor in some patients may cure the hypersecretory pituitary adenoma and its accompanying endocrinopathy. Pituitary infarction may also be a subclinical event (silent pituitary apoplexy), resulting in improvement of pituitary hormone hypersecretion without impairing the secretion of other anterior pituitary hormones.
Hypopituitarism may be the initial clinical manifestation of infiltrative disease processes such as sarcoidosis, hemochromatosis, and Langerhan histiocytosis.
Sarcoidosis—The most common intracranial sites of involvement of sarcoidosis are the hypothalamus and pituitary gland. At one time, the most common endocrine abnormality in patients with sarcoidosis was thought to be diabetes insipidus; however, many of these patients actually have centrally mediated disordered control of thirst that results in polydipsia and polyuria, which in some cases explains the abnormal water metabolism. Deficiencies of multiple anterior pituitary hormones have been well documented in sarcoidosis and are usually secondary to hypothalamic insufficiency. Granulomatous involvement of the hypothalamic-pituitary unit is occasionally extensive, resulting in visual impairment, and therefore, may simulate the clinical presentation of a pituitary or hypothalamic tumor.
Hemochromatosis— Hypopituitarism, particularly hypogonadotropic hypogonadism, is a prominent manifestation of iron storage disease—either primary (hereditary) hemochromatosis or transfusional iron overload. Hypogonadism occurs in most such cases and is often the initial clinical feature of iron excess; complete iron studies should be considered in any patient presenting with unexplained hypogonadotropic hypogonadism. If the diagnosis is established early, hypogonadism in hemochromatosis may be reversible with iron depletion. Pituitary deficiencies of TSH, GH, and ACTH may occur later in the course of the disease and are not reversible by iron chelation therapy.
Langerhan histiocytosis— In this disorder, the infiltration of multiple organs by well-differentiated histiocytes, is often heralded by the onset of diabetes insipidus and anterior pituitary hormone deficiencies. Most histologic and biochemical studies have indicated that this infiltrative process involves chiefly the hypothalamus, and hypopituitarism occurs only as a result of hypothalamic damage.
Severe head trauma may cause anterior pituitary insufficiency and diabetes insipidus. Posttraumatic anterior hypopituitarism may be due to injury to the anterior pituitary, the pituitary stalk, or the hypothalamus. Pituitary insufficiency with growth retardation has been described in battered children who suffer closed head trauma with subdural hematoma.
Lymphocytic hypophysitis resulting in anterior hypopituitarism is a distinct entity, occurring most often in women during pregnancy or in the postpartum period. It may present as a mass lesion of the sella turcica with visual field disturbances simulating pituitary adenoma. An autoimmune process with extensive infiltration of the gland by lymphocytes and plasma cells destroys the anterior pituitary cells. These morphologic features are similar to those of other autoimmune endocrinopathies (eg, thyroiditis, adrenalitis, and oophoritis). About 50% of patients with lymphocytic hypophysitis have other endocrine autoimmune disease, and circulating pituitary autoantibodies have been found in several cases. It is presently uncertain how this disorder should be diagnosed and treated. It must be considered in the differential diagnosis of women with pituitary gland enlargement and hypopituitarism during pregnancy or the postpartum period.
Lymphocytic hypophysitis may result in isolated hormone deficiencies (especially ACTH or prolactin). Consequently, women with this type of hypopituitarism may continue to menstruate while suffering from secondary hypothyroidism or hypoadrenalism.
Both surgical and radiation therapy to the pituitary gland may compromise its function. The anterior pituitary is quite resilient during transsphenoidal microsurgery, and despite extensive manipulation during the search for microadenomas, anterior pituitary function is usually preserved. The dose of conventional radiation therapy presently employed to treat pituitary tumors is 4500 to 5000 cGy and results in a 50% to 60% incidence of hypothalamic and pituitary insufficiency. Such patients most frequently have modest hyperprolactinemia (PRL 30-100 ng/mL [1.3-4.5 nmol/L]) with GH and gonadotropin failure; TSH and ACTH deficiencies are less common. Heavy particle (proton beam) irradiation and gamma knife radiosurgery for pituitary tumors results in a 15% to 55% incidence of hypopituitarism. Irradiation of tumors of the head and neck (nasopharyngeal cancer, brain tumors) and prophylactic cranial irradiation in leukemia may also cause hypopituitarism. The clinical onset of pituitary failure in such patients is usually insidious and results from both pituitary and hypothalamic injury.
Although many infectious diseases, including tuberculosis, syphilis, and mycotic infections, have been implicated as causative agents in pituitary hypofunction, antimicrobial drugs have now made them rare causes of hypopituitarism.
In some patients with hypopituitarism, no underlying cause is found. These may be isolated (see discussion later) or multiple deficiencies. Familial forms of hypopituitarism characterized by a small, normal, or enlarged sella turcica have been described. Both autosomal recessive and X-linked recessive inheritance patterns have been reported. A variety of complex congenital disorders may include deficiency of one or more pituitary hormones (eg, Prader-Willi syndrome, septo-optic dysplasia). Although progress has been made into understanding the genetic basis for some of these disorders, the pathogenesis remains uncertain.
Isolated (monotropic) deficiencies of the anterior pituitary hormones have been described. Some of these have been associated with mutations in the genes coding for the specific hormones. Others, particularly GH deficiency, have been associated with mutations in genes necessary for normal pituitary development as noted.
GH deficiency—In children, congenital monotropic GH deficiency may be sporadic or familial. These children, who may experience fasting hypoglycemia, have a gradual deceleration in growth velocity after 6 to 12 months of age. Diagnosis must be based on failure of GH responsiveness to provocative stimuli and the demonstration of normal responsiveness of other anterior pituitary hormones. Monotropic GH deficiency and growth retardation have also been observed in children suffering severe emotional deprivation. This disorder is reversed by placing the child in a supportive psychosocial milieu. A more detailed description of GH deficiency and growth failure is provided in Chapter 6.
ACTH deficiency—Monotropic ACTH deficiency is rare and is manifested by the signs and symptoms of adrenocortical insufficiency. LPH deficiency has also been noted in such patients. The defect in these patients may be due to primary failure of the corticotrophs to release ACTH and its related peptide hormones or may be secondary to impaired secretion of CRH by the hypothalamus. Most acquired cases of monotropic ACTH deficiency are presumed to be due to lymphocytic hypophysitis.
Gonadotropin deficiency—Isolated deficiency of gonadotropins is not uncommon. Kallmann syndrome initially described in the 1940s, is characterized by an isolated defect in GnRH secretion associated with maldevelopment of the olfactory center with hyposmia or anosmia; X-linked recessive, autosomal dominant, and autosomal recessive patterns of inheritance are seen. Sporadic cases occur, and other neurologic defects such as color blindness and nerve deafness have been reported. At least five Kallmann syndrome genes have been identified: KAL1, FGFR1, FGF8, PROKR2, and PROK2. KAL1 mutations are responsible for the X-linked form of the disease and result in decreased expression of the extracellular glycoprotein anosmin-1. This in turn interferes with the normal embryonic development and migration of GnRH-secreting neurons. Because anterior pituitary function is otherwise intact, young men with isolated hypogonadotropic hypogonadism develop a eunuchoid appearance, since testosterone deficiency results in failure of epiphysial closure (see Chapter 12). In women, a state of hypogonadotropic hypogonadism manifested by oligomenorrhea or amenorrhea often accompanies weight loss, emotional or physical stress, and athletic training. Anorexia nervosa and marked obesity both result in hypothalamic dysfunction and impaired gonadotropin secretion. Hypothalamic hypogonadism has also been observed in overtrained male athletes. Sickle cell anemia also causes hypogonadotropic hypogonadism due to hypothalamic dysfunction and results in delayed puberty. Clomiphene treatment has been effective in some cases. Isolated gonadotropin deficiency may also be seen in the polyglandular autoimmune syndrome; this deficiency is related to selective pituitary gonadotrope failure from autoimmune hypophysitis. Other chronic illnesses (eg, poorly controlled diabetes, malnutrition) may result in gonadotropin deficiency. Isolated deficiencies of both LH and FSH without an obvious cause such as those described have been reported but are rare. In addition, acquired partial gonadotropin deficiency may occur in middle-aged men. The cause and exact frequency of this disorder are unknown.
TSH deficiency—Monotropic TSH deficiency is rare and can be caused by a reduction in either hypothalamic TRH secretion (tertiary hypothyroidism) or pituitary TSH secretion (secondary hypothyroidism). These defects have reported in association with gene mutations, empty sella, lymphocytic hypophysitis, and pituitary tumors. Some patients with chronic renal failure also appear to have impaired TSH secretion.
Prolactin deficiency—PRL deficiency almost always indicates severe intrinsic pituitary damage, and panhypopituitarism is usually present. However, isolated PRL deficiency has been reported after lymphocytic hypophysitis. Deficiencies of TSH and PRL have been noted in patients with pseudohypoparathyroidism.
Multiple hormone deficiencies isolated from other pituitary damage—Multiple hormone deficiencies result from abnormal pituitary development related to abnormalities of the genes encoding the transcription factors, PIT-1 (TSH, GH, and PRL) and PROP-1 (TSH, GH, PRL, LH, FSH, and ACTH).
The onset of pituitary insufficiency is usually gradual, and the classic course of progressive hypopituitarism is an initial loss of GH and gonadotropin secretion followed by deficiencies of TSH, then ACTH, and finally PRL.
Impairment of GH secretion causes decreased growth in children but may be clinically occult in adult patients. GH deficiency is associated with a decreased sense of well-being and a lower health-related quality of life. Decreased muscle mass and increased fat mass can also be seen, although this may be difficult to discern in any given individual.
Hypogonadism, manifested by amenorrhea in women and decreased libido or erectile dysfunction in men, may antedate the clinical appearance of a hypothalamic-pituitary lesion. The only symptom of PRL deficiency is failure of postpartum lactation.
Hypothyroidism caused by TSH deficiency generally simulates the clinical changes observed in primary thyroid failure; however, it is usually less severe, and goiter is absent. Cold intolerance, dry skin, mental dullness, bradycardia, constipation, hoarseness, and anemia have all been observed; gross myxedematous changes are uncommon.
ACTH deficiency causes adrenocortical insufficiency, and its clinical features resemble those of primary adrenal failure. Weakness, nausea, vomiting, anorexia, weight loss, fever, and hypotension may occur. The zona glomerulosa and the renin-angiotensin system are usually intact; therefore, the dehydration and sodium depletion seen in Addison disease are uncommon. However, these patients are susceptible to hypotension, shock, and cardiovascular collapse, because glucocorticoids are necessary to maintain vascular reactivity, especially during stress. In addition, because of their gradual onset, the symptoms of secondary adrenal insufficiency may go undetected for prolonged periods, becoming manifest only during periods of stress. Hypoglycemia aggravated by GH deficiency may occur with fasting and has been the initial presenting feature of some patients with isolated ACTH deficiency. In contrast to the hyperpigmentation that occurs during states of ACTH excess (Addison disease, Nelson syndrome), depigmentation and diminished tanning have been described as a result of ACTH insufficiency. In addition, lack of ACTH-stimulated adrenal androgen secretion will cause a decrease in body hair if gonadotropin deficiency is also present.
Abnormal findings on physical examination may be subtle and require careful observation. Patients with hypopituitarism are not cachectic. A photograph of a cachectic patient with “Simmonds syndrome” that appeared in some older textbooks of endocrinology caused confusion. That particular patient probably suffered from anorexia nervosa and was found to have a normal pituitary gland at postmortem examination.
Patients with pituitary failure are usually slightly overweight. The skin is fine, pale, and smooth, with fine wrinkling of the face. Body and pubic hair may be deficient or absent, and atrophy of the genitalia may occur. Postural hypotension, bradycardia, decreased muscle strength, and delayed deep tendon reflexes occur in more severe cases. Neuro-ophthalmologic abnormalities depend on the presence of a large intrasellar or parasellar lesion.
Laboratory and Other Findings
These may include anemia (related to thyroid and androgen deficiency and chronic disease), hypoglycemia, hyponatremia (related to hypothyroidism and hypoadrenalism, which cause inappropriate water retention, not sodium loss), and low-voltage bradycardia on electrocardiographic testing. Hyperkalemia, which is common in primary adrenal failure, is not present. Adult GH deficiency is associated with decreased red blood cell mass, increased LDL cholesterol, and decreased bone mass.
Assessment of Target Gland Function (Figure 4–17)
Diagnostic evaluation of hypothalamic-pituitary-target gland hypofunction.
If endocrine hypofunction is suspected, pituitary hormone deficiencies must be distinguished from primary failure of the thyroid, adrenals, or gonads. Basal determinations of each anterior pituitary hormone are useful only if compared to target gland secretion. Baseline laboratory studies should include thyroid function tests (free T4) and determination of serum testosterone levels. Testosterone is a sensitive indicator of hypopituitarism in women as well as in men. In women, a substantial decrease in testosterone is commonly observed in pituitary failure related to hypofunction of the two endocrine glands responsible for its production—the ovary and the adrenal. Adrenocortical reserve should initially be evaluated by a rapid ACTH stimulation test.
Because hyperprolactinemia (discussed later), regardless of its cause, leads to gonadal dysfunction, serum PRL should be measured early in the evaluation of hypogonadism.
Differentiation of Primary and Secondary Hypofunction
Subnormal thyroid function as shown by appropriate tests, a low serum testosterone level, or an impaired cortisol response to the rapid ACTH stimulation test requires measurement of basal levels of specific pituitary hormones. In primary target gland hypofunction, such as autoimmune polyglandular syndromes types 1 and 2 (APS 1 and 2), TSH, LH, FSH, or ACTH will be elevated. Low or normal values for these pituitary hormones suggest hypothalamic-pituitary dysfunction.
Provocative endocrine testing may then be employed to confirm the diagnosis and to assess the extent of hypofunction. At present, these tests are not required in most patients.
Treatment of secondary adrenal insufficiency, like that of primary adrenal failure, must include glucocorticoid support (see Chapter 9). Hydrocortisone (15-25 mg/d orally) or prednisone (5-7.5 mg/d orally) in two or three divided doses provides adequate glucocorticoid replacement for most patients. The minimum effective dosage should be given in order to avoid iatrogenic hypercortisolism. Increased dosage is required during periods of stress such as illness, surgery, or trauma. Patients with only partial ACTH deficiency may need steroid treatment only during stress. A two- to threefold increase in steroid dosage during the stressful situation should be recommended, followed by gradual tapering as the stress resolves. Unlike primary adrenal insufficiency, ACTH deficiency does not usually require mineralocorticoid therapy. Patients with adrenal insufficiency should wear medical alert bracelets so they may receive prompt treatment in case of emergency.
The management of patients with secondary hypothyroidism must be based on clinical grounds and the circulating concentration of serum thyroxine (see Chapter 7). The treatment of secondary and tertiary hypothyroidism is identical to that for primary thyroid failure. Full oral replacement dose of levothyroxine sodium is 1.6 μ g/kg daily (0.1-0.15 mg/d is usually adequate). Response to therapy is monitored clinically and with measurement of serum free thyroxine levels, which should be maintained in the mid to upper range of normal. Measurement of TSH levels is obviously of no value in the management of these patients.
Caution: Because thyroid hormone replacement in patients with hypopituitarism may aggravate even partial adrenal insufficiency, the adrenal hormone deficiency should be treated first.
The object of treatment of secondary hypogonadism is to replace sex steroids and restore fertility (see Chapters 12 and 13).
Estrogens and progesterone—In premenopausal women, estrogen replacement is essential. Adequate estrogen treatment maintains secondary sex characteristics (eg, vulvar and vaginal lubrication), prevents osteoporosis, and abolishes vasomotor symptoms, with an improvement in sense of well-being. Many estrogen preparations are available (eg, oral estradiol, 1-2 mg daily; conjugated estrogens, 0.3-1.25 mg orally daily; or transdermal estradiol, 0.05-0.1 mg daily). Estrogens should be cycled with a progestin compound (eg, medroxyprogesterone, 5-10 mg orally daily during the last 10 days of estrogen therapy each month) to induce withdrawal bleeding and prevent endometrial hyperplasia. Many oral contraceptive pill combinations are also clinically available.
Ovulation induction—Ovulation can often be restored in women with hypothalamic-pituitary dysfunction (see Chapter 13). In patients with gonadal failure of hypothalamic origin, clomiphene citrate may cause a surge of gonadotropin secretion resulting in ovulation. Pulsatile subcutaneous injections of GnRH with an infusion pump can also be used to induce ovulation and fertility in women with hypothalamic dysfunction. Combined treatment with FSH (human menopausal gonadotropins; menotropins) and LH (chorionic gonadotropin) can be utilized to provoke ovulation in women with intrinsic pituitary failure. This form of therapy is expensive, and multiple births are a risk (see Chapter 13).
Androgens in women—Because of a deficiency of both ovarian and adrenal androgens, some women with hypopituitarism have diminished libido despite adequate estrogen therapy. Although experience is limited, small doses of long-acting androgens (testosterone enanthate, 25-50 mg intramuscularly every 4-8 weeks) may be helpful in restoring sexual activity without causing hirsutism. In addition, some reports have suggested that oral dehydroepiandrosterone (DHEA) in doses of 25 to 50 mg/d may restore plasma testosterone levels to normal. A transdermal delivery system is being evaluated for use in women, but efficacy appears to be modest and the long-term safety is unknown.
Androgens in men—The treatment of male hypogonadism is discussed in Chapter 12. Testosterone gels (available in packets in doses of 2.5, 5, or 10 g, or from a metered-dose pump in 1.25 g increments) and testosterone patches (in doses of 2.5 or 5 mg) are applied daily. A transbuccal formulation is administered at a dose of 30 mg twice daily. Other therapeutic preparations include intramuscular testosterone enanthate or cypionate in doses of 100 mg every week or 200 mg every 2 weeks. Testosterone undecanoate is an intramuscular preparation available in several countries that can be given every 3 months. Oral testosterone preparations available in the United States are rarely used out of concern for hepatic side effects.
Spermatogenesis—Spermatogenesis can be achieved in many patients with the combined use of hCG and recombinant FSH. If pituitary insufficiency is of recent onset, therapy with hCG alone may restore both fertility and adequate gonadal steroid production. Pulsatile GnRH infusion pumps have also been used to restore fertility in male patients with secondary hypogonadism.
Growth Hormone (Also See Chapter 6)
Human GH (hGH) produced by recombinant DNA technology is available for use in children with hypopituitarism and for adults with GH deficiency and known pituitary disease. Some studies indicate improvement in body composition, bone density, psychologic well-being, and functional status with GH therapy. However, the long-term benefits and risks remain to be established. In adults, GH is usually administered subcutaneously, once per day in a dosage of 2 to 5 μ g/kg. Monitoring of effectiveness is accomplished by measurement of IGF-I, and the dosage of GH is adjusted accordingly (up to about 10 μ g/kg/d). Side effects (eg, edema, paresthesias, arrhythmias, glucose intolerance, diabetes) should be assessed. Contraindications to GH therapy include the presence of diabetic retinopathy, active malignancy, intracranial hypertension, or airway obstruction in individuals with Prader-Willi syndrome.
Advances in endocrinologic and neuroradiologic research in recent years have allowed earlier recognition and more successful therapy of pituitary adenomas. Prolactinomas are the most common type, accounting for about 60% of primary pituitary tumors; GH hypersecretion occurs in approximately 20%; and ACTH excess in 10%. Hypersecretion of TSH, the gonadotropins, or alpha subunits is unusual. Nonfunctional tumors currently represent only 10% of all pituitary adenomas, and some of these may in fact be gonadotropin-secreting or alpha subunit-secreting adenomas. The differential diagnosis of nonpituitary sellar and parasellar masses is listed in Table 4–10.
Table 4–10 Differential Diagnosis of Sellar and Parasellar Masses (Excluding Pituitary Adenomas). ||Download (.pdf)
Table 4–10 Differential Diagnosis of Sellar and Parasellar Masses (Excluding Pituitary Adenomas).
- Rathke cleft cyst
- Arachnoid cyst
- Dermoid cyst
|Nonadenomatous pituitary hyperplasia|
- Lactotroph hyperplasia during pregnancy
- Somatotroph hyperplasia from ectopic GHRH-secreting tumor
- Thyrotroph, gonadotroph hyperplasia
- Germ cell tumor (ectopic pinealoma)
|Metastatic lesions (breast, lung)|
- Optic glioma
|Granulomatous, inflammatory, infectious|
- Lymphocytic hypophysitis
- Histiocytosis X
- Pituitary abscess
Early clinical recognition of the endocrine effects of excessive pituitary secretion, especially the observation that PRL excess causes secondary hypogonadism, has led to early diagnosis of pituitary tumors before the appearance of late manifestations such as sellar enlargement, panhypopituitarism, and suprasellar extension with visual impairment.
Pituitary microadenomas are defined as intrasellar adenomas less than 1 cm in diameter that present with manifestations of hormonal excess without sellar enlargement or extrasellar extension. Panhypopituitarism does not occur, and such tumors can usually be treated successfully.
Pituitary macroadenomas are those larger than 1 cm in diameter and cause generalized sellar enlargement. Tumors 1 to 2 cm in diameter confined to the sella turcica can usually be successfully treated; however, larger tumors—especially those with suprasellar, sphenoid sinus, or lateral extensions—are much more difficult to manage. Panhypopituitarism and visual loss increase in frequency with tumor size and suprasellar extension.
Insights into the pathogenesis and biologic behavior of pituitary tumors have been gained from studies of pituitary tumor clonality and somatic mutations. Analyses of allelic X inactivation of specific genes has shown that most pituitary adenomas are monoclonal, a finding most consistent with a somatic mutation model of tumorigenesis; polyclonality of tumors would be expected if tonic stimulation by hypothalamic-releasing factors were the mechanism underlying neoplastic transformation. In fact, transgenic animals expressing GHRH have exhibited pituitary hyperplasia but not pituitary adenomas. One somatic mutation has been found in 30% to 40% of GH-secreting tumors (but not in leukocytes from the same patients). Point mutations in the alpha subunit of the GTP-binding protein responsible for activation of adenylyl cyclase result in constitutive stimulation of pituitary cell growth and function. In studies of anterior pituitary cell ontogeny, PIT-1 has been identified as a transcription factor important in pituitary differentiation. The restriction of its expression to somatotrophs, lactotrophs, and thyrotrophs may account for the plurihormonal expression seen in some tumors. A host of other candidate genes have been described, including the pituitary tumor transforming gene (PTTG). Overexpression of this gene has been found in all pituitary tumor types and may promote tumorigenesis through cell cycle disruption, stimulation of fibroblast growth factor secretion, and abnormal chromatid separation. Several genetic syndromes are associated with pituitary tumors including multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney syndrome, and familial acromegaly.
Pituitary adenomas are treated with surgery, irradiation, or drugs to suppress hypersecretion by the adenoma or its growth. The aims of therapy are to correct hypersecretion of anterior pituitary hormones, to preserve normal secretion of other anterior pituitary hormones, and to remove or suppress the adenoma itself. These objectives are currently achievable in most patients with pituitary microadenomas; however, in the case of larger tumors, multiple therapies are frequently required and may be less successful.
The transsphenoidal microsurgical approach to the sella turcica, now done endoscopically in most centers, is the procedure of choice; transfrontal craniotomy is required only in the rare patient with massive suprasellar extension of the adenoma. In the transsphenoidal procedure, the surgeon approaches the pituitary from the nasal cavity through the sphenoid sinus, removes the anterior-inferior sellar floor, and incises the dura. The adenoma is selectively removed; normal pituitary tissue is identified and preserved. Success rates approach 90% in patients with microadenomas. Major complications, including postoperative hemorrhage, cerebrospinal fluid leak, meningitis, and visual impairment, occur in less than 5% of patients and are most frequent in patients with large or massive tumors. Transient diabetes insipidus lasting a few days to 1 to 2 weeks occurs in approximately 15%; permanent diabetes insipidus is rare. A transient form of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with symptomatic hyponatremia occurs in 10% of patients within 5 to 14 days of transsphenoidal pituitary microsurgery. These abnormalities of water balance can occur within days of each other making medical management difficult. A triphasic response of diabetes insipidus, SIADH, and diabetes insipidus is occasionally encountered and thought to be due to early hypothalamic dysfunction, followed by release of ADH from the degenerating pituitary, and then depletion of ADH stores. Surgical hypopituitarism is rare in patients with microadenomas but approaches 5% to 10% in patients with larger tumors. The perioperative management of such patients should include glucocorticoid administration in stress doses (see Chapter 9) and postoperative assessment of daily weight, fluid balance, and electrolyte status to look for evidence of diabetes insipidus. Mild diabetes insipidus is managed by giving fluids orally; in more severe cases—urine output greater than 5 to 6 L/24 h—ADH therapy in the form of desmopressin, or DDAVP, can be administered intranasally, orally, subcutaneously, or parenterally (see Chapter 5). SIADH is managed by fluid restriction; however, in more severe cases, hypertonic saline may be required. ADH receptor antagonists (tolvaptan is given orally and conivaptan is administered intravenously) are also now available for use in some patients (see section on SIADH).
Pituitary irradiation should be reserved for patients who have had incomplete resection of larger pituitary adenomas and whose tumors are not amenable to, or have failed, medical therapy.
Conventional irradiation—Conventional irradiation using high-energy sources, in total doses of 4000 to 5000 cGy given in daily doses of 180 to 200 cGy, is most commonly employed. The response to radiation therapy is slow, and 5 to 10 years may be required to achieve the full effect (see section on Acromegaly). Treatment is ultimately successful in about 80% of patients with acromegaly but in only about 55% to 60% of patients with Cushing disease. The response rate in prolactinomas is not precisely known, but tumor progression is prevented in most patients. Morbidity during radiotherapy is minimal, although some patients experience malaise and nausea, and serous otitis media may occur. Hypopituitarism is common, and the incidence increases with time following radiotherapy—about 50% to 60% at 5 to 10 years. Rare late complications include damage to the optic nerves and chiasm, seizures, and radionecrosis of brain tissue. Recent studies from the United Kingdom have shown that conventional radiotherapy is a major risk factor for excess mortality in acromegaly.
Gamma knife radiosurgery—This form of radiotherapy utilizes stereotactic CT-guided cobalt-60 gamma radiation to deliver high radiation doses to a narrowly focused area. Remission rates have been reported in the range of 43% to 78%. An adequate distance of the pituitary tumor from the optic chiasm is needed to prevent radiation-induced damage. Repeat treatments put patients at higher risk of new visual or third, fourth, or sixth cranial nerve deficits.
Proton stereotactic radiotherapy—Experience with this modality is limited. In one study, 52% of patients with Cushing disease had clinical remission. A similar rate of new pituitary hormone deficiencies was seen, although no visual complications or brain injury was reported.
Medical management of pituitary adenomas became feasible with the availability of bromocriptine, a dopamine agonist that suppresses both PRL and tumor growth in patients with prolactinomas. Somatostatin analogs are useful in the therapy of acromegaly and some TSH-secreting adenomas. Specifics of the use of these and other medications are discussed later.
Patients undergoing transsphenoidal microsurgery should be reevaluated 4 to 8 weeks postoperatively to document that complete removal of the adenoma and correction of endocrine hypersecretion has been achieved. Prolactinomas are assessed by basal PRL measurements, GH-secreting tumors by glucose suppression testing and IGF-I levels, and ACTH-secreting adenomas by measurement of urine-free cortisol and the response to low-dose dexamethasone suppression (see later). Other anterior pituitary hormones—TSH, ACTH, and LH/FSH—should also be assessed as described earlier in the section on endocrine evaluation. In patients with successful responses, yearly evaluation should be performed to watch for late recurrence; late hypopituitarism does not occur after microsurgery. MRI is not necessary in patients with normal postoperative pituitary function but should be utilized in patients with persistent or recurrent disease.
Follow-up of patients treated by pituitary irradiation is also essential, because the response to therapy may be delayed and the incidence of hypopituitarism increases with time. Yearly endocrinologic assessment of both the hypersecreted hormone and the other pituitary hormones is recommended.
PRL hypersecretion is the most common endocrine abnormality due to hypothalamic-pituitary disorders, and PRL is the hormone most commonly secreted in excess by pituitary adenomas.
The understanding is that PRL hypersecretion causes not only galactorrhea but also gonadal dysfunction, and the use of PRL measurements in screening such patients has permitted recognition of these PRL-secreting tumors before the development of sellar enlargement, hypopituitarism, or visual impairment. Thus, plasma PRL should be measured in patients with galactorrhea, suspected hypothalamic-pituitary dysfunction, or sellar enlargement and in those with unexplained gonadal dysfunction, including amenorrhea, infertility, decreased libido, or impotence (Table 4–11).
Table 4–11 Indications for Prolactin Measurement. ||Download (.pdf)
Table 4–11 Indications for Prolactin Measurement.
|Enlarged sella turcica|
|Suspected pituitary tumor|
Unexplained male hypogonadism or infertility
PRL-secreting pituitary adenomas arise most commonly from the lateral wings of the anterior pituitary, but with progression they fill the sella turcica and compress the normal anterior and posterior lobes. Tumor size varies greatly from microadenomas to large invasive tumors with extrasellar extension. Most patients have microadenomas (ie, tumors <1 cm in diameter at diagnosis).
Prolactinomas usually appear chromophobic on routine histologic study, reflecting the inadequacy of the techniques used. The cells are small and uniform, with round or oval nuclei and scanty cytoplasm, and secretory granules are usually not visible with routine stains. The stroma contains a diffuse capillary network.
Electron microscopic examination shows that prolactinoma cells characteristically contain secretory granules that usually range from 100 to 500 nm in diameter and are spherical. Larger granules (400-500 nm), which are irregular or crescent-shaped, are less commonly seen. The cells show evidence of secretory activity, with a large Golgi area, nucleolar enlargement, and a prominent endoplasmic reticulum. Immunocytochemical studies of these tumors have confirmed that the secretory granules indeed contain PRL.
The clinical manifestations of PRL excess are the same regardless of the cause (see later). The classic features are galactorrhea and amenorrhea in women and decreased libido or impotence in men. Although the sex distribution of prolactinomas is approximately equal, microadenomas are much more common in women, presumably because of earlier recognition of the endocrine consequences of PRL excess.
Galactorrhea occurs in the majority of women with prolactinomas and is much less common in men. It is usually not spontaneous, or may be present only transiently or intermittently. The absence of galactorrhea despite markedly elevated PRL levels is probably due to concomitant deficiency of the gonadal hormones required to initiate lactation (see Chapter 16).
In women—Amenorrhea, oligomenorrhea with anovulation, or infertility is present in approximately 90% of women with prolactinomas. These menstrual disorders usually present concurrently with galactorrhea if it is present but may either precede or follow it. The amenorrhea is usually secondary and may follow pregnancy or oral contraceptive use. Primary amenorrhea occurs in the minority of patients who have onset of hyperprolactinemia during adolescence. The necessity of measuring PRL in patients with unexplained primary or secondary amenorrhea is emphasized by several studies showing that hyperprolactinemia occurs in as many as 20% of patients with neither galactorrhea nor other manifestations of pituitary dysfunction. A number of these patients have been shown to have prolactinomas.
Gonadal dysfunction in these women is due to interference with the hypothalamic-pituitary-gonadal axis by the hyperprolactinemia and except in patients with large or invasive adenomas is not due to destruction of the gonadotropin-secreting cells. This has been documented by the return of menstrual function following reduction of PRL levels to normal by drug treatment or surgical removal of the tumor. Although basal gonadotropin levels are frequently within the normal range despite reduction of sex steroid levels in hyperprolactinemic patients, PRL inhibits both the normal pulsatile secretion of LH and FSH and the midcycle LH surge, resulting in anovulation. The positive feedback effect of estrogen on gonadotropin secretion is also inhibited; in fact, patients with hyperprolactinemia are usually estrogen deficient.
Estrogen deficiency in women with prolactinomas may be accompanied by decreased vaginal lubrication, other symptoms of estrogen deficiency, and low bone mass as assessed by bone densitometry. Other symptoms may include weight gain, fluid retention, and irritability. Hirsutism may also occur, accompanied by elevated plasma levels of dehydroepiandrosterone (DHEA) sulfate. Patients with hyperprolactinemia may also suffer from anxiety and depression. In small clinical trials, treatment with dopamine agonists has been shown to improve psychologic well-being in such patients.
In men—In men, PRL excess may also occasionally cause galactorrhea; however, the usual manifestations are those of hypogonadism. The initial symptom is decreased libido, which may be dismissed by both the patient and physician as due to psychosocial factors; thus, the recognition of prolactinomas in men is frequently delayed, and marked hyperprolactinemia (PRL > 200 ng/mL [9.1 nmol/L]) and sellar enlargement are usual. Unfortunately, prolactinomas in men are often not diagnosed until late manifestations such as headache, visual impairment, or hypopituitarism appear; virtually all such patients have a history of sexual or gonadal dysfunction. Serum testosterone levels are low, and in the presence of normal or subnormal gonadotropin levels, PRL excess should be suspected as should other causes of hypothalamic-pituitary-gonadal dysfunction (see section on Hypopituitarism). Impotence also occurs in hyperprolactinemic males. Its cause is unclear, because testosterone replacement may not reverse it if hyperprolactinemia is not corrected. Male infertility accompanied by reduction in sperm count is a less common initial complaint.
In general, the growth of prolactinomas is slow; several studies have shown that most microadenomas do not change significantly in size, and macroadenomas tend to grow very slowly.
The many conditions associated with hyperprolactinemia are listed in Table 4–8. Pregnancy, hypothalamic-pituitary disorders, primary hypothyroidism, and drug ingestion are the most common causes.
Hypothalamic lesions frequently cause PRL hypersecretion by decreasing the secretion of dopamine that tonically inhibits PRL release; the lesions may be accompanied by panhypopituitarism. Similarly, traumatic or surgical section of the pituitary stalk leads to hyperprolactinemia and hypopituitarism. Nonfunctional pituitary macroadenomas frequently cause mild hyperprolactinemia by compression of the pituitary stalk or hypothalamus.
Pregnancy leads to a physiologic increase in PRL secretion; the levels increase as pregnancy continues and may reach 200 ng/mL (9.1 nmol/L) during the third trimester. Following delivery, basal PRL levels gradually fall to normal over several weeks but increase in response to breast feeding. Hyperprolactinemia persisting for 6 to 12 months or longer following delivery is an indication for evaluation. PRL levels are also high in normal neonates.
Several systemic disorders lead to hyperprolactinemia. Primary hypothyroidism is a common cause, and measurement of thyroid function, and especially TSH, should be part of the evaluation. In primary hypothyroidism, there is hyperplasia of both thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. This may result in significant pituitary gland enlargement, which may be mistaken for a PRL-secreting pituitary tumor. The PRL response to TRH is usually exaggerated in these patients. PRL may also be increased in liver disease, particularly in patients with severe cirrhosis, and in patients with chronic renal failure.
PRL excess and galactorrhea may also be caused by breast disease, nipple stimulation, disease or injury to the chest wall, and spinal cord lesions. These disorders increase PRL secretion by stimulation of afferent neural pathways. Artifactual elevations in PRL levels may be observed in the presence of anti-PRL antibodies or of macroprolactinemia. In the latter, a high-molecular-weight complex of PRL molecules maintains immunologic activity, but minimal or no bioactivity. Macroprolactinemia can be assessed with polyethylene glycol precipitation of serum samples.
The most common cause of hyperprolactinemia is drug ingestion, and a careful history of drug intake must be obtained. Elevated PRL levels, galactorrhea, and amenorrhea may occur following estrogen therapy or oral contraceptive use, but their persistence should suggest prolactinoma. Many other drugs also cause increased PRL secretion and elevated plasma levels (see Table 4–8). PRL levels are usually less than 200 ng/mL (9 nmol/L), and the evaluation should focus on discontinuation of the drug or medication and reevaluation of the patient after several weeks. In patients in whom drug withdrawal is not feasible, neuroradiologic studies, if normal, usually exclude prolactinoma.
The evaluation of patients with galactorrhea or unexplained gonadal dysfunction with normal or low plasma gonadotropin levels should first include a history regarding menstrual status, pregnancy, fertility, sexual function, and symptoms of hypothyroidism or hypopituitarism. Current or previous use of medication, drugs, or estrogen therapy should be documented. Basal PRL levels, gonadotropins, thyroid function tests, and TSH levels should be established, as well as serum testosterone in men. Liver and kidney function should be assessed. A pregnancy test should be performed in women with amenorrhea.
Patients with galactorrhea but normal menses may not have hyperprolactinemia and usually do not have prolactinomas. If the PRL level is normal, they may be reassured and followed with sequential PRL measurements. Those with elevated levels require further evaluation as described later.
When other causes of hyperprolactinemia have been excluded, the most likely cause of persistent hyperprolactinemia is a prolactinoma, especially if there is associated hypogonadism. Because currently available suppression and stimulation tests do not distinguish PRL-secreting tumors from other causes of hyperprolactinemia, the diagnosis must be established by the assessment of both basal PRL levels and neuroradiologic studies. Patients with large tumors and marked hyperprolactinemia usually present little difficulty. With very rare exceptions, basal PRL levels greater than 200 to 300 ng/mL (9.1-13.7 nmol/L) are virtually diagnostic of prolactinoma. In addition, because there is a general correlation between the PRL elevation and the size of the pituitary adenoma, these patients usually have sellar enlargement and obvious macroadenomas. Similarly, if the basal PRL level is between 100 and 200 ng/mL (4.5 and 9.1 nmol/L), the cause is usually prolactinoma. These patients may have either micro- or macroadenomas; however, with basal levels of PRL greater than 100 ng/mL (4.5 nmol/L), the PRL-secreting tumor is usually radiologically evident, and again the diagnosis is generally straightforward. Patients with mild to moderate hyperprolactinemia (20-100 ng/mL [0.9-4.5 nmol/L]) present the greatest difficulty in diagnosis, because both PRL-secreting microadenomas and the many other conditions causing hyperprolactinemia (see Table 4–8) cause PRL hypersecretion of this degree. In such patients, MRI frequently demonstrates a definite pituitary microadenoma. Scans showing only minor or equivocal abnormalities should be interpreted with caution, because of the high incidence of false-positive scans in the normal population (see Neuroradiologic Evaluation, above). Because the diagnosis cannot be either established or excluded in patients with normal or equivocal neuroradiologic studies, they require further evaluation or serial assessment (see later). Dilutions of prolactin samples can be performed in patients with modest prolactin elevation or macroadenomas to rule out interference from the high-dose hook effect; large quantities of antigen can impair antigen-antibody binding, resulting in erroneously low prolactin measurements in some immunoassays.
Satisfactory control of PRL hypersecretion, cessation of galactorrhea, and return of normal gonadal function can be achieved in most patients with PRL-secreting microadenomas. In patients with hyperprolactinemia, ovulation should not be induced without careful assessment of pituitary anatomy, because pregnancy may cause further expansion of these tumors as discussed later.
Although most microadenomas do not progress, treatment of these patients is recommended to restore normal estrogen levels and fertility and to prevent early osteoporosis secondary to persistent hypogonadism. In addition, medical or surgical therapy is more successful in these patients than in those with larger tumors. All patients with PRL-secreting macroadenomas should be treated, because of the risks of further tumor expansion, hypopituitarism, and visual impairment. Patients with persistent hyperprolactinemia and hypogonadism and normal neuroradiologic studies—that is, those in whom prolactinoma cannot be definitely established—may be managed by observation if hypogonadism is of short duration. However, in patients whose hypogonadism has persisted for more than 6 to 12 months, dopamine agonists should be used to suppress PRL secretion and restore normal gonadal function. In women with macroprolactinomas, replacement estrogen therapy should be initiated only after PRL hypersecretion has been controlled by dopamine agonist therapy since estrogen stimulates lactotroph hyperplasia and may increase tumor size. In this regard, periodic measurement of serum PRL should be performed in women with microadenomas on estrogen therapy who are not also receiving dopamine agonist therapy.
Bromocriptine became available in the United States more than 30 years ago and was the first effective medical therapy for pituitary adenomas; however, cabergoline is more potent, much longer acting, and better tolerated. Cabergoline has, therefore, become the dopamine agonist of choice in the therapy of prolactinomas.
Bromocriptine—Bromocriptine stimulates dopamine receptors and has effects at both the hypothalamic and pituitary levels. It is effective therapy for a PRL-secreting pituitary adenoma and directly inhibits PRL secretion by the tumor. Doses of 2.5 to 5 mg daily are often effective. However, at present, cabergoline is the therapy of choice
Cabergoline—Cabergoline, a newer nonergot dopamine agonist, is administered once or twice a week and has a better side-effect profile than bromocriptine. It is as effective as bromocriptine in reducing macroadenoma size and is more effective in reducing PRL levels. It has been used successfully in most patients previously intolerant or resistant to bromocriptine. Cabergoline should be started at a dosage of 0.25 mg twice per week and increased if necessary to 0.5 mg twice per week. Although several recent studies have demonstrated associations between cabergoline and cardiac valve disease in patients treated for Parkinson disease, clinically relevant valve disease in patients treated for prolactinoma appears to be rare, likely because doses used to manage symptoms of Parkinsonism are often 20 to 30 times higher and administered daily rather than twice weekly. The risk also appears to be related to the affinity of different dopamine agonists for valvular serotonin (5-HT2B) receptors. Until larger, prospective safety studies are available, some authorities recommend echocardiographic evaluation in patients who are expected to need long-term treatment, especially at high doses.
Microadenomas—Cabergoline is successful in about 90% of patients, and very few are intolerant or resistant. Correction of hyperprolactinemia allows recovery of normal gonadal function; ovulation and fertility are restored, so that mechanical contraception should be advised if pregnancy is not desired. Bromocriptine induces ovulation in most female patients who wish to become pregnant. In these patients with microadenomas, the risk of major expansion of adenoma during the pregnancy is less than 2%; however, both the patient and the physician must be aware of this potential complication. Current data do not indicate an increased risk of multiple pregnancy, abortion, or fetal malformations in pregnancies occurring in women taking dopamine agonists; however, patients should be instructed to discontinue these drugs at the first missed menstrual period and obtain a pregnancy test. Although no late toxicity has yet been reported other than the side effects noted above, questions about possible long-term risk are currently unanswered. Maternal hyperprolactinemia should not be harmful to the developing fetus; prolactin increases normally during pregnancy and does not appear to cross the placenta.
Macroadenomas—Dopamine agonists are effective in controlling hyperprolactinemia in patients with PRL-secreting macroadenomas even when basal PRL levels are markedly elevated. Dopamine agonists may be used either as initial therapy or to control residual hyperprolactinemia in patients unsuccessfully treated with surgery or radiotherapy. Dopamine agonists should not be used to induce ovulation and pregnancy in women with untreated macroadenomas, because the risk of tumor expansion and visual deficits in the later part of pregnancy is approximately 15% to 25%. These patients should first have tumor volume decreased with medical therapy or be treated with surgery prior to induction of ovulation.
Dopamine agonists normalize PRL secretion in about 60% to 70% of patients with macroadenomas and also reduce tumor size in about the same percentage of patients. Reduction of tumor size may occur within days to weeks following institution of therapy. The drugs have been used to restore vision in patients with major suprasellar extension and chiasmal compression.
Long-Term Remission—Current studies suggest that 30% to 40% of patients with micro- and macroadenomas will remain in long-term remission after withdrawal of cabergoline therapy of 2 to 3 years duration provided that they have normalization of PRL levels and tumor shrinkage. Larger macroadenomas (> 2.0 cm) are likely to recur, and long-term dopamine agonist therapy should be continued in these patients.
Transsphenoidal microsurgery is the surgical procedure of choice in patients with prolactinomas.
Microadenomas—In patients with microadenomas, remission, as measured by restitution of normal PRL levels, normal menses, and cessation of galactorrhea, is achieved in 85% to 90% of cases. Success is most likely in patients with basal PRL levels under 200 ng/mL (9.1 nmol/L) and duration of amenorrhea of less than 5 years. In these patients, the incidence of surgical complications is less than 2%, and hypopituitarism is a rare complication. Thus, in this group of patients with PRL-secreting microadenomas, PRL hypersecretion can be corrected, gonadal function restored, and secretion of TSH and ACTH preserved. Recurrence rates vary considerably in reported series. In our experience, approximately 85% of patients have had long-term remissions, and 15% have had recurrent hyperprolactinemia.
Macroadenomas—Transsphenoidal microsurgery is considerably less successful in restoring normal PRL secretion in patients with macroadenomas; many clinicians would treat these patients with dopamine agonists alone. The surgical outcome is directly related to tumor size and the basal PRL level. Thus, in patients with tumors 1 to 2 cm in diameter without extrasellar extension and with basal PRL levels less than 200 ng/mL (9.1 nmol/L), transsphenoidal surgery is successful in about 80% of cases. In patients with higher basal PRL levels and larger or invasive tumors, the success rate—defined as complete tumor resection and restoration of normal basal PRL secretion—is 25% to 50%. Although progressive visual loss or pituitary apoplexy is a clear indication for surgery, the great majority of these patients should be treated with dopamine agonists.
Conventional radiation therapy is reserved for patients with PRL-secreting macroadenomas who have persistent hyperprolactinemia and who have not responded to attempts to control their pituitary adenomas with surgery or dopamine agonists. In this group of patients, radiotherapy with 4000 to 5000 cGy prevents further tumor expansion, although PRL levels usually do not fall into the normal range. Impairment of anterior pituitary function occurs in approximately 50% to 60% of patients. Experience with gamma knife radiosurgery in prolactinomas is limited and rates of remission and reduction in tumor volume have been reported with varying degrees of success.
Selection of Therapy for Prolactinomas
The selection of therapy for prolactinomas depends on the wishes of the patient, the patient's plans for pregnancy and tolerance of medical therapy, and the availability of a skilled neurosurgeon.
All patients should be treated to prevent the occasional tumor progression, loss of bone mass, and the other effects of prolonged hypogonadism. Medical therapy with cabergoline effectively restores normal gonadal function and fertility, and pregnancy carries only a small risk of tumor expansion. Those patients who respond should be treated for 2 to 3 years, and then the drug should be withdrawn to determine if long-term remission will occur. Patients who have recurrence of hyperprolactinemia after cabergoline withdrawal may resume the drug or choose to have surgical excision. Transsphenoidal adenectomy, either initially or after a trial of dopamine agonist therapy, carries little risk when performed by an experienced neurosurgeon and offers a high probability of long-term remission.
Primary surgical therapy in these patients usually does not result in long-term remission, so medical therapy is the primary therapy of choice, particularly when the patient's PRL levels are greater than 200 ng/mL (9.1 nmol/L) and the tumor is larger than 2 cm. Although transsphenoidal microsurgery rapidly decreases tumor size and decompresses the pituitary stalk, the optic chiasm, and the cavernous sinuses, there is usually residual tumor and hyperprolactinemia. Thus, these patients require additional therapy with dopamine agonists. Although tumor growth and PRL secretion can be controlled by medical therapy in most patients, therapeutic failure can result from drug intolerance, poor compliance, or resistance. Radiation therapy is reserved for postsurgical patients with residual adenomas who are not controlled with dopamine agonists.
GH-secreting pituitary adenomas are second in frequency to prolactinomas and cause the classic clinical syndromes of acromegaly and gigantism.
The characteristic clinical manifestations are the consequence of chronic GH hypersecretion, which in turn leads to excessive generation of IGF-I, the mediator of most of the effects of GH (see Chapter 6). Although overgrowth of bone is the classic feature, GH excess causes a generalized systemic disorder with deleterious effects and an increased mortality rate, although deaths are rarely due to the space-occupying or destructive effects of pituitary adenoma per se.
Acromegaly and gigantism are virtually always secondary to a pituitary adenoma. Ectopic GHRH secretion has been identified as another cause of GH hypersecretion and acromegaly in a few patients with carcinoid or islet cell tumors. Reports of intrapituitary GHRH-secreting gangliocytomas in direct contiguity with GH-secreting somatotroph adenomas and a report of a GHRH-secreting hypothalamic hamartoma in a patient with acromegaly provide a link between ectopic and eutopic GHRH production. Ectopic secretion of GH per se is very rare but has been documented in a few lung tumors.
In adults, GH excess leads to acromegaly, the syndrome characterized by local overgrowth of bone, particularly of the skull and mandible. Linear growth does not occur, because of prior fusion of the epiphyses of long bones. In childhood and adolescence, the onset of chronic GH excess leads to gigantism. Most of these patients have associated hypogonadism, which delays epiphysial closure and the combination of IGF-I excess and hypogonadism leads to a striking acceleration of linear growth. Most patients with gigantism also have features of acromegaly if GH hypersecretion persists through adolescence and into adulthood.
Pituitary adenomas causing acromegaly are usually more than 1 cm in diameter when the diagnosis is established. These tumors arise from the lateral wings of the anterior pituitary; less than 10% are diagnosed as microadenomas.
GH-secreting adenomas are of two histologic types: densely and sparsely granulated. However, there appears to be no difference in the degree of GH secretion or clinical manifestations in these patients. About 15% of GH-secreting tumors also contain lactotrophs, and these tumors thus hypersecrete both GH and PRL.
Etiology and Pathogenesis
In most cases, excessive pituitary GH secretion is a primary pituitary disorder. A somatic mutation in the Gs protein leading to excessive cAMP production has been identified in 40% of GH-secreting adenomas. Pituitary adenomas are present in virtually all patients and are usually greater than 1 cm in diameter; hyperplasia alone is rare, and nonadenomatous anterior pituitary tissue does not exhibit somatotroph hyperplasia when examined histologically. In addition, there is a return of normal GH levels and dynamic control of GH secretion following selective removal of the pituitary adenoma.
In acromegaly, GH secretion is increased and its dynamic control is abnormal. Secretion remains episodic; however, the number, duration, and amplitude of secretory episodes are increased, and they occur randomly throughout the 24-hour period. The characteristic nocturnal surge is absent, and there are abnormal responses to suppression and stimulation. Thus, glucose suppressibility is lost (see Diagnosis, later), and GH stimulation by hypoglycemia is usually absent. TRH and GnRH may cause GH release, whereas these substances do not normally stimulate GH secretion. Dopamine and dopamine agonists such as bromocriptine and apomorphine, which normally stimulate GH secretion, paradoxically cause GH suppression in about 70% to 80% of patients with acromegaly.
Most of the deleterious effects of chronic GH hypersecretion are caused by its stimulation of excessive amounts of IGF-I (see Chapter 6), and plasma levels of this protein are increased in acromegaly. The growth-promoting effects of IGF-I (DNA, RNA, and protein synthesis) lead to the characteristic proliferation of bone, cartilage, and soft tissues and increase in size of other organs to produce the classic clinical manifestations of acromegaly. The insulin resistance and carbohydrate intolerance seen in acromegaly appear to be direct effects of GH and not due to IGF-I excess.
The sex incidence of acromegaly is approximately equal; the mean age at diagnosis is approximately 40 years; and the duration of symptoms is usually 5 to 10 years before the diagnosis is established.
Acromegaly is a chronic disabling and disfiguring disorder with increased late morbidity and mortality if untreated. Although spontaneous remissions have been described, the course is slowly progressive in the great majority of cases.
Early manifestations (Table 4–12) include soft tissue proliferation, with enlargement of the hands and feet and coarsening of the facial features. This is usually accompanied by increased sweating, heat intolerance, oiliness of the skin, fatigue, and weight gain.
Table 4–12 Clinical Manifestations of Acromegaly in 100 Patients. ||Download (.pdf)
Table 4–12 Clinical Manifestations of Acromegaly in 100 Patients.
Manifestations of GH excess
- Acral enlargement
- Soft tissue overgrowth
- Lethargy or fatigue
- Weight gain
- Joint pain
- Acanthosis nigricans
- Renal calculi
Disturbance of other endocrine functions
- Glucose intolerance
- Irregular or absent menses
- Decreased libido or impotence
- Enlarged sella
- Visual deficit
At diagnosis, most patients have classic manifestations, and acral and soft tissue changes are always present. Bone and cartilage changes affect chiefly the face and skull. These changes include thickening of the calvarium; increased size of the frontal sinuses, which leads to prominence of the supraorbital ridges; enlargement of the nose; and downward and forward growth of the mandible, which leads to prognathism and widely spaced teeth. Soft tissue growth also contributes to the facial appearance, with coarsening of the features and facial and infraorbital puffiness. The hands and feet are predominantly affected by soft tissue growth; they are large, thickened, and bulky, with blunt, spade-like fingers (Figure 4–18) and toes. A bulky, sweaty handshake frequently suggests the diagnosis, and there are increases in ring, glove, and shoe sizes. There is generalized thickening of the skin, with increased oiliness and sweating. Acne, sebaceous cysts, and fibromata mollusca (skin tags and papillomas) are common, as is acanthosis nigricans of the axillae and neck and hypertrichosis in women.
Markedly increased soft tissue bulk and blunt fingers in a middle-aged man with acromegaly.
These bony and soft tissue changes are accompanied by systemic manifestations, which include hyperhidrosis, heat intolerance, lethargy, fatigue, and increased sleep requirement. Sleep apnea, both obstructive and central, is very common in patients with acromegaly. This has particular importance for the anesthesiologist who must take special precautions to protect the airway during surgery. Moderate weight gain usually occurs. Paresthesias, usually due to carpal tunnel compression, occur in 70%; sensorimotor neuropathies occur uncommonly. Bone and cartilage overgrowth leads to arthralgias and in longstanding cases to degenerative arthritis of the spine, hips, and knees. Photophobia of unknown cause occurs in about half of cases and is most troublesome in bright sunlight and during night driving.
GH excess leads to generalized visceromegaly, clinically evident as thyromegaly and enlargement of the salivary glands. Enlargement of other organs is usually not clinically detectable.
Hypertension occurs in about 25% of patients and cardiomegaly in about 15%. Cardiac enlargement may be secondary to hypertension, atherosclerotic disease, or, rarely, to acromegalic cardiomyopathy. Renal calculi occur in 11% secondary to the hypercalciuria induced by GH excess.
Other endocrine and metabolic abnormalities are common and may be due either to GH excess or to mechanical effects of the pituitary adenoma. Glucose intolerance and hyperinsulinism occur in 50% and 70% of patients, respectively, owing to GH-induced insulin resistance. Overt clinical diabetes occurs in a minority, and diabetic ketoacidosis is rare. Hypogonadism occurs in 60% of female and 46% of male patients and is of multifactorial origin; tumor growth and compression may impair pituitary gonadotropin secretion, and associated hyperprolactinemia (see later) or the PRL-like effect of excessive GH secretion may impair gonadotropin and gonadal function. In men, low total plasma testosterone levels may be due to GH suppression of sex hormone–binding globulin (SHBG) levels; in these cases, plasma-free testosterone levels may be normal, with normal gonadal function. With earlier diagnosis, hypothyroidism and hypoadrenalism due to destruction of the normal anterior pituitary are unusual and are present in only 13% and 4% of patients, respectively. Galactorrhea occurs in about 15% and is usually caused by hyperprolactinemia from a pituitary adenoma with a mixed cell population of somatotrophs and lactotrophs. Gynecomastia of unknown cause occurs in about 10% of men. Although acromegaly may be a component of multiple endocrine neoplasia (MEN) type 1 syndrome, it is distinctly unusual, and concomitant parathyroid hyperfunction or pancreatic islet cell tumors are rare.
When GH hypersecretion is present for many years, late complications occur, including progressive cosmetic deformity and disabling degenerative arthritis. In addition, the mortality rate is increased; after age 45, the death rate in acromegaly from cardiovascular and cerebrovascular atherosclerosis, respiratory diseases, and colon cancer is two to four times that of the normal population. Death rates tend to be higher in patients with hypertension, cardiovascular disease, or clinical diabetes mellitus.
Space-occupying manifestations of the pituitary adenoma are also common in acromegaly (eg, 65% of patients have headache). Although visual impairment was usually present in older series, it now occurs in only 15% to 20%, because most patients are now diagnosed because of the manifestations of GH excess.
In addition to elevations in IGF-I and GH, postprandial plasma glucose may be elevated, and serum insulin is increased in 70% of cases. Elevated serum phosphate (due to increased renal tubular resorption) and hypercalciuria appear to be due to direct effects of GH or IGF-I.
Plain films (Figure 4–19) show sellar enlargement in 90% of cases. Thickening of the calvarium, enlargement of the frontal and maxillary sinuses, and enlargement of the jaw can also be seen. Radiographs of the hand show increased soft tissue bulk, “arrowhead” tufting of the distal phalanges, increased width of intra-articular cartilages, and cystic changes of the carpal bones. Radiographs of the feet show similar changes, and there is increased thickness of the heel pad (normal, <22 mm).
Radiologic signs in acromegaly. Left: Skull with enlarged sella turcica and frontal sinuses, thickening of the calvarium, and enlargement of the mandible. Center: Hand with enlarged sesamoid bone and increased soft tissue shadows. Right: Thickened heel pad.
(Reproduced, with permission, from Levin SR. Manifestations and treatment of acromegaly. Calif Med. 1972;116:57).
Acromegaly is usually clinically obvious and can be readily confirmed by assessment of GH secretion; basal fasting GH levels (normal, 1-5 ng/mL [46-232 pmol/L]) are greater than 10 ng/mL (465 pmol/L) in more than 90% of patients and range from 5 ng/mL (232 pmol/L) to greater than 500 ng/mL (23,000 pmol/L), with a mean of approximately 50 ng/mL (2300 pmol/L). However, single measurements are not entirely reliable, because GH secretion is episodic in acromegaly and because other conditions may increase GH secretion (see discussed later).
Suppression with oral glucose is the simplest and most specific dynamic test for acromegaly. In healthy subjects, oral administration of 100 g of glucose causes a reduction of the GH level to less than 1 ng/mL (47 pmol/L) at 60 minutes. In acromegaly, GH levels may decrease, increase, or show no change; however, they do not decrease to less than 1 ng/mL (47 pmol/L), and this lack of response establishes the diagnosis.
Supersensitive GH assays have been developed and are becoming commercially available. With these assays, normal individuals may suppress GH levels to less than 0.1 ng/mL. Thus, the criteria expressed above may need to be adjusted in the near future.
Measurement of IGF-I (see Chapter 6) is a useful means of establishing the diagnosis of GH hypersecretion. IGF-I results must be interpreted according to age- and sex-adjusted normative data. IGF-I levels directly reflect GH activity. IGF-I has a long half-life, so that IGF-I levels fluctuate much less than GH levels. IGF-I levels are elevated in virtually all patients with acromegaly (normal ranges vary widely in different laboratories, and some commercial assays are not reliable).
Radiographic localization of the pituitary adenoma causing acromegaly is usually straightforward (see Neuroradiologic Evaluation, above). In virtually all patients, tumor location and size can be shown by MRI; 90% have tumors greater than 1 cm in diameter that are readily visualized. In the rare patient with normal neuroradiologic studies, an extrapituitary ectopic source of GH or GHRH should be considered. If scans suggest diffuse pituitary enlargement or hyperplasia, ectopic GHRH should also be suspected.
Other Causes of GH or IGF-I Hypersecretion
The presence of clinical features of GH excess, elevated GH and IGF-I secretion, and abnormal GH dynamics, together with the demonstration of a pituitary tumor by neuroradiologic studies, are diagnostic of acromegaly. However, other conditions associated with GH hypersecretion must be considered in the differential diagnosis. These include anxiety, exercise, acute illness, chronic renal failure, cirrhosis, starvation, protein-calorie malnutrition, anorexia nervosa, and type I (insulin-dependent) diabetes mellitus. Estrogen therapy may increase GH responsiveness to various stimuli. These conditions may be associated with abnormal GH suppressibility by glucose and by abnormal GH responsiveness to TRH; however, patients with these conditions do not have clinical manifestations of GH excess and are thus readily differentiated from patients with acromegaly. In addition, the conditions listed above do not lead to elevation of IGF-I concentrations. Use of testosterone or the contraceptive depot medroxyprogesterone acetate has been associated with modest elevations in IGF-I.
Ectopic GH or GHRH Secretion
These rare patients with acromegaly due to ectopic secretion of GH or GHRH have typical clinical manifestations of acromegaly. This may occur in lung carcinoma, carcinoid tumors, and pancreatic islet cell tumors. These syndromes should be suspected in patients with a known extrapituitary tumor who have GH excess or in those with clinical and biochemical features of acromegaly who have radiologic procedures that show normal pituitary glands or that suggest diffuse pituitary enlargement or hyperplasia.
All patients with acromegaly should undergo therapy to halt progression of the disorder and to prevent late complications and excess mortality. The objectives of therapy are removal or destruction of the pituitary tumor, reversal of GH hypersecretion, and maintenance of normal anterior and posterior pituitary function. These objectives are currently attainable in most patients, especially those with smaller tumors and only moderate GH hypersecretion. In patients with large tumors who have marked GH hypersecretion, several therapies are usually required to achieve normal GH secretion.
The criteria for an adequate response to therapy continue to evolve. Recent reports described increased late mortality in patients with GH levels by radioimmunoassay greater than 2.5 ng/mL (116 pmol/L) after therapy. Therefore, current guidelines for remission are a fasting GH of 1 ng/mL (47 pmol/L) or less and a glucose-suppressed GH of 1 ng/mL (47 pmol/L) or less accompanied by a normal level of IGF-I.
The initial therapy of choice is transsphenoidal microsurgery because of its high success rate, rapid reduction of GH levels, the low incidence of postoperative hypopituitarism, and the low surgical morbidity rate. Patients with persisting GH hypersecretion after surgery should currently be treated medically with somatostatin analogs, dopamine agonists, or a GH receptor antagonist. Radiation therapy should be reserved for those patients with inadequate responses to surgery and medical therapy.
Transsphenoidal selective adenoma removal is the procedure of choice; craniotomy is necessary in the rare patient in whom major suprasellar extension precludes the transsphenoidal approach. Successful reduction of GH levels is achieved in approximately 60% to 80% of patients. In those with small or moderate-sized tumors (<2 cm), success is achieved in more than 80%, whereas in those with larger tumors and basal GH levels greater than 50 ng/mL (2325 pmol/L)—and particularly in those with major extrasellar extension of the adenoma—successful responses occur in only 30% to 60%. Recurrence rates in those with a successful initial response are low (about 5% of patients at our institution). Surgical complications (discussed earlier) occur in less than 2%.
Octreotide acetate, a somatostatin analog, was the first effective medical therapy for patients with acromegaly. However, the drug required high doses (100-500 μ g) given subcutaneously three times daily. Its use in acromegaly has been superseded by sustained-release somatostatin analogs with activities lasting up to 1 month. Preparations include octreotide LAR and lanreotide acetate given by injection every 4 weeks. Octreotide LAR normalizes GH and IGF-I levels in 75% of patients when used at doses of 20 to 40 mg/mo; however, tumor reduction occurs in a much smaller percentage. These long-acting agents have become the therapy of choice for patients with residual GH hypersecretion following surgery. Side effects of this class of agents consist mainly of gastrointestinal symptoms and the development of gallstones. Impaired glucose tolerance has been reported in some studies. The dopamine agonist cabergoline normalizes IGF-I levels in about 30% of acromegalic patients when used at doses of 1 to 2 mg/wk. However, it has not been commonly used as sole therapy. When cabergoline is added to somatostatin analog therapy, the number of patients with normalization of GH and IGF-I levels is increased.
Pegvisomant, the latest medical therapy for acromegaly, is a GH receptor antagonist. In doses of 10 to 20 mg/d given by subcutaneous injection, it reduces IGF-I levels to normal in more than 90% of patients. Although there are concerns regarding the continued excess GH secretion and possible tumor progression, serious problems have not arisen to date. Pegvisomant is effective, but its use is limited by cost and the need for daily injection. Therefore, it is currently used mainly in those patients who have failed therapy with surgery and somatostatin analogs.
Conventional supervoltage irradiation in doses of 4500 to 5000 cGy, although ultimately successful in 60% to 80% of patients, should not be used, because GH levels may not return to normal until 10 to 15 years after therapy. In one series, GH levels were under 10 ng/mL (460 pmol/L) in only 38% of patients at 2 years posttreatment; however, at 5 and 10 years, 73% and 81% had achieved such levels. The incidence of hypopituitarism is appreciable, and in this series hypothyroidism occurred in 19%, hypoadrenalism in 38%, and hypogonadism in approximately 50% to 60% of patients as a consequence of radiotherapy. Gamma knife radiosurgery has also been used for tumors confined to the sella. Current series, although limited, suggest remission rates of about 50% to 70% at 2 years following therapy.
In patients with successful reduction in GH hypersecretion, there is cessation of bone overgrowth. In addition, these patients experience considerable clinical improvement, including reduction in soft tissue bulk of the extremities, decreased facial puffiness, increased energy, and cessation of hyperhidrosis, heat intolerance, and oily skin. Bony changes typically do not regress. Headache, carpal tunnel syndrome, arthralgias, sleep apnea, and photophobia are also reversible with successful therapy. Glucose intolerance and hyperinsulinemia as well as hypercalciuria are also reversed in most cases.
Recent studies have also shown that the excess mortality associated with acromegaly can be reversed if GH levels are normalized.
Posttreatment assessment includes evaluation of GH secretion, anterior pituitary function, and tumor size. Patients undergoing surgery should be seen 4 to 8 weeks after the operation for assessment of GH secretion and pituitary function. Those with persistent GH hypersecretion (> 1 ng/dL [47 pmol/L]) should receive further therapy with somatostatin analogs. Patients with postoperative GH levels under 1 ng/mL (47 pmol/L) should have follow-up GH and IGF-I determinations at 6-month intervals for 2 years and yearly thereafter to rule out recurrences. Recurrent elevations in IGF-I should prompt a repeat MRI of the sella. Late hypopituitarism after surgery alone does not occur. GH replacement therapy in patients with history of acromegaly and hypopituitarism is controversial and further studies are needed.
ACTH-Secreting Pituitary Adenomas: Cushing Disease
In 1932, Harvey Cushing documented the presence of small basophilic pituitary adenomas in six of eight patients with clinical features of adrenocortical hyperfunction. Years later, ACTH hypersecretion was identified from such tumors and found to be the cause of bilateral adrenal hyperplasia. Pituitary ACTH hypersecretion (Cushing disease) is now recognized as the most common cause of spontaneous hypercortisolism (Cushing syndrome) and must be distinguished from the other forms of adrenocorticosteroid excess—ectopic ACTH syndrome and adrenal tumors (see Chapter 9).
ACTH-secreting pituitary tumors exist in virtually all patients with Cushing disease. These tumors are usually benign microadenomas under 10 mm in diameter; 50% are 5 mm or less in diameter, and microadenomas as small as 1 mm have been described. These tumors in Cushing disease are either basophilic or chromophobe adenomas and may be found anywhere within the anterior pituitary. Rarely, ACTH-secreting tumors are large, with invasive tendencies, and malignant tumors have rarely been reported.
Histologically, the tumors are composed of compact sheets of uniform, well-granulated cells (granule size, 200-700 nm by electron microscopy) with a sinusoidal arrangement and a high content of ACTH and its related peptides (β-LPH, β-endorphin). A zone of perinuclear hyalinization (Crooke changes) is frequently observed as a result of exposure of the corticotroph cells to prolonged hypercortisolism. A specific ultrastructural finding in these adenomas is the deposition of bundles of perinuclear microfilaments that encircle the nucleus; these are the ultrastructural equivalent of Crooke hyaline changes seen on light microscopy. In contrast to the adenoma's cells, ACTH content in the portion of the anterior pituitary not involved with the tumor is decreased.
Diffuse hyperplasia of anterior pituitary corticotrophs or adenomatous hyperplasia, presumed to result from hypersecretion of CRH, occurs rarely.
The adrenal glands in Cushing disease are enlarged, weighing 12 to 24 g (normal, 8-10 g). Microscopic examination shows a thickened cortex due to hyperplasia of both the zona reticularis and zona fasciculata; the zona glomerulosa is normal. In some cases, ACTH-secreting pituitary adenomas cause bilateral nodular hyperplasia; the adrenals show diffuse bilateral cortical hyperplasia and the presence of one or more nodules that vary from microscopic to several centimeters in diameter, with multiple small nodules being the most common.
The weight of current evidence is that Cushing disease is a primary pituitary disorder and that hypothalamic abnormalities are secondary to hypercortisolism. The endocrine abnormalities in Cushing disease are as follows: (1) hypersecretion of ACTH, with bilateral adrenocortical hyperplasia and hypercortisolism; (2) absent circadian periodicity of ACTH and cortisol secretion; (3) absent responsiveness of ACTH and cortisol to stress (hypoglycemia or surgery); (4) abnormal negative feedback of ACTH secretion by glucocorticoids; and (5) subnormal responsiveness of GH, TSH, and gonadotropins to stimulation.
Evidence that Cushing disease is a primary pituitary disorder is based on the high frequency of pituitary adenomas, the response to their removal, and the interpretation of hypothalamic abnormalities as being secondary to hypercortisolism. In addition, molecular studies have found that nearly all corticotroph adenomas are monoclonal. These findings suggest that ACTH hypersecretion arises from a spontaneously developing pituitary adenoma and that the resulting hypercortisolism suppresses the normal hypothalamic-pituitary axis and CRH release, thereby abolishing the hypothalamic regulation of circadian variability and stress responsiveness.
Analysis of the response to therapy by pituitary microsurgery sheds some light on the pathogenesis of Cushing disease. Selective removal of pituitary microadenomas by transsphenoidal microsurgery corrects ACTH hypersecretion and hypercortisolism in most patients. After selective removal of the pituitary adenoma, the following return to normal: the circadian rhythmicity of ACTH and cortisol, the responsiveness of the hypothalamic-pituitary axis to hypoglycemic stress, and the dexamethasone suppressibility of cortisol secretion.
Cushing disease presents with the signs and symptoms of hypercortisolism and adrenal androgen excess (see Chapter 9). The onset of these features is usually insidious, developing over months or years. Obesity (with predominantly central fat distribution), hypertension, glucose intolerance, and gonadal dysfunction (amenorrhea or impotence) are common features. Other common manifestations include moon (rounded) facies, plethora, osteopenia, proximal muscle weakness, easy bruisability, psychologic disturbances, violaceous striae, hirsutism, acne, poor wound healing, and superficial fungal infections. Unlike patients with the classic form of ectopic ACTH syndrome, patients with Cushing disease rarely have hypokalemia, weight loss, anemia, or hyperpigmentation. Virilization, observed occasionally in patients with adrenal carcinoma, is unusual in Cushing disease. Clinical symptoms related to the ACTH-secreting primary tumor itself, such as headache or visual impairment, are rare because of the small size of these adenomas.
The usual age range is 20 to 40 years, but Cushing disease has been reported in infants and in patients over 70. There is a female:male ratio of approximately 8:1. In contrast, the ectopic ACTH syndrome occurs more commonly in men (male:female ratio of 3:1).
The initial step in the diagnosis of an ACTH-secreting pituitary adenoma is the documentation of endogenous hypercortisolism, which is confirmed by increased urine-free cortisol secretion, abnormal cortisol suppressibility to low-dose dexamethasone, and/or abnormal late night salivary cortisol measurement. The differentiation of an ACTH-secreting pituitary tumor from other causes of hypercortisolism must be based on biochemical studies, including the measurement of basal plasma ACTH levels and central venous sampling, to detect a central to peripheral gradient of ACTH levels (see Chapter 9). The diagnosis and differential diagnosis of Cushing syndrome are presented in Chapter 9.
Transsphenoidal microsurgery is the procedure of choice in Cushing disease. A variety of other therapies—operative, radiologic, pharmacologic—are discussed below.
Selective transsphenoidal resection of ACTH-secreting pituitary adenomas is the initial treatment of choice. At operation, meticulous exploration of the intrasellar contents by an experienced neurosurgeon is required. The tumor, which is usually found within the anterior lobe tissue, is selectively removed, and normal gland is left intact.
In about 85% of patients with microadenomas, selective microsurgery is successful in correcting hypercortisolism. Surgical damage to anterior pituitary function is rare, but most patients develop transient secondary adrenocortical insufficiency requiring postoperative glucocorticoid support until the hypothalamic-pituitary-adrenal axis recovers, usually in 2 to 18 months. The role of total hypophysectomy is currently unclear, however; hemihypophysectomy based on central venous sampling lateralization is successful in only about 50% to 70% of patients.
By contrast, transsphenoidal surgery is successful in only 25% of the 10% to 15% of patients with Cushing disease with pituitary macroadenomas or in those with extrasellar extension of tumor.
Transient diabetes insipidus occurs in about 10% of patients, but other surgical complications (eg, hemorrhage, cerebrospinal fluid rhinorrhea, infection, visual impairment, permanent diabetes insipidus) are rare. Hypopituitarism occurs only in patients who undergo total hypophysectomy.
Before the introduction of pituitary microsurgery, bilateral total adrenalectomy was the preferred treatment of Cushing disease and may still be employed in patients in whom other therapies are unsuccessful. Total adrenalectomy, which can now be performed laparoscopically, corrects hypercortisolism but produces permanent hypoadrenalism, requiring lifelong glucocorticoid and mineralocorticoid therapy. The ACTH-secreting pituitary adenoma persists and may progress, causing hyperpigmentation and invasive complications (Nelson syndrome; see below). Persistent hypercortisolism may occasionally follow total adrenalectomy as ACTH hypersecretion stimulates adrenal remnants or congenital rests.
Conventional radiotherapy of the pituitary is of benefit in patients who have persistent or recurrent disease following pituitary microsurgery. In these patients, reported remission rates are 55% to 70% at 1 to 3 years after radiotherapy.
Gamma knife radiosurgery achieves remission rates of 65% to 75%. However, as noted above, both forms of radiotherapy cause late loss of pituitary function in more than 50% of patients and visual deficits can occur with damage to the optic chiasm or cranial nerves.
Drugs that inhibit adrenal cortisol secretion are useful in Cushing disease, often as adjunctive therapy (see Chapter 9). No drug currently available successfully suppresses pituitary ACTH secretion.
Ketoconazole, an imidazole derivative, has been found to inhibit adrenal steroid biosynthesis. It inhibits the cytochrome P450 enzymes P450scc and P450c11. In daily doses of 600 to 1200 mg, ketoconazole has been effective in the management of Cushing syndrome. Hepatotoxicity is common, however, but may be transient. Metyrapone, which inhibits P450c11, and aminoglutethimide, which inhibits P450scc, have also been utilized to reduce cortisol hypersecretion. Metyrapone is only available directly through the manufacturer and aminoglutethimide is no longer manufactured in the United States.
The use of these drugs is accompanied by increased ACTH levels that may overcome the enzyme inhibition. In addition, they cause gastrointestinal side effects that may limit their effectiveness. More effective control of hypercortisolism with fewer side effects is obtained by combined use of these agents. Adequate data are not available on the long-term use of these drugs as the sole treatment of Cushing disease. Thus, ketoconazole and aminoglutethimide ordinarily are used while awaiting a response to therapy or in the preparation of patients for surgery.
The adrenolytic drug mitotane results in adrenal atrophy predominantly of the zonae fasciculata and reticularis. Remission of hypercortisolism is achieved in approximately 80% of patients with Cushing disease, but most relapse after therapy is discontinued. Mitotane therapy is limited by the delayed response, which may take weeks or months, and by the frequent side effects, including severe nausea, vomiting, diarrhea, somnolence, and skin rash.
The anesthesia induction agent etomidate inhibits P450c11. It must be given intravenously and is generally reserved for life-threatening cases of hypercortisolism resistant to conventional therapy or when oral medications are contraindicated.
Pharmacologic inhibition of ACTH secretion in Cushing disease has also been attempted with cyproheptadine, bromocriptine, and cabergoline. However, few patients have had successful responses, and the use of these agents is not recommended.
The clinical appearance of an ACTH-secreting pituitary adenoma following bilateral adrenalectomy as initial therapy for Cushing disease was first described by Nelson and coworkers in 1958. However, with the evolution of pituitary microsurgery as the initial therapy for Cushing disease, the Nelson syndrome is now a rare occurrence.
It now seems likely that Nelson syndrome represents the clinical progression of a preexisting adenoma after the restraint of hypercortisolism on ACTH secretion and tumor growth is removed. Thus, following adrenalectomy, the suppressive effect of cortisol is no longer present, ACTH secretion increases, and the pituitary adenoma may progress.
Prior to the development of transsphenoidal surgery, when bilateral adrenalectomy was the initial therapy for Cushing disease, the incidence of Nelson syndrome ranged from 10% to 78% depending on what criteria were used for diagnosis (see Chapter 9). In one series, approximately 30% of patients adrenalectomized for Cushing disease developed classic Nelson syndrome with progressive hyperpigmentation and an obvious ACTH-secreting tumor; another 50% developed evidence of a microadenoma without marked progression; and about 20% never developed a progressive tumor. The reasons for these differences in clinical behavior are uncertain. Prophylactic pituitary radiotherapy is controversial. At present, when adrenalectomy is utilized only in those patients who fail pituitary microsurgery, the incidence of Nelson syndrome is less than 10%. Nevertheless, continued examination, including plasma ACTH levels and MRI, is required following bilateral adrenalectomy in patients with Cushing disease.
The pituitary tumors in patients with classic Nelson syndrome can be among the most aggressive and rapidly growing of all pituitary tumors. These patients present with hyperpigmentation and with manifestations of an expanding intrasellar mass lesion. Visual field defects, headache, cavernous sinus invasion with extraocular muscle palsies, and even malignant changes with local or distant metastases may occur. Pituitary apoplexy may also complicate the course of these tumors.
Plasma ACTH levels are markedly elevated, usually over 1000 pg/mL (222 pmol/L) and often as high as 10,000 pg/mL (2220 pmol/L). MRI defines the extent of the tumor.
Pituitary surgery by the transsphenoidal approach is the initial mode of treatment. Complete resection is usually not possible, because of the large size of these tumors. Conventional radiotherapy or gamma knife radiosurgery is employed postoperatively in patients with residual tumor or extrasellar extension.
Thyrotropin-Secreting Pituitary Adenomas
TSH-secreting pituitary adenomas are rare tumors manifested as hyperthyroidism with goiter in the presence of elevated TSH. Patients with TSH-secreting tumors are often resistant to routine ablative thyroid therapy, requiring large, often multiple doses of 131I and several operations for control of thyrotoxicosis. Histologically, the tumors are chromophobe adenomas. They are often very large and cause visual impairment, which alerts the physician to a pituitary abnormality. Patients with these tumors do not have extrathyroidal systemic manifestations of Graves disease such as ophthalmopathy or dermopathy.
The diagnosis is based on findings of hyperthyroidism (elevated T4 or T3) with elevated serum TSH and alpha subunit, and neuroradiologic studies consistent with pituitary tumor. The differential diagnosis includes those patients with primary hypothyroidism (thyroid failure) that develops major hyperplasia of pituitary thyrotrophs and lactotrophs with sellar enlargement and occasional suprasellar extension. These patients can be identified by symptoms of hypothyroidism and low thyroid hormone levels. Thyroid hormone resistance may be more difficult to exclude as T4 and T3 levels can also be elevated. These patients, however, tend to be clinically euthyroid or hypothyroid, have a family history of thyroid hormone resistance, and generally do not present with sellar masses. Alpha subunit levels in these patients are usually not elevated.
Treatment should be directed initially at the adenoma via the transsphenoidal microsurgical approach. However, additional therapy is usually required because of the large size of these adenomas.
Somatostatin analogs normalize TSH and T4 levels in more than 70% of these patients when given in doses similar to those used for the treatment of acromegaly (see discussion earlier). Shrinkage of the tumor has been observed in about 40% of patients.
If tumor growth and TSH hypersecretion cannot be controlled by surgery and somatostatin analogs, the next step is pituitary irradiation. In addition, such patients may also require ablative therapy of the thyroid with either 131I or surgery to control their thyrotoxicosis.
Nonfunctional Pituitary Adenomas
“Nonfunctional” chromophobe adenomas once represented approximately 80% of all primary pituitary tumors; however, with clinical application of radioimmunoassay of anterior pituitary hormones, these tumors currently account for only about 10% of all pituitary adenomas. Thus, the great majority of these chromophobe adenomas have now been documented to be PRL-secreting; a smaller number secrete TSH or the gonadotropins.
Nonfunctional tumors are usually large when the diagnosis is established; headache and visual field defects are the usual presenting symptoms. However, endocrine manifestations are usually present for months to years before the diagnosis is made, with gonadotropin deficiency being the most common initial symptom. Hypothyroidism and hypoadrenalism are also common, but the symptoms are subtle and may be missed.
Evaluation should include MRI and visual field testing; endocrine studies should include assessment of pituitary hormones and end-organ function to determine whether the adenoma is hypersecreting or whether hormonal replacement is needed.
Because these tumors are generally large, both surgery and radiation therapy are usually required to prevent tumor progression or recurrence. In the absence of an endocrine index of tumor hypersecretion such as PRL excess, serial scans at yearly intervals are required to assess the response to therapy and to detect possible recurrence.