Principles and Practice of Endocrinology and Metabolism



Pathogenesis of Hypopituitarism


Other Mechanical or Compressive Lesions




Infiltrations and Infections


General Principles

Clinical Presentation and Diagnostic Tests
Adrenocorticotropin Deficiency



Laboratory Assessment
Thyroid-Stimulating Hormone Deficiency



Laboratory Assessment
Gonadotropin Deficiency in Men



Laboratory Assessment
Gonadotropin Deficiency in Women



Laboratory Assessment
Growth Hormone Deficiency



Laboratory Assessment
Prolactin Dysregulation



Laboratory Assessment
Anterior Pituitary Hormone Hypersecretion
Vasopressin Dysregulation
Oxytocin Dysregulation
Conditions that Mimic Hypopituitarism
Endocrine Replacement Therapy

General Principles

Glucocorticoid Replacement

Thyroid Hormone Replacement

Gonadal Steroid Replacement

Testosterone Replacement

Estrogen Replacement

Growth Hormone Replacement

Vasopressin Replacement

Prolactin and Oxytocin
Chapter References

The pituitary gland comprises anterior and posterior divisions. The anterior pituitary gland secretes adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin. The posterior pituitary gland secretes antidiuretic hormone (ADH) and oxytocin. Signs and symptoms of hypopituitarism result from reduced secretion of one or more of these hormones. Although some patients have total failure of pituitary function (i.e., panhypopituitarism), more commonly, only one or several hormones are deficient (i.e., partial hypopituitarism). Deficiency of only one pituitary hormone is called selective or isolated hypopituitarism. This chapter will deal primarily with deficiencies of anterior pituitary hormones of adults (see Chap. 25 and Chap. 26 for a more complete discussion of deficiencies of ADH and oxytocin and Chap. 18 and Chap. 198 for pediatric neuroendocrine and GH dysregulation).
The most common selective deficiencies are those of GH or the gonadotropins. In progressive loss of pituitary function, as with a slowly growing pituitary adenoma, TSH, ACTH, and ADH are often the last to be diminished, not uncommonly in that order. Because the causes and manifestations of hypopituitarism are protean, the prevalence of hypopituitarism is difficult to estimate accurately. However, the major cause of hypopituitarism is pituitary tumors. Prevalence of pituitary tumors in the United States was reported to be 22,517, although this is probably an underestimate.1
Anterior pituitary hormone deficiencies lead to end-organ failure (e.g., diminished ACTH leads to decreased adrenal cortisol production). Syndromes associated with pituitary hormone insufficiency are termed secondary or central (e.g., decreased adrenal cortisol production that is due to diminished ACTH secretion is termed secondary or central hypoadrenalism). Technically, hormone deficiency syndromes resulting from hypothalamic failure should be called tertiary, but hypothalamic hormones are not measured in clinical practice. Consequently, conditions resulting from inadequate levels of either hypothalamic or pituitary hormones are referred to as secondary hormone deficiencies.
In general, pituitary hormone levels vary widely throughout the day and are dependent on feedback inhibition by target organ hormones. An exception to this is the maintenance of normal prolactin levels via tonic inhibition of prolactin secretion by dopamine.2,3 An essential concept in the evaluation of pituitary dysfunction is that except for prolactin, measurement of pituitary hormone levels alone has no role in the diagnosis of pituitary hormone insufficiency. For example, a normal level of TSH does not rule out secondary hypothyroidism. It is important to remember that low thyroid hormone levels should lead to increased levels of TSH. Therefore, a “normal” or frankly low level of TSH in the presence of low thyroid hormone levels may be evidence of secondary hypothyroidism.
A variety of symptoms and signs—resulting from mass lesions (e.g., tumors) affecting the pituitary gland and from pituitary hormone deficiencies—may suggest hypopituitarism. Moreover, manifestations of hypopituitarism are often nonspecific and subtle; recognition is frequently delayed and misdiagnosis is common. The signs and symptoms of hormonal deficiency are inadequately relieved by symptomatic measures but respond well to specific hormone replacement therapy.
Table 17-1 lists many of the causes of hypopituitarism. There are no reliable statistics for the percentage of patients in each subgroup, but pituitary tumors represent the largest single category, and a pituitary adenoma (see Chap. 11) is the most common single cause of hypopituitarism in adults.

TABLE 17-1. Pathogenesis of Hypopituitarism

Pituitary adenomas originate within the sella from one of the cell types found in the anterior pituitary. They may be secretory, with a resultant increase in the serum concentration of one of the pituitary hormones and evidence of, for example, Cushing syndrome or acromegaly. Alternatively, the adenoma may be clinically nonfunctioning, without evidence of hormonal hypersecretion; however, some clinically nonfunctioning tumors secrete hormonal precursors with diminished or absent biologic activity.4 Even when an adenoma is hypersecretory, concomitant evidence of hypopituitarism is common because of the tumor effects on adjacent nontumorous pituitary tissue. Patients with microadenomas (<10 mm)may or may not have hormone deficiencies; they most commonly have diminished gonadotropin secretion.5,6 At least 30% of patients with macroadenomas (>10 mm) have a deficiency of one or more pituitary hormones, most commonly GH.1
Craniopharyngiomas(see Chap. 11) may be sellar—or more often, suprasellar—and frequently contain calcifications. These tumors are congenital and may cause growth retardation, diabetes insipidus (DI), or mass-related symptoms. They commonly cause hypopituitarism in children, but symptoms may not appear until adulthood.7
Other tumors can occur in the pituitary or hypothalamic area and cause compression and hypopituitarism. Among the many possibilities are meningiomas, gliomas, and metastases, especially from breast and lung cancer. Pinealomas (see Chap. 10) are worthy of special mention because they often respond well to radiotherapy. If the computed tomography (CT) or magnetic resonance imaging (MRI) scan shows a tumor in the pineal area, the serum and cerebrospinal fluid should be tested for a-fetoprotein and b-human chorionic gonadotropin, and the cerebrospinal fluid cytology should be checked. In the past, when biopsy of the pineal area was associated with a much greater risk, treatment was customarily initiated based on the previously described tests alone if the results were compatible with the diagnosis of pinealoma. However, these results were sometimes misleading. Biopsies in the pineal area can be done more safely now, and some physicians recommend that the diagnosis be confirmed by biopsy before treatment is initiated.8
The mechanisms by which pituitary tumors cause hypopituitarism include mechanical compression of normal pituitary tissue and interference with delivery of hypothalamic hormones to the pituitary via the hypothalamic-hypophysial portal system. In addition, supraphysiologic prolactin levels may diminish hypothalamic gonadotropin-releasing hormone (GnRH) secretion, resulting in decreased gonadotropin secretion and hypogonadism. A patient with a pituitary tumor of any size may have a deficiency of one or any combination of hormones. Therefore, upon diagnosis of a pituitary tumor, before therapy, the hypothalamic–pituitary–adrenal (HPA) axis and hypothalamic–pituitary–thyroid (HPT) axis should be evaluated, and prolactin should be measured. Evaluation of other axes may be undertaken, depending on individual circumstances. Hypopituitarism caused by a pituitary tumor may be reversible; surgical removal of the tumor or shrinkage via medical therapy is often accompanied by return of normal pituitary function. However, treatment of pituitary tumors with surgery or radiotherapy may worsen or cause hypopituitarism.
The discovery of an enlarged sella turcica on a skull radiographic film suggests a pituitary tumor. However, the empty sella syndrome (see Chap. 11 and Chap. 20) is another common cause of an enlarged sella.9 The sella may be enlarged and the pituitary gland compressed by pressure from meningeal tissue that has herniated into the sella. Although the pituitary is atrophic and the sella cavity appears empty on radiologic studies, because there is sufficient residual functioning pituitary tissue, the patient is typically endocrinologically normal; nevertheless, hormonal deficiencies occasionally occur. A CT or MRI scan of the head can usually differentiate a pituitary tumor from the empty sella syndrome. Usually no pituitary tumor is present, but there occasionally may be a microadenoma in the residual pituitary tissue.
A neurosurgical procedure in the pituitary-hypothalamic region may lead to pituitary tissue destruction and hypopituitarism.10 Severe head trauma, particularly if complicated by a basal skull fracture, may result in interruption of the pituitary stalk and consequent hypopituitarism.11 Rarely, an intrasellar carotid artery aneurysm can cause compression and destruction of pituitary tissue and hypopituitarism.12
The pituitary gland enlarges during pregnancy, making it more vulnerable to a reduction in blood flow. Sheehan syndrome results from ischemic pituitary necrosis, which typically follows an episode of severe hypotension during pregnancy, usually a result of major blood loss at the time of delivery or shortly thereafter.13 Symptoms are often obvious soon after delivery, but they may be delayed. The patient typically is unable to lactate postpartum and experiences amenorrhea or hypomenorrhea. Hypothyroidism usually occurs, and there may be concomitant hypoadrenalism. Sheehan syndrome has become much less common as obstetric techniques have improved. Rarely, the physician may see similar pituitary necrosis in a male or nonpregnant female patient who presumably has severely compromised pituitary blood flow from, for example, diabetes mellitus or sickle cell disease.
The acute and often dramatic symptoms of pituitary apoplexy (see Chap. 11) result from hemorrhagic infarction of a pituitary adenoma; hypopituitarism may result.14 A pituitary tumor may have been diagnosed previously, or apoplexy may be its first recognized clinical manifestation. The patient may report severe headache and then become comatose; there may be an accompanying loss of vision and ophthalmoplegia from pressure on adjacent neural structures. A head CT scan shows hemorrhage in the pituitary area, and decompressive surgery may be needed on an emergency basis. Occasionally, a pituitary tumor may be totally destroyed by pituitary apoplexy, resulting in remission of hormonal and mechanical effects and cure of hormonal hypersecretion.14a An imaging study of a patient with a pituitary tumor may show evidence of old hemorrhage into the tumor, but the patient typically cannot recall any symptoms that might have been associated or may remember a severe headache without other complications. Such limited hemorrhages are much more common than the larger hemorrhages that cause the clinical syndrome of pituitary apoplexy.
Pituitary infarction from any cause may be life threatening; hormone replacement therapy with glucocorticoids and thyroid hormone should not be delayed and should be initiated before diagnosis. Pituitary imaging and neurosurgical consultation should be obtained immediately. With expedient, proper management, most patients do well.
Radiotherapy (see Chap. 22), specifically to the pituitary area or as part of broader treatment of a head or neck tumor, may cause hypopituitarism.15,16 Radiotherapy-induced hypopituitarism is dose dependent and often delayed. Most patients who receive radiotherapy will go on to develop partial or complete hypopituitarism. However, the length of time from the administration of radiotherapy to the onset of pituitary hormone deficiencies is highly variable. Therefore, patients who have received any form of pituitary or head and neck radiotherapy should undergo evaluation of pituitary function at regular intervals for life. Patients should be educated about symptoms of pituitary hormone deficiency and should be instructed to contact a physician if any of these symptoms develop. Some practitioners recommend evaluation of pituitary hormone axes every 3 months for the first year after radiotherapy and then yearly thereafter.1 The regular interim visits should include evaluation of the HPA and HPT axes and measurement of prolactin. Axes that are failing but not yet in the abnormal range should be evaluated more frequently, or hormone replacement therapy should be initiated, depending on the clinical situation. In general, practitioners should have a low threshold for initiating hormone replacement therapy.
Lymphocytic hypophysitis refers to an autoimmune process that involves the anterior pituitary gland; it is most commonly seen in women in late pregnancy or postpartum, although it may occur in nonpregnant women or in men. There may be clinical signs of a pituitary mass or hypopituitarism, and there may be accompanying evidence of autoimmune disease elsewhere in the endocrine system.17
Many infiltrative or infectious processes can occasionally cause anterior or posterior pituitary dysregulation (see Table 17-1 and Chap. 11 and Chap. 213). These diseases usually present with their respective classic signs and symptoms. Occasionally, hypopituitarism is the first, only, or most severe manifestation.
There are several miscellaneous causes of hypopituitarism, including the inevitable idiopathic classification.18 One unfortunately common—although potentially preventable—cause is the discontinuation of hormone therapy in someone who has been receiving replacement for a known endocrine deficiency or who has been receiving pharmacologic doses for a nonendocrine disease. Patients taking glucocorticoid replacement therapy for primary or secondary hypoadrenalism have limited or no endogenous glucocorticoid production and should receive larger doses when significant physiologic stress occurs. In particular, pharmacologic (supraphysiologic) doses of glucocorticoids given as therapy for nonendocrine diseases, such as rheumatoid arthritis, may lead to adrenal atrophy and impair one’s ability to produce endogenous glucocorticoids. Importantly, patients who have received pharmacologic doses of glucocorticoids for 2 weeks or more may be at risk for hypoadrenalism, even after the glucocorticoids have been discontinued. After discontinuation, these patients may have the capacity to produce sufficient amounts of endogenous glucocorticoids during normal day-to-day functioning, but have a diminished capacity to produce sufficient glucocorticoids during times of significant physiologic stress for as long as 1 year afterward (see also Chap. 78).
Another category worthy of comment is Kallmann syndrome (see Chap. 16 and Chap. 115), a form of isolated gonadotropin deficiency that sometimes can be diagnosed by history alone.19 Usually, the patient consults a physician because he failed to go through puberty. If a very poor or absent sense of smell has been present since birth, it is likely that the patient has Kallmann syndrome, a congenital and sometimes familial form of hypogonadotropic hypogonadism, which is caused by a developmental failure of neuronal migration of the olfactory neurons and of the neurons responsible for GnRH secretion. Aplasia of the olfactory gyri and absence of the olfactory bulbs and tracts may be detected by MRI scan. This syndrome is not accompanied by a pituitary tumor or by clinical failure of the other pituitary functions. The physician must specifically inquire about the sense of smell, because the patient usually does not volunteer this seemingly insignificant detail. (Because the anosmia or hyposmia is congenital in Kallmann syndrome, a later onset might indicate a tumor, trauma, or sinusitis.) Selective deficiency of GH may occur as a familial or sporadic phenomenon (see Chap. 12 and Chap. 198).
The history and physical examination (Fig. 17-1; see Table 17-1 and Table 17-2) will usually help in the selection of subsequent laboratory studies. Some hormonal deficiencies or even a mass lesion may be inapparent from the history and physical examination alone and can be detected only by an appropriate laboratory and radiologic survey. The laboratory evaluation for hypopituitarism can be divided into initial screening tests and supplemental tests that should be considered if the initial results are abnormal (Table 17-3).

FIGURE 17-1. Hypopituitarism. A 55-year-old man with recent-onset hypopituitarism caused by a clinically nonfunctioning pituitary tumor. The skin is pale, and there is an almost total lack of body hair. Test results revealed a deficiency of gonadotropins and thyroid-stimulating hormone.

TABLE 17-2. Symptoms and Signs of Hypopituitarism

TABLE 17-3. Laboratory Evaluation of Hypopituitarism

The most effective initial approach to detecting adrenal or gonadal hypofunction is to assay the target gland hormones, even if the underlying defect is thought to be at the pituitary level. The serum concentrations of the target gland hormones are less variable than pituitary hormone levels and are generally more useful for differentiating subnormal from normal target gland function. If any of these target hormone values are diminished, the serum levels of the corresponding pituitary hormones should be measured. Because primary hypothyroidism is commonly seen in clinical practice, and because serum TSH is a very sensitive test used to diagnose primary hypothyroidism, many clinicians are in the habit of measuring TSH to diagnose hypothyroidism. However, if secondary hypothyroidism is suspected, the target gland hormone (free thyroxine [FT4]) should be measured. Evaluation of GH deficiency in adults is typically not undertaken unless definite pituitary pathology is documented. Serum prolactin is usually measured as part of any evaluation for hypogonadism or hypopituitarism.
If a target gland hormone is definitely deficient, and the corresponding pituitary hormone concentration is clearly elevated, the diagnosis is primary target-gland failure. If, however, the pituitary hormone value is subnormal, this is consistent with deficiency at the level of the pituitary or hypothalamus. In the presence of frank target gland failure, a normal pituitary hormone concentration in the serum may represent biologically hypoactive hormone.20
The tests recommended in Table 17-3 usually provide good discrimination between normal and abnormal endocrine states, but false-positive and false-negative results are seen, often in conjunction with certain medications and diseases. Table 17-4 lists the factors that can lower hormone values and cause false-positive diagnoses, and those that raise the hormone values and could obscure a true-positive result. Four general mechanisms account for most of this interference. First, the target gland hormones of the thyroid, adrenal gland, and gonads circulate partially bound to specific carrier proteins; any medication or disease that changes the hepatic synthesis of a carrier protein also changes the concentration of total hormone, even if the hormonally active free fraction remains constant throughout. Second, hypersecretion or hyposecretion of one pituitary hormone may cause a change in the concentration of another pituitary hormone. The latter abnormality disappears when the former is corrected by appropriate therapy. The suppression of gonadotropins by hyperprolactinemia is one example. Another is the increase of serum TSH concentration that occasionally can be seen in untreated primary or secondary hypoadrenalism.21 Third, diseases that affect urinary excretion (e.g., uremia, nephrotic syndrome) or alter hepatic degradation (e.g., various liver diseases, hypothyroidism)—as well as severe, stressful illness—may alter hormone concentrations. The euthyroid sick syndrome, common in intensive care units or among other similarly stressed patients, mimics the laboratory findings of secondary hypothyroidism.22 Fourth, some medications are a potential source of error. Phenytoin and high doses of salicylates can bind to the hormonal binding sites on thyroxine (T4) binding proteins; this results in a decrease in total T4 concentration, but the FT4 determination remains unaltered. The information summarized in Table 17-4 can alert the physician to most cases of potential misinterpretation. However, if the clinical picture and the test results do not initially seem to agree, the prudent course is to review both carefully before rejecting either.

TABLE 17-4. Some Causes for Decreased or Increased Hormone Values Other Than Intrinsic Disease of the Respective Endocrine Gland

All patients with hypopituitarism should have an MRI or CT scan (see Chap. 20). In many cases, an MRI study is preferable, because it provides better anatomic detail, may detect a microadenoma that is not visible on a CT scan, is better able to demonstrate whether a mass lesion is impinging on the chiasm, and can better differentiate an aneurysm from other mass lesions. However, an MRI is more expensive than a CT scan, and in some clinical situations a CT scan is sufficient (e.g., if the only purpose is to rule out a large tumor that would be easily seen with either technique). With current methods, some small pituitary tumors cannot be detected by either imaging method. Absence of a visible mass does not definitively rule out a tumor, and periodic follow-up examinations may be indicated. When MRI or CT is performed, it should be a “dedicated” study with thin sections through the sellar and suprasellar area, performed with and without contrast.1,23
If a pituitary mass is found, neuroophthalmologic examination should be conducted by an ophthalmologist, including the determination of visual fields by computerized threshold or Goldmann perimetry (see Chap. 19). Periodic follow-up examinations also may be indicated, as after surgical removal of a pituitary tumor to determine whether there has been a change from the preoperative examination or as one of several ways to monitor a pituitary mass lesion for possible progression.
Additional tests may be indicated when certain specific diagnoses are being considered. In a patient with DI and a negative MRI result with no obvious underlying cause, sarcoidosis should be considered, and a cerebrospinal fluid examination for protein; a chest radiograph; and hepatic, bone marrow, or lymph node biopsy should be performed. Rarely, hemochromatosis (see Chap. 131) or other infiltrative or infectious disease may manifest as hypopituitarism (see Table 17-1). The physician should consider such a possibility and carry out appropriate screening tests if there are clues suggesting one of these conditions.
In a patient with a known pituitary or hypothalamic tumor, some preoperative endocrine testing is indicated, although the neurosurgery may result in further changes in endocrine status (Table 17-5). Hypothyroidism and hypoadrenalism should be sought. Untreated hypothyroidism increases the risk of an operative procedure; it is prudent to consider delaying pituitary exploration until the hypothyroidism is safely corrected.24

TABLE 17-5. Management of Hypopituitarism: Intercurrent Illnesses, Long-Term Follow-Up, and Perioperative Care at the Time of Pituitary Surgery

If hypoadrenalism and hypothyroidism coexist, the hypoadrenalism should be treated before, or along with, any hypothyroidism; restoration to a euthyroid state without correction of concomitant hypoadrenalism sometimes precipitates acute hypoadrenalism with adrenal crisis. If a pituitary tumor is clinically nonfunctioning, the physician may wish to obtain additional tests preoperatively to determine if the tumor is secreting one or more hormonal products that may be clinically silent. Prolactin, FSH, LH, and the a-Subunit are all substances that under certain circumstances may fail to produce associated signs or symptoms. The a-subunit is a polypeptide chain that is part of the structures of FSH, LH, and TSH; the serum concentration of free a-subunit is increased above normal if a pituitary tumor secretes this peptide. If hypersecretion of any of these products is found, another measurement later in the course can serve as an additional criterion of the completeness of surgical resection or tumor recurrence. It is especially important to measure prolactin because the first-line therapy of a prolactin-secreting adenoma is usually dopamine agonist therapy and not surgery (see Chap. 13).
After pituitary surgery, close endocrinologic and neurosurgical evaluation is required (see Chap. 23 and Table 17-5). The immediate postoperative period should include measurement of serum sodium and urine-specific gravity at regular intervals, at first several times per day and then less frequently, for as long as 2 weeks after surgery. This regimen should diagnose immediate or delayed onset of DI or the syndrome of inappropriate ADH (SIADH); these conditions may occur with any manipulation of the pituitary or hypothalamus (see Chap. 25 and Chap. 208). Stress doses of glucocorticoid supplementation should have been initiated preoperatively and may be tapered as the patient improves postoperatively. However, maintenance doses of glucocorticoids should continue until adequate functioning of the HPA axis is confirmed. Obviously, replacement of any target gland deficiencies should continue postoperatively. The first follow-up appointment should occur as early as needed, but definitely within the first month after discharge from the hospital. Intervals between subsequent visits during the first year after surgery can be individualized. Each postoperative visit should include a history and physical examination designed to determine the presence of hypopituitarism. Evaluation of HPA and HPT axis function and serum sodium should occur multiple times during the first postoperative year. Evaluation of HPA axis function and management of glucocorticoid therapy after surgery for Cushing disease or Cushing syndrome may be quite complex (see Chap. 14, Chap. 23 and Chap. 75). Patients cured of Cushing disease or Cushing syndrome may require a protracted course of glucocorticoid supplementation. Medical therapy of Cushing syndrome may render the patient hypoadrenal, and replacement glucocorticoids and/or mineralocorticoids may be necessary.
The initial evaluation of hypopituitarism (including stimulation and suppression tests, 24-hour urine collections, visual field testing, and head CT or MRI scan) often can be conducted on an outpatient basis, unless the patient is acutely ill at the time of presentation. It is best to start with simple tests of baseline target-organ secretion and then to be selective in applying the many available additional tests. If a pituitary tumor is discovered and surgery is planned, the initial hormonal survey can be limited, and more extensive evaluation can be deferred until after surgery, at which time the need for long-term replacement therapy is determined.
Patients with hypopituitarism should have laboratory tests repeated annually or more often, depending on the clinical situation. In progressive forms of hypopituitarism, testing enables the detection of new deficits before they become symptomatic, and testing also can be used to monitor the adequacy of established hormonal regimens. The evaluation of pituitary and end-organ function is more completely discussed elsewhere (see Chap. 33, Chap. 74 and Chap. 114). For long-term surveillance, if hypopituitarism has been caused by a definite or suspected mass lesion, annual visual field testing is usually indicated. The frequency of head CT scanning or MRI is individualized, because both tests are expensive and the former involves radiation and iodide-contrast exposure. During the year immediately after removal of a mass lesion, the neurosurgeon or endocrinologist may wish to obtain more than one scan. If the lesion remains stable, the frequency of MRI or CT scans may revert to annual examinations for 1 or 2 years and then less fequently, unless there is some clinical suggestion of a recurrence. If a secretory tumor has been resected, a later rise in the serum concentration of the relevant hormone is one reason to suspect a recurrence and to repeat the CT or MRI scan.
It is important to recognize when symptoms are not caused by hypopituitarism. Patients with proven hypopituitarism may also develop other, more common conditions with symptoms that may be confused with the nonspecific symptoms of endocrine disease. For instance, anxiety and depression are common, and patients with hypopituitarism are not immune to such problems. In the presence of a new symptom, it should not be automatically assumed that the hormonal regimen should be changed. If endogenous serum hormone concentrations are normal, if the patient is already at the conventional upper limit of hormonal drug dosage, or if the patient has previously been stable on that dosage for many months, another diagnosis should be sought. A careful history and physical examination should be obtained, and hormone measurements should be repeated and other pertinent tests performed before making any medication changes.
Patients with hypopituitarism first seek medical attention for relief of symptoms and signs related to (a) a space-occupying lesion in the sella turcica or parasellar region, and/or (b) pituitary hormone dysregulation (see Table 17-2).
In general, the larger the lesion in the sella turcica or parasellar region, the more likely is the lesion to compress surrounding structures, leading to pressure-related phenomena. A patient with a functioning pituitary tumor may present to a clinician with symptoms or signs of hormone excess (see Chap. 12, Chap. 13, Chap. 14, Chap. 15 and Chap. 16), pressure symptoms, and/or symptoms of diminished pituitary hormone secretion. Most commonly, a patient with a nonfunctioning pituitary tumor or other space-occupying lesion first seeks medical attention for pressure symptoms, even when hormonal deficiencies antedate these phenomena.
Headache, caused by traction on the meningeal membranes, is a common manifestation of a space-occupying sellar lesion. Often, such headaches are nonpulsatile, dull and poorly localized, and difficult or impossible to differentiate from many other forms of headache. Routine radiologic studies cannot be recommended to look for the small percentage of headache patients with pituitary tumors, unless there are additional clues such as new onset, progressive worsening, or incapacitating headaches; or an accompanying hormonal, ophthalmologic, or neurologic abnormality. Space-occupying lesions may compress the optic chiasm and lead to reports of diminished visual acuity or decreased peripheral vision. Further evaluation during the physical examination or by more formal methods of visual field testing may reveal deficits suggesting chiasmal compression (e.g., bitemporal hemianopia, superior lateral quadrantanopia; see Chap. 19).25 Extraocular muscle paresis caused by pressure on the cranial nerves or nuclei lateral to the sella is seen occasionally. A large lesion can cause hypothalamic symptoms (see Chap. 9) or result in anosmia, seizures, or even symptoms of frontal or temporal lobe dysfunction. Stroke and subarachnoid bleeding are rare but more acute manifestations associated with very large sellar lesions and pituitary apoplexy, both of which may interrupt the sellar or parasellar vasculature.
When a patient is suspected of having definite hypoadrenalism, hypothyroidism, or hypogonadism, the corresponding pituitary hormone should be assayed to determine whether the deficiency is primary (i.e., disease of the target gland itself) or secondary (i.e., insufficient stimulation of the target gland by the corresponding pituitary hormone). If the relevant pituitary hormone concentration is not clearly elevated, as it should be in the absence of feedback control, but instead is in the normal or subnormal range, a pituitary or hypothalamic cause must be suspected. To more accurately diagnose hypopituitarism, the pituitary hormone value should be checked before hormonal replacement is begun, because the exogenous target gland hormone would suppress the corresponding pituitary hormone. However, treatment, if urgent, need not always wait for the result.
Each anterior pituitary hormone is part of a tightly regulated axis composed of hypothalamic factors and target organ factors. Each component of the axis is involved in feedback regulation of the other components (see Chap. 12, Chap. 13, Chap. 14, Chap. 15 and Chap. 16). Pituitary hormones can be diminished alone or in combination; therefore, consideration of hypothalamic-pituitary target organ axes individually will provide a logical framework for diagnosing the complex and overlapping manifestations of hypopituitarism.
The HPA axis is the most crucial and may be the most challenging pituitary axis to evaluate, because symptoms and signs of ACTH and cortisol deficiency are often nonspecific. Selective ACTH deficiency is rare; usually, other pituitary hormones are deficient as well.26
Physiologic effects of cortisol are protean. Consequently, cortisol deficiency often leads to subtle, nonspecific manifestations, but may be life threatening. Symptoms include weakness, fatigue, weight loss, and diminished sense of well-being. If a patient has neuroglycopenic symptoms and documented fasting hypoglycemia, evaluation for ACTH deficiency is indicated, along with a search for other causes (see Chap. 158 and Chap. 161). Abdominal distress, including nausea and vomiting, is often noted. A history of recently discontinued glucocorticoids should be sought.
Protracted secondary ACTH deficiency may lead to pale skin—including nipples and areolae—with decreased ability to tan. Diminished axillary and pubic hair may occur, especially in women. Postural hypotension is often seen; the pulse rate may be inappropriately normal or slow if concomitant hypothyroidism is present. With more acute hypoadrenalism, or during time of significant physiologic stress, patients may present with shock, which can be resistant to therapy.
The HPA axis comprises a tightly regulated feedback loop. The hypothalamus secretes corticotropin-releasing hormone (CRH) into the portal circulation, which is transported to the pituitary. There it acts to stimulate ACTH secretion into the peripheral circulation. ACTH stimulates cortisol secretion from the adrenal glands. Cortisol feeds back to inhibit CRH and ACTH secretion. Most cortisol is bound to cortisol-binding globulin (CBG), although the much smaller free or unbound component is the bioactive fraction. Factors that alter CBG production may affect total serum cortisol levels, which may not accurately reflect the free cortisol fraction. Estrogen stimulates hepatic production of CBG, whereas cirrhosis, nephrotic syndrome, and hyperthyroidism may lower CBG. However, in most clinical contexts, the total serum cortisol level is used to determine whether the adrenal glands are functioning properly. Many glucocorticoid preparations cross-react with the cortisol assay and should be avoided within 24 hours of testing.
In secondary hypoadrenalism, ACTH deficiency leads to decreased cortisol production by the adrenals; however, mineralocorticoid production typically remains adequate. Importantly, with most causes of primary hypoadrenalism, mineralocorticoid insufficiency is also present. Serum cortisol levels in normal persons and patients with hypoadrenalism often overlap considerably. Normally, serum cortisol levels demonstrate a diurnal variation. Peak cortisol levels usually occur between 6:00 and 8:00 a.m. and nadir at around 10:00 p.m. to midnight. With secondary hypoadrenalism, this diurnal variation may be maintained, but cortisol levels will be lower at any given time throughout the day. If CRH or ACTH secretion is abruptly interrupted, serum cortisol will drop to very low levels, often within hours. Therefore, pituitary apoplexy, Sheehan syndrome, and postoperative ACTH deficiency should be treated as emergent, potentially life-threatening situations. If hypoadrenalism is suspected and the patient is hypotensive, therapy with hydrocortisone, 100 mg intravenously every 8 hours, should not be delayed for diagnostic purposes. However, in this situation, measurement of the serum cortisol and ACTH level just before administration of glucocorticoids will be helpful diagnostically. Although the literature is often conflicting on this subject, one review provided the following guidelines: While a patient is hypotensive, a serum cortisol level ³18 µg/dLis evidence of adequate HPA axis function. A level of 13 to 18 µg/dL is indeterminate, and hydrocortisone administration should be continued until further testing can be carried out. A serum cortisol level of 5 to 13 µg/dL is presumptive evidence of hypoadrenalism, and a level <5 µg/dL is regarded as definite evidence of hypoadrenalism.27 If hypoadrenalism is diagnosed, a high ACTH level suggests primary hypoadrenalism, whereas a low or “normal” ACTH level suggests secondary hypoadrenalism.
With patients who are more stable, a variety of diagnostic tests can be utilized to determine whether hypoadrenalism exists. With each of these tests, an ACTH level may be drawn depending on the clinical context. Here, too, a frankly high ACTH level in a hypoadrenal patient would argue for primary hypoadrenalism, whereas a “normal” or low level would argue for secondary hypoadrenalism. The simplest test of the HPA axis is a cortisol level drawn between 6:00 and 8:00 a.m. A value of ³19µg/dL indicates an intact HPA axis, whereas a level <3µg/dLis definite evidence of hypoadrenalism.27 A value of 3 to 19µg/dLis indeterminate and requires further testing. Because most patients with or without hypoadrenalism will have values in the indeterminate range, this test is of limited value.
The cosyntropin stimulation test is a convenient, safe, and generally reliable dynamic test of the HPA axis. Cosyntropin, the synthetic bioactive portion of ACTH, is injected intravenously at a dose of 250 µg, and serum cortisol is measured at 0, 30, and 60 minutes. A cortisol level ³18µg/dLat any point indicates that the adrenal glands can be stimulated adequately.27 In most situations, this means that the HPA axis is intact. A lower value might indicate secondary hypoadrenalism. (See Chap. 76 and Chap. 241 for the use of the ACTH test in primary hypoadrenalism [Addison disease].)
It should be noted that if secondary hypoadrenalism has occurred within the recent past (usually taken to mean the preceding few weeks), atrophy of the adrenal gland, normally seen with ACTH deficiency, may not have had sufficient time to occur. Consequently, endogenous adrenal production of cortisol may be insufficient because of lack of endogenous ACTH, whereas pharmacologically augmented cortisol production using intravenously administered cosyntropin may still be possible. Cosyntropin, 250 µg intravenously, is a supraphysiologic stimulus of cortisol production. This has led to interest in the use of ACTH 1 µg intravenously in place of a 250-µg dose as being possibly a more discriminating test of HPA axis integrity.28
The most reliable dynamic test of HPA axis function is the insulin tolerance test (ITT). The rationale is that severe hypoglycemia produces maximal physiologic stress and should stimulate the entire HPA axis leading to augmented cortisol production. The test is carried out by administering regular insulin 0.1 to 0.15 U/kg intravenously and measuring serum cortisol and blood glucose levels at 0, 30, and 60 minutes. Blood glucose at 30 and/or 60 minutes must be <40 mg/dL for the test to be valid. A cortisol level ³18µg/dL indicates an intact HPA axis, whereas a value <18 µg/dL may indicate secondary hypoadrenalism. This test is contraindicated in elderly patients and with patients who have seizures or those with cardiovascular or psychiatric disease. A physician must be present and the intravenous catheter must remain in place with a 50% dextrose solution available in case of hypoglycemia.
The metyrapone test, like the ITT, is a test of the entire HPA axis. Metyrapone blocks 11b-hydroxylase activity in the adrenal gland; 11b-hydroxylase catalyzes the conversion of 11-desoxy-cortisol (11-S) to cortisol in the final step of the cortisol biosynthetic pathway. Therefore, if metyrapone is given to a normal individual, cortisol production decreases; this stimulates the pituitary to secrete ACTH. ACTH then stimulates the cortisol biosynthetic pathway in the adrenal gland. However, because metyrapone is blocking the final step, 11-S accumulates. Proper functioning of the HPA axis is confirmed by an 11-S value >7.0 µg/dL. In a patient with secondary hypoadrenalism, diminished cortisol does not lead to a rise in ACTH, and the 11-S level remains £7µg/dL. The metyrapone test requires an inpatient stay and may precipitate symptomatic adrenal insufficiency.
A less reliable test of hypoadrenalism, the urine free cortisol (UFC), measures free cortisol in a 24-hour urine collection. This test measures only the amount of cortisol that exceeds the binding capacity of CBG and is excreted in the urine; UFC levels are within the reference range in 20% of patients with hypoadrenalism.29 In contrast, UFC is a good screening test for cortisol excess (see Chap. 14).
Symptoms and signs of secondary hypothyroidism are similar to those seen with primary hypothyroidism, although they often are milder. The essential diagnostic differences relate to interpretation of the results of the laboratory assessment.
Cold intolerance, constipation, fatigue, and lethargy are common symptoms. Weight gain despite diminished appetite may occur. Patients or family members may note a slowing of cognitive and motor function as well as a deepening and hoarseness of the voice. Muscle cramping, including symptoms of carpal tunnel syndrome, is sometimes present. Women of childbearing years may report menorrhagia.
On physical examination, a myxedematous appearance with pale, cool skin that appears dry and doughy, and a large protruding tongue may be noted. Pulse rate is often slow and pulse pressure narrowed. Hair may be dry and sparse. Relaxation phase of the reflexes is prolonged. With more advanced hypothyroidism, hypothermia, hypoglycemia, stupor, and respiratory depression may, if left untreated, lead to death. In addition, children may demonstrate other age-dependent manifestations. Congenital hypothyroidism, although rarely of pituitary origin, may lead to cretinism (see Chap. 47). Linear growth may be inhibited in children and adolescents, leading to short stature.
The hypothalamus releases thyrotropin-releasing hormone (TRH) into the portal circulation. TRH is transported to the pituitary gland, where it causes release of TSH into the peripheral circulation. TSH binds to the thyroid, leading to release of T4 and, to a lesser extent, the bioactive thyroid hormone, triiodothyronine (T3). T4 is converted to T3 in peripheral tissues, including the pituitary. Both T4 and T3 exist primarily bound to thyroid-binding globulin and other blood proteins. The free fractions of T4 and T3 are the clinically important components. Many laboratories now utilize direct measurement of FT4, which is the preferable way to measure serum T4. However, sometimes the total T4 and T uptake are used to calculate a FT4 index (FT4I), which estimates the FT4 by taking into account variations in binding protein levels.
In secondary hypothyroidism, TSH deficiency leads to low levels of FT4. Therefore, an FT4 (or FT4I), as well as a sensitive TSH assay, must be obtained. The FT4 will be low, whereas TSH will be normal or subnormal. In contrast, with primary hypothyroidism, FT4 is diminished but TSH is elevated as a compensatory response. The T3 level can be normal or near normal in early hypothyroidism and is not usually measured as part of the initial workup. The FT4 can differentiate hypothyroidism from most nonthyroidal laboratory abnormalities.20 However, if the clinical setting suggests the possibility of the euthyroid sick syndrome (see Chap. 36), the FT4 may be low, with a normal or subnormal TSH. This is thought to be a compensatory response that down-regulates metabolism during physiologic stress, thereby preventing excessive catabolism. The underlying illness that is causing euthyroid sick syndrome should be treated; therapy with thyroid hormone is not recommended and may be harmful. In this situation, additional tests may be helpful; nevertheless, the clinician should be cautious in diagnosing hypothyroidism secondary to pituitary disease when a patient is experiencing a physically stressful illness or a period of caloric deprivation.
Rarely, a patient with long-standing primary hypothyroidism may develop significant pituitary enlargement and even chiasmal symptoms. Presumably, this occurs from chronic stimulation of the pituitary gland by the negative-feedback mechanism.30 Furthermore, a patient rarely may have a pituitary tumor that secretes bioactive TSH or may have resistance to thyroid hormone. Both of these conditions can result in elevated or normal serum concentrations of TSH with concomitantly elevated thyroid hormone levels (see Chap. 21 and Chap. 32).
A stimulation test with TRH is sometimes proposed to help differentiate secondary from tertiary (hypothalamic) hypothyroidism, but normal and abnormal results overlap considerably. Hence, this test result is often equivocal and should not be relied on as the sole criterion (see Chap. 33).
Most manifestations of decreased gonadotropin secretion in men are attributable to the resultant low testosterone levels. However, testosterone is converted to estrogens, and some manifestations of low LH and FSH may be due to low estrogen levels. Symptoms and signs of hypogonadism in men may be present for years before being appreciated and often are mistakenly attributed to normal aging. The patient’s sexual partner may be the first to notice and, when appropriate, should also be queried about symptoms and signs.
In men with secondary hypogonadism, decreased libido, impotence, and infertility are common. The patient may note that he shaves less frequently and that there is a decline in the rate of progression of male pattern hair loss. With long-standing hypogo-nadism, fatigue and a loss of muscularity may be noted. A history of hyposmia or anosmia may be elicited from patients with Kallmann syndrome. If symptoms begin before or during puberty, the patient may demonstrate lack of deepening of the voice, no need for deodorant, and concerns about social acceptance. In some cases, it may be difficult to differentiate hypogonadotropic hypogonadism from delayed puberty (see Chap. 7, Chap. 91 and Chap. 92).31
Evidence on physical examination includes pale skin with decreased axillary, facial, and pubic hair. Small, soft testes and a small prostate gland may be noted. In cases where onset was before or during puberty, a small penis and eunuchoid body habitus may be appreciated. Osteopenia and osteoporosis may be associated with hypogonadism from any cause (see Chap. 64).
GnRH is secreted in a pulsatile fashion into the pituitary portal circulation and is the major regulator of LH secretion. For every pulse of GnRH secreted into the portal circulation, a resultant pulse of LH is secreted into the peripheral circulation. Peripheral LH stimulates testosterone production by the testes. Along with other factors, GnRH also regulates FSH secretion. Spermatogenesis is dependent on testosterone and FSH.
The initial test of this axis should be a serum total testosterone or a serum free testosterone. Testosterone, like T4, is partially bound to serum proteins, and any alteration in the binding proteins also changes the total testosterone level. If a total serum testosterone is obtained initially and is found to be abnormal, this finding should be confirmed with a serum free testosterone measurement (see Chap. 114 for a discussion of free testosterone measurements).32 Moreover, a low serum testosterone measurement should be followed up with a serum LH and FSH determination. In secondary hypogonadism, LH and FSH levels will be in the normal or subnormal range despite a low total or free testosterone level. In primary hypogonadism, total testosterone and free testosterone levels are low, but LH and FSH levels are elevated as a compensatory response. When viewed by adult norms, normal children have hypogonadotropic values of LH and FSH, and these assays are usually omitted prepubertally. (Hyperprolactinemia is a possible cause of hypogonadotropic hypogonadism, and a determination of prolactin should be part of any laboratory assessment of hypogonadism.) Because a stimulation test with GnRH rarely provides clinically useful information for the individual patient, the author does not currently recommend it as part of routine management (see Chap. 16). If desired, in adults, testicular function can be evaluated with a semen analysis. Moreover, routine blood work in hypogonadal men may demonstrate a normocytic anemia.
Disrupted menstrual function, a very early manifestation of gonadotropin deficiency, often prompts premenopausal women to seek medical attention earlier in the course of hypogonadism than do men.
In women with secondary hypogonadism, menstrual dysfunction that manifests as dysfunctional uterine bleeding, oligomenorrhea, amenorrhea, or infertility is common. Diminished libido may occur. With persistence of hypogonadism, atrophy of breast tissue and of the vagina and labia may be noted. The latter may lead to dyspareunia. If prolactin is increased, galactorrhea may result. With Sheehan syndrome, failure to lactate postpartum may be noted. Hypogonadism with onset before or during puberty may result in delayed puberty; reports of lack of development of secondary sexual characteristics, including delayed menarche, and concerns about social acceptance may be present.
Physical examination may reveal decreased axillary and pubic hair, and breast and genital atrophy (as well as expressible galactorrhea, if hyperprolactinemia is present). Osteopenia and osteoporosis are associated with hypogonadism from any cause (see Chap. 64). Signs of hypogonadism in adolescent girls include persistence of prepubertal body habitus with delayed breast, genital, and pubic hair development.
Peripheral LH stimulates estradiol and to a lesser extent testosterone production by the ovary. Along with other factors, GnRH also regulates FSH secretion. Ovulation is dependent on estradiol and FSH.
In general, no laboratory assessment is necessary if the patient reliably describes entirely normal menstrual cycles; the hormone assays usually are normal if the menses are normal. One exception to this is that hyperprolactinemia may be present even if menses are normal. If the menses are not perfectly normal, a serum estradiol value should be obtained, and if it is low, the physician also should obtain serum FSH, LH, and prolactin concentrations. Postmenopausal women suspected of having hypogonadism should have serum FSH, LH, and prolactin measured. Postmenopausal women typically have increased FSH and LH levels; thus, “normal” or subnormal values are consistent with secondary hypogonadism. Increased prolactin is associated with many causes of hypopituitarism.
Extensive research has led to improved characterization of the consequences of GH deficiency in adults and to a better understanding of the risks and benefits of treatment. Patient subgroups include those who have childhood-onset GH deficiency that persists into adulthood and those who have adult-onset GH deficiency. Although the presentation and response to therapy overlap considerably, variation between the subgroups has been noted.33 The adult-onset subgroup frequently has other concomitant pituitary hormone deficiencies. Both subgroups may exhibit a varied constellation of symptoms and signs, and often have difficult diagnostic and management issues. GH replacement is expensive, requires many resources, and provides variable— although often profound—benefit to adult patients. Therefore, it is important to identify patients at risk for GH deficiency and prudently utilize confirmatory diagnostic tests on the patients who might be appropriate candidates for GH replacement. Because of the complexity of the diagnostic and management issues surrounding GH deficiency in adults, it is advisable to have an endocrinologist involved throughout the care of these patients.
Adult patients with GH deficiency may report increased abdominal adiposity and reduced muscle mass that leads to decreased strength, reduced vitality and energy, and a diminished exercise capacity. Impaired psychological well-being is a major component of the GH deficiency syndrome in adults. A depressed and sometimes labile mood, anxiety, and social isolation are common symptoms.34 Children with GH deficiency may report short stature compared with peers. A history of childhood GH deficiency should be sought in all patients with suspected hypopituitarism.
Signs are often very subtle and nonspecific. Affect may be depressed or labile. Patients may be obese with centrally distributed fat. Skin may be thin and dry, and extremities may be cool because of poor venous circulation.34 Parental heights may be used to calculate the predicted height of the patient; this may afford an objective criterion on which to base a diagnosis of short stature in cases of childhood-onset GH deficiency (see Chap. 7).
The hypothalamus secretes GH-releasing hormone into the pituitary portal circulation. GH-releasing hormone is transported to the pituitary, where it stimulates pulsatile GH secretion into the peripheral circulation. GH acts at liver and other tissues to induce insulin-like growth factor-I (IGF-I) synthesis and secretion. IGF-I is thought to mediate most of the metabolic and growth-enhancing effects of GH (see Chap. 12).
GH levels vary significantly throughout the day, and considerable disagreement exists about what constitutes laboratory confirmation of GH deficiency in adults. One definition of GH deficiency, in a patient with a compatible history, is a negative response to a standard GH stimulation test. A negative response may be taken to mean a peak serum GH of <5 ng/mL when measured by radioimmunoassay using a polyclonal antibody or <2.5 ng/mL when measured by immunoradiometric assay using monoclonal antibodies.35 Because hypoglycemia stimulates GH secretion, the ITT is a reliable way to detect GH deficiency in adults. Serum samples for GH and glucose are collected every 15 to 30 minutes for 90 minutes after administration of insulin. The same prior-mentioned caveats and patient contraindications apply to the ITT when it is utilized to evaluate for GH deficiency. Other provocative testing agents have been used, including clonidine and arginine. For an outline of GH stimulation tests and a discussion of diagnostic criteria for GH deficiency in children, see Chapter 12, Chapter 18 and Chapter 198. A serum IGF-I level is not a sensitive and specific test on which, alone, to base the diagnosis of GH deficiency. There are many factors—including a complex set of binding proteins, age, and gender—that determine serum IGF-I levels. A low serum IGF-I value is helpful but not diagnostic, and a normal value does not rule out GH deficiency.
Osteopenia and osteoporosis are more prevalent in adults with GH deficiency; bone densitometry may be helpful as corroborative diagnostic information and to guide therapy. Measurement of plasma lipid and lipoprotein levels often reveals a profile consistent with an increased risk of coronary artery disease.34 Formal muscle strength, exercise testing, and body composition testing is individualized.
Prolactin elevation may occur because of oversecretion by a pituitary adenoma that may or may not be detectable on pituitary imaging. Moreover, several medications and certain physiologic processes may increase prolactin (see Table 17-4); a slightly elevated value should be repeated (see Chap. 13).36 Rarely, serum prolactin may be elevated because of macroprolactinemia.37 In this condition, the serum contains a large-molecular-mass form of prolactin that is immunoreactive but without significant bioactivity. If the serum prolactin level is >200 ng/mL but no pituitary tumor is visible by appropriate MRI, this possibility should be considered.
Hyperprolactinemia may be asymptomatic; an elevated serum value may be a clue to the presence of a pituitary tumor or pituitary stalk impingement.36 However, prolactin elevation from any cause may result in signs and symptoms of hypogonadism in men or women.37,38 A history of osteopenia or osteoporosis may be present.
If hyperprolactinemia results in hypogonadism, the usual signs in men and women may occur (see respective sections of this chapter). Gynecomastia may occur in men. Galactorrhea occurs more commonly in women because estrogen priming of breast tissue facilitates this process.
Serum prolactin should be measured as part of any general screening for pituitary dysfunction (see Chap. 13). A persistently elevated prolactin value, without a pharmacologic, physiologic, or nonpituitary pathologic explanation (see Table 17-4) should be considered abnormal and likely due to a prolactin-secreting pituitary adenoma, even if pituitary imaging studies fail to demonstrate an abnormality. A moderately elevated serum prolactin may occur in disease or injury involving the hypothalamus. For serum prolactin, the upper limit of the normal range depends on which assay is used, but is typically 15 ng/mL for men and 20 ng/mL for women. Pituitary microadenomas that secrete prolactin (microprolactinomas) and macroadenomas that do not secrete prolactin but impinge on the pituitary stalk are typically associated with serum prolactin levels <250 ng/mL.36 In contrast, macroadenomas that secrete prolactin (macroprolactinomas) are typically associated with prolactin levels >250 ng/mL.36 Low prolactin levels are rare but may lead to failure of postpartum lactation.
If the serum concentration of a pituitary hormone is shown to be inappropriately elevated (not just appropriately increased in response to a target gland deficiency), there may be a pituitary tumor present and concomitant hyposecretion of other pituitary hormones. Patients with symptoms of the amenorrhea-galactorrhea syndrome (see Chap. 13), acromegaly (see Chap. 12), or Cushing disease (see Chap. 14 and Chap. 75) must be strongly suspected of harboring a hypersecretory pituitary tumor. The mechanism of any associated hyposecretion could be the compression of normal surrounding pituitary tissue by the tumor. However, in the case of a prolactin-secreting adenoma, concomitant hypogonadism may be caused by the hormonal effect of a high serum level of prolactin, suppressing gonadotropin production and decreasing the gonadal response to the gonadotropins.39 Almost always, first-line treatment of a prolactinoma is dopamine agonist therapy; hence, measurement of serum prolactin should be part of the preoperative evaluation.
Vasopressin (i.e., ADH) is synthesized in the magnocellular neurons of the anterior hypothalamus and transported and stored in the posterior pituitary gland. Vasopressin is secreted into the peripheral circulation and acts on the renal tubular cells to prevent free water loss. Serum osmolarity—and, to a lesser extent, volume status—regulate posterior pituitary vasopressin secretion. Deficiency of vasopressin may lead to polyuria, polydipsia, and free water loss with resultant hypernatremia. This condition is known as central diabetes insipidus (central DI) and can be temporary or permanent. It is common to lose several liters of water daily. Central DI usually indicates damage to the hypothalamus, either via suprasellar extension of a sellar or brain mass, trauma, or after extensive surgical resection. Appropriate secretion of vasopressin can often be seen with posterior pituitary damage if the hypothalamus remains intact. A patient who is alert, able to sense thirst, and can get to unlimited free water usually can drink enough to keep pace with free water losses. Of course, these patients need exogenous vasopressin treatment. However, a patient with DI and an altered sensorium or who is not able to get to free water is in a life-threatening situation; free water replacement and exogenous vasopressin treatment are urgently required. DI has other nonpituitary causes (see Chap. 25 and Chap. 206).
Vasopressin excess causes SIADH and may result in free water retention and resultant hyponatremia. Among other causes, hypothalamic and/or pituitary pathology may lead to SIADH. This condition, too, may be temporary or permanent. SIADH may be asymptomatic initially, and when more advanced, severe hyponatremia can result in stupor, seizure, coma, or death. Treatment is primarily with free water restriction. SIADH also has nonpituitary causes (see Chap. 25 and Chap. 206).
Diagnosis of central DI or SIADH is typically made by a history of polyuria or polydipsia, or by detecting serum sodium abnormalities in patients with known hypothalamic/pituitary pathology. Serum sodium and urinespecific gravity should be measured on all patients suspected of hypopituitarism. Patients who have undergone pituitary manipulation should have serum sodium measured routinely in the immediate postoperative period and at regular intervals for 2 weeks after surgery, because onset of SIADH or DI can be delayed (see Table 17-5). More extensive testing may be necessary (see Chap. 25 and Chap. 206).
Oxytocin deficiency is rare and may result in problems during parturition (see Chap. 25). Oxytocin is not routinely measured.
The syndrome of hypopituitarism frequently includes nonspe-cific symptoms, such as weakness and fatigue. Because such symptoms are frequently psychogenic or, if organic, may be secondary to a variety of diseases, it is not cost-effective to screen specifically for hypopituitarism unless there are additional clues.
Two specific syndromes may superficially mimic hypopituitarism. Anorexia nervosa (see Chap. 128) is a form of deliberate chronic starvation, most commonly seen in young women and likely to have a psychiatric cause.40 The presence of amenorrhea with low gonadotropin levels and borderline low thyroid function test results suggests pituitary disease, but these are compensatory hormonal changes seen in any form of starvation. A patient with anorexia nervosa appears obviously emaciated, an unexpected component of hypopituitarism.
In the syndrome of autoimmune polyglandular hypofunction(see Chap. 197), hormonal deficiencies of two or more endocrine glands are common, and if these are target glands of the pituitary, a pituitary cause naturally is considered.41 However, measurement of the relevant pituitary hormones in this syndrome indicates that these are primary rather than secondary deficiencies. Furthermore, there may be other endocrine deficiencies that cannot be explained by hypopituitarism, such as diabetes mellitus or hypoparathyroidism. Circulating serum antibodies directed against endocrine tissues are often present. Lymphocytic hypophysitis also may be a component of this syndrome, but this represents a true cause of hypopituitarism.
Hypopituitarism can be an exceptionally satisfying condition to treat; most of its endocrine signs and symptoms can be completely relieved by suitable hormone replacement therapy. There are two general principles for prescribing a replacement regimen. First, the physician should perform suitable testing and treat only patients who are demonstrably borderline or deficient. Second, when there is failure of an endocrine target gland (e.g., thyroid, adrenal, gonad), regardless of whether the deficiency is primary or secondary, the physician should replace the target-gland hormone (e.g., cortisol) rather than the corresponding pituitary hormone (e.g., ACTH). Table 17-6 lists some commonly used endocrine replacement medications and typical adult doses.

TABLE 17-6. Maintenance Medications for Hypopituitarism

When testing demonstrates borderline-low secretion of a hormone, particularly cortisol, in an asymptomatic patient, it is unclear whether the patient should be treated. Many patients with lower-than-normal glucocorticoid secretion can tolerate even a major stress adequately, but, if possible, it is prudent not to take this risk. If the baseline serum cortisol concentration is borderline deficient, some physicians believe that extended treatment is better because the patient acquires the habit of taking glucocorticoid and may be more likely to think of increasing the dose appropriately at the time of an intercurrent illness. Others prefer to have the patient keep a supply of cortisol at home and take it only for intercurrent illness. The choice of treatment plan should be individualized.
More informed choices can be made if the physician becomes familiar with local costs of the various relevant diagnostic tests and of medications. In general, the costs of maintenance endocrine medications are low and are not of significant economic concern, with the exceptions of GH therapy and gonadotropin treatment to promote fertility. For long-term follow-up, the most cost-effective strategy is to minimize hospitalizations. A central part of this strategy is to schedule follow-up office visits every 6 to 12 months after the patient is clinically stable. At these visits, the physician can answer questions and continue to educate the patient about his or her disease, as well as maintain a good rapport with the patient. This will increase the likelihood that the patient will phone for advice at a time when prompt treatment of an intercurrent illness can help prevent complications and hospitalization.
Cortisol (i.e., hydrocortisone) or cortisone can be used for replacement therapy. Cortisone is converted to cortisol after ingestion. Cortisol is the predominant glucocorticoid secreted by the human adrenal gland, and an adult produces ~10 mg daily in the unstressed state.42 There is a diurnal rhythm, with greater secretion in the morning and less in the evening. The serum half-life is ~1 hour.
When cortisol is used for adrenal replacement in the adult, it is commonly given in dosages of 30 mg daily; for example, 20 mg each morning and 10 mg each afternoon or evening. For smaller individuals, 20 mg daily is sufficient (e.g., 10 mg twice daily). This cortisol dosage exceeds normal daily adrenal secretion, but there are losses in absorption; also, undoubtedly, one to three doses daily is a less efficient mode of administration than the more continuous natural secretion. In the occasional patient who cannot reliably remember to take more than one dose daily, it may be best to give the entire dose in the morning (rather than risk undertreatment), or to use a glucocorticoid with a longer pharmacologic half-life. Some authors suggest every other day therapy. Cortisone is used interchangeably with cortisol, with 25 mg of cortisone considered equivalent to 20 mg of cortisol. Usually, there is little to favor one compound over the other, except habit or price. However, in severe liver disease, cortisol is preferable because the conversion of cortisone to cortisol occurs in that organ. Prednisone also can be substituted for cortisol, using the assumption that 5 mg of prednisone is equivalent to 20 mg of cortisol. Replacement doses of dexamethasone are not well defined, and there is considerable individual variation; the plasma disappearance half-life is longer than 4 hours, and once-daily dosing is often adequate. A typical dose would be 0.5 mg given at bedtime, with a range of 0.25 to 0.75 mg.
Although cortisol can be assayed in blood and urine, such determinations are not particularly useful in determining a replacement dose of cortisol for an individual patient. The serum half-life is short, so that the serum concentration can be above or below the normal range much of the time, even when a patient is responding well to the dose. The free cortisol in a 24-hour urine sample is often elevated on conventional cortisol dosage regimens.
Most patients do well on any of the aforementioned dosage regimens, manifesting no overt evidence of hypoadrenalism or Cushing syndrome. (However, one report suggests that in men with Addison disease, commonly used replacement doses of glucocorticoids may be associated with a low bone mineral density.43) Even allowing for the lesser efficiency of intermittent oral administration, it seems likely that the customarily used replacement doses are appropriate for most individuals. If, while using one of these regimens, a patient still has chronic symptoms that suggest hypoadrenalism, the physician should check for medication error or noncompliance. If neither is found, the symptoms are likely to be due to a cause other than hypoadrenalism. Some individuals experience a pleasant “high” with supraphysiologic doses of glucocorticoid, leading them to complain when they are returned to true replacement doses.44 A patient’s desire for euphoria is not a reason to continue higher-than-replacement doses indefinitely.
A patient with untreated or undertreated hypopituitarism potentially may be more vulnerable at the time of an intercurrent illness because of a lack of hormonal homeostatic mechanisms. Before therapy, or if therapy is insufficient, such patients are very sensitive to infections, surgical procedures, or drugs such as sedatives or narcotics. Glucocorticoid doses conventionally are increased for significant physical illness or for operative procedures in an attempt to mimic the normal physiologic response to such situations. Interestingly, studies of patients undergoing operative procedures suggest that conventionally prescribed “stress doses” of glucocorticoid are larger and are maintained for a longer period than usually would be needed to mimic normal cortisol production.45,46 A renal transplantation group reports that they no longer increase baseline immunosuppressive doses of glucocorticoid (5 to 10 mg of prednisone daily), even when patients are stressed by sepsis or surgery, and they believe such doses have been sufficient.47 It is likely that the same would be true for intercurrent illnesses. However, until further data are available, the recommendation is to give conventional stress doses during times of intercurrent illness and perioperatively when there is no known contraindication to that approach. For some situations, however—such as surgery of a diabetic patient whose disease becomes difficult to control on higher glucocorticoid doses, or for a patient who becomes psychotic with high glucocorticoid doses—there are reasons to minimize the dosage. In such a situation, the author gives only the equivalent of two or three times the usual replacement doses on the day of surgery and taper to replacement doses within 3 days in the absence of postoperative complications. The patient should be monitored carefully for possible signs of hypoadrenalism and given supplemental glucocorticoid if indicated. Hypoadrenal symptoms are readily reversed if recognized and treated promptly. Table 17-5 summarizes current recommendations concerning glucocorticoid administration in the presence of intercurrent illness or perioperatively.
Patients whose hypoadrenalism is secondary to ACTH deficiency usually secrete normal or near-normal quantities of aldosterone in response to the still intact renin-angiotensin system, although their responses to salt restriction are not completely normal.48 Hyponatremia in a patient with untreated hypopituitarism is most likely due to hypersecretion of ADH, rather than to mineralocorticoid deficiency; there usually is no evidence of salt or volume depletion, and the hyponatremia is rapidly corrected by glucocorticoid.49 In contrast to patients with Addison disease, patients with secondary hypoadrenalism rarely need replacement therapy with the mineralocorticoid fludrocortisone. Moreover, cortisol has some intrinsic mineralocorticoid activity; occasionally it may be necessary to provide a small dose of fludrocortisone for a patient taking a synthetic glucocorticoid, such as dexamethasone, that has less mineralocorticoid activity.
Perioperative management of patients undergoing surgery that will affect the pituitary gland presents special challenges (see Chap. 23 and Table 17-5). Evaluation of HPA axis function and management of glucocorticoid therapy after surgery for Cushing disease or Cushing syndrome may be quite complex (see Chap. 14 and Chap. 75). Patients cured of Cushing disease may require a protracted course of glucocorticoid supplementation. Medical therapy of Cushing syndrome may render the patient hypoadrenal, and replacement glucocorticoids and/or mineralocorticoids may be necessary.
L-thyroxine (L-T4) is the preferred replacement medication for patients with hypothyroidism (see Chap. 45). A typical replacement dosage of L-T4 is 75 to 150 µg daily, with some patients requiring as little as 50 µg and others as much as 200 µg daily; the total replacement dose is usually ~1.6 µg/kg per day. Elderly patients may need ~25 to 50 µg less than younger individuals.50,51 and 52 One dose daily is sufficient, because the half-life of L-T4 is ~1 week. The serum level of FT4 is used to judge the adequacy of the L-T4 dose. The aim for most patients is to keep the FT4 in the mid-normal range. If this goal is achieved, it is assumed that the body will convert T4 to T3 at a physiologically appropriate rate, and monitoring of the serum T3 level is not required. The serum TSH, which is most helpful in choosing the correct replacement dosage in primary hypothyroidism, cannot serve this purpose in secondary hypothyroidism, a condition caused by a deficiency of TSH. If an individual is elderly, has cardiovascular disease, or is severely hypothyroid, it is prudent to start with 25 µg per day and gradually increase the dose by 25 µg per month until the FT4 or FT4I normalizes. If the patient has none of these risk factors, the initial dose of 50 µg per day may be increased more rapidly in 25- to 50-µg increments. The correction of hypothyroidism in a patient with unrecognized hypoadrenalism can precipitate overt hypoadrenal crisis; the physician should begin glucocorticoid therapy before or along with the L-T4 if there is concomitant hypoadrenalism. Severe hypothyroidism, resulting in myxedema coma, may initially require large doses of L-T4.
A hypogonadal state is not life threatening, and emergency therapy is not needed. Adults with a deficiency are treated with estrogens or androgens to improve sexual functioning and for a general feeling of enhanced vigor and well-being (Fig. 17-2). In the premenopausal woman, estrogen helps to protect against osteopenia and osteoporosis. However, if hyperprolactinemia is present, therapy with bromocriptine should be tried first, because the resultant suppression of prolactin may return the gonadotropins and the target gland hormones to normal. There also is concern that if a prolactinoma is present, its growth may be stimulated by estrogens. The same phenomenon may be seen with the administration of testosterone, presumably because of partial conversion of testosterone to estradiol.53 Moreover, replacement of the gonadal hormones is relatively ineffective in the presence of hyperprolactinemia.38 Testosterone therapy in hypogonadal men may avert or improve osteoporosis, restores skin and body hair to normal, and is beneficial to muscle function. Gonadal hormone replacement may be contraindicated in patients with a history of certain medical conditions (e.g., breast cancer, phlebitis, and pulmonary embolism in women, and cancer of the prostate or breast in men). Consequently, patients receiving long-term gonadal replacement therapy should be monitored for the possible development of breast or prostate cancer to allow prompt discontinuation of the hormone.
Men may be treated with parenteral, transdermal, or oral androgens (see Fig. 17-2; see Chap. 119). The parenterally and transdermally administered androgen preparations are potent and have fewer important side effects than oral androgens. A testosterone transdermal system consists of a patch that is applied directly to the skin surface at 10:00 p.m. and delivers testosterone continuously; this regimen results in a serum testosterone concentration profile that mimics the normal circadian variation observed in healthy young men. A typical starting dose is one 5-mg patch. The dose can be increased or decreased to keep the morning testosterone level in the normal range. The most common adverse effect is irritation at the site of application of the patch. This can be treated with over-the-counter topical hydrocortisone cream applied after patch removal.

FIGURE 17-2. Clinically nonfunctioning pituitary tumor in a 53-year-old man. A, Skull radiograph film shows an enlarged, ballooned sella turcica (arrow) with eroded anterior and posterior clinoid processes. B, The patient has pale, “pasty” facies with no beard and fine wrinkling of the skin. Testing revealed gonadotropin deficiency. C, One year after having received testosterone injections every 3 weeks, the patient has responded to therapy.

A traditional, reliable method of androgen replacement in men uses long-acting testosterone esters given intramuscularly, with effects lasting as long as 3 weeks. Typical dosages are 200 mg of testosterone cypionate or testosterone enanthate every 2 to 3 weeks or 300 mg every 3 weeks. Because the active androgen is testosterone itself, allergic or idiosyncratic reactions are not expected, unless there is a reaction to one of the other ingredients (e.g., cottonseed oil, sesame oil). Dose and schedule of administration should be adjusted to keep maximum and minimum levels in the normal range.
Oral androgens are often ineffective and may be associated with side effects such as cholestatic hepatitis, hepatic tumors, and peliosis hepatis. Their use is rapidly falling out of favor.
Elderly men with benign prostatic hypertrophy may develop urinary retention with the initiation of testosterone therapy; therefore, smaller doses may be appropriate. Moreover, the initiation of androgen therapy in a man who has not previously attained puberty results in physical changes and changes in libido, degree of aggression, and general outlook. Some male patients who have been hypogonadal for long periods may abandon androgens because these mental and behavioral changes are psychologically threatening. Therefore, starting doses should be smaller and should be increased very gradually (see Chap. 92 and Chap. 119).
Premenopausal women are usually given cyclic oral estrogens, along with a progestogen for the final portion of the cycle (see Chap. 100). A typical regimen is 1 to 2 mg of micronized estradiol or 0.9 to 1.25 mg of conjugated estrogens daily for 25 consecutive days each month, taken orally (or estradiol, 0.05 to 0.1 mg per day, transdermally), with the addition of a progestogen, such as 5 to 10 mg of medroxyprogesterone acetate or 0.35 mg of norethindrone daily for the last 12 to 14 days of estrogen administration. Monthly withdrawal bleeding is expected. Standard oral contraceptive preparations containing a cyclic estrogen and progestogen are another option (see Chap. 104). Postmenopausal estrogen replacement regimens are discussed in Chapter 100.
In secondary hypogonadism, the gonads are usually intrinsically normal; they are lacking gonadotropin stimulation. Female patients with hypopituitarism are potentially capable of having fertility temporarily restored.54 The use of gonadotropins and other drugs to restore fertility in such patients is discussed in Chapter 97 and Chapter 103.
Adults with GH deficiency may start therapy with 0.006 mg/kg per day (0.018 IU/kg per day) given as a daily subcutaneous injection. The dose may be increased based on relief of symptoms and signs, and should be limited by adverse effects. The aim is to keep the IGF-I level in the age- and sex-matched normal range. The maximum dose is 0.0125 mg/kg per day (0.0375 IU/kg per day).35 Adverse effects include peripheral edema, arthralgias and myalgias, headache, paresthesias, and carpal tunnel syndrome.
A child with short stature resulting from GH deficiency should be evaluated for possible treatment if the epiphyses remain open (see Chap. 12, Chap. 18 and Chap. 198).55
ADH deficiency may lead to partial or total DI and has several forms of treatment (see Chap. 26). DI may be masked in the presence of hypoadrenalism and may come to clinical attention only after glucocorticoid therapy is initiated.
Prolactin and oxytocin deficiency are not treated in clinical practice.

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