Anatomy and physiology of the pituitary gland

The pituitary gland weighs about 0.5 to 1 g and is divided into anterior and posterior lobes. The pituitary gland sits in the sella turcica immediately behind the sphenoid sinus. Cavernous sinuses are located laterally on each side of the sella, inclusive of the internal carotid artery and cranial nerves III, IV, V₁, V₂ and VI. Magnetic resonance imaging (MRI) is the best method for the visualization of hypothalamic-pituitary anatomy, because the optic chiasm, vascular structures, and tumor extension to cavernous sinuses can be well visualized compared with other imaging techniques (Fig. 1).

Anterior pituitary hormones are regulated by hypothalamic releasing and inhibitory hormones and negative feedback action of the target glandular hormones at the pituitary and hypothalamic levels ( Table 1 ). Among pituitary hormones, only the secretion of prolactin is increased in the absence of hypothalamic influence, because it is mainly under tonic suppression by dopamine, the main prolactin inhibitory factor. All anterior pituitary hormones are secreted in a pulsatile fashion and tend to follow a diurnal pattern.

Antidiuretic hormone (ADH, vasopressin) is produced by the supraoptic and paraventricular nuclei of the hypothalamus and travel in the axons through the pituitary stalk to the posterior pituitary gland. The chief physiologic stimulus of ADH secretion is an increase in serum osmolality and a decrease in plasma volume, resulting in water reabsorption at the level of the distal collecting ducts of the kidneys. Small increments in serum osmolality, more than 290 mOsm/kg, lead to a prompt secretion of ADH.

Summary

• MRI is the best method for visualization of hypothalamic-pituitary anatomy.
• In the event of pituitary stalk compression. the secretion of prolactin is increased.

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Pituitary tumors

Definition and Prevalence

Pituitary adenomas arise from adenohypophyseal cells and are almost always benign ( Table 2 ). They are arbitrarily designated as microadenomas (smaller than 10 mm in diameter) and macroadenomas (equal to or larger than 10 mm in diameter). The true incidence and prevalence of pituitary adenomas are difficult to establish; however, autopsy studies have suggested that up to 20% of normal individuals may harbor pituitary microadenomas. ¹

Pituitary adenomas are rarely associated with parathyroid and neuroendocrine hyperplasia or neoplasia as part of the multiple endocrine neoplasia type I (MEN I) syndrome. Pituitary carcinomas are extremely rare, but metastases from other solid malignancies (mainly breast and lung) can occur.

Recent advances in molecular biology have confirmed that most pituitary adenomas are monoclonal in origin. Some possible underlying mechanisms include overexpression of pituitary oncogenes, inactivation of tumor suppressor genes, hypersecretion of hypothalamus-releasing hormones, and/or hyposecretion of inhibitory hormones.

Signs and Symptoms

Pituitary tumors may manifest with signs and symptoms related to pituitary hypofunction, specific hormone(s) hypersecretion, and/or mass effect (Box 1). Impingement on the chiasm or its branches by a pituitary tumor may result in visual field defects; the most common is bitemporal hemianopsia (Fig. 2). Lateral extension of the pituitary mass to the cavernous sinuses may result in diplopia, ptosis, or altered facial sensation. Among the cranial nerves, the third nerve is the most commonly affected. There is no specific headache pattern associated with pituitary tumors and, in some patients, the headache is unrelated to pituitary adenoma.

Diagnosis

A pituitary tumor smaller than 4 mm is found in up to 10% of MRI scans of the pituitary gland. Pituitary MRI is the preferred diagnostic imaging technique in patients suspected to have a pituitary pathology, including pituitary adenomas (Fig. 3). Once a pituitary adenoma is found, it is necessary to determine the type of adenoma (secretory or nonsecretory), pituitary function, and whether there is any visual field defect. Hormonal evaluation can usually be performed on an outpatient basis, according to the clinical picture (see later, “Hypopituitarism” and “Pituitary Excess Hormone Secretion”).

Treatment

The goals for treatment of a pituitary tumor include reduction or complete removal of the tumor, elimination of mass effect, if present, normalization of hormone hypersecretion, and restoration of normal pituitary function. Some patients, especially those with large tumors, may require several therapeutic modalities, including medical, surgical, and radiation therapies. The most important factor in pituitary surgery is the availability of a qualified neurosurgeon. The referring physician has the responsibility of referring the patient to an experienced neurosurgeon, who may only be available in a neuroendocrine (pituitary) center. In general, once a patient has been diagnosed with a pituitary tumor, lifelong medical follow-up is necessary to detect early recurrence, monitor hormone replacement, and treat any complications related to the tumor.

Summary

• Definition and Prevalence
• Up to 20% of normal individuals may harbor a pituitary microadenoma.
• A pituitary tumor smaller than 4 mm is found in up to 10% of MRI scans of the pituitary gland.
• Pituitary adenomas are rarely associated with parathyroid and neuroendocrine hyperplasia or neoplasia as part of multiple endocrine neoplasia type I (MEN I).

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Hypopituitarism

Pituitary adenomas are the most common cause of hypopituitarism, but other causes include parasellar diseases, pituitary surgery, radiation therapy, inflammatory and granulomatous diseases. and head injury. The sequential loss of pituitary hormones deficiency secondary to a mass effect is in the following order: growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and prolactin. Isolated deficiencies of various anterior pituitary hormones can occur. In general, pituitary microadenomas are rarely associated with hypopituitarism. Diabetes insipidus is almost never seen in patients with pituitary adenomas, except in those with very large tumors extending superiorly, affecting the hypothalamus.

Somatotropin (Growth Hormone) Deficiency

Clinical Features

The symptoms of GH deficiency in adults may be subtle, consisting of decreased muscle strength and exercise tolerance, and reduced sense of well-being (e.g., diminished libido, social isolation). Patients with GH deficiency have increased body fat and decreased lean body mass, and may have decreased bone mineral density.

Diagnosis

Levels of random GH and gender- and age-adjusted insulin-like growth factor-1 (IGF-1) are not reliable to diagnose GH deficiency because GH secretion is pulsatile, and up to 65% of patients with GH deficiency may have a normal IGF-1 level. Therefore, GH deficiency is best evaluated by dynamic testing, including the insulin tolerance test or GH–releasing hormone (RH)/arginine test. ² Almost all patients with more than two types of pituitary axis deficiency and a low IGF-1 level can be assumed to have GH deficiency and usually do not need any dynamic testing.

Treatment

Growth hormone therapy results in decreased body fat and increased muscle mass in almost all patients with growth hormone deficiency. Other benefits may include improvements in bone density, cardiac function, lipid profile, and general sense of well-being. The most common side effects of GH therapy include fluid retention, arthralgia, and carpal tunnel syndrome. These side effects are usually dose-related, minimized with gradual dose titration; if present, they improve with dose reduction.

Gonadotropin Deficiency

Clinical Features

In reproductive-aged women, gonadotropin deficiency causes infertility and oligomenorrhea or amenorrhea. It is often associated with lack of libido, hot flashes, and dyspareunia. In men, hypogonadism is diagnosed less often, because decreased libido and impotence may be considered as functions of aging. Hypogonadism is often diagnosed retrospectively in men and postmenopausal women when patients present with mass effect. Osteopenia is a consequence of long-standing hypogonadism and responds to hormone replacement therapy.

Diagnosis

Gonadotropin deficiency is diagnosed in the presence of low or normal LH and FSH levels in postmenopausal women, in reproductive-aged women with amenorrhea, or in men with low testosterone levels (lower than 200 ng/dL). Measurement of gonadotropin and estradiol levels in reproductive-aged women with irregular menstruation is usually not informative. The presence of normal menstruation is the best indicator of the integrity of the gonadotropin axis in women of reproductive age.

Treatment

Testosterone may be replaced by intramuscular injection or a transdermal patch or gel. Oral testosterone is not recommended because of the potential risk for liver toxicity. Transdermal preparations provide more physiologic and consistent testosterone concentrations, but at a higher cost compared with intramuscular testosterone injections. The serum prostate-specific antigen (PSA) level, hematocrit, and lipid profile should be monitored in men during testosterone replacement therapy. Estrogen replacement is necessary in hypogonadal women of reproductive age to prevent osteoporosis and to treat hot flashes, decreased libido, and vaginal dryness.

Corticotropin Deficiency

Clinical Features

Patients with ACTH deficiency maintain their mineralocorticoid secretion because aldosterone is regulated primarily by the renin-angiotensin system and serum potassium concentration. Symptoms usually include chronic malaise, fatigue, anorexia, low-grade fever, and hypoglycemia. Severe hypotension, hyperkalemia, and hyperpigmentation are not present, although an acute severe illness may precipitate vascular collapse, because cortisol is necessary for the maintenance of vascular tone. Patients may present with hyponatremia, which is secondary to inappropriate ADH secretion.

Diagnosis

An ACTH stimulation test and early morning (8 am) plasma cortisol level measurement are reasonable initial assays for evaluation of the corticotropin axis. An early morning cortisol level lower than 3 μg/dL confirms adrenal insufficiency, and a level higher than 15 μg/dL makes the diagnosis highly unlikely. Cortisol levels in the range of 3 to 15 μg/dL are indeterminate and should be further evaluated by the cosyntropin stimulation test (CST), which can be performed at any time during the day. The standard-dose CST uses an IV or intramuscular injection of 250 μg cosyntropin with plasma cortisol levels determined before and 30 minutes after the injection. A normal response is a plasma cortisol concentration higher than 18 μg/dL at 30 minutes. Patients with mild partial or recent-onset pituitary ACTH or hypothalamic corticotropin-releasing hormone (CRH) deficiency (e.g., within 2 to 4 weeks after pituitary surgery) may have a normal response to 250 μg CST because the adrenal glands have not undergone sufficient atrophy and still respond to very high concentrations of ACTH stimulation. The sensitivity of the CST to pick up mild adrenal insufficiency improves with use of the low-dose CST (1 μg IV ACTH ^1–24 ). However, this may result in a higher false-positive rate. The lack of a commercially available 1-μg cosyntropin dose may lead to a potential for error. In most clinical situations, the 30-minute cortisol value during standard-dose CST has a diagnostic accuracy close to that of low-dose CST. ³ The insulin tolerance test is considered the gold standard test for evaluation of the hypothalamic-pituitary-adrenal (HPA) axis, but it needs to be performed by experienced clinicians and is usually not needed for everyday clinical practice.

Treatment

The suggested replacement regimen is 15 to 20 mg hydrocortisone/day, usually given in two or three divided doses, with the highest dose given in the morning. Patients should be instructed to double their replacement dosage for 2 to 3 days in case of an acute disease and should be covered by stress doses of hydrocortisone if undergoing surgery.

Thyrotropin Deficiency

Clinical Features

The symptoms of thyrotropin (TSH) deficiency are similar to those in patients with primary hypothyroidism, including malaise, fatigue, leg cramps, dry skin, and cold intolerance. The degree of hypothyroidism depends on the duration and severity of the thyrotropin deficiency.

Diagnosis

The diagnosis cannot be established only through measurement of TSH because these patients may have a normal TSH level. For this reason, if secondary hypothyroidism is clinically suspected, TSH and free thyroxine (T₄; or free T₄ index) should be measured together. Usually, patients have a low or normal TSH level along with a low free T₄ level.

Treatment

Therapy of patients with thyrotropin deficiency is similar to those with primary hypothyroidism. The levothyroxine replacement dose should be adjusted according to the patient's clinical status and free T₄ and triiodothyronine (T₃) levels, but not TSH. In general, one should try to keep the free T₄ level in the upper normal range while the free T₃ level stays in the normal range. It is important to evaluate the corticotropin axis before the initiation of levothyroxine replacement, because therapy in those with underlying undiagnosed ACTH deficiency may result in an adrenocortical crisis secondary to an increase in metabolic demand.

Lactotropin (Prolactin) Deficiency

This is an uncommon finding in patients with pituitary disorders but may be seen in those with extensive pituitary hemorrhage or infarct. It is associated with lack of lactation in women, such as those with Sheehan's syndrome. There is no clearly defined clinical disorder associated with prolactin deficiency in men.

Summary

• Growth Hormone Deficiency
• Growth hormone is usually the first pituitary hormone deficiency to occur secondary to a pituitary tumor.
• Most patients with GH deficiency have increased body fat and decreased lean body mass.
• Determination of random GH and gender- and age-adjusted IGF-1 levels are not reliable to diagnose GH deficiency.

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Excess pituitary hormone secretion

Prolactinomas

Prolactinomas are pituitary adenomas that secret prolactin in varying degrees and account for about 30% to 40% of all pituitary adenomas. They may be seen in any age group but are more common in women, with a peak incidence during the childbearing years.

Clinical Features

Women of reproductive age mainly present with oligomenorrhea, amenorrhea, galactorrhea, or infertility. Men and postmenopausal women usually come to medical attention because of mass effect, such as headaches and visual field defects. Many men with hyperprolactinemia do not report any sexual dysfunction, but once treated effectively for hyperprolactinemia, most realize that problems exist, including decreased libido and impotence. Osteopenia effects trabecular bone more than cortical bone and can be seen in both hyperprolactinemic hypogonadal women and men. Restoration of normal gonadal function halts bone loss and increases bone mineral density.

Diagnosis

Hyperprolactinemia can be physiologic or pathologic (Box 2). If a high prolactin (PRL) level is found, the test should be repeated at least once before proceeding with further diagnostic evaluation and treatment. Pregnancy should always be ruled out. Biochemical analysis to evaluate renal and hepatic function and the TSH determination should be carried out. The drug history is an important part of the initial evaluation, because some medications are associated with hyperprolactinemia and their discontinuation for at least 3 days, if possible, will avoid any further and often expensive workup (Fig. 4). The PRL level usually, but not always, correlates with the size of the prolactinoma. Most patients with a serum prolactin level above 100 μg/L and almost all patients with a prolactin level above 200 μg/L harbor a prolactinoma. A serum prolactin level below 100 μg/L in the presence of a large pituitary adenoma is suggestive of stalk compression.

There are two main pitfalls in the diagnosis of prolactinoma—macroprolactinemia and the hook effect. Macroprolactin is a complex of PRL and, mostly, immunoglobulin G (IgG) antibody. It is usually not bioactive and has been reported in up to 20% of hyperprolactinemic sera. It is best diagnosed with a polyethylene glycol precipitation. In general, I look for it in patients with hyperprolactinemia who lack the typical clinical manifestations associated with hyperprolactinemia, such as hypogonadism. The hook effect is usually seen in cases of giant prolactinomas. It is extremely rare in tumors smaller than 3 cm. The very high amount of circulating PRL results in antibody saturation of the immunoradiometric assay, leading to an artificially lower prolactin level confusing the clinical picture with the stalk effect. ⁴ To avoid the hook effect, some institutions, including ours, have changed to a two-step immunoradiometric assay process.

Treatment

All patients with macroprolactinoma and most patients with microprolactinomas require treatment. Some indications for treatment of patients with microprolactinomas include bothersome galactorrhea, oligomenorrhea or amenorrhea, infertility, and sexual dysfunction. Medical therapy with dopamine agonists is the therapy of choice for most patients, because this is effective in decreasing adenoma size and restoration of a normal prolactin level in most patients. Dopamine agonists usually restore a visual field defect to an extent similar to that obtained by surgery. Therefore, a visual field defect associated with prolactinomas is not a neurosurgical emergency. Cabergoline (Dostinex) and bromocriptine (Parlodel) are potent inhibitors of PRL secretion and often result in tumor shrinkage. Dopamine agonists should be initiated slowly, because side effects often occur at the beginning of treatment. The most common side effects of dopamine agonists include nausea, headache, dizziness, nasal congestion, and constipation. Cabergoline is more potent, may be taken only twice weekly, and is better tolerated by most patients.

Surgery is reserved for patients who are intolerant of or refractory to medical therapy. Radiation therapy may be considered for patients who tolerate dopamine agonists poorly and cannot be cured by surgery (e.g., tumor invasion of cavernous sinuses).

Pregnancy and Prolactinoma

Women of childbearing age with prolactinomas who undergo therapy with dopamine agonists need to be warned that restoration of ovulation may be immediate, even before their first normal menstruation. Because of considerable worldwide experience with the drug, bromocriptine is the drug of choice for women who want to become pregnant. For that reason, I switch our patients on cabergoline to bromocriptine if pregnancy is desired, unless the patient cannot tolerate bromocriptine. Most patients are instructed to stop dopamine agonists once pregnancy is confirmed. There is no need for routine measurement of serum prolactin levels during pregnancy because prolactin levels increase during pregnancy. Patients are advised to report if they develop severe headaches or vision disturbances. I routinely perform the Humphrey visual field test during each trimester but reserve MRI without gadolinium only for those with a visual field defect or progressive headache. Women who wish to breast-feed after pregnancy should not be given dopamine agonist therapy after delivery. Such patients need to be re-evaluated to see whether they need to resume dopamine agonists once they have finished with breast-feeding.

National Guidelines

In June 2005, an ad hoc expert committee formed by the Pituitary Society convened during the Ninth International Pituitary Congress in San Diego, California. Discussions were held that resulted in the formulation of guidelines about the diagnosis and management of prolactinomas. ⁵ In general, I favor a similar approach, which has been summarized earlier, with few exceptions. The guidelines recommend that when a drug suspected to be the cause of hyperprolactinemia cannot be stopped or changed to another medication, the evaluation should include MRI of the sella to exclude a mass lesion. In spite of a low yield, I agree with such an approach before the patient can be assured about the absence of a stalk effect secondary to a large sellar mass.

The panel recommended that the hook effect be excluded in all new patients with pituitary macroadenomas who have normal or mildly elevated prolactin levels. However, I disagree with this broad recommendation and find it to be unnecessary. Almost all patients with the hook effect have mild elevations of prolactin levels and have tumors larger than 3 cm. Thus, routine evaluation of all patients with macroadenoma and normal prolactin levels for the hook effect is unnecessary.

There have been some reports about the association of high-dose ergot-derived dopamine agonists, such as cabergoline and pergolide, with valvular heart disease, especially in patients with Parkinson's disease. ⁶ Considering the superior efficacy and tolerability of cabergoline, I do not believe that routinely switching patients on cabergoline to non–ergot-derived dopamine agonists such as bromocriptine is indicated at this point. However, I do recommend periodic echocardiographic surveillance of patients on long-term therapy with cabergoline until further studies involving patients on low-dose therapy have been completed.

Acromegaly

Acromegaly is caused by a GH-secreting pituitary adenoma in more than 99% of patients. At diagnosis, about 75% of patients have macroadenomas. The annual incidence is about three or four cases per 1,000,000, which is likely an underestimate. The mean age at diagnosis is about 45 years.

Clinical Features

The clinical picture of acromegaly occurs insidiously (Box 3). Patients with full-blown acromegalic features are not difficult to diagnose, but only experienced physicians will be suspicious about early changes occurring in this disease (Fig. 5). Excess growth hormone before the fusion of the epiphyseal growth plates results in gigantism. Patients may present with mass effect, including a visual field defect and hypopituitarism. Cardiovascular abnormalities include hypertension, left ventricular hypertrophy, diastolic dysfunction, and arrhythmias, which may lead to cardiomyopathy. Sleep apnea is frequent and it is often of central rather than peripheral origin. Patients may develop peripheral neuropathy of the motor and sensory nerves, with muscular atrophy, neuropathic joints and other sequelae of nerve dysfunction. Acromegalic patients probably carry an increased risk of malignancy such as premalignant adenomatous colon polyps and colon cancer, although published data vary greatly in their findings.

Diagnosis

Because of the pulsatile nature of GH secretion, random GH levels can overlap in acromegalic patients and normal individuals. IGF-1 has a longer plasma half-life than GH and is the best single test for the diagnosis of patients with acromegaly (Fig. 6). The oral glucose tolerance test (OGTT) may be used as the gold standard test to confirm the diagnosis of acromegaly in some patients with borderline IGF-1 levels. Normal individuals suppress their GH level to less than 1 μg/L (lower than 0.3 ng/mL using very sensitive GH assays) within 2 hours after the ingestion of a 75-g oral glucose solution. ⁷

Treatment

Acromegaly is associated with increased morbidity and mortality if untreated. Biochemically, the goal of therapy for most patients is to achieve a normal gender- and age-adjusted IGF-1 level. A surgical approach is the treatment of choice for most patients presenting with acromegaly, even if a cure cannot be achieved. Even a subtotal resection of the tumor will improve the efficacy of subsequent adjuvant therapy. Conventional fractionated radiotherapy is effective for tumor size control but multiple studies have shown poor long-term results in regard to normalization of the IGF-1 level. Radiosurgery (gamma knife) achieves remission faster and is more effective in the normalization of the IGF-1 level compared with fractionated radiotherapy, but the rate of hypopituitarism seems to be similar.

Medical treatment of acromegaly has become more widely accepted because the limitations of radiation and surgical therapy have become evident. Octreotide and its long-acting form (Sandostatin LAR Depot) inhibit GH secretion by binding to specific receptors for somatostatin and its analogues, resulting in normalization of the IGF-1 level in about 65% to 70% of patients. The most common side effects are gastrointestinal, including diarrhea, abdominal pain, and nausea. Gallbladder sludge and cholelithiasis have been reported in up to 25% of patients on long-term therapy with somatostatin analogues, but in my experience they have been much less common, which may be related to geographic variations. Dopamine agonists have been reported to have varying efficacy in patients with acromegaly but may be an attractive first-line medical therapy in those with cosecretion of prolactin and GH. The addition of a dopamine agonist to somatostatin analogue therapy may increase biochemical remission.

Pegvisomant is the latest medical treatment for acromegaly. The drug has increased affinity to GH receptors compared with native GH and inhibits its dimerization, which is necessary for the action of GH. It is administered once daily and is usually reserved for those not responding to other medical therapies. It is effective, with normalization of the IGF-1 level seen in up to 97% of patients. Because of its mechanism of action and associated increase in GH during therapy, tumor size needs to be monitored during therapy. Liver function test results need to be closely monitored during therapy and the drug should be discontinued if liver enzyme levels increase to more than three times the upper normal level. During therapy with pegvisomant, the IGF-1 and not the serum GH value should be used to monitor therapy.

National Guidelines

Several consensus guidelines have been published on acromegaly. These include the guidelines of the Pituitary Society and European Neuroendocrine Association, and the Canadian consensus guidelines for diagnosis and management of acromegaly, published in 2005 and 2006, respectively. ^8,9

In general, I follow a similar approach for the diagnosis and management of patients with acromegaly, with a few exceptions. The guidelines indicate that primary medical therapy can be justified for those in whom surgery is not expected to be curative and that radiotherapy should be the last resort. I believe that surgical debulking, even for those for whom surgery would not be curative, should be tried before adjuvant therapies such as medical therapy and radiotherapy are considered. Such an approach would improve the likelihood of biochemical remission and may make gamma knife radiotherapy technically feasible. In my experience, gamma knife radiotherapy achieves a similar biochemical remission as somatostatin analogues in a relatively short time and may be an attractive therapy following surgical debulking for patients with residual disease. Medical therapies are costly and do not offer a cure, which makes compliance an issue. I use medical therapy as a bridge for patients who undergo gamma knife radiotherapy. For young patients with normal pituitary function in whom fertility is desired, medical therapy should be considered because most patients undergoing radiotherapy, including gamma knife radiotherapy, would suffer from panhypopituitarism. The result of fractionated radiotherapy in treating acromegaly is unsatisfactory and should be used as the last resort for such patients. I treat patients with octreotide for about one month before surgery for symptomatic improvement and to decrease soft tissue swelling, which may reduce anesthesia complications. The benefits of a longer duration of preoperative medical therapy to improve surgical outcomes has been suggested but is currently not the standard of care until more data are available.

Cushing's Disease

Cushing's syndrome (CS) comprises symptoms and signs associated with prolonged exposure to inappropriately high levels of plasma free glucocorticoids. Exogenous glucocorticoid intake is the most common cause of CS. The endogenous causes are divided into ACTH-dependent and ACTH-independent CS (Box 4).

Clinical Features

It is important to keep in mind that there is no pathognomic sign or symptom for Cushing's syndrome. A high clinical suspicion, attention to suggestive clinical features (Box 5), and an appropriate screening test are the keys to early diagnosis of CS. In contrast to pale striae that occur postpartum or with weight gain, the striae in CS are usually red-purple in color, more than 1 cm in width, and located on the abdomen, upper thighs, breasts, and arms (Fig. 7). The skin is thinned and wrinkled (Liddle's sign—“cigarette paper” aspect of the dorsa of the hands) and minimal trauma results in easy bruising, with poor wound healing. The face has a plethoric appearance, and acne may be present. Increased skin pigmentation is rare and only occurs in the ectopic ACTH syndrome. In my experience, supraclavicular and dorsocervical fat pads (buffalo hump) and moon face are nonspecific and may be seen in many patients evaluated in obesity clinics.

Reproductive dysfunction in CS is caused by the direct inhibitory effect of cortisol on the gonadotropin axis and, in some cases, associated hyperandrogenism and hyperprolactinemia. Women complain of menstrual irregularity (84%) and hirsutism (especially vellous hypertrichosis of the face), and men and women exhibit loss of libido (100% in some reports). Psychiatric abnormalities occur in 50% of patients, with agitated depression and lethargy being the most common manifestations. Glucocorticoid excess has profound effects on bone, causing poor linear growth in children and osteoporotic vertebral collapse and pathologic fractures in adults. Hypertension is present in 75% of patients with CS and thromboembolic events are more common than in the general population. Given the immunosuppressive effects of glucocorticoids, patients with CS may experience the reactivation of tuberculosis or fungal infections (e.g., tinea versicolor, nail mycoses, opportunistic infections). Ocular effects include increased intraocular pressure, exophthalmos, and cataracts. Glucose intolerance and diabetes are present in 50% of patients and hypokalemic alkalosis in 10% to 15%.

Patients with ectopic CS may not exhibit many of these clinical features. Given the severe nature of the disease, its rapid course, and the high levels of ACTH and cortisol, patients may present with weight loss, myopathy, peripheral edema, glucose intolerance, and hypokalemic alkalosis.

Pseudo-Cushing's disease refers to features of CS along with some evidence of hypercortisolism that resolve after resolution of the underlying cause, such as chronic alcoholism, psychiatric disorders (e.g., major depression, anxiety disorder, obsessive-compulsive disorder), anorexia nervosa, morbid obesity, and poorly controlled diabetes. Cyclic CS is characterized by periods of excess alternating with intervals of normal or decreased cortisol production, which occur rarely in some patients with CS. Of the various causes, there is a higher likelihood of pituitary tumor as the underlying cause of cyclic CS.

Diagnosis

After exclusion of the exogenous administration of glucocorticoids, two steps are involved in the diagnosis of CS—demonstration of inappropriate cortisol secretion and determination of its cause. Because of the challenging nature of CS, it is important to follow a stepwise evaluation, know the limitations of each test, and avoid shortcuts.

Establishing the Diagnosis of Cushing's Syndrome.

Screening for CS may be done by midnight salivary cortisol level determination, 1-mg dexamethasone suppression test (DST), or 24-hour urinary free cortisol (UFC) level measurement (Fig. 8). ¹⁰ The 1-mg DST is performed by the administration of 1 mg dexamethasone at 11 pm, followed by the measurement of the plasma cortisol level at 8 am, with a cortisol level lower than 1.8 μg/dL being a normal response. Although the 1-mg DST is excellent for ruling out CS, with less than 2% false-negative test results, false-positive results can be seen in as many as 40% of patients without CS, depending on the population studied. A positive test result needs to be confirmed by 24-hour UFC or salivary cortisol level determination. In my experience, the midnight salivary cortisol level determination has been an excellent tool to evaluate patients suspected of having CS and is easy to perform. It has a sensitivity rate of more than 96% for diagnosing CS but is associated with a false-positive rate of about 8%. It is important to ensure that the patient has a normal sleeping pattern before relying on the salivary cortisol test for the evaluation of CS. Values of the 24-hour UFC test more than five or six times upper normal for the assay are usually diagnostic for CS, especially once repeated and confirmed. It is important to be familiar with assay-specific normative values for their interpretation.

The low-dose DST test or combined low-dose DST and CRH stimulation test may be used for differentiating between CS and pseudo-Cushing's syndrome with more than 95% diagnostic accuracy. The latter consists of the oral administration of 0.5 mg dexamethasone every 6 hours for eight doses, starting at noon, followed by the IV administration of 100 μg CRH at 8 am (2 hours after the last dose of dexamethasone). A plasma cortisol level higher than 1.4 μg/dL at 15 minutes after the CRH injection is strongly suggestive of CS. Some drugs, such as phenytoin, phenobarbital, and rifampin, increase the clearance rate of dexamethasone, which may be associated with a false-positive result during the DST. Thus, in some cases, it may be necessary to measure the plasma dexamethasone level. It is also important to keep in mind the effect of increased cortisol binding protein on the serum cortisol level during pregnancy and in women taking estrogen.

If the clinical suspicion of CS is strong but initial screening test results are normal, the patient should be re-evaluated in 2 or 3 months because CS is usually a progressive disease. Another clinical scenario that may be associated with normal screening tests is cyclic CS, which needs to be ruled out by periodic evaluation. Fortunately, true cyclic CS is a rare condition.

Differential Diagnosis: ACTH-Dependent Versus Primary Adrenal Disease.

Once CS is biochemically confirmed, the plasma ACTH level should be measured, preferably in the morning. A suppressed or low ACTH level (lower than 10 pg/mL) is consistent with ACTH-independent CS and should be followed by a dedicated adrenal computed tomography (CT) scan. ACTH values of 10 to 20 pg/mL may be seen in patients with adrenal and pituitary causes for CS; these patients should undergo a CRH stimulation test. A flat response of ACTH to CRH during the test is suggestive of an adrenal cause, but a more than 50% increase in the ACTH value during the test is consistent with Cushing's disease. ACTH levels higher than 20 pg/mL suggest an ACTH-dependent CS. About 90% of patients with ACTH-dependent CS have a pituitary cause and the rest are ectopic in origin. Pituitary magnetic resonance imaging (MRI) with gadolinium enhancement should be performed. The presence of a pituitary adenoma more than 6 mm in diameter is strongly suggestive of Cushing's disease, but 50% of patients with Cushing's disease do not have any abnormality on MRI. ACTH levels tend to be higher in ectopic CS compared with Cushing's disease, but there is significant overlap.

Most of our patients with ACTH-dependent CS undergo bilateral inferior petrosal sinus sampling (BIPSS) to differentiate ectopic CS from Cushing's disease; this is the gold standard for differentiating Cushing's disease from ectopic CS. The test should be performed by an experienced neuroradiologist in a center with experience in the procedure. A patient with more than a 50% increase in the ACTH level during the CRH stimulation test, more than 80% suppression of the morning cortisol level (8 to 9 am) during the high-dose DST, and a pituitary adenoma larger than 6 mm can be assumed to have Cushing's disease and should be sent to surgery. When the diagnostic workup suggests an ectopic source, CT scanning of the neck, chest, and abdomen should be carried out. The most common causes of ectopic CS include bronchial, thymic, or pancreatic carcinoids, islet cell pancreatic tumors, medullary thyroid cancer, and pheochromocytoma.

Treatment

Surgical removal of an ACTH-secreting pituitary tumor is the treatment of choice. Availability of an experienced neurosurgeon is crucial, with about an 80% long-term remission rate following surgery. A low (lower than 3 μg/dL) or undetectable cortisol level postoperatively, with the patient off glucocorticoids, is considered to be a good marker for long-term cure. For those not cured by surgery, other options include a second operation and gamma knife radiotherapy. Bilateral adrenalectomy is reserved for those who continue to be hypercortisolemic.

Medical therapy for Cushing's syndrome has limited value because of the associated toxicity and gradual decrease in efficacy. It is mainly used for short-term symptomatic control or pre-paration of the patient before surgery. Of the available agents, ketoconazole is most commonly used. During therapy, liver function test results need to be closely monitored. Some reports have indicated the efficacy of cabergoline, a dopamine agonist, in a subpopulation of patients with CS; this may be worth a trial before initiating ketoconazole.

Surgery is the preferred therapy of choice for ectopic CS if the tumor can be located. Octreotide scanning has a limited value in those with a negative CT scan. Bilateral adrenalectomy is performed to correct hypercortisolemia for those in whom the tumor is not found.

National Guidelines

During an international workshop in Italy in October 2002, a consensus statement about the diagnosis and complications of CS was developed. ¹¹ The workshop recommended a low threshold for screening patients for CS, including patients with metabolic syndrome, especially if they are young and resistant to conventional treatment. It was emphasized that if the diagnosis of CS is suspected clinically but initial screening test results are normal, the patient should be re-evaluated at a later date and invasive procedures postponed. The workshop described the high-performance liquid chromatography (HPLC) assay for urinary free cortisol as highly sensitive and specific. In my experience, in spite of the theoretic superiority of the HPLC assay for the measurement of the 24-hour UFC level, the former is associated with higher false-positive results compared with the radiochemiluminometric assay. Although the consensus statement ¹¹ briefly discussed the promising results from the midnight salivary cortisol test, I believe that in patients with a normal sleep pattern, salivary cortisol level determination should usually be part of the routine diagnostic workup for CS, especially if early disease is suspected. I am in agreement that a 2-day low-dose DST–CRH stimulation test is labor intensive; however, it is often valuable to differentiate CS from pseudo-Cushing's. In general, once a patient has been diagnosed with a pituitary tumor, lifelong medical follow-up is necessary to detect early recurrence, monitor hormone replacement, and treat any complications related to the tumor.

Thyrotropin-Secreting Adenoma

Thyrotropin (TSH)-secreting pituitary adenomas account for less than 1% of all pituitary tumors and are a rare cause of hyperthyroidism. The number of reported cases has significantly increased in the last two decades as a consequence of the routine use of ultrasensitive immunoradiometric assays for measuring TSH levels. The mean age at presentation is about 40 years, with a slight female predominance. Cosecretion of other pituitary hormones, including growth hormone, prolactin, and gonadotropins, may occur.

Clinical Features

Symptoms secondary to hyperthyroidism and goiter are the initial complaints in most patients, followed by pituitary mass effect if the disease remains undiagnosed. ¹² Menstrual disturbances and galactorrhea have been reported in about 30% of patients. Many patients have undergone therapy aimed at the thyroid gland, including thyroidectomy and radioactive iodine ablation at the time of presentation.

Diagnosis

The most important biochemical feature is elevation of serum thyroid hormone levels (T₄ and T₃), with an inappropriately normal or elevated TSH level. Patients with hyperthyroidism suspected to have TSH-secreting pituitary adenomas must be distinguished from those with the syndrome of resistance to thyroid hormone. Such patients may present with signs and symptoms of hyperthyroidism, especially those with thyroid hormone resistance at the pituitary level. Features that include normal serum sex hormone–binding globulin and elevated alpha subunit levels, flat response to TRH stimulation, presence of a pituitary tumor on MRI, and lack of a significant decrease of TSH in response to T₃ (lower than 25%) are suggestive of a TSH-secreting pituitary adenoma.

Treatment

Surgery is the primary therapeutic approach. Radiation is generally used for those with a residual tumor. Somatostatin analogues are effective in most patients for the control of excess TSH production, lead to improvement in hyperthyroidism, and may help decrease tumor size. Beta blockers should be initiated in patients with uncontrolled hyperthyroidism but antithyroid medications may be used only shortly before surgery—if somatostatin analogues cannot be used—because long-term use may result in stimulation of tumor growth.

National Guidelines

There are no consensus statements for the evaluation and therapy of patients with TSH-secreting pituitary adenomas. Most experts' opinions are based on personal experience in referral centers with a relatively small number of patients. ¹² It is extremely important that any patient presenting with endogenous hyperthyroidism and an elevated or normal TSH level be further evaluated for the presence of a TSH-secreting pituitary adenoma. I have seen patients with TSH-secreting pituitary adenomas who have been diagnosed by their physicians as having primary hypothyroidism caused by mild elevation of the TSH level; their dosage of levothyroxine was thus gradually increased over the years because of the TSH level continuing to be elevated. This problem is at least partly related to relying only on TSH as an indicator of thyroid status. I believe that all patients suspected to have a thyroid disorder should have at least one set of complete thyroid function tests carried out, including T₄ and T₃ level determination, before following TSH as an indicator of thyroid status.

Summary

• Prolactinoma
• A high PRL level should be retested at least once and pregnancy should always be ruled out.
• Most patients with s serum prolactin level above 100 ¼g/L and almost all patients with a prolactin level above 200 ¼g/L harbor a prolactinoma.
• Medical therapy with dopamine agonists is the therapy of choice for most patients with prolactinomas.
• Bromocriptine is the drug of choice for women who want to become pregnant.

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Nonfunctional glycoprotein-secreting pituitary adenomas

Nonfunctional glycoprotein-secreting pituitary adenomas are the most common pituitary tumors. Many clinically nonfunctioning pituitary adenomas are glycoprotein-producing tumors. They may secrete intact glycoprotein hormones or their alpha and beta subunits.

Clinical Features

These usually manifest with clinical features related to mass effect, including visual field defect, hypopituitarism, headache, and cranial nerve palsy. They may also be diagnosed during an imaging study for an unrelated problem, such as head injury (see later, “Pituitary Incidentaloma”). There is usually a delay in diagnosis because many of the symptoms, including headache, decreased energy, and low libido, may be attributed to stress, depression, or aging. The lack of a recognizable clinical syndrome may occur because of inefficient or variable secreted hormones and lack of biologic activity of the secreted glycoprotein. Rarely, patients with glycoprotein-producing adenomas may present with ovarian hyperstimulation, elevated testosterone level, or premature puberty.

Diagnosis

Once the diagnosis is suspected, the patient should undergo MRI scanning of the pituitary gland. Patients with a sellar mass pressing on the optic chiasm should have a Humphrey visual field test. Pituitary function should be evaluated, specially in those with a macroadenoma. Patients with pituitary stalk compression (stalk effect) usually have prolactin levels lower than 100 ng/mL.

Treatment

Patients with small, nonfunctional, pituitary adenomas usually undergo a period of observation; however, the standard treatment for those with mass effect is surgery, mainly through the trans-sphenoidal approach. Radiotherapy is indicated for those with a residual pituitary tumor following surgical debulking or those who may not be a suitable surgical candidate. The use of high-dose dopamine agonists has been associated with a decrease in tumor size in about 10% of patients.

National Guidelines

There are no consensus statements for the evaluation and therapy of patients with nonfunctional glycoprotein-secreting pituitary adenomas. Most experts' opinions are based on personal experience in large referral centers. ¹³ The approach to patients with pituitary macroadenomas abutting or exerting minimal pressure on the optic chiasm, but associated with a normal visual field (VF) test result, is controversial. Although close follow-up with serial MR imaging and a VF test may be an option, I recommend surgery for most patients because these tumors tend to grow and there is an increased risk of pituitary apoplexy. The alpha subunit level may be elevated in about 10% to 20% of patients with nonfunctional pituitary adenomas and is followed by some clinicians as a tumor marker. In my experience, the alpha subunit level is an unreliable tumor marker for postoperative follow-up, with poor correlation with serial MRI findings.

Summary

• Patient usually present with mass effect, including visual field defect, hypopituitarism, headache, and cranial nerve palsy.
• Once the diagnosis is suspected, MR imaging of the pituitary gland is the imaging study of choice.
• Patients with tumors pressing on the optic chiasm should undergo a Humphrey visual field test.
• There is no effective medical therapy for most patients with nonfunctional pituitary adenomas.
• The alpha subunit is an unreliable tumor marker for postoperative follow-up.

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Pituitary incidentaloma

A pituitary incidentaloma is defined as a sellar mass discovered by CT or MRI in the absence of any symptoms or clinical findings suggestive of a pituitary disease. Small microadenomas have been reported in up to 27% of pituitary autopsy series in those without suspected pituitary disease. The prevalence of pituitary incidentalomas found by MRI is about 10% and most are microadenomas.

Incidentally found pituitary masses may result in significant anxiety in patients because of the fear of future problems, including tumor growth. Some subclinical hypersecretory pituitary adenomas may be associated with increased morbidity. For example, subclinical Cushing's disease may contribute to poor control of blood sugar and blood pressure levels. Pituitary microadenomas do not generally cause any disruption of normal pituitary function, but patients with incidental macroadenomas may have hypopituitarism, visual field defects, or both.

For patients with microadenoma, the major clinical issue is to rule out subclinical pituitary hormone hypersecretion. ¹⁴ The initial workup should be limited and include determination of serum prolactin and IGF-1 levels. The 24-hour UFC test has a low yield in the absence of any clinical features suggestive of Cushing's disease and is not indicated.

Patients with a hormonally inactive pituitary microadenoma do not need therapy but the size of the pituitary tumor should be followed in one year by MRI. I do not recommend continued MRI surveillance in patients with nonfunctional microadenomas unless there are new symptoms, including worsening of headache or development of a visual field defect. However, patients with macroadenomas and no mass effect need to be monitored by serial MR imaging.

Summary

• The prevalence of pituitary incidentalomas found by MRI is about 10%; most are microadenomas.
• All patients should have their serum prolactin and IGF-1 levels measured.
• In the absence of any change in the clinical picture, continued MRI surveillance of patients with incidentally discovered nonfunctional pituitary microadenomas is unnecessary.

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Lymphocytic hypophysitis

Lymphocytic hypophysitis is a rare inflammatory lesion of the pituitary gland, commonly affecting young women during late pregnancy or in the postpartum period. This disorder is believed to have an autoimmune pathogenesis, with increased association with other autoimmune disorders, mainly Hashimoto's thyroiditis and Addison's disease. The clinical manifestations may be secondary to mass effect or an inflammatory process such as headaches, a visual field abnormality, and partial or total hypopituitarism. The corticotropin axis is the most frequently affected axis. The chronologic association with pregnancy or the postpartum period and isolated ACTH deficiency may be diagnostic clues.

Trans-sphenoidal surgery is the therapy of choice for those with pituitary mass effect. Corticosteroids had been advocated to reduce inflammation and have been effective in some patients to reduce the mass size. Most experts agree on the necessity for close monitoring of patients with this condition, with periodic biochemical evaluation of those with varying degrees of hypopituitarism, because some patients may have partial or full recovery of their pituitary axes.

Summary

• Lymphocytic hypophysitis is a rare inflammatory lesion of the pituitary gland, mostly seen in young women during pregnancy or in the postpartum period.
• Corticotropin (ACTH) deficiency is the most frequently seen pituitary hormone deficiency.

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Empty sella

The empty sella is defined as a sella, which, regardless of its size, is completely or partly filled with cerebrospinal fluid. An empty sella of normal size is a frequent incidental autopsy finding. An empty sella is called secondary when it is seen after surgery, irradiation, or medical treatment for a pituitary pathology (Fig. 9). Most patients have no pituitary dysfunction, but partial or complete pituitary insufficiency has been reported. The discovery of an empty sella needs to be followed by an endocrine evaluation to determine whether there is any associated pituitary dysfunction. Manage-ment usually involves reassurance and hormone replacement, if necessary.

Summary

• An empty sella of normal size is a frequent incidental autopsy finding.
• Patients should have an endocrine evaluation to determine any associated hypopituitarism.

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Pituitary apoplexy

Pituitary apoplexy is a rare endocrine emergency resulting from hemorrhagic infarction of a preexisting pituitary tumor (Fig. 10). The clinical manifestations of this syndrome are related to rapid expansion of the tumor secondary to hemorrhage, with compression of the pituitary gland and the perisellar structures leading to headache, hypopituitarism, visual field defect, and cranial nerve palsies ( Table 3) . ¹⁵ Headache is the most prominent symptom in most patients with clinically evident pituitary apoplexy. Once pituitary apoplexy is suspected, stress dose corticosteroids (e.g., dexamethasone 2 mg every 6 hours IV) should be initiated and pituitary MRI performed. Patients with mass effect would benefit from tumor and blood clot debulking leading to resolution of visual field defects and improvement of cranial nerve palsies in most patients. Sheehan's syndrome is the result of ischemic infarction of a normal pituitary gland leading to hypopituitarism secondary to postpartum hemorrhage and hypotension.

Table 3: Manifesting Signs and Symptoms of Pituitary Apoplexy

Summary

• Headache is the most prominent symptom in patients with pituitary apoplexy.
• Once pituitary apoplexy is suspected, stress dose glucocorticoids should be initiated and pituitary MRI performed.

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Diabetes insipidus

Diabetes insipidus (DI) is characterized by the chronic excretion of abnormally large volumes (more than 50 mL/kg) of dilute urine. The true prevalence of DI is unknown, but it is usually underdiagnosed because the symptoms and signs are benign and many patients ignore them or are unaware of them. There are four major types of DI—central (neurogenic) DI, nephrogenic DI, primary polydipsia, and gestational DI. Central DI is secondary to inadequate ADH secretion that is insufficient to concentrate the urine (Box 6).

Clinical Features

Diabetes insipidus by itself is usually well tolerated and results in few symptoms, including polydipsia and polyuria. Nocturia of a large urine volume is often the primary reason for which patients seek medical attention. Diabetes insipidus in most patients is not associated with any abnormality on the physical examination or routine laboratory evaluation, except a low urine osmolality. Overt disturbances in fluid and electrolytes are uncommon unless some other factors interfere with the normal compensatory mechanism of polydipsia, such as loss of consciousness.

Diagnosis

Once diabetes mellitus has been excluded, patients should have their 24-hour urinary volume measured during ad lib fluid intake. DI is diagnosed in those with abnormally high urinary output (more 50 mL/kg/day), low urinary osmolality (lower than 300 mOsm/kg), and an appropriate creatinine level (14 to 18 mg/kg body weight) as an indicator of an accurate 24-hour urine collection. ¹⁶ Measurement of spot urine osmolality is usually unreliable to exclude or make the diagnosis of DI, because it may be decreased significantly in an otherwise healthy person who drinks large amounts of water and can be increased to normal by fasting in a patient with partial DI. Patients with DI who are conscious usually have sufficient thirst to maintain a normal serum sodium level in spite of polyuria. Once the diagnosis has been established, the next step is to differentiate the type of DI. A water deprivation test may need to be performed by an experienced endocrinologist to differentiate among types of partial DI. Posterior pituitary enhancement on MRI with gadolinium is a good assay of ADH reserve, keeping in mind that up to 20% of normal individuals do not have a bright spot (Fig. 11). Rarely, a patient with autoimmune central DI may have a bright spot in the posterior pituitary because of the presence of oxytocin.

Treatment

The therapy of choice for central DI is the administration of the ADH analogue desmopressin (DDAVP). It is available in a subcutaneous form or as an oral or nasal spray. The spray or oral form of desmopressin is usually started at bedtime and is gradually titrated for the desired antidiuretic effect. The duration of response should be determined individually because there is considerable variation. The therapy for patients with central DI should be initiated and adjusted by an experienced physician.

Summary

• Frequent nocturia of a large urine volume is often the primary reason for which patients seek medical attention.
• Diabetes insipidus (DI) in most patients is not associated with any abnormality on physical examination or routine laboratory evaluation, except a low urine osmolality.
• Prior to the workup of DI, diabetes mellitus needs to be ruled out.
• A 24-hour urine volume measurement during ad lib fluid intake is the initial test of choice for the evaluation of patients suspected to have DI.
• Once the diagnosis has been established, the next step is to differentiate the type of DI.

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Suggested Readings

• Diagnosis and complications of Cushing's syndrome: A consensus statement. J Clin Endocrinol Metab. 88: 2003; 5593-5602.
• Diagnosis and treatment of acromegaly and its complications: Consensus guidelines. J Endocrinol Invest. 28: 2005; 43-47.
• Guidelines of the pituitary society for the diagnosis and management of prolactinomas. Clin Endocrinol. 65: 2006; 265-273.
• The prevalence of pituitary adenomas: A systematic review. Cancer. 101: 2004; 613-619.
• Canadian consensus guidelines for the diagnosis and management of acromegaly. Clin Invest Med. 29: 2006; 29-39.
• Cushing's syndrome: Important issues in diagnosis and management. J Clin Endocrinol Metab. 91: 2006; 3746-3753.
• Giant invasive pituitary prolactinoma with falsely low serum prolactin: The significance of ‘hook effect.’. J Neurooncol. 79: 2006; 41-43.
• Basal and glucose-suppressed GH levels less than 1 microg/L in newly diagnosed acromegaly. Pituitary. 6: 2003; 175-180.
• Evaluation and management of pituitary incidentalomas—revisiting an acquaintance. Nat Clin Pract Endocrinol Metab.. 2: 2006; 138-145.
• Evaluation and treatment of adult growth hormone deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 9: 2006; 1621-1634.
• TSH-secreting pituitary adenomas: Follow-up of 11 cases and review of the literature. Pituitary.. 10: 2007; 307-310.
• Diabetes insipidus. Endocrinol Metab Clin North Am. 24: 1995; 549-572.
• Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 356: 2007; 29-38.
• Treatment of patients with a pituitary adenoma: One clinician's experience. Neurosurg Focus. 16: 2004; E1.
• Pituitary tumor apoplexy: Characteristics, treatment, and outcomes. Neurosurg Focus. 16: 2004; E6.