Published: June 2012
The pituitary gland weighs about 0.5 to 1 g and is divided into anterior and posterior lobes. It sits in the sella turcica immediately behind and superior to 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 (Fig. 1).
Anterior pituitary hormones are regulated by hypothalamic releasing and inhibitory hormones and by negative feedback 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 inhibitory factor. Antidiuretic hormone (ADH, vasopressin) is produced by the supraoptic and paraventricular nuclei of the hypothalamus and travels in the axons through the pituitary stalk to the posterior pituitary gland.
|Target Gland||Hypothalamic Regulatory
|Pituitary Hormone||Feedback Hormone|
|Thyroid gland||TRH||TSH||T4, T3|
|Gonad||LHRH||FSH||Inhibin, E2, T|
|Many organs||GHRH, SMS||GH||IGF-1|
ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CRH, corticotropin-releasing hormone; E2, estradiol; GHRH, growth hormone-releasing hormone; IGF-1, insulin-like growth factor 1; LHRH, luteinizing hormone-releasing hormone; PIF, prolactin release inhibitory factor; SMS, somatostatin; T, testosterone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone.
Pituitary adenomas arise from adenohypophyseal cells and are almost always benign (Table 2). They are arbitrarily designated as microadenomas (<10 mm) and macroadenomas (≥10 mm). Autopsy studies suggest that up to 20% of normal persons harbor pituitary microadenomas.1 Pituitary tumors discovered by computed tomography (CT) or magnetic resonance imaging (MRI) examination, in the absence of any symptoms or clinical findings, are referred to as pituitary incidentalomas. The prevalence of pituitary incidentalomas found by MRI is about 10%, and the majority are microadenomas.2
|Adenoma Type||Prevalence (%)|
|GH cell adenoma||15|
|PRL cell adenoma||30|
|GH and PRL cell adenoma||7|
|ACTH cell adenoma||10|
|Gonadotropic cell adenoma||10|
|TSH cell adenoma||1|
ACTH, adrenocorticotropic hormone; GH, growth hormone; PRL, prolactin; TSH, thyroid-stimulating hormone.
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.
Pituitary tumors can manifest with signs and symptoms of pituitary hypofunction, hormone hypersecretion, or mass effect. Impingement on the chiasma by a pituitary tumor results in visual field defects, most commonly bitemporal hemianopia (Fig. 2). Patients with sellar mass pressing on the optic chiasma should have a Humphrey visual field test. Lateral extension of the pituitary mass to the cavernous sinuses can result in diplopia, ptosis, or altered facial sensation. There is no specific headache pattern associated with pituitary tumors and, in some patients, the headache is unrelated to pituitary adenoma.
MRI is the best method for the visualizing hypothalamic-pituitary anatomy. Once a pituitary adenoma is found, it is necessary to determine the type of adenoma (secretory vs. nonsecretory), pituitary function, and whether there is any visual field defect.
The goals for treatment of a pituitary tumor include reduction or complete removal of the tumor, elimination of mass effect, normalization of hormone hypersecretion, and restoration of normal pituitary function. Some patients, especially those with large tumors, require several therapeutic modalities, including medical, surgical, and radiation therapies. The most important factor in pituitary surgery is the availability of an experienced neurosurgeon.
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 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 at presentation.
The symptoms of GH deficiency in adults are 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 they might have decreased bone mineral density.
Random measurements of GH and gender- and age-adjusted insulin-like growth factor-1 (IGF-1) levels are not reliable to diagnose GH deficiency because GH secretion is pulsatile, and up to 65% of patients with GH deficiency 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.3
In reproductive-aged women, gonadotropin deficiency causes infertility and oligomenorrhea or amenorrhea. It is often associated with lack of libido, hot flushes, and dyspareunia. In men, hypogonadism is diagnosed less often, because decreased libido and impotence may be considered 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.
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 (<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.
Testosterone may be replaced by intramuscular injection, transdermal patch, or a gel. Oral testosterone is not recommended because of the potential risk for liver toxicity. 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 flushes, decreased libido, and vaginal dryness.
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. Patients might present with hyponatremia, which is secondary to inappropriate ADH secretion.
An ACTH stimulation test and early morning (8 am) plasma cortisol level measurement are reasonable initial tests for evaluating 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, and 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 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 carry a medical alert, 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.
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 diagnosis cannot be established only through measurement of TSH because these patients might have a normal TSH level. For this reason, if secondary hypothyroidism is clinically suspected, TSH and free thyroxine (T4) should be measured together. Usually, patients have a low or normal TSH level along with a low free T4 level.
Therapy for TSH deficiency is similar to that for primary hypothyroidism. The levothyroxine replacement dose should be adjusted according to the patient’s clinical status and free T4 and free 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 initiating levothyroxine replacement, because therapy in those with underlying undiagnosed ACTH deficiency can result in an adrenocortical crisis secondary to an increase in metabolic demand.
Prolactinomas are pituitary adenomas that secret prolactin in varying degrees and account for about 30% of all pituitary adenomas. They are seen in all age groups but are more common in women, with a peak incidence during the childbearing years.
Clinical features of prolactinomas may be related to excess prolactin and associated secondary hypogonadism or mass effect. 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. All patients with macroprolactinomas 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.
Hyperprolactinemia can be physiologic or pathologic (Box 1). 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 prevent any further and often expensive workup (Fig. 3). The majority of patients with a serum prolactin level above 100 μg/L have prolactinoma. A serum prolactin level lower than 100 μg/L in the presence of a large pituitary adenoma suggests stalk compression.
|Box 1 Differential Diagnosis of Hyperprolactinemia|
|Pregnancy, postpartum, suckling, stress, intercourse, exercise|
|Prolactinomas, mixed pituitary tumors, pituitary tumors or disorders with stalk effect|
|Hypothalamic, stalk disorder|
|Aneurysm, inflammatory or granulomatous disease, tumors such as craniopharyngioma and meningioma, metastasis, trauma, radiotherapy|
|Neuroleptics, metoclopramide, verapamil, methyldopa, reserpine, opiates, cocaine|
|Tricyclic antidepressants, monoamine oxidase inhibitors, some selective serotonin reuptake inhibitors (SSRIs)|
|Chronic renal failure|
|Chest wall disorders|
|Spinal nerve or cord lesion|
|Mostly secondary to a small microprolactinoma not identified by magnetic resonance imaging|
Dopamine agonists are the therapy of choice for most patients, and they are effective in decreasing adenoma size and restoring normal prolactin level in most patients. Dopamine agonists usually restore visual field defects to an extent similar to surgery.4 Therefore, visual field defects associated with prolactinomas are not a neurosurgical emergency. Cabergoline and bromocriptine are potent inhibitors of PRL secretion and often cause tumor shrinkage. Dopamine agonists should be initiated slowly, because side effects often occur at the beginning of treatment. The most common side effects include nausea, headache, dizziness, nasal congestion, and constipation. Bromocriptine is the drug of choice in women planning pregnancy because there is considerable worldwide experience with the drug. Cabergoline is more potent, may be taken only twice a week, and is better tolerated by most patients. Few reports associate high-dose cabergoline with valvular heart disease in patients with Parkinson’s disease, but risk seems to be insignificant with the doses used for treatment of prolactinoma.5-6 Surgery is reserved for patients who are intolerant of or refractory to medical therapy. Radiation therapy may be considered for patients who poorly tolerate dopamine agonists and cannot be cured by surgery.
Acromegaly is a rare disease caused by a GH-secreting pituitary adenoma in more than 99% of patients. At diagnosis, about 75% of patients have macroadenomas. The mean age at diagnosis is about 45 years. Clinical features of acromegaly may be related to excess GH or IGF-1 or to associated mass effect including hypopituitarism, because most patients present with pituitary macroadenomas (Box 2 and Fig. 4). Excess growth hormone before the fusion of the epiphyseal growth plates results in gigantism. 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.
|Box 2 Clinical Features of Patients with Acromegaly|
|Arthralgias, neuropathic joints|
|Carpal tunnel syndrome|
|Coarsening of facial features|
|Hypertension, congestive heart failure, arrhythmias|
|Impaired glucose tolerance, diabetes mellitus|
|Malocclusion and tooth gaps|
|Pituitary mass effect, including headache and visual field defect|
|Sensory and motor peripheral neuropathies|
|Snoring, sleep apnea|
|Symptoms associated with hyperprolactinemia|
|Thick and coarse skin, skin tags|
Because of the pulsatile nature of GH secretion, random GH levels can overlap in acromegalic patients and normal persons. IGF-1 has a longer plasma half-life than GH and is the best single test for the diagnosing acromegaly (Fig. 5).7 Acromegaly is associated with increased morbidity and mortality if untreated. The goal of therapy for most patients is to achieve a normal sex- and age-adjusted IGF-1 and GH less than 2 ng/mL.8
Surgery 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. Medical treatment of acromegaly has gained significance since the limitations of radiation and surgical therapy have become evident. Somatostatin analogues inhibit GH secretion mainly by binding to somatostatin receptors and result in normalization of IGF-1 in up to 65% 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 most patients were asymptomatic. Dopamine agonists have variable efficacy in patients with acromegaly but may be an attractive first-line therapy, especially in those with cosecretion of prolactin and GH. Pegvisomant has higher affinity to GH receptors than native GH but inhibits its dimerization, which is necessary for the action of GH. It is administered once daily and is usually reserved for patients not responding to other medical therapies. It is very effective, normalizing IGF-1 in up to 95% of patients. The tumor size and liver function need to be monitored during therapy. During therapy with pegvisomant, IGF-1 is used to monitor therapy. Radiotherapy is reserved for patients who cannot be cured by surgery and do not respond to or tolerate medical therapy.
Cushing’s syndrome (CS) comprises symptoms and signs associated with prolonged exposure to inappropriately high levels of plasma free glucocorticoids (Box 3). Exogenous glucocorticoid intake is the most common cause of CS. The endogenous causes are divided into ACTH-dependent and ACTH-independent CS (Box 4). In contrast to pale striae that occur postpartum or with weight gain, the striae in CS are usually red-purple, more than 1 cm wide, and located on the abdomen, upper thighs, breasts, and arms (Fig. 6). Increased skin pigmentation is rare and only occurs in the ectopic ACTH syndrome. Supraclavicular and dorsocervical fat pads (buffalo hump) and moon face are nonspecific and are seen in many patients of obesity clinics. Women complain of menstrual irregularity (84%) and hirsutism (especially vellous hypertrichosis of the face), and men and women exhibit loss of libido (≤100%). Psychiatric abnormalities occur in 50% of patients, with agitated depression and lethargy being the most common manifestations. A high clinical suspicion, attention to suggestive clinical features (see Box 3), and an appropriate screening test are the keys to early diagnosis of CS (Fig. 7).9 Because of the challenging nature of diagnosing CS, it is important to follow a stepwise evaluation, know the limitations of each test, and avoid shortcuts.
|Box 3 Clinical Features Suggesting Cushing’s Syndrome|
|Wide purplish striae (>1 cm)|
|Box 4 Causes of Endogenous Cushing’s Syndrome|
|ACTH-Dependent Cushing’s Syndrome|
|Cushing’s disease (67%)|
|Ectopic ACTH secretion (12%)|
|Ectopic CRH secretion (<1%)|
|ACTH-Independent Cushing’s Syndrome|
|Adrenal adenoma (10%)|
|Adrenal carcinoma (8%)|
|Micro- and macronodular adrenal hyperplasia (1%)|
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
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 occurs in some patients with CS.
Surgical removal of the ACTH-secreting pituitary tumor is the treatment of choice.10 Availability of an experienced neurosurgeon is crucial, and the long-term remission rate is about 60 to 80% following surgery. A low (<3 μg/dL) or undetectable postoperative cortisol level off glucocorticoids is considered to be a good marker for long-term cure. For those not cured by the surgery, other options include reoperation and 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. Among the available agents, ketoconazole is the most commonly used. During therapy, liver function tests need to be closely monitored.
Thyrotropin (TSH)-secreting pituitary adenomas account for less than 1% of all pituitary tumors. The mean age at presentation is about 40 years, with a slight female predominance. Symptoms secondary to hyperthyroidism and goiter are the initial complaints in most patients, followed by pituitary mass effect if the disease remains undiagnosed. The most important biochemical feature is elevation of serum thyroid hormone levels (T4 and T3), with an inappropriately normal or elevated TSH level.
In patients with TSH-secreting adenomas, surgery is the primary therapeutic approach. Radiation is generally used for those with residual tumor. Somatostatin analogues are effective in most patients for control of excess TSH production leading to improvement in hyperthyroidism and possibly to a decrease in tumor size.11 Beta blockers should be initiated in patients with uncontrolled hyperthyroidism, and antithyroid medications may be used only for a short period before surgery (if somatostatin analogues cannot be used) because long-term use can stimulate tumor growth.
Nonfunctional and glycoprotein-secreting pituitary tumors account for about 25% to 30% of all pituitary adenomas. Many clinically nonfunctional pituitary adenomas are glycoprotein-producing tumors. They can secrete intact glycoprotein hormones or their alpha and beta subunits. They usually manifest with clinical features related to mass effect, including visual field defect, hypopituitarism, and headache.12
Patients with small nonfunctional pituitary adenomas are usually observed; however, the standard treatment for those with mass effect is surgery, mainly through the trans-sphenoidal approach. Radiotherapy is indicated in those with residual pituitary tumor following surgical debulking or in those who are not surgical candidates. The use of high-dose dopamine agonists has been associated with a decrease in tumor size in only about 10% of patients.
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 probably has autoimmune pathogenesis and is associated with other autoimmune disorders, mainly Hashimoto’s thyroiditis and Addison’s disease. The clinical manifestations relate to mass effect or hypopituitarism. The corticotropin axis is the most commonly affected axis. The chronologic association with pregnancy or the postpartum period and isolated ACTH deficiency is a diagnostic clue.
Trans-sphenoidal surgery is the therapy of choice for those with pituitary mass effect. It is important to monitor patients with varying degrees of hypopituitarism, because some have partial or full recovery of their pituitary axes.
The empty sella is defined as a sella that, regardless of its size, is completely or partly filled with cerebrospinal fluid. An empty sella of normal size is a common incidental autopsy finding. An empty sella is called secondary when it is seen after surgery, irradiation, or medical treatment for a pituitary pathology. 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. Management usually involves reassurance and hormone replacement, if necessary.
Pituitary apoplexy is a rare endocrine emergency resulting from hemorrhagic infarction of a preexisting pituitary tumor (Fig. 8). The clinical manifestations 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.13 Headache is the most prominent symptom in most patients with clinically evident pituitary apoplexy. Once pituitary apoplexy is suspected, stress-dose glucocorticoids (e.g., dexamethasone 4 mg every 8 hours IV) should be initiated and pituitary MRI should be performed. Patients with mass effect benefit from tumor and blood clot debulking, which leads to resolution of visual field defects and improvement of cranial nerve palsies in most patients.
Diabetes insipidus (DI) is characterized by the chronic excretion of abnormally large volumes (>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.
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. In most patients, DI 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 other factors interfere with the normal compensatory mechanism of polydipsia, such as loss of consciousness.
Once diabetes mellitus and hypercalcemia have been excluded, patients should have their 24-hour urinary volume measured during ad libitum fluid intake. DI is diagnosed in those with abnormally high urinary output (>50 mL/kg/day), low urinary osmolality (<300 mOsm/kg), and an appropriate creatinine excretion (14-18 mg/kg body weight) as an indicator of an accurate 24-hour urine collection.14 Measurement of spot urine osmolality is usually unreliable to exclude or diagnose 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.
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.