The pituitary gland is located in the sella turcica posterior to the sphenoid sinus. The optic chiasm is located superior to the pituitary gland, and the carotid arteries are lateral (Figure 2). The gland is composed of the anterior pituitary (adenohypophysis), which is glandular tissue, and the posterior pituitary gland (neurohypophysis), which arises from neural tissue. A rich portal vascular network connects the hypothalamus to the anterior pituitary, whereas the posterior pituitary gland consists of nerve endings projected from neurons in the supraoptic and paraventricular nuclei in the hypothalamus. Both the portal network and hypothalamic neurons travel from the hypothalamus to the pituitary through the pituitary stalk. The carotid arteries provide blood to the pituitary through the hypophysial arteries, and venous drainage occurs by means of the petrosal sinuses to the jugular vein.
Stimulatory and inhibitory hormones, secreted into the portal blood by the hypothalamus, regulate the anterior pituitary, and the posterior pituitary hormones are synthesized in the hypothalamic nuclei and travel through neurons to be released by the posterior pituitary gland.
The anterior pituitary secretes six pituitary hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, thyroid-stimulating hormone (TSH), and growth hormone (GH). Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus in pulses, which in turn control the release of LH and FSH. LH and FSH regulate male and female reproduction including stimulation of the gonads to produce testosterone and estrogen, as well as stimulation of ovarian follicles and spermatogenesis (see Reproductive Disorders). Corticotropin-releasing hormone (CRH), produced in the hypothalamus, stimulates the production of ACTH in the pituitary, which then stimulates cortisol production from the adrenal glands. Prolactin is synthesized in the lactotroph cells. Its synthesis and secretion is suppressed by hypothalamic dopamine, which traverses the pituitary stalk through the portal circulation. TSH is released in response to stimulation from thyrotropin-releasing hormone (TRH) produced in the hypothalamus. TSH binds to receptors on the thyroid, resulting in synthesis and secretion of thyroid hormone. GH release is regulated by two hypothalamic hormones, growth hormone-releasing hormone (GHRH), which stimulates GH release, and somatostatin, which inhibits GH release.
The posterior pituitary gland secretes oxytocin, necessary for parturition and lactation, and antidiuretic hormone (ADH), which maintains water balance.
Table 16 lists the pituitary hormones and the initial evaluation for suspected pituitary excess or deficiency of each hormone.
When a pituitary lesion is discovered incidentally on imaging obtained for an unrelated reason, the lesion is termed a “pituitary incidentaloma.” Small incidentally noted pituitary lesions are quite common. In patients undergoing MRI for nonpituitary reasons, microadenomas are found in 10% to 38%, whereas incidental macroadenomas are seen in 0.2%. Most pituitary incidentalomas are benign nonfunctional pituitary adenomas; however, a small percentage may be Rathke cleft cysts, craniopharyngiomas, or meningiomas. In patients with a history of malignancy, metastatic disease should be considered. Pituitary adenomas measuring 1 cm or larger are macroadenomas; those measuring less than 1 cm are microadenomas (see Evaluation of Pituitary Tumors).
Empty sella is also typically an incidental finding on imaging done for a nonpituitary-related reason. It is a radiologic finding, rather than a medical condition. This term is used when the sella turcica is enlarged and not entirely filled with pituitary tissue. No gland may be visualized, or it is inordinately small. Primary empty sella is the result of herniation of subarachnoid space into the sella, compressing the normal pituitary gland. Primary empty sella is caused by incompetence of the sellar diaphragm, increased intracranial pressure, or volumetric changes in the pituitary gland (as can occur in pregnancy, particularly in multiparous women). Secondary empty sella can be related to infarction of a pituitary tumor or other causes including infection, autoimmune disease, trauma, or radiotherapy.
Patients with an empty sella usually have normal pituitary function because there is gland present, but it is lining the enlarged sella, like the rind of an orange. All patients with empty sella should have clinical assessment for signs and symptoms of pituitary deficiencies. Hyperprolactinemia, the most common pituitary abnormality in empty sella, can be treated with dopamine agonist therapy when needed. Asymptomatic patients should be screened with 8 AM cortisol level measurement, as well as TSH and free T4 measurement. Additional testing should be targeted to the pituitary axes if there are signs or symptoms of deficiency.
Patients with no initial abnormalities are unlikely to develop hormonal or radiologic changes. Because of the theoretical risk of progression, however, it is recommended that asymptomatic patients with empty sella have repeat endocrine, radiologic, and ophthalmologic evaluation in 24 to 36 months. If no progression, further evaluation can be limited to those who require it clinically.
The pituitary gland can also be affected by other pathologic processes, such as autoimmune disease, infection, infiltrative diseases, metastatic disease, or infarction (Table 17).
There are a number of drugs that can affect pituitary gland function. Any hormone administered exogenously provides negative feedback to the normal cells in the pituitary gland. Exogenous estrogen or testosterone will suppress the gonadotropins, LH and FSH, whereas excess exogenous thyroid hormone will suppress TSH. Likewise, physiologic and supraphysiologic doses of glucocorticoids will suppress ACTH. Opiates have a number of effects. Most notably, chronic opioid use suppresses gonadotroph function, resulting in hypogonadotropic hypogonadism, and is increasingly recognized as a cause of ACTH deficiency.
A relatively new class of drugs, checkpoint-blocking antibodies, has been associated with pituitary abnormalities related to hypophysitis. These drugs, including nivolumab, ipilimumab, tremelimumab, and pembrolizumab, are used to treat metastatic melanoma, renal cell carcinoma, non–small cell lung cancer, and head and neck cancers. Hypophysitis occurs in 0.5% to 5% of patients and often presents with headache and fatigue. Endocrine evaluation usually reveals secondary adrenal insufficiency (ACTH deficiency) and secondary hypothyroidism (TSH deficiency), as well as low levels of LH, GH, and prolactin. Imaging demonstrates enhancement and/or enlargement of the pituitary gland with thickening of the pituitary stalk. Diabetes insipidus is uncommon. Treatment includes replacement of the hormone deficiencies along with high-dose glucocorticoids to treat the inflammatory process. Despite resolution of the inflammation, hormone deficiencies often persist.
Mass effects of pituitary tumors most commonly include compression of the pituitary gland resulting in hormone deficiencies or compression of the optic chiasm most commonly resulting in bitemporal hemianopsia; other patterns of visual loss can also occur. Stalk compression can lead to hyperprolactinemia. Headaches can be a symptom of pituitary tumors but do not correlate well with tumor size. Headache alone is not an indication for surgery.
Pituitary deficiencies related to compression of the gland can vary from an isolated hormone deficiency, most often gonadotropin deficiency, to panhypopituitarism (deficiency of all anterior pituitary hormones).
Similarly, pituitary tumors can have variable effects on compression of surrounding structures. A rapidly growing pituitary tumor or rapid expansion due to pituitary apoplexy (sudden hemorrhage or infarction of a pituitary adenoma) causing compression of the optic chiasm may result in complete bitemporal hemianopsia or even blindness. Pituitary apoplexy may even result in cranial nerve (CN) palsies of CNs III, IV, and VI, whereas a slowly growing pituitary tumor that abuts the optic chiasm may cause minimal or no loss in peripheral vision. All patients with pituitary tumors that abut or compress the optic chiasm should have an evaluation by an ophthalmologist (preferentially a neuro-ophthalmologist). Any abnormality on visual examination is an indication for surgery, unless the tumor is a prolactinoma.
Pituitary tumors can invade the cavernous sinus but rarely cause mass effect on brain tissue or narrowing of the carotid within the cavernous sinus.
In patients with a pituitary tumor on CT imaging, a dedicated pituitary MRI with and without contrast with dynamic cuts through the sella should be obtained. A formal visual field examination is required for any tumor that abuts or compresses the optic chiasm.
Pituitary hypersecretion should be ruled out by measurement of prolactin and insulin-like growth factor 1 (IGF-1). Evaluation for Cushing disease is not necessary in patients without signs or symptoms of cortisol excess.
Pituitary tumors can also cause hypopituitarism. Screening for hypopituitarism is recommended in all pituitary tumors regardless of symptoms with measurement of FSH, LH, cortisol, TSH, free thyroxine (T4), and additionally total testosterone in men. Hypogonadotropic hypogonadism can be assessed in premenopausal women through menstrual history. A history of oligomenorrhea or amenorrhea would raise concern for hypogonadotropic hypogonadism and require further hormone testing, whereas a history of normal menses would essentially rule out hypogonadotropic hypogonadism. Abnormal baseline testing may prompt further stimulatory testing to confirm hypopituitarism (Table 18), and referral to an endocrinologist is recommended.
If a patient does not require surgical intervention for mass effect or pituitary hypersecretion, repeat pituitary hormone assessment and imaging is performed in 6 months for macroadenomas and then yearly if no change.
Microadenomas should be reassessed with imaging in 1 year and then every 1 to 2 years thereafter. Repeat evaluation of pituitary function is not necessary in microadenomas if initial testing is normal and there has been no change clinically or in the pituitary MRI.
After 3 years of imaging follow up for a pituitary tumor (both microadenomas and macroadenomas), imaging can be performed less frequently, as long as clinical status of the patient remains stable.
Patients with a nonfunctioning pituitary tumor should be referred for neurosurgical evaluation if any of the following are present: visual deficits related to the tumor, a lesion abuts or compresses the chiasm or optic nerves on pituitary MRI, or pituitary apoplexy with visual disturbance. Surgery should also be considered for a tumor with clinically significant growth, such as growth toward the optic chiasm, and for patients with new loss of endocrine function. Women with a macroadenoma close to the optic chiasm who are planning pregnancy may benefit from surgical decompression of the pituitary tumor due to the risk of enlargement during pregnancy. Microadenomas rarely increase in size during pregnancy. The most common surgical approach for these tumors is transsphenoidal through the nares or mouth. Occasionally, craniotomy is needed for very large tumors. Most nonfunctioning macroadenomas will have immunocytochemistry consistent with a gonadotroph adenoma and are clinically “silent” (without hypersecretion of functional gonadotropins).
Hypopituitarism is defined as one or more pituitary hormone deficiencies. It can occur as a result of compression of the normal pituitary cells by a tumor or as a complication of cranial surgery or radiation therapy. Somatotrophs and gonadotrophs appear to be the most sensitive to injury, so GH as well as LH and FSH are the most common pituitary deficiencies. ACTH and TSH deficiency are less common, but more serious.
Pituitary apoplexy and Sheehan syndrome (pituitary infarction associated with postpartum hemorrhage) can cause acute life-threatening hypopituitarism due to ACTH deficiency.
A full list of causes of hypopituitarism can be found in Table 19.
Panhypopituitarism occurs when a patient lacks adequate production of all anterior pituitary hormones, usually due to a large tumor or complications of pituitary surgery. These patients require daily replacement of thyroxine and cortisol. Replacement of sex steroids and GH is individualized, based on the clinical situation and evaluation of risks and benefits of treatment. Patients with panhypopituitarism should wear medical alert identification as a deficiency of glucocorticoids can be life threatening.
The most common cause of adrenocorticotropic hormone (ACTH) deficiency is iatrogenic following administration of exogenous glucocorticoids and suppression of ACTH production. Oral, injectable (intraarticular, intramuscular), and even occasionally topical glucocorticoids can suppress ACTH. Inhaled glucocorticoids attenuate the recovery of endogenous ACTH production but rarely cause suppression of ACTH production directly. Patients with iatrogenic adrenal insufficiency have intact renin-aldosterone systems; they are at lower risk for hypotension and adrenal crisis.
Glucocorticoids prescribed in supraphysiologic doses for 3 weeks or longer should be tapered off to allow recovery of the pituitary-adrenal axis. Once the glucocorticoid dose is close to physiologic (equivalent of 15-20 mg hydrocortisone), hydrocortisone should be substituted. The dose can then be reduced by 5 mg every 1 to 2 weeks as tolerated. AM-only dosing may facilitate recovery of the adrenal axis.
Once on physiologic AM-only hydrocortisone, the adrenal axis can then be tested for recovery. An 8 AM cortisol level higher than 10 µg/dL (276 nmol/L) after withholding glucocorticoids for 24 hours suggests recovery of the pituitary-adrenal axis. This should be confirmed with an ACTH stimulation test. Despite recovery of the pituitary-adrenal axis, patients may take longer to recover their ability to respond to stress and may require stress-dose or sick-day dosing of glucocorticoids in the setting of an illness for up to a year.
ACTH deficiency can also occur in the setting of damage to the pituitary gland. Symptoms of secondary cortisol deficiency can include fatigue, malaise, weight loss, nausea, vomiting, asymptomatic hypoglycemia, dizziness, and hyponatremia. Because only cortisol production is affected (mineralocorticoid production is intact), patients do not develop hyperkalemia and are less likely to have hypotension. Furthermore, patients with secondary adrenal insufficiency do not develop hyperpigmentation. Nonetheless, patients with secondary adrenal insufficiency do require physiologic glucocorticoid replacement and stress dosing during illness.
Morning cortisol levels less than 3 µg/dL (82.8 nmol/L) are diagnostic of cortisol deficiency; however, a morning cortisol level greater than 15 µg/dL (414 nmol/L) likely rules it out. Patients with cortisol levels between 3 and 15 µg/dL (82.8-414 nmol/L) should undergo an ACTH stimulation test (see Table 18). A peak cortisol level greater than or equal to 18 µg/dL (496.8 nmol/L) at 0, 30, or 60 minutes rules out cortisol deficiency. Once diagnosed, secondary adrenal insufficiency should be treated with hydrocortisone 15 to 20 mg in two divided doses, such as 10 to 15 mg in the morning and 5 mg in the afternoon. In the setting of an emergency such as pituitary apoplexy, an immediate intravenous dose of 100 mg hydrocortisone should be administered.
Glucocorticoid dosing must be adjusted in the setting of physiologic stress or acute illness. Administering two to three times the baseline dose of cortisol replacement for 2 to 3 days is usually sufficient for minor to moderate illness including minor or moderate surgery. In patients with major physiologic stress including major surgery or active labor, 100 mg hydrocortisone should be administered by intravenous injection followed by a continuous infusion of 200 mg every 24 hours or 50 mg intravenous injection every 6 hours (see Disorders of the Adrenal Glands).
Deficiency of thyroid-stimulating hormone (TSH) results in the inability of the thyroid gland to produce thyroxine (T4). The result is insufficient T4 production with low or inappropriately normal TSH. The clinical symptoms of secondary hypothyroidism are the same as seen with primary hypothyroidism.
The treatment is daily administration of levothyroxine. TSH cannot be used to monitor therapy and should not be measured. Dosing based on TSH level can lead to underdosing. Free T4 should be used to monitor dose adequacy and should be maintained in the mid to upper half of the normal range. While it takes 6 to 8 weeks for TSH to accurately reflect thyroid hormone status in primary hypothyroidism, free T4 levels can be checked 2 to 3 weeks after a dose change to assess for adequacy in secondary hypothyroidism.
Gonadotropin deficiency can be a result of pituitary disease or a result of gonadotropin-releasing hormone (GnRH) deficiency as is seen in Kallmann syndrome and hypothalamic amenorrhea. Certain drugs, including opiates, can also suppress GnRH. Deficiency of gonadotropins, LH and FSH, results in deficiency of male and female sex hormones. The combination of low or inappropriately normal LH and FSH with low sex steroids is termed “central” or “hypogonadotropic” hypogonadism.
Treatment of hypogonadotropic hypogonadism can usually be achieved by replacing sex steroids in those with no contraindication and who do not desire fertility; testosterone treatment in men and combined estrogen-progesterone treatment in premenopausal women are used. While oral contraceptive pills may be more acceptable in young women for this purpose, other forms of estrogen and progesterone (such as estradiol patch with cycled oral progesterone) may be preferred in certain cases. In men and women who desire fertility, replacement of gonadotropins is necessary because exogenous testosterone and estrogen suppresses spermatogenesis in men and ovulation in women, respectively.
Growth hormone (GH) is necessary for linear growth. Deficiency of GH in children causes short stature. Symptoms of growth hormone deficiency in adults are more subtle and include fatigue, loss of muscle mass, and increased ratio of fatty tissue to lean mass.
While isolated GH deficiency can occur in children, idiopathic isolated GH deficiency in adults is quite rare. Only patients with a history of hypothalamic or pituitary disease, surgery or radiation to these areas, head trauma, or other pituitary hormone deficiencies should be considered for evaluation of adult-onset isolated GH deficiency.
Owing to the pulsatile nature of GH, direct measurement is uninterpretable and GH deficiency should be assessed through measurement of insulin-like growth factor 1 (IGF-1). An IGF-1 level below the normal range for gender and age is highly suggestive of GH deficiency, whereas a normal IGF-1 level does not completely rule out growth hormone deficiency if pretest suspicion is high. Provocative tests such as an insulin tolerance test or GHRH-arginine test can be performed in consultation with an endocrinologist to establish the diagnosis of adult GH deficiency.
Benefits of treatment in those with GH deficiency include improvement in exercise capacity, body composition, and bone density. The decision to start growth hormone replacement should be individualized. It is contraindicated in the setting of malignancy or with an untreated pituitary tumor because of the potential for stimulation of tumor growth. Additionally, caution should be used in those with diabetes mellitus as it may worsen hyperglycemia. When therapy is indicated in adults, GH can be replaced with a low-dose daily injection titrated to a normal IGF-1 level and clinical assessment.
Pituitary tumors are considered functional when they secrete pituitary hormones in excess. The most common functional pituitary tumors are prolactinomas. Although pituitary tumors that produce ACTH or GH are less common, they are important to recognize because of the clinical consequences. TSH-secreting adenomas are a very rare cause of hyperthyroidism. Pituitary tumors rarely cosecrete more than one excess hormone. Cosecretion most commonly occurs with GH and prolactin.
The most common cause of hyperprolactinemia is physiologic, related to pregnancy and lactation. Physiologic stress, coitus, sleep, and nipple stimulation are other nonpathologic causes of mild hyperprolactinemia. A comprehensive list of causes of hyperprolactinemia is provided in Table 20. Symptoms of hyperprolactinemia include amenorrhea, and sometimes galactorrhea, in premenopausal women. Men often present later with symptoms of mass effect or hypogonadism, such as decreased libido or difficulty with erections; less commonly, they experience gynecomastia and breast tenderness.
The most common cause of pathologic non–tumor-related hyperprolactinemia is medications. Of patients taking typical antipsychotics (see Table 20), 40% to 90% will have hyperprolactinemia caused by the dopamine antagonist effect of these medications. While medication-induced hyperprolactinemia most often results in prolactin levels of 25 to 100 ng/mL (25-100 µg/L), drugs such as metoclopramide, risperidone, and phenothiazines can lead to prolactin levels above 200 ng/mL (200 µg/L). Confirming that the hyperprolactinemia is related to medication can be challenging. If possible, the offending medication should be withheld for 3 days to determine whether prolactin levels return to normal.
Discontinuation of any psychotropic drug should be done only in consultation with the patient's psychiatrist. If the medication cannot be withheld and the prolactin elevation cannot be correlated to the timing of the drug initiation, a pituitary MRI should be performed to rule out prolactinoma. Antipsychotic medication-induced hyperprolactinemia is best treated in consultation with the patient's psychiatrist by switching to a drug that is less likely to cause hyperprolactinemia. While asymptomatic hyperprolactinemia related to medication does not require treatment, patients with hypogonadism should be treated with estrogen or testosterone to preserve bone mass. Treating medication-induced hyperprolactinemia with a dopamine agonist (cabergoline or bromocriptine) is controversial as it can exacerbate psychosis.
An MRI of the pituitary is indicated in all patients with unexplained hyperprolactinemia. Assessment and treatment decisions are then based on the prolactin level and MRI findings.
A prolactin level above 500 ng/mL (500 µg/L) is diagnostic of a macroprolactinoma. While levels greater than 250 ng/mL (250 µg/L) are suggestive of a macroprolactinoma, there are some medications that can raise prolactin to this level. Prolactin levels generally correlate with tumor size. Therefore when a macroadenoma is present with a prolactin level below 100 ng/mL (100 µg/L), pituitary stalk compression from a nonfunctioning tumor should be suspected for the cause of the hyperprolactinemia, rather than prolactinoma.
Patients with asymptomatic microadenomas do not require treatment. Women with hypogonadism related to a microadenoma can be treated with a combined oral contraceptive if they do not desire fertility or with a dopamine agonist if they do. Postmenopausal women with microadenomas do not require treatment.
In patients with macroadenomas, dopamine agonist therapy is recommended to lower prolactin, reduce tumor size, and restore gonadal function. Cabergoline is the preferred agent because of its superior efficacy in lowering prolactin and tumor shrinkage compared with bromocriptine. In addition, cabergoline dosing is twice per week compared with 1 to 3 times daily for bromocriptine. Prolactin can be monitored 2 to 4 weeks after initiation of therapy and then every 3 to 4 months once stable. MRI should be repeated for a microadenoma in 1 year. If both the tumor and prolactin are stable at 1 year follow up, no further imaging is needed. A macroadenoma should be reimaged 3 months after medical therapy and then every 6 to 12 months until stability is confirmed. Reimaging should be performed if the prolactin level rises despite therapy.
Surgery is not first-line therapy because up to 50% of prolactinomas recur after resection. Surgery should only be considered for prolactinomas in symptomatic patients who cannot tolerate dopamine agonist therapy or whose tumors do not shrink or even grow while on dopamine agonist therapy.
Due to lactotroph hyperplasia in pregnancy, there is concern for enlargement of prolactinomas in pregnancy. Because microadenomas are not likely to enlarge during pregnancy, dopamine agonist therapy should be discontinued when pregnancy is discovered. However, patients who have macroadenomas without prior surgical or radiation therapy have a significant risk of tumor growth. Surgical tumor debulking prior to pregnancy or dopamine agonist therapy throughout pregnancy may be required in these patients. Bromocriptine is the preferred agent in pregnancy.
Patients with macroadenomas should be monitored with visual field testing each trimester while those with microadenomas can be monitored clinically. Headaches or visual field changes should prompt a noncontrast pituitary MRI.
Acromegaly is caused by excess secretion of GH from a pituitary tumor in 95% of patients. In fewer than 5% of patients with GH excess, a growth hormone-releasing hormone (GHRH)-secreting tumor or neuroendocrine tumor is the cause of acromegaly. When GH-secreting pituitary tumors are present in children prior to puberty, the result is increased longitudinal growth resulting in gigantism. While gigantism is easily recognized in children, features of excess growth hormone are more subtle in adults, often not recognized for many years. A list of clinical features of acromegaly can be found in Table 21.
An IGF-1 level should be obtained to screen for suspected acromegaly. In those with an elevated level, an oral glucose tolerance test should be performed to confirm the diagnosis (see Table 18). A level above 1 ng/mL (1 µg/L) confirms the diagnosis of acromegaly. Once GH excess is demonstrated, a pituitary MRI should be obtained.
Transsphenoidal resection (TSR) of the GH-secreting tumor is the mainstay of therapy. Those who do not achieve remission with surgery can be treated with medical therapy and/or stereotactic radiation. Somatostatin analogues are the medications of choice as they result in reduction of tumor size as well as reduction in GH levels. Pegvisomant, a GH receptor antagonist, can be used in combination with a somatostatin analogue when needed; cabergoline can sometimes be used as well. Stereotactic radiotherapy (gamma knife) is used in certain cases. Once remission is achieved, MRI and IGF-1 levels are followed annually.
Patients with acromegaly can have increased mortality due to heart disease, sleep apnea, and cancer, but risk returns to baseline when IGF-1 is kept in the normal range. Appropriate screening and treatment for comorbidities are as important as managing the IGF-1 level.
Thyroid-stimulating hormone (TSH)-secreting pituitary tumors are extremely rare. Signs and symptoms of a TSH-secreting adenoma are those seen in hyperthyroidism, although laboratory evaluation reveals elevated T4 and T3 levels with an inappropriately normal or elevated TSH level. Once other causes of the laboratory abnormalities have been excluded (thyroid assay interference, thyroid hormone resistance, or familial dysalbuminemic hyperthyroxinemia), a pituitary MRI should be performed. TSR of the TSH-producing tumor is the treatment of choice. Medical therapy with somatostatin analogues can be used to control hyperthyroidism prior to surgery and following surgery in those who do not achieve remission.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) results in water retention with resultant hyponatremia, often severe. CNS disorders (trauma, stroke, brain metastases, infection) drugs, pulmonary disease, and pituitary surgery (3-7 days postoperatively) can result in excess release of ADH. SIADH is a diagnosis of exclusion. Treatment involves correcting the underlying pathology, fluid restriction, vasopressin receptor antagonists, and hypertonic saline in severe hyponatremia. If hypertonic saline is being considered, consultation with an endocrinologist or nephrologist is recommended (see MKSAP 18 Nephrology).
Cushing syndrome is a term used to describe hypercortisolism regardless of the cause; Cushing disease (the most common cause of endogenous Cushing syndrome) is the term used to describe hypercortisolism as a result of excess ACTH secretion from a pituitary tumor. Symptoms and signs of Cushing syndrome are listed in Table 22.
The diagnosis of Cushing syndrome is made by first establishing evidence of hypercortisolism (see Disorders of Adrenal Glands). Measuring ACTH establishes whether it is ACTH-dependent or ACTH-independent.
Once diagnosis of ACTH-dependent Cushing syndrome is established, a pituitary MRI should be performed for confirmation. If no pituitary tumor is seen or if the tumor is less than 6 mm, a high-dose 8-mg dexamethasone suppression test (DST) is done to evaluate for the presence of an ectopic ACTH-producing tumor (lung, pancreas, thymus carcinoma most commonly), which is highly resistant to dexamethasone suppression. Inferior petrosal sinus sampling (IPSS) is often recommended prior to TSR to confirm a pituitary source of ACTH excess due to low sensitivity and specificity of the high-dose DST.
The treatment of choice is TSR of the pituitary adenoma. Remission is generally defined by a morning serum cortisol level less than 5 µg/dL (138 nmol/L) within 7 days of surgery. Patients require glucocorticoid replacement postoperatively until the normal corticotroph cells recover from prolonged cortisol suppression. Recovery can take up to a year, and occasionally there is no recovery and the patient will require life-long cortisol replacement therapy.
If remission is not achieved following surgery, radiation or medical therapy (Table 23) may be required. Rarely, bilateral adrenalectomy is needed in patients unresponsive to all other therapies; these patients will require life-long glucocorticoid and mineralocorticoid replacement for acquired primary adrenal insufficiency. In addition, there is the risk of pituitary tumor enlargement following adrenalectomy (Nelson syndrome) due to unfettered stimulation of ACTH production.
Patients with Cushing disease require imaging and biochemical follow-up (urine free cortisol or late-night salivary cortisol measurement) every year for several years, and then on a less frequent basis. The first biochemical sign of recurrence is often elevated late-night salivary cortisol levels. Recurrences are managed by repeat TSR, radiation, and/or medical therapy.