Diagnosis Key Points

• If one pituitary hormone insufficiency is documented, the other pituitary hormones should be tested.

• An 8 am plasma cortisol level less than 5 ^g/dL strongly suggests hypocortisolism; a level greater than18 ^g/dL excludes ACTH deficiency.

• Serum free T4 must be used with serum TSH concentration in assessing thyroid function.

• Normal or subnormal LH level in menopausal or amenorrheic women, in the presence of a low estradiol level, indicates secondary hypogonadism (in men, low testosterone level).

• Diagnosis of GH deficiency requires provocative testing.

Since the presenting complaints can be subtle, clinicians should have a high index of suspicion to diagnose hypopituitarism (Toogood and Stewart, 2008). If the clinical manifestations fit hypogonadism, hypothyroidism, or adrenal insufficiency, those hormonal tests should be ordered to confirm the diagnosis. If one pituitary hormone insufficiency is documented, every attempt should be made to test the status of the other pituitary hormones as well. The underlying etiology of the disease should be determined by computed tomography (CT) or magnetic resonance imaging (MRI) of the hypothalamic-pituitary area. Occasionally, angiography is needed when carotid artery aneurysm is suspected, or to define the blood supply of the tumor. Formal ophthalmo-logic examination with visual field evaluation should be ordered if the patient is symptomatic or has a pituitary mass lesion.

Pituitary hormone secretion is episodic, and in general, dynamic testing is more valuable than single, baseline hormone measurements. For practical reasons, however, the screening can be done with pituitary hormone and target hormone measurements simultaneously. For evaluating suspected hypopituitarism, tests include thyroid function, LH, serum testosterone in men and estradiol in women, IGF-1 (because GH has a short half-life in blood), prolactin, and morning cortisol. Provocative testing for GH and ACTH reserve may be required as well. Patients with known pituitary disease and deficiency of ACTH, TSH, or gonadotropins have a 95% chance of a subnormal provocative stimulus for GH. Also, patients with known pituitary disease and a serum IGF-1 concentration lower than normal can be presumed to have GH deficiency (Gharib et al., 2003). Provocative tests for GH are either physiologic (sleep or exercise) or pharmacologic such as insulin-induced hypoglycemia, GHRH with arginine, and levodopa with arginine tests (Biller et al.,

2002). GH deficiency is diagnosed when GH does not rise above 5 ng/mL in response to two or more stimuli.

A plasma cortisol level less than 5 ^/dL at 8 am on two occasions in the patient with a disorder known to cause hypopituitarism strongly suggests hypocortisolism, and in the presence of normal or low serum ACTH concentration, it establishes the diagnosis of secondary adrenal insufficiency. Conversely, a cortisol level of 18 ^/dL or greater virtually excludes the diagnosis of ACTH deficiency.

To evaluate ACTH reserve, insulin hypoglycemia test (0.10.15 U/kg IV) should be done. A normal cortisol response to adequate hypoglycemic stimulus (blood glucose <50 mg/dL) is either an incremental level of 6 to 10 ^/dL or an absolute level greater than 20 ^/dL. The test allows for concomitant evaluation of GH reserve; however, it is contra-indicated in elderly patients and those with coronary artery disease or epilepsy (Nowak and Mooradian, 2007). An alternative is the metyrapone test, 750 mg orally every 4 hours for six doses, which assesses the sensitivity of the pituitary to the negative inhibition by cortisol. Metyrapone blocks 11p-hydroxylase, an enzyme that catalyzes the final step in cortisol biosynthesis. The decrease in cortisol secretion after metyrapone is given should result in a compensatory increase in the ACTH level. The level of the precursor steroid 11-deoxycortisol should also increase. A normal response is an increase in serum 11-deoxycortisol level greater than10 ^/dL, when serum cortisol level is reduced to less than 8 \ig/ dL, indicating adequate suppression of glucocorticoid synthesis. In the more convenient overnight test, metyrapone, 30 mg/kg orally, is administered at midnight. An increase in the 8 am serum 11-deoxycortisol level to more than 7 ^/dL is found in healthy persons. If symptomatic postural hypotension occurs after metyrapone administration, hydrocortisone should be administered exogenously.

Cosyntropin, 250 |tg intramuscularly (IM) or intravenously (IV), should result in an increase in the serum cortisol level of 18 ^/dL or greater at 60 minutes in normal subjects. The test may not reliably determine the ACTH reserve, especially in those with recent ACTH deficiency, in whom the adrenal glands may not be sufficiently atrophied. Some controversy surrounds whether the 1^g cosyntropin stimulation test (IV only) may be more sensitive for the diagnosis of subtle secondary adrenal insufficiency.

Thyrotropin (TSH) deficiency is diagnosed when low baseline free T4 and low or normal TSH is documented on more than one measurement. Gonadotropin deficiency in men is tested with measurements of baseline LH, FSH, and total testosterone. Serum samples are drawn between 8 and 10 am, and low concentrations should be confirmed with a second serum sample. The 8 to 10 am serum testosterone concentration generally should be 300 to 1000 ng/dL. A low testosterone value (<200 ng/dL) with low or normal LH is indicative of hypogonadotropic hypogonadism. For serum total testosterone levels between 200 and 400 ng/dL, free testosterone level should also be ordered (Mooradian and Korenman, 2006). The presence of amenorrhea in premenopausal women, along with low estrogen level (<30 pg/mL), establishes the diagnosis of HH. In menopausal women the absence of elevated FSH and LH is sufficient for the diagnosis.

Elevated serum prolactin level in a hypogonadal patient suggests a pituitary adenoma. Prolactin deficiency often indicates severe intrinsic pituitary disease and is uncommon without concomitant deficiencies of other anterior pituitary hormones.

Conditions known to mimic hypopituitarism should be excluded when evaluating patients, including anorexia nervosa, protein-calorie malnutrition, systemic illness, chronic renal failure, and liver cirrhosis.

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