Hyperpituitarism Workup

Updated: Jun 30, 2020
  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Robert P Hoffman, MD  more...
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Laboratory Studies


The following laboratory studies are usually included in the workup:

  • Serum prolactin (PRL): A single PRL measurement may be sufficient to diagnose a prolactinoma if the value is greater that 200 ng/mL. Because PRL is secreted in a pulsatile fashion, a mildly increased concentration may be difficult to interpret. In this situation, casual morning samples obtained on 3 separate days should be examined before a prolactinoma is diagnosed. The serum PRL level is roughly proportional to the mass of the tumor. Small tumors can cause elevations of serum PRL lower than those values commonly observed with hyperprolactinemia from other causes.

  • Thyrotropin-releasing hormone (TRH) stimulation test: In healthy patients, intravenous TRH results in a brisk rise in serum PRL in 15-30 minutes, with peak values at least twice the baseline value. In contrast, patients with PRL-secreting tumors usually show little or no PRL increment in response to TRH, rarely exceeding a 100% rise. Patients with elevated serum PRL from other causes usually show a more normal response, with a rise in PRL of at least 100% following administration of TRH.

Adrenocorticotropic hormone–releasing adenoma

Tests that may be included in the workup are as follows:

  • Urinary steroid excretion: Urinary free cortisol (UFC) excretion is a direct measurement of cortisol not bound to plasma protein and is the most reliable and useful test for assessing cortisol secretion rate. Several 24-hour UFC measurements should be obtained. UFC values should be corrected for the child's body surface area. Daily UFC excretion in excess of 70 µg (over 24 consecutive hours) in the unstressed child is highly suggestive of hypercortisolism.

  • Plasma cortisol: Normal plasma cortisol values are highest from 6-8 am, declining during the day to less than 50-80% of morning values from 8 pm to midnight. Loss of this diurnal variation of plasma cortisol is typical of Cushing disease. Cortisol should be sampled at 30-minute intervals from 6-8 am and from 8 pm to midnight.

  • Dexamethasone suppression testing: A useful screening test for hypercortisolism is the inability of dexamethasone (0.3-0.5 mg/m2, maximum dose 1 mg) administered at 11 pm to suppress the subsequent 8-am plasma cortisol concentration to less than 5 µg /dL. The suppression of 24-hour UFC excretion by more than 50% with high-dose dexamethasone (120 µg /kg/d divided qid), but not by low-dose dexamethasone (30 µg /kg/d divided qid), suggests a primary hypothalamic-pituitary disorder. Lack of suppression to high-dose dexamethasone suggests an adrenal tumor or the ectopic secretion of adrenocorticotropic hormone (ACTH).

  • Plasma ACTH: Elevated or high-normal values of plasma ACTH concentration in the presence of hypercortisolism suggest that the primary pathology is due to excess ACTH secretion of pituitary or nonpituitary origin. Consistently suppressed plasma ACTH concentrations suggest that the primary disorder lies in the adrenal glands.

  • Corticotropin-releasing hormone (CRH) stimulation testing: The ACTH and cortisol responses to CRH generally are flat in the ectopic ACTH syndrome and in hypercortisolism secondary to an adrenal tumor, whereas both remain intact in Cushing disease.

  • Inferior petrosal sinus sampling

    • Sampling for ACTH venous gradients during petrosal sinus catheterization in the areas of pituitary venous drainage can offer preoperative diagnosis of a corticotropinoma and lateralization of an ACTH-secreting microadenoma to the right or left hemisphere of the pituitary gland. A gradient in ACTH levels before and/or after CRH from either side of 2 or greater can localize a microadenoma in the pituitary in over 95% of the patients and can provide lateralization information in as many as 75% of cases. Thus, even very small tumors that are not visualized by MRI can be identified and excised surgically. Of note, this procedure should be performed only in large centers with extensive experience.

    • Because no healthy patient would undergo such an invasive procedure, the referring physician must advise families that appropriate reference ranges are not available. Thus, interpretation of these data are not straightforward. Indeed, these data often obscure the management and substantially inconvenience patients and their families with an interstate trip to an elite medical center.

Growth hormone–releasing adenoma

The following studies are often included in the workup:

  • Serum insulin-like growth factor-I (IGF-I): Measurement of serum IGF-I concentration is a sensitive screening test for acromegaly. Serum total (and free) IGF-I levels closely correlate to 24-hour mean integrated growth hormone (GH) secretion. An elevated IGF-I level in a patient with appropriate clinical suspicion almost always indicates GH excess. Potential confusion may arise when evaluating healthy adolescents because significantly higher IGF-I levels occur during puberty than those during adulthood. For accurate control comparison, the IGF-I level must be compared with that of control subjects who are matched for age, gender, and Tanner stage. Note that a single measurement of GH is inadequate, because GH is secreted in a pulsatile manner during deep sleep (at night). Therefore, the use of a random GH measurement can lead to both false-positive and false-negative results and provides practically no clinically relevant data.

  • Serum insulin-like growth factor-binding protein-3 (IGFBP-3): IGFBP-3 levels may also be useful in the diagnosis of GH excess. In patients with confirmed somatotroph adenomas, increased IGFBP-3 level has been reported as a sensitive marker of GH hypersecretion and may be elevated even when circulating IGF-I levels are within the reference range.

  • Inability to suppress serum GH levels during an oral glucose tolerance test (OGTT): The single best laboratory criterion for diagnosing GH excess is failure to suppress serum GH levels to less than 5 ng/dL within 3 hours after a 1.75-g/kg oral glucose challenge (maximum dose is 75 g). This test essentially indicates the loss of negative feedback by IGF-I on GH secretion. Glucose induces insulin secretion, which suppresses hepatic IGFBP-1 release, thereby increasing circulating free IGF-I, which suppresses pituitary GH secretion. These test findings can be misleading in patients who have diabetes.


Imaging Studies

If laboratory findings suggest pituitary hormone excess, the presence of a pituitary adenoma should be confirmed using magnetic resonance imaging (MRI). A T1-weighted spin-echo MRI scan of the pituitary before and after administration of gadolinium (Gd) is the imaging modality of choice for detecting pituitary adenomas. [11]

Coronal and sagittal images should be obtained at 3-mm intervals before and after contrast, focusing on the pituitary region. Adenomas are slow to take up Gd compared with the surrounding normal pituitary tissue and therefore appear as hypoenhancing lesions.

In some cases, a pituitary mass is not identified. Be aware that a pituitary microadenoma can be occult and that an ectopic tumor rarely occurs.

Conventional T1-weighted MRI still is only able to detect approximately one third to one half of microadenomas.

Magnetic resonance imaging (MRI) may have a role in the diagnosis of Cushing disease. In one series, MRI with spoiled gradient recalled echo (SPGR) sequences detected adenomas in 15% of patients that were not detected by standard spin echo. [12] More sensitive imaging of the adenoma in Cushing disease confers several advantages, including confirmation of the diagnosis and location and avoidance of the risks of inferior petrosal sinus sampling; positive MRI findings help confirm the diagnosis of Cushing disease. Nevertheless, MRI has limited accuracy in the prediction of dural invasion.