Diagnostic testing for hypopituitarism

INTRODUCTION — 

The diagnosis of hypopituitarism, defined as deficient secretion of one or more pituitary hormones because of pituitary or hypothalamic disease, is made by documenting subnormal secretion of these pituitary hormones in defined circumstances. Each pituitary hormone must be tested separately, since there is a variable pattern of hormone deficiency among patients with hypopituitarism. Diagnostic testing for hypopituitarism will be discussed here. The causes, clinical manifestations, and treatment of hypopituitarism are reviewed separately. (See "Causes of hypopituitarism" and "Clinical manifestations of hypopituitarism" and "Treatment of hypopituitarism".)

INDICATIONS FOR TESTING — 

The impetus to measure pituitary hormones is the suspicion that the secretion of one or more may be subnormal [1,2]. This suspicion can be based upon the knowledge that the patient has either a lesion (eg, a sellar mass) known to cause hypopituitarism or a symptom (eg, amenorrhea in premenopausal females) known to be caused by hypopituitarism. The knowledge that the patient has a lesion that can cause hypopituitarism is by itself sufficient reason to test for hypopituitarism because some patients with hypopituitarism have no symptoms or have symptoms and do not report them. Hormonal hyposecretion should be evaluated in any patient who has a discrete sellar mass ≥1 cm or diffuse enlargement of the pituitary of any size. (See "Causes, presentation, and evaluation of sellar masses" and "Pituitary incidentalomas".)

CORTICOTROPIN

Evaluate for ACTH deficiency — For normal health, the basal secretion of corticotropin (ACTH) must be sufficient to maintain the serum cortisol concentration within the normal range. For survival, it must increase to raise serum cortisol concentrations in times of physical stress.

Morning serum cortisol — To test basal ACTH secretion, we suggest measuring a morning serum cortisol (at 6 to 9 AM) (algorithm 1).  

The interpretation of the cortisol result depends on the type of assay that is used to measure it.

Using an assay with a normal range of 5 to 25 mcg/dL [138 to 690 nmol/L], the results should be interpreted as follows:

Low — A serum cortisol value of ≤3 mcg/dL [80 nmol/L], confirmed by a second determination, is strong evidence of cortisol deficiency, which in a patient with a disorder known to cause hypopituitarism is usually the result of that disorder. (See "Diagnosis of adrenal insufficiency in adults", section on 'Basal serum cortisol testing'.)

Such a finding in the absence of any known cause of hypopituitarism mandates measurement of plasma ACTH. A plasma ACTH value not higher than normal is inappropriately low and establishes the diagnosis of secondary adrenal deficiency (ie, pituitary or hypothalamic disease). A value higher than normal documents primary adrenal insufficiency (ie, adrenal disease). (See "Determining the etiology of adrenal insufficiency in adults".)

Normal — A serum cortisol value of ≥18 mcg/dL (500 nmol/L) indicates that basal ACTH secretion is sufficient and also that it is probably sufficient for times of physical stress.

Indeterminate results — A serum cortisol value >3 mcg/dL (80 nmol/L) but <1 mcg/dL (500 nmol/L) that is confirmed on repeat determination is an indication to evaluate ACTH reserve.

Interpretation of basal morning cortisol results are reviewed in greater detail separately. (See "Diagnosis of adrenal insufficiency in adults", section on 'Suspected chronic adrenal insufficiency'.)

There are varying opinions among experts about the best approach to evaluating ACTH reserve in patients with an indeterminate morning serum cortisol. Many experts use the cosyntropin stimulation test because of its availability and ease of administration, while others choose the metyrapone test [1,3,4]. (See 'Metyrapone test' below.)

Cosyntropin stimulation test — The rationale for the administration of cosyntropin (ACTH) is that the adrenal glands atrophy when they have not been stimulated for a prolonged period; as a result, they do not secrete cortisol normally in response to a bolus dose of ACTH. The major advantages of the cosyntropin test over the metyrapone test are drug availability and ease of administration. The major disadvantage is that it may not be reliable in patients with recent ACTH deficiency, as may occur soon after pituitary surgery, pituitary apoplexy, or brain or pituitary stalk trauma, when the adrenal glands still maintain responsiveness to ACTH.

The test is usually performed by administering 0.25 mg (25 units) of cosyntropin (synthetic ACTH 1-24) intramuscularly or intravenously and measuring serum cortisol at baseline and 30 and 60 minutes postinjection. Interpretation of cosyntropin stimulation test results are reviewed in detail separately (algorithm 1). (See "Diagnosis of adrenal insufficiency in adults", section on 'Interpretation of results'.)

Only the absolute thresholds are used to exclude or diagnose adrenal insufficiency. Incremental or percent increases in cortisol should not be used to assess the response to ACTH.

Our approach to interpreting the peak serum cortisol value after ACTH administration is as follows (algorithm 1) [5-9] (see "Diagnosis of adrenal insufficiency in adults", section on 'Interpretation of results'):

●<14 mcg/dL (390 nmol/L) – Adrenal insufficiency likely.

●≥14 to <18 mcg/dL (390 to 500 nmol/L) – The interpretation of the cortisol result depends on the type of assay that is used to measure it (table 1) and the clinical likelihood of adrenal insufficiency in an individual patient. (See "Diagnosis of adrenal insufficiency in adults", section on 'Interpretation of results'.)

●≥18 mcg/dL (500 nmol/L) – Adrenal insufficiency generally excluded regardless of assay used to measure cortisol.

Exceptions include measurements obtained within four to six weeks of interventions (such as pituitary surgery or radiation) that may damage the hypothalamus or pituitary, or measurements obtained in patients with abnormal corticosteroid-binding globulin (CBG) levels.

In practice, this test may be less useful because a patient who has such severe ACTH deficiency that the adrenal glands do not respond normally to cosyntropin will also probably have an 8 to 9 AM basal serum cortisol value that is ≤3 mcg/dL (83 nmol/L) and therefore will not need a test of ACTH reserve. On the other hand, a patient who has partial ACTH deficiency may have falsely normal results [10,11].

Metyrapone test — Metyrapone testing is particularly useful for patients with recent ACTH deficiency (eg, post transsphenoidal surgery). The rationale for the administration of metyrapone is that it blocks 11-beta-hydroxylase (CYP11B1), the enzyme that catalyzes the conversion of 11-deoxycortisol to cortisol, resulting in a reduction in cortisol secretion (figure 1). The ensuing fall in serum cortisol should, if the hypothalamic-pituitary-adrenal axis is normal, cause an increase in ACTH secretion and therefore an increase in adrenal steroidogenesis up to and including 11-deoxycortisol.

The metyrapone test is performed as an overnight, single-dose test and is interpreted based on blood levels of 11-deoxycortisol. (See "Metyrapone stimulation tests", section on 'Procedure'.)

●Normal subjects – In normal subjects, administration of 750 mg of metyrapone orally every four hours for 24 hours results in a decline in 8 AM serum cortisol to less than 7 mcg/dL (172 nmol/L) and an elevation in 8 AM serum 11-deoxycortisol to ≥10 mcg/dL (289 nmol/L) at the end of the 24 hours (figure 2). Patients taking phenytoin metabolize metyrapone more rapidly than normal; as a result, each metyrapone dose should be 1500 mg.

After the 8 AM blood sample is taken at the end of the 24 hours, 100 mg of hydrocortisone should be administered intravenously to reverse the cortisol deficiency caused by the metyrapone.

●Patients with hypothalamic-pituitary disease – In patients who have decreased ACTH reserve due to hypothalamic or pituitary disease, the serum 11-deoxycortisol concentration will be less than 10 mcg/dL (289 nmol/L) and the serum cortisol <7 mcg/dL (172 nmol/L) at the end of 24 hours (figure 3) [12].

Interpretation of the metyrapone test requires adequate inhibition of cortisol production. If the serum 11-deoxycortisol concentration at the end of 24 hours is <10 mcg/dL (289 nmol/L) but the serum cortisol concentration is ≥7 mcg/dL (193 nmol/L), the reason for the insufficient rise in 11-deoxycortisol may be insufficient inhibition by metyrapone. In this case, reasons for insufficient inhibition should be sought, such as failure to take all of the metyrapone, rapid metabolism, and malabsorption. The test should then be repeated using a double dose of metyrapone.

The metyrapone test is reviewed in greater detail separately. (See "Metyrapone stimulation tests".)

Insulin-induced hypoglycemia test — We no longer suggest this test because of the risks of hypoglycemia, particularly in older patients or those with underlying cardiovascular or cerebrovascular disease or a seizure disorder. The rationale for this test is that hypoglycemia induced by insulin administration is a sufficient stress to stimulate ACTH and therefore cortisol secretion. In addition, the test correlates relatively well with the serum cortisol response to surgical stress. However, inducing hypoglycemia can be dangerous in older adult patients and those with cardiovascular or cerebrovascular disease or a seizure disorder. Constant monitoring is required during the first hour after the administration of insulin. (See "Insulin-induced hypoglycemia test protocol".)

THYROTROPIN — 

Hypothyroidism in patients who have pituitary or hypothalamic disease is the result of thyrotropin (TSH) deficiency. Unlike in patients who have thyroid disease, TSH secretion does not increase as the T4 concentration decreases, so the serum TSH concentration cannot be used to diagnose secondary hypothyroidism. The diagnosis is made by measuring total or free T4. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Central hypothyroidism'.)

GONADOTROPINS — 

The approach to the diagnosis of gonadotropin deficiency in a patient with known hypothalamic or pituitary disease varies with the sex of the patient.

Males — In a male with hypopituitarism, luteinizing hormone (LH) deficiency can best be detected by measurement of the serum testosterone concentration. If it is repeatedly low at 8 to 10 AM and the LH concentration is low or normal, the patient has secondary hypogonadism. When the serum testosterone concentration is low, the serum LH concentration is usually within the normal range, but low compared with elevated values in primary hypogonadism. If fertility is an issue, a semen analysis should be performed. (See "Clinical features and diagnosis of male hypogonadism".)

Females — In a female of premenopausal age who has pituitary or hypothalamic disease but normal menses, no tests of LH or follicle-stimulating hormone (FSH) secretion are needed because a normal menstrual cycle is a better indicator of intact pituitary-gonadal function than biochemical tests.

Gonadotropin secretion in a female of premenopausal age who has amenorrhea is tested by measuring serum FSH and estradiol. A low estradiol and FSH that is not elevated indicate secondary hypogonadism.

Additional evaluation of menstrual cycle disorders, including amenorrhea, is reviewed in detail separately (algorithm 2). (See "Evaluation and management of secondary amenorrhea", section on 'Laboratory testing' and "Evaluation and management of secondary amenorrhea", section on 'Assessment of estrogen status'.)

GROWTH HORMONE — 

The availability of growth hormone for treatment of abnormal body composition in adults who have growth hormone deficiency increases the interest in testing growth hormone secretion in patients who have hypothalamic or pituitary disease.

Measurement of basal serum growth hormone concentration does not distinguish reliably between normal and subnormal growth hormone secretion in adults. Three other criteria, however, are useful:

●Deficiencies of multiple other pituitary hormones – The likelihood that the growth hormone response to all provocative stimuli will be subnormal in patients who have organic pituitary disease, eg, a macroadenoma, and deficiencies of corticotropin (ACTH), thyrotropin (TSH), and gonadotropins is approximately 95 percent [13].

●Serum insulin-like growth factor-1 (IGF-1) – A serum IGF-1 concentration lower than the age-specific lower limit of normal in a patient who has organic pituitary disease confirms the diagnosis of growth hormone deficiency [14].

●Provocative tests of growth hormone secretion – Either insulin-induced hypoglycemia or the combination of arginine and growth hormone-releasing hormone (GHRH) is a potent stimulus of growth hormone release. Subnormal increases in the serum growth hormone concentration (<5.1 ng/mL for the former and <4.1 ng/mL for the latter) in a patient who has organic pituitary disease confirms the diagnosis of growth hormone deficiency (figure 4) [14]. (See "Growth hormone deficiency in adults", section on 'Provocative tests'.)

If a provocative test is necessary, we prefer the arginine-GHRH test because it carries minimal risk, whereas the insulin tolerance test carries the risk of neuroglycopenic symptoms, and in older adults, seizures and angina. However, GHRH is no longer available in the United States. Other stimuli, such as arginine alone, clonidine, L-DOPA, and the combination of arginine and L-DOPA are much weaker and therefore more likely to give false-positive results [14]. All tests of growth hormone secretion are more likely to give false-positive results in obesity. The provocative tests are reviewed in more detail separately. (See "Growth hormone deficiency in adults", section on 'Provocative tests'.)

PROLACTIN — 

The only known physiologic role of prolactin is to stimulate lactation after childbirth. Females who have severe hypopituitarism due to hypothalamic or pituitary disease may, in the postpartum period, have a serum prolactin concentration that is inappropriately low and not be able to breastfeed. Recombinant human prolactin (r-hPRL), although not commercially available, has been used experimentally in an open-label, pilot study of five females with prolactin deficiency due to Sheehan syndrome or other causes [15]. (See "Treatment of hypopituitarism", section on 'Prolactin deficiency'.)

No data are available about serum prolactin concentrations in females without known pituitary disease who are unable to breastfeed. Routine testing for prolactin deficiency is not currently performed, as it is difficult to distinguish low from normal serum prolactin concentrations, and there is no standardized test of prolactin reserve.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)

SUMMARY AND RECOMMENDATIONS

●Indications for testing – Pituitary function should be tested when a patient is found to have a disease that affects the hypothalamus or pituitary or a symptom known to be caused by hypopituitarism. Each pituitary hormone that the clinician thinks is clinically important needs to be tested separately. (See "Causes of hypopituitarism".)

●ACTH – Corticotropin (ACTH) secretion is tested by measuring serum cortisol at 6 to 9 AM on two or more occasions; if the value is <3 mcg/dL, the patient has cortisol deficiency, and if >18 mcg/dL, the patient has cortisol sufficiency. If the value is persistently intermediate, a test of ACTH reserve, such as a cosyntropin stimulation test or metyrapone test, should be performed (algorithm 1). (See 'Evaluate for ACTH deficiency' above.)

●TSH – To evaluate thyrotropin (TSH) secretion, we measure serum total or free T4 concentrations. The serum TSH concentration should not be used to make the diagnosis, because it is usually within the normal range, although sometimes low or even slightly high and, therefore, it is not helpful. (See 'Thyrotropin' above.)

●Gonadotropins – Gonadotropin secretion in a male is tested by measuring the serum total testosterone concentration on two or more occasions at 8 to 10 AM. A low testosterone, assuming he is not obese (or free testosterone if he is obese), and luteinizing hormone (LH) that is not elevated indicate secondary hypogonadism.

Gonadotropin secretion in a female of premenopausal age who has amenorrhea is tested by measuring estradiol. A low estradiol and follicle-stimulating hormone (FSH) that is not elevated indicate secondary hypogonadism. (See 'Gonadotropins' above.)

●Growth hormone – Growth hormone secretion can be assumed to be subnormal if the patient has: organic pituitary disease; deficiencies of ACTH, TSH, and gonadotropins; and either an age-specific low serum insulin-like growth factor-1 (IGF-1) concentration or a subnormal growth hormone response to a test of growth hormone stimulation. (See 'Growth hormone' above.)