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Diagnostic testing for hypopituitarism

Diagnostic testing for hypopituitarism
Author:
Peter J Snyder, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Jan 2024.
This topic last updated: Apr 26, 2023.

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 known to cause hypopituitarism or a symptom known to be caused by hypopituitarism. The knowledge that the patient has a lesion that can cause hypopituitarism, eg, a sellar mass, is by itself sufficient reason to test for hypopituitarism because some patients with hypopituitarism have no symptoms. (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 8 to 9 AM), and the results should be interpreted as follows:

Low — A serum cortisol value of ≤3 mcg/dL (83 nmol/L, normal range 5 to 25 mcg/dL [138 to 690 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.

Such a finding in the absence of any known cause of hypopituitarism mandates measurement of serum ACTH. A serum 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 (497 nmol/L) indicates that basal ACTH secretion is sufficient and also that it is probably sufficient for times of physical stress.

Indeterminate — A serum cortisol value >3 mcg/dL (83 nmol/L) but <18 mcg/dL (497 nmol/L) that is persistent on repeat determination is an indication to evaluate ACTH reserve.

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. (See 'Metyrapone test' below.)

Cosyntropin stimulation test — As noted, there is disagreement among experts on the best approach to evaluating ACTH reserve in patients with an indeterminate morning serum cortisol. While the author of this topic uses the metyrapone test, Endocrine Society Clinical Practice Guidelines and many experts suggest the cosyntropin stimulation test when a morning serum cortisol is indeterminate [1,3,4]. The major advantages of the cosyntropin test over the metyrapone test are drug availability and ease of administration.

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 test is usually performed by administering 0.25 mg (25 units) of cosyntropin (synthetic ACTH 1-24) intramuscularly or intravenously and measuring serum cortisol 60 minutes later. A serum cortisol concentration of ≥18 mcg/dL (497 nmol/L) is considered a normal response. (See "Diagnosis of adrenal insufficiency in adults", section on 'Recent ACTH deficiency'.)

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 [5,6].

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.

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) [7].

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. (See "Metyrapone stimulation tests".)

The advantages of the metyrapone test are that it can be administered to adults of any age and the results correlate reasonably well with the serum cortisol response to surgical stress. The principal disadvantage is that the patient must be observed in an inpatient setting so that blood pressure and pulse can be measured lying and standing before each four-hourly dose for 24 hours. If postural hypotension occurs, the test should be terminated by administration of 100 mg of hydrocortisone intravenously. Of note, other experts perform this test on an outpatient basis based upon data in a number of studies suggesting its safety [8-13]. One potential concern with this test is the declining number of clinical laboratories that routinely perform serum 11-deoxycortisol testing.

A shorter version of this test involves the administration of a single 750 mg dose of metyrapone at midnight and measurements of serum 11-deoxycortisol and cortisol at 8 AM [14]. It may not, however, separate normal from abnormal as well as the longer test.

Insulin-induced hypoglycemia test — The rationale for this test is that hypoglycemia induced by insulin administration is a sufficient stress to stimulate ACTH and therefore cortisol secretion. The test is performed by administering 0.1 unit of insulin per kg of body weight and measuring serum glucose and cortisol before and 15, 30, 60, 90, and 120 minutes after the injection [15]. In normal subjects, serum cortisol increases to ≥18 mcg/dL (498 nmol/L) if the serum glucose falls to <50 mg/dL (2.8 mmol/L). (See "Insulin-induced hypoglycemia test protocol".)

The advantage of this test is that the results also correlate relatively well with the serum cortisol response to surgical stress. The disadvantages are that hypoglycemia can be dangerous in older adult patients and those with cardiovascular or cerebrovascular disease or a seizure disorder and that constant monitoring is required during the first hour after the administration of insulin. The monitoring is necessary to detect neuroglycopenic symptoms, which should be treated with intravenous glucose (see "Insulin-induced hypoglycemia test protocol"). For these reasons, we prefer the metyrapone test.

THYROTROPIN — Hypothyroidism in patients who have pituitary or hypothalamic disease is the result of thyrotropin (TSH) deficiency and, therefore, unlike in patients who have thyroid disease, an elevated serum TSH concentration cannot be used to make the diagnosis of hypothyroidism. The serum TSH concentration is usually not low either, except when the hypothyroidism is treated. Screening for hypothyroidism in patients with pituitary or hypothalamic disease is therefore performed by measuring thyroxine, either free T4 or total T4 and T3 uptake. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Secondary and tertiary (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 not elevated, 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, the sperm count should be determined. (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 more sensitive indicator of intact pituitary-gonadal function than any biochemical test. If the female has oligomenorrhea or amenorrhea, serum LH or FSH should be measured to be sure it is not high due to ovarian disease. In addition, the following two tests should be obtained:

Measurement of serum estradiol

Administration of medroxyprogesterone, 10 mg daily for 10 days (the progestin challenge test), to determine if vaginal bleeding occurs after the 10-day.

Many experts no longer administer this test, and instead rely on serum estradiol and/or endometrial thickness on pelvic ultrasound to assess estrogen status.(See "Evaluation and management of secondary amenorrhea", section on 'Assessment of estrogen status'.)

A low serum estradiol concentration and/or absence of vaginal bleeding indicate estradiol deficiency as a consequence of gonadotropin deficiency and warrant consideration of estrogen treatment. Normal results, in association with oligomenorrhea or amenorrhea, could indicate sufficient gonadotropin secretion to maintain normal basal estradiol secretion but insufficient to cause ovulation and normal progesterone secretion. This situation should prompt consideration of intermittent progestin as one treatment option.

The serum LH response to a single bolus dose of gonadotropin-releasing hormone (GnRH) is not helpful in distinguishing secondary hypogonadism due to pituitary disease from that due to hypothalamic disease, as the response may be normal or subnormal in both groups.

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 [16].

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 [17].

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) [17].

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 [17]. 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 main physiologic role of prolactin is for lactation. 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 [18]. (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. Each pituitary hormone that the clinician thinks is clinically important to a patient needs to be tested separately. (See "Causes of hypopituitarism".)

ACTH Corticotropin (ACTH) secretion is tested by measuring serum cortisol at 8 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 metyrapone test or cosyntropin stimulation test, should be performed. (See 'Evaluate for ACTH deficiency' above.)

TSH To evaluate thyrotropin (TSH) secretion, we measure either free T4 or total thyroxine (T4) and triiodothyronine (T3) uptake. 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 man 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 woman 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.)

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  2. Alexandraki KI, Grossman A. Management of Hypopituitarism. J Clin Med 2019; 8.
  3. Agha A, Tomlinson JW, Clark PM, et al. The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 2006; 91:43.
  4. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101:364.
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  14. Jubiz W, Meikle AW, West CD, Tyler FH. Single-dose metyrapone test. Arch Intern Med 1970; 125:472.
  15. Landon J, Greenwood FC, Stamp TC, Wynn V. The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin, and the comparison of this procedure with other tests of pituitary and adrenal function. II. In patients with hypothalamic or pituitary dysfunction or anorexia nervosa. J Clin Invest 1966; 45:437.
  16. Hartman ML, Crowe BJ, Biller BM, et al. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab 2002; 87:477.
  17. Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2002; 87:2067.
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