Hypopituitarism laboratory findings
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A subnormal or reduced concentration of pituitary hormones is diagnostic of hypopituitarism. Patients with complete hormonal deficiencies are mostly symptomatic and have low serum concentrations of both, the pituitary hormones as well as the target-organ hormones. Patients having partial hormonal deficiencies are detected by dynamic tests/stimulatory tests such as corticotropin stimulation, insulin-induced hypoglycemia and metyrapone test. Corticotropin deficiency is detected by assessing basal cortisol secretion. Patients with intermediate cortisol levels need to be tested for adrenocorticotrophic hormone (ACTH) reserve. There are several tests to check the ACTH reserve. Metyrapone test is preferred over others as it is applicable to all adults with no age restriction and has good correlation with stress related cortisol response. Patients with hypopituitarism are screened for hypothyroidism by measuring thyroxine, total thyroxine (T4) and triiodothyronine (T3) uptake, and free T4. Gonadotropin deficiency is confirmed with low estradiol, low testosterone, and low/normal serum FSH/LH. Growth hormone deficiency is confirmed with provocative tests (insulin induced hypoglycemia and arginine and GHRH combination) for growth hormone (GH) secretion resulting in subnormal levels of serum GH levels, serum insulin-like growth factor-1 levels lower than the age-specific lower limit of normal and deficiency of more than one pituitary hormones, such as ACTH, TSH, and gonadotropins. ADH deficiency is assessed by water deprivation test and ADH suppression test. Prolactin deficiency can be confirmed by directly measuring prolactin levels on more than one occasion as its secretion is episodic but it is not done routinely as it is not clinically significant.
- Patients with complete hormonal deficiencies are mostly symptomatic and have low serum concentrations of both, the pituitary hormones (thyrotropin, corticotropin, and luteinizing hormone) as well as the target-organ hormones (thyroxine, cortisol, and testosterone)
- Patients having partial hormonal deficiencies are detected by dynamic tests/stimulatory tests, such as corticotropin stimulation, insulin-induced hypoglycemia, and metyrapone test
- A subnormal or reduced concentration of pituitary hormones is diagnostic of hypopituitarism. Amongst all pituitary hormones, the first and the most common hormonal deficiency seen in hypopituitarism is growth hormone deficiency followed by deficiencies of gonadotropins (FSH, LH), TSH, ACTH, and prolactin.
- Any history of a lesion causing hypopituitarism or a symptom suggestive of hypopituitarism is an indication for testing for hypopituitarism.
- Laboratory findings consistent with laboratory diagnosis of panhypopituitarism depends upon the specific hormonal deficiency and may include:
- Hyponatremia (due to increased vasopressin secretion)
- Normochromic, normocytic anemia
- Elevated total and low-density lipoprotein (LDL) cholesterol levels
- Low high-density lipoprotein (HDL) cholesterol level
Dynamic tests for making a diagnosis of hypopituitarism
Following dynamic tests can be used to make a diagnosis of hypopituitarism:
|Growth hormone||Insulin tolerance||
|GHRH + arginine||
|Corticotropin standard dose (250 μg)||
|Corticotropin low dose (1 μg)||
|ADH||Water deprivation test||
||Diabetes insipidus (DI): Plasma osmolality >295 mOsm/L with inappropriately hypotonic urine (urine osmolality/plasma osmolality ratio <2) during the fluid deprivation confirms DI (test is discontinued)
Partial/primary polydipsia: With partial DI or primary polydipsia, urine concentrates partially during the water deprivation test (300–800 mOsm/kg), and further investigation is required including a prolonged water deprivation test or DDAVP therapeutic trial
Notes for water deprivation test:
- If plasma osmolality > 305 mOsm/kg or if 3% loss of body weight with plasma osmolality > 305 mOsm/kg, proceed to DDAVP administration earlier. If urine output has not decreased and/or urine osmolality/plasma osmolality ratio < 2, but the plasma osmolality has not concentrated to >295 mOsm/kg, continue water deprivation for a further hour and measure plasma and urine osmolality. Offer DDAVP after this.
- Continue measuring urine osmolality hourly for the next 4 h (after DDVAP administration) and measure hourly urine volumes.
- Stop test if >3% weight loss occurs.
IV: Intravenous, IM: Intramuscular, GH: Growth hormone, GHD: Growth hormone deficiency, BMI: Body mass index
(a) Basal ACTH secretion:
The normal range of serum cortisol is 5 to 25 mcg/dL (138 to 690 nmol/L). Serum cortisol levels are measured at 8 to 9 am and results are interpreted as follows:
|Serum cortisol||Basal adrenocorticotrophic hormone (ACTH)|
|Low: ≤3 mcg/dL (83 nmol/L)||Cortisol deficiency|
|High: ≥18 mcg/dL (497 nmol/L)||No cortisol deficiency even in times of stress|
|Intermediate: >3 mcg/dL (83 nmol/L)
<18 mcg/dL (497 nmol/L)
|Needs evaluation for ACTH reserve|
(b) ACTH reserve:
- Patients with intermediate cortisol levels need to be tested for ACTH reserve. There are several tests to check the ACTH reserve. Metyrapone test is preferred over others as it is applicable to all adults with no age restriction and has good correlation with stress related cortisol response. The major disadvantage of the test is that it needs inpatient observation for blood pressure and pulse monitoring to prevent postural hypotension.
- Insulin-induced hypoglycemia test is not preferred as it needs continuous monitoring for hypoglycemic symptoms during the first hour of insulin administration in patients who are elderly and have cardiovascular or cerebrovascular issues or a seizure disorder. Hypoglycemia is treated with intravenous glucose.↵The standard or low dose cosynotropin stimulation test is not recommended as it can give falsely normal results. The corticotropin-releasing hormone test indicates pituitary-adrenal function and is as reliable as insulin-induced hypoglycemia test but has a limitation that only a small number of patients can be evaluated and may cause transient nausea.
Metyrapone blocks 11-beta-hydroxylase (CYP11B1), an enzyme that catalyzes the last step in cortisol production resulting in decreased cortisol and increased 11-deoxycortisol concentration. In this test 750 mg of Metyrapone is administered orally every 4 hours for 24 hours. Serum cortisol and 11-deoxycortisol concentration are checked at 8 am after 24 hours and the results are interpreted as follows:
|Subject||Cortisol level||11-deoxycortisol level|
|Normal subjects||< 7 mcg/dL (172 nmol/L)||≥10 mcg/dL (289 nmol/L)|
|Patients with decreased ACTH reserve||<7 mcg/dL (172 nmol/L)||<10 mcg/dL (289 nmol/L)|
Patients with hypopituitarism are screened for hypothyroidism by measuring:
- Thyroxine (T4)
- Total thyroxine (T4) and triiodothyronine (T3) uptake
- Free T4
- Thyrotropin-releasing hormone test may be used to confirm thyrotropin deficiency but reduced response is commonly seen in normal elderly subjects and it may cause transient urge to urinate, metallic taste in mouth, arrhythmia and hypotension
|Condition||Serum T3||Serum free T4||Serum TSH|
|Central hypothyroidism||Low or normal||Low or low-normal||Low, normal, or slightly high|
Gonadotropin-releasing hormone test may be used to detect serum levels for gonadotropins (follicle stimulating hormones and luteinizing hormones) but repeated stimulations by gonadotropin-releasing hormone are required to make a diagnosis.
Secondary hypogonadism can be confirmed in an amenorrheic woman having:
- Low testosterone
The following tests and laboratory findings can be used to confirm growth hormone (GH) deficiency in a patient having an organic pituitary disease:
(a) Provocative tests for growth hormone (GH) secretion resulting in subnormal levels of serum GH levels.
|GH provocative tests||Serum GH levels|
|Insulin induced hypoglycemia||<5.1 ng/mL|
|Arginine and GHRH combination||<4.1 ng/mL|
(b) Serum insulin-like growth factor-1 levels lower than the age-specific lower limit of normal. This test is useful in children but not in adults as up to 1/3rd of adults with confirmed GH deficiency have normal IGF-1 levels.
(c) Deficiency of more than one pituitary hormones e.g ACTH, TSH and gonadotropins. For more information on laboratory findings click here.
5.Antidiuretic hormone (ADH) deficiency
(a) Water deprivation test:
It is used to differentiate psychogenic polydipsia from diabetes insipidus. Water intake is restricted with continuous monitoring (as patients with psychogenic polydipsia try even to drink the toilet water) and hourly measurements of serum and urine osmolalities. Results are interpreted as follows:
|Condition||Serum osmolality||Urine osmolality|
(b) Vasopressin stimulation test:
This test is used to differentiate central from nephrogenic diabetes insipidus. Serum and urine osmolalities are measured 1 hour after administration of either subcutaneous 1-2mcg of desmopressin (DDAVP) or 5 units of aqueous vasopressin. The results are interpreted as follows:
|Diabetes insipidus||Serum osmolality||Urine osmolality|
|Nephrogenic||no change||no change|
Prolactin deficiency can be confirmed by directly measuring prolactin levels on more than 1 occasion as its secretion is episodic. Serum prolactin level may be increased in a patient with hypothalamic or pituitary lesion but is rarely low. The following are the salient features associated with prolactin level testing:
- Hypoprolactinemia is a marker of severe pituitary damage in patients having structural pituitary disease
- It is important to measure serum prolactin level as it can give an idea about the location of lesion
- Routine testing is not done because:
- Thyrotropin-releasing hormone test is not very useful as it can't differentiate between prolactinomas and other causes of hyperprolactinemia.
- ↑ Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH (2016). "Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 101 (11): 3888–3921. doi:10.1210/jc.2016-2118. PMID 27736313.
- ↑ Toogood AA, Beardwell CG, Shalet SM (1994). "The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism". Clin. Endocrinol. (Oxf). 41 (4): 511–6. PMID 7955461.
- ↑ Benvenga S, Campenní A, Ruggeri RM, Trimarchi F (2000). "Clinical review 113: Hypopituitarism secondary to head trauma". J. Clin. Endocrinol. Metab. 85 (4): 1353–61. doi:10.1210/jcem.85.4.6506. PMID 10770165.
- ↑ Kelly DF, Gonzalo IT, Cohan P, Berman N, Swerdloff R, Wang C (2000). "Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report". J. Neurosurg. 93 (5): 743–52. doi:10.3171/jns.2000.93.5.0743. PMID 11059653.
- ↑ Beshyah SA, Johnston DG (1999). "Cardiovascular disease and risk factors in adults with hypopituitarism". Clin. Endocrinol. (Oxf). 50 (1): 1–15. PMID 10341850.
- ↑ de Boer H, Blok GJ, Voerman HJ, Phillips M, Schouten JA (1994). "Serum lipid levels in growth hormone-deficient men". Metab. Clin. Exp. 43 (2): 199–203. PMID 8121302.
- ↑ Rosén T, Edén S, Larson G, Wilhelmsen L, Bengtsson BA (1993). "Cardiovascular risk factors in adult patients with growth hormone deficiency". Acta Endocrinol. 129 (3): 195–200. PMID 8212983.
- ↑ Fleseriu M, Gassner M, Yedinak C, Chicea L, Delashaw JB, Loriaux DL (2010). "Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review". Endocr Pract. 16 (1): 64–70. doi:10.4158/EP09153.OR. PMID 19833587.
- ↑ Loriaux DL, Fleseriu M (2009). "Relative adrenal insufficiency". Curr Opin Endocrinol Diabetes Obes. 16 (5): 392–400. doi:10.1097/MED.0b013e3283307d53. PMID 19654538.
- ↑ Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi CH, Clayton RN, Courtney CH, Gonc EN, Maghnie M, Rose SR, Soule SG, Tordjman K (2008). "Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis". J. Clin. Endocrinol. Metab. 93 (11): 4245–53. doi:10.1210/jc.2008-0710. PMID 18697868.
- ↑ 11.0 11.1 Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W (1998). "Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease". J. Clin. Endocrinol. Metab. 83 (5): 1558–62. doi:10.1210/jcem.83.5.4831. PMID 9589655.
- ↑ Schmidt IL, Lahner H, Mann K, Petersenn S (2003). "Diagnosis of adrenal insufficiency: Evaluation of the corticotropin-releasing hormone test and Basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease". J. Clin. Endocrinol. Metab. 88 (9): 4193–8. doi:10.1210/jc.2002-021897. PMID 12970286.
- ↑ Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ (2016). "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 101 (2): 364–89. doi:10.1210/jc.2015-1710. PMC 4880116. PMID 26760044.
- ↑ Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML (2011). "Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline". J. Clin. Endocrinol. Metab. 96 (6): 1587–609. doi:10.1210/jc.2011-0179. PMID 21602453.
- ↑ Clark PM, Neylon I, Raggatt PR, Sheppard MC, Stewart PM (1998). "Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders". Clin. Endocrinol. (Oxf). 49 (3): 287–92. PMID 9861317.
- ↑ Charmandari E, Nicolaides NC, Chrousos GP (2014). "Adrenal insufficiency". Lancet. 383 (9935): 2152–67. doi:10.1016/S0140-6736(13)61684-0. PMID 24503135.
- ↑ Spark RF (1971). "Simplified assessment of pituitary-adrenal reserve. Measurement of serum 11-deoxycortisol and cortisol after metyrapone". Ann. Intern. Med. 75 (5): 717–23. PMID 4330677.
- ↑ Jubiz W, Meikle AW, West CD, Tyler FH (1970). "Single-dose metyrapone test". Arch. Intern. Med. 125 (3): 472–4. PMID 4313728.
- ↑ Landon J, Greenwood FC, Stamp TC, Wynn V (1966). "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. 45 (4): 437–49. doi:10.1172/JCI105358. PMC 292718. PMID 5949228.
- ↑ Streeten DH, Anderson GH, Bonaventura MM (1996). "The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test". J. Clin. Endocrinol. Metab. 81 (1): 285–90. doi:10.1210/jcem.81.1.8550765. PMID 8550765.
- ↑ Soule SG, Fahie-Wilson M, Tomlinson S (1996). "Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism". Clin. Endocrinol. (Oxf). 44 (2): 137–40. PMID 8849565.
- ↑ Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M (1991). "Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test". J. Clin. Endocrinol. Metab. 72 (4): 773–8. doi:10.1210/jcem-72-4-773. PMID 2005201.
- ↑ Soule S, Van Zyl Smit C, Parolis G, Attenborough S, Peter D, Kinvig S, Kinvig T, Coetzer E (2000). "The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism". Clin. Endocrinol. (Oxf). 53 (2): 221–7. PMID 10931104.
- ↑ Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Torpy DJ, Jackson RV (2001). "Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests". Clin. Endocrinol. (Oxf). 55 (5): 625–33. PMID 11894974.
- ↑ Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ (2002). "The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency". Clin. Endocrinol. (Oxf). 56 (4): 533–9. PMID 11966747.
- ↑ Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH (2016). "ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis". J. Clin. Endocrinol. Metab. 101 (2): 427–34. doi:10.1210/jc.2015-1700. PMID 26649617.
- ↑ Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD (1985). "Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone". N. Engl. J. Med. 312 (17): 1085–90. doi:10.1056/NEJM198504253121703. PMID 2984564.
- ↑ Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ (2002). "Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?". J. Clin. Endocrinol. Metab. 87 (2): 477–85. doi:10.1210/jcem.87.2.8216. PMID 11836272.
- ↑ Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, Stavrou S, Kleinberg DL, Chipman JJ, Hartman ML (2002). "Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency". J. Clin. Endocrinol. Metab. 87 (5): 2067–79. doi:10.1210/jcem.87.5.8509. PMID 11994342.
- ↑ "Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency". J. Clin. Endocrinol. Metab. 83 (2): 379–81. 1998. doi:10.1210/jcem.83.2.4611. PMID 9467545.
- ↑ Toogood AA, Jones J, O'Neill PA, Thorner MO, Shalet SM (1998). "The diagnosis of severe growth hormone deficiency in elderly patients with hypothalamic-pituitary disease". Clin. Endocrinol. (Oxf). 48 (5): 569–76. PMID 9666868.
- ↑ Baylis PH, Cheetham T (1998). "Diabetes insipidus". Arch. Dis. Child. 79 (1): 84–9. PMC 1717616. PMID 9771260.
- ↑ Toledano Y, Lubetsky A, Shimon I (2007). "Acquired prolactin deficiency in patients with disorders of the hypothalamic-pituitary axis". J. Endocrinol. Invest. 30 (4): 268–73. doi:10.1007/BF03346292. PMID 17556861.
- ↑ Mukherjee A, Murray RD, Columb B, Gleeson HK, Shalet SM (2003). "Acquired prolactin deficiency indicates severe hypopituitarism in patients with disease of the hypothalamic-pituitary axis". Clin. Endocrinol. (Oxf). 59 (6): 743–8. doi:10.1046/j.1365-2265.2003.01916.x. PMID 14974916.