Hypopituitarism laboratory findings: Difference between revisions

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==Overview==
==Overview==
A subnormal or reduced concentration of [[Pituitary hormone|pituitary hormones]] is diagnostic of hypopituitarism. [[Corticotropin]] [[deficiency]] is detected by assessing basal [[cortisol]] secretion. Patients with intermediate cortisol levels need to be tested for [[Adrenocorticotropic 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]], [[Thyroxine|total thyroxine (T4)]] and [[Triiodothyronine|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|insulin-like growth factor-1]] levels lower than the age-specific lower limit of normal and deficiency of more than one [[Pituitary hormone|pituitary hormones]] e.g [[Adrenocorticotropic hormone|ACTH]], [[Thyroid-stimulating hormone|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 1 occasion as its secretion is episodic but it is not done routinely as it is not clinically significant.
A subnormal or reduced concentration of [[Pituitary hormone|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 [[Adrenocorticotropic hormone|adrenocorticotrophic hormone]] ([[Adrenocorticotropic hormone|ACTH]]) reserve. There are several tests to check the [[Adrenocorticotropic hormone|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 [[Screening (medicine)|screened]] for [[hypothyroidism]] by measuring [[thyroxine]], [[Thyroxine|total thyroxine (T4)]] and [[Triiodothyronine|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|growth hormone (GH)]] secretion resulting in subnormal levels of [[serum]] [[Growth hormone|GH]] levels, serum [[Insulin-like growth factor|insulin-like growth factor-1]] levels lower than the age-specific lower limit of normal and deficiency of more than one [[Pituitary hormone|pituitary hormones]], such as [[Adrenocorticotropic hormone|ACTH]], [[Thyroid-stimulating hormone|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.


==Laboratory Findings==
==Laboratory Findings==
*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 with complete [[hormonal]] deficiencies are mostly [[symptomatic]] and have low [[serum]] concentrations of both, the [[pituitary]] hormones ([[thyrotropin]], [[corticotropin|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
*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 hormone|pituitary hormones]] is diagnostic of hypopituitarism.<ref name="pmid27736313">{{cite journal |vauthors=Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH |title=Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=11 |pages=3888–3921 |year=2016 |pmid=27736313 |doi=10.1210/jc.2016-2118 |url=}}</ref>
*A subnormal or reduced concentration of [[Pituitary hormone|pituitary hormones]] is [[diagnostic]] of hypopituitarism.<ref name="pmid27736313">{{cite journal |vauthors=Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH |title=Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=11 |pages=3888–3921 |year=2016 |pmid=27736313 |doi=10.1210/jc.2016-2118 |url=}}</ref> 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]], [[Luteinizing hormone|LH]]), [[TSH]], [[Adrenocorticotropic hormone|ACTH]], and [[prolactin]].<ref name="pmid7955461">{{cite journal |vauthors=Toogood AA, Beardwell CG, Shalet SM |title=The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism |journal=Clin. Endocrinol. (Oxf) |volume=41 |issue=4 |pages=511–6 |year=1994 |pmid=7955461 |doi= |url=}}</ref><ref name="pmid10770165">{{cite journal |vauthors=Benvenga S, Campenní A, Ruggeri RM, Trimarchi F |title=Clinical review 113: Hypopituitarism secondary to head trauma |journal=J. Clin. Endocrinol. Metab. |volume=85 |issue=4 |pages=1353–61 |year=2000 |pmid=10770165 |doi=10.1210/jcem.85.4.6506 |url=}}</ref><ref name="pmid11059653">{{cite journal |vauthors=Kelly DF, Gonzalo IT, Cohan P, Berman N, Swerdloff R, Wang C |title=Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report |journal=J. Neurosurg. |volume=93 |issue=5 |pages=743–52 |year=2000 |pmid=11059653 |doi=10.3171/jns.2000.93.5.0743 |url=}}</ref>
*Any history of a lesion causing hypopituitarism or a symptom suggestive of hypopituitarism is an indication for testing for hypopituitarism.
*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 may include:
*Laboratory findings consistent with laboratory diagnosis of [[panhypopituitarism]] depends upon the specific [[hormonal]] deficiency and may include:<ref name="pmid10341850">{{cite journal |vauthors=Beshyah SA, Johnston DG |title=Cardiovascular disease and risk factors in adults with hypopituitarism |journal=Clin. Endocrinol. (Oxf) |volume=50 |issue=1 |pages=1–15 |year=1999 |pmid=10341850 |doi= |url=}}</ref><ref name="pmid8121302">{{cite journal |vauthors=de Boer H, Blok GJ, Voerman HJ, Phillips M, Schouten JA |title=Serum lipid levels in growth hormone-deficient men |journal=Metab. Clin. Exp. |volume=43 |issue=2 |pages=199–203 |year=1994 |pmid=8121302 |doi= |url=}}</ref><ref name="pmid8212983">{{cite journal |vauthors=Rosén T, Edén S, Larson G, Wilhelmsen L, Bengtsson BA |title=Cardiovascular risk factors in adult patients with growth hormone deficiency |journal=Acta Endocrinol. |volume=129 |issue=3 |pages=195–200 |year=1993 |pmid=8212983 |doi= |url=}}</ref>
**Hyponatremia (due to increased vasopressin secretion)
**[[Hyponatremia]] (due to increased [[vasopressin]] [[secretion]])
**Normochromic, normocytic anemia
**[[Normochromic anemia|Normochromic]], [[normocytic anemia]]
**Eosinophilia
**[[Eosinophilia]]
**
**Elevated total and [[low-density lipoprotein]] ([[Low density lipoprotein|LDL]]) [[cholesterol]] levels
===Corticotropin:===
**Low [[High density lipoprotein|high-density lipoprotein]] ([[High density lipoprotein|HDL]]) [[cholesterol]] level


==== Basal ACTH secretion: ====
=== Dynamic tests for making a diagnosis of hypopituitarism ===
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:
Following dynamic tests can be used to make a diagnosis of hypopituitarism:<ref name="pmid19833587">{{cite journal |vauthors=Fleseriu M, Gassner M, Yedinak C, Chicea L, Delashaw JB, Loriaux DL |title=Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review |journal=Endocr Pract |volume=16 |issue=1 |pages=64–70 |year=2010 |pmid=19833587 |doi=10.4158/EP09153.OR |url=}}</ref><ref name="pmid19654538">{{cite journal |vauthors=Loriaux DL, Fleseriu M |title=Relative adrenal insufficiency |journal=Curr Opin Endocrinol Diabetes Obes |volume=16 |issue=5 |pages=392–400 |year=2009 |pmid=19654538 |doi=10.1097/MED.0b013e3283307d53 |url=}}</ref><ref name="pmid18697868">{{cite journal |vauthors=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 |title=Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=11 |pages=4245–53 |year=2008 |pmid=18697868 |doi=10.1210/jc.2008-0710 |url=}}</ref><ref name="pmid9589655">{{cite journal |vauthors=Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W |title=Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=5 |pages=1558–62 |year=1998 |pmid=9589655 |doi=10.1210/jcem.83.5.4831 |url=}}</ref><ref name="pmid12970286">{{cite journal |vauthors=Schmidt IL, Lahner H, Mann K, Petersenn S |title=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 |journal=J. Clin. Endocrinol. Metab. |volume=88 |issue=9 |pages=4193–8 |year=2003 |pmid=12970286 |doi=10.1210/jc.2002-021897 |url=}}</ref><ref name="pmid26760044">{{cite journal |vauthors=Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ |title=Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=2 |pages=364–89 |year=2016 |pmid=26760044 |pmc=4880116 |doi=10.1210/jc.2015-1710 |url=}}</ref><ref name="pmid21602453">{{cite journal |vauthors=Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML |title=Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=6 |pages=1587–609 |year=2011 |pmid=21602453 |doi=10.1210/jc.2011-0179 |url=}}</ref><ref name="pmid9861317">{{cite journal |vauthors=Clark PM, Neylon I, Raggatt PR, Sheppard MC, Stewart PM |title=Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders |journal=Clin. Endocrinol. (Oxf) |volume=49 |issue=3 |pages=287–92 |year=1998 |pmid=9861317 |doi= |url=}}</ref><ref name="pmid24503135">{{cite journal |vauthors=Charmandari E, Nicolaides NC, Chrousos GP |title=Adrenal insufficiency |journal=Lancet |volume=383 |issue=9935 |pages=2152–67 |year=2014 |pmid=24503135 |doi=10.1016/S0140-6736(13)61684-0 |url=}}</ref>
{| class="wikitable"
{| class="wikitable"
!Serum cortisol
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hormone
!Basal ACTH
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Test
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Procedure
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Normal response
|-
| rowspan="5" |'''[[Growth hormone]]'''
| rowspan="2" |'''[[Insulin]] tolerance'''
|
* Administer [[insulin]], 0.05–0.15 U/kg [[Intravenous|IV]]
|
* [[Glucose]] should drop <40 mg/dL, (2.2 mmol/L)
|-
|
* Sample [[blood]] at − 30, 0, 30, 60, 120 min for [[Growth hormone|GH]] and [[glucose]]
|
* [[Growth hormone|GH]] should be >3–5 μg/L
 
* Cut-offs for [[Growth hormone|GH]] response are [[BMI]] related 
|-
| rowspan="2" |'''[[GHRH]] + [[arginine]]'''  
|
* Administer [[Growth hormone-releasing hormone|GHRH]], 1 μg/kg (max 100 μg) iv followed by an [[arginine]] [[infusion]] 0.5 g/kg (max 35 g) over 30 min
|
* Can give false normal [[Growth hormone|GH]] response if GHD is due to [[hypothalamic]] damage (eg, after [[radiation]])
|-
|
* Sample [[blood]] at 0, 30, 45, 60, 75, 90, 105, and 120 min for [[GH]]
|
* [[Growth hormone|GH]] >4 μg/L, but cutoffs for [[Growth hormone|GH]] response should be correlated to [[Body mass index|BMI]] ([[obesity]] may blunt [[Growth hormone|GH]] response to stimulation)
|-
|'''[[Glucagon]]'''
|
* Administer [[glucagon]], 1 mg (1.5 mg if weight >90 kg) [[Intramuscular|IM]]
 
* Sample [[blood]] at 0, 30, 60, 90, 120, 150, 180, 210, and 240 min for [[Growth hormone|GH]] and [[glucose]]
|
* GH >3 μg/L, but cutoffs for [[Growth hormone|GH]] response should be correlated to [[Body mass index|BMI]] ([[Obesity]] may blunt [[GH]] response to stimulation)
|-
| rowspan="4" |'''ACTH'''
| rowspan="2" |'''[[Insulin]] tolerance'''
|
* Administer [[insulin]], 0.05–0.15 U/kg [[Intravenous|IV]]
|
* [[Glucose]] should drop <40 mg/dL (2.2 mmol/L)
|-
|
* Sample [[blood]] at −30, 0, 30, 60, and 120 min for [[cortisol]] and [[glucose]]
|
* Peak [[cortisol]] should be >500–550 nmol/L (>18.1–20 μg/dL) depending on [[assay]]
|-
|'''[[Corticotropin]] standard dose (250 μg)'''
|
* Administer [[Adrenocorticotropic hormone|ACTH]] 1–24 ([[cosyntropin]]), 250 μg [[Intramuscular|IM]] or [[Intravenous|IV]]
 
* Sample blood at 0, 30, and 60 min for [[cortisol]]
|
* [[Cortisol]] should be at 30 or 60 min >500–550 nmol/L (>18.1–20 μg/dL) depending on [[assay]]
|-
|'''[[Corticotropin]] low dose (1 μg)'''
|
* Administer [[Adrenocorticotropic hormone|ACTH]] 1–24 ([[cosyntropin]]), 1 μg [[Intravenous|IV]]
 
* Sample [[blood]] at 0 and 30 min for [[cortisol]]
|
* [[Cortisol]] should be at 30 min >500 nmol/L (18.1 μg/dL) depending on [[assay]]
|-
|'''[[Antidiuretic hormone|ADH]]'''
|'''Water deprivation test''' 
|
* Initiate [[fluid]] deprivation for 8h (starting from 8 AM)
 
* Weigh patient at beginning of testing, then measure weight and [[urine]] volume hourly during the test
 
* Measure [[plasma]] and urine [[osmolality]] every 2–3 hours
 
* At 4 PM administer [[Desmopressin (patient information)|DDAVP]] 2 μg im and allow patient to drink freely
 
|[[Diabetes insipidus|'''Diabetes insipidus (DI)''']]: [[Plasma]] [[osmolality]] >295 mOsm/L with inappropriately [[hypotonic]] [[urine]] ([[urine]] [[osmolality]]/[[plasma]] [[osmolality]] ratio <2) during the [[fluid]] deprivation confirms [[Diabetes insipidus|DI]] (test is discontinued)
* '''[[Central DI]]:''' After administering [[Desmopressin (patient information)|DDAVP]], [[urine]] [[osmolality]] >800 mOsm/kg with [[central DI]]
* '''[[Nephrogenic DI]]:''' After administering [[DDAVP]], [[urine]] [[osmolality]] <300 mOsm/kg with [[nephrogenic DI]]
'''[[Polydipsia|Partial/primary polydipsia]]:''' With partial [[Diabetes insipidus|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 [[Desmopressin (patient information)|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 [[Desmopressin (patient information)|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.'' 
''Legend:''
 
''[[Intravenous|IV]]: [[Intravenous]], [[Intramuscular|IM]]: [[Intramuscular]], [[Growth hormone|GH]]: [[Growth hormone]], GHD: [[Growth hormone deficiency]], [[BMI]]: [[Body mass index]]''
 
===1.[[Corticotropin]]:===
 
==== (a) Basal [[Adrenocorticotropic hormone|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:
{| class="wikitable"
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum cortisol
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Basal adrenocorticotrophic hormone (ACTH)
|-
|-
|'''Low''': ≤3 mcg/dL (83 nmol/L)
|'''Low''': ≤3 mcg/dL (83 nmol/L)
Line 37: Line 134:
|}
|}


==== ACTH reserve: ====
==== (b) [[Adrenocorticotropic hormone|ACTH]] reserve: ====
Patients with intermediate [[cortisol]] levels need to be tested for [[Adrenocorticotropic hormone|ACTH]] reserve. There are several tests to check the [[Adrenocorticotropic hormone|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. It has a drawback that it needs [[inpatient]] observation for [[blood pressure]] and [[Pulse|pulse monitoring]] to prevent [[postural hypotension]].  
*Patients with intermediate [[cortisol]] levels need to be tested for [[Adrenocorticotropic hormone|ACTH]] reserve. There are several tests to check the [[Adrenocorticotropic hormone|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|pulse monitoring]] to prevent [[postural hypotension]].  
Insulin-induced hypoglycemia test is not preferred as it needs continuous monitoring for neuroglycopenic symptoms during the first hour of [[insulin]] administration in patients who are elderly and have [[cardiovascular]] or [[Cerebrovascular disease|cerebrovascular]] issues or a [[seizure disorder]]. [[Hypoglycemia]] is treated with [[intravenous]] [[glucose]].
*[[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 disease|cerebrovascular]] issues or a [[seizure disorder]]. [[Hypoglycemia]] is treated with [[intravenous]] [[glucose]].↵The standard or low dose [[ACTH stimulation test|cosynotropin stimulation test]] is not recommended as it can give falsely normal results.<ref name="pmid4330677">{{cite journal |vauthors=Spark RF |title=Simplified assessment of pituitary-adrenal reserve. Measurement of serum 11-deoxycortisol and cortisol after metyrapone |journal=Ann. Intern. Med. |volume=75 |issue=5 |pages=717–23 |year=1971 |pmid=4330677 |doi= |url=}}</ref><ref name="pmid4313728">{{cite journal |vauthors=Jubiz W, Meikle AW, West CD, Tyler FH |title=Single-dose metyrapone test |journal=Arch. Intern. Med. |volume=125 |issue=3 |pages=472–4 |year=1970 |pmid=4313728 |doi= |url=}}</ref><ref name="pmid5949228">{{cite journal |vauthors=Landon J, Greenwood FC, Stamp TC, Wynn V |title=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 |journal=J. Clin. Invest. |volume=45 |issue=4 |pages=437–49 |year=1966 |pmid=5949228 |pmc=292718 |doi=10.1172/JCI105358 |url=}}</ref><ref name="pmid8550765">{{cite journal |vauthors=Streeten DH, Anderson GH, Bonaventura MM |title=The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=1 |pages=285–90 |year=1996 |pmid=8550765 |doi=10.1210/jcem.81.1.8550765 |url=}}</ref><ref name="pmid8849565">{{cite journal |vauthors=Soule SG, Fahie-Wilson M, Tomlinson S |title=Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism |journal=Clin. Endocrinol. (Oxf) |volume=44 |issue=2 |pages=137–40 |year=1996 |pmid=8849565 |doi= |url=}}</ref><ref name="pmid2005201">{{cite journal |vauthors=Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M |title=Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test |journal=J. Clin. Endocrinol. Metab. |volume=72 |issue=4 |pages=773–8 |year=1991 |pmid=2005201 |doi=10.1210/jcem-72-4-773 |url=}}</ref><ref name="pmid9589655">{{cite journal |vauthors=Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W |title=Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=5 |pages=1558–62 |year=1998 |pmid=9589655 |doi=10.1210/jcem.83.5.4831 |url=}}</ref><ref name="pmid10931104">{{cite journal |vauthors=Soule S, Van Zyl Smit C, Parolis G, Attenborough S, Peter D, Kinvig S, Kinvig T, Coetzer E |title=The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism |journal=Clin. Endocrinol. (Oxf) |volume=53 |issue=2 |pages=221–7 |year=2000 |pmid=10931104 |doi= |url=}}</ref><ref name="pmid11894974">{{cite journal |vauthors=Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Torpy DJ, Jackson RV |title=Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests |journal=Clin. Endocrinol. (Oxf) |volume=55 |issue=5 |pages=625–33 |year=2001 |pmid=11894974 |doi= |url=}}</ref><ref name="pmid11966747">{{cite journal |vauthors=Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ |title=The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency |journal=Clin. Endocrinol. (Oxf) |volume=56 |issue=4 |pages=533–9 |year=2002 |pmid=11966747 |doi= |url=}}</ref><ref name="pmid26649617">{{cite journal |vauthors=Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH |title=ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=2 |pages=427–34 |year=2016 |pmid=26649617 |doi=10.1210/jc.2015-1700 |url=}}</ref> The [[corticotropin-releasing hormone]] test indicates [[Pituitary gland|pituitary]]-[[Adrenal gland|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]].
The standard or low dose cosynotropin stimulation test is not recommended as it can give falsely normal results.<ref name="pmid4330677">{{cite journal |vauthors=Spark RF |title=Simplified assessment of pituitary-adrenal reserve. Measurement of serum 11-deoxycortisol and cortisol after metyrapone |journal=Ann. Intern. Med. |volume=75 |issue=5 |pages=717–23 |year=1971 |pmid=4330677 |doi= |url=}}</ref><ref name="pmid4313728">{{cite journal |vauthors=Jubiz W, Meikle AW, West CD, Tyler FH |title=Single-dose metyrapone test |journal=Arch. Intern. Med. |volume=125 |issue=3 |pages=472–4 |year=1970 |pmid=4313728 |doi= |url=}}</ref><ref name="pmid5949228">{{cite journal |vauthors=Landon J, Greenwood FC, Stamp TC, Wynn V |title=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 |journal=J. Clin. Invest. |volume=45 |issue=4 |pages=437–49 |year=1966 |pmid=5949228 |pmc=292718 |doi=10.1172/JCI105358 |url=}}</ref><ref name="pmid8550765">{{cite journal |vauthors=Streeten DH, Anderson GH, Bonaventura MM |title=The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=1 |pages=285–90 |year=1996 |pmid=8550765 |doi=10.1210/jcem.81.1.8550765 |url=}}</ref><ref name="pmid8849565">{{cite journal |vauthors=Soule SG, Fahie-Wilson M, Tomlinson S |title=Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism |journal=Clin. Endocrinol. (Oxf) |volume=44 |issue=2 |pages=137–40 |year=1996 |pmid=8849565 |doi= |url=}}</ref><ref name="pmid2005201">{{cite journal |vauthors=Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M |title=Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test |journal=J. Clin. Endocrinol. Metab. |volume=72 |issue=4 |pages=773–8 |year=1991 |pmid=2005201 |doi=10.1210/jcem-72-4-773 |url=}}</ref><ref name="pmid9589655">{{cite journal |vauthors=Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W |title=Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=5 |pages=1558–62 |year=1998 |pmid=9589655 |doi=10.1210/jcem.83.5.4831 |url=}}</ref><ref name="pmid10931104">{{cite journal |vauthors=Soule S, Van Zyl Smit C, Parolis G, Attenborough S, Peter D, Kinvig S, Kinvig T, Coetzer E |title=The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism |journal=Clin. Endocrinol. (Oxf) |volume=53 |issue=2 |pages=221–7 |year=2000 |pmid=10931104 |doi= |url=}}</ref><ref name="pmid11894974">{{cite journal |vauthors=Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Torpy DJ, Jackson RV |title=Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests |journal=Clin. Endocrinol. (Oxf) |volume=55 |issue=5 |pages=625–33 |year=2001 |pmid=11894974 |doi= |url=}}</ref><ref name="pmid11966747">{{cite journal |vauthors=Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ |title=The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency |journal=Clin. Endocrinol. (Oxf) |volume=56 |issue=4 |pages=533–9 |year=2002 |pmid=11966747 |doi= |url=}}</ref><ref name="pmid26649617">{{cite journal |vauthors=Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH |title=ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=2 |pages=427–34 |year=2016 |pmid=26649617 |doi=10.1210/jc.2015-1700 |url=}}</ref>


==== Metyrapone test: ====
==== Metyrapone test: ====
[[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 administerred [[Oral|orally]] every 4hrs for 24hr. Serum [[cortisol]] and 11-deoxycortisol concentration is checked at 8am after 24hr and the results are interpreted as follows:
[[Metyrapone]] blocks [[11-b-hydroxylase deficiency|11-beta-hydroxylase]] (CYP11B1), an [[enzyme]] that [[catalyzes]] the last step in [[cortisol]] production resulting in decreased [[cortisol]] and increased [[11-Deoxycortisol|11-deoxycortisol]] concentration. In this test 750 mg of [[Metyrapone]] is administered [[Oral|orally]] every 4 hours for 24 hours. Serum [[cortisol]] and [[11-Deoxycortisol|11-deoxycortisol]] concentration are checked at 8 am after 24 hours and the results are interpreted as follows:
{| class="wikitable"
{| class="wikitable"
!
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subject
!Cortisol level
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Cortisol level
!11-deoxycortisol level
! align="center" style="background:#4479BA; color: #FFFFFF;" + |11-deoxycortisol level
|-
|-
|Normal subjects
|Normal subjects
Line 58: Line 154:
|}
|}


=== Thyrotropin: ===
=== 2.Thyrotropin: ===
Patients with hypopituitarism are screened for [[hypothyroidism]] by measuring:<ref name="pmid2984564">{{cite journal |vauthors=Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD |title=Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone |journal=N. Engl. J. Med. |volume=312 |issue=17 |pages=1085–90 |year=1985 |pmid=2984564 |doi=10.1056/NEJM198504253121703 |url=}}</ref>
Patients with hypopituitarism are [[Screening (medicine)|screened]] for [[hypothyroidism]] by measuring:<ref name="pmid2984564">{{cite journal |vauthors=Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD |title=Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone |journal=N. Engl. J. Med. |volume=312 |issue=17 |pages=1085–90 |year=1985 |pmid=2984564 |doi=10.1056/NEJM198504253121703 |url=}}</ref>
*[[Thyroxine]]  
*[[Thyroxine]] ([[T4]])
*Total [[thyroxine]] (T4) and [[triiodothyronine]] (T3) uptake
*Total [[thyroxine]] ([[Thyroxine|T4]]) and [[triiodothyronine]] ([[Triiodothyronine|T3]]) uptake
*Free [[T4]].
*[[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, [[Arrhythmias|arrhythmia]] and [[hypotension]]
{| class="wikitable"
{| class="wikitable"
!
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Condition
!Serum T3
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum T3
!Serum free T4
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum free T4
!Serum TSH
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum TSH
|-
|-
|Central [[hypothyroidism]]
|Central [[hypothyroidism]]
Line 75: Line 172:
|}
|}


=== Gonadotropins ===
=== 3.Gonadotropins ===
[[Gonadotropin-releasing hormone]] test may be used to detect [[serum]] levels for [[gonadotropins]] ([[Follicle-stimulating hormone|follicle stimulating hormones]] and [[Luteinizing hormone|luteinizing hormones]]) but repeated stimulations by [[gonadotropin-releasing hormone]] are required to make a diagnosis.
 
'''Females:'''


=== Females: ===
Secondary [[hypogonadism]] can be confirmed in an [[Amenorrhea|amenorrheic]] woman having:
Secondary [[hypogonadism]] can be confirmed in an [[Amenorrhea|amenorrheic]] woman having:
* Low [[estradiol]]
* Low [[estradiol]]
* Low/normal serum [[FSH]]/[[LH]]
* Low/normal [[serum]] [[FSH]]/[[LH]]
'''Males:'''
* Low [[testosterone]]


=== Males: ===
* Low/normal [[serum]] [[FSH]]/[[LH]]
* Low [[testosterone]]


* Low/normal serum [[FSH]]/[[LH]]
=== 4.Growth hormone ===
The following tests and laboratory findings can be used to confirm [[growth hormone]] ([[Growth hormone|GH]]) deficiency in a patient having an organic [[pituitary]] disease:<ref name="pmid11836272">{{cite journal |vauthors=Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ |title=Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=2 |pages=477–85 |year=2002 |pmid=11836272 |doi=10.1210/jcem.87.2.8216 |url=}}</ref><ref name="pmid11994342">{{cite journal |vauthors=Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, Stavrou S, Kleinberg DL, Chipman JJ, Hartman ML |title=Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=5 |pages=2067–79 |year=2002 |pmid=11994342 |doi=10.1210/jcem.87.5.8509 |url=}}</ref><ref name="pmid9467545">{{cite journal |vauthors= |title=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 |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=2 |pages=379–81 |year=1998 |pmid=9467545 |doi=10.1210/jcem.83.2.4611 |url=}}</ref><ref name="pmid9666868">{{cite journal |vauthors=Toogood AA, Jones J, O'Neill PA, Thorner MO, Shalet SM |title=The diagnosis of severe growth hormone deficiency in elderly patients with hypothalamic-pituitary disease |journal=Clin. Endocrinol. (Oxf) |volume=48 |issue=5 |pages=569–76 |year=1998 |pmid=9666868 |doi= |url=}}</ref>


=== Growth hormone ===
'''(a)''' Provocative tests for [[growth hormone]] ([[Growth hormone|GH]]) [[secretion]] resulting in subnormal levels of [[serum]] [[GH]] levels.
The following criteria can be used to confirm [[Growth hormone|GH]] deficiency in a patient having an organic [[pituitary]] disease.<ref name="pmid11836272">{{cite journal |vauthors=Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ |title=Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=2 |pages=477–85 |year=2002 |pmid=11836272 |doi=10.1210/jcem.87.2.8216 |url=}}</ref><ref name="pmid11994342">{{cite journal |vauthors=Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, Stavrou S, Kleinberg DL, Chipman JJ, Hartman ML |title=Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=5 |pages=2067–79 |year=2002 |pmid=11994342 |doi=10.1210/jcem.87.5.8509 |url=}}</ref><ref name="pmid9467545">{{cite journal |vauthors= |title=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 |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=2 |pages=379–81 |year=1998 |pmid=9467545 |doi=10.1210/jcem.83.2.4611 |url=}}</ref><ref name="pmid9666868">{{cite journal |vauthors=Toogood AA, Jones J, O'Neill PA, Thorner MO, Shalet SM |title=The diagnosis of severe growth hormone deficiency in elderly patients with hypothalamic-pituitary disease |journal=Clin. Endocrinol. (Oxf) |volume=48 |issue=5 |pages=569–76 |year=1998 |pmid=9666868 |doi= |url=}}</ref>
*Provocative tests for [[Growth hormone|GH]] secretion resulting in subnormal levels of serum [[GH]] levels.
{| class="wikitable"
{| class="wikitable"
!GH provocative tests
! align="center" style="background:#4479BA; color: #FFFFFF;" + |GH provocative tests
!Serum GH levels
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum GH levels
|-
|-
|[[Insulin]] induced [[hypoglycemia]]
|[[Insulin]] induced [[hypoglycemia]]
Line 100: Line 199:
|<4.1 ng/mL
|<4.1 ng/mL
|}
|}
* Serum [[Insulin-like growth factor-I|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 [[Growth hormone|GH]] deficiency have normal [[IGF-1]] levels.
'''(b)''' [[Serum]] [[Insulin-like growth factor-I|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 [[Growth hormone|GH]] deficiency have normal [[IGF-1]] levels.
* Deficiency of more than one [[pituitary]] hormones e.g [[Adrenocorticotropic hormone|ACTH]], [[TSH]] and [[gonadotropins]].
 
'''(c)''' Deficiency of more than one [[pituitary]] [[hormones]] e.g [[Adrenocorticotropic hormone|ACTH]], [[TSH]] and [[gonadotropins]].
For more information on laboratory findings click [[Growth hormone deficiency laboratory findings#Laboratory Findings|here]].


===Antidiuretic hormone (ADH) deficiency===  
===5.Antidiuretic hormone (ADH) deficiency===  
====Water deprivation test:====
====(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:<ref name="pmid9771260">{{cite journal |vauthors=Baylis PH, Cheetham T |title=Diabetes insipidus |journal=Arch. Dis. Child. |volume=79 |issue=1 |pages=84–9 |year=1998 |pmid=9771260 |pmc=1717616 |doi= |url=}}</ref>
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]] [[Osmolality|osmolalities]]. Results are interpreted as follows:<ref name="pmid9771260">{{cite journal |vauthors=Baylis PH, Cheetham T |title=Diabetes insipidus |journal=Arch. Dis. Child. |volume=79 |issue=1 |pages=84–9 |year=1998 |pmid=9771260 |pmc=1717616 |doi= |url=}}</ref>


{| class="wikitable"
{| class="wikitable"
!
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Condition
!Serum osmolality
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum osmolality
!Urine osmolality
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Urine osmolality
|-
|-
|[[Psychogenic polydipsia]]
|[[Psychogenic polydipsia]]
Line 121: Line 222:
|}
|}


====Vasopressin stimulation test:====
====(b) Vasopressin stimulation test:====
This test is used to differentiate central from [[nephrogenic diabetes insipidus]]. Serum and urine [[Osmolality|osmolalities]] are measured 1hr after administration of either [[subcutaneous]] 1-2mcg of [[Desmopressin|Desmopressin (DDAVP)]] or 5 units of [[aqueous]] [[vasopressin]]. The results are interpreted as follows:
This test is used to differentiate [[Central DI|central]] from [[nephrogenic diabetes insipidus]]. [[Serum]] and [[urine]] [[Osmolality|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:
{| class="wikitable"
{| class="wikitable"
!Diabetes insipidus
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Diabetes insipidus
!Serum osmolality
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Serum osmolality
!Urine osmolality
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Urine osmolality
|-
|-
|[[Central DI|Central]]
|[[Central DI|Central]]
Line 137: Line 238:
|}
|}


=== Prolactin: ===
=== 6.Prolactin: ===
* [[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.It is important to measure serum prolactin level as it can give an idea about the location of lesion and the cause of hypogonadism
[[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:<ref name="pmid17556861">{{cite journal |vauthors=Toledano Y, Lubetsky A, Shimon I |title=Acquired prolactin deficiency in patients with disorders of the hypothalamic-pituitary axis |journal=J. Endocrinol. Invest. |volume=30 |issue=4 |pages=268–73 |year=2007 |pmid=17556861 |doi=10.1007/BF03346292 |url=}}</ref><ref name="pmid14974916">{{cite journal |vauthors=Mukherjee A, Murray RD, Columb B, Gleeson HK, Shalet SM |title=Acquired prolactin deficiency indicates severe hypopituitarism in patients with disease of the hypothalamic-pituitary axis |journal=Clin. Endocrinol. (Oxf) |volume=59 |issue=6 |pages=743–8 |year=2003 |pmid=14974916 |doi=10.1046/j.1365-2265.2003.01916.x |url=}}</ref>
* Routine testing is not done because
* Hypoprolactinemia is a marker of severe [[Pituitary gland|pituitary]] damage in patients having structural [[Pituitary gland|pituitary]] disease
** It is difficult to differentiate between low and normal serum [[prolactin]] concentrations
* 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:
** It is difficult to differentiate between low and normal [[serum]] [[prolactin]] concentrations
** Clinically not relevant unless a woman wishes to [[Lactation|lactate]]
** Clinically not relevant unless a woman wishes to [[Lactation|lactate]]
** There is no standardized test to assess [[prolactin]] reserve.
** There is no standardized test to assess [[prolactin]] reserve
 
* [[Thyrotropin-releasing hormone]] test is not very useful as it can't differentiate between [[prolactinomas]] and other causes of [[hyperprolactinemia]].


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
 
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{{WH}}
{{WS}}
{{WS}}
[[Category:Medicine]]
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Latest revision as of 22:19, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Overview

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.

Laboratory Findings

Dynamic tests for making a diagnosis of hypopituitarism

Following dynamic tests can be used to make a diagnosis of hypopituitarism:[8][9][10][11][12][13][14][15][16]

Hormone Test Procedure Normal response
Growth hormone Insulin tolerance
  • Glucose should drop <40 mg/dL, (2.2 mmol/L)
  • GH should be >3–5 μg/L
  • Cut-offs for GH response are BMI related 
GHRH + arginine  
  • Administer GHRH, 1 μg/kg (max 100 μg) iv followed by an arginine infusion 0.5 g/kg (max 35 g) over 30 min
  • Sample blood at 0, 30, 45, 60, 75, 90, 105, and 120 min for GH
  • GH >4 μg/L, but cutoffs for GH response should be correlated to BMI (obesity may blunt GH response to stimulation)
Glucagon
  • Administer glucagon, 1 mg (1.5 mg if weight >90 kg) IM
  • Sample blood at 0, 30, 60, 90, 120, 150, 180, 210, and 240 min for GH and glucose
  • GH >3 μg/L, but cutoffs for GH response should be correlated to BMI (Obesity may blunt GH response to stimulation)
ACTH Insulin tolerance
  • Glucose should drop <40 mg/dL (2.2 mmol/L)
  • Peak cortisol should be >500–550 nmol/L (>18.1–20 μg/dL) depending on assay
Corticotropin standard dose (250 μg)
  • Sample blood at 0, 30, and 60 min for cortisol
  • Cortisol should be at 30 or 60 min >500–550 nmol/L (>18.1–20 μg/dL) depending on assay
Corticotropin low dose (1 μg)
  • Cortisol should be at 30 min >500 nmol/L (18.1 μg/dL) depending on assay
ADH Water deprivation test 
  • Initiate fluid deprivation for 8h (starting from 8 AM)
  • Weigh patient at beginning of testing, then measure weight and urine volume hourly during the test
  • At 4 PM administer DDAVP 2 μg im and allow patient to drink freely
 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:

  • 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. 

Legend:

IV: Intravenous, IM: Intramuscular, GH: Growth hormone, GHD: Growth hormone deficiency, BMI: Body mass index

1.Corticotropin:

(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) 

but

<18 mcg/dL (497 nmol/L)

Needs evaluation for ACTH reserve

(b) ACTH reserve:

Metyrapone test:

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)

2.Thyrotropin:

Patients with hypopituitarism are screened for hypothyroidism by measuring:[27]

Condition Serum T3 Serum free T4 Serum TSH
Central hypothyroidism Low or normal Low or low-normal Low, normal, or slightly high

3.Gonadotropins

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.

Females:

Secondary hypogonadism can be confirmed in an amenorrheic woman having:

Males:

4.Growth hormone

The following tests and laboratory findings can be used to confirm growth hormone (GH) deficiency in a patient having an organic pituitary disease:[28][29][30][31]

(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:[32]

Condition Serum osmolality Urine osmolality
Psychogenic polydipsia Normal ↑
Diabetes insipidus ↑ -

(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
Central ↓ ↑
Nephrogenic no change no change

6.Prolactin:

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:[33][34]

  • 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:
    • It is difficult to differentiate between low and normal serum prolactin concentrations
    • Clinically not relevant unless a woman wishes to lactate
    • There is no standardized test to assess prolactin reserve

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Beshyah SA, Johnston DG (1999). "Cardiovascular disease and risk factors in adults with hypopituitarism". Clin. Endocrinol. (Oxf). 50 (1): 1–15. PMID 10341850.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Loriaux DL, Fleseriu M (2009). "Relative adrenal insufficiency". Curr Opin Endocrinol Diabetes Obes. 16 (5): 392–400. doi:10.1097/MED.0b013e3283307d53. PMID 19654538.
  10. ↑ 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. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Charmandari E, Nicolaides NC, Chrousos GP (2014). "Adrenal insufficiency". Lancet. 383 (9935): 2152–67. doi:10.1016/S0140-6736(13)61684-0. PMID 24503135.
  17. ↑ 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.
  18. ↑ Jubiz W, Meikle AW, West CD, Tyler FH (1970). "Single-dose metyrapone test". Arch. Intern. Med. 125 (3): 472–4. PMID 4313728.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ "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.
  31. ↑ 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.
  32. ↑ Baylis PH, Cheetham T (1998). "Diabetes insipidus". Arch. Dis. Child. 79 (1): 84–9. PMC 1717616. PMID 9771260.
  33. ↑ 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.
  34. ↑ 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.

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