Delayed puberty laboratory findings: Difference between revisions
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==Overview== | ==Overview== | ||
First line tests in the diagnosis of delayed puberty are [[complete blood count]], [[erythrocyte sedimentation rate]], [[creatinine]], [[electrolytes]], [[bicarbonate]], [[alkaline phosphatase]], [[albumin]], [[thyrotropin]], free [[thyroxine]], [[Luteinizing hormone|luteinizing hormone (LH)]], [[Follicle stimulating hormone|follicle stimulating hormone (FSH)]], [[Insulin-like growth factor-1|insulin-like growth factor (IGF-1)]], and [[testosterone]]. For specific familial disorders some special laboratory tests may be needed, such as anti-[[gliadin]] [[antibody]] and anti-[[tissue transglutaminase]] [[antibody]] (i.e., [[Celiac disease]] diagnosis) or anti-neutrophil cytoplasmic antibodies (i.e., [[inflammatory bowel disease]] diagnosis). Second line tests are [[Gonadotropin releasing hormone|gonadotropin-releasing hormone (GnRH)]], [[Human chorionic gonadotropin|human chorionic gonadotropin (hCG)]] test, [[inhibin]] B, [[prolactin]], and [[Growth hormone|growth hormone (GH)]] test. | |||
==Laboratory Findings== | ==Laboratory Findings== | ||
=== Biochemistry laboratory tests === | === Biochemistry laboratory tests === | ||
* | *The laboratory tests are [[complete blood count]], [[erythrocyte sedimentation rate]], [[creatinine]], [[electrolytes]], [[bicarbonate]], [[alkaline phosphatase]], [[albumin]], [[thyrotropin]], and free [[thyroxine]]. | ||
* | *For specific familial disorders some special laboratory tests may be needed, such as anti-[[gliadin]] [[antibody]] and anti-[[tissue transglutaminase]] [[antibody]] (i.e., [[Celiac disease]] diagnosis) or anti-neutrophil cytoplasmic antibodies (i.e., [[inflammatory bowel disease]] diagnosis). | ||
<span style="font-size:85%">'''Abbreviations:''' '''CBC:''' [[Complete blood count]], '''ESR:''' [[Erythrocyte sedimentation rate]], '''Cr:''' [[Creatinine]], '''HCO3:''' [[Bicarbonate]], '''Alb:''' [[Albumin]], '''T4:''' [[Thyroxin]], '''TSH:''' [[Thyroid stimulating hormone]], '''Anti TTg Ab:''' Anti [[transglutaminase]] antibody, '''ANCA:''' [[ANCA|Antineutrophil cytoplasmic antibody]], '''LH:''' [[Luteinizing hormone]], '''FSH:''' [[Follicle stimulating hormone]], '''IGF-1:''' [[Insulin-like growth factor-1|Insulin-like growth factor 1]], '''GnRH:''' [[Gonadotropin releasing hormone| | <span style="font-size:85%">'''Abbreviations:''' '''CBC:''' [[Complete blood count]], '''ESR:''' [[Erythrocyte sedimentation rate]], '''Cr:''' [[Creatinine]], '''HCO3:''' [[Bicarbonate]], '''Alb:''' [[Albumin]], '''T4:''' [[Thyroxin]], '''TSH:''' [[Thyroid stimulating hormone]], '''Anti TTg Ab:''' Anti [[transglutaminase]] antibody, '''ANCA:''' [[ANCA|Antineutrophil cytoplasmic antibody]], '''LH:''' [[Luteinizing hormone]], '''FSH:''' [[Follicle stimulating hormone]], '''IGF-1:''' [[Insulin-like growth factor-1|Insulin-like growth factor 1]], '''GnRH:''' [[Gonadotropin releasing hormone|Gonadotropin-releasing hormone]], '''hCG:''' [[Human chorionic gonadotropin]], '''PRL:''' [[Prolactin]], '''GH:''' [[Growth hormone]], '''Cl:''' [[Chlorine]], '''WBC:''' [[White blood cell]], '''RBC:''' [[Red blood cell]], '''HGB:''' [[Hemoglubin|Hemoglobin]], '''MCV:''' [[Mean corpuscular volume]], '''AIDS:''' [[Acquired immunodeficiency syndrome]], '''Lymph:''' [[Lymphocyte]].</span> | ||
{| class="wikitable" | {| class="wikitable" | ||
! rowspan="2" |Delayed puberty | ! rowspan="2" |Delayed puberty | ||
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==== Complete blood count ==== | ==== Complete blood count ==== | ||
* Some patients with delayed [[puberty]] may have reduced concentration of [[hemoglobin]], which is usually suggestive of [[anemia]] as the underlying cause. | * Some patients with delayed [[puberty]] may have reduced concentration of [[hemoglobin]], which is usually suggestive of [[anemia]] as the underlying cause. | ||
* Some patients with delayed [[puberty]] may have elevated number of [[lymphocytes]], which is usually suggestive of [[viral infections]] ([[mumps]], [[coxsackie]]) as | * Some patients with delayed [[puberty]] may have elevated number of [[lymphocytes]], which is usually suggestive of [[viral infections]] ([[mumps]], [[coxsackie]]) as the underlying cause. | ||
* Decreasing number of [[lymphocytes]] (especially [[CD4+ cell|CD4s]]) may reveal [[AIDS]], as an underlying cause of delayed [[puberty]].<ref name="pmid19337023">{{cite journal |vauthors=Majaliwa ES, Mohn A, Chiarelli F |title=Growth and puberty in children with HIV infection |journal=J. Endocrinol. Invest. |volume=32 |issue=1 |pages=85–90 |year=2009 |pmid=19337023 |doi=10.1007/BF03345686 |url=}}</ref> | * Decreasing number of [[lymphocytes]] (especially [[CD4+ cell|CD4s]]) may reveal [[AIDS]], as an underlying cause of delayed [[puberty]].<ref name="pmid19337023">{{cite journal |vauthors=Majaliwa ES, Mohn A, Chiarelli F |title=Growth and puberty in children with HIV infection |journal=J. Endocrinol. Invest. |volume=32 |issue=1 |pages=85–90 |year=2009 |pmid=19337023 |doi=10.1007/BF03345686 |url=}}</ref> | ||
==== Erythrocyte sedimentation rate ==== | ==== Erythrocyte sedimentation rate ==== | ||
An elevated [[Erythrocyte sedimentation rate|erythrocyte sedimentation rate (ESR)]] is diagnostic of | * An elevated [[Erythrocyte sedimentation rate|erythrocyte sedimentation rate (ESR)]] is diagnostic of underlying [[diseases]] that may cause delayed [[puberty]]. | ||
==== Creatinine ==== | ==== Creatinine ==== | ||
Some patients with delayed [[puberty]] may have elevated concentration of [[creatinine]], which is usually suggestive of [[renal disease]] as the underlying cause.<ref name="pmid26112575">{{cite journal |vauthors=Bacchetta J |title=[Puberty and chronic kidney disease] |language=French |journal=Arch Pediatr |volume=22 |issue=5 Suppl 1 |pages=169–71 |year=2015 |pmid=26112575 |doi=10.1016/S0929-693X(15)30084-1 |url=}}</ref> | * Some patients with delayed [[puberty]] may have elevated concentration of [[creatinine]], which is usually suggestive of [[renal disease]] as the underlying cause.<ref name="pmid26112575">{{cite journal |vauthors=Bacchetta J |title=[Puberty and chronic kidney disease] |language=French |journal=Arch Pediatr |volume=22 |issue=5 Suppl 1 |pages=169–71 |year=2015 |pmid=26112575 |doi=10.1016/S0929-693X(15)30084-1 |url=}}</ref> | ||
==== Electrolytes ==== | ==== Electrolytes ==== | ||
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==== Bicarbonate ==== | ==== Bicarbonate ==== | ||
Reduced [[bicarbonate]] concentration in serum may reveal the [[metabolic acidosis]] due to various causes, mostly [[Chronic kidney diseas|chronic kidney injury]], as the underlying cause of delayed [[puberty]].<ref name="pmid26112575" /> | * Reduced [[bicarbonate]] concentration in serum may reveal the [[metabolic acidosis]] due to various causes, mostly [[Chronic kidney diseas|chronic kidney injury]], as the underlying cause of delayed [[puberty]].<ref name="pmid26112575" /> | ||
==== Alkaline phosphatase ==== | ==== Alkaline phosphatase ==== | ||
An elevated concentration of serum [[alkaline phosphatase]] is diagnostic of any [[liver]] or [[bone]] diseases, as the underlying cause of delayed [[puberty]]. | * An elevated concentration of serum [[alkaline phosphatase]] is diagnostic of any [[liver]] or [[bone]] diseases, as the underlying cause of delayed [[puberty]]. | ||
* [[Histiocytosis]], [[galactosemia]] induced [[hepatomegaly]], and [[Gaucher's disease|Gaucher's diseases]] are some of the examples. | |||
[[Histiocytosis]], [[galactosemia]] induced [[ | |||
==== Albumin ==== | ==== Albumin ==== | ||
Some patients with delayed [[puberty]] may have reduced concentration of serum [[albumin]], which is usually suggestive of [[liver]] or [[renal]] disease as underlying cause.<ref name="pmid23444474">{{cite journal |vauthors=Upreti V, Dhull P, Patnaik SK, Kumar KV |title=An unusual cause of delayed puberty: Berardinelli- Seip syndrome |journal=J. Pediatr. Endocrinol. Metab. |volume=25 |issue=11-12 |pages=1157–60 |year=2012 |pmid=23444474 |doi= |url=}}</ref> | * Some patients with delayed [[puberty]] may have reduced concentration of serum [[albumin]], which is usually suggestive of [[liver]] or [[renal]] disease as the underlying cause.<ref name="pmid23444474">{{cite journal |vauthors=Upreti V, Dhull P, Patnaik SK, Kumar KV |title=An unusual cause of delayed puberty: Berardinelli- Seip syndrome |journal=J. Pediatr. Endocrinol. Metab. |volume=25 |issue=11-12 |pages=1157–60 |year=2012 |pmid=23444474 |doi= |url=}}</ref> | ||
==== Thyrotropin ==== | ==== Thyrotropin ==== | ||
An elevated concentration of serum [[Thyroid stimulating hormone|thyroid stimulating hormone (TSH)]] is diagnostic of [[hypothyroidism]], as underlying cause of delayed [[puberty]].<ref name="PalmertDunkel2012" /> | * An elevated concentration of serum [[Thyroid stimulating hormone|thyroid stimulating hormone (TSH)]] is diagnostic of [[hypothyroidism]], as the underlying cause of delayed [[puberty]].<ref name="PalmertDunkel2012" /> | ||
==== Free thyroxine ==== | ==== Free thyroxine ==== | ||
* A reduced concentration of serum free [[thyroxine]] (T4) is diagnostic of [[hypothyroidism]], as the underlying cause of delayed [[puberty]].<ref name="PalmertDunkel2012" /> | |||
==== Anti-gliadin antibody ==== | ==== Anti-gliadin antibody ==== | ||
Some patients with delayed [[puberty]] may have positive anti [[gliadin]] antibody, which is usually suggestive of [[Celiac disease]] as underlying cause.<ref name="pmid120659302">{{cite journal |vauthors=Bona G, Marinello D, Oderda G |title=Mechanisms of abnormal puberty in coeliac disease |journal=Horm. Res. |volume=57 Suppl 2 |issue= |pages=63–5 |year=2002 |pmid=12065930 |doi=58103 |url=}}</ref> | * Some patients with delayed [[puberty]] may have the positive anti-[[gliadin]] antibody, which is usually suggestive of [[Celiac disease]] as the underlying cause.<ref name="pmid120659302">{{cite journal |vauthors=Bona G, Marinello D, Oderda G |title=Mechanisms of abnormal puberty in coeliac disease |journal=Horm. Res. |volume=57 Suppl 2 |issue= |pages=63–5 |year=2002 |pmid=12065930 |doi=58103 |url=}}</ref> | ||
==== Anti-tissue transglutaminase antibody ==== | ==== Anti-tissue transglutaminase antibody ==== | ||
Some patients with delayed [[puberty]] may have positive anti [[tissue transglutaminase]] [[antibody]], which is usually suggestive of [[Celiac disease]] as underlying cause.<ref name="pmid12065930">{{cite journal |vauthors=Bona G, Marinello D, Oderda G |title=Mechanisms of abnormal puberty in coeliac disease |journal=Horm. Res. |volume=57 Suppl 2 |issue= |pages=63–5 |year=2002 |pmid=12065930 |doi=58103 |url=}}</ref> | * Some patients with delayed [[puberty]] may have positive anti-[[tissue transglutaminase]] [[antibody]], which is usually suggestive of [[Celiac disease]] as the underlying cause.<ref name="pmid12065930">{{cite journal |vauthors=Bona G, Marinello D, Oderda G |title=Mechanisms of abnormal puberty in coeliac disease |journal=Horm. Res. |volume=57 Suppl 2 |issue= |pages=63–5 |year=2002 |pmid=12065930 |doi=58103 |url=}}</ref> | ||
==== Anti-neutrophil | ==== Anti-neutrophil cytoplasmic antibodies ==== | ||
Some patients with delayed [[puberty]] may have positive anti-neutrophil | * Some patients with delayed [[puberty]] may have positive [[Anti-neutrophil cytoplasmic antibody|anti-neutrophil cytoplasmic antibodies]], which is usually suggestive of [[Inflammatory bowel disease|inflammatory bowel disease (IBD)]] as the underlying cause.<ref name="pmid24957008">{{cite journal |vauthors=Sanderson IR |title=Growth problems in children with IBD |journal=Nat Rev Gastroenterol Hepatol |volume=11 |issue=10 |pages=601–10 |year=2014 |pmid=24957008 |doi=10.1038/nrgastro.2014.102 |url=}}</ref> | ||
=== Hormonal laboratory tests === | === Hormonal laboratory tests === | ||
==== Luteinizing hormone (LH) ==== | ==== Luteinizing hormone (LH) ==== | ||
* It is measured | * It is measured in the morning, using immunochemiluminometric (ICMA) or immunofluorometric (IFMA) assays. The lower limit of detection is at or below 0.1 IU/liter. | ||
* When the [[LH]] level is very low, ICMA measures would be at least half of the IFMA measures.<ref name="pmid17284632">{{cite journal |vauthors=Resende EA, Lara BH, Reis JD, Ferreira BP, Pereira GA, Borges MF |title=Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=4 |pages=1424–9 |year=2007 |pmid=17284632 |doi=10.1210/jc.2006-1569 |url=}}</ref> | * When the [[LH]] level is very low, ICMA measures would be at least half of the IFMA measures.<ref name="pmid17284632">{{cite journal |vauthors=Resende EA, Lara BH, Reis JD, Ferreira BP, Pereira GA, Borges MF |title=Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=4 |pages=1424–9 |year=2007 |pmid=17284632 |doi=10.1210/jc.2006-1569 |url=}}</ref> | ||
* [[LH]] more than 0.6 by IFMA or 0.2 by ICMA shows central [[puberty]] | * [[LH]] more than 0.6 by IFMA or 0.2 by ICMA shows central [[puberty]] onset (high [[specificity]], low [[sensitivity]]). If [[sexual characteristics]] are not shown up it may show primary [[hypogonadism]].<ref name="pmid17284632" /> | ||
* Generally, [[LH]] is better marker for [[puberty]] | * Generally, [[LH]] is a better marker for [[puberty]] onset, while [[FSH]] is a better marker for [[gonadal failure]].<ref name="PalmertDunkel2012">{{cite journal|last1=Palmert|first1=Mark R.|last2=Dunkel|first2=Leo|title=Delayed Puberty|journal=New England Journal of Medicine|volume=366|issue=5|year=2012|pages=443–453|issn=0028-4793|doi=10.1056/NEJMcp1109290}}</ref> | ||
==== Follicle stimulating hormone (FSH) ==== | ==== Follicle stimulating hormone (FSH) ==== | ||
* It is measured on the morning, using ICMA or IFMA assays. These tests lower limit of detection is at or below 0.1 IU/liter. | * It is measured on the morning, using ICMA or IFMA assays. These tests lower limit of detection is at or below 0.1 IU/liter. | ||
* When the [[FSH]] level is very low, ICMA measures would be at least half of the IFMA measures.<ref name="pmid17284632" /> | * When the [[FSH]] level is very low, ICMA measures would be at least half of the IFMA measures.<ref name="pmid17284632" /> | ||
* [[FSH]] less than 0.2 by ICMA or 0.1 IU/liter by IFMA reflects [[hypogonadotropic hypogonadism]], not diagnostic.<ref name="pmid20371659">{{cite journal |vauthors=Grinspon RP, Ropelato MG, Gottlieb S, Keselman A, Martínez A, Ballerini MG, Domené HM, Rey RA |title=Basal follicle-stimulating hormone and peak gonadotropin levels after gonadotropin-releasing hormone infusion show high diagnostic accuracy in boys with suspicion of hypogonadotropic hypogonadism |journal=J. Clin. Endocrinol. Metab. |volume=95 |issue=6 |pages=2811–8 |year=2010 |pmid=20371659 |doi=10.1210/jc.2009-2732 |url=}}</ref> | * [[FSH]] less than 0.2 by ICMA or 0.1 IU/liter by IFMA reflects [[hypogonadotropic hypogonadism]], but it is not diagnostic.<ref name="pmid20371659">{{cite journal |vauthors=Grinspon RP, Ropelato MG, Gottlieb S, Keselman A, Martínez A, Ballerini MG, Domené HM, Rey RA |title=Basal follicle-stimulating hormone and peak gonadotropin levels after gonadotropin-releasing hormone infusion show high diagnostic accuracy in boys with suspicion of hypogonadotropic hypogonadism |journal=J. Clin. Endocrinol. Metab. |volume=95 |issue=6 |pages=2811–8 |year=2010 |pmid=20371659 |doi=10.1210/jc.2009-2732 |url=}}</ref> | ||
* Some patients with delayed [[puberty]] may have above normal [[FSH]] level, which is usually suggestive of [[Inhibin|inhibin B]] deficiency and | * Some patients with delayed [[puberty]] may have above normal [[FSH]] level, which is usually suggestive of [[Inhibin|inhibin B]] deficiency and primary [[gonadal failure]] as underlying cause (high [[sensitivity]], high [[specificity]]). | ||
==== Insulin like growth factor (IGF-1) ==== | ==== Insulin-like growth factor (IGF-1) ==== | ||
* It has to measured within 2 hours of sampling, to avoid false increase. The tests that measure the [[IGF-1]] without [[IGF]] binding proteins interpretation are favorable only. | * It has to be measured within 2 hours of sampling, to avoid a false increase. The tests that measure the [[IGF-1]] without [[IGF]] binding proteins interpretation are favorable only. | ||
* [[IGF-1]] is a reflector of [[GH]] serum level. When it is elevated | * [[IGF-1]] is a reflector of [[GH]] serum level. When it is elevated before or after treatment, [[GH deficiency]] is less probable as the underlying cause of delayed [[puberty]]. | ||
* When [[GH deficiency]] is suspected, [[GH]] provocation | * When [[GH deficiency]] is suspected, [[GH]] provocation tests are necessary to approve the diagnosis.<ref name="ImranPelkey2010">{{cite journal|last1=Imran|first1=Syed Ali|last2=Pelkey|first2=Michael|last3=Clarke|first3=David B.|last4=Clayton|first4=Dale|last5=Trainer|first5=Peter|last6=Ezzat|first6=Shereen|title=Spuriously Elevated Serum IGF-1 in Adult Individuals with Delayed Puberty: A Diagnostic Pitfall|journal=International Journal of Endocrinology|volume=2010|year=2010|pages=1–4|issn=1687-8337|doi=10.1155/2010/370692}}</ref> | ||
==== Testosterone ==== | ==== Testosterone ==== | ||
* It is measured | * It is measured in the morning. The lower limit of detection is at or below 10 ng/liter (0.35 nm/L). The [[testosterone]] level has [[diurnal]] variation. | ||
* Morning serum level of equal or more than 20 ng/dL (0.7 nmol/L) is showing that the [[secondary sexual characteristics]] will be presented in 12 to 15 months.<ref name="pmid8421096">{{cite journal |vauthors=Wu FC, Brown DC, Butler GE, Stirling HF, Kelnar CJ |title=Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys |journal=J. Clin. Endocrinol. Metab. |volume=76 |issue=1 |pages=26–31 |year=1993 |pmid=8421096 |doi=10.1210/jcem.76.1.8421096 |url=}}</ref> | * Morning serum level of equal or more than 20 ng/dL (0.7 nmol/L) is showing that the [[secondary sexual characteristics]] will be presented in 12 to 15 months.<ref name="pmid8421096">{{cite journal |vauthors=Wu FC, Brown DC, Butler GE, Stirling HF, Kelnar CJ |title=Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys |journal=J. Clin. Endocrinol. Metab. |volume=76 |issue=1 |pages=26–31 |year=1993 |pmid=8421096 |doi=10.1210/jcem.76.1.8421096 |url=}}</ref> | ||
==== Gonadotropin releasing hormone (GnRH) ==== | ==== Gonadotropin-releasing hormone (GnRH) ==== | ||
* It is measured | * It is measured at any time of the day. | ||
* Very high serum levels of [[LH]] (5-8 IU/liter) or dramatic [[LH]] response ( | * Very high serum levels of [[LH]] (5-8 IU/liter) or dramatic [[LH]] response (compared to [[FSH]]) to [[GnRH]] stimulation test are suggestive of [[puberty]] onset.<ref name="pmid17284632" /> | ||
* [[LH]] value of less than 0.8 IU/liter or FSH value of less than 1.1 IU/liter, by IFMA after [[GnRH]], are more reflective of [[hypogonadotropic hypogonadism]] in boys.<ref name="pmid17284632" /> | * [[LH]] value of less than 0.8 IU/liter or FSH value of less than 1.1 IU/liter, by IFMA after [[GnRH]], are more reflective of [[hypogonadotropic hypogonadism]] in boys.<ref name="pmid17284632" /> | ||
==== Human chorionic gonadotropin (hCG) test ==== | ==== Human chorionic gonadotropin (hCG) test ==== | ||
* | * The test consists of daily [[intramuscular]] or [[subcutaneous]] injections of [[hCG]]. | ||
* The peak concentration of [[testosterone]] to both 3-day and 19-day tests is much lower in [[hypogonadotropic hypogonadism]] in contrast with [[Constitutional growth delay|CDGP]].<ref name="PalmertDunkel2012" /> | * The peak concentration of [[testosterone]] to both 3-day and 19-day tests is much lower in [[hypogonadotropic hypogonadism]] in contrast with [[Constitutional growth delay|CDGP]].<ref name="PalmertDunkel2012" /> | ||
* If the [[GnRH]] test (peak [[LH]] of 2.8 IU/liter) and [[hCG]] test (peak [[testosterone]] | * If the [[GnRH]] test (peak [[LH]] of 2.8 IU/liter) and [[hCG]] test (peak [[testosterone]] of 275 ng/dL (9.5 nmol/liter) in a 19-day test) combined with each other, the [[sensitivity]] and [[specificity]] become 100%.<ref name="pmid19017752">{{cite journal |vauthors=Segal TY, Mehta A, Anazodo A, Hindmarsh PC, Dattani MT |title=Role of gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=3 |pages=780–5 |year=2009 |pmid=19017752 |doi=10.1210/jc.2008-0302 |url=}}</ref> | ||
==== Inhibin B ==== | ==== Inhibin B ==== | ||
* It is measured | * It is measured at any time of the day. | ||
* An elevated baseline [[inhibin]] B in boys is diagnostic of [[CDGP]]. Plasma level of more than 35 pg/ml in prepubertal boys present 100% of both [[sensitivity]] and [[specificity]], for [[CDGP]].<ref name="pmid20826577">{{cite journal |vauthors=Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne S, Rouleau S, Lahlou N |title=Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty |journal=J. Clin. Endocrinol. Metab. |volume=95 |issue=12 |pages=5225–32 |year=2010 |pmid=20826577 |doi=10.1210/jc.2010-1535 |url=}}</ref> | * An elevated baseline [[inhibin]] B in boys is diagnostic of [[CDGP]]. Plasma level of more than 35 pg/ml in prepubertal boys present 100% of both [[sensitivity]] and [[specificity]], for [[CDGP]].<ref name="pmid20826577">{{cite journal |vauthors=Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne S, Rouleau S, Lahlou N |title=Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty |journal=J. Clin. Endocrinol. Metab. |volume=95 |issue=12 |pages=5225–32 |year=2010 |pmid=20826577 |doi=10.1210/jc.2010-1535 |url=}}</ref> | ||
* Plasma level of more than 65 pg/ml in boys with [[tanner stage]] 2 [[genitalia]] present 80%-86% [[sensitivity]] and 88%-92% [[specificity]] | * Plasma level of more than 65 pg/ml in boys with [[tanner stage]] 2 of [[genitalia]] present 80%-86% [[sensitivity]] and 88%-92% [[specificity]] for [[CDGP]]. | ||
* Lack of [[inhibin]] B in boys may reveal [[Gonadal failure|primary germinal failure]].<ref name="PalmertDunkel2012" /> | * Lack of [[inhibin]] B in boys may reveal the [[Gonadal failure|primary germinal failure]].<ref name="PalmertDunkel2012" /> | ||
==== Prolactin ==== | ==== Prolactin ==== | ||
* There are only few indications. The [[prolactin]] level is | * There are only a few indications. The [[prolactin]] level is increased by [[stress]], [[exercise]], [[sleep]], [[hypothyroidism]], and some medications. | ||
* Some patients with delayed [[puberty]] may have elevated concentration of [[prolactin]], which is usually suggestive of [[hypothalamic]]-[[pituitary]] tumors causing [[hypogonadotropic hypogonadism]] | * Some patients with delayed [[puberty]] may have elevated concentration of [[prolactin]], which is usually suggestive of [[hypothalamic]]-[[pituitary]] tumors causing [[hypogonadotropic hypogonadism]] as the underlying cause. | ||
* In patients with asymptomatic [[hyperprolactinemia]], it may be necessary to measure the macroplrolactin ( | * In patients with asymptomatic [[hyperprolactinemia]], it may be necessary to measure the macroplrolactin (an inactivated form of [[prolactin]]).<ref name="pmid24397058">{{cite journal |vauthors=Ali L, Adeel A |title=Role of basal and provocative serum prolactin in differentiating idiopathic hypogonadotropic hypogonadism and constitutional delayed puberty--a diagnostic dilemma |journal=J Ayub Med Coll Abbottabad |volume=24 |issue=2 |pages=73–6 |year=2012 |pmid=24397058 |doi= |url=}}</ref> | ||
==== Growth hormone (GH) test ==== | ==== Growth hormone (GH) test ==== | ||
* A reduced concentration of [[Growth hormone|growth hormone (GH)]] is diagnostic of [[GH]] deficiency, as the underlying cause of delayed [[puberty]]. | |||
* A reduced concentration of [[Growth hormone|growth hormone (GH)]] is diagnostic of [[GH]] deficiency, as underlying cause of delayed [[puberty]]. | |||
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==References== | ==References== | ||
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[[Category:Disease]] | [[Category:Disease]] | ||
[[Category:Medicine]] | |||
[[Category:Pediatrics]] | |||
[[Category:Endocrinology]] | [[Category:Endocrinology]] | ||
[[Category: | [[Category:Mature chapter]] | ||
[[Category:Developmental biology]] | |||
[[Category:Sexuality and age]] | |||
[[Category:Sexual health]] | |||
[[Category:Growth disorders]] | |||
[[Category:Congenital disorders]] | |||
[[Category:Up-To-Date]] | |||
Latest revision as of 21:15, 29 July 2020
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Delayed puberty Microchapters |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]
Overview
First line tests in the diagnosis of delayed puberty are complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, free thyroxine, luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin-like growth factor (IGF-1), and testosterone. For specific familial disorders some special laboratory tests may be needed, such as anti-gliadin antibody and anti-tissue transglutaminase antibody (i.e., Celiac disease diagnosis) or anti-neutrophil cytoplasmic antibodies (i.e., inflammatory bowel disease diagnosis). Second line tests are gonadotropin-releasing hormone (GnRH), human chorionic gonadotropin (hCG) test, inhibin B, prolactin, and growth hormone (GH) test.
Laboratory Findings
Biochemistry laboratory tests
- The laboratory tests are complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, and free thyroxine.
- For specific familial disorders some special laboratory tests may be needed, such as anti-gliadin antibody and anti-tissue transglutaminase antibody (i.e., Celiac disease diagnosis) or anti-neutrophil cytoplasmic antibodies (i.e., inflammatory bowel disease diagnosis).
Abbreviations: CBC: Complete blood count, ESR: Erythrocyte sedimentation rate, Cr: Creatinine, HCO3: Bicarbonate, Alb: Albumin, T4: Thyroxin, TSH: Thyroid stimulating hormone, Anti TTg Ab: Anti transglutaminase antibody, ANCA: Antineutrophil cytoplasmic antibody, LH: Luteinizing hormone, FSH: Follicle stimulating hormone, IGF-1: Insulin-like growth factor 1, GnRH: Gonadotropin-releasing hormone, hCG: Human chorionic gonadotropin, PRL: Prolactin, GH: Growth hormone, Cl: Chlorine, WBC: White blood cell, RBC: Red blood cell, HGB: Hemoglobin, MCV: Mean corpuscular volume, AIDS: Acquired immunodeficiency syndrome, Lymph: Lymphocyte.
| Delayed puberty
underlying diseases |
First line tests | Second line tests | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CBC | ESR | Cr | Electrolyte | HCO3 | ALK | Alb | T4 | TSH | Anti gliadin Ab | Anti TTg Ab | ANCA | LH | FSH | IGF-1 | Testosterone | GnRH | hCG test | Inhibin B | PRL | GH | |
| Idiopathic hypogonadotropic hypogonadism | - | - | - | - | - | - | - | - | - | - | - | - | ↓↓ | ↓↓ | - | ↓ | ↓↓↓ | - | - | - | - |
| Hypergonadotropic hypogonadism | - | - | - | - | - | - | - | - | - | - | - | ↑↑ | ↑↑ | - | ↓↓↓ | ↑ | - | - | - | - | |
| Constitutional delay of growth and puberty (CDGP) | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | + | ↑ | - | - |
| Kallmann syndrome | - | - | - | - | - | - | - | - | - | - | - | - | ↓↓ | ↓↓ | - | ↓↓ | ↓↓ | - | - | - | - |
| Cystic fibrosis | - | ↑ | ↑ | Cl disturbance | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Asthma | ↑ Eosinophil | - | - | - | ↓ | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Inflammatory bowel disease | ↑ WBC | ↑↑ | - | - | - | - | - | - | - | - | - | + | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Celiac disease | - | - | - | ↓ | - | - | ↓↓ | - | - | + | + | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Juvenile rheumatoid arthritis | ↑ WBC | ↑↑ | - | - | - | ↑ | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Anorexia nervosa/Bulimia | ↓ HGB | - | - | ↓ | - | - | ↓ | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Sickle cell disease | ↓ HGB | ↑ | ↑ | - | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Hemosiderosis | - | ↑↑ | ↑ | ↑ | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Thalassemia | ↓ HGB, ↓ MCV | - | - | - | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Chronic renal disease | ↓ HGB | ↑↑ | ↑↑ | ↑↑ | ↓↓ | - | ↓↓ | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| AIDS | ↓ CD4+ | ↑↑ | - | - | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Diabetes mellitus | ↓ HGB | ↑↑ | - | - | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Hypothyroidism | - | - | - | - | - | - | ↓ | ↓↓ | ↑↑ | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | - |
| Hyperprolactinemia | - | - | - | - | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | ↑ | - |
| Growth hormone deficiency | - | - | - | - | - | - | ↓ | - | - | - | - | - | ↓ | ↓ | ↓ | ↓ | ↓ | - | - | - | + |
| Cushing syndrome | - | - | - | - | - | - | - | - | - | - | - | - | ↓ | ↓ | - | ↓ | ↓ | - | - | - | + |
| Chemotherapy/Radiation therapy | Pancytopenia | - | ↑↑ | ↑↑ | ↓↓ | ↑↑ | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Mumps, Coxsackie | ↑ Lymph | ↑↑ | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | ↑ | - | - |
| Galactosemia | - | - | ↑ | ↑ | ↓ | ↑↑ | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Autoimmune oophiritis | ↑ Lymph | ↑↑ | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | - | ↑ | - | - | - | - |
| Autoimmune orchitis | ↑ Lymph | ↑↑ | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | + | ↑ | - | - |
| Turner syndrome | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Noonan syndrome | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Fragile X premutation | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Cryptorchidism | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Gonadal dysgenesis | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Vanishing testes syndrome | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
| Testicular torsion/trauma | - | - | - | - | - | - | - | - | - | - | - | - | ↑ | ↑ | - | ↓ | ↑ | - | - | - | - |
Complete blood count
- Some patients with delayed puberty may have reduced concentration of hemoglobin, which is usually suggestive of anemia as the underlying cause.
- Some patients with delayed puberty may have elevated number of lymphocytes, which is usually suggestive of viral infections (mumps, coxsackie) as the underlying cause.
- Decreasing number of lymphocytes (especially CD4s) may reveal AIDS, as an underlying cause of delayed puberty.[1]
Erythrocyte sedimentation rate
- An elevated erythrocyte sedimentation rate (ESR) is diagnostic of underlying diseases that may cause delayed puberty.
Creatinine
- Some patients with delayed puberty may have elevated concentration of creatinine, which is usually suggestive of renal disease as the underlying cause.[2]
Electrolytes
- Some patients with delayed puberty may have elevated serum sodium, potassium, or any other electrolytes, which is usually suggestive of renal disease as the underlying cause.[2]
- Increasing calcium and magnesium may reflect the effect of radiation or chemotherapy as the cause of delayed puberty.
Bicarbonate
- Reduced bicarbonate concentration in serum may reveal the metabolic acidosis due to various causes, mostly chronic kidney injury, as the underlying cause of delayed puberty.[2]
Alkaline phosphatase
- An elevated concentration of serum alkaline phosphatase is diagnostic of any liver or bone diseases, as the underlying cause of delayed puberty.
- Histiocytosis, galactosemia induced hepatomegaly, and Gaucher's diseases are some of the examples.
Albumin
- Some patients with delayed puberty may have reduced concentration of serum albumin, which is usually suggestive of liver or renal disease as the underlying cause.[3]
Thyrotropin
- An elevated concentration of serum thyroid stimulating hormone (TSH) is diagnostic of hypothyroidism, as the underlying cause of delayed puberty.[4]
Free thyroxine
- A reduced concentration of serum free thyroxine (T4) is diagnostic of hypothyroidism, as the underlying cause of delayed puberty.[4]
Anti-gliadin antibody
- Some patients with delayed puberty may have the positive anti-gliadin antibody, which is usually suggestive of Celiac disease as the underlying cause.[5]
Anti-tissue transglutaminase antibody
- Some patients with delayed puberty may have positive anti-tissue transglutaminase antibody, which is usually suggestive of Celiac disease as the underlying cause.[6]
Anti-neutrophil cytoplasmic antibodies
- Some patients with delayed puberty may have positive anti-neutrophil cytoplasmic antibodies, which is usually suggestive of inflammatory bowel disease (IBD) as the underlying cause.[7]
Hormonal laboratory tests
Luteinizing hormone (LH)
- It is measured in the morning, using immunochemiluminometric (ICMA) or immunofluorometric (IFMA) assays. The lower limit of detection is at or below 0.1 IU/liter.
- When the LH level is very low, ICMA measures would be at least half of the IFMA measures.[8]
- LH more than 0.6 by IFMA or 0.2 by ICMA shows central puberty onset (high specificity, low sensitivity). If sexual characteristics are not shown up it may show primary hypogonadism.[8]
- Generally, LH is a better marker for puberty onset, while FSH is a better marker for gonadal failure.[4]
Follicle stimulating hormone (FSH)
- It is measured on the morning, using ICMA or IFMA assays. These tests lower limit of detection is at or below 0.1 IU/liter.
- When the FSH level is very low, ICMA measures would be at least half of the IFMA measures.[8]
- FSH less than 0.2 by ICMA or 0.1 IU/liter by IFMA reflects hypogonadotropic hypogonadism, but it is not diagnostic.[9]
- Some patients with delayed puberty may have above normal FSH level, which is usually suggestive of inhibin B deficiency and primary gonadal failure as underlying cause (high sensitivity, high specificity).
Insulin-like growth factor (IGF-1)
- It has to be measured within 2 hours of sampling, to avoid a false increase. The tests that measure the IGF-1 without IGF binding proteins interpretation are favorable only.
- IGF-1 is a reflector of GH serum level. When it is elevated before or after treatment, GH deficiency is less probable as the underlying cause of delayed puberty.
- When GH deficiency is suspected, GH provocation tests are necessary to approve the diagnosis.[10]
Testosterone
- It is measured in the morning. The lower limit of detection is at or below 10 ng/liter (0.35 nm/L). The testosterone level has diurnal variation.
- Morning serum level of equal or more than 20 ng/dL (0.7 nmol/L) is showing that the secondary sexual characteristics will be presented in 12 to 15 months.[11]
Gonadotropin-releasing hormone (GnRH)
- It is measured at any time of the day.
- Very high serum levels of LH (5-8 IU/liter) or dramatic LH response (compared to FSH) to GnRH stimulation test are suggestive of puberty onset.[8]
- LH value of less than 0.8 IU/liter or FSH value of less than 1.1 IU/liter, by IFMA after GnRH, are more reflective of hypogonadotropic hypogonadism in boys.[8]
Human chorionic gonadotropin (hCG) test
- The test consists of daily intramuscular or subcutaneous injections of hCG.
- The peak concentration of testosterone to both 3-day and 19-day tests is much lower in hypogonadotropic hypogonadism in contrast with CDGP.[4]
- If the GnRH test (peak LH of 2.8 IU/liter) and hCG test (peak testosterone of 275 ng/dL (9.5 nmol/liter) in a 19-day test) combined with each other, the sensitivity and specificity become 100%.[12]
Inhibin B
- It is measured at any time of the day.
- An elevated baseline inhibin B in boys is diagnostic of CDGP. Plasma level of more than 35 pg/ml in prepubertal boys present 100% of both sensitivity and specificity, for CDGP.[13]
- Plasma level of more than 65 pg/ml in boys with tanner stage 2 of genitalia present 80%-86% sensitivity and 88%-92% specificity for CDGP.
- Lack of inhibin B in boys may reveal the primary germinal failure.[4]
Prolactin
- There are only a few indications. The prolactin level is increased by stress, exercise, sleep, hypothyroidism, and some medications.
- Some patients with delayed puberty may have elevated concentration of prolactin, which is usually suggestive of hypothalamic-pituitary tumors causing hypogonadotropic hypogonadism as the underlying cause.
- In patients with asymptomatic hyperprolactinemia, it may be necessary to measure the macroplrolactin (an inactivated form of prolactin).[14]
Growth hormone (GH) test
- A reduced concentration of growth hormone (GH) is diagnostic of GH deficiency, as the underlying cause of delayed puberty.
| Delayed puberty | |||||||||||||||||||||||||||||||||||||||||||||||
| Clinical suspicion to delayed puberty (Absent growth spurt along with lack of testicular enlargement or breast development) | |||||||||||||||||||||||||||||||||||||||||||||||
| First line evaluation • Biochemical analyses • Bone age radiography • Basal serum LH, FSH, IGF-1, TSH, free thyroxine, and testosterone (in boys) | |||||||||||||||||||||||||||||||||||||||||||||||
| Reduced or normal LH and FSH | Elevated FSH or LH | ||||||||||||||||||||||||||||||||||||||||||||||
| Growth rate as prepubertal | Growth rate lower than prepubertal | ||||||||||||||||||||||||||||||||||||||||||||||
| Constitutional delay of growth and puberty (CDGP) | Gonadotropin releasing hormone (GnRH) deficiency | Transient hypogonadotropic hypogonadism | Permanent hypogonadotropic hypogonadism | Hypergonadotropic hypogonadism | |||||||||||||||||||||||||||||||||||||||||||
| Second line evaluation | Second line evaluation | Second line evaluation | |||||||||||||||||||||||||||||||||||||||||||||
| • GnRH test • hCG stimulation test • Serum inhibin B • Olfactory-function test • Genetic testing • MRI | Evaluating more underlying diseases: • MRI • Prolactin | Evaluating more underlying diseases: • Karyotype • Serum inhibin B | |||||||||||||||||||||||||||||||||||||||||||||
| Low BMI | Normal BMI | High BMI | |||||||||||||||||||||||||||||||||||||||||||||
| • GI disorder • Malnutrition • Anorexia | • Hypothyreosis • Hyperprolactinemia • Multiple pituitary hormone deficiency | • Glucocorticoid excess (iatrogenic, Cushing’s disease) • Hypothyroidism | |||||||||||||||||||||||||||||||||||||||||||||
| Follow up Evaluate the need for the induction of secondary sex characteristics | Treat underlying disease | Treat with sex steroids | |||||||||||||||||||||||||||||||||||||||||||||
References
- ↑ Majaliwa ES, Mohn A, Chiarelli F (2009). "Growth and puberty in children with HIV infection". J. Endocrinol. Invest. 32 (1): 85–90. doi:10.1007/BF03345686. PMID 19337023.
- ↑ 2.0 2.1 2.2 Bacchetta J (2015). "[Puberty and chronic kidney disease]". Arch Pediatr (in French). 22 (5 Suppl 1): 169–71. doi:10.1016/S0929-693X(15)30084-1. PMID 26112575.
- ↑ Upreti V, Dhull P, Patnaik SK, Kumar KV (2012). "An unusual cause of delayed puberty: Berardinelli- Seip syndrome". J. Pediatr. Endocrinol. Metab. 25 (11–12): 1157–60. PMID 23444474.
- ↑ 4.0 4.1 4.2 4.3 4.4 Palmert, Mark R.; Dunkel, Leo (2012). "Delayed Puberty". New England Journal of Medicine. 366 (5): 443–453. doi:10.1056/NEJMcp1109290. ISSN 0028-4793.
- ↑ Bona G, Marinello D, Oderda G (2002). "Mechanisms of abnormal puberty in coeliac disease". Horm. Res. 57 Suppl 2: 63–5. doi:58103 Check
|doi=value (help). PMID 12065930. - ↑ Bona G, Marinello D, Oderda G (2002). "Mechanisms of abnormal puberty in coeliac disease". Horm. Res. 57 Suppl 2: 63–5. doi:58103 Check
|doi=value (help). PMID 12065930. - ↑ Sanderson IR (2014). "Growth problems in children with IBD". Nat Rev Gastroenterol Hepatol. 11 (10): 601–10. doi:10.1038/nrgastro.2014.102. PMID 24957008.
- ↑ 8.0 8.1 8.2 8.3 8.4 Resende EA, Lara BH, Reis JD, Ferreira BP, Pereira GA, Borges MF (2007). "Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children". J. Clin. Endocrinol. Metab. 92 (4): 1424–9. doi:10.1210/jc.2006-1569. PMID 17284632.
- ↑ Grinspon RP, Ropelato MG, Gottlieb S, Keselman A, Martínez A, Ballerini MG, Domené HM, Rey RA (2010). "Basal follicle-stimulating hormone and peak gonadotropin levels after gonadotropin-releasing hormone infusion show high diagnostic accuracy in boys with suspicion of hypogonadotropic hypogonadism". J. Clin. Endocrinol. Metab. 95 (6): 2811–8. doi:10.1210/jc.2009-2732. PMID 20371659.
- ↑ Imran, Syed Ali; Pelkey, Michael; Clarke, David B.; Clayton, Dale; Trainer, Peter; Ezzat, Shereen (2010). "Spuriously Elevated Serum IGF-1 in Adult Individuals with Delayed Puberty: A Diagnostic Pitfall". International Journal of Endocrinology. 2010: 1–4. doi:10.1155/2010/370692. ISSN 1687-8337.
- ↑ Wu FC, Brown DC, Butler GE, Stirling HF, Kelnar CJ (1993). "Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys". J. Clin. Endocrinol. Metab. 76 (1): 26–31. doi:10.1210/jcem.76.1.8421096. PMID 8421096.
- ↑ Segal TY, Mehta A, Anazodo A, Hindmarsh PC, Dattani MT (2009). "Role of gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty". J. Clin. Endocrinol. Metab. 94 (3): 780–5. doi:10.1210/jc.2008-0302. PMID 19017752.
- ↑ Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne S, Rouleau S, Lahlou N (2010). "Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty". J. Clin. Endocrinol. Metab. 95 (12): 5225–32. doi:10.1210/jc.2010-1535. PMID 20826577.
- ↑ Ali L, Adeel A (2012). "Role of basal and provocative serum prolactin in differentiating idiopathic hypogonadotropic hypogonadism and constitutional delayed puberty--a diagnostic dilemma". J Ayub Med Coll Abbottabad. 24 (2): 73–6. PMID 24397058.