Delayed puberty laboratory findings: Difference between revisions

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==Overview==
==Overview==
[[Laboratory]] findings consistent with the diagnosis of delayed [[puberty]] include first line and second line tests. First line tests are including [[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]]; In case of specific familial disorders, some especial laboratory tests may be needed, indeed. These laboratory tests are including anti-[[gliadin]] [[antibody]] and anti-[[tissue transglutaminase]] [[antibody]] (i.e., [[Celiac disease]] diagnosis) or anti-neutrophil cythoplasmic antibodies (i.e., [[inflammatory bowel disease]] diagnosis). Second line testes are including [[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.
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 ===
*In order to evaluating any other underlying [[diseases]], many [[biochemistry]] laboratory tests could be considered. These laboratory tests are including [[complete blood count]], [[erythrocyte sedimentation rate]], [[creatinine]], [[electrolytes]], [[bicarbonate]], [[alkaline phosphatase]], [[albumin]], [[thyrotropin]], and free [[thyroxine]].  
*The laboratory tests are [[complete blood count]], [[erythrocyte sedimentation rate]], [[creatinine]], [[electrolytes]], [[bicarbonate]], [[alkaline phosphatase]], [[albumin]], [[thyrotropin]], and free [[thyroxine]].  
*In case of specific familial disorders, some especial laboratory tests may be needed, indeed. These laboratory tests are including anti-[[gliadin]] [[antibody]] and anti-[[tissue transglutaminase]] [[antibody]] (i.e., [[Celiac disease]] diagnosis) or anti-neutrophil cythoplasmic antibodies (i.e., [[inflammatory bowel disease]] diagnosis).
*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|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 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 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 [[CD4+ cell|CD4s]]) may reveal [[AIDS]], as 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 most of the underlying [[diseases]] that may cause delayed [[puberty]].
* 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 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 ====
* Some patients with delayed [[puberty]] may have elevated serum [[sodium]], [[potassium]], or any other [[electrolytes]], which is usually suggestive of [[renal disease]] as underlying cause.<ref name="pmid26112575" />
* 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.<ref name="pmid26112575" />
* Increasing [[calcium]] and [[magnesium]] may reflect the effect of [[Radiation therapy|radiation]] or [[chemotherapy]] as the cause of delayed [[puberty]].
* Increasing [[calcium]] and [[magnesium]] may reflect the effect of [[Radiation therapy|radiation]] or [[chemotherapy]] as the cause of delayed [[puberty]].


==== Bicarbonate ====
==== Bicarbonate ====
Reduced [[bicarbonate]] concentration in serum may reveal the [[metabolic acidosis]] due to various causes, mostly [[Chronic kidney diseas|chronic kidney injury]], as 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 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 [[hepatomgaly]], and [[Gaucher's disease|Gaucher's diseases]] are some of examples.


==== 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 ====
An reduced concentration of serum free [[thyroxine]] (T4) is diagnostic of [[hypothyroidism]], as underlying cause of delayed [[puberty]].<ref name="PalmertDunkel2012" />
* 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 cythoplasmic antibodies ====
==== Anti-neutrophil cytoplasmic antibodies ====
Some patients with delayed [[puberty]] may have positive anti-neutrophil cythoplasmic antibodies, which is usually suggestive of [[Inflammatory bowel disease|inflammatory bowel disease (IBD)]] as 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>
* 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 on the morning, using immunochemiluminometric (ICMA) or immunofluorometric (IFMA) assays. These tests lower limit of detection is at or below 0.1 IU/liter.
* 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]] initiation (high [[specificity]], low [[sensitivity]]). If [[sexual characteristics]] are not shown up it may show primary [[hypogonadism]].<ref name="pmid17284632" />
* [[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]] initiation, while [[FSH]] is 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>
* 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 of primary [[gonadal failure]] as underlying cause (high [[sensitivity]], high [[specificity]]).
* 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, before or after treatment, it is assumed as less probability of [[GH deficiency]] as underlying cause of delayed [[puberty]].  
* [[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 testes 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>
* 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 on the morning. The tests lower limit of detection is at or below 10 ng/liter (0.35 nm/L). The [[testosterone]] level has [[diurnal]] variation.
* 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 on any times of day.  
* It is measured at any time of the day.  
* Very high serum levels of [[LH]] (5-8 IU/liter) or dramatic [[LH]] response (compare to [[FSH]]) to [[GnRH]] stimulation test are suggestive of [[puberty]] onset.<ref name="pmid17284632" />   
* 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 ====
* It is consist of daily [[intramuscular]] or [[subcutaneous]] injections of [[hCG]].
* 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]] in 19-day test of 275 ng/dL (9.5 nmol/liter)) combined with each other, the [[sensitivity]] and [[specificity]] are became 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>
* 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 on any times of day.  
* 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]], for [[CDGP]].
* 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 influenced by [[stress]], [[exercise]], [[sleep]], [[hypothyroidism]], and some medications; all increase the level.
* 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 underlying cause.
* 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 (inactivate 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>
* 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 ====
* It is measured on any times of day.
* 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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[[Category:Disease]]
[[Category:Disease]]
[[Category:Medicine]]
[[Category:Pediatrics]]
[[Category:Endocrinology]]
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[[Category:Needs content]]
[[Category:Mature chapter]]
 
[[Category:Developmental biology]]
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[[Category:Sexuality and age]]
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[[Category:Sexual health]]
[[Category:Growth disorders]]
[[Category:Congenital disorders]]
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Latest revision as of 21:15, 29 July 2020

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

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: HemoglobinMCV: 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

Erythrocyte sedimentation rate

Creatinine

Electrolytes

Bicarbonate

Alkaline phosphatase

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

Free thyroxine

Anti-gliadin antibody

Anti-tissue transglutaminase antibody

Anti-neutrophil cytoplasmic antibodies

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

Inhibin B

Prolactin

Growth hormone (GH) test

 
 
 
 
 
 
 
 
 
 
 
 
 
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

  1. 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. 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.
  3. 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. 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.
  5. 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.
  6. 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.
  7. 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. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.

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