Delayed puberty laboratory findings: Difference between revisions

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__NOTOC__
__NOTOC__
{{Delayed puberty}}
{{Delayed puberty}}
{{CMG}}; {{AE}}
{{CMG}}; {{AE}}{{EG}}


==Overview==
==Overview==
An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
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==
 
=== 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|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"
! rowspan="2" |Delayed puberty
underlying diseases
! colspan="16" |First line tests
! colspan="5" |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 puberty|Constitutional delay of growth and puberty (CDGP)]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| +
|↑
| -
| -
|-
|[[Kallmann syndrome]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↓↓
|↓↓
| -
|↓↓
|↓↓
| -
| -
| -
| -
|-
|[[Cystic Fibrosis|Cystic fibrosis]]
| -
|↑
|↑
|Cl disturbance
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Asthma]]
|↑ Eosinophil
| -
| -
| -
|↓
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Inflammatory Bowel Disease|Inflammatory bowel disease]]
|↑ WBC
|↑↑
| -
| -
| -
| -
| -
| -
| -
| -
| -
| +
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Celiac Disease|Celiac disease]]
| -
| -
| -
|↓
| -
| -
|↓↓
| -
| -
| +
| +
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Juvenile Rheumatoid Arthritis|Juvenile rheumatoid arthritis]]
|↑ WBC
|↑↑
| -
| -
| -
|↑
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Anorexia Nervosa|Anorexia nervosa]]/[[Bulimia]]
|↓ HGB
| -
| -
|↓
| -
| -
|↓
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Sickle Cell Disease|Sickle cell disease]]
|↓ HGB
|↑
|↑
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Hemosiderosis]]
| -
|↑↑
|↑
|↑
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Thalassemia]]
|↓ HGB, ↓ MCV   
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Chronic Renal Disease|Chronic renal disease]]
|↓ HGB
|↑↑
|↑↑
|↑↑
|↓↓
| -
|↓↓
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[AIDS]]
|↓ CD4+
|↑↑
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Diabetes Mellitus|Diabetes mellitus]]
|↓ HGB
|↑↑
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Hypothyroidism]]
| -
| -
| -
| -
| -
| -
|↓
|↓↓
|↑↑
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
| -
| -
|-
|[[Hyperprolactinemia]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↓
|↓
| -
|↓
|↓
| -
| -
|↑
| -
|-
|[[GH deficiency|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 syndrome|Fragile X premutation]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↑
|↑
| -
|↓
|↑
| -
| -
| -
| -
|-
|[[Cryptorchidism]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↑
|↑
| -
|↓
|↑
| -
| -
| -
| -
|-
|[[Gonadal dysgenesis]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↑
|↑
| -
|↓
|↑
| -
| -
| -
| -
|-
|[[Vanishing testes syndrome]]
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
| -
|↑
|↑
| -
|↓
|↑
| -
| -
| -
| -
|-
|[[Testicular torsion]]/[[Physical trauma|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 [[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 ====
* An elevated [[Erythrocyte sedimentation rate|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.<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 ====
* 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]].
 
==== 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" />
 
==== 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 disease|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.<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 ====
* 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 ====
* 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 ====
* 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 ====
* 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 cytoplasmic antibodies ====
* 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 ===
 
==== 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.<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]] onset (high [[specificity]], low [[sensitivity]]). If [[sexual characteristics]] are not shown up it may show primary [[hypogonadism]].<ref name="pmid17284632" />
* 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>


OR
==== 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.<ref name="pmid17284632" />
* [[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 primary [[gonadal failure]] as underlying cause (high [[sensitivity]], high [[specificity]]).


Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
==== 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.<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>


OR
==== 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.<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>


[Test] is usually normal among patients with [disease name].
==== 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.<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" />


OR
==== 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" />
* 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>


Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
==== 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]].<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 of [[genitalia]] present 80%-86% [[sensitivity]] and 88%-92% [[specificity]] for [[CDGP]].
* Lack of [[inhibin]] B in boys may reveal the [[Gonadal failure|primary germinal failure]].<ref name="PalmertDunkel2012" />


OR
==== 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]]).<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>


There are no diagnostic laboratory findings associated with [disease name].
==== Growth hormone (GH) test ====
==Laboratory Findings==
* A reduced concentration of [[Growth hormone|growth hormone (GH)]] is diagnostic of [[GH]] deficiency, as the underlying cause of delayed [[puberty]].
The most valuable blood tests are the [[gonadotropin]]s, because elevation confirms immediately a defect of the [[gonad]]s or deficiency of the [[sex steroid]]s. In many instances, screening tests such as a [[full blood count|complete blood count]], general chemistry screens, [[thyroid]] tests, and [[urinalysis]] may be worthwhile.
 
*There are no diagnostic laboratory findings associated with [disease name].
{{Family tree/start}}
OR
{{Family tree | | | | | | | | | | | | | | A01 | | | | | | | | A01= '''Delayed puberty'''}}
*An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
{{Family tree | | | | | | | | | | | | | | |!| | | | | | | | | }}
*[Test] is usually normal among patients with [disease name].
{{Family tree | | | | | | | | | | | | | | B01 | | | | | | | | B01= '''''Clinical suspicion to delayed puberty''''' <br> (Absent [[growth spurt]] along with <br> lack of [[testicular]] enlargement or [[breast]] development)}}
*Laboratory findings consistent with the diagnosis of [disease name] include
{{Family tree | | | | | | | | | | | | | | |!| | | | | | | | | }}
**[Abnormal test 1]
{{Family tree |boxstyle=text-align: left; background: #7FFFD4; color: #000000; | | | | | | | | | | | | | | C01 | | | | | | | | C01= '''''First line evaluation''''' <br>• Biochemical analyses<br>• [[Bone age]] radiography <br>• Basal serum [[LH]], [[FSH]], [[IGF-1]], [[TSH]], free [[thyroxine]], and [[testosterone]] (in boys)}}
**[Abnormal test 2]
{{Family tree | | | | | | | | |,|-|-|-|-|-|^|-|-|-|-|-|.| | |}}
**[Abnormal test 3]
{{Family tree | | | | | | | | C01 | | | | | | | | | | C02 | | C01= Reduced or normal [[LH]] and [[FSH]]| C02= Elevated [[FSH]] or [[LH]]}}
{{Family tree | | | | |,|-|-|-|^|-|-|-|.| | | | | | | |!| | | }}
{{Family tree | | | | D01 | | | | | | D02 | | | | | | |!| | | D01= Growth rate as prepubertal|D02= Growth rate lower than prepubertal}}
{{Family tree | | |,|-|^|-|.| | | |,|-|^|-|.| | | | | |!| | | }}
{{Family tree |boxstyle=background:#A1CAF1; color: #000000; | | D01 | | D02 | | D03 | | D04 | | | | D05 | | D01=[[Constitutional delay of puberty|Constitutional delay of growth and puberty (CDGP)]]|D02=[[Gonadotropin releasing hormone| Gonadotropin releasing hormone (GnRH)]] deficiency|D03=Transient [[hypogonadotropic hypogonadism]]|D04=Permanent [[hypogonadotropic hypogonadism]]|D05=Hypergonadotropic hypogonadism}}
{{Family tree | | | | | |,|'| | | |`|-|v|-|'| | | | | |!| | | }}
{{Family tree |boxstyle=background: #7FFFD4; color: #000000; | | | | | I01 | | | | | I01 | | | | | | I01 | | I01= '''''Second line evaluation'''''}}
{{Family tree | | | | | |!| | | | | | |!| | | | | | | |!| | | }}
{{Family tree |boxstyle=text-align: left; | | | | | E01 | | | | | E02 | | | | | | E03 | | E01=• [[GnRH]] test<br>• [[hCG]] stimulation test<br>• Serum [[inhibin B]]<br>• [[Olfactory]]-function test<br>• [[Genetic]] testing<br>• [[MRI]]|E02= Evaluating more underlying diseases: <br>• [[MRI]]<br>• [[Prolactin]]|E03= Evaluating more underlying diseases: <br>• Karyotype<br>• Serum [[inhibin B]]}}
{{Family tree | | | | | |!| | |,|-|-|-|+|-|-|-|.| | | |!| | | }}
{{Family tree | | | | | |!| | F01 | | F02 | | F03 | | |!| | | F01= Low [[BMI]]|F02= Normal [[BMI]]|F03= High [[BMI]]}}
{{Family tree | | | | | |!| | |!| | | |!| | | |!| | | |!| | | }}
{{Family tree |boxstyle=text-align: left; background:#A1CAF1; color: #000000; | | | | | |!| | G01 | | G02 | | G03 | | |!| | | G01=• GI disorder<br>• [[Malnutrition]]<br>• [[Anorexia]]|G02=• [[Hypothyreosis]]<br>• [[Hyperprolactinemia]]<br>• Multiple [[pituitary]] hormone deficiency|G03=• [[Glucocorticoid]] excess ([[iatrogenic]], [[Cushing’s disease]])<br>• [[Hypothyroidism]]}}
{{Family tree | | | | | |!| | |`|-|-|-|+|-|-|-|'| | | |!| | | }}
{{Family tree | | | | | H01 | | | | | H02 | | | | | | H03 | | H01= Follow up<br>Evaluate the need for the induction of [[secondary sex characteristics]]|H02= Treat underlying [[disease]]|H03= Treat with [[sex steroids]]}}
{{Family tree | | | | | | | | | | | | | | | | | | | | | | }}
{{Family tree | | | | | | | | | | | | | | | | | | | | | | }}
{{Family tree | | | | | | | | | | | | | | | | | | | | | | }}


*Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
{{Family tree/end}}


==References==
==References==
{{reflist|2}}
{{reflist|2}}
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Medicine]]
[[Category:Pediatrics]]
[[Category:Endocrinology]]
[[Category:Endocrinology]]
[[Category:Needs content]]
[[Category:Mature chapter]]
 
[[Category:Developmental biology]]
{{WS}}
[[Category:Sexuality and age]]
{{WH}}
[[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: 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

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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