Delayed puberty laboratory findings

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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
Delayed puberty underlying diseases	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

• 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.

Template:WS Template:WH

[pmid19337023-1] 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.

[pmid26112575-2] 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.

[pmid23444474-3] 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.

[PalmertDunkel2012-4] 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.

[pmid120659302-5] 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.

[pmid12065930-6] 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.

[pmid24957008-7] 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.

[pmid17284632-8] 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.

[pmid20371659-9] 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.

[ImranPelkey2010-10] 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.

[pmid8421096-11] 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.

[pmid19017752-12] 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.

[pmid20826577-13] 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.

[pmid24397058-14] 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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