The differential diagnosis of constitutional delay of puberty and hypogonadotropic hypogonadism in boys

BACKGROUND. The problem of differential diagnosis of constitutional delay of puberty/CDP and hypogonadotropic hypogonadism/HH in boys is discussed, as boys have similar genetic mechanisms and appearance.

AIMS: to determine accuracy of the criteria for the differential diagnosis of CDP and HH.

MATERIALS. The study included 56 boys 14.4±0.7 years old with delayed puberty (G1P1-3/testicular volume <3 сm³). We excluded patients with hypergonadotropic hypogonadism, treated with sex steroids or gonadotropins for 12 months, with endocrine/somatic diseases affecting puberty. At the first visit, we evaluated anthropometric data, bone age, testicular volume, hormones and the results of the gonadotropin-releasing hormone test (GnRH) agonist test and the human chorionic gonadotropin test (hCG) test. The HH was defined by a testicular volume <3 сm³ after 2 years follow-up. The patients were divided into two groups: the first group with CDP and testicles ≥3 cm³ (n=50) and the second group with HH and testicles <3 cm³ (n=6).

RESULTS. At the first visit in boys with CDP corrected target height was less (Me SDS –1.8 vs –0,4, р=0.02), bone age was less (Ме SDS –2.5 vs –0.2 р=0.03), testicular volume was more (Ме 1.9 vs 0.5, p=0.0003), hormones were significantly higher, such as LH (Ме 1.1 vs 0.1 mIU/ml, p=0.0002), FSH (Ме 1.9 vs 0.2 IU/l, p=0.00007), inhibin B (Ме 142.3 vs 31.3 pg/ml, p=0.00009), max LH (Ме 18.9 vs 0.6 mIU/ml, p=0.00007), max LH/FSH (Ме 2.3 vs 0.4, p=0.0002) on the GnRH agonist test and Δ testosterone (Ме 14.4 vs 1.1 nmol/l, p=0.0001) on the hCG test than in boys with HH. The LH ≥0.3 mIU/ml had 86% sensitivity, 100% specificity; max LH/FSH ≥1 – 92% sensitivity, 100% specificity; Δ testosterone ≥2.7 nmol/l on the hCG test – 98% sensitivity, 100% specificity for differential diagnosis of CDP and HH in boys. However, max LH ≥3.5 mIU/ml on the GnRH agonist test, FSH ≥0.5 IU/l, inhibin B ≥58 pg/ml had 100% sensitivity and specificity for diagnosis of CDP.

CONCLUSIONS. The inhibin B ≥58 pg/ml, LH ≥0.3 mIU/ml, FSH ≥0.5 IU/l or max LH ≥3.5 mIU/ml, max LH/FSH ≥1,0 on the GnRH agonist test, Δ testosterone ≥2.7 nmol/l on the hCG test have an excellent accuracy for the differential diagnosis of CDP and HH in prepubertal boys with delayed puberty.

delayed puberty, hypogonadotropic hypogonadism, constitutional delay of puberty, inhibin B, chorionic gonadotropin, testosterone

1. Дедов И.И., Семичева Т.В., Петеркова В.А. Половое развитие детей: норма и патология. М.: Колор Ит Студио; 2002. Dedov II, Semicheva TV, Peterkova VA. Polovoe razvitie detei: norma i patologia. M.: Color It Studio; 2002. (In Russ.).

2. Шабалов Н.П., Лисс В.Л., Нагорная И.И. Диагностика и лечение эндокринных заболеваний у детей и подростков. Под ред. Шабалова Н.П. М.: МЕДпресс; 2002. Shabalov NV, Liss VL, Nagornaya II. Diagnostica i lechenie endokrinnuch zabolevanyi u detei i podrostkov. Ed by Shabalov N.V. M.: MEDpress; 2002. (In Russ.).

3. Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547-564. doi: https://doi.org/10.1038/nrendo.2015.112

4. Harrington J, Palmert MR. Clinical review: distinguishing constitutional delay of growth and puberty from isolated hypogonadotropichypogonadism: critical appraisal of available diagnostic tests. J Clin Endocrinol Metab. 2012;97(9):3056-3067. doi: https://doi.org/10.1210/jc.2012-1598

5. Varimo T, Miettinen PJ, Känsäkoski J, et al. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod. 2017;32(1): 147-153. doi: https://doi.org/10.1093/humrep/dew294

6. Coutant R, Biette-Demeneix E, Bouvattier C, et al. Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J Clin Endocrinol Metab. 2010;95(12):5225-5232. doi: https://doi.org/10.1210/jc.2010-1535

7. Rohayem J, Nieschlag E, Kliesch S, Zitzmann M. Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology. 2015;3(5):882-887. doi: https://doi.org/10.1111/andr.12088

8. Андрианова Е.А., Безлепкина О.Б., Васюкова О.В. и др. Федеральные клинические рекомендации (протоколы) по ведению детей с эндокринными заболеваниями. Под ред. Дедова И.И., Петерковой В.А. М.: Практика; 2014. Andrianova EA, Bezlepkina OB, Vasyukova OV i dr. Federal’nye klinicheskie rekomendatsii (protokoly) po vedeniy detei s endokrinnumi zabolevaniiami. Ed by Dedov I.I., Peterkova V.A. M.: Praktika; 2014. (In Russ.).

9. Binder G, Schweizer R, Blumenstock G, Braun R. Inhibin B plus LH vs GnRH agonist test for distinguish constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism in boys. Clin Endocrinol. 2015;82(1):100-105. doi: https://doi.org/10.1111/cen.12613

10. Дедов И.И., Тюльпаков А.Н., Петеркова В.А. Соматотропная недостаточность. М.: ИндексПринт; 1998. Dedov II, Tulpakov AN, Peterkova VA. Somatotropnaia nedostatochnost’. M.: IndexPrint; 1998. (In Russ.).

11. Sun QH, Zheng Y, Zhang XL, Mu YM. Role of gonadotropin-releasing hormone stimulation test in diagnosing gonadotropin deficiency in both males and females with delayed puberty. Chin Med J. 2015;128(18):2439-2443. doi: https://doi.org/10.4103/0366-6999.164926

12. Kauschansky A, Dickerman Z, Phillip M, et al. Use of GnRH agonist and human chorionic gonadotropin tests for differentiating constitutional delayed puberty from gonadotropin deficiency in boys. Clin Endocrinol (Oxf). 2002;56(5):603-607. doi: https://doi.org/10.1046/j.1365-2265.2002.01520.x

13. Martin MM, Martin AL. Constitutional delayed puberty in males and hypogonadotropic hypogonadism: a reliable and cost-effective approach to differential diagnosis. J Pediatr Endocrinol Metab. 2005;18(9):909-916. doi: https://doi.org/10.1515/jpem.2005.18.9.909

14. Segal TY, Mehta A, Anazodo A, et al. 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. 2009;94(3):780-785. doi: https://doi.org/10.1210/jc.2008-0302

15. Grinspon RP, Ropelato MG, Gottlieb S, et al. 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. 2010;95(6):2811-2818. doi: https://doi.org/10.1210/jc.2009-2732

16. Sequera AM, Fideleff HL, Boquete HR, et al. Basal ultrasensitive LH assay: a useful tool in the early diagnosis of male pubertal delay. J Pediatr Endocrinol Metab. 2002;15(5):589-596. doi: https://doi.org/10.1515/jpem.2002.15.5.589

17. Yazici M, Sahin M, Bolu EJ, et al. Prediction of testosterone response to human chorionic gonadotropin in isolated hypogonadotropic hypogonadism patients. J Natl Med Assoc. 2009;101(1):71-76. doi: https://doi.org/10.1016/s0027-9684(15)30814-2

18. Seminara SB, Hayes FJ, Crowley WF. Gonadotropin-releasing hormone deficiency in the human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann’s Syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998;19(5):521-539. doi: https://doi.org/10.1210/edrv.19.5.0344

19. Degros V, Cortet-Rudelli C, Soudan B, et al. The human chorionic gonadotropin test is more powerful than the gonadotropin-releasing hormone agonist test to discriminate male isolated hypogonadotropic hypogonadism from constitutional delayed puberty. Eur J Endocrinol. 2003;149(1):23-29. doi: https://doi.org/10.1530/eje.0.1490023

20. Odink RJ, Schoemaker J, Schoute E, et al. Predictive value of serum follicle-stimulating hormone levels in the differentiation between hypogonadotropic hypogonadism and constitutional delay of puberty. Hormone Research in Paediatrics. 1998;49:279-287. Horm Res. 1998;49(6):279-287. doi: https://doi.org/10.1159/000023187

21. Sukumar SP, Bhansali A, Sachdeva N, et al. Diagnostic utility of testosterone priming prior to dynamic tests to differentiate constitutional delay in puberty from isolated hypogonadotropic hypogonadism. Clin Endocrinol (Oxf). 2017;86(5):717-724. doi: https://doi.org/10.1111/cen.13321