Preview

Problems of Endocrinology

Advanced search

A new way for the differential diagnosis of hypogonadotropic hypogonadism and constitutional delay of puberty in adolescent men aged 13.5–17 years

https://doi.org/10.14341/probl13419

Abstract

BACKGROUND: Differential diagnosis of hypogonadotropic hypogonadism (HH) and constitutional delay of puberty (CDP) is extremely important since with the latter puberty begins and completes without any medical intervention and in the case of HH puberty does not occur or is incomplete. Failure to start treatment on time leads to medical and psychosocial maladjustment of the patient.
AIM: Development of a method for differential diagnosis of hypogonadotropic hypogonadism and constitutional delay of puberty in boys 13.5–17 years old by scoring the levels of LH, FSH, testosterone and inhibin B.
MATERIALS AND METHODS: The study group was formed by adolescent men 13.5–17 years old with delayed puberty including all observations. Anamnesis, stage of puberty, testicular volume were assessed; serum levels of LH, FSH, testosterone (T) were determined by chemiluminescent analysis and inhibin B, AMH by ELISA. Stimulation tests were performed with triptorelin and human chorionic gonadotropin (3 days). Patients were followed up for 6–24 months.
RESULTS: The study included adolescent men at the age of 13.5–17 years with delayed puberty: 56 for the purpose of development a method of differential diagnosis, 30 for its control (control group). We`ve created a method that allows differentiate HH and CDP. Through the ROC-analysis the most sensitive and specific HH markers were identified. The basal levels of LH, FSH, T, and inhibin B were selected as most available for outpatient testing. Based on the results of our own research and scientific data we selected ranges of values and rated LH, FSH, T and inhibin B depending on them (marks). Then we assigned the coefficients (k) for each hormone. Scores were calculated by multiplying the marks by k then summed and normalized to the maximum amount the patient could get. To increase the accuracy of diagnosis an age coefficient was introduced. The result of the calculation was the result of the scoring (S). S for CDP (10.65 [3.13–14.91]) differed significantly from that for HH (76.46 [57.79–83.74]) (p< 0.001). Diagnoses based on S (<21.16 and ≥55.07) in the control group were confirmed by follow up data in 97% cases. An algorithm for the differential diagnosis of HH and CDP by using S has been developed.
CONCLUSION: The result of scoring of LH, FSH, testosterone, inhibin B levels ≥55.07 makes it possible to diagnose hypogonadotropic hypogonadism, < 21.16 — constitutional delay of puberty with a high probability. In the case of score ≥21.16 but < 55.07, calculation of the inhibin B/AMH ratio and/or stimulation tests are required.

About the Authors

Y. L. Skorodok
Saint-Petersburg state pediatric medical university
Russian Federation

Yulia L. Skorodok, PhD, MD

Saint-Petersburg



I. Y. Ioffe
Saint-Petersburg state pediatric medical university
Russian Federation

Irina Y. Ioffe, MD

2 Litovskaya street, 194100, Saint-Peterburg



E. V. Plotnikova
Saint-Petersburg state pediatric medical university
Russian Federation

Elena V. Plotnikova, PhD, MD

Saint-Petersburg



I. I. Nagornaya
Saint-Petersburg state pediatric medical university
Russian Federation

Irena I. Nagornaya, PhD, MD

Saint-Petersburg



L. A. Zhelenina
Saint-Petersburg state pediatric medical university
Russian Federation

Liudmila A. Zhelenina, MD, PhD, Professor

Saint-Petersburg



A. V. Kozhevnikova
Saint-Petersburg state pediatric medical university
Russian Federation

Anzhelika V. Kozhevnikova, MD

Saint-Petersburg



References

1. Federal’nye klinicheskie rekomendacii (protokoly) po vedeniyu detej s endokrinnymi zabolevaniyami. Ed by Dedov II, Peterkova VA — Moscow: Praktika; 2014. (in Russ.)]

2. Palmert MR, Dunke, L. Delayed puberty. New England Journal of Medicine, 2012;366(5):443–453. doi: https://doi.org/10.1056/nejmcp1109290

3. Liss VL. Diagnostika i lechenie endokrinnyh zabolevanij u detej i podrostkov: uchebn. posobie. 6th ed. Shabalov NP. ed. Moscow: MEDpress–inform; 2022 (In Russ.)

4. Kalinichenko NYU, Chugunov IS, Rajgorodskaya NYU et al. Gipogonadizm u detej i podrostkov. Klinicheskie rekomendacii. Moscow; 2021, 56 p. (In Russ.)] Available from: https://library.mededtech.ru/rest/documents/klinrekti_gipogonadiz/#table_u3urm7

5. Raivio T, Miettinen PJ. Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: Genetics, management and updates. Best Pract Res Clin Endocrinol Metab. 2019;33(3):101316. doi: https://doi.org/10.1016/j.beem.2019.101316

6. Babenko AYU. Age-related androgen deficiency: at the peak of controversy. Russkij medicinskij zhurnal. Medicinskoe obozrenie. 2019; 3(10):II pp. 92–95 (In Russ.)

7. Butler G, Purushothaman P. Delayed puberty. Minerva Pediatrica, 2021;72(6). doi: https://doi.org/10.23736/s0026-4946.20.05968-x

8. Gaudino R, De Filippo G, Bozzola E, et al. Current clinical management of constitutional delay of growth and puberty. Ital J Pediatr. 2022. doi: https://doi.org/10.1186/s13052-022-01242-5

9. 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. doi: https://doi.org/10.1038/nrendo.2015.112

10. Latyshev OY, et al. The differential diagnosis of constitutional delay of puberty and hypogonadotropic hypogonadism in boys. Problems of Endocrinology [Preprint] (In Russ.)]. doi: https://doi.org/10.14341/probl10339

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

12. Hafez M, El Dayem SMA, El Mougy F, et al. The role of anti-Mullerian and inhibin B hormones in the evaluation of 46,XY disorders of sex development. J Pediatr Endocrinol Metab. 2014;27(9-10). doi: https://doi.org/10.1515/jpem-2013-0355

13. 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

14. Berman RE, Kligman RM, Dzhenson HB. Pediatriya po Nel’sonu. Baranova AA. editor, Moscow: Rid Elsiver (in Russ.); 2009; 2; 992 p.

15. Grinspon RP, Rey RA. Anti-müllerian hormone and sertoli cell function in paediatric male hypogonadism. Horm Res Paediatr. 2010. doi: https://doi.org/10.1159/000277140

16. Andersson A-M, Juul A, Petersen JH, Mller J, Groome NP, Skakkebæk NE. Serum Inhibin B in Healthy Pubertal and Adolescent Boys: Relation to Age, Stage of Puberty, and FollicleStimulating Hormone, Luteinizing Hormone, Testosterone, and Estradiol Levels1. J Clin Endocrinol Metab. 1997;82(12):3976-3981. doi: https://doi.org/10.1210/jcem.82.12.4449

17. Rosstat [internet] Population of St. Petersburg according to the results of the All-Russian Population Census 2020 [cited 2021 Mar 2]. Available from: https://78.rosstat.gov.ru/folder/27595

18. Sequera AM, Fideleff HL, Boquete HR, Pujol AB, Suárez MG, Ruibal GF. Basal ultrasensitive LH assay: A useful tool in the early diagnosis of male pubertal delay? J Pediatr Endocrinol Metab. 2002. doi: https://doi.org/10.1515/JPEM.2002.15.5.589

19. Trabado S, Maione L, Bry-Gauillard H, et al. Insulin-like Peptide 3 (INSL3) in Men With Congenital Hypogonadotropic Hypogonadism/Kallmann Syndrome and Effects of Different Modalities of Hormonal Treatment: A Single-Center Study of 281 Patients. J Clin Endocrinol Metab. 2014;99(2):E268-E275. doi: https://doi.org/10.1210/jc.2013-2288

20. Gao Y, Du Q, Liu L, Liao Z. Serum inhibin B for differentiating between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty: a systematic review and meta-analysis. Endocrine. 2021. doi: https://doi.org/10.1007/s12020-020-02582-0


Supplementary files

1. Figure 1. Scoring result in patients with hypogonadotropic hypogonadism and constitutional delay of sexual development.
Subject
Type Исследовательские инструменты
View (176KB)    
Indexing metadata ▾
2. Figure 2. Sensitivity and specificity of the threshold values of the scoring result in relation to hypogonadotropic hypogonadism.
Subject
Type Исследовательские инструменты
View (230KB)    
Indexing metadata ▾
3. Figure 3. ROC curve characterizing the reliability of the diagnosis of hypogonadotropic hypogonadism based on the scoring result.
Subject
Type Исследовательские инструменты
View (178KB)    
Indexing metadata ▾
4. Figure 4. Algorithm for differential diagnostics of hypogonadotropic hypogonadism and constitutional delay of sexual development using a scoring system (S is the result of the scoring system, T is testosterone, T (FPT3) is testosterone stimulated by a triple administration of human chorionic gonadotropin, HG is hypogonadotropic hypogonadism, CPPD is constitutional delay of sexual development).
Subject
Type Исследовательские инструменты
View (819KB)    
Indexing metadata ▾

Review

For citations:


Skorodok Y.L., Ioffe I.Y., Plotnikova E.V., Nagornaya I.I., Zhelenina L.A., Kozhevnikova A.V. A new way for the differential diagnosis of hypogonadotropic hypogonadism and constitutional delay of puberty in adolescent men aged 13.5–17 years. Problems of Endocrinology. 2024;70(6):106-117. (In Russ.) https://doi.org/10.14341/probl13419

Views: 599


ISSN 0375-9660 (Print)
ISSN 2308-1430 (Online)