Abstract
Objectives
Urinary luteinizing hormone (uLH) and urinary follicle-stimulating hormone (uFSH) have been shown to be useful screening and management tools for children with central precocious puberty. However, studies on uLH and uFSH reference intervals are scarce. Therefore, we aimed to establish reference intervals for uLH and uFSH, according to age, sex, and pubertal status in apparently healthy children aged 6–11 years.
Methods
We performed detection capability, precision, accuracy by recovery, linearity, agreement analysis, and stability testing to analyze the method performance of uLH and uFSH. The Clinical Laboratory Standards Institute’s C28-A3 criteria was used to establish the reference intervals.
Results
Both uLH and uFSH were stable at 4 °C for 52.6 h and 64.8 days, respectively. The total imprecision of uFSH is within the manufacturer’s claim, while the total imprecision of uLH remained within tolerable bias. Both uLH and uFSH could be measured with acceptable detection capability. The recovery rates of the hormones were 87.6–98.8% and 102.8–103.4%, respectively, and therefore within acceptable limits. There were significant correlations between the serum and urine concentrations (LH: r=0.91, p<0.001; FSH: r=0.90, p<0.001). The reference intervals of uLH and uFSH were established according to age, sex, and pubertal status.
Conclusions
We established reference intervals for uLH and uFSH based on age, sex and pubertal status to provide a non-invasive clinical screening tool for precocious puberty in children aged 6–11 years.
Funding source: Key Research and Development Program of Zhejiang Province
Award Identifier / Grant number: 2020C03121
Acknowledgments
We thank Mark Cleasby, PhD from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the language of a draft of this manuscript.
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Research funding: This work was supported by the Key Research and Development Program of Zhejiang Province (2020C03121).
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Author contributions: CW and YY conceived and designed the study. MF and YZ participated in the physical examination and sample collecting. KY, YZ, and SM contributed to recording the baseline characteristics and sample transportation. DY, YH, and MD participated in the sample analysis and data collection. YY analyzed the data and drafted the manuscript. CW was responsible for supervision and funding acquisition. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and this study was approved by the Clinical Research Ethics Committee of the First Hospital of Zhejiang University School of Medicine (reference number: (2020) IIT (300)).
References
1. Bradley, SH, Lawrence, N, Steele, C, Mohamed, Z. Precocious puberty. Br Med J 2020;368:l6597. https://doi.org/10.1136/bmj.l6597.Search in Google Scholar
2. Latronico, AC, Brito, VN, Carel, JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol 2016;4:265–74. https://doi.org/10.1016/s2213-8587(15)00380-0.Search in Google Scholar
3. Carel, JC, Eugster, EA, Rogol, A, Ghizzoni, L, Palmert, MR, Antoniazzi, F, et al.. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123:e752–62. https://doi.org/10.1542/peds.2008-1783.Search in Google Scholar PubMed
4. Eckert, KL, Wilson, DM, Bachrach, LK, Anhalt, H, Habiby, RL, Olney, RC, et al.. A single-sample, subcutaneous gonadotropin-releasing hormone test for central precocious puberty. Pediatrics 1996;97:517–9. https://doi.org/10.1542/peds.97.4.517.Search in Google Scholar
5. Cheuiche, AV, da Silveira, LG, de Paula, LCP, Lucena, IRS, Silveiro, SP. Diagnosis and management of precocious sexual maturation: an updated review. Eur J Pediatr 2021;180:3073–87. https://doi.org/10.1007/s00431-021-04022-1.Search in Google Scholar PubMed
6. Penco, A, Bossini, B, Giangreco, M, Vidonis, V, Vittori, G, Grassi, N, et al.. Should pediatric endocrinologists consider more carefully when to perform a stimulation test? Front Endocrinol 2021;12: 660692. https://doi.org/10.3389/fendo.2021.660692.Search in Google Scholar PubMed PubMed Central
7. Brito, VN, Batista, MC, Borges, MF, Latronico, AC, Kohek, MB, Thirone, AC, et al.. Diagnostic value of fluorometric assays in the evaluation of precocious puberty. J Clin Endocrinol Metab 1999;84:3539–44. https://doi.org/10.1210/jcem.84.10.6024.Search in Google Scholar PubMed
8. Houk, CP, Kunselman, AR, Lee, PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls. Pediatrics 2009;123:e1059–63. https://doi.org/10.1542/peds.2008-1180.Search in Google Scholar PubMed
9. Pasternak, Y, Friger, M, Loewenthal, N, Haim, A, Hershkovitz, E. The utility of basal serum LH in prediction of central precocious puberty in girls. Eur J Endocrinol 2012;166:295–9. https://doi.org/10.1530/eje-11-0720.Search in Google Scholar PubMed
10. Resende, EA, Lara, BH, Reis, JD, Ferreira, BP, Pereira, GA, Borges, MF. Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children. J Clin Endocrinol Metab 2007;92:1424–9. https://doi.org/10.1210/jc.2006-1569.Search in Google Scholar PubMed
11. Demir, A, Voutilainen, R, Juul, A, Dunkel, L, Alfthan, H, Skakkebaek, NE, et al.. Increase in first morning voided urinary luteinizing hormone levels precedes the physical onset of puberty. J Clin Endocrinol Metab 1996;81:2963–7. https://doi.org/10.1210/jcem.81.8.8768859.Search in Google Scholar PubMed
12. Zung, A, Burundukov, E, Ulman, M, Glaser, T, Rosenberg, M, Chen, M, et al.. The diagnostic value of first-voided urinary LH compared with GNRH-stimulated gonadotropins in differentiating slowly progressive from rapidly progressive precocious puberty in girls. Eur J Endocrinol 2014;170:749–58. https://doi.org/10.1530/eje-14-0010.Search in Google Scholar
13. Kolby, N, Busch, AS, Aksglaede, L, Sørensen, K, Petersen, JH, Andersson, AM, et al.. Nocturnal urinary excretion of FSH and LH in children and adolescents with normal and early puberty. J Clin Endocrinol Metab 2017;102:3830–8. https://doi.org/10.1210/jc.2017-01192.Search in Google Scholar PubMed
14. Apter, D, Bützow, TL, Laughlin, GA, Yen, SS. Gonadotropin-releasing hormone pulse generator activity during pubertal transition in girls: pulsatile and diurnal patterns of circulating gonadotropins. J Clin Endocrinol Metab 1993;76:940–9. https://doi.org/10.1210/jc.76.4.940.Search in Google Scholar
15. Shim, YS, An, SH, Lee, HJ, Kang, MJ, Yang, S, Hwang, IT. Random urinary gonadotropins as a useful initial test for girls with central precocious puberty. Endocr J 2019;66:891–903. https://doi.org/10.1507/endocrj.ej19-0071.Search in Google Scholar PubMed
16. Ji, C, Ma, G, Zhang, L, Cheng, T, Ma, J, Li, Y, et al.. Screening for overweight and obesity among school-age children and adolescents. People’s Republic of China: National Health Commission; 2018.Search in Google Scholar
17. Marshall, WA, Tanner, JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303. https://doi.org/10.1136/adc.44.235.291.Search in Google Scholar PubMed PubMed Central
18. Marshall, WA, Tanner, JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23. https://doi.org/10.1136/adc.45.239.13.Search in Google Scholar PubMed PubMed Central
19. ClSI. Evaluation of detection capability for clinical laboratory measurement procedures; approved guideline—second edition. CLSI document EP17-A2 (ISBN 1-56238-795-2 [Print]; ISBN 1-56238-796-0 [Electronic]). 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA: Clinical and Laboratory Standards Institute; 2012.Search in Google Scholar
20. Aarsand, AK, Fernandez-Calle, P, Webster, C, Coskun, A, Gonzales-Lao, E, Diaz-Garzon, J, et al.. The EFLM biological variation database 2022. Available from: https://biologicalvariation.eu/[Accessed 11 May 2022].Search in Google Scholar
21. National Center for Clinical Laboratories (NCCL). 2022 external quality assessment programs in laboratory medicine [Internet]. Available from: https://www.nccl.org.cn/showEqaPlanProDetail?id=502.Search in Google Scholar
22. CLSI. Evaluation of precision performance of quantitative measurement methods; approved guideline—second edition. CLSI document EP5-A2 (ISBN 1-56238-542-9). 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA: CLSI; 2004.Search in Google Scholar
23. CNAS. Guidance on the verification of quantitative measurement procedures used in the clinical chemistry: China National Accreditation Service for Conformity Assessment; 2019.Search in Google Scholar
24. CLSI. Evaluation of the linearity of quantitative measurement procedures: a statistical approach; approved guideline. CLSI document EP6-A (ISBN 1-56238-498-8). 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA: CLSI; 2003.Search in Google Scholar
25. CLSI. Assessment of equivalence or suitability of specimen types for medical laboratory measurement procedures. 1st ed CLSI guideline EP35. Wayne, PA: Clinical and Laboratory Standards Institute; 2019.Search in Google Scholar
26. CLSI. Measurement procedure comparison and bias estimation using patient samples. Approved guideline, 3rd edn. CLSI document EP09-A3. Wayne, PA: Clinical Laboratory Standards Institute; 2013.Search in Google Scholar
27. Gómez-Rioja, R, Segovia Amaro, M, Diaz-Garzón, J, Bauçà, JM, Martínez Espartosa, D, Fernández-Calle, P. A protocol for testing the stability of biochemical analytes. Technical document. Clin Chem Lab Med 2019;57:1829–36.10.1515/cclm-2019-0586Search in Google Scholar PubMed
28. Pum, JKW. Evaluating sample stability in the clinical laboratory with the help of linear and non-linear regression analysis. Clin Chem Lab Med 2020;58:188–96. https://doi.org/10.1515/cclm-2019-0596.Search in Google Scholar PubMed
29. CLSI. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline—third edition. CLSI document C28-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.Search in Google Scholar
30. Harris, EK, Boyd, JC. Statistical bases of reference values in laboratory medicine. Boca Raton: CRC Press; 1995.10.1201/9781482273151Search in Google Scholar
31. Neely, EK, Hintz, RL, Wilson, DM, Lee, PA, Gautier, T, Argente, J, et al.. Normal ranges for immunochemiluminometric gonadotropin assays. J Pediatr 1995;127:40–6. https://doi.org/10.1016/s0022-3476(95)70254-7.Search in Google Scholar
32. Fitschen, W, Clayton, BE. Urinary excretion of gonadotrophins with particular reference to children. Arch Dis Child 1965;40:16–26. https://doi.org/10.1136/adc.40.209.16.Search in Google Scholar
33. Ma, Y, Xu, Z, Gu, G, Ren, F, Jin, H, Zhu, W. Effects of storage conditions on urinary LH and FSH measurement using immunochemiluminometric assay. Clin Lab 2018;64:877–82. https://doi.org/10.7754/Clin.Lab.2017.171011.Search in Google Scholar
34. Pan, XF, Wang, L, Pan, A. Epidemiology and determinants of obesity in China. Lancet Diabetes Endocrinol 2021;9:373–92. https://doi.org/10.1016/s2213-8587(21)00045-0.Search in Google Scholar
35. Chen, C, Zhang, Y, Sun, W, Chen, Y, Jiang, Y, Song, Y, et al.. Investigating the relationship between precocious puberty and obesity: a cross-sectional study in Shanghai. China 2017;7:e014004. https://doi.org/10.1136/bmjopen-2016-014004.Search in Google Scholar PubMed PubMed Central
36. Chen, S, Binns, CW, Zhang, Y. The importance of definition in diagnosing obesity: a review of studies of children in China. Asia Pac J Publ Health 2012;24:248–62. https://doi.org/10.1177/1010539512441617.Search in Google Scholar PubMed
37. Zhu, MQ, Fu, JF, Li, L, Gong, CX, Chen, SK. Epidemiologic study on current pubertal development in Chinese school-aged children. J Zhejiang Univ 2013;42:396.Search in Google Scholar
38. Liu, Y, Yu, T, Li, X, Pan, D, Lai, X, Chen, Y, et al.. Prevalence of precocious puberty among Chinese children: a school population-based study. Endocrine 2021;72:573–81. https://doi.org/10.1007/s12020-021-02630-3.Search in Google Scholar PubMed
39. Demir, A, Dunkel, L, Stenman, UH, Voutilainen, R. Age-related course of urinary gonadotropins in children. J Clin Endocrinol Metab 1995;80:1457–60. https://doi.org/10.1210/jcem.80.4.7714124.Search in Google Scholar PubMed
40. Zhan, S, Huang, K, Wu, W, Zhang, D, Liu, A, Dorazio, RM, et al.. The use of morning urinary gonadotropins and sex hormones in the management of early puberty in Chinese girls. J Clin Endocrinol Metab 2021;106:e4520–30. https://doi.org/10.1210/clinem/dgab448.Search in Google Scholar PubMed PubMed Central
41. Radicioni, A, Lenzi, A, Spaziani, M, Anzuini, A, Ruga, G, Papi, G, et al.. A multicenter evaluation of immunoassays for follicle-stimulating hormone, luteinizing hormone and testosterone: concordance, imprecision and reference values. J Endocrinol Invest 2013;36:739–44. https://doi.org/10.1007/bf03347112.Search in Google Scholar
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2022-0296).
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