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      Serum inhibin B for differentiating between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty: a systematic review and meta-analysis

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          Abstract

          Purpose

          The distinction between congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) in patients with delayed puberty is difficult to distinguish, but important for timely treatment. The aim of this study is to perform a systematic review and meta-analysis to determine the diagnostic performance of serum inhibin B (INHB) levels for differentiating CHH and CDGP.

          Methods

          PubMed, EMBASE, and Cochrane Library databases were systematically searched from the date of database inception to November 10, 2019 for studies examining the use of serum INHB to discriminate between CHH and CDGP. Pooled odds ratios (OR), sensitivity, specificity, and 95% confidence intervals (CI) were calculated. The Quality Assessment of Diagnostic Studies-2 (QUADAS-2) was used to assess the quality of the included studies. Sub-analyses were performed including that based on testicular volume (TV) and study design.

          Results

          Seven studies, comprising of 349 patients (96 CHH and 253 CDGP), were included in the meta-analysis. For differentiating between CHH and CDGP, INHB level exhibited good diagnostic accuracy with a pooled sensitivity of 92% (95% confidence interval [CI]: 0.86–0.96, I 2 = 0.4%, p = 0.4343), specificity of 92% (95% CI: 0.88–0.94, I 2 = 68.1%, p = 0.0009), and pooled area under the receiver operating characteristic curve (AUC) of 0.9619. The cut-off values of INHB for boys were 56, 66, 80, 96, 94.7, 111, and 113 pg/ml (assay method standardized to Gen II ELISA). Sub-analyses showed that testicular volume and study design could be a source of statistically significant heterogeneity in specificity. In boys with a testicular volume of ≤3 ml, INHB performed well with a sensitivity of 92%, specificity of 98%, and AUC of 0.9956.

          Conclusion

          INHB exhibits excellent diagnostic efficiency in distinguishing CHH from CDGP, especially in boys with severe puberty deficiency (TV ≤ 3 ml).

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          QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

          Penny F Whiting, Anne Rutjes, Marie E Westwood … (2011)
          In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.
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            Meta-DiSc: a software for meta-analysis of test accuracy data

            Javier Zamora, Víctor Abraira, Alfonso Muriel … (2006)
            Background Systematic reviews and meta-analyses of test accuracy studies are increasingly being recognised as central in guiding clinical practice. However, there is currently no dedicated and comprehensive software for meta-analysis of diagnostic data. In this article, we present Meta-DiSc, a Windows-based, user-friendly, freely available (for academic use) software that we have developed, piloted, and validated to perform diagnostic meta-analysis. Results Meta-DiSc a) allows exploration of heterogeneity, with a variety of statistics including chi-square, I-squared and Spearman correlation tests, b) implements meta-regression techniques to explore the relationships between study characteristics and accuracy estimates, c) performs statistical pooling of sensitivities, specificities, likelihood ratios and diagnostic odds ratios using fixed and random effects models, both overall and in subgroups and d) produces high quality figures, including forest plots and summary receiver operating characteristic curves that can be exported for use in manuscripts for publication. All computational algorithms have been validated through comparison with different statistical tools and published meta-analyses. Meta-DiSc has a Graphical User Interface with roll-down menus, dialog boxes, and online help facilities. Conclusion Meta-DiSc is a comprehensive and dedicated test accuracy meta-analysis software. It has already been used and cited in several meta-analyses published in high-ranking journals. The software is publicly available at .
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              Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.

              Ulrich Boehm, Pierre-Marc Bouloux, Mehul Dattani … (2015)
              Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ∼50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ∼10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.
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                Author and article information

                Contributors
                Zhihong Liao:
                ORCID: http://orcid.org/0000-0003-1257-0767
                liaozhh@mail.sysu.edu.cn
                Journal
                Journal ID (nlm-ta): Endocrine
                Journal ID (iso-abbrev): Endocrine
                Title: Endocrine
                Publisher: Springer US (New York )
                ISSN (Print): 1355-008X
                ISSN (Electronic): 1559-0100
                Publication date (Electronic): 19 January 2021
                Publication date PMC-release: 19 January 2021
                Publication date (Print): 2021
                Volume: 72
                Issue: 3
                Pages: 633-643
                Affiliations
                GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Endocrinology and Metabolism, Hospital of Sun Yat-sen University, ; Guangzhou, Guangdong PR China
                Author information
                http://orcid.org/0000-0003-1257-0767
                Article
                Publisher ID: 2582
                DOI: 10.1007/s12020-020-02582-0
                PMC ID: 8159787
                PubMed ID: 33464540
                SO-VID: bbf89fc7-1687-45a3-af93-e711667d9279
                Copyright © © The Author(s) 2021
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 11 February 2020
                Date accepted : 1 December 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/http://dx.doi.org/10.13039/501100010843, Guangzhou Science, Technology and Innovation Commission;
                Award ID: 201604020090
                Award Recipient :
                Categories
                Subject: Meta- Analysis
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media, LLC, part of Springer Nature 2021

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: inhibin b,congenital hypogonadotropic hypogonadism,constitutional delay of growth and puberty,meta-analysis
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: inhibin b, congenital hypogonadotropic hypogonadism, constitutional delay of growth and puberty, meta-analysis

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