Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2024 Jan 3;190(1):S1-S11.
doi: 10.1093/ejendo/lvad166.

Gonadotropins for pubertal induction in males with hypogonadotropic hypogonadism: systematic review and meta-analysis

Emma C Alexander  1 , Duaa Faruqi  2 , Robert Farquhar  2 , Ayesha Unadkat  2 , Kyla Ng Yin  1 , Rebecca Hoskyns  1 , Rachel Varughese  3 , Sasha R Howard  1   4
Affiliations
Meta-Analysis

Gonadotropins for pubertal induction in males with hypogonadotropic hypogonadism: systematic review and meta-analysis

Emma C Alexander et al. Eur J Endocrinol. .

Abstract

Objective: Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical treatment with testosterone promotes virilization but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for the achievement of pubertal outcomes in males with hypogonadotropic hypogonadism.

Design: Systematic review and meta-analysis.

Methods: A systematic review of Medline, Embase, Global Health, and PsycINFO databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomized Studies of Interventions/National Heart, Lung, and Blood Institute tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713).

Results: After screening 3925 abstracts, 103 studies were identified including 5328 patients from 21 countries. The average age of participants was <25 years in 45.6% (n = 47) of studies. Studies utilized human chorionic gonadotropin (hCG) (n = 93, 90.3% of studies), human menopausal gonadotropin (n = 42, 40.8%), follicle-stimulating hormone (FSH) (n = 37, 35.9%), and gonadotropin-releasing hormone (28.2% n = 29). The median reported duration of treatment/follow-up was 18 months (interquartile range 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size, and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% confidence interval [CI] 82%-91%) as compared with hCG alone (40%, 95% CI 25%-56%). However, study heterogeneity and treatment variability were high.

Conclusions: This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomized studies are needed.

Keywords: Kallmann syndrome; gonadotropins; hypogonadotropic hypogonadism; puberty; spermatogenesis.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors declare that there is there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

Figure 1.
Figure 1.
PRISMA flow diagram for study screening and selection.
Figure 2.
Figure 2.
Plot of pre- and post-treatment average testicular volumes after treatment with (A) hCG and (B) hCG + FSH. Bilateral volumes were halved for plotting, and all methods of measurement were included. IQR, interquartile range.
Figure 3.
Figure 3.
Plot of pre- and post-treatment average penile length after treatment with (A) hCG and (B) hCG + FSH.
Figure 4.
Figure 4.
Meta-analysis of proportions for spermatogenesis achieved by hCG + FSH in patients with hypogonadotropic hypogonadism—pooled proportion (random effect) 0.86 (95% CI 0.82-0.91). CI, confidence interval.
Figure 5.
Figure 5.
Percentage of patients experiencing key adverse effects: meta-analysis of proportions (with 95% confidence interval) using a random effects model. FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin.
See this image and copyright information in PMC

References

    1. Varimo T, Miettinen PJ, Känsäkoski J, Raivio T, Hero M. 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. 10.1093/humrep/dew294 - DOI - PubMed
    1. Swee DS, Quinton R. Congenital hypogonadotrophic hypogonadism: minipuberty and the case for neonatal diagnosis. Front Endocrinol (Lausanne). 2019;10:97. 10.3389/fendo.2019.00097 - DOI - PMC - PubMed
    1. Dodé C, Hardelin J-P. Kallmann syndrome. Eur J Hum Genet. 2009;17(2):139–146. 10.1038/ejhg.2008.206 - DOI - PMC - PubMed
    1. Salenave S, Trabado S, Maione L, Brailly-Tabard S, Young J. Male acquired hypogonadotropic hypogonadism: diagnosis and treatment. Ann Endocrinol (Paris). 2012;73(2):141–146. 10.1016/j.ando.2012.03.040 - DOI - PubMed
    1. Becker M, Hesse V. Minipuberty: why does it happen? Horm Res Paediatr. 2020;93(2):76–84. 10.1159/000508329 - DOI - PubMed