Authors’ reply to a commentary on “Testosterone therapy in boys with constitutional delay of growth and puberty: a PubMed-based systematic review and exploratory meta-analysis”
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To the editor,
We thank Boltaboeva et al. for their thoughtful commentary [1] on our systematic review and exploratory meta-analysis [2] of testosterone therapy in boys with constitutional delay of growth and puberty (CDGP). We address each point raised below.
1. Genetic and familial factors
We agree these are biologically important. Across the 20 studies we reviewed, spanning 4 decades, none systematically reported family history or genotyped known self-limited-delayed-puberty loci (e.g., FGFR1, GNRHR, HS6ST1, IL17RD) [3]. This reflects a gap in the primary literature rather than in our synthesis methodology; because the variable was unreported at source, it could not be extracted as a moderator. We agree genetic and familial characterization is an unaddressed modifier of treatment response that future prospective studies should capture.
2. Nutritional, clinical, and socioeconomic factors
These variables were inconsistently reported across the included studies. Most nonrandomized cohorts were vulnerable to confounding by indication, and nutritional status, body composition, and chronic disease burden plausibly contribute to this same pathway. This limitation resides in the primary studies, most of which predate routine collection of these covariates, rather than in our review’s scope. Future controlled trials should prospectively record these covariates so their contribution to treatment response can be formally assessed.
3. Baseline HPG (hypothalamic-pituitary-gonadal)-axis hormonal profile (luteinizing hormone, follicle-stimulating hormone, sex steroids)
This is the most clinically important of the 4 points raised. Most included studies reported baseline gonadotropin and testosterone only to confirm a prepubertal or early-pubertal state at enrollment, not to stratify or predict treatment response. None used baseline luteinizing hormone, follicle-stimulating hormone, inhibin B, or anti-mullerian hormone to distinguish boys with self-limiting delay from those with evolving hypogonadotropic hypogonadism. We agree this is an important evidence gap that future trials, ideally combined with GnRH-stimulation testing, should address.
4. Short-term height velocity versus final adult height
This distinction was a central focus of our review rather than an omission. Our meta-analysis (pooled mean difference 2.40 cm/yr, 95% confidence interval 1.49–3.32; 2 controlled studies, 46 boys) was explicitly restricted to short-term height velocity and described as exploratory throughout. Separately, our narrative synthesis examined final and near-final adult-height outcomes across independent long-term follow-up studies included in our review (e.g., Martin et al. [4]; Dogan et al. [5]), which consistently found no clinically meaningful adverse effect of brief, low-dose testosterone on adult height, with the exception of Martin’s higher-dose regimen, which could compromise final height through accelerated epiphyseal maturation. As stated in our Discussion and Conclusion, a modern, adequately powered randomized trial with standardized long-term auxologic and bone-age follow-up to final height remains needed.
In conclusion, we thank Boltaboeva et al. [1] for highlighting genetic, nutritional, and baseline endocrine characterization as unaddressed modifiers of treatment response. These, alongside standardized long-term auxologic follow-up, should be incorporated as explicit design elements in the prospective, genotype- and phenotypestratified trial that our review calls for, to meaningfully advance individualized management of boys with CDGP.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.