Content of review 1, reviewed on April 10, 2023

This is a well written paper that examines a clear question of how testosterone therapy as GAHT impacts bone health after GnRH agonist treatment. A mouse model is used to mimic typical treatment provided to trans boys with GnRH agonist therapy initiated at onset of early puberty followed by testosterone therapy given at either early puberty or late puberty. This is a clinically relevant question, that is difficult to answer in humans and as such, this study is a valuable addition to the literature. It is reassuring to clinicians and patients-alike to see that subsequent testosterone therapy after GnRHa reverses deleterious effects of GnRHa alone on body composition and bone, and this should be highlighted in the conclusion.

The introduction provides a well developed rationale with clear aims. Materials and methods are clearly outlined.

Major comments:
1. I would suggest outlining the hypotheses for each aim more clearly. Results paragraph 1: Move the hypothesis and aim to the introduction rather than in the results section.
2. There should also be further explanations of the limitations of extrapolating rodent bone studies to humans; particularly the continued longitudinal bone growth and lack of intracortical remodeling cand how these factors may affect the bone and be considered when thinking about translation to humans.
3. Conclusions: I would recommend revising the conclusion. It is stated that “this model provides future opportunities to study the effects of GnRHa and GAH on other tissues and aspects of physiology”. What in particular? I would recommend adding a conclusion outlining the clinical inferences of your findings. Should we be unconcerned about bone health in trans boys? Should we endeavour to not delay GAH after GnRHa if deemed clinically appropriate?

Minor comments relate to presentation:
Title: Change "testosteron" to "testosterone"
Abstract sentence 1: Change “presents” to “present”. i.e. “Transgender young increasingly present at paediatric gender services”
Introduction paragraph 2: add the word “few” i.e. “In the last few decades,” or change “decades” to “decade”.

Otherwise this is a clinically relevant preclinical study which is informative for those treating trans youth.

Source

    © 2023 the Reviewer.

Content of review 2, reviewed on April 26, 2023

The authors have addressed all comments adequately and have improved the manuscript.

Source

    © 2023 the Reviewer.

References

    Vanessa, D., Silvia, C., Stefanie, D., Sarah, E. K., Vera, S., Ri, K. N., Karel, D., Jolien, V. D., Roger, V., Christa, M., Leen, A., Brigitte, D., Geert, C., Frank, C., Martine, C., Dirk, V. 2023. Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys. Journal of Bone and Mineral Research.