Uncovering the effects of gender affirming hormone therapy on skeletal muscle and epigenetics: protocol for a prospective matched cohort study in transgender individuals (the GAME study)

Jones, Patrice; Voisin, Sarah; Nolan, Brendan J; Landen, Shanie; Michaux, Jacques; Newell, Beau; Zwickl, Sav; Cook, Teddy; Wong, Alex Fang Qi; Palmer, Andrew S.; Garnham, Andrew; Alvarez-Romero, Javier; Mohandas, Namitha; Seale, Kirsten; Cheung, Ada S; Eynon, Nir

doi:10.1136/bmjopen-2022-060869

Cited by 8 publications

(6 citation statements)

References 43 publications

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“…Our understanding of the impact of GAHT on physical performance is based on retrospective data with no prospective longitudinal controlled studies. Further research is underway ( 125 ).…”

Section: Discussionmentioning

confidence: 99%

The Impact of Gender-Affirming Hormone Therapy on Physical Performance

Cheung

Zwickl

Miller³

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context The inclusion of transgender people in elite sport has been a topic of debate. This narrative review examines the impact of gender affirming hormone therapy (GAHT) on physical performance, muscle strength and markers of endurance. Evidence Acquisition MEDLINE and Embase were searched using terms to define the population (transgender), intervention (GAHT) and physical performance outcomes. Evidence Synthesis Existing literature is comprised of cross-sectional or small uncontrolled longitudinal studies of short duration. In non-athletic trans men starting testosterone therapy, within 1 year, muscle mass and strength increased, and by 3 years, physical performance (push-ups, sit-ups, run time) improved to the level of cisgender men. In non-athletic trans women, feminising hormone therapy increased fat mass by approximately 30% and decreased muscle mass by approximately 5% after 12 months and steadily declined beyond 3 years. Whilst absolute lean mass remains higher in trans women, relative percentage lean mass and fat mass (and muscle strength corrected for lean mass), hemoglobin and VO2 peak corrected for weight was no different to cisgender women. After 2 years of GAHT, no advantage was observed for physical performance measured by running time or in trans women. By 4 years, there was no advantage in sit-ups. Whilst push-ups performance declined in trans women, a statistical advantage remained relative to cisgender women. Conclusions Limited evidence suggests that physical performance of non-athletic trans people who have undergone GAHT for at least 2 years approaches that of cisgender controls. Further controlled longitudinal research is needed in trans athletes and non-athletes.

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“…Our understanding of the impact of GAHT on physical performance is based on retrospective data with no prospective longitudinal controlled studies. Further research is underway ( 125 ).…”

Section: Discussionmentioning

confidence: 99%

The Impact of Gender-Affirming Hormone Therapy on Physical Performance

Cheung

Zwickl

Miller³

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…Thus, a variety of tissues are affected primarily and secondarily during puberty onset. Interestingly, using hormonal therapy for gender transitioning can also lead to epigenetic modifications of a variety of cells [103] and is being investigated in tissues [129]. Therefore, the onset of puberty leads to a variety of epigenetic modifications to both prepare for reproductive activities and also the growth and maturation that occurs during the post-puberty adolescent period.…”

Section: During Puberty and Gender Transitioningmentioning

confidence: 99%

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

Hart

2024

IJMS

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For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45–50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic “modification-demodification-remodification” paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause.

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“…Of relevance is a well-controlled prospective matched cohort study (the GAME Study) just commenced by the authors that aim to address this limitation and examine a wider range of performance and muscle measures. 107 Further, it is notable for highlighting that no studies exist comparing fitness and performance measures between trans individuals who commenced before and after the onset of puberty, and the related effects of puberty blockers; this is an area of future research, given recent policies made by FINA to exclude trans people from competing in elite competitions, unless they began GAHT pre-puberty, 20 it is of interest to understand the effects of puberty blockers on measures of sports performance. Importantly, most studies have been conducted in untrained trans cohorts, with it was unclear whether findings are generalizable to athletes.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Implications of gender-affirming endocrine care for sports participation

Moreland

Cheung

Hiam

et al. 2023

Therapeutic Advances in Endocrinology

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Many transgender (trans) individuals utilize gender-affirming hormone therapy (GAHT) to promote changes in secondary sex characteristics to affirm their gender. Participation rates of trans people in sport are exceedingly low, yet given high rates of depression and increased cardiovascular risk, the potential benefits of sports participation are great. In this review, we provide an overview of the evidence surrounding the effects of GAHT on multiple performance-related phenotypes, as well as current limitations. Whilst data is clear that there are differences between males and females, there is a lack of quality evidence assessing the impact of GAHT on athletic performance. Twelve months of GAHT leads to testosterone concentrations that align with reference ranges of the affirmed gender. Feminizing GAHT in trans women increases fat mass and decreases lean mass, with opposite effects observed in trans men with masculinizing GAHT. In trans men, an increase in muscle strength and athletic performance is observed. In trans women, muscle strength is shown to decrease or not change following 12 months of GAHT. Haemoglobin, a measure of oxygen transport, changes to that of the affirmed gender within 6 months of GAHT, with very limited data to suggest possible reductions in maximal oxygen uptake as a result of feminizing GAHT. Current limitations of this field include a lack of long-term studies, adequate group comparisons and adjustment for confounding factors (e.g. height and lean body mass), and small sample sizes. There also remains limited data on endurance, cardiac or respiratory function, with further longitudinal studies on GAHT needed to address current limitations and provide more robust data to inform inclusive and fair sporting programmes, policies and guidelines.

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Uncovering the effects of gender affirming hormone therapy on skeletal muscle and epigenetics: protocol for a prospective matched cohort study in transgender individuals (the GAME study)

Cited by 8 publications

References 43 publications

The Impact of Gender-Affirming Hormone Therapy on Physical Performance

The Impact of Gender-Affirming Hormone Therapy on Physical Performance

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

Implications of gender-affirming endocrine care for sports participation

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