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)

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Abstract

Introduction

Gender affirming hormone therapy (GAHT) is increasingly used by transgender individuals and leads to shifts in sex hormone levels. Skeletal muscle is highly responsive to hormone activity, with limited data on the effects of GAHT on different human tissues. Here, we present the protocol for the GAME study (the effects of Gender Affirming hormone therapy on skeletal Muscle training and Epigenetics), which aims to uncover the effects of GAHT on skeletal muscle ‘omic’ profiles (methylomics, transcriptomics, proteomics, metabolomics) and markers of skeletal muscle health and fitness.

Methods and analysis

This study is a prospective age-matched cohort study in transgender adults commencing GAHT (n=80) and age-matched individuals not commencing GAHT (n=80), conducted at Austin Health and Victoria University in Victoria, Australia. Assessments will take place prior to beginning GAHT and 6 and 12 months into therapies in adults commencing GAHT. Age-matched individuals will be assessed at the same time points. Assessments will be divided over three examination days, involving (1) aerobic fitness tests, (2) muscle strength assessments and (3) collection of blood and muscle samples, as well as body composition measurements. Standardised diets, fitness watches and questionnaires will be used to control for key confounders in analyses. Primary outcomes are changes in aerobic fitness and muscle strength, as well as changes in skeletal muscle DNA methylation and gene expression profiles. Secondary outcomes include changes in skeletal muscle characteristics, proteomics, body composition and blood markers. Linear mixed models will be used to assess changes in outcomes, while accounting for repeated measures within participants and adjusting for known confounders.

Ethics and dissemination

The Austin Health Human Research Ethics Committee (HREC) and Victoria University HREC granted approval for this study (HREC/77146/Austin-2021). Findings from this project will be published in open-access, peer-reviewed journals and presented to scientific and public audiences.

Trial registration number

ACTRN12621001415897; Pre-results.

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Most cited references 43

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Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study

M. Janssen, A Simon Pickard, Dominik Golicki … (2012)

Purpose The aim of this study was to assess the measurement properties of the 5-level classification system of the EQ-5D (5L), in comparison with the 3-level EQ-5D (3L). Methods Participants (n = 3,919) from six countries, including eight patient groups with chronic conditions (cardiovascular disease, respiratory disease, depression, diabetes, liver disease, personality disorders, arthritis, and stroke) and a student cohort, completed the 3L and 5L and, for most participants, also dimension-specific rating scales. The 3L and 5L were compared in terms of feasibility (missing values), redistribution properties, ceiling, discriminatory power, convergent validity, and known-groups validity. Results Missing values were on average 0.8 % for 5L and 1.3 % for 3L. In total, 2.9 % of responses were inconsistent between 5L and 3L. Redistribution from 3L to 5L using EQ dimension-specific rating scales as reference was validated for all 35 3L–5L-level combinations. For 5L, 683 unique health states were observed versus 124 for 3L. The ceiling was reduced from 20.2 % (3L) to 16.0 % (5L). Absolute discriminatory power (Shannon index) improved considerably with 5L (mean 1.87 for 5L versus 1.24 for 3L), and relative discriminatory power (Shannon Evenness index) improved slightly (mean 0.81 for 5L versus 0.78 for 3L). Convergent validity with WHO-5 was demonstrated and improved slightly with 5L. Known-groups validity was confirmed for both 5L and 3L. Conclusions The EQ-5D-5L appears to be a valid extension of the 3-level system which improves upon the measurement properties, reducing the ceiling while improving discriminatory power and establishing convergent and known-groups validity.

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A new predictive equation for resting energy expenditure in healthy individuals.

M. D. Mifflin, S T St Jeor, L A Hill … (1990)

A predictive equation for resting energy expenditure (REE) was derived from data from 498 healthy subjects, including females (n = 247) and males (n = 251), aged 19-78 y (45 +/- 14 y, mean +/- SD). Normal-weight (n = 264) and obese (n = 234) individuals were studied and REE was measured by indirect calorimetry. Multiple-regression analyses were employed to drive relationships between REE and weight, height, and age for both men and women (R2 = 0.71): REE = 9.99 x weight + 6.25 x height - 4.92 x age + 166 x sex (males, 1; females, 0) - 161. Simplification of this formula and separation by sex did not affect its predictive value: REE (males) = 10 x weight (kg) + 6.25 x height (cm) - 5 x age (y) + 5; REE (females) = 10 x weight (kg) + 6.25 x height (cm) - 5 x age (y) - 161. The inclusion of relative body weight and body-weight distribution did not significantly improve the predictive value of these equations. The Harris-Benedict Equations derived in 1919 overestimated measured REE by 5% (p less than 0.01). Fat-free mass (FFM) was the best single predictor of REE (R2 = 0.64): REE = 19.7 x FFM + 413. Weight also was closely correlated with REE (R2 = 0.56): REE = 15.1 x weight + 371.

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Is Open Access

Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance

David Handelsman, Angelica L Hirschberg, Stéphane Bermon (2018)

Abstract Elite athletic competitions have separate male and female events due to men’s physical advantages in strength, speed, and endurance so that a protected female category with objective entry criteria is required. Prior to puberty, there is no sex difference in circulating testosterone concentrations or athletic performance, but from puberty onward a clear sex difference in athletic performance emerges as circulating testosterone concentrations rise in men because testes produce 30 times more testosterone than before puberty with circulating testosterone exceeding 15-fold that of women at any age. There is a wide sex difference in circulating testosterone concentrations and a reproducible dose-response relationship between circulating testosterone and muscle mass and strength as well as circulating hemoglobin in both men and women. These dichotomies largely account for the sex differences in muscle mass and strength and circulating hemoglobin levels that result in at least an 8% to 12% ergogenic advantage in men. Suppression of elevated circulating testosterone of hyperandrogenic athletes results in negative effects on performance, which are reversed when suppression ceases. Based on the nonoverlapping, bimodal distribution of circulating testosterone concentration (measured by liquid chromatography–mass spectrometry)—and making an allowance for women with mild hyperandrogenism, notably women with polycystic ovary syndrome (who are overrepresented in elite athletics)—the appropriate eligibility criterion for female athletic events should be a circulating testosterone of <5.0 nmol/L. This would include all women other than those with untreated hyperandrogenic disorders of sexual development and noncompliant male-to-female transgender as well as testosterone-treated female-to-male transgender or androgen dopers.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2022

Publication date (Electronic): 10 May 2022

Volume: 12

Issue: 5

Electronic Location Identifier: e060869

Affiliations

[1 ]departmentInstitute for Health and Sport , Victoria University , Footscray, Victoria, Australia

[2 ]departmentTrans Health Research Group, Department of Medicine (Austin Health) , The University of Melbourne , Heidelberg, Victoria, Australia

[3 ]departmentDepartment of Endocrinology (Austin Health) , The University of Melbourne , Heidelberg, Victoria, Australia

[4 ]departmentPride in Sport , ACON Health , Surry Hills, New South Wales, Australia

Author notes

[Correspondence to ] Professor Nir Eynon; Nir.Eynon@ 123456vu.edu.au

AC and NE are joint senior authors.

Author information

Patrice R Jones http://orcid.org/0000-0002-4948-1445

Brendan J Nolan http://orcid.org/0000-0001-8836-165X

Alex Wong http://orcid.org/0000-0002-3666-5261

Article

Publisher ID: bmjopen-2022-060869

DOI: 10.1136/bmjopen-2022-060869

PMC ID: 9096568

PubMed ID: 35545400

SO-VID: f84e876d-7483-40e4-b3a5-2226be9191d2

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 12 January 2022

Date accepted : 28 April 2022

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ScienceOpen disciplines: Medicine

Keywords: sex steroids & hrt,sports medicine,molecular biology,genetics,clinical physiology

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ScienceOpen disciplines: Medicine

Keywords: sex steroids & hrt, sports medicine, molecular biology, genetics, clinical physiology

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)

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Chinese Journal of School Health

Most cited references 43

Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study

A new predictive equation for resting energy expenditure in healthy individuals.

Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance

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