Testosterone and androgen receptors in females: what is possible with resistance training?

Endogenous testosterone, a sex steroid hormone, is 10–15 times lower in females than adult males, and its anabolic effects via interaction with androgen receptors underpin many of the profound sex differences in human physical performance (Handelsman et al., 2018; Senefeld et al., 2019). Its anabolic effects on both anatomy and physiology explain why pubescent and adult males are stronger, more powerful and faster over long and short distances than females of similar age, training and talent (Hunter & Senefeld, 2024; Hunter et al., 2023; Senefeld & Hunter, 2024). The sex differences in physical performance widen dramatically during puberty with the rise of endogenous testosterone in young males (Senefeld et al., 2019). In females, the anabolic effect of high levels of exogenous testosterone administered at levels above female physiological ranges is evidenced with the increased muscle mass and performance in several scenarios. These include the increase in muscle mass, strength and power after gender-affirming hormone therapy in transgender men (female-to-man) (Harper et al., 2021; Roberts et al., 2021); experimental studies conducted in females even after 10 weeks of testosterone treatment (Hirschberg et al., 2020); and state-wide doping initiatives among elite athletes (Franke & Berendonk, 1997). Little is known, however, about the effects of the relatively low physiological levels of endogenous testosterone, which vary between females, on their muscle mass and strength, nor in response to exercise training (Alexander et al., 2022). Although most circulating testosterone is bound to carrier proteins (e.g. sex hormone-binding globulin) and thus biologically inactive, a small fraction (∼1–3%) is free (unbound) and thus bioavailable (Alexander et al., 2022). Free testosterone is measured as the ratio of total testosterone to sex hormone-binding globulin (free androgen index) and as quantified in a highlighted study in this issue of The Journal of Physiology by Alexander et al. (2024). Furthermore, the content and activation of the androgen receptor, which is ubiquitous in skeletal muscle, might be important in anabolic effects of endogenous testosterone in females, although little is known. This is the setting for the unique and timely study conducted by Alexander et al. (2024) addressing endogenous testosterone concentrations and the role of the androgen receptor in muscle mass and strength in young premenopausal females. Notably, this study is refreshing in its attention to female physiology and the response to exercise. This thorough and translational study comes at a time when experimental studies in biomedical sciences and exercise physiology in the laboratory setting on females are still relatively few compared with those on males (Cowan et al., 2023; James et al., 2023; O'Halloran, 2020). In this context, Alexander et al. (2024) aimed to understand whether the muscle mass and strength of the quadriceps muscle in young premenopausal females was related to: (i) total testosterone and/or bioavailable concentrations of testosterone; and (ii) androgen receptor content and activation, before and in response to 12 weeks of resistance training. The authors adopted the difficult integrative approach of conducting both in vivo whole-body and whole-limb experiments and in vitro experiments on primary myocytes derived from muscle biopsies. The findings are intriguing. At baseline (before training), testosterone concentrations varied among females between 1.1 and 3.1 nmol l−1 (mean of 2.0 ± 0.6 nmol l−1). However, both bound and bioavailable testosterone were not associated with baseline muscle mass or any measure of performance including strength and power in the young females, despite previous studies (see Alexander et al., 2022) showing weak associations with bioavailable testosterone. Thus, the low concentration of testosterone within the physiological range of females might not be a significant predictor of muscle mass and performance, although these findings do not negate the anabolic effects of testosterone at higher concentrations in females. There is likely to be a sigmoidal relationship between testosterone and the anabolic effect on skeletal muscle (Hunter & Senefeld, 2024). There were several notable insights from the 12 weeks of resistance training. First, after training (and as expected), primary measures of strength increased markedly by 27% and power by 13%. Thigh muscle cross-sectional area increased by 5.9% and was accompanied by an increase in some molecular markers of protein synthesis (Akt protein by 13%) but not others, including mTOR complex 1 signalling, which is involved with skeletal muscle hypertrophy, at least in the skeletal muscle of males (Roberts et al., 2023). Second, although there was no increase in testosterone (bound or free) after the 12 weeks of resistance training in the female participants, the fraction of bioavailable free testosterone prior to training was positively related to muscle hypertrophy in the leg muscles with training. Thus, this study sheds light onto the regulatory role of the anabolic response of female skeletal muscle with training, which appears to be dependent on the small fraction of bioavailable testosterone, although, given the small effect sizes, the extent/degree of this regulatory role requires further investigation. The findings on the role of the androgen receptor, content and activation were more complex. The in vitro experiments on cultured muscle cells confirmed a rapid growth of androgen receptor protein content and localization of androgen receptor to the nucleus within 24 h of testosterone treatment of female muscle myocytes, as has also been shown in muscle fibres from young males (Sinha-Hikim et al., 2004). However, in contrast to males, the androgen receptor protein content was negatively associated with muscle cross-sectional area in females prior to training, although this association was not maintained after resistance training. Along with findings from a recent study (Hatt et al., 2024), these data suggest sex-specific differences in the regulation of androgen receptors in skeletal muscle. Notably, Alexander et al. (2024) set the scene for many additional studies about the regulatory role of sex steroid hormones and receptors on skeletal muscle with exercise, particularly in older women, who are vulnerable to age-related loss of muscle mass. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. Sole author. None.