Sports Medicine (2019) 49:1637–1650

https://doi.org/10.1007/s40279-019-01132-7

REVIEW ARTICLE

Resistance Training and Skeletal Muscle Protein Metabolism

in Eumenorrheic Females: Implications for Researchers
and Practitioners
Olivia E. Knowles1 · Brad Aisbett1 · Luana C. Main1 · Eric J. Drinkwater2 · Liliana Orellana3 · Séverine Lamon1

Published online: 12 June 2019

© Springer Nature Switzerland AG 2019

Abstract
Resistance training is essential for health and performance and confers many benefits such as increasing skeletal muscle
mass, increasing strength and power output, and improving metabolic health. Resistance training is a major component of
the physical activity guidelines, yet research in female populations is limited. Recent increases in the promotion of, and the
participation by, females in sport and exercise, highlight the need for an increase in understanding of evidence-based best
practice exercise prescription for females. The aim of this review is to provide an overview of the current research regarding
resistance training performance and skeletal muscle adaptation in females, with a focus on the hormonal variables that may
influence resistance training outcomes. Findings suggest that the menstrual cycle phase may impact strength, but not skeletal
muscle protein metabolism. In comparison, oral contraception use in females may reduce skeletal muscle protein synthesis,
but not strength outcomes, when compared to non-users. Future research should investigate the role of resistance training in
the maintenance of skeletal muscle protein metabolism during pregnancy, menopause and in athletes experiencing relative
energy deficiency in sport. The review concludes with recommendations for researchers to assist them in the inclusion of
female participants in resistance training research specifically, with commentary on the most appropriate methods of control-
ling for, or understanding the implications of, hormonal fluctuations. For practitioners, the current evidence suggests possible
resistance training practices that could optimise performance outcomes in females, although further research is warranted.

1 Introduction
Key Points
The increasing development of and investment in women’s
Females performing resistance training achieve similar
professional sporting leagues represents an important plat-
relative strength and hypertrophy gains compared to
form for promoting physical activity and exercise in the
males and may be able to optimise performance or mus-
female population [1, 2]. However, research that informs
cle adaptation by emphasising training frequency during
practitioners of best-practice methods for maximising
the follicular phase of the menstrual cycle, or with com-
exercise performance and training adaptation in females
bined strength/power training throughout the cycle.
is limited. In the top-ranked ‘sport science’ category jour-
nals, 39% of study participants are female, but only 4–13% The oral contraceptive pill, but not the menstrual cycle,
of participant groups in original research are made up of may negatively influence skeletal muscle protein turno-
ver in response to resistance training. Further evidence
is needed to determine the influence of endogenous and
* Séverine Lamon
[email protected] exogenous estrogen, and other key hormones, on resist-
ance training outcomes in young females.
1
Institute for Physical Activity and Nutrition, School
of Exercise and Nutrition Sciences, Deakin University, 221 Researchers are encouraged to include female cohorts in
Burwood Highway, Geelong, Burwood, VIC 3125, Australia resistance training research, and a number of strategies
2
Centre for Sport Research, School of Exercise and Nutrition could be employed to ensure they investigate a homog-
Sciences, Deakin University, Geelong, VIC, Australia enous cohort or control for potentially confounding
3
Biostatistics Unit, Faculty of Health, Deakin University, variables.
Geelong, VIC, Australia

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1638 O. E. Knowles et al.

females only [3]. This suggests that a large proportion of and skeletal muscle adaptations that result from resistance
the exercise prescription information for females is based on training in females. Thereafter, the unique variables that
research conducted in males. Hence, there is a need to better may influence resistance training outcomes in females are
understand the exercise and training outcomes for physically discussed. Finally, a summary of the practical implications
active females and female athlete populations [3, 4]. Under- for researchers conducting resistance training studies with
standing the outcomes of exercise for females is critical for female cohorts, and for practitioners training female clients
exercise professionals and coaches to appropriately prescribe or athletes, is presented.
training. The ability to implement exercise training inter-
ventions that are specifically designed to optimise females’
performance and health will transform the sport and health 2 Sex Differences in Resistance Training
sector with an evidence-based approach for females aspiring Performance and Skeletal Muscle
to reach fitness and health goals. Adaptation
Resistance training is a critical component of an athlete’s
training programme to improve skeletal muscle strength and As in many aspects of sport performance, sex differences
power, reduce the likelihood of injury and rehabilitate any exist in muscle strength and adaptation to resistance training.
injuries [5]. Further, the idea that ‘resistance training is med- Males demonstrate up to 157% greater relative upper and
icine’ is now well established [6], with recent high-impact 60% greater relative lower body strength, respectively, than
reviews highlighting the benefits of resistance training for females in resistance exercise tests such as one repetition
increasing skeletal muscle mass [7] and reversing skeletal maximum (1 RM) testing [17]. Females also demonstrate
muscle loss [8], reducing body fat [9], improving cardiovas- 73% greater relative lower body strength compared to their
cular [10], metabolic [11] and mental [12] health, and pro- upper body strength, yet this difference in relative muscle
moting physical function and strength [13]. The maintenance group strength is not observed in males [17]. In contrast,
of skeletal muscle mass preserves or improves the health females demonstrate approximately twofold lower muscle
and functional capacity of skeletal muscle. Skeletal muscle fatigability [18]. Studies that have tested relative strength at
cells are made up of ~ 80% proteins [14, 15] and skeletal 20–70% of maximum voluntary contraction report 46–87%
muscle mass is regulated by the balance between the rate of greater fatigue resistance in females in comparison to males
protein synthesis and the rate of protein degradation in the [19]. However, the advantage females hold over males in fat-
muscle [15]. Resistance exercise stimulates contraction- and igability may dissipate at intensities beyond 80% 1 RM [19].
hormone-induced signalling pathways that upregulate skel- Additionally, females training at the same relative workload
etal muscle protein synthesis in the cell [7]. Acute increases (i.e. an equal volume at a given percent of 1 RM) as males
in muscle protein synthesis after resistance exercise translate need less recovery time for force return both immediately
to the adaptive hypertrophic response to long-term resistance post-exercise and over 24 h [18, 20, 21]. These differences
training [16]. Therefore, skeletal muscle protein metabolism may be explained by sex-specific lean body mass distribu-
underpins the benefits of resistance training in improving tion, or by the greater proportion of type I muscle fibres in
short- and long-term health and performance. females that are more resistant to fatigue than type IIa and
The relationship between resistance training and skeletal IIx muscle fibres [22].
muscle adaptation has received substantially less attention While various sex differences exist in skeletal muscle
in females than in males. This relative lack of research in strength and structure, several established resistance training
females is mostly owing to researchers’ reluctance to account methods for increasing muscle strength and hypertrophy are
for the additional variability in dependent variables that is equally valid for both males and females. In trained males
created by factors that are unique to females, such as the and females, multiple-set training is superior to single-set
menstrual cycle, pregnancy, breastfeeding, hormonal con- training [23, 24] and exercise sequence dictates the volume
traceptives, or menopause [4]. However, it is the complex- load output for each exercise performed in a training ses-
ity of the female biological and physiological systems that sion [25, 26]. It follows that the relative performance adap-
makes research in this population so important. Researchers tation (e.g. relative increased maximal strength output) to
need to understand the interplay between these systems and long-term resistance training is similar between males and
decide how best to account for their interaction in their study females performing the same resistance training protocols.
designs so they can accurately forecast training implications With up to 20 weeks of the same resistance training proto-
for the wider female exercise community [4]. Therefore, the col, relative percentage strength increases from baseline are
aim of this review is to outline key considerations for resist- similar in males and females [27–29], and sometimes up to
ance training research conducted with females. The review 10% greater in females [30, 31]. Nevertheless, while males
first presents a brief overview of the performance outcomes
Resistance Training and Skeletal Muscle Protein Metabolism in Females 1639

and females may respond similarly to resistance training 3 Hormonal Factors Influencing
protocols for developing strength, albeit females at a lower the Resistance Training Response
absolute load, there may be optimal training approaches to and Adaptation in Females
maximise performance adaptations in females [32, 33].
Understanding how females can most effectively make The hormonal environment, both basal and exercise induced,
improvements in strength is not only relevant to health and is one of several key mechanisms for resistance training
performance, but also to certain occupational circumstances adaptation. A bout of resistance exercise triggers the secre-
whereby a minimum standard must be met, e.g. strength tion of specific hormones, which engage with their recep-
requirements for military personnel. Females performing tors on or within the target cell [44]. These ligand-receptor
combined strength and power training may make greater interactions initiate a cascade of events, leading to specific
relative improvements compared with their male counter- physiological outcomes such as an increase in muscle pro-
parts as judged in multi-joint exercises such as the 1-RM tein synthesis [44]. The following sections discuss how
squat, 1-RM bench press, and 1-RM high pull, when com- hormones, both endogenous and exogenous (e.g. hormonal
pared with six months of combined strength and hypertrophy contraceptives), may affect skeletal muscle protein metabo-
training [32]. Low-volume high-intensity training, typical of lism and adaptation to training.
strength or power but not hypertrophy training, may there-
fore be most suitable for strength adaptations in female par- 3.1 Endogenous Sex Hormones and the Menstrual
ticipants [32]. Certainly, there may be an upper threshold Cycle in Young Females
for the volume of resistance training (i.e. sets per muscle
group) performed by trained females to achieve optimal Estrogens and androgens are groups of endogenous sex hor-
muscle hypertrophy and strength gains [33]. Some authors mones that are produced by both males and females [44].
have proposed that females may have a greater capacity for Testosterone is the most abundant androgen hormone [45].
neural adaptations over hypertrophic adaptations [34–36], By binding the androgen receptor at the surface of the mus-
which could explain these findings. While neural adapta- cle fibre, testosterone increases intracellular calcium release
tions are beyond the scope of this review, it is important to and activates the pathways that promote muscle protein syn-
consider that strength develops through a combination of thesis [46] while inhibiting the pathways that promote mus-
neural, structural and hypertrophic adaptations [36]. cle protein degradation [47]. Testosterone also stimulates
Muscle protein synthesis is a primary component of the growth hormone (GH) secretion [45]. The level of testoster-
skeletal muscle anabolic response following resistance exer- one found in females is about 10% of that in males [45, 48].
cise [16]. Muscle protein synthesis increases similarly in In males, resistance exercise triggers the release of testos-
females and males in the immediate 1- to 5-h post-resistance terone [45, 49]. The resulting elevated anabolic environment
training and remains elevated, compared with resting levels, may promote skeletal muscle hypertrophy [50], potentially
up to 26 h post-training with feeding [37]. In their study, by enhancing androgen receptor content [51], a key factor
West et al. [37] disregarded the female menstrual cycle in driving relative increases in skeletal muscle hypertrophy in
their protocol because of previous findings that skeletal mus- males [52]. In females, the exercise-induced testosterone
cle protein metabolism is not influenced by the menstrual response is limited, with most studies finding no testoster-
cycle phase (discussed in Sect. 3.1) [38]. Their findings are one response post-resistance exercise [49, 53–55]. Androgen
perhaps unsurprising, given that males and females express receptor protein content in females is however upregulated at
similar basal protein synthesis and protein degradation rates a faster rate than in males following an acute bout of resist-
in skeletal muscle, when normalised to lean mass [39]. This ance exercise [48]. This upregulation is not sufficient to
lack of difference in skeletal muscle protein synthesis rates counteract females’ low baseline level of testosterone, nor
[37] is in line with the frequent observation that relative does testosterone fluctuate across the menstrual cycle [56].
increases in muscle cross-sectional area with long-term Consequently, females have little opportunity to capitalise
resistance training are similar in males and females [31, on the anabolic effects of testosterone and, in addition to the
40]. This suggests that sex differences in lean muscle mass intrinsic (e.g mechanical loading) and extrinsic (e.g. protein
and absolute strength and hypertrophy across the lifespan ingestion) factors, must rely on other sex and non-sex hor-
[28, 41, 42] may be driven by other mechanisms, including mones to increase skeletal muscle protein synthesis.
mechanical (e.g. sarcomerogenesis) or metabolic stress (e.g. Estrogen and progesterone are two primary sex hor-
elevated hormone release) [43]. Based on the known sex dif- mones that fluctuate with, and regulate, the menstrual cycle.
ferences in circulating hormone levels, the following section Approximately 50% of both active and elite female athletes
examines the role that anabolic and catabolic hormones may perceive that their menstrual cycle affects their exercise
play in females’ responses to resistance training. training and performance [57]. The menstrual cycle is part
1640 O. E. Knowles et al.

of the human reproductive process and is made up of two

phases: the follicular phase, which is characterised by the
onset of menses, and the luteal phase, which is characterised
by the onset of ovulation (Fig. 1) [58]. From the early- to
mid-follicular phase, estrogen and progesterone levels are
low, with a spike in estrogen occurring during the late-fol-
licular phase, meaning that the ratio of estrogen to proges-
terone is at its largest [58, 59]. Following ovulation, both
progesterone and estrogen levels are high before decreasing
again prior to menses (Fig. 1) [58, 59].
The possible implications of the surge in estrogen during
the late-follicular phase on resistance training performance
are evident from findings that maximal force is increased
from the follicular phase to ovulation and declines in the
early to mid-luteal phase [60–62]. The area under the
Fig. 1  Hormonal fluctuation with a eumenorrheic menstrual cycle
curve of estradiol (the most abundant estrogen) increases (based on a 28-day cycle with ovulation occurring at day 14). EF
for 65–95 min following an acute bout of resistance exer- early follicular, EL early luteal, LF late follicular, LL late luteal, MF
cise, but substantially more so in the luteal phase compared mid-follicular, ML mid-luteal
with the follicular phase [63, 64]. Estradiol then remains
up to 21% higher than resting levels at 24 h post-resistance
exercise [65]. Long-term resistance training studies sup- reduce protein catabolism in males [77] and post-menopau-
port a possible causal relationship between the heightened sal females [78]. Hormone replacement therapy using an
estrogen-progesterone ratio and performance, with greater estrogen-only [79] or combined estrogen-progesterone [80,
muscle diameters and strength observed with up to 4 months 81] supplement in post-menopausal females has demon-
of resistance training performed frequently in the follicular strated increases in muscle mass and/or strength, possibly
phase (e.g. five times per week in the follicular phase and owing to an increase in estradiol by up to 50% with supple-
two times per week in the luteal phase) compared with train- mentation [80, 81]. Multiple comprehensive reviews detail
ing performed frequently in the luteal phase or consistently the impact of estrogen on the skeletal muscle of early- and
(e.g. three times per week) throughout the cycle [66–68]. post-menopausal females [42, 70, 71], which may be rel-
Interestingly, each of these training studies used a lower evant in understanding the role of estrogen in young females.
body hypertrophy protocol of 8–12 repetitions at ~ 80% 1 However, it is also important to consider that the reduction in
RM, with appropriate overload progressively implemented. muscle strength in the early-mid luteal phase (i.e. post-ovu-
In contrast, one study found no effect of menstrual cycle- lation) coincides with reduced maximal motor unit discharge
based training frequency on strength or hypertrophy using rates, which may be influenced by the drop in estrogen and
an upper body protocol [69]. Importantly, while Wikstrom- increase in progesterone in this phase [82]. Certainly, the
Frisen et al. [66] included a control group who trained with effects of estrogen on skeletal muscle are promising, yet
constant frequency throughout the menstrual cycle, each of there remains a need to determine how young females (i.e. of
the studies discussed had a number of limitations in their menstruating age) performing resistance training can exploit
design or implementation, indicating that the results should naturally occurring surges in endogenous estrogen to max-
be taken with caution. Further research is needed to under- imise skeletal muscle strength and hypertrophy.
stand how menstrual cycle-based periodisation for hyper- Progesterone may also play a role in skeletal muscle
trophy training could be a feasible approach for females metabolism. Progesterone increases immediately following
performing resistance training. resistance exercise in the mid-luteal phase, but not in the
Several authors have suggested that estrogens may influ- early-follicular phase, and remains elevated up to 30 min
ence skeletal muscle hypertrophy [42, 70, 71]. When bound post-resistance exercise [64]. Smith et al. [83] found that
to its receptors, estrogen upregulates intracellular signalling progesterone administration increases skeletal muscle pro-
pathways that stimulate skeletal muscle protein synthesis, tein synthesis rate, albeit in post-menopausal sedentary
such as the Akt/mechanistic target of rapamycin pathway females. In contrast, some authors propose a catabolic effect
(mTOR) [72]. Circulating estrogen enhances myoblast pro- of progesterone [84–86]. Landau and Poulos [86] reported
liferation in vitro [73] and muscle size in rodents in vivo that a large dose of progesterone (equivalent to that excreted
[74]. Estrogen may also play a key role in muscle repair in the first trimester of pregnancy) is associated with reduced
and regeneration through the activation and proliferation of serum amino acid levels, indicating an increase in protein
satellite cells [75, 76]. The administration of estrogen might degradation. To date, only one study of young females has
Resistance Training and Skeletal Muscle Protein Metabolism in Females 1641

tested protein myofibrillar rates following a resistance exer- the early follicular phase, emphasising training frequency
cise session performed in the follicular and luteal phases during the luteal phase does not result in greater increases
of the menstrual cycle, with no difference found between in hypertrophy or strength over time [66]. Authors have sug-
phases [38]. Importantly, Miller et al. [38] conducted test- gested that this increased GH production during the luteal
ing in the early-follicular phase and the early- to mid-luteal phase may arise from greater circulating estradiol because
phase, when the ratio of estrogen to progesterone secretion estrogen plays a role in GH axis neuro-regulation in both
is small. It has been suggested that the individual effects rodents and humans [94]. Growth hormone secretion also
of endogenous progesterone and estrogen may counteract increases following hormone (estrogen) replacement therapy
each other when produced at a similar rate [42]. The estro- in post-menopausal females [95]. Further research is needed
gen-progesterone ratio is largest (i.e. the difference between to determine if the peak of estrogen during the late-follicular
estrogen and progesterone secretion is large) during the late- phase may stimulate greater resistance exercise-induced GH,
follicular phase [58, 59]. Importantly, emphasising training which could promote greater training adaptations during this
frequency during the follicular phase coincides with greater phase.
strength and hypertrophy improvements over time [66–68]. In contrast to the anabolic hormones discussed so far,
Therefore, resistance exercise in the late-follicular phase of cortisol is a catabolic hormone that, among other roles, is
the menstrual cycle could potentially promote greater skel- upregulated in response to psychological and physiological
etal muscle protein synthesis than in other phases. Previous stress [96]. Stress induced at the whole-body level and the
authors have highlighted that research is needed to com- skeletal-muscle level with resistance training can elicit an
pare muscle protein synthesis rates between the early and increase in cortisol [54]. In turn, supraphysiological levels of
late follicular phases to understand the effect of estrogen cortisol increase skeletal muscle protein degradation, as well
independent of progesterone [42]. However, until research as markers of protein degradation, in both human and rodent
in this space is available, we have recommended (Sect. 5) muscle cells [97, 98]. Further, findings demonstrate that cor-
for researchers to avoid exercise testing in the late-follicular tisol decreases muscle protein synthesis in humans [99] and
phase because of potential changes in strength or muscle that a mix of catabolic hormones including cortisol increases
protein synthesis rates. These recommendations also warrant muscle protein breakdown in humans [100]. The secretion of
further research. cortisol in response to resistance exercise is similar between
males and females [37]. While it is unclear whether corti-
3.2 Endogenous Non‑Sex Hormones in Young sol secretion remains consistent across the menstrual cycle
Females [56, 101] or increases in the luteal/ovulatory phase [102],
rodent models suggest that cortisol is downregulated by
Growth hormone (GH), insulin-like growth factor 1 (IGF-1) testosterone [103] and stimulated by estrogen [104]. Given
and cortisol are non-sex hormones that play an important that females secrete little, if any, testosterone in response to
role in resistance training-induced skeletal muscle protein resistance exercise, these rodent models may explain why
metabolism [37, 87]. Growth hormone regulates carbohy- only males show a cortisol adaptation to long-term training
drate, lipid and protein metabolism in a number of tissues, [27] with a reduction in baseline serum levels that may aid
with a key role in promoting the release of IGF-1 from their hypertrophic adaptation. Further research is needed to
the liver [88]. In turn, IGF-1 directly upregulates skeletal determine if an increase in cortisol with estrogen during the
muscle protein synthesis by activating the PI3k/Akt/mTOR luteal phase [102] might counteract the beneficial GH pro-
pathway [88]. Resistance exercise stimulates large bursts file during this phase [63, 64] and explain females’ greater
of GH in males and females [89]. However, there is mixed adaptation to resistance training performed in the follicular
evidence to support a correlation between the acute resist- phase [66–68].
ance exercise-induced GH response with the magnitude of
muscle hypertrophy in males [54, 89–91]. Interestingly, the 3.3 Hormonal Contraceptive Use
area under the curve for GH-levels post-resistance exercise
is greater in females than in males [37]. Further, the GH Another consideration for researchers and practitioners is
response in females is greater with high-volume short-rest hormonal contraceptive use. Many females use hormonal
resistance exercise compared with a low-volume high-rest contraception to regulate their menstrual cycle or prevent
prescription [54, 89, 92]. While basal GH and IGF-1 remain pregnancy [105]. Hormonal contraceptives include the con-
stable across the menstrual cycle [93], there is evidence that traceptive pill, implant rod, contraceptive patch, progestogen
resistance training-induced GH secretion is greater during injection, vaginal ring and the hormonal intrauterine device
the mid-luteal phase than the early follicular phase [63, 64]. (IUD). While the most common methods for contraception
Despite a greater acute increase in circulating GH after vary regionally, use of oral contraceptive (OC) pills is more
resistance exercise in the mid-luteal phase compared with prevalent than other methods in Australia whereas the IUD is
1642 O. E. Knowles et al.

more commonly used in European countries compared with 18–21 of the pill cycle and non-OC users during days 3–6
other countries [106]. Studies conducted in the USA and of menstruation, therefore exposing all participants to low
Norway indicate that hormonal contraceptive use is particu- endogenous estradiol and progesterone, and highlighting
larly common amongst athletes, with up to 57% of female the influence of high exogenous hormone levels on skeletal
athletes using OC [107, 108] and 9% using an IUD [107]. muscle protein synthesis. Interestingly, the authors sug-
The hormonal IUD (a progestogen-only device) has been gest that the inhibiting effect of third-generation OC pills
shown to reduce muscle mass after 12 months [109]; how- on myofibrillar protein synthesis may be due to the greater
ever, confounding variables such as age and physical activity progesterone level compared with second-generation OC
were not considered in the analyses. No other evidence exists pills [118, 119]. However, this hypothesis and how it relates
regarding the effect of the IUD or implant rod on skeletal to muscle hypertrophy needs further research.
muscle strength, hypertrophy or protein metabolism with Collectively, the studies discussed have used a myriad of
resistance training. In contrast, the combined OC pill, the OC formulations, and it is therefore difficult to interpret the
most common form of OC, is more widely researched. The true impact of OC use on resistance training and skeletal
combined OC pill contains a synthetic estrogen (ethinyle- muscle outcomes. Further, muscle protein metabolism in
stradiol) and one of six synthetic progestogens [110]. The males is influenced by training status [120], therefore inves-
combined OC pill is also split into four generations depend- tigating the interaction between training status and OC is
ent on their type of progesterone [111]. The OC pill reduces warranted. Research comparing the type, composition or
endogenous estrogen, progestogen and testosterone [110, generation of OC is needed to reliably understand the out-
112] to low but consistent levels. Therefore, the level of comes for female OC users performing resistance training.
circulating sex steroids is dependent on the dose of synthetic
hormones delivered in each OC pill. The dose of synthetic
hormone differs between monophasic, biphasic and triphasic 4 Future Directions
OC, as well as the brand of pill [110]; a US study of female
participants using OC pills found 67% used a monophasic Whilst the research investigating the interaction between
pill and 88 different brands of OC pills were reportedly used resistance training and skeletal muscle protein metabolism
[111]. As such, there may be a large variation in hormo- in females is sparse, the different stages of the lifespan have
nal fluctuations between individuals taking the OC pill that hardly been considered. While the heavy resistance train-
could impact skeletal muscle strength, hypertrophy and pro- ing typically performed by elite or recreational athletes is
tein metabolism. contraindicated during pregnancy, athletes who are pregnant
Despite, or perhaps because of, potential hormonal or postnatal need specific exercise guidelines [121]. Estro-
variation, no differences in maximal strength have been gen and progesterone production markedly increase during
found between resistance-trained females with or with- pregnancy, and then rapidly decline in the immediate post-
out OC during acute performance tests [113] or following partum period [122]. Interestingly, acute maximal strength
up to 4 months of resistance training [66, 114]. Maximal does not change in untrained females between trimesters,
strength is also unaffected by differences in monophasic nor between in vitro fertilisation phases [123]. As low- to
OC androgenicity (i.e. the dose of synthetic progestogen), moderate-intensity resistance training is indicated dur-
tested at various stages of the menstrual cycle [115]. Fur- ing pregnancy and postpartum periods, further research is
ther, maximal strength does not differ during each phase needed to understand the implications of hormonal changes
of the OC cycle itself (including five brands of combined on resistance exercise outcomes and skeletal muscle protein
monophasic OC) [113, 115]. Interestingly, OC use increases metabolism during these stages of life.
sex hormone-binding globulin (more so in third- and fourth- In contrast to pregnancy and the postnatal period, meno-
generation OC pills), which has a high affinity for testoster- pause is characterised by a reduction in estrogen by up to
one, binding it and making it inactive [112]. Further, OC 67% and an accelerated loss of skeletal muscle mass by up
administration may also increase GH levels but decrease to 1% per year after the onset of menopause [71, 124]. Acute
IGF in second- and fourth-generation OC pills [116, 117]. A muscle strength is lost during and after menopause; how-
down-regulation of anabolic hormones could possibly play ever, resistance training can attenuate this loss in strength
a role in changes in skeletal muscle protein balance with and muscle mass [80, 124]. Notably, post-menopausal
ingestion of OC pills. In support of this theory, the myofi- females have a faster post-absorptive muscle protein syn-
brillar protein fractional synthesis rate was lower in female thesis rate than pre-menopausal females over a 5-h period
third-generation, but not second-generation, OC users com- [83], although this response is reduced with feeding [125].
pared with non-OC users following prolonged submaximal The upregulation of catabolic gene expression in post-meno-
resistance exercise [118]. In this study, Hansen et al. [118] pausal females (without hormone replacement therapy) [83]
tested second- and third-generation OC users during days may explain the loss of muscle mass despite upregulated
Resistance Training and Skeletal Muscle Protein Metabolism in Females 1643

basal muscle protein synthesis. However, this hypothesis, that some adaptations to strength training are influenced
as well as the role of resistance training in contributing to by the menstrual cycle, such as strength output [66, 67].
protein synthesis rates in post-menopausal females, requires Other findings imply no change in muscle protein syn-
further research. Understanding the outcomes associated thesis with menstrual cycle phase [38] but given that this
with hormone replacement therapy in this population will was measured at only two time points, and not around
also contribute to increasing our knowledge of the role of ovulation, these findings should be taken with caution.
hormones in the maintenance of skeletal muscle mass in When in doubt or if a pilot study cannot be performed,
females in general. it is safe to assume that the primary outcome may be
Relative energy deficiency in sport (RED-S) is another sex dependent and/or menstrual cycle dependent. While
potential concern for female athletes. RED-S is characterised some sex differences are apparent (e.g. absolute strength,
by, but not limited to, impaired metabolic rate, muscle pro- fatigability), researchers should remain confident that
tein synthesis, menstrual function, bone health and immu- female and male participants who perform the same
nity caused by relative energy deficiency [126]. Emerging resistance training protocol are likely to have a similar
literature suggests that the physiological impairments asso- relative acute muscle protein synthesis response to train-
ciated with RED-S may negatively impact muscle strength ing along with similar relative hypertrophy and strength
[126]. One study demonstrated that females with menstrual adaptation. For sex comparisons, it is therefore recom-
disturbances (i.e. low estradiol and progesterone) have an mended that researchers present strength, hypertrophy
attenuated GH response to an acute bout of resistance exer- and skeletal muscle protein metabolism data in relative
cise [64]. Further research is needed to understand the impli- values (i.e. the change from baseline) rather than absolute
cations that an impaired anabolic hormone response may values.
have on muscle protein synthesis. RED-S can develop from • As best practice for both male and female cohorts, in a
a reduction in energy intake, an increase in training load range of research domains, it is also important to con-
(intensity and/or volume), or a combination of both factors sider and implement eligibility criteria specifying partici-
[126]. Athletes experiencing RED-S may therefore benefit pants’ training status and stage of growth across the lifes-
from menstrual cycle-based periodised resistance training, pan (i.e. pubescent, young, pregnant, pre-menopausal,
given findings showing that when resistance training volume post-menopausal) to ensure a homogenous sample.
(frequency) is increased for 2 weeks during either the fol- • The menstrual cycle typically ranges from 25 to 34 days
licular or luteal phase, sex or other hormones such as cortisol [58]. Regardless of the duration of the intervention,
and GH are not impaired [127]. Certainly, further research researchers should collect a menstrual diary for at least
is needed to identify training methods that maximise perfor- two complete cycles prior to testing. This way, research-
mance and reduce negative exercise-related health problems ers can appropriately schedule laboratory visits or, when
in female athletes. possible, moderate findings for hormonal variations
across the cycle. Similarly, the menstrual diary should
be completed for at least one cycle during and post-
5 Implications for Research on Resistance intervention, which will allow research teams to confirm
Training in Females the timing of particular testing sessions, relative to the
menstrual cycle, and therefore contextualise unexpected
Including female participants in resistance training research individual findings. When possible, menstrual records
is essential to establish the associated health and perfor- should be supplemented by venous blood collection, uri-
mance outcomes for the female population. Additionally, nary collection, or basal body temperature monitoring
there are some occupational settings, such as military posi- at key time points across the menstrual cycle and pre/
tions or emergency services, where the physical strength post-intervention. For example, ovulation is expected to
requirements for males and females are equal [128], thus occur at or shortly following the nadir of basal body tem-
understanding the training outcomes for both sexes is criti- perature, which is then followed by a steep rise in basal
cal. The following sections provide practical suggestions for body temperature [129]. Measuring body temperature at
researchers wanting to include females in research investi- waking each morning can be used to track this pattern.
gating the effect of resistance training. These suggestions • Importantly, the type of analyses required to moderate for
may also be useful for researchers including female partici- hormone levels would only be possible in large studies
pants in other exercise physiology domains. with enough female participants with outcomes measured
at different stages of the cycle, which greatly exceeds
• It should first be determined whether the anticipated pri- the typical cohort size used in laboratory-based exercise
mary outcome is likely to be sex dependent and/or men- physiology research.
strual cycle dependent. Examples from this review show
1644 O. E. Knowles et al.

• While a homogenous sample is preferable, when testing avoided to rule out the potential impact of excessive
both eumenorrheic and OC-using females, endogenous differences in the estrogen/progesterone ratio.
estrogen and progesterone levels in the early follicular
phase are low for both groups and can therefore be con-
sidered alike when testing in this phase of the menstrual 6 Practical Implications for Resistance
cycle [130]. Previous authors [110, 130] have recom- Training in Females
mended that inclusion criteria for OC users should be
limited to a single brand, type and generation of OC to While females and males performing the same resistance
reduce hormonal variation. However, this approach is training protocols may have similar skeletal muscle pro-
considered difficult to practically implement given the tein synthesis responses [37] and performance adaptations
wide range of OC brands used by females. Therefore, [27–29], the differences in hormonal responses to resistance
it is recommended that for OC and other contraceptive exercise suggest that there may be ways to optimise the train-
methods, that researchers control for a single type of ing adaptations for females performing resistance training.
contraception (e.g. monophasic OC or hormonal IUD) The following points provide a summary of the current evi-
and set limits about the acceptable dosage of synthetic dence for practitioners prescribing resistance training for
progesterone and/or estradiol, which will in turn limit female populations.
the number of brands included. While not the perfect
approach, this may be a practical strategy to account for • Females may acquire strength more efficiently with low-
exogenous and endogenous hormone production between volume high-intensity training (i.e. combined strength
participants. and power training) as opposed to high-volume moder-
• For ‘acute interventions’, with a duration less than one ate-intensity training (i.e. combined strength and hyper-
phase (i.e. 4 days): trophy training) [32]. However, high-volume moderate-
intensity training elicits a greater GH response than
– The ideal approach is a cross-over design where each low-volume high-intensity training in females, which
participant acts as her own control and all interven- may be more beneficial for obtaining hypertrophy goals
tions are tested during the same phase of the cycle. [89]. While the nuances of the response may differ, these
– When a cross-over design is not possible, all women recommendations are the same as for males.
should be tested in the same stage of their menstrual • Females may also achieve greater strength and hypertro-
cycle. phy gains by training with high frequency in the follicular
– When neither option is available, it is recommended phase of their menstrual cycle (e.g. five times per week in
that participants are tested during the early follicu- the follicular phase and two times per week in the luteal
lar and mid-late luteal phase when the ratio between phase), compared to training with a high frequency in the
estrogen and progesterone is small (see Sect. 3.1 for luteal phase or with constant frequency throughout the
background detail). entire menstrual cycle (e.g. three times per week) [66,
67]. This 2-week high-frequency training approach may
• For non-acute interventions, with a duration less than one
be more feasible to implement for recreationally active
complete cycle:
females or individual sport athletes rather than team sport
athletes whose menstrual cycles are unlikely to be syn-
– If feasible, we recommend using a cross-over design
chronised with their team mates.
where each participant acts as their own control and
• Use of OC has been shown to have no impact on skeletal
to follow the recommendations above.
muscle strength [113] and no published data exist regard-
– When not possible to use a cross-over design, the
ing the interaction between OC and muscle hypertrophy.
start of the intervention should occur in the same
Further research is needed to determine the impact of
phase for each participant. The ovulation phase
specific types and brands of OC on skeletal muscle
should be avoided to rule out the potential impact of
adaptations. Importantly, the use of OC may have other
excessive differences in the oestrogen/progesterone
performance-related benefits including the reduction of
ratio.
premenstrual symptoms that could negatively impact per-
• For long-term interventions, with a duration of more than formance [105].
one complete cycle: • Ultimately, it is important that females are provided with
individualised and periodised resistance training pro-
– Intervention testing, as well as pre- and post-inter- grammes that consider their menstrual cycle and hor-
vention testing, should start in the same phase for monal contraceptives, as well as amenorrhea, pregnancy
each participant. The ovulation phase should be or menopause, for optimal results wherever practical. The
Table 1  Effect of sex, menstrual cycle, contraceptive use and pregnancy on acute responses and adaptations to resistance training
Acute response to resistance exercise Adaptation to resistance training
Strength performance, e.g. 1 Muscle protein metabolism Hormonal response Muscle strength Muscle hypertrophy
RM, MVC or training load
output

Sex ↓ Absolute strength in females ↔ Muscle protein synthesis ↑ Testosterone in males [37] ↔ Relative strength [27–29], ↔ Muscle relative cross-sectional
[17] rate [37] ↑ GH, cortisol in females [37] some evidence of ↑ relative area [31, 40]
↓ Relative strength in females ↔ IGF-1 [37] strength in females [30, 31]
[17]
Resistance Training and Skeletal Muscle Protein Metabolism in Females

Menstrual cycle ↑ In FP compared to early LP ↔ Between early FP and mid- ↑ Estradiol, progesterone in mid- ↑ With high frequency training ↑ Muscle diameter with high fre-
[62] LP [38] LP [64] in FP compared to LP [66, 67] quency training in FP compared
↔ Estradiol, progesterone in to LP [66, 67]
early FP [64]
↑ GH in mid-LP compared to
early FP [63, 64]
↔ Or ↑ cortisol in LP [102]
↔ Testosterone, IGF-1 [56]
Contraceptive use ↔ Between OC users and non- ↓ Muscle protein FSR in third- ↑ GH in OC users compared to ↔ Between OC users and non-
users [113, 115] generation OC users compared non-users [117] users [66, 114]
↔ OC androgenicity [113, 115] with non-users [118]
↔ Monophasic OC phases [113,
115]

FP follicular phase, FSR fractional synthesis rate, GH growth hormone, IGF-1 insulin-like growth factor 1, LP luteal phase, MVC maximum voluntary contraction, OC oral contraceptive, 1 RM
one repetition maximum, ↑ significantly increased, ↓ significantly decreased, ↔ no significant difference
1645
1646 O. E. Knowles et al.

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