(14796805 - Journal of Endocrinology) Androgen and Estrogen Actions On Male Physical Activity - A Story Beyond Muscle

Journal of F Jardí et al.
Androgens and physical activity 238:1 R31–R52

Endocrinology
REVIEW
Androgen and estrogen actions on male physical

activity: a story beyond muscle
Ferran Jardí1, Michaël R Laurent2,3, Vanessa Dubois2,†, Nari Kim1, Rougin Khalil1, Brigitte Decallonne1,
Dirk Vanderschueren1 and Frank Claessens2
1Clinical
and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
2MolecularEndocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
3Gerontology and Geriatrics, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
Correspondence should be addressed to F Jardí: ferran.jardi@kuleuven.be
†(V Dubois is now at INSERM UMR1011, University of Lille and Institut Pasteur de Lille, Lille, France)
Abstract
Physical inactivity is a pandemic that contributes to several chronic diseases and poses a Key Words
significant burden on health care systems worldwide. The search for effective strategies ff physical activity
Journal of Endocrinology
to combat sedentary behavior has led to an intensification of the research efforts to ff exercise
unravel the biological substrate controlling activity. A wide body of preclinical evidence ff muscle
makes a strong case for sex steroids regulating physical activity in both genders, albeit ff brain
the mechanisms implicated remain unclear. The beneficial effects of androgens on ff androgens
muscle as well as on other peripheral functions might play a role in favoring adaptation
to exercise. Alternatively or in addition, sex steroids could act on specific brain circuitries
to boost physical activity. This review critically discusses the evidence supporting a role
for androgens and estrogens stimulating male physical activity, with special emphasis
on the possible role of peripheral and/or central mechanisms. Finally, the potential
Journal of Endocrinology
translation of these findings to humans is briefly discussed. (2018) 238, R31–R52
Introduction
Physical inactivity has emerged as a global health crisis, according to self-reported measures (Hallal et al. 2012).
being the fourth leading cause of death worldwide Accelerometer data show even lower rates of adherence
according to the World Health Organization (WHO) among adolescents, with only 8% of 12- to 15-year-old
(WHO 2009). Not meeting the minimum physical individuals attaining sufficient physical activity (Troiano
activity recommendations (WHO 2010) is estimated to et al. 2008). Taking into consideration the prevalence and
cause 6% of the burden of disease from coronary heart risks associated with physical inactivity, as well as the
disease, 7% of type 2 diabetes and 10% of both breast and fact that it can be easily and effectively prevented (Heath
colon cancer (Lee et al. 2012). In contrast, 15 min of daily et al. 2012), it is without surprise that the promotion
moderate-intensity exercise reduces all-cause mortality of physical activity has become a public health priority
by 14% and extends by 3 years the life expectancy (Kohl et al. 2012).
(Wen et al. 2011). Notwithstanding, one-third of adults The predisposition to engage in physical activity is
worldwide are physically inactive and the prevalence a highly complex trait in humans, probably determined
increases dramatically among adolescents, with four out by the interaction of biological, psychological, social and
of five not reaching the minimum recommended levels environmental factors (Bauman et al. 2012). The role for
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Journal of F Jardí et al. Androgens and physical activity 238:1 R32
Endocrinology
a biological substrate influencing the levels of physical running in females is abolished upon gonadectomy and
activity is a relatively recent concept supported by several can be restored following treatment with E2 (Berchtold
lines of evidence, including human studies but mostly et al. 2001). Based on these and other preclinical data,
preclinical investigations (Bouchard & Rankinen 2006). sex steroids have been suggested as strong candidates
Based on a cohort of 37,000 twin pairs, Stubble et al. for contributing to the biological substrate influencing
described that the heritability of exercise participation physical activity (Lightfoot 2008). Androgens are well
ranged between 48% and 71% (Stubbe et al. 2006). known for their potent anabolic actions on muscle and
Nevertheless, the extent to which genetic factors explain we have previously reviewed the cellular targets and
adult exercise behavior is highly heterogenic between molecular pathways implicated (Dubois et al. 2012).
studies, most likely due to differences in the methodology Therefore, it is conceivable that testosterone increases
used to assess physical activity (Simonen et al. 2002, activity in males by favoring adaptation to exercise
Eriksson et al. 2006). In addition, candidate gene studies (peripheral mechanisms). In addition or alternatively
have pointed out several hormonal- and neurotransmitter- thereto, testosterone could act on the specific brain neural
related genes associated with physical activity (Stefan et al. circuitries that have been identified to control physical
2002, Salmen et al. 2003, Simonen et al. 2003, Loos et al. activity levels (central mechanisms). Our understanding
2005). However, the two genome-wide association studies of the neural basis underpinning the effects of sex steroids
(GWAS) published so far do not support a prominent role on activity has advanced markedly over the last decade.
for most of these candidate genes (De Moor et al. 2009, Nevertheless, most of these studies have focused on the
Kim et al. 2014). This inconsistency might be explained female brain (reviewed in Xu et al. 2017), whilst the
in part by the limitations of physical activity data based central mechanisms implicated in male activity are less
on questionnaires or diaries, which show poor accuracy documented.
in detecting light-to-moderate activities and are prone to The recent publication of large clinical trials of
error because of individual biases (Strath et al. 2013). The testosterone therapy in elderly men has reignited
latter caveat is overcome by recent efforts to implement the debate on the risks and benefits of testosterone
the use of automated monitors in physical activity replacement (Basaria et al. 2010, Snyder et al. 2016,
research. Nonetheless, the strongest body of evidence Storer et al. 2016). In this context, the positive impact
supporting that physical activity is biologically regulated of testosterone stimulating physical activity and the
still comes from preclinical studies. underlying mechanisms of action represent an additional
Androgens and estrogens are key regulators of consideration for testosterone replacement in elderly,
reproductive organs but also exert multiple effects on mobility-impaired, frail or sarcopenic men. Here, we
non-reproductive tissues, including brain, muscle, adipose review the data supporting a role for androgens and
tissue and bone. Testosterone, the principal circulating estrogens regulating male physical activity and provide
androgen, may stimulate the androgen receptor (AR) an overview of the potential mechanisms implicated.
either directly, or indirectly following 5 alpha-reduction How sex steroids control physical activity in females is
to dihydrotestosterone (DHT), as well as the estrogen reviewed in Lightfoot (2008) and Xu et al. (2017). We
receptors (ERα and ERβ) after testosterone aromatization will first review some basic concepts regarding physical
into estradiol (E2) (Callewaert et al. 2010). Even though activity and then discuss several lines of preclinical
research into the biological control of physical activity evidence supporting the notion. In the following sections,
has intensified in recent years, early findings in the 1920s we will review the impact of androgens in the physical
already showed that wheel running in male rats was ability to partake in exercise and examine the specific
abolished after orchiectomy (ORX) (Gans 1927). Later brain circuits that could be underlying the regulation of
studies pinpointed testosterone as the gonadal product activity by testosterone. In the last section, we will briefly
stimulating wheel running, albeit the extent to which discuss what is known regarding the effects of androgens
prior aromatization into E2 was required remained debated and estrogens on physical activity in men.
(see discussion in the ‘Replacement and pharmacological
studies in adult rodents’ section). Physical activity is a
sexually dimorphic trait in rodents (Eikelboom & Mills Categories of physical activity
1988), with females being more active than males and
with fluctuations according to the estrous cycle (Wollnik Physical activity is defined as any bodily movement
& Turek 1988). Similar to what is observed in males, wheel produced by skeletal muscles that results in energy

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expenditure (Caspersen et al. 1985). Although the term animals, thus inducing a substantial psychological stress
‘exercise’ is often interchanged with physical activity, (Sasaki et al. 2016). In addition, rodents do not always
exercise is indeed a subset of physical activity that is display consistent swimming behaviors and some animals
planned and structured and implies a purpose to achieve will just float, bob and/or dive (American Physiological
health or fitness benefits (Caspersen et al. 1985). In our Association 2007). Therefore, we focused on voluntary
daily life, we also engage in incidental physical activity wheel running, in which animals have a complete control
when performing home- or work-related activities or on the amount and intensity of exercise.
during transportation (Strath et al. 2013). Nevertheless,
the latter activities can be performed in an exercise
manner and thus it is not always straightforward to Preclinical evidence supporting a role for
discern between the voluntary (planned) and incidental androgens and estrogens regulating male
(spontaneous) domains of physical activity (Garland physical activity
et al. 2011). Notably, an increase in energy expenditure
associated with non-exercise activity has been shown Most of our knowledge regarding the role of biological
to prevent fat gain in humans (Levine 1999). Therefore, factors controlling physical activity derives from rodent
physical activity derived from daily tasks may also play a studies and thus the overall significance to human
role in disease prevention and should be included together health remains to be determined. Nevertheless, evidence
with exercise when assessing physical activity. from preclinical studies in rats and mice clearly shows
With regard to preclinical animal studies, wheel the importance of androgens and normal AR and ERα
running in rodents has been extensively used as a signaling in the regulation of male activity.
model of human exercise (Garland et al. 2011, Novak
et al. 2012). Similar to the ‘runner’s high’ experienced
Replacement and pharmacological studies in
during endurance exercise in humans, wheel running
adult rodents
is rewarding for rodents and both rats and mice show
preference for environments previously associated with The first observations showing that ORX abrogates wheel
running (Lett et al. 2001, Fernandes et al. 2015). When running activity in rats date from almost a century ago
given free access to running wheels, mice reduce the time (Gans 1927). Subsequent studies extended these findings
spent in cage floor activity at the expense of wheel running to mice as well as other rodent species (Daan et al. 1975,
time, the net result being an increase in their total activity Morin & Cummings 1981, Dark & Zucker 1984, Jechura
levels (De Visser et al. 2005, Silvennoinen et al. 2014). et al. 2000) and demonstrated the implication of testicular
Spontaneous physical activity (SPA) refers to the non- testosterone production (Daan et al. 1975, Roy & Wade
exercise component of activity and therefore should not 1975). It is now well established that replacement with
be used as interchangeable for wheel running, although testosterone rescues wheel running activity in a gradual
very often these two parameters correlate reasonably dose-response manner following ORX (Butler et al. 2012).
well. There are several methods to assess SPA in rodents, For instance, the average daily distance run by ORX mice
including infrared photobeams, radiotelemetry, video increases from 1 to almost 4 km following 2 weeks of
tracking systems or force plates (Silvennoinen et al. 2014, treatment with physiological doses of testosterone (Jardí
Teske et al. 2014, Chabert et al. 2016). The main difference et al. 2018). Consequently, the combination of testosterone
between these approaches is their accuracy in detecting and wheel running mediates an adaptational shift to a
ambulation and climbing as well as more subtle stationary more oxidative fiber profile in the skeletal muscle of ORX
movements, such as grooming or feeding. Regardless of the (Allen et al. 2001, Ibebunjo et al. 2011). In gonadally
method used, a long (i.e., hours) period of acclimatization intact male rats, administration of supraphysiological
to the activity chamber is required to discharge the doses of testosterone also increases running distances
novelty effects on locomotion (Teske et al. 2014). Studies (McGinnis et al. 2007). Similar to humans, aging in male
failing to meet the former methodological requirement mice is associated with a progressive decline in activity
were excluded from this review. It is important to note (Fig. 1; Hamrick et al. 2006) and this can be partly
that we focus here on volitional activity, and therefore attenuated by the combination of exogenous testosterone
do not include preclinical studies using forced exercise and low-intensity physical training (Guo et al. 2012). It is
capacity tests. Forced treadmill running or swimming important to note, however, that the concentrations of
require the use of aversive stimuli to motivate the testosterone in male mice appear to remain constant with

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(2.3 km vs. 3.8 km; Jardí et al. 2018) and both testosterone

and DHT were equally effective restoring SPA (Jardí
et al. 2018). It is noteworthy that DHT metabolites
5α-androstane-3α, 17β-diol (3α-diol) and 5α-androstane-
3β, 17β-diol (3β -diol) may initiate behavioral processes
through AR-independent mechanisms, namely by acting
on gamma-aminobutyric acid (GABA) type A (Frye et al.
1996) or ERs (Frye et al. 2008a). Nevertheless, we showed
that DHT failed to rescue wheel running in AR knockout
(ARKO) mice, ruling out the implication of AR-independent
Figure 1 mechanisms (Jardí et al. 2018). Additionally, the activity
Changes in SPA with age in male C57BL/6 mice. Mean values are shown
with standard error means as vertical bars. (Data from Hamrick et al.
of ORX+testosterone-treated mice was partially lowered
2006.) by the AR antagonist enzalutamide (Wu et al. 2016),
further supporting the involvement of AR signaling
aging (Hamrick et al. 2006), in contrast to what is observed in the stimulation of wheel running (Jardí et al. 2018).
in elderly men (Wu et al. 2008). Thus, it is unlikely that Taken together, these data make a strong case for the
a reduced androgen bioactivity is the main driver of the contribution of AR to the effects of androgens on activity,
decreased SPA in old mice, even when this is responsive at least in male mice, though its importance is somewhat
to testosterone supplementation in the setting of physical less compared to aromatization and ER signaling.
training. In an attempt to investigate the estrogenic component
Many of the actions of testosterone in male behavior of testosterone actions, ORX rats and mice have been
are mediated by estrogen receptors (ERs). For instance, treated with systemic E2 (Roy & Wade 1975, Ogawa et al.
testosterone acts predominantly as a prohormone for E2 in 2003, Bowen et al. 2011, 2012, Blattner & Mahoney 2015,
the programming of male-typical and territorial behavior Royston et al. 2016). It should be noted, however, that the
in mice, although execution of this behavior relies on physiological relevance of this approach is uncertain and
the AR (Wu et al. 2009). It remains debated whether this deserves special consideration. Serum E2 concentrations
dual androgenic and estrogenic action of testosterone in both gonadally intact and ORX+testosterone-, but not
also applies to physical activity. Initially, testosterone was E2-treated mice, are below the limit of detection of sensitive
suggested to stimulate wheel running exclusively through analysis methods using mass spectrometry (McNamara
aromatase-dependent mechanisms (Stern & Murphy 1971, et al. 2010, Nilsson et al. 2015, Laurent et al. 2016b), the
Roy & Wade 1975). Treatment with E2 was more effective ‘gold standard’ for sex steroids measurements. Circulating
than testosterone in stimulating wheel running in ORX levels of E2 are also extremely low in male rats, at the level
rats and the non-aromatizable androgen DHT showed no of a few picograms per milliliter (Quignot et al. 2012).
effects (Roy & Wade 1975). Also in ORX rats, biologically Therefore, a ‘physiological’ E2 dose is virtually impossible
effective doses of the antiandrogen cyproterone acetate to define in male rodents, and most ‘replacement’ doses
failed to inhibit the stimulatory actions of testosterone are almost by definition supraphysiological. Remarkably,
on wheel running (Stern & Murphy 1971). In accordance, aromatase is highly expressed in several brain regions
treatment with the 5α-reductase inhibitor dutasteride did of male rodents, including the bed nucleus of the stria
not alter the levels of wheel running in male Zucker obese terminalis, the olfactory tubercle, the medial amygdala
rats (Sato et al. 2013). In the latter study, however, the lack (MeA) and the hypothalamus, suggesting a role for the
of effects could be potentially explained by the already autocrine and paracrine actions of estrogens (Zhao
low levels of wheel running of these animals (Stern & et al. 2007, Stanić et al. 2014). Overall, we cannot draw
Johnson 1977) and/or by a compensatory effect related conclusions about the physiological role of E2 on physical
to the secondary increases in testosterone concentrations activity levels based on studies treating male rodents with
(Amory et al. 2007). Later studies challenged the notion systemic E2, even when pharmacological doses of E2
of aromatase being indispensable for testosterone effects restore wheel running following ORX (Roy & Wade 1975,
on wheel running. In male mice, treatment with DHT Ogawa et al. 2003, Bowen et al. 2011, 2012, Blattner &
partly restored the drop in wheel running following Mahoney 2015, Royston et al. 2016). Although treatment
ORX (Karatsoreos et al. 2007, Iwahana et al. 2008), with the aromatase inhibitors letrozole and exemestane
although to a lesser extent compared with testosterone did not affect wheel running either in gonadally intact

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or ORX+testosterone-treated mice (Bowen et al. 2011), The reduction of SPA following ORX, however, was only
this study needs further technical validations. The partially rescued by MK-4541 (Chisamore et al. 2016). In
ultimate proof of the role of ERs on male physical activity a similar pattern, treatment with SARM-2f completely
comes from studies in knockout mice lacking ERα or restored muscle mass in ORX mice but was less effective
the aromatase enzyme (see discussion in the ‘Global KO increasing their wheel running activity (Morimoto
mouse models’ section). et al. 2018). In a preclinical mouse model of muscular
dystrophy, an enobosarm analog extended the survival of
Androgenic-anabolic steroids (AAS) and selective mice but failed to increase their low SPA (Ponnusamy et al.
androgen receptor modulators (SARMS) 2017). Nevertheless, the severity of the pathology of these
AAS are synthetic derivatives of testosterone that were mice may have impeded an increase in their SPA levels.
developed in an attempt to maximize the anabolic The effects of SARMs on physical activity are worthy of
activity of testosterone. The prolonged abuse of AAS further study and could represent an additional benefit in
in men is related to several psychiatric adverse effects, the treatment of muscle wasting conditions.
including irritability, mood swings, mania (‘steroid
rage’ at supraphysiological doses) and depression
Perinatal studies
(Pope & Katz 1994, Bjørnebekk et al. 2017). Although
scarce, a few preclinical studies have explored whether So far, we discussed how androgens stimulate physical
doses of AAS that model human abuse patterns affect activity in adult rodents. It is noteworthy that behavioral
physical activity levels. In contrast to testosterone, both responses to sex steroids during adulthood are influenced
nandrolone (McGinnis et al. 2007, Tanehkar et al. 2013) by sex steroids acting on the nervous system during early
and stanozolol (McGinnis et al. 2007) reduced wheel critical periods. In their seminal work in 1959, Phoenix
running activity in gonadally intact male rats. Similarly, et al. were the first to dichotomize hormonal effects in
the combination of nandrolone and methandrostenolone two groups: organizational vs. activational (Phoenix et al.
decreased voluntary wheel running in mice (Onakomaiya 1959). The organizational-activational theory states that
et al. 2014). Paradoxically, despite the detrimental effects hormones sculpt neural tissues during development so
of nandrolone on wheel running in male rats (McGinnis that they respond differentially to hormonal activation
et al. 2007, Tanehkar et al. 2013), the combination of both in adulthood (Phoenix et al. 1959). The study of the
interventions improved their running endurance (Vanzyl organizational effects of sex steroids has mainly focused
et al. 1995). As for the mechanisms of action, AAS and on the programming of mating behavior (Arnold 2009).
endogenous testosterone differ in both the affinity to Although less evidence is available for non-sexual
bind AR and the ability to be aromatized (Bergink et al. behavior, the results from several preclinical studies
1985, Fragkaki et al. 2009). Possibly, AAS regimes reduce suggest that the perinatal sex steroid milieu might also
wheel running by interfering with the endogenous determine physical activity in adulthood.
testosterone production and hence E2 (Barone et al. The perinatal surges of testosterone in male rodents
2017). Alternatively, AAS might act directly on several during the late embryogenic period and the first hours
neurotransmitter systems in the brain that affect physical of life are critical for the male brain to become capable
activity (Mhillaj et al. 2015). of producing male sexual behavior (masculinization)
The need to improve both the benefit/risk profile and whilst losing its ability to respond in a female-like pattern
pharmacokinetics of androgens spurred the development (defeminization; Lenz & McCarthy 2010 for review on this
of selective androgen receptor modulators (SARMs) topic). Apart from the perinatal period, a growing body of
(Mohler et al. 2009). SARMs received initially a great evidence shows that during puberty, testosterone is also
deal of clinical attention for their potential use in the required for the full masculinization and defeminization
treatment of muscle wasting conditions. To date, yet, none of male brain (Schulz et al. 2004, De Lorme & Sisk 2016,
of these compounds has shown unequivocal efficacy in Sano et al. 2016). Paradoxically, the organizational
clinical trials (Almeida et al. 2017). Preclinical data show effects of testosterone on the developing male brain are
that SARMs display a better myotrophic index compared actually driven by ERs, suggesting the implication of
to their steroidal analogues. In ORX mice, treatment brain aromatase activity (Ogawa et al. 2000, Wu et al.
with the SARM MK-4541 led to an increase in muscle 2009, Juntti et al. 2010). In females, prepubertal estrogen
mass and function comparable to DHT but without the levels are very low, and the traditional dogma states
sparing effects on seminal vesicles (Chisamore et al. 2016). that sexual behavior is merely the result of the absence

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of perinatal testosterone organizational actions. Recent treatment (Royston et al. 2016). From these observations,
data challenge the latter hypothesis demonstrating that it is reasonable to assume that the neonatal testosterone
E2 actions outside the perinatal period are required for surge programs male physical activity and that this
the normal development of female sexual behavior (Brock might involve aromatase-dependent processes (Fig. 2).
et al. 2011). The neural substrate underlying the persistent In support of this premise, female rats treated neonatally
and irreversible effects of sex steroid actions on the with androgens develop a resistance to E2 stimulation of
developing brain remains mostly unknown. Although not wheel running in adulthood, which can be prevented by
an exhaustive list, some suggested mechanisms include treating pups with antisense oligodeoxynucleotides to
epigenetic modulation (Nugent et al. 2015), regulation of ER mRNA (Blizard 1983, McCarthy et al. 1993, Royston
cell death and proliferation (Wu et al. 2009) and changes et al. 2016). Whether the neural mechanisms underlying
in synaptic patterning (Schwarz et al. 2008). the organizational effects of testosterone on activity are
Activity is a sexually dimorphic behavior in rodents, similar to those described for mating behavior remains
with females showing higher levels of wheel running and to be investigated. Similarly, the organizational effects
SPA compared to males (Eikelboom & Mills 1988). Gender of testosterone outside the perinatal window on physical
differences in activity remain after gonadectomy and activity (i.e. puberty) await confirmation.
thus cannot be explained by hormonal dimorphism in
adulthood (Gentry & Wade 1976, Blizard 1983, Broida &
Global KO mouse models
Svare 1984, Bowen et al. 2012, Kuljis et al. 2013). Differences
in sex chromosomes as such are also insufficient to explain Studies in transgenic mice lacking either steroid hormone
the dimorphism in activity, as evidenced by studies using receptors or the aromatase enzyme provide further insights
the mouse model of 4 core genotypes, in which sex into the role of sex steroids regulating physical activity.
chromosome complement is independent of gonadal However, the interpretation of the results obtained from
phenotype (De Vries et al. 2002, Kuljis et al. 2013). In a these mouse models is hampered by alterations of the
similar pattern to XX females, ovariectomy of mice with a hypothalamic–pituitary–gonadal (HPG) axis. In addition,
deletion of the testis-determining gene Sry results in running it is reasonable to expect changes in the sex-steroid-
longer distances than ORX males (Kuljis et al. 2013). dependent brain organization (see previous section)
Accumulating literature suggests a role for sex steroid caused by the gene deletion during development.
actions during the perinatal period determining gender
differences in activity. ORX at postnatal day 0 (P0) Androgen receptor knockout (ARKO) mice
results in higher levels of SPA than that at P5, 10 or 25 Several ARKO mouse models targeting either exon 1, 2 or 3
in male mice (Broida & Svare 1984). Also in male mice, have been generated using the Cre-LoxP system (Fan et al.
estrogen deficiency during early life leads to a higher 2005, Ophoff et al. 2009a, Rana et al. 2011). Our group
wheel running response in adulthood following E2 reported an almost complete abrogation of wheel running
Figure 2
Schematic overview of the overall proposed
mechanisms of action of testosterone on male
activity (see text). A, androgens; CNS, central
nervous system; E2, estradiol; PNS, peripheral
nervous system; +, stimulatory effect; ++,
dominant stimulatory effect.

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as well as a reduced SPA in exon 2-deleted male ARKO mice show increased levels of serum testosterone (Callewaert
(Ophoff et al. 2009a). A similar low activity phenotype was et al. 2009), are less active than their wild-type (WT)
observed in mice with a targeted disruption of AR exon 1 littermates when given access to running wheels (Blattner
(Fan et al. 2005) and in a DNA-binding domain ARKO mouse & Mahoney 2012), and develop elevated adiposity in late-
model that only retains non-genomic actions (Rana et al. life (Heine et al. 2000). As shown first in the seminal work of
2011). The fact that global ARKO mice are less physically Ogawa et al. and later confirmed by others, the stimulatory
active might predispose them to develop late-onset actions of E2 treatment on wheel running activity are
adiposity (Fan et al. 2005, Rana et al. 2011). Global ARKO abrogated in ERαKO mice (Ogawa et al. 2003, Dworatzek
mice appear to suffer from an impaired gonadal testosterone et al. 2014, Blattner & Mahoney 2015). This is not the case
production (Callewaert et al. 2009) and might therefore not for ERβKO mice in which the response to E2 is unaffected
be useful to discern between purely AR-mediated effects and (Ogawa et al. 2003). Therefore, the estrogenic regulation
those secondary to E2 deficiency. Indeed, treatment with of wheel running in males is primarily mediated by ERα,
testosterone completely restored wheel running in male though this does not exclude the possibility that ERβ plays
ARKO mice, an effect associated with a normalization of a role in modulating the circadian-rhythm patterns of
their E2 concentrations in brain (Jardí et al. 2018). Thus, it activity, as shown for females (Royston et al. 2014).
is reasonable to assume that the low activity phenotype of
ARKO mice is derived in large part from a lack of testosterone ‘Non-classical’ ER knock-in (NERKI) mice
substrate for aromatization into E2. Transgenic mice with a knock-in mutation in the ERα
selectively abolishing estrogen response element (ERE)
Aromatase knockout mice binding were originally generated to distinguish between
Mice in which E2 biosynthesis is disrupted by deletion classical and non-classical ERα actions in vivo (Jakacka
of the Cyp19a1 gene represent a useful tool to study the et al. 2002). Male ‘non-classical’ ER knock-in mice (NERKI)
implication of E2 in the regulation of male physiological mice show a reduced wheel running activity that does not
processes (Cooke et al. 2017). Most studies in male increase following challenge with E2 (Blattner & Mahoney
aromatase KO mice agree that both wheel running (Watai 2012, 2015). Based on these observations, it is tempting to
et al. 2007, Brockman et al. 2011) and SPA (Hill et al. speculate that ERα actions on wheel running activity are
2007) are diminished in the absence of E2. Nevertheless, dependent on ERα binding to ERE elements.
one study reported increased levels of wheel running in
male aromatase KO mice, as part of a broader spectrum of G-protein-coupled receptor 30 knockout
compulsive behaviors (Hill et al. 2007). It should be noted (GPR30KO) mice
that the authors analyzed pre-plateau phases of activity, The G-protein-coupled receptor 30 (GPR30) has been
which could have led to a mistaken estimation of the proposed as a membrane ER (Langer et al. 2010). There
‘true’ levels of wheel running. Be that as it may, aromatase are important phenotypic differences between the four
KO mice also show an impaired negative feedback of the independent GPR30KO mouse models available, most
HPG axis, with higher levels of serum testosterone and likely reflecting that other factors apart from deletion of
gonadotropins (Fisher et al. 1998, Jones et al. 2000, Öz GPR30 are contributing to the observed effects (Langer
et al. 2000). The fact that aromatase KO mice display a et al. 2010). In two different GPR30KO mouse models,
low activity phenotype even in the presence of excess males exhibited normal SPA levels (Sharma et al. 2013,
testosterone indicates a crucial role for aromatization in Kastenberger & Schwarzer 2014), but another study reported
the testosterone-induced stimulation of male physical that GPR30KO male mice displayed a mild reduction
activity. Supporting this notion, male aromatase KO mice in wheel running as well as an impaired left-ventricular
do not show an ORX-induced reduction of wheel running cardiac function (Delbeck et al. 2011). It therefore remains
(Brockman et al. 2011). uncertain whether GPR30 is physiologically relevant for
physical activity, and if so, if it contributes to E2-induced
Estrogen receptor α (ERα-) and β knockout responses and/or initiates independent mechanisms.
(ERβKO) mice
The generation of ERα and ERβKO mice has advanced Sex-hormone-binding globulin transgenic
our understanding of the mechanisms implicated in the (SHBG-tg) mice
estrogenic regulation of male physiology (Cooke et al. Sex-hormone-binding globulin (SHBG) is a high-affinity
2017). Similar to male aromatase KO mice, ERαKO mice binding protein for testosterone, DHT and E2 that is found

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circulating in humans but is almost completely lacking in et al. 2012) and, in turn, the capacity to exercise. In other
rodent serum. We recently showed in a humanized mouse words, testosterone might influence both the motivation
model expressing human SHBG that testosterone needs and/or the ability to partake in activity, referred here as
to be biologically available (i.e. not bound to SHBG) to central and peripheral actions, respectively (Fig. 2). Note
produce its stimulatory effects on wheel running (Jänne that the term ‘peripheral’ as applied to this classification
et al. 1998, Jardí et al. 2018). In SHBG-tg mice, the does not preclude the implication of the central nervous
majority of testosterone is bound by SHBG and cannot system (CNS) in the observed effects.
enter target tissues by the canonical way (Laurent et al.
2016a,b). Male SHBG-tg mice display features of a mild
Peripheral actions
androgen deficiency phenotype, including a 50% decrease
in wheel running activity (Jardí et al. 2018). As the decline In the next section, we will examine whether androgens
of androgen bioactivity in elderly men is also only mild provide greater tolerance to exercise by improving muscle
(Wu et al. 2008), SHBG-tg mice may be a more suitable strength, motor skills, metabolism and/or other peripheral
animal model to study late-onset hypogonadism than parameters in male rodents.
ORX.
The interpretation of studies using constitutive KO Muscle mass and strength
mice for steroid hormone receptors or the aromatase Both the mass and the ex vivo contractility of hindlimb
enzyme is subject to several limitations, including muscles show a mild reduction following ORX or AR
alterations of the HPG axis, developmental compensatory deletion in male mice (Axell et al. 2006, MacLean et al.
mechanisms and the impossibility to distinguish tissue- 2008, De Naeyer et al. 2014, Dubois et al. 2014). The
specific contributions. Nonetheless, findings in both differences in strength disappear when normalized for
aromatase and ERKO mice indicate that testosterone muscle weight, suggesting that the intrinsic contractile
actions on physical activity require normal aromatase and properties of muscle remain unaltered (Axell et al. 2006,
ERα functions. In contrast, we cannot draw conclusions MacLean et al. 2008, Hourdé et al. 2009, De Naeyer et al.
about the implication of AR from studies in global ARKO 2014). However, in five different myoblast or satellite-
mice because of their severe hypogonadism. However, cell-specific ARKO models, the mass and contractility
replacement and pharmacological studies made clear of hindlimb muscles were not, or marginally, affected
that the contribution of AR to testosterone effects cannot (Ophoff et al. 2009b, Chambon et al. 2010, Dubois et al.
be dismissed as minimal or trivial (see discussion in 2014, Ferry et al. 2014, Rana et al. 2016), whilst all five
the ‘Replacement and pharmacological studies in adult models showed a partial decrease in the weight of the
rodents’ section). androgen-sensitive perineal muscles. Nevertheless, the
expression of AR in the muscle cell lineage was required
for the full gain in muscle mass induced by mechanical
Mechanisms implicated in the effects of loading (Ferry et al. 2014), an effect that could be related
androgens and estrogens on male to the modulation of a reserve pool of adult muscle stem
physical activity cells by androgens (Kim et al. 2016). An overview of
the main features of the different muscle-specific ARKO
Despite the large amount of preclinical data showing models is presented in Table 1. Overall, the former studies
that androgens and estrogens control physical activity suggest a role for non-myocytic AR mediating the modest
in males, the mechanisms involved are not well actions of androgens on murine muscle. In this regard,
understood. Due to their pleiotropic nature, sex steroids a recent study points toward neuronal AR contributing
could stimulate physical activity by acting on multiple to maintain hindlimb muscle mass but not contractility
organs or systems. Of particular interest, the use of in male mice (Davey et al. 2017). The cellular targets
genetic techniques to manipulate neuronal pools in a underlying the anabolic actions of androgens on muscle
selective manner has allowed the identification of several have been reviewed by Dubois et al. (2012).
sex-steroid-responsive neural circuitries implicated in The ex vivo contractility studies referred to in the
the drive to engage in physical activity (Musatov et al. earlier sections do not support a role for an intrinsic
2007, Xu et al. 2011, 2015, Correa et al. 2015). Besides muscle dysfunction impairing the physical ability of ORX
these central mechanisms, androgens could also increase and ARKO mice. Yet, these findings do not exclude the
activity levels by improving muscle function (Dubois possibility that androgens regulate the neuromuscular

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function in vivo. Exercise training potentiates the
lox hemizygous mice show a phenotype of hyperandrogenization; bAR expression also reduced in brain and fat; cas assessed by SV weight; dtreadmill running; edetermined by DXA; frotarod test;
SPA
ND
ND
ND
ND
ND
ND
ND
ND
ND
(↑)
↓
stimulatory effects of androgens on muscle mass and
↑, increased; (↑), SPA restored to control values following normalization of testosterone levels; ((↑)), not statistically significant; ↓, decreased; =, unchanged; (=), minor impact on fatigue but no
strength (Guo et al. 2012, Cozzoli et al. 2013). Indeed, the
changes in maximal muscle tension; ND, not determined; neu, neurons; sat, satellite cells; skm, skeletal muscle myofibers; SPA, spontaneous physical activity; SV, seminal vesicles; testosterone,
running
Wheel
ND combination of both interventions benefits endurance

ND
ND
ND
ND
ND
=
=
=
↓
capacity in rodents (Vanzyl et al. 1995, Georgieva &
Boyadjiev 2004, Cozzoli et al. 2013), presumably through
increasing muscle function. However, ORX per se
performance
Motor
diminishes grip strength by only about 5–15% in some

ND
ND
ND
ND
ND
ND
ND
ND
=d
=d
=f but not all studies (Borst et al. 2007, Windahl et al. 2011,
White et al. 2013, Chisamore et al. 2016). The discrepancies
between studies might be due to the lack of sensitivity of
Contractile
function
the conventional forelimb grip strength test (Takeshita

ND
ND
ND
ND
ND
ND
ND
(=)
(=)
=
↓
et al. 2017). Additionally, the motivation to hold onto the

grid may vary between mice, causing inconsistencies in
the results. Be that as it may, a modest reduction (~10%) in
strength
grip strength was also found in two muscle-specific ARKO

Grip
ND
ND
ND
ND
ND
ND
ND
=
↓
↓
mouse models (Chambon et al. 2010, Dubois et al. 2014)

(Table 1). However, this did not impede muscle-specific
ARKO mice from displaying similar performances to their
Muscle
mass
ND
ND
WT littermates in both the voluntary wheel running and

=e
=
=
=
=
↓
the forced treadmill tests (Table 1). Overall, we conclude

that it is unlikely that the mild loss of muscle function
Serum testosterone/SV weight
following androgen deficiency in male mice is the main

driver of their low activity phenotype.
Motor skills
((↑))
ND
ND
=c
=c
↑c
↑c
=
↑
Preclinical data show that testosterone deficiency exerts

detrimental effects on male CNS health (Khasnavis et al.
Table 1 Overview of muscle- and neuronal-specific ARKO mouse models.
2013, Jayaraman et al. 2014, Atallah et al. 2017). In mice,

prepubertal ORX led to a poor performance in the rotarod
test, which the authors associated with a loss of midbrain
dopaminergic neurons (Khasnavis et al. 2013). Conversely,
Dubois et al. (2014, 2015),
also in the rotarod test, male testicular-feminized (Tfm)

Chambon et al. (2010)
Chambon et al. (2010)
Ophoff et al. (2009b)
mice expressing a non-functional AR performed better

Raskin et al. (2009)
Davey et al. (2017)

Jardí et al. (2017b)
Jardí et al. (2018)
Juntti et al. (2010)

Rana et al. (2016)
Rana et al. (2016)
than their WT littermates (Rizk et al. 2005). Although

Yu et al. (2013)
this might seem unexpected at first, the increased rotarod

performance of Tfm mice could be due to their lower
body weight, since these two variables share an inverse
correlation (Mao et al. 2015). Confirming the latter results,
Ref
expression retained in the hypothalamus.
male ARKO mice showed normal motor skills despite

their loss in striatal dopamine concentrations, a fact that
ARNeu;Thy1CreER(g)
might be explained by compensatory adaptations during

ARNeu;SynapsinICre
ARskm;HSACre(a,b)
ARNeu+glia;NesCre
ARNeu+glia;NesCre
ARNeu;CamKIIαCre
ARskm;MCKCre(a)
ARsat+skm;MyoD
ARskm;HSACreER
Mouse strain
ARskm;MCKCre
ontogeny (Jardí et al. 2018). In contrast to prepubertal

ARskm;HSACre
castration, ORX adult rodents showed an altered

performance in neither the rotarod test nor a nigrostriatal
pathology (Kritzer et al. 2001, Frye et al. 2008b, Khasnavis
et al. 2013). In the beam-walking test, which detects more
testosterone.
Myofibers
subtle motor coordination deficits, one study showed that

Cell type
Neurons
ORX mice performed worse than sham-operated controls

gAR
aAR
(McDermott et al. 1994). However, the performance in

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the latter test is in part influenced by motivational factors maintaining the capacity of male rodents for endurance
(McDermott et al. 1994, Curzon et al. 2009, Deacon 2013). activities. In contrast to what is observed in the voluntary
Regarding peripheral nerve health, both ORX and wheel running test, both ARKO mice and ORX rats
treatment with the antiandrogen flutamide reduced perform as well as control animals when forced to run
the synthesis of myelin proteins in the sciatic nerve of in a treadmill (Ophoff et al. 2009a, Petroianu et al. 2010).
male rodents (Magnaghi et al. 1999, 2004, Jayaraman Therefore, we conclude that androgens must act through
et al. 2014). In male mice, the decrease in myelin sheath other mechanisms beyond muscle to stimulate physical
was associated with macrophage infiltration (Jayaraman activity. Nevertheless, it is still possible that the increase
et al. 2014). Also in male mice, however, nerve function in activity over time potentiates the peripheral actions of
as assessed by sciatic nerve conductance studies was not androgens so that they acquire a greater importance in
altered following either ORX or ARKO (Jardí et al. 2018). sustaining activity (Fig. 2).
Taken together, we conclude that the adverse actions
of androgen deficiency on male neural health do not seem
Central actions
to translate into a deterioration of motor performance
that would limit physical activity, at least in adult rodents. In the next section, we will review the available findings
This does not preclude a role for androgens improving supporting the notion that testosterone is mainly acting
motor functional recovery in animal models of neural centrally to boost physical activity in male rodents.
disease (Uchida et al. 2009, Yoo & Ko 2012, Ponnusamy
et al. 2017). Central-nervous-system-specific KOs
In the mouse brain, AR and ERα display a moderate-to-
Other peripheral actions high regionalized expression profile, both showing a high
Skeletal muscle metabolism is critical to maintain fuel expression in the hypothalamus and brainstem, whilst AR
homeostasis during exercise. In both male rats and mice, levels are also abundant in the hippocampus and cerebral
androgen deficiency decreases muscle glycogen stores cortex (Gofflot et al. 2007, Lein et al. 2007, Mahfouz et al.
(Ramamani et al. 1999, Dubois et al. 2016), a suggested 2016). Four different whole brain ARKO mouse models
risk factor for fatigue development (Xirouchaki et al. have been generated so far, allowing to explore the impact
2016). Conversely, testosterone promotes glucose uptake of AR signaling in the nervous tissue without interfering
in skeletal muscle, although it is not clear to what extent with its peripheral functions (Raskin et al. 2009, Juntti
these effects are dependent on local AR actions (Sato et al. et al. 2010, Yu et al. 2013, Davey et al. 2017). An overview
2008, Ibebunjo et al. 2011, Dubois et al. 2016, Kelly et al. of the main features of the different neuronal ARKO
2016). In male mice, deletion of myogenic AR did not models is presented in Table 1. All four models show
affect either muscle glycogen stores (Ophoff et al. 2009b) an intact peripheral masculinization but unfortunately
or glucose tolerance (Dubois et al. 2016), in contrast to that have an impaired negative feedback of the HPG axis in
observed in both liver- (Lin et al. 2008) and adipose-tissue- males, resulting in higher serum levels of testosterone
specific ARKO mice (McInnes et al. 2012). The mechanisms and increased seminal vesicle weights (Raskin et al. 2009,
by which testosterone acts on metabolic pathways have Juntti et al. 2010, Yu et al. 2013, Davey et al. 2017). It is
been reviewed elsewhere (Kelly & Jones 2013). Besides nevertheless clear that the neuronal AR is required for the
metabolism, long-term ORX might affect exercise full expression of both male-typical sexual and aggressive
capacity in rodents by attenuating cardiac contractility, behaviors (Raskin et al. 2009, Juntti et al. 2010, Marie-Luce
as suggested by both in vivo echocardiographic and ex et al. 2013). Regarding physical activity, one study reported
vivo studies (Sebag et al. 2011, Eleawa et al. 2013). These an increase in SPA in Nestin-Cre neuronal ARKO mice,
alterations in cardiac contractile function could arise from although levels were restored to control values following
testosterone modulating Ca2+ handling in ventricular normalization of testosterone levels, pointing to an
myocytes, as recently reviewed (Ayaz & Howlett 2015). implication of the altered HPG axis in the observed effects
Additionally, androgens might influence adaptation to (Raskin et al. 2009). Contrarily, both SPA and wheel running
exercise by affecting hemoglobin and hematocrit levels were reduced by 60% in CamKII-Cre neuronal ARKO
(Bhasin et al. 2012), bone (Vanderschueren et al. 2014) mice, which retains only non-DNA-binding-dependent
and/or lung function (Townsend et al. 2012). However, AR actions (Davey et al. 2017). The latter results support
overall, the actions of androgens on these parameters or the interpretation that AR exerts a predominant role in
on muscle do not appear to play an indispensable role in the regulation of male physical activity by testosterone.

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Nonetheless, the above-mentioned studies did not include to estrogens in females, regulate male energy expenditure
littermates carrying the Cre transgene as controls. This is by acting on AR and/or ER-positive hypothalamic
particularly important since Cre-driven transgenes might neurons. Hypothalamic testosterone implants restored
exert independent effects on behavioral outcomes (Harno wheel running activity in ORX mice (Model et al. 2015).
et al. 2013, Chen et al. 2016). There is also the possibility However, since testosterone can diffuse to adjacent brain
that brain AR deletion at early stages may have indirectly areas, these might also be implicated in the observed
interfered with the organizational actions of testosterone effects. According to unpublished data of Ogawa et al.
by altering the HPG axis. To circumvent this caveat, we (Sano et al. 2013), site-specific ERα knockdown in the
recently generated a tamoxifen-inducible neuronal ARKO VMH completely abolished estrogen-induced facilitation
mouse model by using the Thy1-CreER, which drives gene of wheel running in male mice, similar to that described
deletion in extrahypothalamic regions of the brain (Jardí in females (Fig. 3). Notwithstanding the aforementioned
et al. 2017a). In contrast to CamKII-Cre neuronal ARKO limitation of treating male mice with estrogens, these
mice, deletion of AR in the CNS of pubertal male Thy1- results suggest that the VMH forms part of the neural
CreER neuronal ARKO mice did not affect wheel running circuitries mediating testosterone-induced wheel running
(Jardí et al. 2017b). The differences between studies could in male mice and highlights the implication of local
be attributed to the residual expression of hypothalamic aromatization in this brain region (Roselli et al. 1985).
AR in our mice (Jardí et al. 2017a). All in all, the study of In contrast to females, however, the regulation of male
neuronal ARKO mice has not provided clear answers so far physical activity by ERα expression in the VMH may
regarding the role of brain androgenic signaling in male involve a distinct module than the ventrolateral region
physical activity. To the best of our knowledge, only one since stimulation of this neuronal cluster did not increase
study reported a whole-brain ERαKO in male mice, but the SPA in male mice (Correa et al. 2015).
authors did not assess physical activity in these animals
(Xu et al. 2011). Medial amygdala
The neuronal basis regulating physical activity
Hypothalamic circuitries likely implies other neuronal circuitries beyond the
The hypothalamus is a key brain region that integrates hypothalamic energy balance systems, such as brain
nutritional, hormonal and neural information to regions involved in emotional and motivational
orchestrate adaptive physiological responses aimed to processing (Fig. 3). MeA neurons projecting to the
maintain the whole-body energy balance (Lenard & hypothalamus play a central role in generating emotional
Berthoud 2008, Schneeberger et al. 2014). Technical responses to chemosensory signals (Keshavarzi et al.
advances in viral-vector-mediated gene manipulation 2014, Takahashi 2014). Compared to other amygdalar
as well as in opto- and chemogenetics have allowed the nuclei, the expression of sex steroid receptors is enriched
identification of hypothalamic circuitries implicated in the MeA (Gofflot et al. 2007). In addition, a high
in the control of energy homeostasis by sex steroids. proportion of MeA neurons are aromatase positive, and
In particular, hypothalamic ERα signaling in female therefore this brain region might be exposed to relatively
rodents has been shown to exert a holistic control of high levels of E2 (Wu et al. 2009, Unger et al. 2015). In
their overall energy balance, influencing food intake as male mice, ERα signaling in the MeA is required for the
well as energy expenditure (Xu et al. 2017 for review on pubertal organizational actions of testosterone on social
this topic). Silencing of ERα in the ventromedial nucleus and sexual behaviors (Sano et al. 2016). In addition, Xu
of the hypothalamus (VMH) by small hairpin RNA et al. provided compelling evidence that ERα signaling
knockdown led to obesity in both female rats and mice, in the MeA stimulated SPA in males and secondarily
an effect associated with a decline in physical activity prevented body weight gain in the setting of high-fat diet
and thermogenesis (Musatov et al. 2007). Remarkably, (Xu et al. 2015). Particularly, deletion of ERα in the MeA
the effects of estrogens on these two parameters of of adult male mice resulted in a low activity phenotype,
energy expenditure seem to be driven by independent whilst the other components of energy expenditure,
ERα modules of the VMH (Xu et al. 2011, Correa et al. namely thermogenesis and resting metabolic rate,
2015). In male mice, global deletion of either AR or ERα remained unaltered (Xu et al. 2015). Together with
results in a decreased energy expenditure that might the VMH (unpublished data of Ogawa et al.), the MeA
predispose them to increased adiposity (Heine et al. 2000, is the only brain region identified so far that could be
Fan et al. 2005). It is not clear whether androgens, similar mediating the stimulatory effects of testosterone on

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male physical activity (Fig. 3). In addition, these findings receptors but also indirectly through the afferent neurons
also imply a role for brain aromatization in testosterone projecting to them (Kritzer & Creutz 2008, Aubele &
regulation of activity, similar to that described for male- Kritzer 2012, Purves-Tyson et al. 2012, Locklear et al.
typical aggressive behavior (Unger et al. 2015). 2017). However, it is not clear if the main contribution of
androgens to the overall dopaminergic tone is at the level
Rewarding and motivational pathways of dopamine synthesis, transport, release, metabolization
Besides the metabolic-regulatory circuitries of the and/or signaling (Aubele & Kritzer 2011, Khasnavis
hypothalamus and the MeA, brain regions controlling et al. 2013, Purves-Tyson et al. 2014, Wang et al. 2016).
rewarding and motivational functions might also be Testosterone restoration of basal extracellular dopamine
involved in the regulation of physical activity (Garland levels in the mesocortical dopaminergic pathway implies
et al. 2011) (Fig. 3). Endurance running generates a AR-dependent mechanisms, though this might not apply
rewarding aftereffect in both humans and rodents to the rest of dopaminergic systems (Kritzer 2003, Aubele
(Boecker et al. 2008, Fernandes et al. 2015). The traditional & Kritzer 2011, Locklear et al. 2017). Amphetamine
view attributes reward functions to dopamine signaling injections induce a hyperlocomotion response in rodents,
in the nucleus accumbens (Wise 2004, Palmiter 2008). which has been ascribed to the drug’s dopamine-releasing
However, recent findings show that other dopamine actions (Salahpour et al. 2008). Notably, ORX increases,
terminal fields are also components of the brain reward whilst testosterone restores the responsiveness to the
system, including the dorsal striatum, amygdala and locomotor effects of amphetamine in both rats and mice
frontal cortex (Wise 2004, Palmiter 2008). Following the (Purves-Tyson et al. 2015, Jardí et al. 2018). Overall, there
withdrawal of running wheels, mice selectively bred for is enough evidence to conclude that androgens influence
high wheel running showed a more pronounced increase the dopamine function in vivo. In addition, we recently
in striatal activation compared to controls (Rhodes et al. showed that systemic administration of the dopamine
2003). Also in male mice, the relative volume of the receptor 2 antagonist L-741,626 reduced by almost 50%
striatum predicted the levels of subsequent wheel running the distance ran by ORX+testosterone-treated mice,
activity on in vivo MRI (Cahill et al. 2015). whilst it had no effect on castrated mice receiving vehicle
Testosterone might act directly on male midbrain (Jardí et al. 2018). Further research is required to narrow
dopamine neurons by binding to their AR and/or ERs down the relevant androgen-responsive components of
Figure 3
Schematic overview of the proposed neuronal
mechanisms by which testosterone increases male
physical activity (see text). A, androgens; DA,
dopamine; E2, estradiol; MeA, medial amygdala;
NAcc, nucleus accumbens; SPA, spontaneous
physical activity; VMH, ventromedial
hypothalamus.

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the dopamine system that might be mediating the effects Nevertheless, other studies using larger cohorts and activity-
of testosterone on physical activity (Jardí et al. 2018). based questionnaires yielded conflicting observations (Amin
To summarize, the control of activity and metabolism et al. 2000, Beutel et al. 2005, Tajar et al. 2012). Similarly,
are regulated in a coupled manner by estrogen-responsive there is no clear evidence from interventional studies that
hypothalamic pathways in females. The implication supports a causal effect of sex steroids on physical activity.
of similar mechanisms in males remains to be proven. Several double-blind, placebo-controlled clinical trials have
Extrahypothalamic inputs coming from brain regions examined the effects of testosterone replacement on both
related to emotional and rewarding processes might muscle as well as functional mobility in large samples of
modulate the homeostatic control exerted by the community-dwelling men with late-onset hypogonadism
hypothalamus. Testosterone might act on the MeA to (Emmelot-Vonk et al. 2008, Srinivas-Shankar et al. 2010,
increase physical activity in males following aromatization Snyder et al. 2016, Storer et al. 2016). Overall, testosterone
into E2 (Fig. 3). The dopamine system is another potential supplementation in hypogonadal men results in modest
candidate mediating the effects of testosterone on gains in muscle mass and strength, but the benefits on
activity, but further research is required to determine the their overall physical function are inconsistent (Emmelot-
mechanisms implicated (Fig. 3). Vonk et al. 2008, Srinivas-Shankar et al. 2010, Snyder et al.
2016, Storer et al. 2016). In addition, testosterone therapy
in men is hampered by its potential adverse effects on the
Human evidence cardiovascular system and the prostate (Basaria et al. 2010).
Therefore, the clinical meaningfulness of testosterone
After reviewing the available data, it is clear that androgens replacement in healthy elderly men with late-onset
regulate physical activity in male rodents, but in men, hypogonadism remains debated. Remarkably, treatment
it remains a question. The etiology of physical activity with testosterone for 6 months did not affect the self-
in humans appears to be much more complex than in reported levels of activity in a cohort of 274 community-
animals, being influenced by the social and cultural dwelling frail elderly men with low levels of testosterone
environments (Bauman et al. 2012). Heritability studies (Srinivas-Shankar et al. 2010). Smaller studies in similar
in twins and families suggest that our drive to engage in patient populations also showed a lack of testosterone effect
exercise is also determined by intrinsic biological processes on activity scores (Kenny et al. 2001, 2010). Contrarily, a
(Simonen et al. 2002, Bouchard & Rankinen 2006, Stubbe positive association between serum testosterone levels and
et al. 2006). Nevertheless, the genetics of physical activity activity scores was found in a cohort of elderly men receiving
remain currently unknown, with only limited genotype– a combined treatment of testosterone and recombinant
phenotype associations found so far. A candidate gene human growth hormone (Sattler et al. 2011). The authors
study in postmenopausal women showed an association hypothesized that this association might reflect a central
between aromatase gene polymorphisms and time spent in action of testosterone on the individual’s mood (Sattler
physical activity (Salmen et al. 2003). This association for et al. 2011). To date, there is no real evidence supporting
the aromatase gene was replicated in a GWAS for leisure- the former premise, with the effects of testosterone on
time exercise behavior but only in one out of the two vitality and mood parameters in elderly men being unclear
populations of adult men included (De Moor et al. 2009). (Snyder et al. 1999, Srinivas-Shankar et al. 2010, Snyder et al.
Polymorphisms in the AR or ERα gene were not associated 2016). More importantly, all previous studies were based on
with the amount of physical activity per week in either activity questionnaires, which show limited reliability and
young or middle-aged men or women (Lorentzon et al. 1999, accuracy (Strath et al. 2013). Thus, caution should be taken
Salmén et al. 2000, Okura et al. 2003, Walsh et al. 2005). when interpreting the data. In conclusion, it is premature to
Aging is associated with a decline in physical activity in both support or reject convincingly the implication of androgens
genders (Jones et al. 2011) as well as with a gradual reduction in physical activity in men.
in serum testosterone, especially its free fraction, in men
(Wu et al. 2008). So far, studies of the association between
late-onset hypogonadism and the age-related decline in Conclusion
activity have produced inconsistent results. A small cross-
sectional study in community-dwelling men showed an A wide body of preclinical evidence makes a strong case
association between low testosterone levels and a decrease for androgens as potential candidates contributing to
in pedometer-recorded step counts (Cobo et al. 2017). the biological basis regulating male physical activity.

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Nonetheless, reliable human studies are lacking and

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Accepted 9 May 2018
Accepted Preprint published online 9 May 2018

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Journal of F Jardí et al.

Androgens and physical activity 238:1 R31–R52

Androgen and estrogen actions on male physical

Correspondence should be addressed to F Jardí: ferran.jardi@kuleuven.be

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(2.3 km vs. 3.8 km; Jardí et al. 2018) and both testosterone

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function in vivo. Exercise training potentiates the

ND combination of both interventions benefits endurance

diminishes grip strength by only about 5–15% in some

the conventional forelimb grip strength test (Takeshita

et al. 2017). Additionally, the motivation to hold onto the

grip strength was also found in two muscle-specific ARKO

mouse models (Chambon et al. 2010, Dubois et al. 2014)

WT littermates in both the voluntary wheel running and

the forced treadmill tests (Table 1). Overall, we conclude

following androgen deficiency in male mice is the main

Preclinical data show that testosterone deficiency exerts

2013, Jayaraman et al. 2014, Atallah et al. 2017). In mice,

also in the rotarod test, male testicular-feminized (Tfm)

mice expressing a non-functional AR performed better

Davey et al. (2017)

Juntti et al. (2010)

than their WT littermates (Rizk et al. 2005). Although

this might seem unexpected at first, the increased rotarod

expression retained in the hypothalamus.

male ARKO mice showed normal motor skills despite

might be explained by compensatory adaptations during

ontogeny (Jardí et al. 2018). In contrast to prepubertal

castration, ORX adult rodents showed an altered

subtle motor coordination deficits, one study showed that

ORX mice performed worse than sham-operated controls

(McDermott et al. 1994). However, the performance in

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http://joe.endocrinology-journals.org © 2018 Society for Endocrinology

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Nonetheless, reliable human studies are lacking and

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http://joe.endocrinology-journals.org © 2018 Society for Endocrinology

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http://joe.endocrinology-journals.org © 2018 Society for Endocrinology

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http://joe.endocrinology-journals.org © 2018 Society for Endocrinology

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http://joe.endocrinology-journals.org © 2018 Society for Endocrinology

Received in final form 29 March 2018

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