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J. Clin. Med. 2022, 11, 6202. https://doi.org/10.3390/jcm11206202 www.mdpi.com/journal/jcm
Review
Relationship between Testosterone and Sarcopenia
in Older-Adult Men: A Narrative Review
Kazuyoshi Shigehara *, Yuki Kato, Kouji Izumi and Atsushi Mizokami
Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science,
13-1, Takaramachi, Kanazawa 920-8641, Japan
* Correspondence: kshigehara0415@yahoo.co.jp; Tel.: +81-76-265-2393; Fax: +81-76-234-4263
Abstract: Age-related decline in testosterone is known to be associated with various clinical symp-
toms among older men and it is possible that the accompanying decline in muscle mass and strength
might lead to a decline in motor and physical functions. Sarcopenia is an important pathophysio-
logical factor associated with frailty in older adults and is diagnosed in older adults as a decrease in
muscle strength, muscle mass, and walking speed, which can lead to a significant decline in the
quality of life and shortened healthy life expectancy. Testosterone directly interacts with the andro-
gen receptor expressed in myonuclei and satellite cells and is also indirectly associated with muscle
metabolism through various cytokines and molecules. Currently, significant correlations between
testosterone and frailty in men have been confirmed by numerous cross-sectional studies. Many
randomized control studies have also supported the beneficial effect of testosterone replacement
therapy (TRT) on muscle volume and strength among men with low to normal testosterone levels.
In the world’s aging society, TRT can be a tool for preventing the onset of sarcopenia in older-adult
men. This narrative review aims to show the relationship between the decline in testosterone with
age, sarcopenia, and frailty, as well as the effects of testosterone replacement therapy on muscle
mass and strength.
Keywords: testosterone; sarcopenia; frailty; muscle
1. Introduction
The aging of the population has been become a worldwide problem and maintaining
and even improving the quality of life (QOL) of middle-aged and older-adult men has
become an important issue. As the population ages, healthy life expectancy becomes in-
creasingly more important than mean life expectancy. Life expectancy refers to the period
from birth to death and includes periods requiring long-term care, while healthy life expec-
tancy indicates the period without significant health issues in daily life. In many developed
countries, the difference between the mean life expectancy and the healthy life expectancy
tends to be greater and extending healthy life expectancy has become a clinical concern.
In men, serum testosterone levels decrease with age by 2–3% annually, a decline as-
sociated with specific symptoms of late-onset hypogonadism (LOH) syndrome [1], whose
various clinical signs and symptoms include decreased libido and sexual desire, muscle
weakness, increased visceral fat, obesity, osteoporosis, deterioration of insulin resistance,
and dyslipidemia, which are significantly associated with aging [1–4]. These clinical signs
and symptoms can often impair the QOL of middle-aged and older-adult men and are
becoming a serious issue in the present aging society. Testosterone replacement therapy
(TRT) is a widely accepted tool for improving these clinical conditions in hypogonadal
men and its clinical use has increased substantially over the past several years [1].
Citation: Shigehara, K.; Kato, Y.;
Izumi, K.; Mizokami, A.
Relationship between Testosterone
and Sarcopenia in Older-Adult Men:
A Narrative Review. J. Clin. Med.
2022, 11, 6202. https://doi.org/
10.3390/jcm11206202
Academic Editor: Wing Hoi Cheung
Received: 30 September 2022
Accepted: 18 October 2022
Published: 20 October 2022
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and institu-
tional affiliations.
Copyright: © 2022 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (https://cre-
ativecommons.org/licenses/by/4.0/).
J. Clin. Med. 2022, 11, 6202 2 of 13
Sarcopenia is an important pathophysiological factor of frailty in older adults and is
diagnosed with a decrease in muscle strength, muscle mass, and low physical perfor-
mance [5]. Sarcopenia and frailty are significantly associated with an increased risk of falls
and fractures in older-adult men, which can lead to a serious decrease in QOL and short-
ening of healthy life expectancy [6,7]. Preventive measures are, therefore, required.
Testosterone is an important hormone for maintaining skeletal muscle mass and
strength in men and numerous previous studies have suggested that testosterone defi-
ciency is significantly associated with the onset of sarcopenia. The present review sum-
marizes the current evidence on the relationship between testosterone and sarcope-
nia/frailty. The review also investigated whether TRT for hypogonadal men with sarco-
penia can improve muscle mass, strength, and physical function.
2. Materials and Methods
A review of the PubMed, MEDLINE, and EMBASE databases was conducted to
search for original articles, systematic reviews, and meta-analyses under following key-
words: “testosterone” or “hypogonadism” or “sarcopenia” or “frailty” or “muscle.” There
were no limitations in terms of language, publication status, or study design. Papers pub-
lished between January 1990 and October 2020 were collected. We also checked the refer-
ences of systematic reviews and meta-analyses carefully to identify additional original
articles for inclusion. Two reviewers screened the search results and the data were col-
lected in June 2022.
The papers suitable for the topic “testosterone and sarcopenia” from the journal da-
tabases were chosen for the present analysis. For “efficacy of testosterone replacement
therapy in sarcopenia”, we reviewed papers published since 2010.
3. Sarcopenia: Definition and Etiology
One of the phenomena of human aging is the progressive decline in skeletal muscle
mass, which can result in negative effects on physical fitness and function. The prevalence
of sarcopenia is ~5–50% in older adults aged 65 years and older [8–10]. In 1989, Irwin Ros-
enberg proposed the term “sarcopenia” (from the Greek “sarx” for flesh and “penia” for
deficiency) for age-related loss of muscle mass [11]. Currently, sarcopenia is defined as
age-related loss of skeletal muscle mass and strength. Various differing definitions of sar-
copenia have been proposed; however, there is still no widely accepted definition [12].
Baumgartner et al. first defined sarcopenia as a decline of less than 2 standard deviations
below the mean of a young reference group in appendicular skeletal muscle mass [13].
Since then, the algorithm proposed by the European Working Group on Sarcopenia in
Older People (the presence of both low muscle mass and low muscle strength or perfor-
mance) [14] and by the Foundation for the National Institutes of Health sarcopenia project
(appendicular lean mass adjusting for body mass index to define low muscle mass) [15]
have been generally used for diagnosing sarcopenia. Recently, the Asian working group
for sarcopenia suggested an alternative algorithm (Figure 1) [16]. This Asian consensus
has plenty in common with the European consensus and the cases with decreased walking
speed or grip strength are defined as individuals with decreased muscle performance.
Those cases accompanied by decreased muscle mass are defined as having sarcopenia.
According to the Asian consensus, the reported prevalence for sarcopenia is 16.5% for
men and 19.9% for women in Japan [17], which is likely to be approximately similar to
that reported previously in other countries [18–20].
J. Clin. Med. 2022, 11, 6202 3 of 13
Figure 1. Algorithm for sarcopenia diagnosis (the Asian working group for sarcopenia).
For certain cases, the cause of the sarcopenia can be clearly identified, whereas no
clear cause can be determined in other cases. Sarcopenia caused only by aging is classified
as “primary” (age related) and sarcopenia caused by activities of daily living, nutrition,
and illness is classified as “secondary sarcopenia” (Table 1). The most common cause of
muscle weakness in older adults is age-related muscle atrophy. In general, skeletal muscle
decreases by 25–30% and muscle strength decreases by 30–40% in individuals in their 70s
when compared with those in their 20s, with muscle mass decreasing by approximately
1–2% every year after 50 years of age [21]. In addition, older-adult men have an increased
risk of developing sarcopenia through various factors, such as lifestyle changes, less exer-
cise, more physical illnesses (severe organ failure, neuromuscular disease, inflammatory
disease, malignant tumors, etc.), undernourishment, and appetite loss. Therefore, the eti-
ology of sarcopenia is often assumed to be multifactorial [22]. Sarcopenia develops con-
currently with changes in hormones (testosterone and growth hormones) and inflamma-
tory cytokines involved in the muscle metabolism due to these causes. In particular, tes-
tosterone is significantly correlated with maintaining bone strength, muscle mass, and
muscle strength among men and it has been found that the pathogenesis of sarcopenia in
men might be associated with testosterone decline with aging.
Table 1. Classification of sarcopenia by causes.
Primary Sarcopenia
Age-related No clear causes other than aging
Secondary Sarcopenia
Daily living-related Bedridden, lack of exercise, ataxia, weight loss
Nutrition-related Malabsorption, gastrointestinal disease, appetite loss, lack
of energy, low protein intake
Disease-related Severe
organ failure, inflammatory diseases, malignancies,
endocrine diseases
4. Testosterone and Sarcopenia
4.1. Testosterone and Muscle Metabolism
More than 95% of serum testosterone is produced by the Leydig cells of the testes
through stimulation by LH from the pituitary gland in males [23]. Testosterone is mostly
bound to sex-hormone-binding globulin or albumin and 1–2% exists in free form; how-
ever, it binds loosely to albumin and can easily become free form [24]. Free testosterone
(FT) is taken up into target cells through the cell membrane and binds to androgen recep-
tor (AR) in the cytoplasm. Testosterone bound to AR is converted to dihydrotestosterone
J. Clin. Med. 2022, 11, 6202 4 of 13
by 5α-reductase. Testosterone and DHT bind to the same AR to form a dimeric complex
and this dimer binds to specific sites on DNA and activates target genes, resulting in the
expression of androgenic actions [25]. In general, the length of the CAG repeats present in
the AR gene shows an inverse relationship, with AR susceptibility and length of their re-
peats differing between the races, with the length increasing in the order of black people,
white people, and Asian people [26].
There are numerous ARs in muscle tissue and testosterone plays an important role
in maintaining muscle mass and strength. It is, therefore, logical to assume that age-re-
lated testosterone decreases are closely associated with the onset of sarcopenia in men.
Conversely, the anabolic effects of testosterone on muscle hypertrophy have been well
established [27].
In human studies, testosterone directly interacts with AR expressed in myonuclei and
satellite cells [28,29], which is a major source for the establishment of hypertrophying
muscle fibers (Figure 2). Testosterone has a potential effect on myogenesis and muscle
hypertrophy by increasing protein synthesis and inhibiting protein degradation in muscle
cells [30,31] and then promoting mitotic activity and differentiation of satellite cells
[29,32]. Numerous in vitro studies have demonstrated the anabolic actions of testosterone
through increases in insulin-like growth factor-1 expression [33,34], beta-catenin and T-
cell factor-4 pathway signaling [35], regulation of peroxisome proliferator-activated re-
ceptor-gamma coactivator 1 alpha, and p38 mitogen-activated protein kinases [36] and
stimulating the hypertrophy of L6 myoblasts in a signal cascade dependent on Ark and
mammalian target of rapamycin [37]. The mechanism by which low testosterone levels
cause muscle atrophy is also being clarified. The catabolic action of testosterone has been
described through the enhancement of muscle atrophy-F-box (atrogin-1) and muscle
RING-finger protein-1 expression [38]. Moreover, an increase in hypertrophied visceral
fat due to testosterone decline contributes to an increase in certain inflammatory cyto-
kines, such as interleukin-6 and tumor necrosis factor (TNF-α), which have catabolic ef-
fects on skeletal muscle [39].
Figure 2. Molecular mechanisms in the development of sarcopenia. IGF-1, insulin-like growth fac-
tor–1; mTOR, mammalian target of rapamycin; TCF-4, T-cell factor-4; PGC-1α, peroxisome prolifer-
ator-activated receptor-gamma coactive tor 1 alpha; MAPK, p38 mitogen-activated protein kinases;
TNF-α, tumor necrosis factor; IL-6, interleukin-6; MuRF-1, muscle atrophy-F-box (atrogin-1) and
muscle RING-finger protein-1. An upward red arrow indicates “increase”, whereas a downward
one indicates "decrease".
J. Clin. Med. 2022, 11, 6202 5 of 13
4.2. Clinical Effects of Testosterone for Muscle
Androgen deprivation therapy (ADT) for prostate cancer can result in decreased
muscle mass and muscle weakness. A prospective study that included 79 patients with
prostate cancer and employed a 12-month ADT reduced the participants’ lean body mass
by 3.8% and increased their body fat percentage by 11% [40]. According to a report exam-
ining 39 patients with prostate cancer, the muscle mass of the rectus femoris, sartorius,
and quadriceps estimated using computed tomography after ADT for 14–20 weeks was
21.8% and 15.4%, and 16.6%, respectively [41]. In general, patients with prostate cancer
who undergo ADT are reported to have 3.0–6.0% lower muscle mass and 15–17% lower
muscle strength than healthy individuals of the same age [42]. These findings suggest that
testosterone decline with age is a trigger for muscle loss among older-adult men.
Several studies have demonstrated an association between serum testosterone levels
and muscle mass and strength in men [43–49]. Appendicular muscle mass was signifi-
cantly correlated with serum FT levels in non-Hispanic white men in a cross-sectional
study from the New Mexico Aging Process Study [43]. In 403 men from The Netherlands,
bioavailable testosterone and luteinizing hormone had a significant correlation with grip
and leg extensor strength [44]. The MINOS cohort study that included 845 French men
also found that the group with the lowest appendicular muscle mass had a significantly
lower FT level [45]. A previous National Health and Nutrition Examination Survey study
of men revealed that higher testosterone levels at physiologic levels were associated with
higher body lean mass and lower body fat mass [46]. A cross-sectional study that included
922 men aged over 60 years found that weaker muscle strength was observed in the men
within the lowest tertile of FT compared with those in the highest tertile (adjusted odds
ratio: 2.28; 95% CI 1.33–3.91) [47]. A recent study that investigated the association between
serum testosterone levels and body composition among 3875 men in China found a posi-
tive correlation between testosterone levels and appendicular lean mass index [48]. A re-
cent systematic review also reported that testosterone could have a potential effect on
muscle mass and strength [49]. Although there are a few studies that failed to identify an
effect for testosterone on muscle strength [50,51], current evidence has likely established
a positive correlation between testosterone and muscle condition.
4.3. Evidence of Testosterone Decrease in Frailty/Sarcopenia
Numerous cross-sectional studies have confirmed significant correlations between
testosterone and frailty in men [52–54]. A Massachusetts cohort study that included 646
men aged 50–86 years investigated the relationship between testosterone and frailty and
its components [52]. Although no association was observed between total testosterone
(TT) or FT levels and the frailty phenotype, there was a significant association between TT
levels and the frailty components of grip strength and physical activity. Cross-sectional
data from the Toledo Study for Healthy Aging that included 552 men showed that the risk
of frailty decreases linearly with testosterone levels (adjusted OR 2.9 (95% CI 1.6–5.1) and
1.6 (95% CI 1.0–2.5) in TT and FT, respectively) [53]. Another cross-sectional study based
on data from the Longitudinal Aging Study Amsterdam (LASA) that included 623 men
also suggested a potential correlation between low TT or bioavailable testosterone levels
and impaired mobility and low muscle strength in men [54]. In a study of 461 individuals
aged 60 years and older, a low FT value (<243 pmol/L) was a significant risk factor for
developing frailty [55]. A recent meta-analysis that included 11 studies reported that TT
(OR 1.37, 95% CI 1.09–1.72) and FT (OR 1.55, 1.06–2.25) were significantly associated with
frailty in older men [56].
A number of longitudinal studies have found an equivocal future risk for developing
frailty and sarcopenia due to low baseline testosterone [57–59]. A longitudinal study that
included 957 community-dwelling adult men in Japan demonstrated that low calculated
FT (OR 2.14, 95% CI 1.06–4.33) and FT (OR 1.83, 95% CI 1.04–3.22) were associated with
the onset of sarcopenia [57]. Another report that included 1445 men from the Framingham
J. Clin. Med. 2022, 11, 6202 6 of 13
Offspring Study revealed that low FT levels were significantly associated with the inci-
dence of mobility, limiting its progression, but was not associated with subjective health,
usual walking speed, or handgrip strength after 6.6 years of follow-up [58]. A longitudinal
study that included 486 men from LASA and 1071 well-functioning men from the Health,
Aging and Body Composition study demonstrated that baseline FT was not associated
with changes in physical performance, walking speed, or muscle strength after 3 years of
follow-up [59]. Further studies are needed to conclude whether low testosterone levels
predict the progression and development of incident frailty and sarcopenia.
5. Efficacy of Testosterone Replacement Therapy for Sarcopenia
5.1. Indication of Testosterone Replacement Therapy
The indication of TRT requires the presence of low serum testosterone level. How-
ever, the cut-off value of serum testosterone for a diagnosis of hypogonadism is still con-
troversial, with multiple international societies’ recommendations [60]. The diagnosis of
hypogonadism for the recommendation of TRT in the guidelines of the Consensus Com-
mittee of the American Urological Association (AUA) is TT ≤ 3.0 ng/mL [61]. On the other
hand, according to the International Society for Sexual Medicine (ISSM), the International
Society for the Study of Aging Males (ISSAM), and the European Association of Urology
(EAU), serum TT levels above 12 nmol/L (346 ng/dL) are normal and TT levels below 8
nmol/L (231 ng/dL) indicate hypogonadism, meaning that TRT may be appropriate
[3,4,62–64]. In cases with borderline TT values of 8–12 nmol/L, hypogonadism should be
diagnosed with calculated FT values.
5.2. Efficacy of Testosterone Replacement Therapy for Sarcopenia
The randomized controlled trials (RCTs) published since 2010 are summarized in Ta-
ble 2 [50,65–82]. Their results varied by target population, type of testosterone formula-
tion, and testosterone dosage. Many of the RCTs investigated the effects on muscle of TRT
among men with low to normal testosterone levels and 15 of 19 RCTs supported certain
merits of TRT on muscle volume [50,67–70,72–77,79–82]. The other four studies, however,
failed to demonstrate that TRT contributes to improving muscle mass or strength
[65,66,71,78]. In one of the RCTs, the study population consists of patients with opioid-
induced hypogonadism, which was a specific population differing from the LOH syn-
drome [65]. The other three studies investigated the efficacy of exercise and/or diet added
to TRT on muscle mass and strength but did not study the direct effects of TRT in isolation
[66,72,78]. These findings suggest that monolithic TRT for hypogonadal men can contrib-
ute to improving muscle mass and strength. However, certain clinical interventions, such
as exercise and diet added to TRT, are likely to be the most important factor for maintain-
ing muscle function among older-adult men.
Table 2. Randomized control trials to investigate the effects of testosterone replacement therapy
(TRT) on muscle (published since 2010).
Author Year Subjects Number TRT Regimens
(Add-on Therapy) Effects Ref.
Kolind
(Denmark) 2022
Hypogonadal men
with opioid-treated
chronic pain
(TT < 12 nmol/L)
41 TRT 20
placebo 21
TU 1000 mg,
intramuscular
for 24 weeks
TRT did not improve muscle function
(leg-press maximal voluntary
contraction, leg
extension power and
handgrip strength).
[65]
Barnouin
(USA) 2021
Hypogonadal men
with obesity
(TT < 10.4 nmol/L)
83 TRT 42
placebo 41
T gel daily
for 6 months
(diet + exercise)
TRT might attenuate the weight loss–
induced reduction in muscle mass.
There was no significant difference in
muscle strength between the two
groups.
[66]
J. Clin. Med. 2022, 11, 6202 7 of 13
Chasland
(Australia) 2021
Men with obesity and
low-
normal serum TT
(TT 6–14 nmol/L)
80 TRT 40
placebo 40
T gel 100 mg/day
for 23 weeks
(exercise)
TRT
increased total, leg, and arm lean
mass but did not affect aerobic
capacity (Vo2peak) and muscle
strength.
[67]
Glintborg
(Denmark) 2020
Men with opioid-
induced
hypogonadism
(TT < 12 nmol/L)
41 TRT 20
placebo 21
TU 1000 mg,
intramuscular
for 24 weeks
TRT increased lean body mass. [68]
Gagliano-Juca
(USA) 2018
Older men with
mobility limitations
(TT <
350 ng/dL or FT
< 50 pg/mL)
99 TRT 46
placebo 53
T gel 100 mg/day
for 6 months
TRT improved muscle strength and
physical function (assessed by loaded
stair-climbing power).
[69]
Storer
(USA) 2017
Eugonadal and
hypogonadal men
(TT 100–
400 ng/dL or
FT < 50 pg/mL)
256 TRT 135
placebo 121
T gel 75 mg/day
for 3 years
TRT strengthened chest-
press strength
and power, and leg-press power. [70]
Ng Tang Fui
(Australia) 2016
Hypogonadal men
with obesity
(TT < 12 nmol/L)
100 TRT 49
placebo 51
TU 1000 mg
intramuscular
for 56 weeks (diet)
TRT did not increase muscle volume
but did
attenuate the reduction in lean
mass by diet compared with the
controls.
[71]
Dias
(USA) 2016 Hypogonadal men
(TT < 350 ng/dL) 39
TRT 13
placebo 9
other 13
T gel 50 mg/day
for 12 months
TRT improved knee strength and fast
gait at 12 months compared with
baseline.
[72]
Konaka
(Japan) 2016 Hypogonadal men
(FT < 10.8 pg/mL) 334 TRT 169
control 165
TE 250 mg/4 weeks
for 52 weeks
TRT improved muscle volume and
grip power. [73]
Magnussen
(Denmark) 2016
Hypogonadal men
with DM
(BioT < 7.3 nmol/L)
43 TRT 22
placebo 21
T gel 50 mg/day
for 24 weeks TRT increased lean body mass. [74]
Sinclair
(Australia) 2016
Hypogonadal men
with cirrhosis
(TT <
12 nmol/L or FT
< 230 pmol/L)
101 TRT 50
placebo 51
TU 1000 mg/6–12
weeks intramuscular
for 12 months
TRT increased total lean body and
appendicular lean muscle mass. [75]
Borst
(USA) 2014 Hypogonadal men
(TT ≤ 300 ng/dL) 60 TRT 31
placebo 29
TE 125 mg/weeks
I intramuscular for 12
months
(finasteride)
TRT
increased upper and lower body
muscle strength by 8–14% and fat-
free
mass by 4.04 kg.
[76]
Giamatti
(Australia) 2014
Hypogonadal men
with type 2 diabetes
mellitus
(TT ≤ 300 ng/dL or
BioT ≤ 70 ng/dL)
88 TRT 45
placebo 43
TU 1000 mg/6–12
weeks intramuscular
for 56 weeks
TRT increased lean body mass. [77]
Stout
(UK) 2012
Men with chronic
heart failure
(TT < 15 nmol/L)
28 TRT 15
placebo 13
Testosterone 100
mg/2 weeks
intramuscular
for 12 weeks
(exercise)
TRT could not improve the shuttle
walk test and hand grip strength
compared with placebo.
[78]
Behre
(Australia) 2012
LOH men
(TT < 15 nmol/L or
BioT < 6.68 nmol/L）
362 TRT 183
placebo 179
T gel 50–75 mg/day
for 6 months TRT increased lean body mass. [79]
Travison
(USA) 2011
Hypogonadal men
with mobility
limitation (TT 100–
350 ng/dL
or FT < 50 pg/mL)
209 TRT 106
placebo 103
T gel 100 mg/day
for 6 months
TRT increased leg-press and chest-
press strength and stair-climbing
power but could not improve walking
speed.
[80]
Atkinson
(UK) 2010 Hypogonadal frail
men (TT < 12 nmol/L)
30 TRT 16
placebo 14
T gel 50 mg/day
For 6 months.
TRT helped preserve muscle
thickness. There was no significant [81]
J. Clin. Med. 2022, 11, 6202 8 of 13
effect of treatment on fascicle length
or pennation angle.
Kenny
(USA) 2010
Hypogonadal frail
men
(TT < 350 ng/dL)
131 TRT 69
placebo 62
T gel 5 mg/day
for 12–24 months
There was an increase in lean mass in
the testosterone group but no
differences in strength or physical
performance.
[50]
Srinivas-
Shankar
(UK)
2010
Hypogonadal frail
men
(TT <
12 nmol/L or FT
< 250 pmol/L)
274 TRT 138
placebo 136
T gel 50 mg/day
for 6 months
Isometric knee extension peak torque
was improved, and lean mass was
increased in the TRT group.
[82]
TRT, testosterone replacement therapy; TT, total testosterone; FT, free testosterone; BioT, bioavaila-
ble testosterone; TU, testosterone undecanoate; TE, testosterone enanthate.
A recent meta-analysis demonstrated that TRT produced an increase in lean body
mass of 2.54 kg (95% CI 1.27–3.80; p < 0.001) and an increase in handgrip strength of 1.58
kg (95% CI 0.17–3.0; p = 0.03) and concluded that TRT showed a beneficial effect on sar-
copenic components, such as muscle mass and strength, as well as on physical perfor-
mance in middle-aged and older adults [83]. Another recent systematic review also sup-
ports certain beneficial contributions of TRT to muscle condition and function [84].
However, there are limited data currently available regarding the direct effects of
TRT on preventing sarcopenia, which is diagnosed based on muscle mass, strength, and
physical functions, and the conclusions drawn from those data have been conflicting
[50,69,72,80]. Two RCTs demonstrated that TRT contributed to an improvement in both
muscle mass/strength and physical performance [69,72]. However, a previous study that
included 209 hypogonadal men with mobility limitations reported that 6 months of TRT
could increase muscle strength and stair-climbing power but could not improve walking
speed [80]. Another study observed a significant increase in lean mass in the TRT group,
whereas there were no differences in strength or physical performance between the con-
trol and TRT groups [50]. Furthermore, clinical studies targeted to Asian people, espe-
cially men, have been extremely limited. Further studies with large numbers of partici-
pants and various races are likely to reach a more definite conclusion regarding the effects
of TRT on sarcopenia.
Studies have examined the dose-dependent effects of testosterone. A study that in-
cluded healthy male adult participants randomly assigned to a weekly administration
group (100 mg of testosterone enanthate weekly in an intramuscular injection) and a monthly
group (alternating months of 100 mg of testosterone or placebo) for 5 months demonstrated
that both groups had an increase in fiber diameter and peak power, with the weekly treatment
being five-fold more effective than the monthly treatment [85]. In addition, a higher dose of
testosterone can affect muscle mass and strength, not only for hypogonadal men but also eu-
gonadal older men and healthy young men [86]. These data suggest that the anabolic effects
of TRT are likely to be dose dependent to a certain extent. However, higher doses are associ-
ated with a high frequency of adverse effects and caution is required.
5.3. Other Systemic Effects of Testosterone Replacement Therapy
In general, TRT is rarely used to treat men solely for sarcopenia and is a widely ac-
cepted tool to improve various symptoms and clinical conditions occurred in hy-
pogonadal men, including decreased libido and sexual desire, depression, muscle weak-
ness, obesity, deterioration of insulin resistance, dyslipidemia, and osteoporosis [1–4].
Many RCTs and systematic reviews demonstrate that TRT can improve libido and sexual
function, mood and energy, quality of life, anemia, bone density, cognitive function, body
composition, in addition to muscle mass and strength [1,2,87–90]. In addition, some recent
studies have supported the long-term use of TRT for 4 to 5 years to obtain beneficial effects
for various metabolic parameters, body composition, and erectile function [91–94].
J. Clin. Med. 2022, 11, 6202 9 of 13
5.4. Adverse Effects and Risks of Testosterone Replacement Therapy
It is widely known that TRT is significantly associated with some adverse effects,
such as erythrocytosis, gynecomastia, liver toxicity, testicular atrophy and infertility, acne,
exacerbate sleep apnea, and potential growth of prostate cancer [1,87,88,95]. In particular,
elderly men who are often candidates for TRT are originally at increased risk of prostate
cancer. Therefore, men who receive TRT should undergo prostate-specific antigen screen-
ing regularly before and during treatment. On the other hand, there is no good evidence
that testosterone administration can convert subclinical prostate cancer to clinically sig-
nificant cancer and can increase risk of prostate cancer [87,95,96]. The association between
TRT and cardiovascular risk is still controversial. Some recent meta-analyses did not
demonstrate a significant association between TRT and any cardiovascular events [97,98].
6. Conclusions
Sarcopenia is an important pathophysiology factor of frailty in older adults and is
diagnosed in older adults with decreased muscle strength, muscle mass, and walking
speed, which can lead to a serious decrease in QOL. Testosterone directly interacts with
the androgen receptor expressed in myonuclei and satellite cells and is then also indirectly
associated with muscle metabolism through various cytokines and molecules. Significant
correlations between testosterone and frailty in men have been confirmed by numerous
cross-sectional studies. In addition, numerous RCTs have supported the beneficial effect
of TRT on muscle mass and strength among men with low to normal testosterone levels.
In the world’s aging society, TRT can be a tool for preventing the development of sarco-
penia in older-adult men, although further RCTs are required.
Author Contributions: Data collection, K.S. and Y.K.; writing—original draft preparation, K.S.;
writing—review and editing, K.S. and K.I.; supervision, A.M. All authors have read and agreed to
the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.
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