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ORIGINAL RESEARCH & REVIEWS
ENDOCRINE
Testosterone Therapy: What We Have Learned From Trials
Giovanni Corona, MD, PhD,
1
Luiz Otavio Torres, MD,
2
and Mario Maggi, MD, PhD
3
ABSTRACT
Introduction: The role of testosterone (T) replacement therapy (TRT) in men is still conflicting. In particular,
safety concerns and cardiovascular (CV) risk related to TRT have not been completely clarified yet. Similarly, the
clear beneficial effects of TRT are far to be established.
Aim: To systematically and critically analyze the available literature providing evidence of the benefit-risk ratio
derived from TRT in aging men.
Methods: A comprehensive PubMed literature search was performed to collect all trials, either randomized
controlled trials (RCTs) or observational studies, evaluating the effects of TRT on different outcomes.
Main Outcome Measure: Whenever possible, data derived from RCTs were compared with those resulting
from observational studies. In addition, a discussion of the available meta-analyses has been also provided.
Results: Data derived from RCT and observational studies clearly documented that TRT can improve erectile function
and libido as well as other sexual activities in men with hypogonadism (total T <12 nM). Conversely, the effect of TRT
on other outcomes, including metabolic, mood, cognition, mobility, and bone, is more conflicting. When hypo-
gonadism is correctly diagnosed and managed, no CV venous thromboembolism or prostate risk is observed.
Clinical Implications: Before prescribing TRT, hypogonadism (total T <12 nM) must be confirmed through
an adequate biochemical evaluation. Potential contraindications should be ruled out, and an adequate follow-up
after the prescription is mandatory.
Strength & Limitations: When correctly diagnosed and administered, TRT is safe, and it can improve several
aspects of sexual function. However, its role in complicated vasculogenic erectile dysfunction is limited.
Conversely, TRT is not recommended for weight reduction and metabolic improvement. Further well-powered
studies are advisable to better clarify TRT for long-term CV risk and prostate safety in complicated patients as
well as in those curatively treated for prostate cancer.
Conclusion: TRT results in sexual function improvement when men with hypogonadism (total T <12 nM) are
considered. Positive data in other outcomes need to be confirmed. Corona G, Torres LO, Maggi M.
Testosterone Therapy: What We Have Learned From Trials. J Sex Med 2020;17:447e460.
Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Testosterone; Testosterone Replacement Therapy; Sexual Desire; Erectile Dysfunction; Cardio-
vascular Risk; Prostate Cancer
INTRODUCTION
Several epidemiological population-based studies have clearly
documented an age-dependent decline of testosterone (T) levels
in men.
1
However, it has also been documented that associated
morbidities influence age-dependent reduction of T levels, which
can be potentially reversible with the improvement of the un-
derlying disorders.
2e4
In line with the aforementioned considerations, the concept of
a functional hypogonadism (HG), in comparison with an organic
one, is emerging.
5
In particular, the latter is an irreversible
condition, usually characterized by very low T levels, due to some
organic damage occurring at any level of the hypothalamus-
pituitary-testis axis, in which the benefit of T replacement
therapy (TRT) is well established. Conversely, functional
HG—probably the most common and previously referred as age-
related or late onset HG—is a potentially reversible form, with
Received July 28, 2019. Accepted November 24, 2019.
1
Endocrinology Unit, Medical Department, Azienda Usl, Maggiore-Bellaria
Hospital, Bologna, Italy;
2
Centro Universitário UniBH, Belo Horizonte, Minas Gerais, Brazil;
3
Sexual Medicine and Andrology Unit, Department of Experimental and
Clinical Biomedical Sciences, University of Florence, Florence, Italy
Copyright ª2019, International Society for Sexual Medicine. Published by
Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jsxm.2019.11.270
J Sex Med 2020;17:447e460 447
borderline low T levels, mainly associated with sexual symptoms,
where the risk/benefit ratio of TRT is more debated.
5
Lifestyle
changes and/or removing the underlying condition is the rec-
ommended strategy to increase endogenous T levels.
5
This po-
sition has been recently endorsed by the U.S. Endocrine Society
6
and, even before, by the Endocrine Society of Australia.
7
Accordingly, the U.S. Food and Drug Administration (FDA)
8
along with Health Canada
9
recommends TRT only in those
subjects with proven “organic”damage of the hypothalamus-
pituitary-testis axis.
To shed light on the possible benefits of TRT in the aging male,
in 2003, the U.S. National Institute on Aging funded a set of
clinical trials. Testosterone Trials (TTrials) were then designed and
performed as a coordinated set of 7, 52-week randomized placebo-
controlled, double-blind trials (RCTs), including 788 men with
hypogonadism (TT <9.4 nM) older than 65 years (mean age
72 years) treated with T gel 1%, in the active arm. The results of
these studies have been published throughout the last 2 years,
providing new evidence on the effects of TRT on aging men.
10
The aim of this review is to systematically and critically
analyze the available literature on the effects of TRT on different
outcomes in aging men. In addition, to better clarify the different
positions released by medical agencies around the world on this
topic, a revision of a worldwide pattern of TRT prescriptions,
observed in the last years, is also reported.
METHODS
The analyses have been conducted based on extensive Medline
search for the identification of all trials, either RCTs or obser-
vational studies, evaluating the effects of TRT on aging men.
The search was conducted including the following keywords
((“testosterone”[MeSH Terms] OR “testosterone”[All Fields])
AND (“therapy”[Subheading] OR “therapy”[All Fields] OR
“therapeutics”[MeSH Terms] OR “therapeutics”[All Fields]))
AND (“humans”[MeSH Terms] AND English [lang] AND
“male”[MeSH Terms]). Publications from January 1, 1969, up
to June 1, 2019, were included. When possible, data derived
from RCTs were compared with those arising from observational
studies. In each section, the results deriving from the TTrials
were closely analyzed and discussed. In addition, results from the
available meta-analyses were also provided. Meta-analyses have
been suggested for addressing questions for which multiple data
sources are in conflict or fail to reach a consensus. In addition,
meta-analysis evaluation is particularly useful when there are a
variety of reports with low statistical power, as pooling data can
improve power and provide a convincing result. Finally, a specific
section was dedicated to the safety concerns related to TRT.
PATTERN OF T PRESCRIPTION
T was chemically synthesized for the first time in 1935 simulta-
neously by Butenandt group in Gottingen and by Ruzicka and
Wettstein in Basel.
11
After its synthesis, T preparations soon became
soon for clinical use, first in the form of pellets and then as injectable
esters.
11
Although T products have been available for almost
80 years, the introduction on the market of more manageable
preparations, including gels and long-acting injectable formulations,
has dramatically expanded the T business over the last 2 decades.
This phenomenon is particularly evident in the United States and
Canada, where the possibility to release specific drug- and disease-
related advertisements has clearly influenced the market.
12,13
Conversely, during the same period, European T sales remained
more stable.
12,13
Besides the aforementioned pattern, at least 3 large
reports, analyzing commercial insurance data, have emphasized a
clear misuse of T prescriptions. In a U.S. claim database survey,
Baillargeon et al,
14
found that among a total of 10,739,815 men,
aged 40 years or older, who were prescribed TRT, between 2001and
2011, only 74.7% had their T measured prior to the prescription.
Similar data have been reported by Muram et al,
15
through the
analysis of another U.S. Insurance Database. Finally, an evaluation
of all outpatient clinics within Veterans Affairs (VA), during fiscal
years 2009e2012, of patients who had not previously received TRT
and received at least 1 T dispensing during the study period, showed
that only 3.1%of them underwent an ideal biochemical and clinical
evaluation before starting therapy.
16
Similarly, the same studies have
documented that TRT was often prescribed only based on unspe-
cific symptoms including fatigue, weakness and depressed mood,
symptoms often present in aging men.
12
TRT OUTCOMES
The previous section has clearly illustrated that some form of
T overuse or misuse has been present since 2000 in everyday
clinical practice. Whether or not this pattern has influenced
claims regarding TRT safety in aging men is still a matter of
intense debate. However, it is important to recognize that all
available guidelines recommend treating with T only symptom-
atic men who present documented reduced T levels, after
appropriate testing. In this section, available evidence of TRT on
different outcomes will be provided and analyzed.
Sexual Function
T profoundly regulates all aspects of sexual function and, in
particular, erectile function and libido.
17e19
In fact, all available
meta-analyses have clearly shown that TRT is effective in
restoring sexual desire and libido in men with hypogonadal (total
T<12 nM; 18 and Table 1). Conversely, no effect was docu-
mented when TRT was administered to subjects with normal
total T, that is above 12 nM.
18
Overall, TRT resulted in a mild
to moderate effect in the vast majority of the available meta-
analyses (Table 1). Sexual effects were proportional to the
increase in T concentration and higher on libido, when
compared with erectile dysfunction (ED). A meta-analysis
including only RCTs based on the International Index of Erec-
tile Function scoring as the final outcome documented that TRT
is able to improve erectile function domain by 2.3 points.
20
According to Rosen et al,
21
this increase could be considered
J Sex Med 2020;17:447e460
448 Corona et al
clinically meaningful only in subjects with mild ED and not in
those with more severe forms. Furthermore, it has been reported
that a higher prevalence of organic conditions, such as obesity
and diabetes, underlining possible vascular damage, attenuated
the positive effect of TRT on patients with ED.
18,19
The aforementioned data are in line with what was derived
from the TTrials (Table 1).
10
Final results showed that TRT, as
compared with placebo, increased sexual interest and sexual ac-
tivity, from flirting to sexual intercourse, with a moderate effect
size, which was inversely related to the baseline T levels and
proportional to the increase in T levels during the study.
10
A
greater effect on libido and sexual activity than on erectile
function was observed.
10
Similar data can be derived from observational, open-label
surveys, which often report even better outcomes for TRT in
improving all aspects of sexual function (Table 1).
18,19
The data observed for libido and ED are not surprising. In
fact, besides hormones, several other factors including psychiat-
ric, relational, or pharmacologic conditions can influence sexual
desire,
17
explaining, at least partially, the limited effects of TRT
on libido. In addition, it is important to recognize that the close
association between cardiovascular (CV) risk factors and ED can
justify the limited role of TRT alone in improving erectile
function in more severe forms of ED. The combination of TRT
and phosphodiesterase type 5 inhibitor (PDE5i) has been sug-
gested in the latter cases. Only one meta-analysis published so far
has investigated this issue.
22
The data confirmed the possible
advantages of using the combined therapy when placebo- and
nonplacebo-controlled trials were considered. However, when
the analysis was restricted to only placebo-controlled RCTs, the
significance of the effect was lost. It is important to recognize that
only a limited number of trials were available at that time and
that many of them enrolled a mixed population of subjects with
eugonadism/hypogonadism.
22
The possible role of TRT in improving ejaculatory function
represents another conflicting issue (Table 1). An association
between delayed ejaculation and reduced T concentrations has
been reported, although not confirmed in all studies.
18,19
Several
register observational surveys have documented that TRT can
improve orgasmic function.
18,19
A placebo-controlled RCT
specifically evaluating ejaculation together with its specific
components, including frequency and force of ejaculation, semen
volume, and bother regarding ejaculatory function documented
that axillary T gel 2% improved all the aforementioned areas,
when compared with placebo.
23
This was confirmed in the meta-
analyses specifically evaluating this issue, although only a limited
number of studies were available.
20,22
Hence, although some
Table 1. Summary of testosterone replacement therapy (TRT) outcomes
TRT outcomes TTtrials Other RCTs Observational studies Meta-analyses
Sexual function
Erectile dysfunction [44 [44 [444 [44
Libido [44 [444 [444 [444
Ejaculation NA [4[44 [4
TRT þPDE5i
Erectile dysfunction NA [44[44 4
Body composition
Fat mass NA Y4Y44 Y4
Lean mass NA [4[44 [4
Body mass index NA Y4Y444 Y4
Weight NA 4Y444 4
Metabolic control
Glucose metabolism NA [44[444 [4
Lipid profile NA [44[444 [44
Blood pressure NA 4[44 4
Bone
Bone mass [4[4[44 [4
Fracture risk NA NA NA NA
Mood/cognition
Depressive symptoms [4[4[44 [4
Cognition 44 [4NA
Mobility
[44[44[4[4
Arbitrary unit (4) is indicated as follows: 4¼mild 44¼moderate, 444¼strong effect. [,Y, and 4indicate positive effect, negative effect, and neutral
effect, respectively.
NA¼not available; PDE5i ¼phosphodiesterase type 5 inhibitor; RCTs ¼randomized controlled trials; TRT ¼testosterone replacement therapy; TTrials ¼
testosterone trials.
J Sex Med 2020;17:447e460
Testosterone Trials 449
positive evidence suggests that TRT can improve ejaculation and
orgasmic function, more placebo-controlled RCTs are advisable
to confirm this effect.
Obesity
A large body of evidence has shown that overweight and obesity
represent risk factors for the development of secondary HG.
24,25
Accordingly, longitudinal data from the European Male Aging
Study have shown that obesity at the baseline and weight gain
during follow-up increased the risk, whereas subjects who lost
weight during the study were more prone to recover from sec-
ondary HG.
26,27
The specific mechanisms underlying obesity-
associated HG have not been completely clarified. However, a
working hypothesis is that the metabolic derangements associated
with obesity can act either at a central or at a peripheral level,
inducing the development of mixed or, more frequently, second-
ary HG.
24,28
Only few RCTs have specifically evaluated the effect
of TRT on obese individuals (Table 1). Fui et al
29
showed that in
obese men (body mass index [BMI] 30 kg/m
2
) with a repeated
total T concentration<12 nM, receiving a very low-energy diet,
TRT is able to improve body composition (reduction of fat mass
and increase of lean mass), without any difference in final weight,
when compared with placebo. Similar results were derived from a
recent meta-analysis investigating the effect of TRT in available
placebo-controlled RCTs (Table 1).
30
Interestingly, the latter
meta-analysis documented that TRT caused equal modifications
in fat and lean mass, which can explain the lack of change observed
in final weight and in the BMI.
30
The main limitation of the
available RCTs is the short duration of the follow-up (<3 years).
Hence, possible long-term effects of TRT on body composition
are unknown. Data derived from observational and uncontrolled
studies, with a longer follow-up, suggest that TRT can eventually
induce a reduction of body weight and BMI, after at least 2 years of
treatment (Table 1).
31
However, it is important to recognize that
uncontrolled studies present important limitations because resid-
ual confounding factors may represent a source of selection bias in
accordance with the nonrandom assignment of T exposure. In fact,
physicians often prefer to treat healthier individuals, and healthier
individuals more often request treatment for their HG-related
problems, thus accounting for better outcomes in this group.
Meta-analyses of available evidence clearly documented that
weight loss, however obtained (low calorie diet or bariatric sur-
gery), and/or physical activity are able to improve T concentrations
and to revert obesity-associated HG.
32
Hence, lifestyle modifica-
tions should be the first approach for improving body composition
and for increasing T levels in obese individuals. However, the
magnitude of T increase after lifestyle modifications is rather
modest (about 2 nmoles/L; 32). Furthermore, therapeutic diets
and behavioral modifications—although reasonable strategies for
protecting against obesity-associated HG—often fail, and a large
proportion of subjects regain weight during follow-up. In addi-
tion, an open question is whether obese, individuals with hypo-
gonadism individuals have the skills to progress safely and
effectively along the continuum of changing their lifestyle. For
instance, physical limitations, including reduced muscle mass and
increased fat mass, might limit their propensity to increase physical
activity. It is therefore conceivable that a short-term TRT trial, by
improving muscle mass, will help obese patients with HG to
overcome their overfed, inactive state to become physically and
psychologically ready for changing their lifestyle. On the other
hand, a combined approach with a controlled dieting program and
TRT might result in a better outcome. Accordingly, by combining
the available evidence with a meta-analytic approach, we previ-
ously reported that TRT might result in better outcomes when
compared with lifestyle modification alone.
33
However, it should
be recognized that the number of the available trials, and the
related amount of patients enrolled, is too limited to draw
conclusions.
Metabolic Syndrome and/or Type 2 Diabetes
The role of TRT in improving metabolic derangements
occurring in type 2 diabetes (T2DM) and metabolic syndrome
(MetS) is conflicting. Only limited numbers of placebo-
controlled RCTs have specifically investigated the effect of
TRT in these populations (Table 1). TIMES-2, the largest study
performed in either T2DM or MetS subjects (n ¼220) was not
able to document a significant reduction in HbA1 concentrations
or the BMI after 26 weeks of T gel 1%, although an improve-
ment in Homeostatic Model Assessment of Insulin Resistance
was reported.
34
This was confirmed even when only patients
with T2DM were analyzed.
34
The largest RCT conducted only
on T2DM is the BLAST (an acronym taken from the UK cities
and towns of Birmingham, Lichfield, Atherstone, Sutton Cold-
field, and Tamworth) study, which included 199 men recruited
from 7 UK diabetes registers.
35
After 30 weeks, long-acting
injectable testosterone undecanoate (TU) resulted in a signifi-
cant improvement of HbA1 concentrations, particularly in
poorly controlled men (baseline HbA1c 58 mmol/mol; 7.5%)
and a decrease in waist circumference, without any significant
modification in the BMI.
35
In contrast to these observations,
Gianatti et al
36
did not observe any improvement in HbA1
concentrations or the Homeostatic Model Assessment of Insulin
Resistance index in 88 men with T2DM after 40 weeks of long-
acting injectable TU, when compared with placebo. However, as
reported in the general population,
30
an improvement in body
composition (reduction of fat mass and increase in lean mass)
was documented in the active arm.
36
Similar considerations can
be derived from available meta-analyses, which documented a
limited improvement of fasting glycemia and insulin resistance,
with even poorer results when only high-quality trials were
considered (Table 1).
37
Long-term registry studies have shown that TRT might
improve glycometabolic control in men with T2DM and MetS, up
to 8 years (Table 1).
38e41
The results of these studies present
important limitations, as reported previously. However, it should
be recognized that the longer follow-up and the differences in the
J Sex Med 2020;17:447e460
450 Corona et al
characteristics of the subjects treated in the observational studies
could explain, at least partially, the difference observed when
compared with placebo-controlled RTCs.
31
Despite these con-
siderations, present evidence suggests that possible contributions
of TRT on glycometabolic outcomes are limited, and TRT cannot
be suggested as an alternative treatment for T2DM or MetS.
The effects of TRT on other parameters of MetS such as
lipid profile and blood pressure are even more conflicting,
and the available evidence is too limited to draw any
conclusions (Table 1).
Bone
Much evidence has documented that bone health requires
circulating sex steroids within the normal range.
42
T concentra-
tions can differentially interfere with bone homeostasis and the risk
of osteoporosis. The possible association between mild HG and
osteopenia/osteoporosis is weak, whereas severe HG (total
T<3.5 nM) is frequently associated with bone loss and osteo-
porosis, independently from the patient's age.
42
2 independent
meta-analyses showed a positive effect of TRT on bone mineral
density (BMD), with a higher effect at the lumber level.
43,44
Similarly, data derived from the TTrials confirmed that TRT
increased BMD in aging men with hypogonadism particularly at
the spine level.
10
Insufficient data have been published to calculate
the effect of TRT on the risk of bone fractures.
42
In addition, the
contribution of TRT on top of antiresorptive treatments in pa-
tients with hypogonadism patients at a high risk of fractures has
not been established. Hence, antiresorptive therapy must be the
first choice of treatment in men with hypogonadism at high risk for
bone fracture. The combination with TRT should be offered in
the presence of HG-related symptoms.
Mood
Several observational studies have documented a relationship
between depressive symptoms and reduced T concentrations.
45
The specific relationship between HG and the incidence of
clinical depression are still unclear.
45
Data derived from the
TTrials showed that TRT modestly improved mood and
depressive symptoms, using several instruments.
10
In line with
these data, the largest meta-analysis published so far, including
1890 men with HG (baseline total T <12 nmol/L or fT <225
pmol/L) from 27 RCTs, documented that a positive effect of
TRT on depression was particularly evident only in patients with
milder symptoms.
46
Information regarding the combination
between an established depressive therapy and TRT is unknown.
Cognition
Reduced T levels have been associated with a precocious
cognitive impairment in subjects treated with androgen depriva-
tion therapy for prostate cancer (PC)
47
and in individuals from the
general population.
48
Despite this evidence, however, the role of
TRT in patients with cognitive impairment is still conflicting.
Among the TTrials, the Cognitive Function Trial was aimed at
assessing the possible improvement of several aspects of cognitive
function in 493 individuals with age-associated memory impair-
ment. The trial failed to demonstrate any effect of TRT on
improving cognitive function, as assessed by a wide range of tests.
10
Mobility
T has been able to increase muscle growth and strength in
several experimental models. Taking advantage of this anabolic
effect, androgenic steroids have been used for increasing physical
performance in an abusive way in several sport competitions.
49
Despite this evidence, the role of TRT in older men with
mobility limitations remains unclear. Steeves et al
50
were unable to
detect any association between overall circulating T levels and the
amount of physical activity using data from men enrolled in the
National Health and Nutrition Examination Survey, a series of
studies designed to assess the health and nutritional status of adults
and children in the United States.
50
Similarly, the Physical
Function and Vitality Trials from the TTrials indicated that TRT
did not substantially result in any improvement on several physical
vitality tests, including the fraction of men whose distance walked
in 6 minutes increased more than 50 m or the absolute increase in
the distance walked.
10
However, when the whole population of the
TTrials was considered, a significant, although modest, positive
effect on these 2 parameters was reported.
10
Similarly, a previous
meta-analysis of the available data documented only dominant
knee extension and dominant handgrip, which showed a tendency
toward improvement with T over placebo.
43
Hence, TRT should
not be used to improve mobility in aging men.
Role of TRT in Specific Subpopulations
Several chronic unhealthy conditions have been associated
with reduced T levels. A limited number of RCTs have assessed a
possible role of TRT in populations with these conditions. This
aspect represents the main limitation for a critical evaluation. In
addition, the population included in the few available RCTs is
often made up of a combination of men with hypogonadism and
men with eugonadism representing another crucial limitation in
data analysis. Hence, available evidence does not suggest using
TRT to improve mortality or morbidity in these populations
(refer the following section).
Subjects with HIV Infections
HIV-1 infection, and in particular wasting syndrome, is
frequently associated with a reduced T concentration. In addition,
men infected with HIV often show a premature decline of serum
T, associated with inappropriately low/normal luteinizing hor-
mone level and with increased visceral fat.
51
Fortunately, the era of
antiretroviral therapy has dramatically reduced the occurrence of
wasting syndrome. Nonetheless, chronic involuntary weight loss
remains a serious problem in subjects with HIV. Johns et al
52
published the first meta-analysis of the available 4 RCT studies
comparing the use of anabolic steroids vs placebo for treating
weight loss in adult men and women infected with HIV. They
J Sex Med 2020;17:447e460
Testosterone Trials 451
showed that anabolic steroids resulted in a small increase in both
lean body mass and body weight. We reported an updated meta-
analysis on the same topic, confirming the positive result on lean
mass.
53
These data were confirmed in a more recent meta-analysis
on the same topic, which included 14 eligible studies.
54
The main limitations related to the published meta-analyses on
this topic are the limited number of available placebo-controlled
RCTs and the high heterogeneity among the different studies.
Opioid-Treated Subjects
The association between reduced T concentrations, androgen
deficiency, and opioid treatment has been documented since the
1970s, when reports emerged in men who were on maintenance
methadone therapy.
55
Available studies evaluating the impact of
opioid treatment on T concentrations in men with chronic non-
cancer pain show that the prevalence of opioid-induced androgen
deficiency ranges from 19% to 86%, depending on the considered T
threshold.
55
Discontinuing opioids may be an option for symp-
tomatic men with reduced T concentrations. If pain relief with
nonopioids is inadequate, or patients are unable to discontinue
opioid treatment, TRT should be considered. A limited number of
studies have evaluated the effects of TRT on men with opioid-
induced androgen deficiency. In the only placebo-controlled RCT
available, TRT reduced mechanical hyperalgesia and improved
sexual desire and overall quality of life.
56
The improvement of sexual
function and pain relief after TRT has been confirmed in other
prospective and retrospective observational trials.
55
Long-Term Glucocorticoid TherapyeTreated Subjects
Long-term glucocorticoid (GC) therapy is the most common
cause of iatrogenic osteoporosis, accounting for 30%e50% of
bone fractures. GC treatment is frequently associated with male
HG by inhibiting the secretion of gonadotropins and by inhib-
iting Leydig cell function.
53
Adult men on GC who develop HG
should theoretically benefit from TRT. However, limited infor-
mation is available. In the first placebo-controlled RCT,
involving 51 men on a mean daily prednisone dose of
12.6 ±2.2 mg, TRT increased muscle mass, muscle strength,
and lumbar spine BMD after 12 months.
57
Similar results were
previously reported in a noneplacebo-controlled RCT dealing
with GC-treated asthmatic men.
58
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) represents
another chronic condition frequently associated with male HG.
53
An available meta-analysis, including only 9 observational studies
and 2,918 men with COPD, concluded that TRT did not improve
exercise capacity outcomes, including peak muscle strength and
peak workload.
59
Limited evidence for improving lean mass in
men with COPD and hypogonadism treated with TRT has been
reported.
53
However, the vast majority of the interventional trials
evaluating the effect of TRT in this population are nonplacebo-
controlled trials, further limiting the evidence.
Chronic Kidney Diseases
Impaired renal function in chronic kidney diseases, and, in
particular, in end-stage renal diseases is frequently associated with
male HG.
53
Some prospective studies have documented that a
low level of T can be considered an independent risk factor for
the progression of the disease and for overall mortality in this
population.
60
However, placebo-controlled RCTs specifically
evaluating the effect of TRT in subjects with chronic kidney
disease or end-stage renal disease are lacking.
Inflammatory Bowel Diseases
Data derived from an animal model and clinical observational
studies have suggested a possible anti-inflammatory effect of
TRT.
61,62
Some registered studies have documented that
normalization of T concentrations in men with hypogonadism
with Crohn's disease might have a positive effect on the clinical
course of the diseases, also evidenced by the improvement of
some biochemical parameters.
63,64
No RCTs specifically evalu-
ating the effect of TRT in patients with inflammatory bowel
diseases are available so far. In addition, data derived from
observational studies have not been replicated by other groups.
53
SAFETY
Safety concerns remain one of the most conflicting issues
related to TRT in age-related or functional HG. In particular,
CV safety, as well as prostate safety, still represents hot and not
completely clarified topics. The evidence related to these subjects
will be analyzed in detail in the section “Cardiovascular Safety.”
Cardiovascular Safety
Few studies (one RCT, 2 observational surveys, and one meta-
analysis) published between 2010 and 2014 created a great claim
in the scientific community, emphasizing a possible increased CV
risk related to TRT.
65e68
These studies present important limita-
tions already recognized elsewhere.
69e71
However, taking into
consideration the results of these studies, in 2015, the FDA issued a
safety notification regarding the misuse of T-containing products,
due to a potential CV and thromboembolic risk.
8
Soon after, similar
considerations were released by Health Canada.
9
Conversely, the
European Medical Agency did not share the FDA's opinion of an
increased CV risk linked to T medication because of the lack of
convincing evidence.
65
These contradictory positions deserve
further consideration.
Overall CV Risk
The first study suggesting a possible increased CV risk related
to TRT was the “Testosterone in Older Men with Mobility
Limitations”(TOM) trial, a double-blind placebo-controlled
RCT aimed at evaluating possible improvements in several
mobility outcomes among more than 200 men with hypo-
gonadism with mobility limitations.
65
The study was prema-
turely interrupted beause of higher CV-related events in the
J Sex Med 2020;17:447e460
452 Corona et al
active arm. However, several limitations have been recognized.
The population enrolled was based on a large group of men with
a high prevalence of associated morbidities that were treated with
a supraphysiological dose of T gel (100 mg daily). In addition,
CV events were not adjudicated. In addition, several minor CV
problems, including self-reported syncope and peripheral edema,
were considered as CV events.
65
More recently, data related to
the CV trial, within the TTrials, have become available.
72
The
study involved 138 subjects, and the primary outcome was to test
the hypothesis that TRT would improve a surrogate CV
outcome such as noncalcified coronary artery plaque volume, as
determined by computed tomographic angiography. The result
of this trial shows that TRT significantly increased coronary
artery plaque progression during 12 months of treatment.
72
Even
in this case, several flaws should be recognized. A larger non-
calcified plaque volume at enrollment was present in the placebo
arm, when compared with that in the active group (317 vs
204 mm
3
). In addition, although the plaque volume showed a
greater increase in the active arm, men enrolled in the T-groups
still had a lower volume at the end point (232 vs 325 mm
3
).
Moreover, at the end point, no differences between groups were
observed in other important outcomes, such as coronary calcium
score and the incidence of CV events among groups.
72
As reported previously, along with the aforementioned RCTs
described, 2 pharmacoepidemiological surveys contributed to the
position supporting an increased CV risk related to TRT. In the
first study, published in 2013, Vigen et al
66
retrospectively
analyzed data including 8,709 American veterans (VA) who
underwent coronary angiography between 2005 and 2011. The
Authors reported that among men with hypogonadism (total
T<10.4 nmol/L), those who were prescribed TRT had an
increased risk of major adverse cardiovascular events (MACEs) or
death from any cause, when compared with those who did not
use the same treatment.
66
Soon after the publication of this
study, Finkle et al
67
reported similar data by analyzing a large
Medicare insurance database including 55,593 subjects. In
particular, they showed that TRT was associated with a 2-fold
increased risk of heart attack among men aged 65 years and
older, which was particularly evident in younger men with a
preexisting history of heart disease.
67
Both studies present
important limitations. The main problem deals with the lack of
information concerning T dosing and measurements during the
follow-up.
71,73
In addition, the comparison group included in
the study by Finkle et al
67
was composed of 167,000 subjects
who were prescribed a PDE5i. The PDE5i has well-known
cardio-protective effects, which should be considered in the
data evaluation.
74
Besides the latter studies, several other phar-
macoepidemiological reports have investigated the possible rela-
tionship between TRT and CV risk.
75
In a first qualitative
analysis of these reports, Alexander et al
76
concluded that all
studies were characterized by a high clinical and methodological
heterogeneity and by a very low quality. Interestingly, by using a
meta-analytic method, we recently confirmed Alexander et al
76
results on a high heterogeneity within these types of studies,
but we were unable to confirm a risk of publication bias. In
addition, our conclusion was that, when overall mortality and
CV mortality and morbidity were considered, TRT resulted as
being protective and not harmful.
75
However, it is important to
recognize that only a limited number of studies were available
with overall poor quality, due to the lack of crucial information
such as the level of T before and during TRT, the number of the
blood samples drawn during treatment, the type of T prepara-
tions used, the dropout number, and the level of hematocrit.
75
RCTs are usually considered the gold standard for testing the
effect of a specific treatment. Until now. 9 systematic meta-
analyses evaluating the effect of TRT on CV risk from
placebo-controlled RCTs are available
68,75e82
(Supplementary
Table 1). The included amount of trials ranges from 19 to 75,
and the number of subjects considered ranges from 1,084 to
8,479. 7 meta-analyses
68,75e78,80e82
reported outcomes on
aggregate CV events as their primary end point, whereas one
79
investigated disaggregate events. In addition, disaggregate
events were also analyzed by 6 studies, whereas 2 reported only
aggregate analyses (Supplementary Table 1). Table 2 shows that
only Xu et al
68
reported an increased CV risk related to TRT.
Conversely, no other meta-analyses found an increased CV risk
related to TRT, when either aggregate or disaggregate CV events
were considered (Table 2). Is important to recognize that, similar
to what was observed in the TOM trial,
65
the meta-analysis by
Xu et al
68
considered a broader definition of CV events, causing
an artificial increase of the overall number of events. Some au-
thors in their meta-analysis have suggested possible differences in
CV risk when the different T preparations were considered.
71
In
particular, Borst et al
47
suggested an increased CV risk related to
the use of oral formulations, whereas Albert et al
49
reported a
possible increased risk using transdermal preparations, when the
analysis was restricted to trials lasting less than 12 months.
71
However, the largest and most updated meta-analysis did not
confirm these data, suggesting a neutral effect when both
aggregate or disaggregate events were considered, independently
from the T preparation considered.
71
Interestingly, our report
showed that an increased CV risk was observed when T was
prescribed at a higher dosage than those recommended by the
available guidelines or when frail men were considered.
75
Erythrocytosis Risk
Increased hematocrit has been inconsistently reported to be a
risk factor for cardiovascular morbidity, mortality, and venous
thromboembolism (VTE). The specific threshold related to an
increased CV risk is still a matter of intense discussion.
83
In
particular, although a hematocrit >54% is considered a well
accepted indication for TRT withdrawal and phlebotomy, the
standard level of hematocrit to be considered for starting TRT is
conflicting.
6,7,84
Much evidence has documented that TRT can
increase hematocrit through different mechanisms, including
direct (positive action on bone marrow erythroid progenitor
J Sex Med 2020;17:447e460
Testosterone Trials 453
Table 2. Odds ratio for aggregate or disaggregate cardiovascular (CV) events as derived from the available meta-analyses
Meta-analyses
considered
CV risk
Overall
CV events MACE AMI
Acute coronary
syndrome
Coronary by-pass
surgery Stroke Arrhythmias
New heart
failure
CV
mortality
Calof et al, 2005
77
1.22 [0.53;2.81] - 0.99 [0.44;2.26] 0.93
[0.39;2.26]
0.79 [0.35;1.79] 0.86 [0.38;1.95] 1.22
[0.53;2.81]
--
Haddad et al, 2007
78
1.82 [0.78;4.23] - 2.24 [0.5,10.02] - 3,703 - - -
Fernández-Balsells
et al, 2010
79
- - - - 1.35 [0.26,6.96] - 3.00
[0.32;27.94]
--
Xu et al, 2013
68
1.54 [1.09;2.18] - - - - - - 1.42
[0.70;2.89]
Corona et al, 2014
80
1.07 [0.69;1.65] 1.64
[0.25;10.63]
0.58 [0.30,1.52] 0.92
[0.43;1.97]
2.09 [0.48;9.17] 0.82 [0.24,2.83] 1.15
[0.43;3.05]
1.64 [0.25,10.63] 1.14
[0.49;2.66]
Borst et al, 2014
81
1.28 [0.76;2.13] - - - - - - - -
Albert et al, 2016
82
1.10 [0.86;1.41] - - - - - - - -
Alexander et al, 2016
76
- - 2.18 [0.63,7.54] - - 2.17 [0.63;7.54] - - 2.18
[0.63;7.54]
Corona et al, 2018
75
1.02 [0.74;1.40] 0.97
[0.64;1.46]
0.84 [0.43;1.65] 0.79
[0.44;142]
- 0.99 [0.44;2.24] - 0.81 [0.27;2.42] 1.12
[0.51;2.48]
Erythrocytosis risk
Calof et al, 2005
77
Level of risk NA Overall population 3.69 [1.82;7.51]
Fernandez-Balsells
et al, 2010
79
Level of risk >50% Overall population 3.15 [1.56;6.35]
Corona et al, 2015
85
Level of risk >52% Overall population 3.62 [1.86;7.05]
T<12 nM and transdermal preparations 4.89 [0.83;28.91]
Corona et al,
75
(present study)
Level of risk >52% Overall population 4.56 [w2.64;7.89]
T<12 nM and transdermal preparations 2.38 [0.26;21.62]
T<12 nM and long acting TU 2.23 [0.68;7.36]
T<12 nM and old T ester preparations 8.03 [3.27;19.72]
Venous thromboembolism risk
Xu et al, 2015
87
Level of risk 5.94 [1.00;35.30]
Corona et al, 2015
85
Level of risk 1.96 [0.75;5.17]
Houghton
et al, 2018
88
Level of risk RCTs 2.05 [0.78;5.39]
Observational case control studies 1.34 [0.78;2.28]
Cohort studies 4.89 [0.83;28.91]
Corona et al,
75
(present study)
Level of risk >52% Overall population 4.56 [2.64;7.89]
T<12 nM and transdermal preparations 2.38 [0.26;21.62]
T<12 nM and long-acting TU 2.23 [0.68;7.36]
T<12 nM and old T ester preparations 8.03 [3.27;19.72]
AMI ¼Acute myocardial infarction; CV ¼cardiovascular; MACE ¼major adverse cardiovascular event; NA ¼not available; RCTs ¼randomized controlled trials; T ¼testosterone.
J Sex Med 2020;17:447e460
454 Corona et al
cells) and indirect (stimulation of endogenous erythropoietin or
inhibition of hepcidin, both involved in the iron pathway
regulation) ones.
83
Accordingly, available meta-analyses, which
analyzed the risk of erythrocytosis due to TRT, in comparison
with placebo, showed that T-treated subjects had a 3- to 4-fold
increased risk of developing an elevated hematocrit
75,77,79,85
(Table 2). Old short-term parenteral T preparations have been
reported to produce the highest risk of erythrocytosis, due to the
high fluctuation of T levels.
83
Accordingly, we previously re-
ported that, when the analysis is limited to those studies applying
transdermal preparations in the active arm and enrolling only
subjects with hypogonadism (T <12 nM), the risk of elevated
hematocrit is not confirmed
85
(Table 2). By using the data from
the most updated meta-analysis on CV risk,
75
we here confirm
that when using either transdermal preparations or long-acting
TU in subjects with hypogonadism (T <12 nM), there is no
increase in the risk of erythrocytosis
85,86
(see also Table 2). This
was not the case when older T ester preparations were consid-
ered, as previously reported (Table 2; 86).
Venous Thromboembolism Risk
Only few placebo-controlled RCTs have investigated a
possible association between VTE risk and TRT. In 2015, Xu
et al,
87
by analyzing the data including only 3 RCTs enrolling
516 subjects, reported that TRT significantly increased VTE
(Table 2). These data were not confirmed by our group when
6 trials were considered, enrolling 1217 and 1,166 patients
treated with TRT or placebo, respectively (88; Table 2). In
line with this view, Houghton et al,
88
by meta-analyzing
placebo-controlled RCTs, including 2236 patients, and 5
observational studies, including 1,249,640 subjects, concluded
that current evidence does not support an association between
TuseandVTEinmen(Table 2). Accordingly, it has been
reported that TRT-related VTE events were frequently asso-
ciated with an undiagnosed thrombophilia-hypofibrinolysis
status, suggesting the relevance of an accurate medical his-
tory before starting TRT.
70
Prostate
The historical view that T is detrimental and harmful for
prostate health is nowadays considered not to be evidence based.
Several data have clarified that androgens not only are involved in
the stimulation of prostate cell proliferation but also play a
crucial role in the regulation of prostate cell differentiation.
89,90
As support of the latter evidence, epidemiological data have
shown that lower (ie, lower effect on prostate cell differentiation)
rather than higher T circulating levels are associated with less
differentiated forms of PC.
89,90
In addition, it is important to
recognize that in accordance with Morgentaler and Traish's
“saturation hypothesis,”during physiological conditions, circu-
lating androgens saturate the human prostate androgen receptors
making the prostate rather insensitive to further T increase.
91
In
line with their hypothesis, both in vitro and clinical evidence
have documented that prostate cell proliferation is observed only
Table 3. Odds ratio for prostate related events as derived from the available meta-analyses
Meta-analyses considered
Number of
trials included
Number of
patients
analyzed
PSA
change (pg/ml)
Prostate
volume (cc) IPSS
Abnormal
PSA levels Prostate biopsy Prostate cancer
Calof et al, 2005
77
19 1,084 - - 1.08 [0.46;2.52] 1.19 [0.67;2.09] 1.87 [0.84;4.15] 1.09 [0.48;2.49]
Fernandez-Balsells
et al, 2010
79
51 2,679 0.10 [0.01;0.21] - 0.29 [0.44;1.02] - 3.82 [0.97;15.00] 0.79 [0.28;2.28]
Cui and Zhang, 2013
92
(short term <12 months)
16 1,030 0.30 [0.09;0.50] 0.93 [1.41;3.27] 0.03 [1.00;0.95] - - -
Cui and Zhang, 2013
92
(Long term >12 months)
0.04 [0.17;0.10] 0.00 [1.39;1.39] 0.31 [0.35;0.98] - - -
Cui et al, 2014
93
(short term <12 months)
22 2,351 0.33 [0.21;0.44] - - 1.52 [0.61;3.78] 0.74 [0.25;2.19] 0.74 [0.25;2.19]
Cui et al, 2014
93
(Long term >12 months)
0.00 [0.17;0.16] - - 1.47 [0.82;2.62] 0.99 [0.24;4.02] 0.99 [0.24;4.02]
Guo et al, 2015
94
16 1,921 0.10 [0.03;0.22] 1.58 [0.60;2.56] 0.01 [0.37;0.39] - - -
Kang et al, 2015
95
15 1,124 0.15 [0.07;0.24] - - 1.02 [0.48;2.20] - -
Boyle et al, 2016
96
27 2,213 0.10 [0.28;0.48] - - - -] 0.87 [0.30;2.50]
IPSS ¼International Prostate Symptom Score; PSA ¼prostatic specific antigen.
J Sex Med 2020;17:447e460
Testosterone Trials 455
at low T concentration levels but disappears when T levels reach
the eugonadal range.
89,90
Several meta-analyses have been published specifically inves-
tigating the role of TRT on prostate safety (see also
Table 3).
77,79,92e96
The number of trials considered ranged from
4 to 26, including 1,084 to 5,464 subjects. In line with what has
previously been reported, TRT induced only a short-term in-
crease in prostatic specific antigen levels (95e65) or in prostate
volume
94
(Table 3). Conversely, when studies lasting more than
12 months were considered, no risk of PC or prostate-related
events were reported (Table 3). Data from the TTrials confirm
these observations, as no difference in prostate-related events or
PC was observed when treated men were compared with those
enrolled in the placebo group at the end point.
10
Similar data can be derived from registry studies. Data from
the Registry of Hypogonadism in Men,a multinational registry of
men with hypogonadism including 999 subjects (mean age
59.1 ±10.5 years) with a follow-up of 3 years, did not document
any difference in prostatic specific antigen levels, total Interna-
tional Prostate Symptom Score (IPSS) (including IPSS obstruc-
tive subscale), or PC in subjects undergoing TRT, when
compared with those untreated.
97
Interestingly, the same study
also indicated that TRT resulted in even lower IPSS irritative
subscale scores, when compared with untreated men.
96
Similar
results were derived from another Italian registry (SIAMO-NOI),
which collected data from 432 men with hypogonadism in 15
centers.
98
In addition, data derived from either animal models or
clinical observations have documented that HG is characterized
by an increased prostate inflammation, particularly evident in
patients with obesity and metabolic disorders, which can
contribute to benign prostatic hyperplasia-related symptoms and
can be improved by TRT, explaining, at least partially, the
aforementioned observations. Accordingly, preliminary data
from a placebo-controlled RCT, involving 120 men with MetS
and benign prostatic hyperplasia, showed that TRT produced a
moderate improvement in lower urinary tract symptoms, asso-
ciated with a significant decline in prostate artery flow velocity
and acceleration, as assessed by transrectal color Doppler ultra-
sound, and with a decrease, in the prostatic tissue, of the
expression of some inflammation-related genes, such as
cyclooxygenase-2, monocyte chemoattractant protein-1, and
related orphan receptor gamma-t.
99
Afinal point to be discussed is related to the effect of TRT in
men treated for PC. A limited number of studies have investi-
gated the role of TRT in men curatively treated after surgery with
radiotherapy for PC. Recently, Telling et al
100
collected and
meta-analyzed information derived from 13 studies including
608 patients, of which 109 had a history of high-risk PC. The
follow-up ranged from one to 189.3 months, and the type of T
preparations used differed among studies. The authors concluded
that TRT did not increase the risk of biochemical recurrence, but
the available evidence is very low, limiting, therefore, the data
interpretation.
100
CONCLUSIONS
Data derived from RCT and observational studies have clearly
documented that TRT can improve erectile function, libido, and
other aspects of sexual activities in men with hypogonadism
(total T <12 nmoles/L). The effect is inversely related to the
baseline T levels and is lower in patients with higher numbers of
associated morbidities. Although several data have documented
that lower T levels are associated with a worse metabolic profile
and a higher CV risk,
101
the specific contribution of TRT in
improving these aspects remains conflicting. In fact, whether the
low T level in men with increased CV risk plays a direct role in
the risk stratification or it represents an adaptive mechanism to a
compromised health status has still not been completely clari-
fied.
37
Hence, based on the available evidence, TRT should not
consider a viable alternative medication to improve metabolic
profile in men with T2DM or MetS or to reduce the risk of bone
fractures in men with osteoporosis. Similar considerations should
be done for mood, cognition, and mobility.
When HG is correctly diagnosed and T is administered as per
the recommended dosage, no CV risk is derived. However, it is
important to recognize that the duration of the available trials is
too short (lower than 3 years) to draw conclusions. In fact,
limited information on possible long-term effects of TRT on CV
risk is available. An industry-supported multicenter RCT is un-
derway to investigate the long-term CV risk of TRT (clinical-
trials.gov: NCT03518034).
Similarly, the evidence published so far does not indicate any
prostate risk related to TRT. However, none of the studies were
sufficiently powered to exclude adverse event risks in the longer
term. Similarly, preliminary positive data of TRT in IPSS
improvement must be confirmed in well-designed long-term
trials. In particular, limited information is available in men with
severe lower urinary tract symptoms (ie, IPSS >19) because they
are usually excluded from RCTs.
Corresponding Author: Giovanni Corona, MD, PhD, Endo-
crinology Unit, Medical Department, Azienda Usl Bologna
Maggiore-Bellaria Hospital, Largo Nigrisoli, 2, 40133 Bologna,
Italy. Tel: þ39-051-6478060; Fax: þ39-051-6478058; E-mail:
jocorona@libero.it
Conflict of Interest: The authors report no conflicts of interest.
Funding: None.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Giovanni Corona; Mario Maggi
(b) Acquisition of Data
Giovanni Corona
(c) Analysis and Interpretation of Data
Giovanni Corona; Mario Maggi
J Sex Med 2020;17:447e460
456 Corona et al
Category 2
(a) Drafting the Article
Giovanni Corona; Mario Maggi; Luiz Otavio Torres
(b) Revising It for Intellectual Content
Giovanni Corona; Mario Maggi; Luiz Otavio Torres
Category 3
(a) Final Approval of the Completed Article
Giovanni Corona; Mario Maggi
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SUPPLEMENTARY DATA
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.jsxm.2019.11.270.
J Sex Med 2020;17:447e460
460 Corona et al
