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Testosterone and weight loss

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Purpose of review The purpose of this article is to examine the contemporary data linking testosterone therapy in overweight and obese men with testosterone deficiency to increased lean body mass, decreased fat mass, improvement in overall body composition and sustained weight loss. This is of paramount importance because testosterone therapy in obese men with testosterone deficiency represents a novel and a timely therapeutic strategy for managing obesity in men with testosterone deficiency. Recent findings Long-term testosterone therapy in men with testosterone deficiency produces significant and sustained weight loss, marked reduction in waist circumference and BMI and improvement in body composition. Further, testosterone therapy ameliorates components of the metabolic syndrome. The aforementioned improvements are attributed to improved mitochondrial function, increased energy utilization, increased motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity. Summary The implication of testosterone therapy in management of obesity in men with testosterone deficiency is of paramount clinical significance, as it produces sustained weight loss without recidivism. On the contrary, alternative therapeutic approaches other than bariatric surgery failed to produce significant and sustained outcome and exhibit a high rate of recidivism. These findings represent strong foundations for testosterone therapy in obese men with testosterone deficiency and should spur clinical research for better understanding of usefulness of testosterone therapy in treatment of underlying pathophysiological conditions of obesity.
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C
URRENT
O
PINION
Testosterone and weight loss: the evidence
Abdulmaged M. Traish
Purpose of review
The purpose of this article is to examine the contemporary data linking testosterone therapy in overweight
and obese men with testosterone deficiency to increased lean body mass, decreased fat mass,
improvement in overall body composition and sustained weight loss. This is of paramount importance
because testosterone therapy in obese men with testosterone deficiency represents a novel and a timely
therapeutic strategy for managing obesity in men with testosterone deficiency.
Recent findings
Long-term testosterone therapy in men with testosterone deficiency produces significant and sustained
weight loss, marked reduction in waist circumference and BMI and improvement in body composition.
Further, testosterone therapy ameliorates components of the metabolic syndrome. The aforementioned
improvements are attributed to improved mitochondrial function, increased energy utilization, increased
motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity.
Summary
The implication of testosterone therapy in management of obesity in men with testosterone deficiency is of
paramount clinical significance, as it produces sustained weight loss without recidivism. On the contrary,
alternative therapeutic approaches other than bariatric surgery failed to produce significant and sustained
outcome and exhibit a high rate of recidivism. These findings represent strong foundations for testosterone
therapy in obese men with testosterone deficiency and should spur clinical research for better
understanding of usefulness of testosterone therapy in treatment of underlying pathophysiological conditions
of obesity.
Keywords
BMI, obesity, testosterone therapy, waist circumference, weight loss
INTRODUCTION
Obesity impacts quality of life and shortens life
expectancy. Obesity is a chronic condition that
cannot be ameliorated simply with lifestyle behav-
ior alone [1,2]. Obesity contributes to insulin resist-
ance, type 2 diabetes (T2DM) and is associated with
a host of comorbidities and therefore represents a
healthcare crisis. Lifestyle changes produce modest
weight loss in the early stages of weight manage-
ment strategies, but a high rate of recidivism is
observed. Treatment of obesity necessitates evi-
dence-based medical interventions [3,4]. Although
lifestyle modifications are highly recommended, as
integral part of strategies designed for treatment and
management of obesity [5 –7], in most patients, such
strategies are not always successful in the long term
because of high rate of recidivism, in part due to lack
of adherence to prescribed regimen [8 11]. The
limited benefits of the current approved drugs,
together with the undesirable adverse side-effects
of such agents in long-term management of obesity
have contributed to reduced adherence rates and to
discontinuation of use [2]. Efforts to target patient
education and increase awareness are warranted.
Desirable outcomes in management of over-
weight and obesity necessitates development and
utilization of new well tolerated and efficacious
agents, which can be used in combination with
lifestyle changes to achieve weight loss. Contempo-
rary approaches to management of obesity include
lifestyle modifications [12] and pharmaco-thera-
peutic agents, such as incretin and glucagon-like
Departments of Biochemistry and Urology, Boston University School of
Medicine, Boston, Massachusetts, USA
Correspondence to Abdulmaged M. Traish, Departments of Biochemistry
and Urology, Boston University School of Medicine, 715 Albany Street,
A502, Boston, MA 02118, USA. Tel: +1 617 638 4578; e-mail:
atraish@bu.edu
Curr Opin Endocrinol Diabetes Obes 2014, 21:313–322
DOI:10.1097/MED.0000000000000086
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where
it is permissible to download and share the work provided it is properly
cited. The work cannot be changed in any way or used commercially.
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REVIEW
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peptide-1 (GLP-1) receptor agonists [13], enzyme
inhibitors (dipeptidyl peptidase inhibitors) [14],
angiopoietin-like proteins [15] and bariatric
surgery [16]. Furthermore, a number of Food and
Drug Administration (FDA)-approved drugs for
treatment of obesity have serious adverse side-
effects and were taken off the market [12,17].
Thus, limited approaches to manage obesity are
available except lifestyle changes, which produce
moderateeffectsonweightlossandinmostcases
are unsustainable. Here, we summarize recent find-
ings related to long-term testosterone therapy that
produces improvement in body composition and
more specifically weight loss, reduction in waist
circumference and BMI. We propose use of testos-
terone therapy as a new strategy for managing
overweight and obesity in men with testosterone
deficiency.
CLINICAL CHALLENGES IN MANAGEMENT
OF OBESITY
Clinicians face complex challenges in their fight to
treat and manage obesity. These include a lack of
well tolerated and effective pharmaco-therapeutic
agents and patients monitoring to safeguard against
serious adverse side-effects. Further, FDA-approved
pharmaco-therapeutic agents offer only modest
benefits in some but not all patients. A more diffi-
cult challenge is patients’ adherence and compli-
ance and the perceived moderate effects and the
undesirable adverse side-effects that contribute
to the limited utility of the available drugs [2].
A number of centrally acting drugs intended to
regulate appetite were employed, however,
agents, such as fenfluramine, dexfenfluramine,
sibutramine, venlafaxine, rimonabant, phenter-
mine diethylpropion; phendimetrazine and benz-
phentamine, were withdrawn from the market
because of adverse side-effects or lack of efficacy
in treatment of obesity [2].
NEW APPROACHES FOR TREATMENT OF
OBESITY IN MEN WITH TESTOSTERONE
DEFICIENCY (HYPOGONADISM)
The prevalence of testosterone deficiency increases
with comorbidities, such as insulin resistance and
T2DM, obesity, hypertension, and cardiovascular
disease (CVD) ranging from 30 to 50% [18 21].
Mulligan et al. [18] reported that approximately
52.4% of all obese men had testosterone levels below
300 ng/dl (10.4 nmol/l). Similarly, Luconi et al. [22]
suggested that approximately 75% of men with
obesity grade III awaiting bariatric surgery had
hypogonadism. In our study of 255 hypogonadal
men, we noted 71% of men were obese and 14.1%
had obesity grade III, using a testosterone cut-off of
12.1 nmol/l [23
&&
]. Testosterone levels are reduced
with increased waist circumference and obesity
[17,24] and approximately 40% of obese nondia-
betic men and 50% of obese diabetic men aged
above 45 years have low free testosterone [18,25].
The concomitant presence of obesity and diabetes
is associated with an additional increase in preva-
lence of testosterone deficiency approaching 34%
[18,19,25,26].
Testosterone therapy in men with testosterone
deficiency (hypogonadism) has profound effects on
body composition, resulting in reduced fat mass,
increased lean body mass (LBM) (Table 1) [27,43,44,
45
&
,46
&&
,47–53] and significant reduction in anthro-
pometric parameters, such as weight, waist circum-
ference and BMI [20,23
&&
,27,37,39,42,43,48,54 56,
57
&
,58
&&
–61
&&
,62
&
,63
&
,64–66] (Table 2). The effects
of testosterone therapy on increased LBM and
reduced fat mass and the changes in anthropometric
parameters were consistently reported in most stud-
ies [20– 22,23
&&
,24– 44,45
&
,46
&&
,47– 56,57
&
,58
&&
–61
&&
,
62
&
,63
&
,64– 66], irrespective of testosterone formu-
lations used or duration of testosterone treatment
(Tables 1 and 2). On the basis of the consistent find-
ings of testosterone therapy, which demonstrated
significant reductions in total body fat mass and
increases in LBM [23
&&
,27– 44,45
&
,46
&&
,47– 56,57
&
,
58
&&
–61
&&
,62
&
,63
&
,64– 66] as well as improvement in
weight loss and reductions in waist circumference
and BMI (Tables 1 and 2), Allan and Mclachlan [68]
proposed the use of testosterone therapy in men
with testosterone deficiency for management of
obesity. Saad et al. [69] further proposed testosterone
therapy as a new potential intervention strategy for
managing obesity in hypogonadal men (testosterone
deficiency). The data from recent studies with long-
term testosterone therapy in men with testosterone
deficiency, using testosterone formulations which
result in sufficient circulating physiological testoster-
one levels and good patient adherence, reported
significant and sustained weight loss, reduced BMI
KEY POINTS
Long-term testosterone therapy in men with testosterone
deficiency improves body composition and quality
of life.
Long-term testosterone therapy in obese men with
testosterone deficiency ameliorates all metabolic
syndrome (MetS) components.
Long-term testosterone therapy in men with testosterone
deficiency, with or without lifestyle modifications, may
prove very effective and useful in the management
of obesity.
Obesity and nutrition
314 www.co-endocrinology.com Volume 21 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and waist circumference [46
&&
,58
&&
–61
&&
,70]. These
findings were corroborated by studies in which
testosterone therapy produced significant and
sustained weight loss [54–56,57
&
,58
&&
–61
&&
,62
&
,63
&
,
64–67] (Table 2).
EFFECTS OF TESTOSTERONE THERAPY
ON OBESE MEN WITH TESTOSTERONE
DEFICIENCY AND VARIOUS GRADES OF
OBESITY
Obesity is categorized into three grades on the basis
of patients’ BMI. BMI ranging from 30 to 34.9 kg/m
2
falls in grade I, whereas BMI ranging from 35 to
39.9 kg/m
2
falls in grade II and BMI more than
40 kg/m
2
is categorized as grade III. Data reported
from three registries [23
&&
,59
&&
–61
&&
], in which long-
term testosterone therapy was evaluated in men
with testosterone deficiency and varying grades of
obesity, suggested that testosterone therapy is effec-
tive in producing weight loss in all three grades of
obesity. As shown in Fig. 1, long-term testosterone
therapy produced significant progressive, sustained
weight loss without recidivism in men with testos-
terone deficiency with various grades of obesity,
[23
&&
,59
&&
–61
&&
]. This reduction in weight was also
associated with marked and significant reduction
in waist circumference (Fig. 2) [23
&&
,59
&&
–61
&&
].
These findings are consistent with those reported
in Table 2 and strongly support the concept that
testosterone therapy in men with testosterone
deficiency represents a novel and useful therapeutic
strategy for treatment and management of obesity
in hypogonadal obese men.
TESTOSTERONE THERAPY IN MEN WITH
TESTOSTERONE DEFICIENCY IS
ASSOCIATED WITH WEIGHT LOSS
Testosterone therapy is associated with weight loss
[23
&&
,42,56,58
&&
,59
&&
] and obesity is associated with
reduced testosterone levels [68,73 77,78
&
,79]. The
Table 1. Testosterone therapy increases lean body mass and reduces total body fat mass in men with testosterone deficiency
Study Testosterone formulation Treatment period Lean body mass Fat mass
Marin et al. [27] Gel 9 months "#
Snyder et al. [28] Patch 36 months "#
Kenny et al. [29] Patch 12 months "#
Crawford et al. [30] Mixed esters 12 months "#
Ferrando et al. [31] TE 6 months "#
Steidle et al. [32] Gel 3 months "#
Wittert et al. [33] Oral TU 12 months "#
Casaburi et al. [34] TE 3 months "#
Page et al. [35] TE 36 months "#
Kapoor et al. [20] Mixed esters 3 months "#
Bhasin et al. [36] TE 5 months "#
Kapoor et al. [37] Mixed esters 3 months "#
Bhasin et al. [38] Gel 6 months "#
Svartberg et al. [39] Injectable TU 12 months "#
Allan et al. [40] Patch 12 months "#
Srinivas-Shankar et al. [41] Gel 6 months "#
Aversa et al. [42] Injectable TU 24 months "#
Aversa et al. [43] Injectable TU 12 months "#
Behre et al. [44] Gel 6 months "#
Finkelstein et al. [45
&
] Gel 4 months "#
Francomano et al. [46
&&
] Injectable TU 60 months "#
Bouloux et al. [47] Oral TU 12 months "#
Pexman-Fieth et al. [48] Gel 6 months "#
Juang et al. [49] Gel 3 months "#
Rodriguez-Tolra et al. [50] Gel/Injectable TU 24 months "#
Frederiksen et al. [51] Gel 6 months "#
Emmelot-Vonk et al. [52] Oral TU 6 months "#
Borst et al. [53] TE 12 months "#
TE, testosterone enanthate; TU, testosterone undecanoate.
Testosterone and weight loss: the evidence Traish
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
potential mechanisms involved in low testosterone
levels in obesity encompass complex mechanisms,
including increased levels of sex hormone binding
globulin (SHBG), low or inappropriate normal levels
of luteinizing hormone, adipocyte dysfunction,
androgen resistance and insulin resistance. Loss of
androgen receptor function increases the number of
adipocytes and the accumulation of visceral fat [80].
Low baseline testosterone predicts obesity in men
[81] and normalization of physiological testosterone
levels reduces the activity of lipoprotein lipase and
tryglycerides [77]. Testosterone treatment results in
improved insulin sensitivity, lipid oxidation and
reduction in fat mass with concomitant gain in
fat free mass. Camacho et al. [78
&
] reported that
weight loss is associated with increased testosterone
levels, a finding supported by Corona et al. [79].
Intervention measures, such as diet and exercise or
surgical treatment of obesity, results in increased
testosterone levels [79,82,83].
Effects of testosterone therapy on
myogenesis and adipogenesis
Androgens regulate myogenesis and inhibit adipo-
genesis [67,84–88]. Maneschi et al. [89] reported
that testosterone therapy preserves visceral adipose
tissue function, and testosterone deficiency results
in derangement and dysfunction of visceral adipose
tissue metabolism. Men with testosterone defi-
ciency and obesity have reduced testosterone levels
and weight loss produces increased total testoster-
one levels [79,78
&
].
Effects of testosterone therapy on
carbohydrate, protein and fat metabolism
Testosterone regulates carbohydrates, proteins and
fat metabolism [79,89] and testosterone therapy in
men with testosterone deficiency results in normal-
ization of glucose utilization and increased lipid
oxidation [90]. Testosterone deficiency affects
energy production and utilization and therefore
upsets this physiological balance resulting in storage
of lipids and increased adipogenesis and altering
mitochondrial function [8994]. Obesity contri-
butes to premature cardiac aging via disrupted
mitochondrial biogenesis and function and is an
independent risk factor for development of heart
failure [92–94]. Testosterone therapy ameliorates
this dysfunction.
Effects of testosterone therapy in men with
testosterone deficiency on fatigue,
motivation, vigor and physical activity
Yu and Traish [95] suggested that testosterone
deficiency contributes to fatigue via alterations of
mitochondrial function and energy production and
Table 2. Effects of testosterone therapy on weight loss, waist circumference and BMI
Study
Testosterone
formulation
Treatment
period
Weight
loss
Waist
circumference
Body mass
index
Marin et al. [27] Gel 9 months ND #ND
Kapoor et al. [20,37] Mixed esters 3 months ND #ND
Svartberg et al. [39] Injectable TU 12 months ND #ND
Heufelder et al. [54] Gel 12 months ND #ND
Aversa et al. [42] Injectable TU 24 months ND #ND
Aversa et al. [43] Injectable TU 12 months ND #ND
Kalinchenko et al. [55] Injectable TU 7 months ## #
Aversa et al. [56] Injectable TU 36 months ND #ND
Zitzmann et al. [57
&
] Injectable TU 9– 12 months ND #ND
Francomano et al. [46
&&
] Injectable TU 60 months ## #
Francomano et al. [58
&&
] Injectable TU 12 months ## #
Haider et al. [59
&&
] Injectable TU 12– 72 months ## #
Haider et al. [60
&&
] Injectable TU 12– 72 months ## #
Saad et al. [23
&&
] Injectable TU 12– 60 months ## #
Yassin and Doros [61
&&
] Injectable TU 12– 60 months ## #
Pexman-Fieth et al. [48] Gel 6 months ## #
Hackett et al. [62
&
,63
&
] Injectable TU 7 and 20 months ## #
Bhattacharya et al. [64,65] Gel 12 months ND #ND
Garcia et al. [66] Injectable TU 24 months ND #ND
Zitzmann et al. [72] Injectable TU 12 –192 months ## #
ND, no data; TU, testosterone undecanoate.
Obesity and nutrition
316 www.co-endocrinology.com Volume 21 Number 5 October 2014
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utilization. Testosterone treatment of 1053 hypo-
gonadal men produced increased quality of life with
reduced fatigue, increased libido and erectile func-
tion and reduced waist circumference [48]. These
findings are supported by several other studies in
which testosterone therapy resulted in improved
motivation, vigor, energy, and reduces fatigue
concomitant with significant reduction in waist
circumference and improvement in quality of life
[44,47,48,57
&
,95]. Healthy volunteers, who received
a single injection of testosterone undecanoate
experienced reduction in fatigue-inertia signifi-
cantly versus placebo [96]. The increased motiv-
ation, energy and reduced fatigue in response to
testosterone therapy significantly contribute to
more physical activity, thus resulting in increased
energy utilization associated with increased muscle
mass and improved mitochondrial function. This,
in part, explains the observed weight loss with tes-
tosterone therapy in men treated for long durations
with appropriate testosterone formulations produc-
ing physiological levels [58
&&
–61
&&
,72]. In contrast,
androgen deprivation therapy (ADT) used in man-
agement of hormone-dependent prostate cancer
results in fatigue and reduces energy and motivation
[95,97].
Effects of testosterone therapy on fat
deposition and vascular health
Weight gain is attributed to 88% increased fat mass,
and weight loss is associated with 72% decrease in
fat mass and 28% decrease in LBM [98]. One of the
key observations in testosterone therapy is that
testosterone increases LBM, thus increasing resting
energy expenditure. Testosterone therapy in men
with testosterone deficiency with or without diet
and physical activity not only produced reduction
in fat mass but also improvements in cardiometa-
bolic function and reduced carotid intima media
thickness (CIMT), epicardial fat and trunk fat
[46
&&
,58
&&
,70]. Also reduction in CIMT was noted
with testosterone but not with diet and physical
exercise alone. Reduction in CIMT with testosterone
therapy was previously demonstrated [42,71].
Testosterone therapy for 18 weeks reduced ectopic
and liver fat in obese men [99
&
], suggesting that
testosterone therapy has a protective effect on the
130
125
*
*
#
*
#
*
#
*
#
*
#
*
#
*
#
*
#
*
*
***
*
#
*
#
*
*
#
120
115
110
105
Weight (kg)
100
95
90
85
Baseline
Gr. I, n = 185
p = 0.0001
p = 0.0018
p = 0.0016
p = 0.0001
Gr. I: –12.55 kg; Gr.II: –20.67 kg; Gr. III: –27.15 kg
*p <0.001 vs baseline # p <0.0001 vs previous year
Gr. II, n = 131
Gr. III, n = 46
177
124
44
169
125
46
159
121
43
141
104
37
126
90
34
84
64
24
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6
FIGURE 1. Testosterone therapy in men with testosterone deficiency and differing grade of obesity produces significant and
sustained weight loss. Hypogonadal men (n¼362) with obesity grade I (Gr. I, n¼185, mean age: 58.39 8.04 years),
grade II (Gr. II, n¼131, mean age: 60.62 5.56 years) and grade III (Gr. III, n¼46, mean age: 60.28 5.39 years)
treated with testosterone undecanoate injections for up to 6 years. Weight expressed in kilogram. Adapted with permission
from [60
&&
].
Testosterone and weight loss: the evidence Traish
1752-296X ß2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-endocrinology.com 317
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
cardiovascular system and reduces the risk of CVD.
Testosterone therapy for 12 months in men with
testosterone deficiency and spinal cord injury sig-
nificantly improved LBM and resting energy and
percentage basal energy expenditure [100]. The pre-
dictors of weight regain are reduced levels of testos-
terone, retinol binding protein 4, SHBG and MetS
[101,102
&
]. These findings support a role for testos-
terone therapy in management of obesity.
TESTOSTERONE THERAPY AMELIORATES
METABOLIC SYNDROME COMPONENTS,
IMPROVES SEXUAL FUNCTION, ENERGY,
MOOD, MOTIVATION AND QUALITY OF
LIFE
Testosterone therapy ameliorated components of
MetS [62
&
,63
&
,64,65,103
&&
,104]. Testosterone ther-
apy significantly improved Homeostasis Model
Assessment (HOMA)-insulin resistance, CIMT and
hsCRP, TNF-a, weight, BMI and waist circumference
[39,42,43,46
&&
,55,58
&&
,70]. A controlled 5-year study
in men with MetS showed significant decreases in
weight, waist circumference, BMI, HbA1c, HOMA-
insulin resistance, total cholesterol, low density
lipoprotein (LDL)-cholesterol, triglycerides, hsCRP,
systolic and diastolic blood pressure, and an increase
in HDL [46
&&
,70]. Long-term testosterone therapy in
men with testosterone deficiency produced a sig-
nificant reduction in total cholesterol, LDL choles-
terol, triglycerides, and increased HDL. Testosterone
treatment reduced fasting glucose, HbA1c, the
nonspecific inflammatory marker hsCRP and liver
enzymes aspartate aminotransferase and alanine
aminotransferase suggesting improvement in
hyperglycemia and a reduction in the inflammatory
response [23
&&
,46
&&
,58
&&
–61
&&
,70,89,105–107]. Fur-
ther, testosterone therapy reduces inflammation,
improves erectile function and increases vigor and
reduces fatigue. These changes in physical and
behavioral activity result in improved quality of life.
CHALLENGES AND LIMITATIONS OF
TESTOSTERONE THERAPY IN OBESE MEN
WITH TESTOSTERONE DEFICIENCY
Among the challenges of testosterone therapy is the
myth that testosterone causes prostate cancer (PCa).
Although this myth has been debunked [108,109],
the fear of physicians from litigation has presented a
120
*
*
#
*
#
*
#
*
#
*
*
#
*
#
*
#
*
#
*
*
**
*
#
*
#
*
*
#
115
110
105
WC (cm)
100
85
Baseline
p = 0.0021 p = NS
p = 0.0004
p = 0.0132
Gr. I: –9.24 cm; Gr.II: –12.29 cm; Gr. III: –12.44 cm
*p <0.0001 vs baseline # p <0.00001 vs previous year
185
131
46
172
125
46
161
122
43
142
104
37
126
90
34
85
64
24
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6
Gr. I, n = 185
Gr. II, n = 131
Gr. III, n = 46
FIGURE 2. Testosterone therapy in men with testosterone deficiency and differing grade of obesity produces marked and
sustained reductions in waist circumference. Waist circumference (cm) in 362 hypogonadal men with obesity grade I (Gr. I,
n¼185, mean age: 58.39 8.04 years), grade II (Gr. II, n¼131, mean age: 60.62 5.56 years) and grade III (Gr. III,
n¼46, mean age: 60.28 5.39 years) Treated with testosterone undecanoate injections for up to 6 years. Adapted from
[60
&&
].
Obesity and nutrition
318 www.co-endocrinology.com Volume 21 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
huge challenge to testosterone therapy in men with
testosterone deficiency [110,111]. Recently, another
challenge was raised suggesting that testosterone
therapy causes myocardial infarctions (MIs), stroke
and death [112–114]. Although these reports suffer
from serious methodological flaws and poor scien-
tific evidence-based medicine, the purported infor-
mation that testosterone therapy is harmful has
confounded the knowledge gained from more than
4 decades of experience with testosterone therapy,
and is in direct contradiction with this large body of
actual patient data [115]. A large number of studies
have shown that testosterone therapy does not
increase the risk of MI, stroke or death [115]. On
the contrary, testosterone deficiency is considered a
risk of CVD [115]. Jespersen et al. [116] reported ADT
is associated with greater risk for MI and stroke in
men with PCa. Keating et al. [117] showed that ADT
is associated with worsening of diabetes control and
increased despite the use of other diabetes medi-
cations.
EXPERT OPINION
One may argue that testosterone therapy has been
around for more than 75 years and no data have
been reported on the effects of testosterone on
weight loss, until recently. So, why now and how
could this be explained? Several key reasons explain
this deficit in the literature. First, most studies
reported on testosterone therapy were of very short
duration and this does not permit necessary tissue
remodeling and changes in LBM and fat mass, which
require longer time periods. Second, testosterone
formulations used in many prior studies did not
provide sustained physiological levels of testoster-
one and in most cases the circulating testosterone
levels were suboptimal, thus resulting in incomplete
responses. Third, in addition, poor patients’ com-
pliance to testosterone therapy is of paramount
importance in the effectiveness of testosterone
therapy. These factors explain, in part, the neutral
effects of testosterone therapy on weight observed in
some studies. Schoenfeld et al. [118] showed that
adherence rates to testosterone therapy are variable
depending on formulations and therefore differing
outcomes are expected.
It should be noted that testosterone deficiency is
associated with a shift in fuel metabolism from lipid
oxidation toward glucose utilization [119] and tes-
tosterone therapy [51,120] increased muscle mass
and lipid oxidation in aging men. Furthermore,
higher endogenous circulating testosterone levels
were associated with reduced loss of LBM in elderly
men [121] and testosterone therapy in frail men
preserves muscle thickness [122]. Thus, it is not
surprising that in obese men with testosterone
deficiency, long-term testosterone therapy with for-
mulations that achieve physiological levels, along
with adequate adherence, produced significant and
sustained weight loss, concomitant with reduction
in waist circumference and BMI (Table 2, Figs 1
and 2) [23
&&
,27– 44,45
&
,46
&&
,47– 56,57
&
,58
&&
–61
&&
,
62
&
,63
&
,64– 66,72]. Further, long-term testosterone
therapy in men with testosterone deficiency pro-
duced improvements in cardio-metabolic function,
ameliorated MetS components, reduced fatigue,
increased vigor and energy and improved quality
of life [62
&
,63
&
,64– 66,103
&&
,104– 107,123]. We sug-
gest that testosterone therapy offers well tolerated
and effective treatment of obesity in men with
testosterone deficiency and this novel approach
provides a unique opportunity to manage obese
men. Other therapeutic targets for the treatment of
obesity have been proposed including hypothalamic
malonyl-CoA and CPT1c [124,125] and GLP-1, oxy-
ntomodulin, peptide YY, gastric inhibitory peptide
and ghrelin [126]. These targets may prove useful in
addition to testosterone therapy.
CONCLUSION
Lifestyle modifications are considered a cornerstone
in combating obesity. However, this is difficult to
maintain over the long term, and the ability to
achieve modest weight loss with lifestyle modifi-
cation is limited, at best. Pharmacotherapy coupled
with lifestyle modification provides an alternative to
combating obesity with lifestyle changes alone. We
propose that testosterone therapy in obese men with
testosterone deficiency offers a well tolerated and
effective therapy and produces sustained and signifi-
cant weight loss. Testosterone therapy increases
LBM, reduces fat mass and produces sustained and
significant weight loss, reduction in waist circum-
ference and BMI. We believe that testosterone
therapy in obese men with testosterone deficiency
is a unique and effective therapeutic approach to
management of obesity. The fact that this therapy
has been used over the past 7 decades to treat hypo-
gonadism (testosterone deficiency) and is proven to
be well tolerated and effective should be an added
tool to the armament for the war on obesity.
Acknowledgements
This work was solely supported by the Department of
Urology, Boston University School of Medicine, Boston,
MA02118, USA. I would like to express my sincere
appreciation to my colleagues Dr Andre T Guay and
Dr Mohit Khera for their thoughtful reading of the
manuscript and for their helpful and constructive com-
ments.
Testosterone and weight loss: the evidence Traish
1752-296X ß2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-endocrinology.com 319
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Conflicts of interest
There are no conflicts of interest.
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Obesity and nutrition
322 www.co-endocrinology.com Volume 21 Number 5 October 2014
... On the other hand, the role of androgen in the regulation of feeding behavior and energy balance does not seem simple. It has been reported that andropause, or late-onset hypogonadism, may induce obesity and metabolic syndrome, and testosterone replacement may potentially be an effective treatment for weight management in obese men with hypogonadism possibly mediated via the androgen receptor (AR) [7][8][9]. It has also been reported in humans that, at physiologic levels, an association exists between higher levels of testosterone and favorable lean and fat measures [10], and testosterone dose-dependently reduced fat mass and increased lean body mass and body weight [11]. ...
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Sex steroids modify feeding behavior and body weight regulation, and androgen reportedly augments food intake and body weight gain. To elucidate the role of endogenous androgens in the feeding regulation induced by reduced glucose availability, we examined the effect of gonadectomy (orchiectomy) on food intake and orexin A neuron’s activity in the lateral hypothalamic/perifornical area (LH/PFA) in response to reduced glucose availability (glucoprivation) induced by 2-deoxy-d-glucose (2DG) administration in male rats. Rats (7W) were bilaterally orchiectomized (ORX group) or sham operated (Sham group). Seventeen days after the surgery, food intake response to 2DG (400 mg/kg, i.v.) was measured for 4 h after the infusion. The same experiment was performed for the immunohistochemical examination of c-Fos-expressing orexin A neurons in the LH/PFA and c-Fos expression in the arcuate nucleus (Arc). Food intake induced by glucoprivation was greater in the ORX group than the Sham group, and the glucoprivation-induced food intake was inversely correlated with plasma testosterone concentration. Glucoprivation stimulated c-Fos expression of the orexin A neurons at the LH/PFA and c-Fos expression in the dorsomedial Arc. The number and percentage of c-Fos-expressing orexin A neurons in the LH/PFA and c-Fos expression in the dorsomedial Arc were significantly higher in the ORX group than the Sham group. This indicates that endogenous androgen, possibly testosterone, diminishes the food intake induced by reduced glucose availability, possibly via the attenuated activity of orexin A neuron in the LH/PFA and neurons in the dorsomedial Arc.
... Moreover, this protective response seems to occur only in boys, which may be explained by hormonal differences between boys and girls, considering that most of the adolescents (≈85%) included in the study were in puberty (Tanner stage >2; Singh et al., 2013). In this setting, boys have higher levels of testosterone, a steroid hormone that stimulate muscle mass increase and cellular metabolism, increasing the resting metabolic rate that facilitates weight loss (Traish, 2014). Serum insulin levels modulate steroidogenesis, with a greater testosterone production associated with increased insulin levels from decreased insulin sensitivity, resulting in a greater mitochondrial oxidative function and an increased resting energy expenditure, facilitating weight loss. ...
... DHEA pellets insertion subcutaneously lowered the systolic blood pressure and reduced the increase in body weight, BMI, and liver weight versus the orchidectomized rats. These results affirmed the past hypothesis that lack of testosterone is associated with higher visceral fat deposition [21] and testosterone replacement, in this case, reduced the visceral fats [22]. It has been demonstrated that testosterone administration in euo-and hypogonadal males resulted in a reduction in body weight and fat deposition [23]. ...
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Objectives: The current work was designed to study the effect of dehydroepiandrosterone (DHEA) on glucose homeostasis, liver functions and hemostatic disturbances in a rat model of bilateral orchidectomy (ORCH). Methods: 32 male rats (n = 8) were randomly assigned into 4 groups; (i) control (sham operated) group; were normal rats in which all surgical procedures were done without ORCH, (ii) Control + DHEA group: as control group but rats were treated with DHEA for 12 weeks, (iii) orchiectomized (ORCH) group: rats had bilateral orchidectomy and (iv) ORCH + DHEA group: orchiectomized rats treated with DHEA for 12 weeks. Four weeks after ORCH, DHEA treatment began and lasted for twelve weeks. By the end of the experiment, the parameters of glucose homeostasis, lipid profile, liver enzymes, bleeding and clotting times (B.T. and C.T.), prothrombin time (P.T.), activated partial thromboplastin time (aPTT), platelet count and aggregation, von-Willebrand factor (vWF), fibrinogen, plasminogen activator inhibitor (PAI-1), fibrin degradation products (FDP), intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), endothelin-1 were measured. Results: ORCH caused significant deteriorations in the parameters of glucose homeostasis, lipid profile, and liver functions (p < 0.05). In addition, lower androgenicity-induced by ORCH caused a significant rise in PAI-1, fibrinogen, FDPs, ET-1 (p < 0.01) with significant shortening of bleeding and clotting times. DHEA replacement therapy significantly decreased glucose, insulin, PAI-1, fibrinogen, ICAM-1, and VCAM-1 when compared to ORCH rats. Conclusion: DHEA ameliorated the metabolic, hepatic, hypercoagulable, and hypofibrinolysis disturbances induced by ORCH.
... Weight gain is a typical feature of castrated animals and is reported experimentally in several species, including chicken [17], rabbits [18], monkeys [19], and others. It is known that testosterone has an anabolic effect and can increase fat-free mass in hypogonadal patients [20]; however, the general tendency of clinical testosterone therapy is causing whole body weight loss [21], in line with our results. ...
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This study aimed to evaluate and compare the effects of co-treatment with purified annatto oil (PAO) or its granules (GRA, Chronic ®) with that of testosterone on the orchiectomy-induced osteoporosis in Wistar rats. After surgery, rats were treated from day 7 until day 45 with testosterone only (TES, 7 mg/kg, IM) or TES + PAO or GRA (200 mg/kg, p.o.). The following parameters were evaluated: food/water intake, weight, HDL, LDL, glucose, triglycerides (TG), total cholesterol (TC), alkaline phosphatase levels, blood phosphorus and calcium contents, femur weight, structure (through scanning electron microscopy), and calcium content (through atomic absorption spectrophotometry). Our results show that orchiectomy could significantly change the blood lipid profile and decrease bone integrity parameters. Testosterone reposition alone could improve some endpoints, including LDL, TC, bone weight, and bone calcium concentration. However, other parameters were not significantly improved. Co-treatment with PAO or GRA improved the blood lipid profile and bone integrity more significantly and improved some endpoints not affected by testosterone reposition alone (such as TG levels and trabeculae sizes). The results suggest that co-treatment with annatto products improved the blood lipid profile and the anti-osteoporosis effects of testosterone. Overall, GRA had better results than PAO.
... In addition to inflammation and oxidative stress, recent studies have showed that PM exposure is related to testosterone levels. Testosterone, a key androgen, participates in many functions throughout the body which include overall and general metabolic rate (Traish, 2014) and reproductive function (Corona et al., 2014). Studies have shown that impaired testosterone production is associated with various reproductive dysfunctions in males, such as hypogonadism, abnormal sperm morphology, decreased sperm count and even infertility (Ohlander et al., 2016). ...
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Background: Population-based studies on the associations of long-term exposure to particulate matter (PM) with androgen and progesterone are still scant. Residential greenness is benefits health by promoting physical activity, reducing air pollution, and improving mental health, but it remains unclear whether it is related to androgen and progesterone levels among humans. Aims: This study aimed to explore the individual and interactive effects of PM and residential greenness on serum testosterone and progesterone levels among rural Chinese adults. Methods: A total of 6017 subjects were recruited from the baseline of the Henan Rural Cohort Study in 2016. Serum testosterone and progesterone were measured with liquid chromatography-tandem mass spectrometry. Particulate matters (PM) (PM1, PM2.5, and PM10) were assessed by machine learning algorithms. Residential greenness was assessed using the normalized difference vegetation index (NDVI) within 500-m, 1000-m, and 3000-m buffers around participants' residences. The effects of air pollutants and residential greenness and their interaction on serum testosterone and progesterone levels were assessed using linear mixed-effects models with township as a random intercept. Results: After adjusting for potential confounding factors, a 1 μg/m3 increase in PM2.5 or PM10 was associated with a 0.037 or 0.030 ng/ml increase in serum testosterone, respectively, in females and with a 0.111 or 0.182 ng/ml decrease in serum progesterone, respectively, in males. A 1 μg/m3 increase in PM1, PM2.5 or PM10 was associated with a 0.222, 0.306, or 0.295 ng/ml decrease in serum progesterone, respectively, among females. Moreover, a 0.1-unit increase in NDVI was associated with a 0.310 ng/ml increase in serum testosterone and a 0.170 ng/ml increased in serum progesterone in males, as well as with a 0.143 ng/ml increase in serum progesterone in females. Interaction effects of PM and residential greenness on serum testosterone and progesterone levels were observed, indicating that the effects of residential greenness on serum testosterone and progesterone were modified by high levels of PM. In addition, physical activity significantly mediated 2.92% of the estimated association between greenness and testosterone levels. Conclusions: Our study suggested that long-term exposure to PM was positively associated with serum testosterone in males but negatively associated with progesterone levels in both genderssin. In addition, positive associations of residential greenness with serum testosterone and progesterone levels were observed, but they were modified by high levels of PM. Furthermore, the estimated effects of residential greenness on testosterone levels were partly mediated by physical activity.
... Testosterone therapy in turn reduces lipoprotein lipase and triglyceride activity, which results in increased lean body mass and decreased fat mass. 33 These reductions in body weight and waist circumference in men with obesity and hypogonadism who are treated with testosterone have been established. 34 And yet, while these benefits for the parameters associated with glycaemia and metabolic syndrome are wellestablished, testosterone supplementation in hypogonadal men appears to improve additional health benefits, including improvements in renal function and other lifestyle markers including fatigue, erectile dysfunction, libido, and motivation with testosterone therapy. ...
Article
Background: While previous studies have demonstrated testosterone's beneficial effects on glycemic control in men with hypogonadism and Type 2 Diabetes, the extent to which these improvements are observed based on the degree of treatment adherence has been unclear. Objectives: To evaluate the effects of long-term testosterone therapy in A1C levels in men with Type 2 Diabetes Mellitus and hypogonadism, controlling for BMI, pre-treatment A1C, and age among different testosterone therapy adherence groups. Materials and methods: We performed a retrospective analysis of 1737 men with diabetes and hypogonadism on testosterone therapy for 5 years of data from 2008-2018, isolating A1C, lipid panels, and BMI results for analysis. Subjects were categorized into adherence groups based on quartiles of the proportion of days covered (> 75% of days, 51-75% of days, 26-50% of days and 0-25% of days), with >75% of days covered considered adherent to therapy. Results: Pre-treatment median A1C was 6.8%. Post-treatment median A1C was 7.1%. The adherent group, >75%, was the only group notable for a decrease in A1C, with a median decrease of -0.2 (p=0.0022). BMI improvement was associated with improved post-treatment A1C (p= 0.007). When controlling for BMI, age, and pre-treatment A1C, the > 75% adherence group was associated with improved post-treatment A1C (p < 0.001). Discussion: When controlling for all studied variables, testosterone adherence was associated with improved post-treatment A1C. The higher the initial A1C at the initiation of therapy, the higher the potential for lowering the patient's A1C with >75% adherence. Further, all groups showed some reduction in BMI, which may indicate that testosterone therapy may affect A1C independent of weight loss. Conclusion: Even when controlling for improved BMI, pre-treatment A1C, and age, testosterone positively impacted glycemic control in diabetes patients with hypogonadism, with the most benefit noted in those most adherent to therapy (>75%).
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Objectives: We aimed to investigate the effect of insulin sensitivity and insulin resistance status at baseline on longitudinal body mass index, and the possible effect modification by sex. Methods: This is a secondary analysis of a randomized intervention community trial, in which a subgroup of 84 adolescents, aged between 10 and 12 years, were analyzed. Body weight, height, and body mass index (BMI) were determined before and after 8 months of follow-up. Glucose and serum insulin were examined at baseline and IR was defined based on the homeostasis model assessment-insulin resistance (HOMA-IR), with a cutoff >2.5 for both genders. Linear mixed-effects models were performed to evaluate the influence of HOMA-IR at baseline on BMI changes over time. Models were adjusted for age, pubertal stage, and stratified by sex. Results: The sample comprised 65.4% of girls and the prevalence of overweight/obesity was 54.7% among girls and 50.0% among boys. The overall prevalence of IR was 75.3%, of which 60.7% for boys and 83.0% for girls. We found an interaction effect by sex (p = .004) for HOMA-IR as a continuous variable, with a decreased BMI rate of change among boys (β = -0.13; p = .03) but not for girls (β = +0.03; p = .36). Longitudinal BMI changes considering IR status at baseline (IR vs. non-IR) did not demonstrate any statistically significant difference for both boys (-0.1 vs. +0.4; p = .28) and girls (+0.7 vs. +1.0; p = .44). Conclusion: Increased HOMA-IR values at baseline were associated with greater BMI reduction over time among boys but not girls, with no influence of IR status.
Chapter
Endocrine disorders like diabetes, adrenal fatigue, hyper and hypothyroidism, menstrual abnormalities, and sexual dysfunctions are growing day by day due to many environmental pollutants and endocrine disrupting chemicals coming from food and breakages. Hormonal imbalances can affect life of millions of people. Herbs and spices normalize the hormone in normal ranges. Hormones are key messengers for controlling almost all body systems. Hormonal imbalance is a troublous condition which has adverse effects on mood, appetite, metabolism, aging, and mental health. Adaptogenic herbs are unique healing herbs that promote hormonal balance, enhance immune functions, and reduce mental stress. These herbs eliminate toxins from the body and detoxify liver from harmful chemicals and endocrine disrupting chemicals. Herbal infusions and their essences have potential to cure hormonal disorders.
Chapter
Furan is common compound that can be found in many products in pure form and as its derivatives. It is abundant in environment as in processed food, industrial process, pharmaceutical products and smoke. When furans are heated, they enhanced oxidative processes in lipids and proteins, and therefore play a toxic role in many cases. In many body systems furans are examined to cause toxic effects. It is commonly formed from four precursors amino acids, carbohydrates, ascorbic acids and PUFA. To detect the presence of furan and its amount in sample many methods have been involved. Most common of them are headspace analysis, headspace sampling by solid phase microextraction, and GCMS. As furan toxic effect is confirmed in many animals and it can be harmful to human health as well. The quantity of furan taken by humans are measured through quantification of furan in many food products. Many health agencies such as EFSA, FDA and IARC determine amount of furan in different foods. Further experiments were conducted to determine its harmful effects. Mouse and rats were mostly used in such tests. In rat metabolism of furan is tested and recorded that 80% of furan was eliminated through different pathways. Furan affects on digestive track is also determined. It mostly affects liver due to its prolonged presence in liver, but it was also observed to be harmful for kidneys. Some products are also tested to mitigate furan toxicity, apigenin and lycopene were found to be effective against furan toxicity. Moreover, furan itself was known to be effective against oxidative stress, which may cause many neurodegenerative disorders.
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Introduction: The role of testosterone supplementation (TS) as a possible treatment for male sexual dysfunction remains questionable. The aim of the present study is to meta-analyse data evaluating the effects of TS on male sexual function and its therapeutic synergism with the use of phosphodiesterase type 5 (PDE5i). Methods: An extensive Medline Embase and Cochrane search was performed including the following words: ‘testosterone’, ‘erectile dysfunction’. All randomized controlled trials (RCTs) comparing the effect of TS vs placebo on sexual function or the effect of TS as add on to PDE5ì s on sexual function were included. Data extraction was performed independently by two of the authors (A.M.I, G.C), and conflicts resolved by the third investigator (M.M). Results.: Out of 1702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5ìs. TS is able to significantly ameliorate erections and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of publication bias was detected. After applying Duval and Tweedie ‘trim and fill’ method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completed supported from pharmaceutical companies (CI (0.04–0.53) and (0.12;0.52) respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed when placebo-controlled studies were selectively analysed. The majority of them, however, included mixed eugonadal/hypogonadal subjects. Conclusions: TS plays positive effects on male sexual function in hypogonadal subjects. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure who persistently retain low T levels are advisable.
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Description: Update of the 2004 U. S. Preventive Services Task Force (USPSTF) recommendation on screening for glaucoma. Methods: The USPSTF reviewed evidence on the benefits and harms of screening for glaucoma and of medical and surgical treatment of early glaucoma. Beneficial outcomes of interest included improved vision-related quality of life and reduced progression of early asymptomatic glaucoma to vision-related impairment. The USPSTF also considered evidence on the accuracy of glaucoma screening tests. Population: This recommendation applies to adults who do not have vision symptoms and are seen in a primary care setting. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary open-angle glaucoma in adults. (I statement)
Article
Importance Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown. A recent randomized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety. Objectives To assess the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease. Design, Setting, and Patients A retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011. Main Outcomes and Measures Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke. Results Of the 8709 men with a total testosterone level lower than 300 ng/dL, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. Of the 1710 outcome events, 748 men died, 443 had MIs, and 519 had strokes. Of 7486 patients not receiving testosterone therapy, 681 died, 420 had MIs, and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. At 3 years after coronary angiography, the Kaplan-Meier estimated cumulative percentages with events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% (95% CI, −1.4% to 13.1%). In Cox proportional hazards models adjusting for the presence of coronary artery disease, testosterone therapy use as a time-varying covariate was associated with increased risk of adverse outcomes (hazard ratio, 1.29; 95% CI, 1.04 to 1.58). There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, P = .41). Conclusions and Relevance Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.