SUPPLEMENT ARTICLE

Effects of Testosterone Administration

on Fat Distribution, Insulin Sensitivity,
and Atherosclerosis Progression
Shalender Bhasin
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine Science,
University of California—Los Angeles School of Medicine

In spite of the widespread belief that testosterone supplementation increases the risk of atherosclerotic heart
disease, evidence to support this premise is lacking. Although supraphysiological doses of testosterone, such
as those used by athletes and recreational body builders, decrease plasma high-density lipoprotein (HDL)
cholesterol concentrations, replacement doses of testosterone have had only a modest or no effect on plasma
HDL in placebo-controlled trials. In epidemiological studies, serum total and free testosterone concentrations
have been inversely correlated with intra-abdominal fat mass, risk of coronary artery disease, and type 2
diabetes mellitus. Testosterone administration to middle-aged men is associated with decreased visceral fat
and glucose concentrations and increased insulin sensitivity. Testosterone infusion increases coronary blood
flow. Similarly, testosterone replacement retards atherogenesis in experimental models of atherosclerosis.
However, the long-term risks and benefits of testosterone administration in human immunodeficiency virus–
infected men with fat redistribution syndrome have not been studied in randomized clinical trials.

There is a widespread perception that testosterone
supplementation adversely affects the plasma lipopro-
tein profile and increases the risk of atherosclerotic
heart disease; this premise is not supported by data
[1, 2]. Thus, the long-term consequences of testos-
terone supplementation on the risk of atherosclerosis
progression remain unknown. Although supraphy-
siological doses of testosterone and nonaromatizable
androgens frequently used by body builders undoubt-
edly decrease plasma high-density lipoprotein (HDL)
cholesterol levels [3–7], physiological testosterone re-
placement in older men has been associated with only
a modest or no decrease in plasma HDL cholesterol
Reprints or correspondence: Dr. Shalender Bhasin, Div. of Endocrinology,
Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine
Science, UCLA School of Medicine, Los Angeles, CA 90059 (sbhasin@ucla.edu).
Clinical Infectious Diseases 2003; 37(Suppl 2):S142–9
 2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3705S2-0018$15.00
[8–11]. Cross-sectional studies of middle-aged men
[12–14] have found a direct, rather than an inverse,
relationship between serum testosterone levels and
plasma HDL cholesterol concentrations, as well as an
inverse correlation between serum testosterone levels
and visceral fat volume. Testosterone supplementation
in middle-aged men who have truncal obesity is as-
sociated with a reduction in visceral fat volume, serum
glucose concentration, and blood pressure and an im-
provement in insulin sensitivity [15–17]. These data
suggest that serum testosterone levels in the range that
is midnormal for healthy young men are consistent
with an optimal cardiovascular risk profile at any age
and that testosterone concentrations either above or
below the physiologically normal male range may in-
crease the risk of atherosclerotic heart disease. In light
of these data, the present review will discuss the ra-
tionale for the use of testosterone supplementation in
HIV-infected men with fat redistribution syndromes.

S142 • CID 2003:37 (Suppl 2) • Bhasin

HIGH PREVALENCE OF LOW TESTOSTERONE
CONCENTRATIONS IN HIV-INFECTED MEN
Although the prevalence of androgen deficiency, defined solely
in terms of low testosterone levels, has decreased with the ad-
vent of potent antiretroviral therapy, androgen deficiency con-
tinues to be a common complication of HIV infection in men.
In an earlier survey of 150 HIV-infected men who attended
our HIV clinic in 1997, approximately one-third had serum
total and free testosterone levels in the hypogonadal range [18].
Other investigators have reported a similar prevalence of hy-
pogonadism in HIV-infected men during the pre-HAART era
[19–27]. A more recent survey [28] of HIV-infected drug users
found the prevalence of low testosterone levels to be 20%. Thus,
androgen deficiency continues to be a common occurrence in
HIV-infected men.
In our survey, 20% of HIV-infected men with low testos-
terone levels had elevated luteinizing hormone (LH) and fol-
licle-stimulating hormone (FSH) levels and hypergonadotropic
hypogonadism [18]. These patients presumably had primary
testicular dysfunction. The remaining 80% had either normal
or low LH and FSH levels; these men with hypogonadotropic
hypogonadism either had a central defect at the hypothalamic
or pituitary site or a dual defect involving both the testis and
the hypothalamic-pituitary centers. The pathophysiology of hy-
pogonadism in HIV infection is complex and involves defects
at multiple levels of the hypothalamic-pituitary testicular axis.
In a recent study, a majority of men with chronic obstructive
lung disease had low total and free testosterone levels [29]. Sim-
ilarly, previous reports have suggested that two-thirds of men
with end-stage renal disease have low total and free testosterone
concentrations [30]. In a recent study of 39 men undergoing
hemodialysis who had end-stage renal disease but not diabetes
mellitus, 24 (62%) had serum total and free testosterone levels
below the lower limit of the normal male range [31].
The pathophysiology of hypogonadism in chronic illness is
multifactorial; defects exist at all levels of the hypothalamic-pi-
tuitary-
testicular axis [32–37]. Malnutrition, mediators and products of
the systemic inflammatory response, drugs such as ketoconazole,
and metabolic abnormalities produced by the systemic illness all
contribute to a decline in testosterone production.
EFFECTS OF SPONTANEOUS AND
EXPERIMENTALLY INDUCED ANDROGEN
DEFICIENCY ON FAT MASS AND
DISTRIBUTION
Seidell et al. [38] examined the relationship between serum free
testosterone levels and visceral fat measured by CT scan in
healthy men aged 30–70 years. Serum free testosterone levels
Testosterone, Insulin Sensitivity, and Atherosclerosis • CID 2003:37 (Suppl 2) • S143
were inversely correlated with visceral fat mass. However, free
testosterone concentrations were measured by a tracer analog
method, which is affected by sex hormone–binding globulin
(SHBG). Because SHBG is decreased by obesity, it is possible
that the apparent relationship between visceral fat and free
testosterone is a reflection of the relationship between SHBG
and visceral fat volume. Similarly, healthy hypogonadal men
have a higher fat mass than age-matched eugonadal controls
[39]. Most conclusive information has emerged from the ele-
gant studies of Mauras et al. [40], who demonstrated that the
experimental induction of androgen deficiency in healthy
young men by administration of a gonadotropin-releasing hor-
mone (GnRH) agonist is associated with a decrease in fat-free
mass and an increase in fat mass. Thus, androgen deficiency,
whether it occurs spontaneously or is induced experimentally,
is associated with increased fat mass, particularly in the visceral
fat compartment.
EFFECTS OF TESTOSTERONE
SUPPLEMENTATION ON WHOLE-BODY
AND REGIONAL FAT DISTRIBUTION
Many, but not all, studies of testosterone replacement in
healthy, young, hypogonadal men have reported a decrease in
fat mass after testosterone supplementation (table 1) [41–43,
45, 46]. Studies that recruited lean, young, hypogonadal men
have not demonstrated significant changes in fat mass [41].
Marin et al. [15–17] reported that testosterone supplementation
in middle-aged men with low to low-normal testosterone con-
centrations is associated with a significant reduction in the
visceral fat cross-sectional area, plasma insulin levels, and blood
glucose concentrations and an improvement in insulin sensi-
tivity. Long-term, placebo-controlled, randomized trials of tes-
tosterone replacement in older men have also been in agree-
ment that testosterone replacement in older men with
low-normal testosterone concentrations is associated with gains
in fat-free mass and a loss of fat mass (table 2) [8–11, 47, 50].
DOSE-DEPENDENT EFFECTS OF
TESTOSTERONE ON WHOLE-BODY AND
REGIONAL FAT DISTRIBUTION IN HEALTHY
YOUNG MEN
To determine the effects of graded doses of testosterone on
regional adipose tissue distribution, we randomized 61 healthy
men, aged 18–35 years, to receive 20 weeks of treatment with
a long-acting GnRH agonist (to suppress endogenous T secre-
tion) plus 1 of 5 weekly intramuscular doses (25, 50, 125, 300,
or 600 mg) of testosterone enanthate (TE) [51]. Energy and
protein intake were standardized. Fat mass was measured by
Table 1. Effects of testosterone replacement on body composition in healthy, hypogonadal men.

Age range, Change in

a a a
Reference years Testosterone regimen Change in fat-free mass Change in fat mass muscle strength

[41] 19–47 TE 100 mg/week for 10 weeks 5.0  0.7 kg (9.9%  1.4%) increase No change by underwater 22  3% increase
by underwater weight and D2O weight and D2O
[42] 22–69 TE or TC 100 mg/week for 18 7  2% increase by bioelectrical 14  4% decrease in % ND
months impedance body fat, 13  4% de-
crease in SC fat
[43] 33–57 TC 3 mg/kg/2 weeks for 6 15% increase by DXA scan 11% decrease ND
months
[44] 19–60 Sublingual testosterone 5 mg 0.9 kg (2%) increase by DXA scan No change No change in arm press, 8.7
3 times/day for 6 months kg increase in leg press
[45] 22–78 Transdermal testosterone 3.1  3.3 kg increase by DXA scan No change No change in isokinetic
patch for 12–36 months strength of knee extension
[46] 19–68 Testosterone gel 50–100 mg/ 2.7  0.3 kg increase by DXA scan 1 kg Leg press strength increased
day for 180 days by 11–13 kg

NOTE. DXA, dual x-ray absorptiometry; ND, not done; TC, Testosterone cypionate; TE, testosterone enanthate.
a
Data are mean, mean  SE, or range.

underwater weighing, dual energy x-ray absorptiometry (DXA),
and MRI of the abdomen and thigh. The combined adminis-
tration of a GnRH agonist plus graded TE doses resulted in
serum nadir testosterone levels of (mean  SE) 221  51,
295  32, 597  89, 1405  230, and 2205  241 ng/dL, re-
spectively. The change in whole-body fat mass was inversely
correlated with testosterone dose and concentration. Whole-
body fat mass, measured by underwater weighing and DXA,
increased significantly in men who received 25 and 50 mg/week
of TE and decreased in those who received 300 and 600 mg/
week. There was a significant reduction in both appendicular
and truncal fat at the 300 and 600 mg/week doses but a sig-
nificant increase at the 25 and 50 mg/week doses. The absolute
change in fat mass was not significantly different between the
trunk and the appendices. The subcutaneous as well as the
intermuscular fat mass decreased significantly in men who re-
ceived the 300- and 600-mg doses. The absolute changes in
subcutaneous and intermuscular fat mass were not significantly
different. There was a significant (analysis of variance, P p
.006) decrease in intra-abdominal fat volume at the 125-mg
(18  41 cm3 decrease) and 600-mg (46  39 cm3 decrease)
doses. The changes in both intra-abdominal and intermuscular
fat mass were negatively correlated with testosterone dose. The
changes in visceral fat mass were also negatively correlated with
serum testosterone concentration. Therefore, changes in tes-
tosterone concentration among healthy young men are asso-
ciated with dose-dependent changes in whole-body fat mass
that reflect changes in both the truncal and appendicular fat
depots.
TESTOSTERONE EFFECTS ON FAT
METABOLISM
Marin et al. [52] studied the uptake and turnover of triglyc-
erides from the peripheral and abdominal subcutaneous fat
depots after the administration of labeled oleic acid. In contrast
to dihydrotestosterone (DHT) and placebo, testosterone inhib-
ited the uptake of label into the abdominal subcutaneous fat,
increased its turnover, and was associated with lower lipopro-
tein lipase (LPL) activity only in the abdominal subcutaneous
fat but not in the femoral subcutaneous fat. Androgens increase
insulin-independent glucose uptake [53] and modulate LPL
activity [54].
TESTOSTERONE EFFECTS ON PLASMA LIPIDS
Testosterone effects on plasma lipids depend on the dose, route
of administration, and type of androgen (whether it is aro-
matizable). Supraphysiological doses of androgens, particularly
those that are administered orally (nonaromatizable andro-
gens), undoubtedly lower plasma HDL and increase low-density
lipoprotein (LDL) cholesterol concentrations [3–7]. A meta-
analysis by Whitsel et al. [55] of 20 studies has shown that healthy
hypogonadal men have higher HDL cholesterol and that phys-
iological testosterone replacement lowers HDL modestly, by 4
mg/dL, on average, and total cholesterol by 5 mg/dL and has no
effect on plasma LDL or triglycerides. Testosterone supplemen-
tation also lowers lipoprotein a and plasminogen activator in-
hibitor 1 (PAI-1). Lower testosterone levels in men are associated
with higher levels of dense LDL particles [56] and prothrombotic
factors [57].
A number of studies have been in agreement that the phys-
iological testosterone replacement of HIV-infected men with
weight loss does not significantly affect plasma lipid levels
[58–61]. Similarly, placebo-controlled, randomized controlled
trials of testosterone replacement in older men have not dem-
onstrated significant changes in plasma HDL cholesterol con-
centrations [8–11].

S144 • CID 2003:37 (Suppl 2) • Bhasin

Table 2. Effects of testosterone supplementation in older men in 7 studies.

Reference Subject characteristics Treatment regimen Change in body composition Change in muscle function Comments
[11] 60–75 years, serum testosterone TE 100 mg/week for 3 months 1.8 kg increase in fat-free mass; No change in grip strength Small increases in PSA and
!400 ng/dL no change in fat mass hematocrit
[47] 69–89 years, bioavailable testos- TE 200 mg every 2 weeks for 3 No change in fat mass or body Increase in grip strength …
terone !75 ng/dL months weight
[8] Healthy men, 51–79 years, TC 200 mg every 2 weeks for 0.9 cm (3%) increase in midarm 4–5 kg increase in grip strength No change in PSA, increase in
serum bioavailable testos- 12 months circumference, no change in hematocrit
terone !60 ng/dL fat mass
[48] Healthy, aged 67  2 years, TE weekly for 4 weeks to Body composition not reported Increase in hamstring and quad- ∼2-fold increase in fractional
testosterone !480 ng/dL increase testosterone to riceps work per repetition; no muscle protein synthesis rate
500–1000 ng/dL change in endurance
[9] Healthy men aged 165 years Scrotal testosterone patch, 6 Lean body mass increased by No change in strength of knee Improved perception of physical
mg/day for 3 years 1.9 kg; fat mass decreased extension and flexion function
by 3 kg
[49] Healthy older men TE ∼150 mg/2 weeks for 3 years FFM increased and fat mass Improvements in some mea- …
decreased sures of muscle strength
[50] Healthy men aged 165 years, Testosterone patch 5 mg daily ⭓1-kg gain in FFM; reduction in Improved strength in association …
bioavailable testosterone !4.4 vs. placebo for 1 year fat mass; no change in body with testosterone replacement
nmol/L mass but not significantly greater
compared with placebo

NOTE. FFM, fat-free mass; PSA, prostate-specific antigen; TC, testosterone cypionate; TE, testosterone enanthate.
TESTOSTERONE AND INSULIN SENSITIVITY
Cross-sectional epidemiological studies have reported a direct
correlation between serum testosterone concentrations and in-
sulin sensitivity [62]. Low testosterone levels are associated with
an increased risk of type 2 diabetes mellitus in men [63, 64].
However, the data from intervention studies on the effects of
testosterone replacement on insulin sensitivity are conflicting.
Marin et al. [15] reported that testosterone administration in
replacement doses to middle-aged men with low-normal tes-
tosterone levels improves insulin sensitivity and lowers serum
insulin levels. However, in a recent dose-response study in
which we administered a range of testosterone doses to healthy
men, the insulin sensitivity index, measured by a frequently
sampled intravenous glucose tolerance test using the Bergman
minimal model, did not significantly change across a range of
testosterone doses and concentrations that were tested [65].
However, the participants in that study were young and very
lean; it is possible that, in middle-aged and older HIV-infected
men with higher fat mass, testosterone replacement might im-
prove insulin sensitivity by reducing fat mass.
Testosterone effects on insulin sensitivity depend on the dose.
For instance, in one study [66], the effects of surgical castration
and testosterone administration on insulin sensitivity were
studied in adult male rats using the insulin clamp method.
Adult male rats became severely insulin resistant when they
were castrated. Physiological testosterone replacement in these
castrated rats restored their insulin sensitivity to levels seen in
intact rats. Supraphysiological doses of testosterone made the
rats insulin resistant again. These beneficial effects of testos-
terone replacement on insulin sensitivity were independent of
free fatty acid concentrations.
EFFECTS OF TESTOSTERONE
SUPPLEMENTATION ON INFLAMMATION
MARKERS
Testosterone replacement in young men does not affect inflam-
mation markers [66, 67]. Thus, C-reactive protein levels in
healthy young men were unaffected by testosterone adminis-
tration across a range of testosterone doses [66]. In another
prospective study of older men, DHT or human chorionic go-
nadotropin administration did not significantly affect high-
sensitivity C-reactive protein, soluble vascular cell adhesion
molecule–1, or soluble intracellular adhesion molecule levels
[67].
TESTOSTERONE EFFECTS ON COAGULATION
AND FIBRINOLYTIC FACTORS
In cross-sectional epidemiological studies, serum testosterone
levels have been positively correlated with tissue plasminogen
S146 • CID 2003:37 (Suppl 2) • Bhasin
activator and inversely correlated with PAI-1, fibrinogen, a-2
anti-plasmin, and factor VIIc levels [57, 68]. Men with hy-
pogonadism have low baseline fibrinolytic activity, which is
accounted for by an increased synthesis of PAI-1. There have
been isolated case reports of stroke and deep-vein thrombosis
in young men who were taking large amounts of androgenic
steroids. However, the results of the intervention studies with
testosterone replacement have been less clear; testosterone ad-
ministration increases the circulating levels of both pro- and
anticoagulant factors.
ASSOCIATION OF SERUM TESTOSTERONE
LEVELS AND HEART DISEASE
Whether a variation of testosterone levels within the normal
range is associated with a risk of coronary artery disease remains
unclear. Of the 30 studies reviewed by Alexandersen et al. [2],
18 reported lower testosterone levels in men with coronary
artery disease, 11 found similar testosterone levels in controls
and men with coronary artery disease, and 1 found higher levels
of dehydroepiandrosterone sulfate. Prospective population-
based studies [2] have not revealed an association between total
testosterone levels and cardiovascular mortality. Male survivors
of myocardial infarction have lower testosterone levels and
higher estradiol:testosterone ratios than age-matched control
subjects. Phillips et al. [69] reported an inverse correlation
between free testosterone levels and the degree of coronary
artery disease in a group of men undergoing coronary angi-
ography. Although the study by English et al. [70] did not find
a correlation between plasma androgen levels and the severity
of coronary artery disease, others who have used quantitative
coronary angiography have found a positive correlation be-
tween androgen levels and the degree of coronary disease. Thus,
cohort and cross-sectional studies have suggested a neutral or
favorable effect of testosterone on coronary heart disease in
men [2].
INTERVENTION STUDIES OF THE EFFECTS OF
TESTOSTERONE SUPPLEMENTATION ON
CORONARY ARTERY DISEASE
A number of studies conducted in the 1940s reported that
testosterone administration improved angina pectoris in men
with coronary artery disease [71, 72]. Testosterone infusion
acutely improves coronary blood flow in dogs and humans [73,
74]. Testosterone relaxes coronary arteries by opening the large-
conductance, calcium-activated potassium channel [75].
TESTOSTERONE RETARDS ATHEROSCLEROSIS
PROGRESSION IN AN ANIMAL MODEL OF
ATHEROSCLEROSIS
In a LDL receptor–deficient mouse model of atherosclerosis
[68], orchiectomy was associated with the accelerated formation
of early atherosclerotic lesions in the aorta. Testosterone sup-
plementation retards the progression of atherosclerotic lesion,
an effect that is blocked by the concomitant administration of
an aromatase inhibitor [76]. Testosterone effects on athero-
sclerosis progression were independent of plasma lipids. These
data provide compelling evidence that testosterone, through its
conversion to estradiol, can retard the progression of athero-
sclerosis in this animal model. Prospective studies are needed
extend these observations to humans, assess the effects of tes-
tosterone on atherosclerosis progression in older men, and
determine whether testosterone effects on atherosclerosis are
mediated through its conversion to estradiol.
SYNOPSIS
Testosterone supplementation decreases the fat mass in men
by inhibiting adipogenic differentiation. Replacement doses of
testosterone are associated with a small reduction or no change
in plasma HDL cholesterol concentrations. Epidemiological
studies have reported an inverse relationship between serum
free testosterone concentrations and visceral fat mass and the
risk of heart disease and type 2 diabetes mellitus. The hypothesis
that physiological testosterone replacement might improve in-
sulin sensitivity and retard atherosclerosis in HIV-infected men
with fat redistribution syndrome should be tested in prospec-
tive, placebo-controlled, clinical trials.
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