The Aging Male 2004;7:312–318

Testosterone therapy in erectile
dysfunction
R. Shabsigh
Department of Urology, Columbia University, New York, USA
Key words: TESTOSTERONE, TESTOGEL1, ERECTILE DYSFUNCTION, HYPOGONADISM, SYMPTOMATIC
LATE-ONSET HYPOGONADISM, NITRIC OXIDE, SILDENAFIL

ABSTRACT
Studies in animals have indicated that the nitric oxide
erectile pathway is testosterone-dependent. Castration
induces erectile dysfunction and a reduction in nitric
oxide synthase-stained nerves in erectile tissue.
Furthermore, castration adversely affects penile hemodynamics and smooth muscle content, leading to venoocclusive dysfunction. Testosterone replenishment
reverses these physiological, biochemical and structural
changes. Several clinical studies have demonstrated the
beneﬁts of a combination of testosterone and sildenaﬁl.
A recently published, multicenter study evaluated the
safety and efﬁcacy of testosterone gel 1% (Testogel1;
Schering AG, Germany/AndroGel1; Solvay Pharmaceuticals) vs. placebo gel in conjunction with
sildenaﬁl, in producing an erectile response in
hypogonadal men who did not respond to treatment
with sildenaﬁl alone for erectile dysfunction. The
selection criteria required subjects to have had erectile

dysfunction for at least 3 months, to be nonresponsive to 100 mg sildenaﬁl and to have low
testosterone levels (5 400 ng/dl). The primary
efﬁcacy measurement was the mean change from
baseline in the Erectile Function domain of the
International Index of Erectile Function (IIEF).
Secondary outcome measures included the mean
change from baseline in the other domains and the
total sum of the IIEF. Subjects were randomized to
receive either testosterone gel + sildenaﬁl, or placebo
gel + sildenaﬁl for 12 weeks. Testosterone therapy
with testosterone gel improved the erectile response to
sildenaﬁl. Therefore, testosterone therapy may be
considered for the treatment of erectile dysfunction in
men with low to low-normal testosterone levels, who
have failed prior treatment with sildenaﬁl alone.
Consequently, it is important to screen for hypogonadism in men who fail PDE5 inhibitors.

INTRODUCTION
inability to achieve and/or maintain an erection
sufﬁcient for satisfactory sexual activity3. Erectile
dysfunction is clearly associated with a decrease in
quality of life, and may lead to depression and,
eventually, the avoidance of sexual activity4,5.
Although erectile dysfunction is multifactorial
in etiology, it is strongly associated with age. The
incidence of complete erectile dysfunction increases from 5% in men 40 years of age to 15% in

Testosterone is the main sexual hormone in
human males, and has a pharmacological effect on
the physiology of sexual function. It is known that
suppression of testosterone in eugonadal adult
males leads to reduced sexual desire and activity1,
and may result in erectile dysfunction.
The prevalence of erectile dysfunction is high,
affecting approximately 30% of men in the US2.
Erectile dysfunction is deﬁned as the consistent

Correspondence: Professor R. Shabsigh, Department of Urology, Columbia University, 161 Fort Washington Avenue, New
York, NY 10032, USA
ª 2004 Parthenon Publishing. A member of the Taylor & Francis Group
DOI: 10.1080/13685530400016540

312

Received 18-07-04
Accepted 19-08-04

Testosterone and erectile dysfunction

men 70 years of age6. With aging, there is a
decline in serum testosterone that may lead to
symptomatic late-onset hypogonadism (SLOH),
of which erectile dysfunction is often a symptom.
While some data suggest that erectile dysfunction
and hypogonadism are independent, it is thought
that a certain threshold of testosterone may be
required for full sexual function7. Testosterone
replacement is indicated in men with SLOH, and
has been demonstrated to signiﬁcantly increase
sexual desire and activity, and the frequency of
erections. Thus, although testosterone deﬁciency
may not always be the causative factor in cases of
age-related erectile dysfunction, it is certainly a
potential cause8, and should be investigated in
patients presenting with erectile dysfunction.

ANDROGEN REGULATION OF
CELLULAR PROLIFERATION
Castrated rats provide a good, albeit not perfect,
animal model of hypogonadism, and studies have
shown that, in rats, penile erection is androgendependent9,10. Studies in castrated rats have
provided morphological evidence of the effects
of testosterone on the penis11–13. Castration
induced apoptosis in speciﬁc cells in the corpora
cavernosa (erectile tissue) of the rat penis,
suggesting that certain cell types are dependent
on testosterone for survival (Figure 1). Replenishment of testosterone after castration induced
new DNA synthesis in the smooth muscle cells,
stroma and blood vessels, and there was a pancellular proliferative effect in the penis (Figure 2).

Figure 1 Castration causes apoptosis in the rat penis.
Adapted from Shabsigh R. The effects of testosterone on
the cavernous tissue and erectile function. World J Urol
1997;15:21–6. Copyright Springer-Verlag 1997

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Shabsigh

ANDROGEN REGULATION OF
NITRIC OXIDE
The physiology of the erectile response is mostly
understood, although gaps in our knowledge
remain. In rats, it has been demonstrated that
penile erections are mediated by nitric oxide
(NO) and are androgen-dependent14–16. Direct
or indirect stimuli can trigger an erectile response
that starts with the release of relaxing substances,
primarily the neurotransmitter NO, from the
nerve endings in the corpora cavernosa. The
effects of NO are mediated via two distinct
second messenger systems: the cyclic guanosine
monophosphate (cGMP) pathway and the cyclic
adenosine monophosphate (cAMP) pathway. NO
stimulates the synthesis of cGMP, leading to the
phosphorylation of cellular membrane proteins
and the efﬂux of calcium. Calcium efﬂux leads to
vasodilation of the penile arteries and sinusoidal
spaces, resulting in an erection7,17. In addition,
NO activates other second messengers such as
prostaglandin E1, leading to the synthesis of
cAMP and an increase in calcium efﬂux7.
It is generally accepted that, in animals,
testosterone stimulates the production of NO.
More speciﬁcally, androgens are thought to
stimulate the synthesis of the neuronal isoform
of nitric oxide synthase (nNOS)16. Studies in
castrated rats have demonstrated a smaller increase
in intracavernosal pressure in response to electrical

Figure 2 Replacement of testosterone after castration
induces new DNA synthesis in the rat penis. Reprinted
from Shabsigh R, Raymond JF, Olsson CA, O’Toole K,
Buttyan R. Androgen induction of DNA synthesis in the
rat penis. Urology 1998;52:723–8. Copyright Elsevier 1998

313

Testosterone and erectile dysfunction

stimulation, compared with uncastrated rats,
suggesting an androgen-dependent portion of
the erectile response16. In addition, molecular
studies have demonstrated that the castrated
animals had a reduction in the level of nNOS
mRNA expression, compared with uncastrated
animals. These results suggest that androgens
mediate the erectile response in the rat penis by
stimulating the expression of nNOS, thus maintaining an adequate supply of NO16.
Although NO is considered to be the predominant vasodilator in the penis, there are other
vasodilatory pathways in the erectile response that
are independent of NO but are androgenregulated18. When castrated rats were treated with
a combination of testosterone and a competitive
inhibitor of NOS (L-nitro-L-arginine methyl
ester), there was an increase in intracavernosal
pressure in response to electrical stimulation,
similar to that observed in uncastrated rats18.
In order to elucidate further the effect of
testosterone on NO and penile innervation, Baba
and colleagues19 assessed three groups of rats:
castrated; castrated with testosterone replacement;
and sham-operated. The rats were subjected to
three types of induced erections: apomorphine (to
study centrally mediated erections), electrical
stimulation and papaverine injections (to study
peripherally induced erections). All three types of
stimulation resulted in signiﬁcantly fewer erections in the castrated rats, compared with rats that
received testosterone treatment or were shamoperated. After sacriﬁce, castrated rats were found
to have fewer nerve ﬁbers in the corpora
cavernosa and dorsal root containing NOS (as
demonstrated by NADPH–diaphorase staining of
penile histological sections), compared with the
other two groups. Thus, testosterone acts on the
nervous system to mediate erection, and, in its
absence, the production and activity of NO may
be down-regulated. Testosterone replacement
can preserve erectile function and NOS-containing neurons in the rat.
The role of testosterone in the human erectile
response is less well understood. Some severely
hypogonadal men continue to have an erectile
response, and, although testosterone therapy in
hypogonadal men with erectile dysfunction may
increase the number and quality of erections,
improvements are observed in only 40–60% of
patients20,21.

314

Shabsigh

TESTOSTERONE THERAPY
Testosterone therapy can improve certain aspects
of male sexual function, including erectile function. Intramuscular injections of testosterone
enanthate and testosterone cypionate have been
widely prescribed. However, this form of treatment is not always ideal, as it may lead to wide
variations in serum testosterone levels22.
The ﬁrst transdermal mode of testosterone
application was a scrotal patch, which had to be
applied once daily on shaved scrotal skin23–26.
Although effective, the scrotal patch did not
become readily accepted, due to the concomitant
supraphysiological levels of dihydrotestosterone
and the unpleasantness of scrotal skin shaving.
Adding an absorption enhancer to the patch made
application on non-scrotal skin possible27.
In a 16-month investigation in 34 hypogonadal
men, a non-scrotal testosterone transdermal system
was shown to increase the frequency, duration and
rigidity of erections, and enhance patient assessment of sexual desire, compared with during the
withdrawal period22. Thus, transdermal testosterone treatment in hypogonadal men signiﬁcantly
enhanced both objective and subjective parameters
of sexual function, relative to the hypogonadal
state, while achieving physiologically normal levels
of serum testosterone and major metabolites.
Despite the efﬁcacy of the transdermal testosterone system, a large number of patients
experienced considerable skin reactions due to
the enhancer28,29. In addition, the reservoir
patches were generally judged to be too large,
uncomfortable, visually obtrusive and noisy29;
therefore, the non-scrotal patch has not become
well established.
These problems in delivery have led to the
development of an open testosterone delivery
system using a 1% hydroalcoholic testosterone gel
(Testogel1; Schering AG, Germany/AndroGel1;
Solvay Pharmaceuticals), which can be applied to
the abdomen, shoulders or upper arms, and
delivers between 5 mg and 10 mg testosterone/
day30–32. This formulation of testosterone has
been demonstrated to increase rapidly serum and
free testosterone levels in hypogonadal men to
within the normal range, and to improve sexual
function and mood. The open system provided
ﬂexibility in dosing, with little skin irritation, and
was well tolerated30,31.

The Aging Male

Testosterone and erectile dysfunction

TESTOSTERONE THERAPY IN
COMBINATION WITH PDE5
INHIBITORS
Phosphodiesterase 5 (PDE5) inhibitors, such as
sildenaﬁl (Viagra1), prevent the degradation of
cGMP by PDE5 in the corpora cavernosa,
thereby enhancing erection. Thus, in order to
obtain an erection, a level of testosterone is
required that supports both NO synthesis and
cGMP synthesis. PDE5 inhibitors help to maintain an erection by preventing cGMP degradation
and, therefore, principally act to improve vasodilation, as opposed to libido, sexual interest and
activity. Consequently, the efﬁcacy of drugs such
as sildenaﬁl may depend on the presence of
adequate levels of testosterone17.
Combination therapy with sildenaﬁl and testosterone in hypogonadal subjects may lead to an
improved ability to achieve and maintain an
erection17,33,34. In a study by Kalinchenko and
colleagues17, 120 men with organic erectile
dysfunction associated with type II diabetes
mellitus, and receiving oral anti-diabetic drugs,
were evaluated for the cause of failure to respond
to treatment with sildenaﬁl citrate. At baseline,
these patients were found to have signiﬁcantly
lower levels of testosterone and depressed libido
than controls (age-matched patients with diabetes
mellitus, receiving treatment, but who responded
positively to treatment with sildenaﬁl citrate).
After 2 weeks of treatment with oral testosterone
undecanoate, testosterone levels were restored to
normal and libido was increased. The subsequent
use of 100 mg sildenaﬁl citrate prior to coitus
induced satisfactory erections in 70% of previous
non-responders (p 5 0.001).
More recently, the use of testosterone gel in
combination with sildenaﬁl citrate has been
evaluated in men with erectile dysfunction and
hypogonadism, who were previously refractory to
monotherapy with sildenaﬁl33. A total of 75 men,
who had experienced erectile dysfunction for a
minimum of 3 months, had low to low-normal
total testosterone (5 400 ng/dl) and had previously failed to respond to sildenaﬁl, were
randomized to 12 weeks of treatment with either
testosterone (50 mg daily) + sildenaﬁl citrate
(100 mg), or placebo + sildenaﬁl citrate
(100 mg). The etiology of erectile dysfunction
was either organic or mixed, and most patients

The Aging Male

Shabsigh

(91%) had experienced erectile dysfunction for
over 1 year – the majority had either moderate or
severe erectile dysfunction. Baseline characteristics were similar in both groups; the mean age was
58.5 years and obesity was common (mean body
mass index, 31.44 kg/m2). The primary efﬁcacy
outcome was the International Index of Erectile
Function (IIEF), while secondary measures were
sexual desire, orgasmic function, satisfaction
(evaluated via a questionnaire) and serum testosterone levels. Evaluations were performed every 4
weeks.
After 12 weeks of treatment, serum testosterone
had signiﬁcantly increased in the group receiving
testosterone, from a baseline level of 300 ng/dl to
500–600 ng/dl (p 4 0.001, compared with placebo) (Figure 3). While there was a slight decrease
at week 12, this was probably due to patient dropout. In contrast, the group who received placebo
showed no change. An interim analysis at 4 weeks
after the start of treatment demonstrated that
erectile function had improved signiﬁcantly from
baseline in the group receiving the testosterone
and sildenaﬁl combination (mean change from
baseline IIEF = 4.4), in contrast to those receiving
placebo and sildenaﬁl (mean change from baseline
IIEF = 2.2) (p = 0.029) (Figure 4). In addition, the

Figure 3 Testosterone levels in patients treated for
erectile dysfunction. Subjects used sildenaﬁl (100 mg) as
needed and applied testosterone gel daily (50 mg
testosterone) in the form of Testogel1 or AndroGel1.
Reprinted from Shabsigh R, Kaufman J, Steidle J,
Padma-Nathan H. Randomized study of testosterone
gel as adjunctive therapy to sildenaﬁl in hypogonadal men
with erectile dysfunction who do not respond to sildenaﬁl
alone. J Urol 2004;172:658–663. Copyright Lippincott
Williams & Wilkins 2004

315

Testosterone and erectile dysfunction

Shabsigh

transdermal administration of testosterone can
improve response to sildenaﬁl34.

CONCLUSIONS

Figure 4 At 4 weeks, treatment with testosterone and
sildenaﬁl had signiﬁcantly improved erectile function
from baseline, compared with placebo (p = 0.029).
Reprinted from Shabsigh R, Kaufman J, Steidle J,
Padma-Nathan H. Randomized study of testosterone
gel as adjunctive therapy to sildenaﬁl in hypogonadal men
with erectile dysfunction who do not respond to sildenaﬁl
alone. J Urol 2004;172:658–63. Copyright Lippincott
Williams & Wilkins 2004

group receiving the testosterone and sildenaﬁl
combination demonstrated signiﬁcant improvements from baseline in orgasmic function
(p = 0.009), overall satisfaction (p = 0.02) and total
score of the sexual function questionnaire
(p = 0.011), compared with the placebo and
sildenaﬁl group. The discovery that a combination
of testosterone treatment and sildenaﬁl could
improve orgasmic function was an important
ﬁnding of this study, as monotherapy with PDE5
inhibitors or prostaglandin E1 can only improve
vasodilation and erectile function.
These ﬁndings are supported by a smaller study,
in which 20 hypogonadal subjects were randomized either to testosterone treatment by patch
administration or to placebo, indicating that

Erectile dysfunction is extremely common and
can impact signiﬁcantly on the quality of life and
self-esteem of sufferers. Erectile dysfunction is
often associated with aging and may be a
symptom of late-onset hypogonadism. Many
men do not respond adequately to treatment
with PDE5 inhibitors or prostaglandin E1 unless
testosterone levels are sufﬁcient. It is important,
therefore, to screen men who present with
erectile dysfunction for low serum testosterone
and hypogonadism, especially if they fail treatment with PDE5 inhibitors.
Clinical trials have demonstrated that testosterone replacement therapy, with products such as
Testogel1/AndroGel1, can rapidly increase levels of testosterone and improve sexual function
and mood in men with hypogonadism30,31.
Testogel1/AndroGel1, in combination with
the PDE5 inhibitor sildenaﬁl, has been demonstrated to improve erectile response and orgasmic
function in patients with erectile dysfunction and
hypogonadism who had previously not responded
to sildenaﬁl monotherapy, compared with placebo33,34. Therefore, testosterone treatment may be
considered for the treatment of erectile dysfunction in men with low to low-normal total
testosterone levels who have failed previous
treatment with sildenaﬁl.
Conﬂict of interest The author presented this
paper at a symposium sponsored by Schering
AG at the XIXth Congress of the European
Association of Urology, Vienna, March 2004.

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