Phosphodiesterase Type 5 Inhibitors,
Sport and Doping
Luigi Di Luigi,MD
; Massimiliano Sansone, MD
; Andrea Sansone, MD
; Roberta Ceci, PhD
Guglielmo Duranti, PhD
; Paolo Borrione, MD
; Clara Crescioli, PhD
; Paolo Sgro
`, MD, PhD
and Stefania Sabatini, BiD
Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil,
vardenafil, and avanafil) are drugs commonly used to treat erectile dys-
function, pulmonary arterial hypertension, and benign prostatic hyper-
plasia. PDE5i are not prohibited by the World Anti-Doping Agency
(WADA) but are alleged to be frequently misused by healthy athletes to
improve sporting performance. In vitro and in vivo studies have reported
various effects of PDE5i on cardiovascular, muscular, metabolic, and
neuroendocrine systems and the potential, therefore, to enhance perfor-
mance of healthy athletes during training and competition. This suggests
well-controlled research studies to examine the ergogenic effects of PDE5i
on performance during activities that simulate real sporting situations are
warranted to determine if PDE5i should be included on the prohibited
WADA list. In the meantime, there is concern that some otherwise healthy
athletes will continue to misuse PDE5i to gain an unfair competitive ad-
vantage over their competitors.
Phosphodiesterases (PDE) are a family of enzymes (from
PDE1 to PDE11) with different selectivity for cyclic nucle-
otides, sensitivity to inhibitors and activators, physiological
roles, and tissue distributions. PDE catalyze the hydrolysis of
cyclic adenosine monophosphate (cAMP) and cyclic guanosine
monophosphate (cGMP) to the corre-
sponding 5-nucleotide monophosphate,
modulating their intracellular levels and
hence affecting different cell functions
in many tissues. Phosphodiesterase type 5
inhibitor (PDE5i) drugs, such as sildenafil,
tadalafil, vardenafil, and avanafil, have
different pharmacokinetic properties that
preferentially inhibit the PDE5 albeit
PDE6, PDE9, and PDE11 also are in-
hibited to a lesser extent (26,31). PDE5i
are approved for treating erectile dys-
function (ED), pulmonary arterial hyper-
tension, and benign prostatic hyperplasia.
Furthermore, other therapeutic applica-
tions have been proposed (e.g.,heart
failure, cardiomyopathy, stroke, meta-
bolic diseases) because of their cardio-
vascular and metabolic effects (9,26).
PDE5i work by influencing nitric oxide (NO)-related
cardiovascular, endocrine and metabolic pathways. NO
impacts cardiovascular hemodynamics, energy metabo-
lism, hormones, and mitochondrial biogenesis through
cGMP-dependent and -independent mechanisms (e.g.,Ca
prostaglandins) (13,15,17). PDE5i enhances the cGMP-
dependent effects of NO by increasing the intracellular
levels of NO-induced cGMP in different tissues. Particularly,
PDE5i influences the pathway downstream of NO: (a) NO
activates soluble guanylate cyclase producing cGMP, an in-
tracellular transduction mediator of NO; (b) intracellular
cGMP is physiologically decreased by the degradative action
of intracellular PDE5; (c) PDE5i inhibits the PDE5 action
thus increasing cGMP bioavailability; and (d) increased
cGMP availability amplifies the cGMP-related pleiotropic
effects of NO.
In addition to the widespread therapeutic use of PDE5i for
ED, there appears to be widespread abuse for recreational
purposes in healthy men (7,25,33). Based on anecdotal reports
and ‘‘doping control forms’’ data (36,39), many healthy ath-
letes (not affected by ED) participating in sports requiring en-
durance and/or competing in hypoxic conditions (i.e.,cycling,
running, rowing, and so on) misuse PDE5i to improve sporting
www.acsm-csmr.org Current Sports Medicine Reports 443
Unit of Endocrinology, Department of Movement, Human and Health
`degli Studi di Roma ‘‘Foro Italico’’, Rome, ITALY;
Section of Medical Pathophysiology, Food Science and Endocrinology,
Department of Experimental Medicine, Sapienza-University of Rome,
Unit of Biology, Genetics and Biochemistry, Department
of Movement, Human and Health Sciences, Universita
`degli Studi di
Roma ‘‘Foro Italico’’, Rome, ITALY; and
Unit of Internal Medicine, De-
partment of Movement, Human and Health Sciences, Universita
Studi di Roma ‘‘Foro Italico’’, Rome, ITALY
Address for correspondence: Luigi Di Luigi, MD, Unit of Endocrinology,
Department of Movement, Human and Health Sciences, Universita
Studi di Roma ‘‘Foro Italico’’, Largo Lauro de Bosis 15, 00135, Rome,
ITALY; E-mail: firstname.lastname@example.org.
Current Sports Medicine Reports
Copyright *2017 by the American College of Sports Medicine
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
performance, as PDE5i medications are not prohibited by the
World Anti-Doping Agency (WADA).
Unfortunately, as is true for other substances already
prohibited by WADA, there are no studies documenting a
specific performance-enhancing effect of PDE5i at either
therapeutic or supratherapeutic doses during real sporting
competitions. However, in vitro and in vivo studies de-
scribing the effects of PDE5i related to physical perfor-
mance enhancement provide a stronger case for prohibiting
PDE5i than some of the currently prohibited drugs. PDE5i
have great potential to enhance exercise capacity due to
their cardiovascular and vasodilatory effects increasing ox-
ygen transport to the exercising muscles, in addition to the
numerous neuroendocrine, muscular, and metabolic effects
PDE5i and Exercise Performance in Healthy Individuals
The capacity of PDE5i to enhance exercise tolerance in
humans affected by cardiovascular diseases is well-documented
(9,23,28,47). However, there is a paucity of information on the
effects of different PDE5i in either normoxia or hypoxia on
maximum aerobic (V
) and anaerobic capacity in healthy
individuals of different ages (i.e., older humans might have a
reduced PDE5i-related sympatholytic effect) (42). This includes
athletes involved in different sports.
In normoxia, a single dose of tadalafil (20 mg) in a healthy
athlete did not substantially influence performance indicators,
such as the ventilatory threshold, V
, exercise tolerance,
or the cardiopulmonary response, during a maximal stan-
dardized exercise test (12). Moreover, the same dose of
tadalafil did not influence the mean and peak power output
values during a 30-s Wingate anaerobic power test, but did
significantly decrease the time to peak power and increased
blood lactate concentrations during recovery. The observed
association between a reduced time to peak power and higher
blood lactate concentration (24) could be related to a possible
effect of PDE5i in stimulating anaerobic glycolysis (46), and
this may benefit performance in sports requiring a rapid at-
tainment of maximum power output.
Sildenafil is one of the first drugs to show increased ex-
ercise capacity in healthy individuals during severe hypoxia
both at sea level and at high altitude at therapeutic doses. In
healthy cyclists and triathletes at simulated high altitude,
sildenafil (50 mgY100 mg) increased stroke volume, cardiac
output, and arterial oxygen saturation (SaO
) during set-
work-rate exercise and significantly lowered 6-km time-
trial time by 15% in a double-blind study versus placebo
(27). In the same study, there were subjects who appeared to
be sildenafil responders and nonresponders with improved
time-trial performances of 39% (P G0.05) and 1.0%, re-
spectively (27). If confirmed, these individual differences
in PDE5i response could explain the observed discrepancies
in the studies evaluating PDE5i-related effects. In healthy
mountaineers and trekkers breathing a hypoxic gas mixture
with 10% fraction of inspired oxygen at low altitude (Giessen,
155-304 m), sildenafil (50 mg) significantly increased SaO
during exercise and reduced systolic pulmonary artery pres-
sure at rest and during exercise (20). Sildenafil also signifi-
cantly increased maximum workload and maximum cardiac
output compared with placebo (20). At the Mount Everest
base camp (elevation 5380 m), sildenafil (50 mg) reduced
systolic pulmonary artery pressure (at rest and during ex-
ercise) and increased maximum workload and cardiac
output (20). Other studies have been unable to replicate
these effects on performance. During acute exposure to
hypobaric hypoxia (elevation, 4000 m) at rest and during
maximal and submaximal (60% V
) exercise, silden-
afil (100 mg) did not impact performance in healthy men or
women (53). Moreover, no effects of sildenafil (50 mg)
were observed on cardiovascular hemodynamics, arterial
oxygen saturation, peak exercise capacity, and 15 or 6 km
time-trial performance in endurance-trained subjects of
either sex at simulated moderate altitude (~2100 and3900 m)
(30,34). These negative findings may be due to methodo-
logical factors, such as altitude (i.e., PDE5i may have greater
effects above 4000 m), duration of exposure to acute or chronic
hypoxia, possible variability of individual response to PDE5i,
or individual hormonal status (i.e., in men affected by ED, se-
rum testosterone levels influence the responsiveness to PDE5i)
Alveolar hypoxia, either natural (e.g., high altitude) or
artificial (e.g., hypoxic tents), may negatively influence ex-
ercise capacity, because hypoxia reduces alveolar partial
oxygen pressure (pPO
) and SaO
, increases pulmonary ar-
terial pressure and enhances the right heart. PDE5i may in-
crease exercise capacity in hypoxic conditions due to the
vasodilatory function and modulatory effects on central ner-
vous system and sympathetic system (i.e., functional sympa-
tholytic effects), heart rate, myocardial contractility, and
alveolar-capillary membrane conductance (23,29,35,42,45,51).
It is likely that the improvement in exercise capacity and
cardiac output observed in healthy subjects during exercise
under hypoxic conditions after PDE5i administration is
due to the blunting effect of PDE5i on pulmonary hyper-
tensive response to hypoxic exercise and to reduced right
ventricular afterload, which is a critical factor limiting ex-
ercise capacity in hypoxia (20,27). Moreover, the possible
presence of responders and nonresponders to PDE5i
may explain the variability in pulmonary hemodynamic,
responses, and in the adaption to acute or
chronic hypoxic conditions.
The reported effects of PDE5i on human physiology un-
der hypoxic conditions could explain the mechanism(s) by
which PDE5i can enhance athletic performance at very high
altitude and/or the response to exercise training performed
in natural or artificial hypoxia.
Intriguingly, PDE5i (e.g., sildenafil) could be a prophylactic
medication for swimming-induced pulmonary edema (SIPE) in
swimmers (38,40). SIPE occurs during immersed exercise, in
susceptible healthy individuals, because of higher pulmonary
artery and wedge pressures, and sildenafil (50 mg) adminis-
tration may reduce the pulmonary pressures and prevent the
hemodynamic pulmonary edema (38,40).
Although the existing data are contradictory, NO donors
per se (e.g., beetroot juice, and so on) could mitigate the
ergolytic effects of hypoxia on cardiorespiratory endurance
(18,19,37,41,44,50). Unfortunately, there is no adequate
information regarding the possible role of other drugs and/or
supplements increasing NO availability and influencing the
individual responses to PDE5i in athletes (1,6,11,16).
444 Volume 16 &Number 6 &November/December 2017 FIMS Article
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
PDE5i and Hormones Adaptation to Exercise
In animals, prolonged sildenafil administration increases
testosterone production by stimulating Leydig cell steroido-
genesis (3). In humans with ED, chronic PDE5i administra-
tion also has been shown to increase serum testosterone and
the testosterone to estrogen ratio, due to increased sexual in-
tercourse, PDE5i-related antiestrogen effects, and/or to direct
effect at testicular levels (8,22,43,52). In healthy men, a single
dose of tadalafil (20 mg) amplified the physiological cortisol
and testosterone responses to a maximal exercise-related stress
in normoxia (Fig. 1), decreasing the testosterone to corti-
sol ratio (13). Interestingly, when compared with placebo,
a slightly prolonged tadalafil administration (20 mgId
for 2 d) reduced the ACTH, cortisol, corticosterone, and
free cortisol index responses to a maximal exercise and in-
creased beta-endorphin and dehydroepiandrosterone sul-
fate (DHEAS) to cortisol ratio during recovery by influencing
the 11b-hydroxysteroid dehydrogenases activity (14,17). In
fact, after tadalafil (20 mgId
for 2 d), higher postexercise
tetrahydrocortisol-to-cortisol ratio and tetrahydrocortisone-
to-cortisone ratio were observed (14). Recently, chronic ad-
ministration of vardenafil reduced dehydroepiandrosterone
(DHEA) levels and increased DHEAS to DHEA ratio in men
with type 2 diabetes, confirming a PDE5i-related modulation
of steroidogenic enzymes by tissue changes in cAMP and
cGMP (48). The fact that there were no effects on cardiore-
spiratory and performance parameters in these studies does
not exclude potential endocrine effects of PDE5i during a spe-
cific competition and/or training. A laboratory exercise can-
not reproduce all the factors influencing the final result
during real competition and many confounding factors exist
makingthelinktoperformanceenhancement and PDE5i dif-
ficult to confirm. Based on the available studies (13,14,17,48),
we believe in athletes that a) acute tadalafil administration
could amplify the positive psychophysical effects of acutely
increased endogenous cortisol and testosterone during sport
competition (e.g., the response to exercise-stress is increased by
tadalafil) (13) and b) chronic tadalafil administration, by
decreasing the adrenal steroids response to exercise-stress,
could be useful during training because of reduced cortisol-
related protein catabolism, increased testosterone-related an-
abolic effects, improved recovery from exercise, and reduced
risk of overtraining (14,17,48).
PDE5i, Muscle, and Metabolism
PDE5i also may act directly on skeletal muscle cells.
In vitro, an acute tadalafil exposure influenced the metabo-
lism of murine C2C12 skeletal muscle cells (46), indicating
that cGMP signaling may play a role also in the regulation of
energy homeostasis. Specifically, acute treatment with 0.5
KM tadalafil improved glucose metabolism through the in-
duction of anaerobic glycolysis with an accompanying de-
crease of aerobic metabolism (46). Studies performed using
isolated human skeletal muscle cells, either myoblasts or
myotubes, showed that tadalafil did not affect lactate, but en-
hanced citrate synthase activity involved in Krebs cycle while
simultaneously increasing free fatty acid release. At the same
time, tadalafil was able to activate the main insulin-dependent
intracellular steps dedicated to cell metabolism regulation,
such as Ras-Raf mitogen-activated protein kinase, protein ki-
nase B/Akt, glycogen synthase kinase 3-A(downstream target
of phosphatidylinositol 3-kinase), and the transcription
factor c-Myc (downstream target of glycogen synthase kinase
3-A), all paths directly engaged in the control of intracellular
nutrient fate and utilization (10). Tadalafil, like insulin, seems
to target and potentiate part of the energy management and
metabolic control in human skeletal muscle cells (Fig. 2).
Recent studies have shown that prolonged tadalafil admin-
istration improved free fatty mass content in nonobese men,
probably via enhanced insulin secretion and estradiol reduc-
tion (4,10,22). PDE5i also may amplify the action of endog-
enous NO on muscle satellite cells (2). Furthermore, after
prolonged tadalafil administration, the endothelial function
increased and correlated directly with insulin and inversely
with estrogen serum levels (4). Moreover, the exposure of
C2C12 cells to increasing tadalafil concentrations (10
M) significantly increased total androgen receptor (AR)
mRNA and protein expression as well as myogenin protein
expression after 24 and 72 h, suggesting a translational action
of PDE5i on AR and on muscle cells (4). After 24-h treatment
with upregulation of AR expression, a significant increase
Figure 1: Box plot of salivary testosterone and cortisol concen-
trations before (Pre-Ex), at the end (Post-Ex), and 30 min after (30-Rec) a
maximal exercise test on cycle ergometer after placebo (open box)and
tadalafil (20 mg; dark box) administration in healthy male athletes.
Lower and upper edges of each box represent the first and third quartile
of observed data. The line-partitioning box corresponds to median
observation and whiskers give range of data. *PG0.05 vs respective
Pre-Ex; †PG0.05 vs placebo (Adapted from Di Luigi L et al., J Clin
Endocrinol Metab. 2008;93:3510Y4).
www.acsm-csmr.org Current Sports Medicine Reports 445
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
of testosterone concentrations in the supernatant of 10
tadalafil-treated cells (2.3 T0.5-fold) compared with untreated
cells was found (PG0.05) (4).
PDE5i administration-related effects on cellular and body
physiology, observed both in animal models and in some
healthy individuals and specific circumstances (e.g., hypoxia),
could potentiate sport performance. The possible effects of
PDE5i on exercise physiology are related both to the type of
PDE5i use (e.g., molecules, doses and length of administration)
and to various individual factors (e.g., age, hormone status,
individual responsiveness, oxygen availability, and so on). In
our opinion, PDE5i should be included in the list of prohibited
substances for athletes, rather than waiting for challenging in-
vestigations on the possible performance enhancing effects of
PDE5i during real-life sporting competition (i.e., in different
sports and experimental conditions), for the already observed
effects of PDE5i on exercise physiology/performance and pos-
sible serious health risk related to their misuse (21).
The authors declare no conflict of interest and do not
have any financial disclosures.
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