Human Reproduction vol.15 no.1 pp.131–134, 2000 Effects of sildenafil (Viagra™) administration on seminal parameters and post-ejaculatory refractory time in normal males* Antonio Aversa1,3, Fernando Mazzilli1, Tiziana
nucleotide phosphodiesterases (PDE) regulate intracellular
Rossi1, Michele Delfino1, Andrea M.Isidori1 and
levels of cAMP and cGMP by hydrolysing them to the
corresponding 5Ј monophosphates (Conti et al., 1995). Ninedifferent PDE isoenzymes (PDE1 to PDE9) have been described
1Cattedra di Andrologia, Dipartimento di Fisiopatologia Medica,
and found to be present at various concentrations in human
University of Rome La Sapienza, Italy and 2Department of
tissues (Soderling et al., 1998a; Fabbri et al., 1999). Previous
Endocrinology, St. Bartholomew’s Hospital, London, UK
studies have shown that mRNA coding for cAMP-specific
3To whom correspondence should be addressed at: Cattedra di
PDE (PDE4A) isoforms are present in mature rat and mouse
Andrologia, Dipartimento di Fisiopatologia Medica, PoliclinicoUmberto I, Viale del Policlinico, 00161 Rome, Italy
germ cells (Naro et al., 1996) and that the expression of theseisoforms is maximal in round spermatids and is maintained in
Sildenafil is a specific inhibitor of phosphodiesterase (PDE)
mature spermatozoa (Soderling et al., 1998b). Nitric oxide
type 5 and represents a powerful therapy for male erectile
synthase (Lewis et al., 1996) and two distinct PDE isoforms
dysfunction (ED) of different aetiology. Recently, sildenafil
(PDE1 and PDE4) are present in human sperm cells (Fisch
has been shown to restore erections in temporary ED related et al., 1998). Sildenafil is a specific and potent inhibitor of
to the need of semen collection for assisted reproductive
cGMP-specific phosphodiesterase (PDE) type-5, which is the
techniques. In this study, we investigated whether sildenafil
predominant PDE isoenzyme responsible for the degradation
administration modifies seminal parameters and/or erectile
of cGMP in the corpus cavernosum, and has also minor
function in normal healthy volunteers. In a double-blind, randomized, placebo-controlled, cross-over two period
and 0.28 µmol/l respectively) (Morales et al., 1998). Sexual
investigation we enrolled 20 healthy male volunteers (mean
stimulation is mandatory for sildenafil to increase nitric oxide
⍨ SE age 32 ⍨ 0.5 years). Subjects were not using any
production and stimulate cGMP production which in turn
medication for the 3 month period prior to the study and
causes trabecular smooth muscle relaxation, cavernosal arteries
were engaged in a stable relationship with proven fertility.
dilatation, increased intracavernosal pressure and penile erec-
The effects of sildenafil (100 mg) on seminal parameters
tion (Fabbri et al., 1997; Goldstein et al., 1998). It has recently
and erectile function after audiovisual sexual stimulation
been shown that some degree of erectile dysfunction may be
were evaluated by semen analysis and by colour-Duplex
present in the male infertile partner especially when assisted
ultrasound (the Resistive Index) respectively. In all subjects,
reproductive techniques are necessary and these men have
sildenafil caused no changes in seminal and erection para-
difficulties in producing spermatozoa on demand at the time
meters when compared to placebo. Interestingly, sildenafil
of egg fertilization (Tur-Kaspa et al., 1999); this temporary
administration led to a marked reduction of the post-
erectile dysfunction can be successfully treated with sildenafil. ejaculatory refractory time (10.8 ⍨ 0.9 min versus 2.6 ⍨
It has been demonstrated that human sperm cells contain as
0.7 min for placebo and sildenafil respectively; P < 0.0001).
yet uncharacterized PDE isoforms which are different from
These results indicate that in normal subjects acute silden-
PDE1 and PDE4, and that the in-vitro inhibition of sperm
afil treatment does not modify semen characteristics and
PDE1 and PDE4 isoenzymes by specific inhibitors stimulates
has a positive influence over the resumption of erections
acrosome reaction and sperm motility (Fisch et al., 1998). following ejaculation in the presence of a continuous erotic
Also, it is known that after acute administration of 100 mg
sildenafil, the drug reaches a concentration of 0.1–0.3 µmol/l
Key words: ejaculation/erectile function/phosphodiesterase
in the ejaculate (Pfizer, Viagra™ data sheet). This concentration
is consistent with a possible inhibitory interaction of sildenafilwith sperm PDE isoforms (Fabbri et al., 1999). In the presentstudy we evaluated the effects of sildenafil administration (100mg) on seminal parameters in young healthy male volunteers. Introduction
The effects of sildenafil on erectile response to audiovisual
The cyclic nucleotides cAMP and cGMP serve as second
sexual stimulation were also investigated.
messengers for a wide variety of extracellular signals suchas neurotransmitters, hormones, light, and odorants. Cyclic
Materials and methods Study design
*This paper was presented at the First International Consultation on
The study design consisted of a prospective double-blind, placebo-
Erectile Dysfunction, Paris, 1–3 July, 1999.
controlled, cross-over, two period investigation. The study blind
European Society of Human Reproduction and Embryology
A.Aversa et al.
was broken after completion of all studies. All subjects enrolledspontaneously in the study after giving an informed consent to the
Table I. Semen analysis in 20 fertile healthy subjects after double-blind placebo-controlled administration of 100 mg sildenafil tablet
study protocol, which was approved by the Ethical Committee of ourInstitution. The inclusion criteria included normal erectile function,
proven fertility, a stable relationship, normal electrocardiogram, no
prior or concomitant serious illness or consumption of medications
during the 3 month period prior to the study. In a double-blind
fashion, 20 subjects (mean Ϯ SE age 32 Ϯ 0.5 years, range 28–37)
were randomly assigned to one of the two study groups, that is 100
mg sildenafil (Viagra™, Pfizer, Sandwich, UK) or placebo, by a
designated hospital pharmacist. All subjects were asked to abstain
from sexual activity, alcohol or cigarette smoking for at least 3 days
VSL ϭ straight line velocity; LIN ϭ linearity.
before each session of the study and were given one tablet of the
medication. All subjects were asked to ingest the test drug 1 h before
aAt 21 frames/s: VSL ജ 23 µm/s and LIN ജ 0.58 (Mazzilli et al., 1999).
admission to the office. The washout period consisted of a 7 day
At 21 frames/s: VSL Ͼ 10 and Ͻ 23 µm/s and LIN ജ 0.58 (Mazzilli
period in which no medication was given. After this time, all subjectswere crossed over to receive the alternative treatment. Differencesbetween treatments were analysed by Student’s t-test for paired dataand analysis of variance. Semen processing
All semen specimens were collected 1 h after sildenafil consumptionand evaluated according to World Health Organization guidelines(WHO, 1992). A combined Bryan and Leishman strain (WHO)was used to assess sperm morphology. Sperm kinematics [motilitypercentages, straight-line velocity (VSL), curvilinear velocity (VCL)and linearity (LIN)] were assessed by a superimposed image analysissystem (SIAS) (Mazzilli et al., 1995; 1999). This system is basedupon superimposition of images and allows for a very accuratemotility analysis; in fact, the operator can verify visually if eachautomatic track corresponds to the real superimposed sperm trackand, when necessary, correct it. Erectile and ejaculatory function studies
Erectile function at baseline was assessed by the administration ofthe Sexual Health Inventory for Men – IIEF 5 to each subject (Rosenet al., 1997). The erection quality after either treatment was assessedduring audiovisual sexual stimulation (AVSS) by each subject andevaluated by an examiner (A.A.) by utilizing colour-power Dopplersonography parameters [(the peak systolic velocities (PSV), the enddiastolic velocity (EDV) and the resistive index (RI)] and the numberand morphology of helicine arterioles (Aversa et al., 1999). The timeto re-obtain erection after ejaculation [post-ejaculatory refractory time
Figure 1. Effects of double-blind placebo or 100 mg sildenafil
(PERT)] was measured with the stop-watch technique by asking the
administration on cavernous arteries inflow (upper panel) and post-
subject to keep self-stimulating immediately after ejaculation and
ejaculatory refractory time (lower panel). Peak systolic velocity
concomitantly by keeping on watching a different AVSS.
(PSV) represents the average value obtained from two cavernousartery measurements. *P Ͻ 0.0001 sildenafil versus placebo.
which were more frequent with sildenafil than placebo (80%
Table I shows the seminal parameters after sildenafil or placebo
versus 5% and 50% versus 5% respectively, P Ͻ 0.0001).
administration. Mean values of sperm number, motility and
Side-effects were always of mild intensity and transient, all
sperm abnormality percentages did not show significant vari-
resolving after 1 h from drug administration.
ations in the two groups considered.
Figure 1 shows the erectile and ejaculatory parameters in
the two groups of treatment. In all subjects after sildenafiladministration while the penile haemodynamic parameters of
The recent appearance of sildenafil (Viagra™) in the European
erection were not different from placebo (Figure 1, upper
markets represented a milestone for the future management of
panel), the post-ejaculatory refractory times were markedly
men with erectile dysfunction and a breakthrough compared
reduced by 4- to 5-fold (Figure 1, lower panel).
with previously available treatments, e.g. intracavernosal and
No modifications in mean blood pressure and heart beat
intraurethral prostaglandin therapies, vacuum devices or penile
values were found after the two treatments (data not shown).
implants. In fact, oral therapy always represents a more suitable
Reported adverse events were facial flushing and headache
option for all men suffering from erectile dysfunction and for
Sildenafil and male reproductive parameters
the couple in the long-term follow-up (Fabbri et al., 1999).
from less than 30 s in Syrian hamsters, some minutes in
Studies on the efficacy and safety of sildenafil in men with
Norway rats, to hours or days in some mammals (Meisel and
erectile dysfunction are well known (Goldstein et al., 1998;
Sachs, 1994). It encompasses two phases: an absolute and a
Morales et al., 1998). There are also anecdotal reports that
relative refractory period. During the former, the male is
sildenafil may improve sexual performance in potent subjects.
insensitive to sexual stimuli as well as being hyporesponsive
To our knowledge, this is the first report on the effects of
to many other stimuli (Meisel and Sachs, 1994). The length
sildenafil administration on reproductive parameters and sexual
of the PERT is biochemically regulated. It is increased by
behaviour in normal healthy volunteers.
dopamine-receptor blockade and electrolytic lesions of dopa-
In the first phase of the study, we evaluated sperm parameters
minergic neurons located in the substantia nigra (McIntosh
in the two groups studied. Nitric oxide synthase (Lewis et al.,
and Barfield, 1984a), whereas it is reduced by specific treatment
1996) and at least two distinct PDE isoforms (PDE1 and PDE4)
with serotonergic neurotoxins and electrolytic lesions of sero-
have been demonstrated to be present in human sperm cells.
tonergic neurons in the dorsal raphe nucleus (McIntosh and
Specific inhibition of PDE1 and PDE4 by 8-methoxy-isobutyl-
Barfield, 1984a,b). These observations are consistent with the
methylxanthine and rolipram selectively stimulated the acro-
presence of both a dopaminergic and a serotonergic control
some reaction and sperm motility respectively (Fisch et al.,
system, which normally exert a positive and inhibitory influence
1998). After assimilation sildenafil circulates in plasma at
over the resumption of mating following ejaculation respect-
micromolar concentrations which can cause a minor inhibition
ively. Since dopamine and serotonin do not utilize cGMP as
second messenger (Schwartz et al., 1998; Duman, 1998), it is
inhibition respectively) and determine transient side-effects
unlikely that sildenafil-induced reduction of the PERT is due
(Morales et al., 1998). In our study the maximal therapeutic
to an interaction with central monoaminergic control pathways.
dose of sildenafil was administered (100 mg) in order to
On the other hand, sildenafil-induced reduction of the post-
achieve maximal drug concentration in seminal fluid and
ejaculatory interval may be explained by its relatively long
investigate eventual sildenafil–spermatozoa interactions. It has
plasma half-life (~4 h) (Morales et al., 1998) and a consequent
been reported that in healthy volunteers, after acute 100 mg
prolonged inhibition of intracavernosal PDE5. These observa-
oral administration, sildenafil is present in seminal fluid in a
tions indicate that sildenafil has a positive influence on the
concentration range of 0.1–0.3 µmol/l (Pfizer, Viagra™ data
resumption of erection after ejaculation and has the potential
sheet). At this concentration sildenafil has the potential to
to facilitate multiple instances of sexual intercourse in the
presence of a continuous erotic stimulus. This is of clinical
1 and perhaps with other as yet uncharacter-
ized PDE isoforms (30–40% out of total PDE activity) present
relevance and implies that use of caution is necessary, especially
in sperm cells (Fisch et al., 1998; Fabbri et al., 1999). In the
in impotent patients suitable for sildenafil treatment and in
present study we showed that in subjects with proven fertility,
whom prolonged sexual activity is contra-indicated, e.g. sub-
sildenafil treatment did not cause any significant changes in
jects with a medical history of coronary heart disease.
the semen parameters studied, i.e. sperm number, and percent-
In conclusion, even if further studies are needed to evaluate
ages of sperm abnormalities and motility. This finding excludes
the effects of chronic sildenafil treatment on fertility capacity,
the presence of acute effects of sildenafil treatment on the
our results indicate that sildenafil has no acute impact on
male fertility profile and emphasizes the possibility of a
sperm function. More important, the ability of sildenafil to
potential use of the drug during assisted reproductive tech-
reduce the post-ejaculatory refractory time in the presence of
niques, when a temporary erectile dysfunction may occur
a continuous erotic stimulus adds a new aspect of interest in
related to the need to produce spermatozoa on demand at the
the research area concerning the regulatory mechanisms of
time of insemination (Tur-Kaspa et al., 1999). Nevertheless,
since the improvements in seminal parameters from PDEinhibitors are small (Fisch et al., 1998), the effects of sildenafil
in oligozoospermic males may be more pronounced and will
Aversa, A., Bonifacio, V., Moretti, C. et al. (1999) Re-dosing of prostaglandin-
be further evaluated in future studies.
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