1 Cattedra di Andrologia, Dipartimento di Fisiopatologia Medica, University of Rome La Sapienza, Italy and 2 Department of Endocrinology, St. Bartholomew's Hospital, London, UK
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Abstract |
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Key words: ejaculation/erectile function/phosphodiesterase inhibitor/reproductive behaviour/semen
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Introduction |
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It has been demonstrated that human sperm cells contain as yet uncharacterized PDE isoforms which are different from PDE1 and PDE4, and that the in-vitro inhibition of sperm PDE1 and PDE4 isoenzymes by specific inhibitors stimulates acrosome reaction and sperm motility (Fisch et al., 1998). Also, it is known that after acute administration of 100 mg sildenafil, the drug reaches a concentration of 0.10.3 µmol/l in the ejaculate (Pfizer, ViagraTM data sheet). This concentration is consistent with a possible inhibitory interaction of sildenafil with sperm PDE isoforms (Fabbri et al., 1999
). In the present study we evaluated the effects of sildenafil administration (100 mg) on seminal parameters in young healthy male volunteers. The effects of sildenafil on erectile response to audiovisual sexual stimulation were also investigated.
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Materials and methods |
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Semen processing
All semen specimens were collected 1 h after sildenafil consumption and evaluated according to World Health Organization guidelines (WHO, 1992). A combined Bryan and Leishman strain (WHO) was used to assess sperm morphology. Sperm kinematics [motility percentages, straight-line velocity (VSL), curvilinear velocity (VCL) and linearity (LIN)] were assessed by a superimposed image analysis system (SIAS) (Mazzilli et al., 1995; 1999
). This system is based upon superimposition of images and allows for a very accurate motility analysis; in fact, the operator can verify visually if each automatic track corresponds to the real superimposed sperm track and, when necessary, correct it.
Erectile and ejaculatory function studies
Erectile function at baseline was assessed by the administration of the Sexual Health Inventory for Men IIEF 5 to each subject (Rosen et al., 1997). The erection quality after either treatment was assessed during audiovisual sexual stimulation (AVSS) by each subject and evaluated by an examiner (A.A.) by utilizing colour-power Doppler sonography parameters [(the peak systolic velocities (PSV), the end diastolic velocity (EDV) and the resistive index (RI)] and the number and morphology of helicine arterioles (Aversa et al., 1999
). The time to re-obtain erection after ejaculation [post-ejaculatory refractory time (PERT)] was measured with the stop-watch technique by asking the subject to keep self-stimulating immediately after ejaculation and concomitantly by keeping on watching a different AVSS.
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Results |
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Discussion |
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In the first phase of the study, we evaluated sperm parameters in the two groups studied. Nitric oxide synthase (Lewis et al., 1996) and at least two distinct PDE isoforms (PDE1 and PDE4) have been demonstrated to be present in human sperm cells. Specific inhibition of PDE1 and PDE4 by 8-methoxy-isobutyl-methylxanthine and rolipram selectively stimulated the acrosome reaction and sperm motility respectively (Fisch et al., 1998
). After assimilation sildenafil circulates in plasma at micromolar concentrations which can cause a minor inhibition of PDE6 and PDE1 activities (ED50 = 1:10 and 1:100 of PDE5 inhibition respectively) and determine transient side-effects (Morales et al., 1998
). In our study the maximal therapeutic dose of sildenafil was administered (100 mg) in order to achieve maximal drug concentration in seminal fluid and investigate eventual sildenafilspermatozoa interactions. It has been reported that in healthy volunteers, after acute 100 mg oral administration, sildenafil is present in seminal fluid in a concentration range of 0.10.3 µmol/l (Pfizer, ViagraTM data sheet). At this concentration sildenafil has the potential to interact with PDE1 and perhaps with other as yet uncharacterized PDE isoforms (3040% out of total PDE activity) present in sperm cells (Fisch et al., 1998
; Fabbri et al., 1999
). In the present study we showed that in subjects with proven fertility, sildenafil treatment did not cause any significant changes in the semen parameters studied, i.e. sperm number, and percentages of sperm abnormalities and motility. This finding excludes the presence of acute effects of sildenafil treatment on the male fertility profile and emphasizes the possibility of a potential use of the drug during assisted reproductive techniques, when a temporary erectile dysfunction may occur related to the need to produce spermatozoa on demand at the time of insemination (Tur-Kaspa et al., 1999
). Nevertheless, since the improvements in seminal parameters from PDE inhibitors are small (Fisch et al., 1998
), the effects of sildenafil in oligozoospermic males may be more pronounced and will be further evaluated in future studies.
In the second phase of the study we compared the erectile and ejaculatory functions after sildenafil and placebo. We clearly showed that, even if penile haemodynamic parameters were unchanged, a marked reduction in post-ejaculatory refractory time occurred after sildenafil compared with placebo. The lack of sildenafil-induced changes in penile rigidity in normal potent subjects is consistent with the assumption that the nitric oxide/cGMP pathway is maximally activated in these subjects. Ejaculatory disturbances are common clinical problems, reported in approximately 40% of adult males (Spector and Carey, 1990). Sildenafil did not influence the ejaculation time and/or ejaculatory attitudes in any of our subjects, but markedly reduced the PERT by 4- to 5-fold. It is known that the post-ejaculatory interval is very variable in different species, e.g. from less than 30 s in Syrian hamsters, some minutes in Norway rats, to hours or days in some mammals (Meisel and Sachs, 1994
). It encompasses two phases: an absolute and a relative refractory period. During the former, the male is insensitive to sexual stimuli as well as being hyporesponsive to many other stimuli (Meisel and Sachs, 1994
). The length of the PERT is biochemically regulated. It is increased by dopamine-receptor blockade and electrolytic lesions of dopaminergic neurons located in the substantia nigra (McIntosh and Barfield, 1984a
), whereas it is reduced by specific treatment with serotonergic neurotoxins and electrolytic lesions of serotonergic neurons in the dorsal raphe nucleus (McIntosh and Barfield, 1984a
,b
). These observations are consistent with the presence of both a dopaminergic and a serotonergic control system, which normally exert a positive and inhibitory influence over the resumption of mating following ejaculation respectively. Since dopamine and serotonin do not utilize cGMP as second messenger (Schwartz et al., 1998
; Duman, 1998
), it is unlikely that sildenafil-induced reduction of the PERT is due to an interaction with central monoaminergic control pathways. On the other hand, sildenafil-induced reduction of the post-ejaculatory interval may be explained by its relatively long plasma half-life (~4 h) (Morales et al., 1998
) and a consequent prolonged inhibition of intracavernosal PDE5. These observations indicate that sildenafil has a positive influence on the resumption of erection after ejaculation and has the potential to facilitate multiple instances of sexual intercourse in the presence of a continuous erotic stimulus. This is of clinical relevance and implies that use of caution is necessary, especially in impotent patients suitable for sildenafil treatment and in whom prolonged sexual activity is contra-indicated, e.g. subjects with a medical history of coronary heart disease.
In conclusion, even if further studies are needed to evaluate the effects of chronic sildenafil treatment on fertility capacity, our results indicate that sildenafil has no acute impact on sperm function. More important, the ability of sildenafil to reduce the post-ejaculatory refractory time in the presence of a continuous erotic stimulus adds a new aspect of interest in the research area concerning the regulatory mechanisms of male copulatory behaviour.
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Notes |
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* This paper was presented at the First International Consultation on Erectile Dysfunction, Paris, 13 July, 1999.
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References |
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Submitted on August 16, 1999; accepted on October 12, 1999.