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ORIGINAL ARTICLE
Year : 2022 | Volume
: 33
| Issue : 2 | Page : 93-98
Sildenafil citrate effects on seminal parameters in male participants with idiopathic infertility; A randomized, double-blind, controlled cross-over clinical trial study
Gholamreza Mokhtari, Ali Hamidi Madani, Ehsan Kazemnezhad Leyli, Alireza Jafari
Urology Research Center, Razi Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
Correspondence Address:
Alireza Jafari
Sardar Jangal Ave, Razi Hospital, Rasht
Iran
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/UROS.UROS_113_21
Purpose: Sildenafil is a phosphodiesterase Type 5 inhibitor, which is a powerful and effective therapy for male erectile dysfunction (ED) and enables to restore temporary ED. The aim of this study was to evaluate the effects of sildenafil on seminal parameters in male participants with idiopathic infertility. Materials and Methods: This randomized, double-blind, controlled cross-over clinical trial study was conducted on 79 participants who had been referred to urology clinics in Rasht. Participants were assigned to two Groups A (n = 40), and B (n = 39). In Phase I, participants in Group A received a pill of sildenafil (50 mg) and then received a pill of placebo after the washout period, and participants in Group B received a pill of placebo and then received a pill of sildenafil after the washout period. In Phase II, participants in Group A received a pill of placebo and then received a pill of sildenafil after the washout period; and participants in group B received sildenafil and then received a placebo after the washout period. Results: The mean age of patients was 34 ± 5 years. There was no significant difference in the mean sperm count before receiving the drug in all groups. Sperm count, motility, morphology, pH, viscosity, and liquefaction time of semen did not significantly change after receiving sildenafil in comparison to their corresponding placebo group (P > 0.05). Conclusion: Sildenafil did not change sperm parameters in treating infertile patients; sildenafil also had no positive effect on semen parameters.
Keywords: Idiopathic infertility, semen parameters, sildenafil
Infertility is a common problem that may affect couples; currently, most of them are seeking medical treatment. Infertility in men is a personal and social problem, and it is clear that it should be treated by safe and effective drugs.[1],[2] Conversely, sexual dysfunction is one of the common complications in more than 50% of men aged 50–70 years.[3],[4] Sexual dysfunction could have negative effects on the quality of life of both youth and elderly individuals.[5]
Sildenafil is identified as a potent and selective phosphodiesterase Type 5 (PDE5) inhibitor. Presently, sildenafil is considered not only as a treatment of erectile dysfunction (ED) but also as a potential treatment option for male idiopathic infertility.[6],[7] It is able to significantly prolong the stiffness duration. Its ability to increase erection in response to visual stimuli would result in complete and successful sexual relationships.[2] Sildenafil could be useful for men with ED at any age, race, and body mass index. It might be beneficial in patients with diabetes, ischemic heart diseases, peripheral vascular diseases, hypertension, depression, and kidney diseases.[8],[9] This drug stimulates Leydig cell secretory function and also enhances prostatic secretory function. It also increases citrate and cholesterol concentrations in the semen, which may preserve the natural morphology of the sperm against osmotic shock and environmental stress. Moreover, studies have indicated that sildenafil increases sperm motility.[10],[11] Hence, sildenafil has a beneficial effect on male infertility.[1],[12]
The evidence reveals that sildenafil administration might have beneficial effects on many sperm parameters, such as sperm count, sperm motility, sperm morphology, semen volume, seminal fructose concentrations, and semen acidity.[12],[13],[14] It has been confirmed that the cyclic AMP, adenosine 3',5'-cyclic monophosphate (cAMP) concentrations, sperm motility, sperm activity, sperm production, sperm quality, and phosphorylation of tyrosine proteins would be increased after inhibition of PDE by sildenafil.[14],[15] However, some controversies exist concerning the effects of sildenafil on sperm motility.[16],[17] Studies have shown that the effects of sildenafil on sperm motility are dependent on its concentration.[13] It seems that sperm motility would be increased in lower plasma sildenafil concentrations, and it would be decreased in higher plasma sildenafil concentrations.[18] This randomized, double-blind, controlled cross-over clinical trial study was conducted to evaluate the effects of oral sildenafil on semen parameters in male participants with idiopathic infertility.
Materials and MethodsStudy design
This randomized, double-blind, placebo-controlled, cross-over clinical trial study was conducted in accordance with ethical guidelines and the Declaration of Helsinki and approved by the urology research center and the Ethics Committee. A total of 79 participants had been referred to the urology clinics in Rasht. Participants with idiopathic infertility in the age range of 25–40 years with normal arousal function were included in the study. Idiopathic infertility is defined as the lack of an obvious cause for couples' infertility and women's inability to get pregnant after at least 12 cycles of unprotected intercourse or after six cycles in women aged > 35 years for whom all standard evaluations are normal. Unexplained infertility is a condition when standard infertility testing has not found a cause for a couple's or a woman's inability to get pregnant. Some reproductive physicians hold that a diagnosis of unexplained infertility is a nondiagnosis. Estimations indicate that 15%–30% of couples with infertility are diagnosed as having unexplained infertility, making it one of the most common causes of infertility. The variation in the estimated percentage of unexplained infertility is due to the fact that experts do not agree on what should constitute “standard infertility testing.” Testing can vary according to the individual's situation and physician's testing protocols. The American Society for Reproductive Medicine's guidelines for standard infertility testing calls for ovulation assessment, hysterosalpingography, semen analysis, and ovarian reserve evaluation. These may be performed in addition to a physical examination and review of medical and sexual history. Both partners may have unexplained fertility problems.[19]
The exclusion criteria were as follows history of acute disease, febrile disease, or medication use 3 months before enrollment; exposure of testicles to high temperatures and cardiovascular disease, hypertension, diabetes mellitus, seasonal allergies, trauma, and history of testicular surgery; alcohol and cocaine dependence and use of cimetidine, spironolactone, erythromycin, corticosteroids, methylxanthine, theophylline, pentoxifylline, aminophylline, and nitrates; living in rural areas with incomplete medical documentation; presence of varicocele; and abnormal hormone levels, normozoospermia, asthenospermia, or teratozoospermia.
The primary outcomes of the study were seminal parameters that were measured by automated sperm quality analyzers (SQA IIC-P, USA).[20]
Study variables included age, sperm count, semen volume, pH, abnormal morphology, semen viscosity, liquefaction time, and sperm motility.
Both participants and questioners did not have any information about the study groups. Drugs were classified as follows: placebo (Marham Daru Company) and sildenafil citrate (Marham Daru Company). Drugs were placed into two separate envelopes and randomly classified. Participants were assigned to two Groups: A (n = 40) and B (n = 39). In Phase I, participants in Group A received sildenafil (50 mg) and placebo after the washout period, whereas participants in Group B received placebo and then sildenafil after the washout period. In Phase II, participants in Group A received placebo and then sildenafil after the washout period, and participants in Group B received sildenafil and then placebo after the washout period. The participants in each group received 50 mg of sildenafil in a single dose, and the washout period took a week for each group. The clinical trial registration number in the “Iranian Registry of Clinical Trial” was IRCT201611291853N12. Ethical approval for this study was obtained from Guilan University of Medical Sciences (approval number: IR. GUMS. REC.1394.79). Written informed consent was obtained from all subjects before the study.
Semen processing
Participants had not ejaculated, smoked, and consumed caffeine for 3 days before receiving the drugs. Semen specimens were collected 1 h after consumption of drugs and evaluated according to the World Health Organization guidelines.[21] To transport the semen, we required the participants to prepare the sperm sample on-site (laboratory) to ensure that the best possible sperm sample was obtained. If the samples were collected outside the clinic, the participants needed to transfer them to the laboratory within 1 h after ejaculation. We advised participants that the semen samples must be kept as close to body temperature as possible. Moreover, the semen samples were stored in the container upright in a plastic bag, with the lid securely tightened. The specimen was not placed in any purse, pocket, or briefcase. The semen samples were stored at 25°C in the laboratory. The semen parameters were measured by automated (SQA IIC-P, USA).[20] The condensation, viscosity, and appearance of specimens were evaluated by automated (SQA IIC-P, USA). Sperm concentration and count were calculated by automated (SQA IIC-P, USA). Sperm morphology was evaluated by eosin-hematoxylin staining. Sperm motility and kinetic were evaluated after 30 min at room temperature. Then, intervention and control groups were replaced after the washout period. Participants underwent a semen analysis approximately 1 week before receiving the first dose of sildenafil and placebo.
Statistical analysis
Data of participants were extracted and then analyzed using SPSS statistical software version 16 IBM SPSS software, USA. Independent t-test and pairwise t-test were conducted. If the variables did not have normal distribution, nonparametric Mann–Whitney and Wilcoxon tests were used (P < 0.05). Two-tailed tests were achieved.
ResultsIn the current study, 237 specimens from 79 participants were studied. The mean age of participants was 34 ± 5 years. The mean sperm counts in 79 patients were approximately 43.94 × 106 per ejaculation. [Table 1] shows semen analysis in 79 participants at the baseline double-blind placebo-controlled, cross-over clinical trial on the administration of 50 mg sildenafil tablet [Table 1]. Conversely, [Table 2] and [Table 3] show semen viscosity and liquefaction time analysis in Groups A and B, including 39 and 40 participants, after double-blind placebo-controlled, cross-over clinical trial pre-post administration of 50 mg sildenafil and placebo tablets (P > 0.05) [Table 2] and [Table 3]. According to the results, 50 mg sildenafil did not have a sufficient effect on sperm motility and sperm viscosity at the baseline (P > 0.05).
Table 2: The comparison of semen quality and liquefaction time between sildenafil and placebo groups at phase I
Table 3: The comparison of semen quality and liquefaction time between sildenafil and placebo groups at phase IIAs shown in [Table 4], 50 mg sildenafil and placebo tablets had no effects on ejaculatory fluid volume, semen viscosity, semen pH, sperm number, and sperm motility after sildenafil administration in both Groups (A and B) at Phase I (P > 0.05) [Table 4]. Moreover, no significant difference was shown between the volume of the ejaculatory fluid, semen viscosity, semen pH, number of sperms, baseline sperm motility, and sperm motility after administration in both Groups (A and B) at Phase II (P > 0.05) [Table 5].
Table 4: Effect of sildenafil and placebo on the changes of ejaculatory fluid volume, semen viscosity, semen pH, sperm count, sperm motility of patients at phase I
Table 5: Effect of sildenafil and placebo on the changes of ejaculatory fluid volume, semen viscosity, semen pH, sperm count, sperm motility of patients at phase II Discussion In this randomized, double-blind, controlled cross-over clinical trial, 79 participants were treated with 50 mg sildenafil and placebo. The mean age of patients was 34 ± 5 years, and the sperm number was 43.94 ± 64.06 (million) per ejaculation [Table 1]. This study demonstrated that 50 mg sildenafil tablet did not have any effect on semen viscosity and liquefaction time in Groups A and B (P > 0.05) [Table 2] and [Table 3]. The results show that 50 mg sildenafil tablet had no effects on ejaculatory fluid volume, semen viscosity, semen PH, sperm number, baseline sperm motility, and sperm motility after sildenafil administration in both Groups (A and B) at Phase I (P > 0.05) [Table 4]. We also found that there was no significant difference in ejaculatory fluid volume, semen viscosity, semen PH, sperm number, baseline sperm motility, and sperm motility after sildenafil administration in both Groups (A and B) at Phase II (P > 0.05) [Table 5].
Glenn et al., Drobnis and Nangia, and Pomara et al. showed that sildenafil has no effect on sperm count.[7],[10],[11] It was argued that PDE5 inhibitors increase secretory function. It is associated with increase in the serum insulin-like peptide concentrations in the sperm.[6] The studies showed that consumption of 100 mg sildenafil would increase sperm motility.[11],[22],[23],[24] Studies showed that Type 4 and Type 5 inhibitors improve sperm motility.[13] Researchers found that a low sildenafil dose had no effect on sperm motility.[25],[26],[27] Pomara et al. also confirmed the positive effects of sildenafil on sperm motility in infertile patients.[11] Moreover, we reported no significant change in morphology, viscosity, and liquefaction time of semen after sildenafil administration compared with placebo. This is consistent with Purvis et al., who found that sildenafil had no significant effect on morphology, viscosity, and liquefaction time of semen after sildenafil administration.[28] Aversa et al. showed that sildenafil (100 mg) did not change sperm parameters of healthy patients and indicated that potential use of medication can be helpful in assisted reproductive techniques when ED temporarily occurs.[6]
Burger et al. and Frantz et al. reported that 125, 250, and 750 ng/mL sildenafil did not significantly change motility and viability of human sperm.[29],[30] Herbert LP et al. also reported that the drug practically did not affect semen parameters and its volume and acidity.[31]
The findings of this study had some limitations. First, this was a single-center study; therefore, the results require further investigation. Second, the erectile and ejaculatory functions of participants were not measured. Third, the sample size of this study was small, and there was low power to detect an effect from sildenafil. Finally, patients only used one dose of sildenafil (50 mg) for evaluation. Hence, further studies seem to be required in this field. Selection bias limits the generalization of these findings because the type of participants in a city or a country could be different with other cities or countries and could be related to descent diversities.
In Iran, sildenafil is the most prescribed medication to treat male sexual problems. To date, different studies have been reported that sildenafil could be useful to sperm function. The current study showed that sildenafil had no significant effect on semen parameters.
ConclusionCurrently, PDE5 enzyme inhibitors, particularly sildenafil, are the first and most popular treatment options for men with impotence. However, the results of this study show that oral sildenafil citrate does not have any significant effect on any of the semen parameters. It is recommended that more studies should be conducted with a larger sample size, higher sildenafil doses (≥100 mg), and longer follow-up period.
Acknowledgment
We thank our colleagues from Urology Research Center, Guilan University of Medical Sciences, who provided insight and expertise that greatly assisted the study although they may not agree with all interpretations/conclusions of this paper. In the end, my coauthors and I decided to list Dr. Soheil Kianfar as a coauthor with a footnote stating that he passed away before publication. Dr. Soheil Kianfar was a urologist at Aria Hospital in Rasht. During the COVID-19 pandemic, Dr. Soheil Kianfar did his best to treat needy patients. He passed away in 2019 in this holy path before the publication of the manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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