|Year : 2017 | Volume
| Issue : 2 | Page : 343-349
The role of sildenafil citrate (viagra) suppositories on endometrial response (thickness and mean resistance index of endometrial spiral artery) in cases of unexplained infertility
Shahinaz El-Shourbagy, Ahmed M. E. Ossman, Ashraf El-Mohamady
Department of Obestetrics and Gynaecology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||01-Aug-2016|
|Date of Acceptance||09-Oct-2016|
|Date of Web Publication||25-Sep-2017|
Department of Obestetrics and Gynaecology, Faculty of Medicine, Tanta University, Tanta, 31111
Source of Support: None, Conflict of Interest: None
The oblective of this study was to evaluate the endometrial response of women with unexplained infertility after treatment with sildenafil citrate (viagra) suppositories.
Unexplained infertility refers to failure to conceive in a couple with no definitive cause. Endometrial thickness (ED TH) and perfusion may have an important contribution to etiopathogenesis of unexplained infertility.
Patients and methods
A total of 50 women with unexplained primary infertility were treated with 25 mg of sildenafil citrate suppositories four times per day for 7 days starting from the fifth day of the menstrual cycle for three cycles. Ultrasonographic measurement of ED TH and the mean resistance index (RI) values of endometrial spiral artery (SA) assessed by transvaginal color-pulsed Doppler ultrasound were measured in women with unexplained infertility before and after sildenafil citrate treatment and compared with an equal number of a fertile control group receiving no treatment. The conception rate and pregnancy outcome were recorded in the two groups.
Women with unexplained infertility in the present study had a significantly thinner endometrium and a higher SA-RI (6.52 + 0.77; 1.00 + 0.23 mm, respectively), meaning lower peri-implantation blood flow compared with fertile controls (11.98 + 1.23; 0.58 + 0.06 mm, respectively). Sildenafil citrate-treated women showed a statistically significant increase in ED TH (8.87 + 0.56 mm; P < 0.001) and a significant decrease in the mean SA-RI (0.61 + 0.07; P < 0.001), yielding a better conception rate.
Treatment with viagra suppositories enhances endometrial blood flow by decreasing the SA-RI and consequently improves endometrial growth and receptivity in cases of unexplained infertility, thus yielding a better conception rate.
Keywords: endometrial blood flow and receptivity, etiopathogenesis, resistance index, transvaginal color-pulsed Doppler ultrasound, unexplained infertility
|How to cite this article:|
El-Shourbagy S, Ossman AM, El-Mohamady A. The role of sildenafil citrate (viagra) suppositories on endometrial response (thickness and mean resistance index of endometrial spiral artery) in cases of unexplained infertility. Menoufia Med J 2017;30:343-9
|How to cite this URL:|
El-Shourbagy S, Ossman AM, El-Mohamady A. The role of sildenafil citrate (viagra) suppositories on endometrial response (thickness and mean resistance index of endometrial spiral artery) in cases of unexplained infertility. Menoufia Med J [serial online] 2017 [cited 2018 Mar 18];30:343-9. Available from: http://www.mmj.eg.net/text.asp?2017/30/2/343/215451
| Introduction|| |
Unexplained infertility refers to the absence of a definable cause for a couple's failure to achieve pregnancy after 12 months of attempting conception despite a thorough evaluation, or after 6 months in women 35 years and older .
Embryo implantation depends on the quality of the ovum and endometrial receptivity. Successful embryo implantation can take place only in a receptive uterus. Adequate growth of the endometrium is indispensable for successful pregnancy. Patients with a thin endometrium showed low pregnancy rates ,. Uterine blood flow is an important factor for endometrial growth and receptivity . High blood flow impedance of uterine radial arteries is associated with poor endometrial growth in patients with a thin endometrium .
Sugino and colleagues , showed that high blood flow impedance of uterine radial arteries impairs the growth of the glandular epithelium and results in a decrease in vascular endothelial growth factor expression, which is a key factor for regulating angiogenesis in the human endometrium. Low vascular endothelial growth factor levels cause poor vascular development, which in turn decreases blood flow in the endometrium. The vicious circle leads to a thin endometrium.
Endometrial receptivity is regulated by many factors including uterine perfusion . Several studies have shown that uterine receptivity is decreased when the uterine artery impedance has been increased during the midluteal phase . Abnormal uterine perfusion may be a contributing factor to etiopathology of infertility, especially in couples with unexplained infertility . Transvaginal Doppler pulsed ultrasound is an important tool for examining the female reproductive system and is a noninvasive method to assess uterine perfusion .
Nitric oxide synthase isoforms in the uterus relaxes vascular smooth muscle through a cyclic GMP-mediated pathway. Sildenafil citrate (viagra), a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of nitric oxide on vascular smooth muscle by preventing the degradation of cyclic GMP ,.
Also, sildenafil is considered as a potential agent in treating pregnant women with intrauterine growth retardation or as a tocolytic agent (anticontraction agent) helping maintenance of pregnancy ,.
Trakakis et al.  used sildenafil as an adjunct to controlled ovarian hyperstimulation protocols as part of an intracytoplasmic sperm injection cycle, and showed that sildenafil improved the ovarian response and resulted in the retrieval of a higher number of mature oocytes, leading to successful pregnancy and, eventually, the delivery of a healthy neonate. Hence, sildenafil improved the ovarian response and oocytes maturation.
Thus, the main objective of this study was to evaluate treatment with sildenafil citrate suppositories in cases of unexplained infertility and to compare their parameters [endometrial thickness (ED TH), resistance index (RI) of endometrial spiral artery (SA), and conception rate] with those of controls (fertile women and women with unexplained infertility before treatment) to reveal the possible role of the sildenafil citrate (viagra) in the treatment of infertile couples.
| Patients and Methods|| |
The study was approved by the ethics committee of Obstetrics and Gynecology, Tanta University, and informed consent was obtained from the patients for this study.
Two groups each of 50 cases were studied. A study group of women aged 21–35 years with unexplained primary infertility, attending the infertility outpatient clinic of Tanta University Hospital from January to December 2014, and a control group of fertile women aged 22–34 years attending for check-up in the same period and receiving no treatment were included.
The study group inclusion criteria were endocrinological demonstration of ovulation (midluteal progesterone value), folliculometery, confirmation of tubal patency, and normal pelvic cavity by hysterosalpingiography and laparoscopy and normal seminal analysis within the WHO guidelines . The exclusion criteria were as follows: women with pelvic pathology including ovarian cysts, polycystic ovary syndrome, endometrial polyps and fibroids, women with an abnormal hormonal profile, for example, hyperprolactinemia, and hormonal therapy or ovarian stimulation during the cycle of the study and significant cardiovascular, liver, or renal disease.
Patients of the study group self-administered 25 mg of sildenafil citrate suppositories (Pfizer Inc., New York, New York, USA) four times per day for 7 days starting from the fifth day of the menstrual cycle and this continued for three cycles . Women were evaluated monthly during treatment. We have not performed a negative control to our cases of unexplained infertility in order not to bother the patients by self-administering placebo suppositories that were only for comparison and not treatment, as we used the parameters of cases before sildenafil citrate treatment as the negative control.
ED TH assessed by gray-scale ultrasound and endometrial vessel characteristics and Doppler velocimetry of the SAs before and after sildenafil citrate suppository treatment together with the conception rate were correlated with those of the control group.
Transvaginal sonography (TVS) was performed in the late follicular phase (1–2 days before ovulation) on the Xario (Toshiba, Tokyo, Japan) machine. The probe was a microconvex device for conducting TVS. Before TVS, the patients were asked to empty the urinary bladder. The examination was performed with the patient in the lithotomy position, with a pillow under the buttocks. The probe was placed inside a condom that contained a coupling gel. Additional gel was placed on the covered probe.
The transducer was introduced into the posterior vaginal fornix and the uterus was scanned longitudinally and transversely. The ED TH was measured at the thickest part in the longitudinal plane. It was measured from the highly reflective interface of the junction of the endometrium and the myometrium. This measurement represented two layers of the endometrium . In the presence of fluid in the endometrial canal, the two-half thickness endometrial measurements were added together .
Blood flow impedance of uterine SAs was evaluated using a computerized vaginal ultrasound with an integrated pulsed color Doppler vaginal scanner (Toshiba) and RI was assessed as reported elsewhere . The SA blood flow pattern was determined by demonstrating pulsatile color signals in the myometrium. After confirming that waveforms were continuous, an average of three to five cardiac cycles were selected for the calculation of the endometrial SA-RI. The mean of the 2 points of SA-RI was used for statistical analyses . Patients were followed up for 12 months after treatment, and we recorded the pregnancy and failure cases.
Statistical analysis was carried out using the software program SPSS for Windows, version 13.0 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were presented as mean and SD. Student's t-test was used to compare means of two independent groups. The receiver operator characteristic curve was used to evaluate the value of resistant indices in the diagnosis of decreased blood flow in unexplained infertility patients and its correlation with ED TH. Validity of the test at a certain cutoff point was represented by sensitivity and specificity. Results were considered significant at a P value of less than or equal to 0.05.
| Results|| |
The present study included 50 women with unexplained primary infertility with a mean age of 26.88 ± 3.42 years and a control group of 50 fertile women with a mean age of 26.84 ± 4.28 years. There was no significant (P = 0.959) difference between infertile and fertile women with regard to their mean age.
In contrast, infertile women had a significantly (P < 0.001) thin ED TH compared with the control group. There was significant increase in ED TH after sildenafil citrate suppository treatment, but still the endometrium was significantly (P < 0.001) thin compared with that of the controls, with sensitivity 88% and a good specificity of 98%.
Infertile women had a significant high value of endometrial SA-RI compared with controls (P < 0.001). A significant decrease in the mean RI value was found in cases that received sildenafil citrate suppository treatment [Figure 1]a,[Figure 1]b,[Figure 1]c. The RI after treatment was significantly lower than the RI before treatment (P < 0.001) with sensitivity 96% and a good specificity of 99% in infertile women. There was no significant difference (P < 0.302) between infertile women after treatment and controls [Table 1]. Infertile women had a significantly higher mean SA-RI, which increased with age [Table 2].
|Figure 1: (a) RI (0.81) in infertile women before sildenafil citrate suppository treatment. (b) RI (0.68) in infertile women after sildenafil citrate suppository treatment. (c) ED TH (8.9 mm) in infertile women after sildenafil citrate suppository treatment. ED TH, endometrial thickness; RI, resistance index.|
Click here to view
|Table 1: Endometrial thickness and resistance index in controls and infertile women before and after sildenafil citrate suppository treatment|
Click here to view
|Table 2: Age group and number of cases (SD) in relation to resistance index in control and infertile women|
Click here to view
The receiver operator characteristic curves of correlation between uterine RI and ED TH was performed to determine the cutoff value of the RI, which was 0.71, providing the best values of sensitivity and specificity for determination of normal and thin endometrium [Figure 2]a and [Figure 2]b.
|Figure 2: (a) ROC curve analysis showing correlation between the RI and endometrial thickness (ED TH). (b) ROC curve analysis showing the sensitivity 88%, specificity 86%, and the cutoff value is 0.7 of RI for the determination of normal and thin endometrium. RI, resistance index; ROC, receiver operating characteristic.|
Click here to view
A positive correlation was found between ED TH and RI before sildenafil citrate suppository treatment and a negative correlation after treatment [Table 3] and [Figure 3]a and [Figure 3]b.
|Table 3: Positive correlation between uterine resistance index and endometrial thickness in infertile women before sildenafil citrate suppository treatment and a negative correlation after treatment|
Click here to view
|Figure 3: (a) Positive correlation between uterine RI and endometrial thickness (ED TH) in infertile women before sildenafil citrate suppository treatment. (b) Negative correlation between uterine RI and ED TH in infertile women after sildenafil citrate suppositories treatment. RI, resistance index.|
Click here to view
Out of 50 women with unexplained infertility, 28 failed to conceive, 22 (40%) women got pregnant, three women failed to continue, and 19 women continued treatment. No significant difference with regard to age was found between cases of pregnancy and cases of nonpregnancy (P ≤ 0.97), and between cases of pregnancy failure and cases of pregnancy continued (P ≤ 0.299) [Table 4].
|Table 4 Pregnancy outcomes in relation to age, endometrial thickness, and resistance index before and after treatment with viagra|
Click here to view
All women who conceived showed a significant (P < 0.001) difference between ED TH and RI before and after treatment with sildenafil citrate suppositories. The three cases that failed to continue pregnancy showed no significant difference (P = 0.088) between ED TH before and after treatment, but had significant (P < 0.001) decrease of RI after treatment with sildenafil citrate suppositories. Failure to continue pregnancy could be attributed to a thin endometrium [Table 4].
| Discussion|| |
Unexplained infertility is one of the most common complaints of couples in a fertility clinic with the prevalence reaching 30%. At present, almost 80% of infertile couples can be helped to have a child.
The present study included 50 women with unexplained infertility with a mean age of 26.88 ± 3.42 years and a control group of 50 fertile women with a mean age of 26.84 ± 4.28 years. There was no significant difference with regard to the mean age between infertile and fertile women (P = 0.959). Such findings coincided with those of other authors ,, who showed no significant differences between infertile and fertile women with regard to the mean age and body mass index. Out of 50 women with unexplained infertility in the present study, 22 (40%) women conceived after treatment with sildenafil citrate (viagra) suppositories, but three women failed to continue with a mean age 29.33 years, showing no significant difference with regard to age compared with pregnant women (P ≤ 0.299).
All infertile women examined in the present study had a significantly (P < 0.001) thin ED TH compared with the control fertile group. This could be the cause of infertility in such cases as adequate growth of the endometrium is indispensable for successful pregnancy as has been reported previously by Takasaki et al.  After treatment of unexplained infertility in women with sildenafil citrate suppositories, a significant increase in the ED TH and receptivity was recorded compared with those before treatment.
This coincided with previous researchers who assessed the value of ED TH reporting a thicker endometrium in conception cycles than in nonconception cycles and found a good correlation between ED TH and the prevalence of conception ,. Friedler et al.  also showed that an ED TH of less than 6 mm has a high negative predictive value for pregnancy. Thus, although 'normal' ED TH does not necessarily predict pregnancy, a thin endometrium means that implantation is difficult to occur.
Our results showed that impedance of SA blood flow 'RI' was significantly increased in the unexplained infertility group compared with controls (P < 0.001). Therefore, the decreased uterine perfusion could be a contributing factor to infertility. The present result showed that the RI of women with unexplained infertility was statistically significantly decreased after treatment with sildenafil citrate suppositories, compared with those before treatment.
Similarly, Steer et al.  suggested that decreased uterine perfusion might be a cause of unexplained infertility. Also, Chien et al.  showed that uterine artery pulsatility index and RI were found to be significantly lower in conception than in nonconception cycles.
The uterine artery may influence the quality and quantity of the SA in the endometrium, but Doppler studies of uterine arteries do not reflect the actual blood flow to the endometrium, as the main bulk of the uterus is the myometrium, to which there are plenty of collateral circulations .
Endometrial blood flow can be evaluated noninvasively by means of color and power Doppler ultrasound. Power Doppler imaging is generally superior to color Doppler imaging for detecting low-velocity flows and visualizing small vessels .
Gong et al.  previously demonstrated that impedance of blood flow to the uterine and SAs change periodically during the normal ovulatory menstrual cycle with the lowest impedance of SA blood flow detected just at the time of the midluteal phase, during which the endometrium has been transformed from the proliferative phase to the secretory phase with rich uterine blood supply and implantation is most likely to occur.
Lilic et al.  and Abdallah et al.  found that good uterine blood flow is necessary for embryo implantation and good pregnancy rates and that higher uterine arterial resistance was associated with a low pregnancy rate and a poor outcome. They added that a decreased uterine perfusion response is a contributing factor to infertility.
The conception rate in the present study after treatment with sildenafil citrate suppositories was good: 22 (44%) cases out of 50. All pregnant patients showed a significant (P < 0.001) increase in the ED TH and decrease in the mean SI-RI. Such findings coincided with Zinger et al.  who showed that vaginal administration of sildenafil citrate improved endometrial growth and pregnancy rates in patients with a thin endometrium by increasing the uterine blood flow. Some workers have reported significant correlation between pregnancy rates and uterine artery Doppler flow values .
However, three cases failed to continue pregnancy, having a nonsignificant (P ≥ 0.088) increase of ED TH but significant (P < 0.001) decrease in the mean SA-RI. The other 19 cases continued till delivery. They showed a significant (P < 0.001) increase in the ED TH together with a significant (P < 0.001) decrease in the mean SA-RI. Therefore, failure to continue pregnancy could be attributed to a thinner endometrium and age more (mean = 29.33 years) than cases of continued pregnancy.
| Conclusion|| |
Treatment by sildenafil citrate suppositories improved uterine SA blood flow through decreasing the SA-RI and are quite beneficial to improve endometrial growth and receptivity in cases of unexplained infertility, thus yielding a better conception rate.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 90:S60.
Richter KS, Bugge KR, Bromer JG, Levy MJ. Relationship between endometrial thickness and embryo implantation, based on 1294 cycles of in vitro
fertilization with transfer of two blastocyst-stage embryos. Fertil Steril 2007; 87:53–59.
El-Toukhy T, Coomarasamy A, Khairy M, Sunkara K, Seed P, Khalaf Y, et al.
The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles. Fertil Steril 2008; 89:832–839.
Ng EH, Chan CC, Tang OS, Yeung WS, Ho PC. The role of endometrial blood flow measured by three-dimensional power Doppler ultrasound in the prediction of pregnancy during in vitro
fertilization treatment. Eur J Obstet Gynecol Reprod Biol 2007; 135:8–16.
Miwa I, Tamura H, Takasaki A, Yamagata Y, Shimamura K, Sugino N. Pathophysiological features of 'thin' endometrium. Fertil Steril 2009; 91:998–1004.
Sugino N, Kashida S, Takiguchi S, Karube A, Kato H. Expression of vascular endothelial growth factor and its receptors in the human corpus luteum during the menstrual cycle and in early pregnancy. J Clin Endocrinol Metab 2000; 85:3919–3924.
Sugino N, Kashida S, Karube-Harada A, Takiguchi S, Kato H. Expression of vascular endothelial growth factor and its receptors in the human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction 2002; 123:379–387.
Yılmaz N, Kılıç S, Madendağ Y, Madendağ İ, Özgün A, Özakşit G, et al.
Endometrial parameters in IVF and IUI administration on elderly women. Turk J Med Sci 2010; 40:343–348.
Gong X, Lı Q, Zhang Q, Zhu G. Predicting endometrium receptivity with parameters of spiral artery blood flow. J Huazhong Univ Sci Technolog Med Sci 2005; 25:335–338
Uysal S, Özün Özbay EP, Ekinci T, Aksüt H, Karasu S, Işık AZ, Soylu F. Endometrial artery Doppler in unexplained infertility. J Turk Ger Gynecol Assoc 2012; 13:169–171.
Steer CV, Tan SL, Mason BA, Campbell S. Mid-luteal-phase vaginal Doppler assessment of uterine artery impedance in a sub-fertile population. Fertil Steril 1994; 61:53–58.
Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod 2000; 15:806–809.
Martin D, Conrad KP. Expression of endothelial nitric oxide synthase by extravillous trophoblast cells in the human placenta. Placenta 2000; 21:23–31.
Sher G, Fisch JD. Effect of vaginal sildenafil on the outcome of in vitro
fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril 2002; 78:1073–1076.
El-Far M, El-Motwally Ael G, Hashem IA, Bakry N. Biochemical role of intravaginal sildenafil citrate as a novel antiabortive agent in unexplained recurrent spontaneous miscarriage: first clinical study of four case reports from Egypt. Clin Chem Lab Med 2009; 47:1433–1438.
Trakakis E, Vaggopoulos V, Sioulas VD, Panagopoulos P, Grammatikakis I, Ambatzi P, Kassanos D. The contribution of sildenafil (Viagra) to ovarian stimulation with gonadotropins in a woman with poor ovarian response. Gynecol Endocrinol 2014; 30:478–480.
Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM, et al.
World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010; 16:231–245.
Van Den Bosch T, van Dendael A, van Schoubroeck, D Wranz PAB, Lombard CJ. Combining vaginal ultrasonography and office endometrial sampling in the diagnosis of endometrial disease in postmenopausal women. Obstet Gynecol 1995; 85:349–352.
Levine D, Gosnik BB, Johnson LA. Change in endometrial thickness in postmenopausal women undergoing hormone replacement therapy. Radiology 1995; 197:603–608.
Tamura H, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, et al.
Different changes in resistance index between uterine artery and uterine radial artery during early pregnancy. Hum Reprod 2008; 23:285–289.
Abdel Razik MA, Farag MAH, Sheta M. Uterine and ovarian arteries blood flow during the mid luteal phase in women with unexplained infertility. Middle East Fert Soc J 2015; 20:209–212.
Takasaki A, Tamura H, Miwa I, Taketani T, Shimamura K, Sugino M. Endometrial growth and uterine blood flow: a pilot study for improving endometrial thickness in the patients with a thin endometrium. Fertil Steril 2010; 93:1851–1858.
Lenz S, Lindenberg S. Ultrasonic evaluation of endometrial growth in women with normal cycles during spontaneous and stimulated cycles. Hum Reprod 1990; 5:377.
Fanchin R. Assessing uterine receptivity in 2001: ultrasonographic glances at the new millennium. Ann N
Y Acad Sci 2001; 943:185–202.
Friedler S, Schenker JG, Herman A, Lewin A. The role of ultrasonography in the evaluation of endometrial receptivity following assisted reproductive treatments: a critical review. Hum Reprod Update 1996; 2:323–335.
Chien LW, Lee WS, Au HK, Tzeng CR Assessment of changes in utero
-ovarian arterial impedance during the peri-implantation period by Doppler sonography in women undergoing assisted reproduction. Ultrasound Obstet Gynecol 2004; 23:496–500.
Ng EH, Chan CC, Tang OS, Yeung WS, Ho PC Relationship between uterine blood flow and endometrial and subendometrial blood flows during stimulated and natural cycles. Fertil Steril 2006; 85:721–727.
Guerriero S, Ajossa S, Lai MP, Risalvato A, Paoletti AM, Melis GB Clinical applications of colour Doppler energy imaging in the female reproductive tract and pregnancy. Hum Reprod Update 1999; 5:515–529.
Lilic V, Tubis-Pavlovic A, Radovic-Janosevic D, Petric A, Stefanovic M, Zivadinovic R. Assessment of endometrial receptivity by color Doppler and ultrasound imaging. Med Pregl 2007; 60:237–240.
Abdalah Y, Naji O, Saso S, Pexsters A, Stalder C, Sur S, et al
. Ultrasound assessment of the peri-implantation uterus: a review. Ultrasound Obstet Gynecol 2012; 39:612–661
Zinger M, Liu JH, Thomas MA. Successful use of vaginal sildenafil citrate in two infertility patients with Asherman's syndrome. J Womens Health (Larchmt) 2006; 15:442–444.
Carbillon L, Perrot N, Uzan M, Uzan S. Doppler ultrasonography and implantation: a critical review. Fetal Diagn Ther 2001; 166:327–332.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]