Sildenafil increased the Applebaum score and pregnancy rate in patients with unexplained infertility: a double-blind randomized controlled trial

Sildenafil increased the Applebaum score and pregnancy rate in patients with unexplained infertility: a double-blind randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sildenafil increased the Applebaum score and pregnancy rate in patients with unexplained infertility: a double-blind randomized controlled trial Jean-Didier Bosenge-Nguma, Antoine Modia O’yandjo, Roland Marini Djang’eing, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3954559/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction : Ovarian stimulation with clomiphene is often associated with low pregnancy rates despite high ovulation rates in patients. Several approaches have been proposed to improve the results of clomiphene induction cycles, including the adjuvant use of sildenafil and estradiol. However, the efficacy of these adjuvants has been assessed in the majority of studies by measuring endometrial thickness, yet some evidence has reported a lack of correlation between endometrial thickness and clinical pregnancy rate. Our study therefore aims to compare the effects of sildenafil on the biophysical profile of the uterus (Applebaum score) and pregnancy rate, in comparison with valerate estradiol, among patients with unexplained infertility undergoing clomiphene induction cycles. Methods : This was a double-blinded, randomized controlled trial that compared two ovarian stimulation protocols in patients with unexplained infertility. Eligible patients who consented to this study were randomly assigned to one of two groups: clomiphene + sildenafil or clomiphene + estradiol valerate. The outcomes measured were clinical pregnancy rates and Applebaum scores. Results : The mean Applebaum scores of patients in the sildenafil group were significantly higher than those in the estradiol group ( P =0.000). The rate of biochemical pregnancy was comparable and not significantly different between both randomization groups ( P =0.385). However, the clinical pregnancy rate was significantly higher in the sildenafil group, at 28.92% versus 20.83% in the control group ( P =0.04). Conclusion : As compared to estradiol valerate, the addition of sildenafil as an adjuvant during clomiphene ovulation induction cycles is associated with a high rate of clinical pregnancy and a good Applebaum score in patients with unexplained infertility. Study registration: Registry: Pan African Clinical Trials Registry Trial n°: PACTR 202310849449401 Date of registration: October 12, 2023. Clomiphene sildenafil estradiol valerate Applebaum score unexplained infertility Kisangani Figures Figure 1 INTRODUCTION Clomiphene is a commonly used drug to induce ovulation due to its low cost, tolerability, and safety profile. Although it can achieve good ovarian stimulation and yield high ovulation rates, studies have often reported low pregnancy rates [ 1 , 2 ], as well as high rates of early abortion associated with clomiphene [ 3 – 5 ]. The anti-estrogenic effects of clomiphene on the endometrium have been identified as factors that may explain the gap between ovulation and pregnancy rates. The successful implantation of an embryo in the endometrium is crucial for the continuation of pregnancy. Endometrial receptivity is the specific time window during the menstrual cycle when the endometrium acquires the ability to attach, nourish, and sustain the blastocyst. This ability is achieved after the endometrium undergoes several histological changes that optimizes its thickness, which is a complex dynamic process regulated by tight coordination between various molecular, cellular, and hormonal mechanisms [ 6 ]. The standard clinical practice of most in vitro fertilization (IVF) centers usually involves evaluating the uterus and endometrium before embryo transfer to attain optimal results when the uterus is receptive for embryo implantation. Various markers have been identified for assessing endometrial receptivity, including histological, biochemical, and genetic markers (such as the Endometrial Receptivity Array (ERA)) as well as ultrasound markers [ 7 ]. Ultrasound assessment of endometrial receptivity is a practical and widely used non-invasive method in resource-limited countries such as the Democratic Republic of Congo. To improve the results of clomiphene induction cycles, several approaches have been proposed, including the adjuvant use of sildenafil due to the anti-estrogenic effects of clomiphene on the endometrium [ 8 ]. Several studies have investigated the effects of sildenafil on endometrial receptivity. Most of these studies have focused on the effect of the drug in preparing the endometrium for embryo transfer and have reported an increase in endometrial thickness following intravaginal administration of sildenafil [ 9 , 10 ]. However, there is also a substantial body of medical literature on the adjuvant use of sildenafil during clomiphene induction cycles. These studies have typically used ultrasound measurements of endometrial thickness to determine the likelihood of treatment success. However, evidence suggests that endometrial thickness may not have a significant correlation with clinical pregnancy rates [ 11 – 14 ]. Instead, some studies suggest that endometrial vascularization, rather than thickness, may be a critical parameter for predicting the chances of implantation in IVF cycles [ 15 ]. Under these conditions, an ideal endpoint would incorporate several parameters, including endometrial thickness and vascularization. This study thus aimed to compare the effects of sildenafil and valerate estradiol on the biophysical profile of the uterus (Applebaum score) and pregnancy rates in patients with unexplained infertility undergoing ovarian induction cycles with clomiphene. METHODS Study design This is a description of a double-blind, randomized controlled trial conducted in two health facilities in the city of Kisangani (Cliniques Universitaires de Kisangani and Clinique des Anges de Kisangani) located within the province of Tshopo, northern Democratic Republic of Congo (DRC), from October 1, 2021, to October 31, 2023. Before being included in this study, the infertile couple underwent a clinical evaluation and standard paraclinical workup to identify the etiological factors of infertility. The paraclinical workup included ultrasounds, hormone and tubal patency tests for the female partner, and a spermiogram for the male partner. The etiological work-up was identical for patients who participated in the study and those who did not. Additional para-clinical examinations were ordered based on each patient's clinical condition and case parameters. If the couple's evaluation did not reveal an apparent cause of infertility, they were deemed infertile due to unexplained causes. The study protocol was thoroughly explained to the participants, and written informed consent was obtained. Sampling and selection criteria The sample size was calculated based on endometrial thickness, which is a reliable indicator of endometrial receptivity. The study considered the findings of Ali Dawood et al. [16] and Fetih et al. [17] regarding the impact of sildenafil and estradiol on endometrial thickness. The sample size formula of Kirkwood et al. [18] was applied based on estimating the difference in means between two independent samples. Assuming a 10% loss due to follow-up rate, the study aimed to recruit 148 patients who met the following inclusion criteria: age between 19 and 35 years old, body mass index (BMI) between 18.5 and 29.9 Kg/m 2 , regular menstrual cycle lasting between 21 and 35 days, good ovarian reserve, bilateral tubal patency, and a spouse with a normal spermiogram according to WHO standards. Exclusion criteria for participation in this study included the presence of infertility due to an etiological factor in one or both spouses, recent hormonal treatment within the past 6 months, contraindications to drugs utilized in this study, history of cardiac, renal, hepatic, metabolic or neurological diseases, and refusal to participate. Randomization and intervention A total of 148 patients with unexplained infertility, who met the inclusion criteria, were randomly assigned to two groups. In the intervention group, patients were administered clomiphene citrate (Clomid®, Doppel Farmaceutici S.r.l., Italy) orally at a dose of 2 x 50mg/day for 5 days, starting on day 3 of the menstrual cycle. Additionally, sildenafil citrate (Penegra®, Zydus Healthcare Ltd, India) was administered orally at a dose of 2 x 25mg/day for 5 days, from day 8 to day 12 of the same menstrual cycle. In the control group, patients were administered clomiphene citrate (Clomid®, Doppel Farmaceutici S.r.l., Italy) orally at a dose of 2 x 50mg/day for 5 days, starting on day 3 of the menstrual cycle, and estradiol valerate (Progynova®, Zydus Healthcare Ltd, India) tablet orally at a dose of 2 x 2mg/day, from day 8 to day 12 of the same menstrual cycle. All drugs utilized in this study underwent quality control at the Laboratory for Analysis and Control of Medicines and Foodstuffs (LACOMEDA), University of Kinshasa, DRC. Randomization was performed using the permuted block technique based on sequences generated by an independent statistician. The drugs were dispensed using closed envelopes, each containing medication for three cycles of ovarian stimulation. The envelope was only opened in the event of treatment discontinuation or when the patient had completed all three treatment cycles. Discontinuation of treatment before the third cycle was indicated in the following cases: a positive pregnancy test, a major adverse event, non-compliance with the drug administration protocol, or withdrawal of consent from the study. During treatment, patients received transvaginal ultrasound monitoring of follicular growth every 24 to 48 hours from day 10 of their menstrual cycle until ovulation was confirmed. Ovulation was induced by administering 5000IU of chorionic gonadotropin (HUCOG®-5000HP, Bharat Serums and Vaccines Limited, India) intramuscularly once until at least one follicle had reached 18 mm in diameter. The couple was advised to have timed-intercourses. Before administering chorionic gonadotropin on the day of ovulation induction, transvaginal ultrasound was used to assess the biophysical profile of the uterus and calculate the Applebaum score. All ultrasound scans were performed by the same operator using the EDAN Acclarix AX8, version 1.2X software (Edan Instruments, INC., 518122 Shenzhen, PR China). The uterine biophysical profile parameters assessed were endometrial thickness, endometrial stratification, endometrial zone 3 blood flow, myometrial echogenicity, uterine artery Doppler flow (assessed by pulsatility index (PI)), myometrial blood flow, and myometrial contractions. The endometrial thickness, measured in millimeters, was determined on the longitudinal section of the uterus by measuring the maximum distance between each myometrial/endometrial interface. Endometrial stratification was assessed on the longitudinal section, and one of three modalities was recorded: no stratification, blurred appearance with five lines, or appearance with five distinct lines. The study analyzed myometrial echogenicity on a longitudinal scan of the uterus, classifying it as either coarse/inhomogeneous or completely homogeneous. Additionally, the presence or absence of blood flow in zone 3 of the endometrium was noted, and uterine Doppler was performed on the ascending branch of the uterine arteries, in their segments located at the same level as the internal os of the cervix, with automatic PI calculation. Myometrial blood flow was measured within the arched vessel, and the presence, absence, or reversal of blood flow at the end of diastole was recorded. Myometrial contraction was observed as endometrial movement, and these contractions propagate from the internal cervical os to the fundus of the uterus during the late follicular phase. Table 1 presents the parameters and their ratings for the Applebaum score. Two weeks after the estimated ovulation date, a serum β hCG test was conducted to confirm pregnancy. Patients with a positive test were scheduled appointments for clinical pregnancy ultrasound confirmation. Individuals with a negative test result resumed a new stimulation cycle on day 3 of their menstrual cycle, using the same drug protocol, for a maximum of three consecutive cycles. Table 1. Applebaum's uterine scoring system [7]. Parameters Modalities Score Endometrial thickness 14 mm 1 Endometrial layering No layering 0 Hazy five-line appearance 1 Distinct five-line appearance 3 Endometrial blood flow within zone 3 Absent 0 Present, but sparse 2 Present multifocal 5 Myometral echogenicity Coarse/inhomogenous echogenicity 1 Relatively homogenous echogenicity 2 Uterine artery Doppler flow evaluated by PI PI > 3.0 0 PI ≥ 2.5-2.99 0 PI ≥ 2.2 – 2.49 1 PI < 2.19 2 Myometral blood flow Absent 0 Present 2 Myometral contractions < 3 contractions in 2 minutes (real-time) 0 ≥ 3 contractions in 2 minutes (real-time) 3 Total 20 ` Expected outcomes The study's primary outcome was the conception rate, determined by the occurrence of pregnancies. Clinical pregnancy was defined as the visualization of one or more gestational sacs with ultrasound scans, whether normal or ectopic [19]. The secondary outcome was the determination of the Applebaum score. Statistical analysis The study results are presented as frequencies, percentages, and means ± standard deviations (SD). The primary and secondary outcomes were assessed based on the number of ovarian stimulation cycles. The main objective was to compare the clinical pregnancy rates between the two treatment protocols used in the study. The conception rate was defined as the number of pregnancies per 100 stimulation cycles [19]. The secondary objective of the study was to compare the biophysical profile between the two randomization groups, by determining the Applebaum score. The parameters of the Applebaum score, including endometrial thickness, endometrial stratification, endometrial zone 3 blood flow, myometrial echogenicity, uterine artery Doppler flow assessed by PI, myometrial blood flow, and myometrial contractions, were determined based on the number of stimulation cycles. To compare proportions, we calculated Pearson's χ2 test with a significance level of P < 0.05. For continuous variables, we used the student’s t-test, and for categorical variables, we measured the strength of association using the relative risk (RR) with its 95% confidence interval (CI). We performed all analyses using the EPI Info TM software version 7.2.2.6. Ethical considerations The ethics committee of the University of Kisangani approved the protocol for this study (Ref. UNIKIS/CER/08/2021). The study was conducted in accordance with the declaration of Helsinki. Patients were provided with explanations of the study's objectives and procedures prior to participation. Participants provided written informed consent before being enrolled into the study. RESULTS Enrolment of participants During the study period, a total of 576 patients with infertility were examined in the two care facilities that were used as study settings. Out of these, 428 were excluded because they did not meet the inclusion criteria or refused to participate in the study. The remaining 148 patients were randomized into two groups: 74 participants were assigned to clomiphene + sildenafil treatment (intervention group), and the other 74 were assigned to clomiphene + estradiol valerate treatment (control group). During the follow-up period, three patients from the intervention group and two patients from the control group were lost to follow-up and withdrawn from the study (refer to Fig. 1). The sildenafil group underwent a total of 168 stimulated cycles, while the control group underwent 171 cycles (fig. 1). Baseline patient characteristics at randomization In this study, the mean age of patients in the study group was 29.04 years, which was comparable to the control group's mean age of 28.89 years. Both groups had a mean duration of attempting to conceive of 4.3 years. Table 2 illustrates that the two randomization groups were similar in terms of socio-demographic and clinical characteristics. Table 2. Baseline patient characteristics at randomization Received treatment Parameters Categorization CC + SC N=71 CC + EV N=72 Student's t-test n(%) n(%) Age 2 years 33(46.48) 30(41.67) > 5 years 24(33.80) 26(36.11) Mean ± SD 4.39±1.98 4.36±2.01 0.920 Type of infertility Primary 26(36.62) 25(34.72) 0.408* Secondary 45(63.38) 47(65.28) Parity Nulliparous 39(54.93) 42(58.33) 0.343* ≥ 1 32(45.07) 30(41.67) Mean ± SD 0.94±1.30 0.87±1.26 0.750 BMI Mean ± SD 22.76±1.13 22.46±0.96 0.095 AFC Mean ± SD 11.51±1.49 11.46±1.23 0.831 AMH Mean ± SD 2.28±0.47 2.31±0.48 0.686 PRL Mean ± SD 16.42±2.63 15.67±2.79 0.097 CC=clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate, N= total number, n =frequency, SD=standard deviation; BMI=body mass index; AFC = Antral follicle count, AMH= antimüllerian hormone; PRL= prolactin; *P-value. Primary outcome (conception rate) The study's primary results were based on complete ovarian stimulation cycles. Out of the 339 cycles stimulated, 334 (98.5%) were completed cycles, while five cycles (1.5%) were cancelled due to an exaggerated response (more than three mature follicles). Table 3 displays the primary results of the study. The two randomized groups had a similar biochemical pregnancy rate of 29.52% in the sildenafil group and 28.05% in the control group ( P =0.385). However, the clinical pregnancy rate was significantly higher in patients who received sildenafil (28.92%) compared to the control group (20.83%) with a P -value of 0.04. Table 3. Primary study results (conception rate) Received treatment Parameters Modalities CC + SC N=166 CC + EV N=168 P- value RR [95% CI] n(%) n(%) Biochemical pregnancy Yes 49(29.52) 46(28.05) 0.385 1.03[0.82-1.30] No 117(70.48) 118(71.95) Clinical pregnancy Yes 48(28.92) 35(20.83) 0.04 1.23[0.98-1.54] No 118(71.08) 133(79.17) CC=clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate, N= total number, n = frequency, RR =relative risk, CI: confidence interval Secondary outcomes of the study (Applebaum score). Table 4 presents the results related to the Applebaum score. The two randomized groups were comparable in terms of endometrial thickness and layering, myometrial echogenicity, blood flow, and contractions. However, the mean Applebaum score was significantly higher in the sildenafil group than in the estradiol group ( P =0.000). Table 4: Applebaum score in the two randomization groups Received treatment Student's t-test Applebaum score parameters CC + SC CC+ EV Mean ± SD Mean ± SD Endometrial thickness 2.55 ± 0.5 2.45 ± 0.55 0.079 Endometrial layering 2.70 ± 0.74 2.68 ± 0.77 0.863 Endometrial blood flow within zone 3 3.99 ± 1.54 2.88 ± 2.65 0.000 Uterine artery Doppler flow evaluated by PI 1.58 ± 0.71 0.89 ± 0.94 0.000 Myometral blood flow 2 ± 0 2 ± 0 NA Myometral echogenicity 1.94 ± 0.05 1.92 ± 0.07 0.537 Myometral contractions 2.29 ± 1.28 2.30 ± 1.27 0.952 Total 17.05 ± 2.82 15.14 ± 2.90 0.000 CC=clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate, SD= standard deviation Applebaum's uterine scoring system and conception rate Table 5 shows the conception rate in relation to the Applebaum score. In the sildenafil group, 30.1% of patients had an Applebaum score of 20, compared to 10.7% in the estradiol group. Additionally, we observed a parallel increase in the clinical pregnancy rate with the Applebaum score. Table 5. Relationship between Applebaum's uterine scoring system and conception rate Received treatment Biochemical pregnancy Clinical pregnancy Score CC + SC N=166 CC + EV N=168 CC + SC N=166 CC + EV N=168 CC + SC N=166 CC + EV N=168 n(%) n(%) n(%) n(%) n(%) n(%) ≤ 13 14(8.4) 39(23.2) 0(0) 1(0.6) 0(0) 1(0.6) 14-16 56(33.7) 74(44.1) 12(7.2) 16(9.5) 11(6.6) 11(6.5) 17-19 46(27.7) 37(22) 16(9.6) 20(11.9) 17(10.2) 14(8.3) 20 50(30.1) 18(10.7) 21(12.7) 9(5.4) 21(12.7) 9(5.4) DISCUSSION Endometrial receptivity is considered a key factor in the successful treatment of infertility [ 20 ]. Various methods have been described in the literature to assess it, including the Applebaum score [ 6 ]. Clomiphene citrate, the drug most commonly prescribed to infertile patients, is known to exert adverse effects on the endometrium. In fact, the use of clomiphene to induce ovulation is often associated with the disparity between high ovulation rates (70–80%) and low pregnancy rates (10–20%) [ 21 ]. High rates of subclinical abortion have also been reported following clomiphene citrate induction cycles [ 22 ]. The low pregnancy rate with clomiphene citrate induction cycles is attributed to its anti-estrogenic effect on the endometrium and cervical mucus [ 22 , 23 ]. Several studies have been conducted to determine the best method for improving endometrial receptivity and thus conception rate at the end of ovarian induction cycles with clomiphene citrate, with mixed results [ 8 , 22 , 24 – 28 ]. In this study, we found that the addition of sildenafil during clomiphene induction cycles resulted in significantly higher Applebaum scores and clinical pregnancy rates, compared with the use of estradiol valerate, in patients with unexplained infertility. In addition, the rate of conception (clinical pregnancy) was higher in patients with an Applebaum score of 20, than in those with a lower scores. Similar results have also been reported by Mohamed et al. [ 29 ] and Kumar et al [ 21 ]. These studies reported an improvement in endometrial thickness and a higher conception rate with the adjuvant use of sildenafil during clomiphene citrate induction cycles. However, other studies suggests that there is no significant correlation between endometrial thickness and clinical pregnancy rates in IVF cycles [ 11 – 14 ]. Endometrial vascularization, determined by three-dimensional power Doppler ultrasound, has been proposed as a parameter that may have a better predictive value over endometrial morphological appearance for implantation rate in IVF cycles [ 15 ]. Other studies recommend the measurement of 4 different parameters for ultrasound assessment of endometrial receptivity: endometrial thickness, endometrial pattern, endometrial volume (measured by three-dimensional ultrasound) and sub-endometrial blood flow (measured by Doppler ultrasound) [ 30 ]. The Applebaum Score used in this study includes a total of 7 parameters and provides an efficient assessment of endometrial receptivity and a good prediction of the success rate of ovarian stimulation. Malhortra et al [ 7 ] reported that a "perfect Applebaum score" of 20 was associated with a 100% conception rate, while scores of 17 to 19 were associated with an 80% conception rate, scores of 14 to 16 were associated with a 60% chance of conception, and scores ≤ 13 resulted in no pregnancy. The same authors also noted that the absence of endometrial flow was always associated with failure to conceive, despite high scores for other parameters. Study limits One of the strengths of this study is that it compares the effects of the adjuvant use of sildenafil with those of another adjuvant (estradiol valerate). There is extensive literature on the efficacy of sildenafil as an adjuvant in a cycle of ovarian stimulation with clomiphene citrate. However, the comparison has generally been with a placebo [ 8 , 31 , 32 ]. Additionally, ultrasound assessment of endometrial receptivity is a non-invasive, convenient, simple, reliable and reproducible method that can be used in resource-limited countries. Weaknesses include the limited number of patients included in the study. Large scale studies will allow us to validate the score in our setting. CONCLUSION The adjuvant oral use of sildenafil during ovulation induction cycles with clomiphene citrate is associated with a good Applebaum score and a high clinical pregnancy rate in patients with unexplained infertility, as compared to estradiol valerate. In addition, the system for assessing the biophysical profile of the uterus (Applebaum score) provides a good assessment of endometrial receptivity. In this study, patients in the sildenafil group had significantly good uterine artery PI ( P = 0.000), good endometrial blood flow ( P = 0.000), and good total uterine Applebaum scores ( P = 0.000) compared with those in the estradiol valerate group. Indeed, sildenafil deserves to be used routinely as an adjuvant in patients undergoing clomiphene citrate therapy to improve the success rate. Abbreviations < : less than ≤ : less than or equal to ≥: greater than or equal to AFC: Antral follicle count AMH: antimüllerian hormone BMI: body mass index CC: clomiphene citrate CI: confidence interval DRC: Democratic Republic of the Congo ERA: Endometrial Receptivity Array EV: estradiol valerate IVF: in vitro fertilization LACOMEDA: Laboratory for Analysis and Control of Medicines and Foodstuffs PI: pulsatility index PRL: prolactin RR: relative risk SC: sildenafil citrate SD: Standard deviation WHO: World Health Organization Declarations Acknowledgements We would like to thank all the patients who agreed to participate in this study. We would like to thank Dr. KOSI Patrick, Dr. BURUBU Junior and Dr. DEMUPONDO Jean-Marie for their many contributions during the recruitment and follow-up of the patients. We would also like to thank Professor Dr. Batina Agasa, former Dean of the Faculty of Medicine and Pharmacy at Unikis, for helping us with all the administrative formalities and for his guidance at every stage of the study. We thank the nurses and technologists who participated in the study. Authors’ contributions J.D.B.N. conceived the protocol, R.M.D. and J.J.SKV. revised it, A.M.O and G.K.B. validated it. J.D.B.N., J.J.SKV and A.M.O. supervised the entire study from realization to data collection and data treatment. J.D.B.N, N.L.O., and A.H.B.C. wrote the manuscript. A.M.O., R.M.D and G.K.B. checked the final version of the manuscript. All the authors approved its final version. Funding This study received financial support from the Faculty of Medicine and Pharmacy of the University of Kisangani and the Fondation des Anges. None of the authors has disclosed any financial relationship with any biotechnology manufacturer, pharmaceutical company, or other commercial entity with an interest in the subject matter or materials discussed in the manuscripts. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate The study received ethical clearance from the research ethics committee of the University of Kisangani. Participation was free and anonymous, based on written consent. Refusal to participate in the study did not impact the infertile couple’s access to appropriate care. Consent for publication Consent signed by participating patients allowed us to disseminate anonymised study findings through publications. Competing interests The authors declare no competing interests. References Sarhan R.M., Salem S.A.M., Elkomy M.H., Albuhayran R.M., Hussein P.R.S., Boshra M.S. 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Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment. Fertil. Steril. 1993; vol. 59(6): 1179-86 Abdel Razik M, El‐Berry S, El‐Nezamy A, Saad A, Abdel Wahab A. Nitric oxide donors increase the pregnancy rate in patients with unexplained infertility undergoing clomiphene citrate stimulation and intrauterine insemination: a randomized controlled pilot study. Gynecol Endocrinol 2017; vol. 33(3):199‐202 Mahran A, Abdelmeged A, Shawki A, Moheyelden A, Mohamed A. Nitric oxide donors improve the ovulation and pregnancy rates in anovulatory women with polycystic ovary syndrome treated with clomiphene citrate: an RCT. Int. J Reprod Biomed 2016;14(1):9‐14 Goel T, Mahey R, Bhatla N, Kalaivani M, Pant S, Kriplani A. Pregnancy after endometrial scratching in infertile couples undergoing ovulation induction and intrauterine insemination cycles-a randomized controlled trial. J Assist Reprod Genet . 2017; vol. 34(8):1051-1058 Cicek N, Eryilmaz OG, Sarikaya E, Gulerman C, Genc Y. Vitamin E effect on controlled ovarian stimulation of unexplained infertile women. J Assist Reprod Genet . 2012 Apr;29(4):325-8 Morsy AA, Sabri NA, Mourad AM, Mojahed EM, Shawki MA. Randomized controlled open-label study of the effect of vitamin E supplementation on fertility in clomiphene citrate-resistant polycystic ovary syndrome. J Obstet Gynaecol Res . 2020 Nov;46(11):2375-2382 Mohamed HI, El-Noury, Soliman AS, Sadek MS and Abd-Elazim SM. Effect of Adding Sildenafil to Clomiphene Citrate Versus Clomiphene Citrate Alone on Endometrial Receptivity in un–Ovulatory PCO Patients. Benha J Appl Sci 2020; vol. 3(3):49-54 Heger A, Sator M, Pietrowski D. Endometrial Receptivity and its Predictive Value for IVF/ICSI-Outcome. Geburtshilfe Frauenheilkd. 2012 Aug;72(8):710-715 Hamid AMA, Elbiaa AMA, Saadoun RA, Rateb A, Madkour WAI. Effect of Adding Sildenafil to Clomiphene Citrate versus Clomiphene Citrate alone on Endometrium in Unexplained Infertility: Cross-Sectional, Non-Randomized Study. Obstet Gynecol Int J 2017; vol. 7(2): 00243 DOI: 10.15406/ogij.2017.07.00243 World Health Organization. WHO laboratory manual for the examination and processing of human semen , 6 th edition. Geneva: World Health Organization; 2021, 292 pages Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3954559","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":272779909,"identity":"c7aec861-f7be-4242-9f04-e68161d3b12b","order_by":0,"name":"Jean-Didier Bosenge-Nguma","email":"data:image/png;base64,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","orcid":"","institution":"Faculty of Medicine and Pharmacy, University of Kisangani","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jean-Didier","middleName":"","lastName":"Bosenge-Nguma","suffix":""},{"id":272779910,"identity":"87608779-166d-4fcd-8f78-bf85c0f87a16","order_by":1,"name":"Antoine Modia O’yandjo","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy, University of Kisangani","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Antoine","middleName":"Modia","lastName":"O’yandjo","suffix":""},{"id":272779911,"identity":"e841f3d2-7b8a-45ff-af3e-6dba9d00e08d","order_by":2,"name":"Roland Marini Djang’eing","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy, University of Kisangani","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Roland","middleName":"Marini","lastName":"Djang’eing","suffix":""},{"id":272779912,"identity":"e76cf710-c928-4208-a436-538f195b6551","order_by":3,"name":"Jean-Jeannot Juakali SKV","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy, University of Kisangani","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jean-Jeannot","middleName":"Juakali","lastName":"SKV","suffix":""},{"id":272779913,"identity":"ca29e663-1592-45e2-b5bf-98df77e2b645","order_by":4,"name":"Noël Labama Otuli","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy, University of Kisangani","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noël","middleName":"Labama","lastName":"Otuli","suffix":""},{"id":272779914,"identity":"1be8015c-eeb7-4ecd-a34b-205942062801","order_by":5,"name":"Alexis Heng Boon CHIN","email":"","orcid":"","institution":"Singapore Fertility and IVF Consultancy Pvt Ltd., 531A Upper Cross Street, #04-95, Hong Lim Complex, 051531 Singapore","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexis","middleName":"Heng Boon","lastName":"CHIN","suffix":""},{"id":272779915,"identity":"6db50f81-b7ee-4271-b3c3-bcff8148cca9","order_by":6,"name":"Gédéon Katenga Bosunga","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy, University of Kisangani","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gédéon","middleName":"Katenga","lastName":"Bosunga","suffix":""}],"badges":[],"createdAt":"2024-02-13 22:19:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3954559/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3954559/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51186540,"identity":"82f8b3cf-7e3b-4cb8-b971-98e3d57c542e","added_by":"auto","created_at":"2024-02-15 15:59:10","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":526396,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart depicting patient enrollment, randomization, follow-up, and analysis of results. CC: clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3954559/v1/6b2c473fa4122734d5c4b099.jpeg"},{"id":54001806,"identity":"2e27c167-ba92-4b7b-a8ba-bc26cd7b9704","added_by":"auto","created_at":"2024-04-03 08:39:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":474910,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3954559/v1/440f2d12-1266-45a5-a3fd-15fee661b2bb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sildenafil increased the Applebaum score and pregnancy rate in patients with unexplained infertility: a double-blind randomized controlled trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eClomiphene is a commonly used drug to induce ovulation due to its low cost, tolerability, and safety profile. Although it can achieve good ovarian stimulation and yield high ovulation rates, studies have often reported low pregnancy rates [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], as well as high rates of early abortion associated with clomiphene [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The anti-estrogenic effects of clomiphene on the endometrium have been identified as factors that may explain the gap between ovulation and pregnancy rates.\u003c/p\u003e \u003cp\u003eThe successful implantation of an embryo in the endometrium is crucial for the continuation of pregnancy. Endometrial receptivity is the specific time window during the menstrual cycle when the endometrium acquires the ability to attach, nourish, and sustain the blastocyst. This ability is achieved after the endometrium undergoes several histological changes that optimizes its thickness, which is a complex dynamic process regulated by tight coordination between various molecular, cellular, and hormonal mechanisms [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe standard clinical practice of most in vitro fertilization (IVF) centers usually involves evaluating the uterus and endometrium before embryo transfer to attain optimal results when the uterus is receptive for embryo implantation. Various markers have been identified for assessing endometrial receptivity, including histological, biochemical, and genetic markers (such as the Endometrial Receptivity Array (ERA)) as well as ultrasound markers [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Ultrasound assessment of endometrial receptivity is a practical and widely used non-invasive method in resource-limited countries such as the Democratic Republic of Congo. To improve the results of clomiphene induction cycles, several approaches have been proposed, including the adjuvant use of sildenafil due to the anti-estrogenic effects of clomiphene on the endometrium [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have investigated the effects of sildenafil on endometrial receptivity. Most of these studies have focused on the effect of the drug in preparing the endometrium for embryo transfer and have reported an increase in endometrial thickness following intravaginal administration of sildenafil [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, there is also a substantial body of medical literature on the adjuvant use of sildenafil during clomiphene induction cycles. These studies have typically used ultrasound measurements of endometrial thickness to determine the likelihood of treatment success. However, evidence suggests that endometrial thickness may not have a significant correlation with clinical pregnancy rates [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Instead, some studies suggest that endometrial vascularization, rather than thickness, may be a critical parameter for predicting the chances of implantation in IVF cycles [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUnder these conditions, an ideal endpoint would incorporate several parameters, including endometrial thickness and vascularization. This study thus aimed to compare the effects of sildenafil and valerate estradiol on the biophysical profile of the uterus (Applebaum score) and pregnancy rates in patients with unexplained infertility undergoing ovarian induction cycles with clomiphene.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a description of a double-blind, randomized controlled trial conducted in two health facilities in the city of Kisangani (Cliniques Universitaires de Kisangani and Clinique des Anges de Kisangani) located within the province of Tshopo, northern Democratic Republic of Congo (DRC), from October 1, 2021, to October 31, 2023. Before being included in this study, the infertile couple underwent a clinical evaluation and standard paraclinical workup to identify the etiological factors of infertility. The paraclinical workup included ultrasounds, hormone and tubal patency tests for the female partner, and a spermiogram for the male partner.\u003c/p\u003e\n\u003cp\u003eThe etiological work-up was identical for patients who participated in the study and those who did not. Additional para-clinical examinations were ordered based on each patient\u0026apos;s clinical condition and case parameters. If the couple\u0026apos;s evaluation did not reveal an apparent cause of infertility, they were deemed infertile due to unexplained causes. The study protocol was thoroughly explained to the participants, and written informed consent was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSampling and selection criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size was calculated based on endometrial thickness, which is a reliable indicator of endometrial receptivity. The study considered the findings of Ali Dawood \u003cem\u003eet al.\u003c/em\u003e [16] and Fetih \u003cem\u003eet al.\u003c/em\u003e [17] regarding the impact of sildenafil and estradiol on endometrial thickness. The sample size formula of Kirkwood et al. [18] was applied based on estimating the difference in means between two independent samples. Assuming a 10% loss due to follow-up rate, the study aimed to recruit 148 patients who met the following inclusion criteria: age between 19 and 35 years old, body mass index (BMI) between 18.5 and 29.9 Kg/m\u003csup\u003e2\u003c/sup\u003e, regular menstrual cycle lasting between 21 and 35 days, good ovarian reserve, bilateral tubal patency, and a spouse with a normal spermiogram according to WHO standards. Exclusion criteria for participation in this study included the presence of infertility due to an etiological factor in one or both spouses, recent hormonal treatment within the past 6 months, contraindications to drugs utilized in this study, history of cardiac, renal, hepatic, metabolic or neurological diseases, and refusal to participate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and intervention\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 148 patients with unexplained infertility, who met the inclusion criteria, were randomly assigned to two groups. In the intervention group, patients were administered clomiphene citrate (Clomid\u0026reg;, Doppel Farmaceutici S.r.l., Italy)\u0026nbsp;orally at a dose of 2 x 50mg/day for 5 days, starting on day 3 of the menstrual cycle. Additionally, sildenafil citrate (Penegra\u0026reg;, Zydus Healthcare Ltd, India) was administered orally at a dose of 2 x 25mg/day for 5 days, from day 8 to day 12 of the same menstrual cycle. In the control group, patients were administered clomiphene citrate (Clomid\u0026reg;, Doppel Farmaceutici S.r.l., Italy) orally at a dose of 2 x 50mg/day for 5 days, starting on day 3 of the menstrual cycle, and estradiol valerate (Progynova\u0026reg;, Zydus Healthcare Ltd, India) tablet orally at a dose of 2 x 2mg/day, from day 8 to day 12 of the same menstrual cycle. All drugs utilized in this study underwent quality control at the Laboratory for Analysis and Control of Medicines and Foodstuffs (LACOMEDA), University of Kinshasa, DRC.\u003c/p\u003e\n\u003cp\u003eRandomization was performed using the permuted block technique based on sequences generated by an independent statistician. The drugs were dispensed using closed envelopes, each containing medication for three cycles of ovarian stimulation. The envelope was only opened in the event of treatment discontinuation or when the patient had completed all three treatment cycles.\u003c/p\u003e\n\u003cp\u003eDiscontinuation of treatment before the third cycle was indicated in the following cases: a positive pregnancy test, a major adverse event, non-compliance with the drug administration protocol, or withdrawal of consent from the study. During treatment, patients received transvaginal ultrasound monitoring of follicular growth every 24 to 48 hours from day 10 of their menstrual cycle until ovulation was confirmed. Ovulation was induced by administering 5000IU of chorionic gonadotropin (HUCOG\u0026reg;-5000HP, Bharat Serums and Vaccines Limited, India) intramuscularly once until at least one follicle had reached 18 mm in diameter.\u003c/p\u003e\n\u003cp\u003eThe couple was advised to have timed-intercourses. Before administering chorionic gonadotropin on the day of ovulation induction, transvaginal ultrasound was used to assess the biophysical profile of the uterus and calculate the Applebaum score.\u003c/p\u003e\n\u003cp\u003eAll ultrasound scans were performed by the same operator using the EDAN Acclarix AX8, version 1.2X software (Edan Instruments, INC., 518122 Shenzhen, PR China). The uterine biophysical profile parameters assessed were endometrial thickness, endometrial stratification, endometrial zone 3 blood flow, myometrial echogenicity, uterine artery Doppler flow (assessed by pulsatility index (PI)), myometrial blood flow, and myometrial contractions.\u003c/p\u003e\n\u003cp\u003eThe endometrial thickness, measured in millimeters, was determined on the longitudinal section of the uterus by measuring the maximum distance between each myometrial/endometrial interface. Endometrial stratification was assessed on the longitudinal section, and one of three modalities was recorded: no stratification, blurred appearance with five lines, or appearance with five distinct lines.\u003c/p\u003e\n\u003cp\u003eThe study analyzed myometrial echogenicity on a longitudinal scan of the uterus, classifying it as either coarse/inhomogeneous or completely homogeneous. Additionally, the presence or absence of blood flow in zone 3 of the endometrium was noted, and uterine Doppler was performed on the ascending branch of the uterine arteries, in their segments located at the same level as the internal os of the cervix, with automatic PI calculation. Myometrial blood flow was measured within the arched vessel, and the presence, absence, or reversal of blood flow at the end of diastole was recorded. Myometrial contraction was observed as endometrial movement, and these contractions propagate from the internal cervical os to the fundus of the uterus during the late follicular phase.\u003c/p\u003e\n\u003cp\u003eTable 1 presents the parameters and their ratings for the Applebaum score. Two weeks after the estimated ovulation date, a serum \u0026beta; hCG test was conducted to confirm pregnancy. Patients with a positive test were scheduled appointments for clinical pregnancy ultrasound confirmation. Individuals with a negative test result resumed a new stimulation cycle on day 3 of their menstrual cycle, using the same drug protocol, for a maximum of three consecutive cycles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Applebaum\u0026apos;s uterine scoring system [7].\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003eParameters\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eModalities\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003eScore\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003eEndometrial thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 7 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e7-9 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e10-14 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt; 14 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eEndometrial layering\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eNo layering\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.35467980295566%\" valign=\"top\"\u003e\n \u003cp\u003eHazy five-line appearance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.645320197044335%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eDistinct five-line appearance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEndometrial blood flow within zone 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eAbsent\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.35467980295566%\" valign=\"top\"\u003e\n \u003cp\u003ePresent, but sparse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.645320197044335%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003ePresent multifocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003eMyometral echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eCoarse/inhomogenous echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eRelatively homogenous\u0026nbsp;echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eUterine artery Doppler flow evaluated by PI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003ePI \u0026gt; 3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.35467980295566%\" valign=\"top\"\u003e\n \u003cp\u003ePI \u0026ge; 2.5-2.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.645320197044335%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.35467980295566%\" valign=\"top\"\u003e\n \u003cp\u003ePI \u0026ge; 2.2 \u0026ndash; 2.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.645320197044335%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003ePI \u0026lt; 2.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003eMyometral blood flow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003eAbsent\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003eMyometral contractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 3 contractions in 2 minutes (real-time)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge; 3 contractions in 2 minutes (real-time)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.78145695364238%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.324503311258276%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;`\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpected outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study\u0026apos;s primary outcome was the conception rate, determined by the occurrence of pregnancies. Clinical pregnancy was defined as the visualization of one or more gestational sacs with ultrasound scans, whether normal or ectopic [19]. The secondary outcome was the determination of the Applebaum score.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study results are presented as frequencies, percentages, and means \u0026plusmn; standard deviations (SD). The primary and secondary outcomes were assessed based on the number of ovarian stimulation cycles. The main objective was to compare the clinical pregnancy rates between the two treatment protocols used in the study. The conception rate was defined as the number of pregnancies per 100 stimulation cycles [19].\u003c/p\u003e\n\u003cp\u003eThe secondary objective of the study was to compare the biophysical profile between the two randomization groups, by determining the Applebaum score. The parameters of the Applebaum score, including endometrial thickness, endometrial stratification, endometrial zone 3 blood flow, myometrial echogenicity, uterine artery Doppler flow assessed by PI, myometrial blood flow, and myometrial contractions, were determined based on the number of stimulation cycles.\u003c/p\u003e\n\u003cp\u003eTo compare proportions, we calculated Pearson\u0026apos;s \u0026chi;2 test with a significance level of P \u0026lt; 0.05. For continuous variables, we used the student\u0026rsquo;s t-test, and for categorical variables, we measured the strength of association using the relative risk (RR) with its 95% confidence interval (CI). We performed all analyses using the EPI Info \u003csup\u003eTM\u003c/sup\u003e software version 7.2.2.6.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethics committee of the University of Kisangani approved the protocol for this study (Ref. UNIKIS/CER/08/2021). The study was conducted in accordance with the declaration of Helsinki. Patients were provided with explanations of the study\u0026apos;s objectives and procedures prior to participation. Participants provided written informed consent before being enrolled into the study.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eEnrolment of participants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period, a total of 576 patients with infertility were examined in the two care facilities that were used as study settings. Out of these, 428 were excluded because they did not meet the inclusion criteria or refused to participate in the study. The remaining 148 patients were randomized into two groups: 74 participants were assigned to clomiphene + sildenafil treatment (intervention group), and the other 74 were assigned to clomiphene + estradiol valerate treatment (control group). During the follow-up period, three patients from the intervention group and two patients from the control group were lost to follow-up and withdrawn from the study (refer to Fig. 1). The sildenafil group underwent a total of 168 stimulated cycles, while the control group underwent 171 cycles (fig. 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline patient characteristics at randomization\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, the mean age of patients in the study group was 29.04 years, which was comparable to the control group\u0026apos;s mean age of 28.89 years. Both groups had a mean duration of attempting to conceive of 4.3 years. Table 2 illustrates that the two randomization groups were similar in terms of socio-demographic and clinical characteristics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Baseline patient characteristics at randomization\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.74626865671642%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.49419568822554%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eReceived treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eParameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCategorization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003eCC + SC\u003c/p\u003e\n \u003cp\u003eN=71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003eCC + EV\u003c/p\u003e\n \u003cp\u003eN=72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003eStudent\u0026apos;s t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 30 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e45(63.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e45(62.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.369*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.581497797356825%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge; 30 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.026431718061673%\" valign=\"top\"\u003e\n \u003cp\u003e26(36.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.788546255506606%\" valign=\"top\"\u003e\n \u003cp\u003e27(37.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.60352422907489%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e29.04(2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e28.89(2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.720\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDuration of attempt at conception\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026le; 2 years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e14(19.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e16(22.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.839*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.013698630136986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt; 2 years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.397260273972602%\" valign=\"top\"\u003e\n \u003cp\u003e33(46.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.589041095890412%\" valign=\"top\"\u003e\n \u003cp\u003e30(41.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.988326848249027%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.544747081712064%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt; 5 years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.455252918287936%\" valign=\"top\"\u003e\n \u003cp\u003e24(33.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.011673151750973%\" valign=\"top\"\u003e\n \u003cp\u003e26(36.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e4.39\u0026plusmn;1.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e4.36\u0026plusmn;2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.920\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003eType of infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003ePrimary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e26(36.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e25(34.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.408*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eSecondary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e45(63.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e47(65.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003eParity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eNulliparous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e39(54.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e42(58.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.343*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e32(45.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e30(41.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e0.94\u0026plusmn;1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e0.87\u0026plusmn;1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.750\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e22.76\u0026plusmn;1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e22.46\u0026plusmn;0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003eAFC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e11.51\u0026plusmn;1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e11.46\u0026plusmn;1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.831\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003eAMH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e2.28\u0026plusmn;0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e2.31\u0026plusmn;0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.686\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.70978441127695%\" valign=\"top\"\u003e\n \u003cp\u003ePRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.036484245439468%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.58374792703151%\" valign=\"top\"\u003e\n \u003cp\u003e16.42\u0026plusmn;2.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91044776119403%\" valign=\"top\"\u003e\n \u003cp\u003e15.67\u0026plusmn;2.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.759535655058043%\" valign=\"top\"\u003e\n \u003cp\u003e0.097\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eCC=clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate, N= total number,\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003en =frequency, SD=standard deviation; BMI=body mass index; AFC = Antral follicle count, AMH= antim\u0026uuml;llerian hormone; PRL= prolactin; *P-value.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome (conception rate)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study\u0026apos;s primary results were based on complete ovarian stimulation cycles. Out of the 339 cycles stimulated, 334 (98.5%) were completed cycles, while five cycles (1.5%) were cancelled due to an exaggerated response (more than three mature follicles). Table 3 displays the primary results of the study. The two randomized groups had a similar biochemical pregnancy rate of 29.52% in the sildenafil group and 28.05% in the control group (\u003cem\u003eP\u003c/em\u003e=0.385). However, the clinical pregnancy rate was significantly higher in patients who received sildenafil (28.92%) compared to the control group (20.83%) with a \u003cem\u003eP\u003c/em\u003e-value of 0.04.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Primary study results (conception rate)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"621\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.281803542673106%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.713365539452496%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.18035426731079%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eReceived treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.628019323671497%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.19645732689211%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.281803542673106%\" valign=\"top\"\u003e\n \u003cp\u003eParameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.713365539452496%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eModalities\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.526570048309178%\" valign=\"top\"\u003e\n \u003cp\u003eCC + SC\u003c/p\u003e\n \u003cp\u003eN=166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.65378421900161%\" valign=\"top\"\u003e\n \u003cp\u003eCC + EV\u003c/p\u003e\n \u003cp\u003eN=168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.628019323671497%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.19645732689211%\" valign=\"top\"\u003e\n \u003cp\u003eRR [95% CI]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.375201288244767%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.619967793880837%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.526570048309178%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.65378421900161%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.628019323671497%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.19645732689211%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.375201288244767%\" colspan=\"2\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eBiochemical pregnancy \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.619967793880837%\" valign=\"top\"\u003e\n \u003cp\u003eYes \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.526570048309178%\" valign=\"top\"\u003e\n \u003cp\u003e49(29.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.65378421900161%\" valign=\"top\"\u003e\n \u003cp\u003e46(28.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.628019323671497%\" valign=\"top\"\u003e\n \u003cp\u003e0.385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.19645732689211%\" valign=\"top\"\u003e\n \u003cp\u003e1.03[0.82-1.30]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.507760532150776%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.625277161862527%\" valign=\"top\"\u003e\n \u003cp\u003e117(70.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.177383592017737%\" valign=\"top\"\u003e\n \u003cp\u003e118(71.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.055432372505543%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.375201288244767%\" colspan=\"2\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eClinical pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.619967793880837%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.526570048309178%\" valign=\"top\"\u003e\n \u003cp\u003e48(28.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.65378421900161%\" valign=\"top\"\u003e\n \u003cp\u003e35(20.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.628019323671497%\" valign=\"top\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.19645732689211%\" valign=\"top\"\u003e\n \u003cp\u003e1.23[0.98-1.54]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.507760532150776%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.625277161862527%\" valign=\"top\"\u003e\n \u003cp\u003e118(71.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.177383592017737%\" valign=\"top\"\u003e\n \u003cp\u003e133(79.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.055432372505543%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eCC=clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate, N= total number,\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003en = frequency, RR =relative risk, CI: confidence interval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes of the study (Applebaum score).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 4 presents the results related to the Applebaum score. The two randomized groups were comparable in terms of endometrial thickness and layering, myometrial echogenicity, blood flow, and contractions. However, the mean Applebaum score was significantly higher in the sildenafil group than in the estradiol group (\u003cem\u003eP\u003c/em\u003e=0.000).\u003c/p\u003e\n\u003cp\u003eTable 4: Applebaum score in the two randomization groups\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.33112582781457%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.58278145695364%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eReceived treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.086092715231787%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eStudent\u0026apos;s t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"57.35849056603774%\" valign=\"top\"\u003e\n \u003cp\u003eApplebaum score parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.32075471698113%\" valign=\"top\"\u003e\n \u003cp\u003eCC + SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.32075471698113%\" valign=\"top\"\u003e\n \u003cp\u003eCC+ EV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eEndometrial thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.55 \u0026plusmn; 0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.45 \u0026plusmn; 0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eEndometrial layering\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.70 \u0026plusmn; 0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.68 \u0026plusmn; 0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.863\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eEndometrial blood flow within zone 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e3.99 \u0026plusmn; 1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.88 \u0026plusmn; 2.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eUterine artery Doppler flow evaluated by PI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e1.58 \u0026plusmn; 0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e0.89 \u0026plusmn; 0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eMyometral blood flow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2 \u0026plusmn; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2 \u0026plusmn; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eMyometral echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e1.94 \u0026plusmn; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e1.92 \u0026plusmn; 0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.537\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eMyometral contractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.29 \u0026plusmn; 1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e2.30 \u0026plusmn; 1.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.952\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.414593698175786%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e17.05 \u0026plusmn; 2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e15.14 \u0026plusmn; 2.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\" valign=\"top\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eCC=clomiphene citrate, SC: sildenafil citrate, EV: estradiol valerate,\u0026nbsp;\u003c/em\u003e\u003cem\u003eSD= standard deviation\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eApplebaum\u0026apos;s uterine scoring system and conception rate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 5 shows the conception rate in relation to the Applebaum score. \u0026nbsp;In the sildenafil group, 30.1% of patients had an Applebaum score of 20, compared to 10.7% in the estradiol group. Additionally, we observed a parallel increase in the clinical pregnancy rate with the Applebaum score.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003eRelationship between Applebaum\u0026apos;s uterine scoring system and conception rate\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.912897822445562%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.96817420435511%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eReceived treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.150753768844222%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eBiochemical pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.96817420435511%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eClinical pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.449664429530202%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eScore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003eCC + SC\u003c/p\u003e\n \u003cp\u003eN=166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCC + EV\u003c/p\u003e\n \u003cp\u003eN=168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003eCC + SC\u003c/p\u003e\n \u003cp\u003eN=166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003eCC + EV\u003c/p\u003e\n \u003cp\u003eN=168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003eCC + SC\u003c/p\u003e\n \u003cp\u003eN=166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003eCC + EV\u003c/p\u003e\n \u003cp\u003eN=168\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.449664429530202%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.449664429530202%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026le; 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e14(8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e39(23.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.449664429530202%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e14-16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e56(33.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e74(44.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e12(7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e16(9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e11(6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e11(6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.449664429530202%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e17-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e46(27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e37(22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e16(9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e20(11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e17(10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e14(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.449664429530202%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e50(30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e18(10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e21(12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e9(5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.751677852348994%\" valign=\"top\"\u003e\n \u003cp\u003e21(12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.261744966442953%\" valign=\"top\"\u003e\n \u003cp\u003e9(5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eEndometrial receptivity is considered a key factor in the successful treatment of infertility [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Various methods have been described in the literature to assess it, including the Applebaum score [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Clomiphene citrate, the drug most commonly prescribed to infertile patients, is known to exert adverse effects on the endometrium. In fact, the use of clomiphene to induce ovulation is often associated with the disparity between high ovulation rates (70\u0026ndash;80%) and low pregnancy rates (10\u0026ndash;20%) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHigh rates of subclinical abortion have also been reported following clomiphene citrate induction cycles [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The low pregnancy rate with clomiphene citrate induction cycles is attributed to its anti-estrogenic effect on the endometrium and cervical mucus [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have been conducted to determine the best method for improving endometrial receptivity and thus conception rate at the end of ovarian induction cycles with clomiphene citrate, with mixed results [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In this study, we found that the addition of sildenafil during clomiphene induction cycles resulted in significantly higher Applebaum scores and clinical pregnancy rates, compared with the use of estradiol valerate, in patients with unexplained infertility. In addition, the rate of conception (clinical pregnancy) was higher in patients with an Applebaum score of 20, than in those with a lower scores. Similar results have also been reported by Mohamed \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and Kumar et al [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These studies reported an improvement in endometrial thickness and a higher conception rate with the adjuvant use of sildenafil during clomiphene citrate induction cycles. However, other studies suggests that there is no significant correlation between endometrial thickness and clinical pregnancy rates in IVF cycles [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEndometrial vascularization, determined by three-dimensional power Doppler ultrasound, has been proposed as a parameter that may have a better predictive value over endometrial morphological appearance for implantation rate in IVF cycles [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Other studies recommend the measurement of 4 different parameters for ultrasound assessment of endometrial receptivity: endometrial thickness, endometrial pattern, endometrial volume (measured by three-dimensional ultrasound) and sub-endometrial blood flow (measured by Doppler ultrasound) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Applebaum Score used in this study includes a total of 7 parameters and provides an efficient assessment of endometrial receptivity and a good prediction of the success rate of ovarian stimulation. Malhortra et al [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] reported that a \"perfect Applebaum score\" of 20 was associated with a 100% conception rate, while scores of 17 to 19 were associated with an 80% conception rate, scores of 14 to 16 were associated with a 60% chance of conception, and scores\u0026thinsp;\u0026le;\u0026thinsp;13 resulted in no pregnancy. The same authors also noted that the absence of endometrial flow was always associated with failure to conceive, despite high scores for other parameters.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy limits\u003c/h2\u003e \u003cp\u003eOne of the strengths of this study is that it compares the effects of the adjuvant use of sildenafil with those of another adjuvant (estradiol valerate). There is extensive literature on the efficacy of sildenafil as an adjuvant in a cycle of ovarian stimulation with clomiphene citrate. However, the comparison has generally been with a placebo [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Additionally, ultrasound assessment of endometrial receptivity is a non-invasive, convenient, simple, reliable and reproducible method that can be used in resource-limited countries. Weaknesses include the limited number of patients included in the study. Large scale studies will allow us to validate the score in our setting.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe adjuvant oral use of sildenafil during ovulation induction cycles with clomiphene citrate is associated with a good Applebaum score and a high clinical pregnancy rate in patients with unexplained infertility, as compared to estradiol valerate. In addition, the system for assessing the biophysical profile of the uterus (Applebaum score) provides a good assessment of endometrial receptivity. In this study, patients in the sildenafil group had significantly good uterine artery PI (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), good endometrial blood flow (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), and good total uterine Applebaum scores (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000) compared with those in the estradiol valerate group. Indeed, sildenafil deserves to be used routinely as an adjuvant in patients undergoing clomiphene citrate therapy to improve the success rate.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e: less than\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026le;\u0026nbsp;: less than or equal to\u003c/p\u003e\n\u003cp\u003e\u0026ge;: greater than or equal to\u003c/p\u003e\n\u003cp\u003eAFC: Antral follicle count\u003c/p\u003e\n\u003cp\u003eAMH: antim\u0026uuml;llerian hormone\u003c/p\u003e\n\u003cp\u003eBMI:\u0026nbsp;body mass index\u003c/p\u003e\n\u003cp\u003eCC: clomiphene citrate\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u003c/p\u003e\n\u003cp\u003eDRC:\u0026nbsp;Democratic Republic of the Congo\u003c/p\u003e\n\u003cp\u003eERA: Endometrial Receptivity Array\u003c/p\u003e\n\u003cp\u003eEV: estradiol valerate\u003c/p\u003e\n\u003cp\u003eIVF: in vitro fertilization\u003c/p\u003e\n\u003cp\u003eLACOMEDA: Laboratory for Analysis and Control of Medicines and Foodstuffs\u003c/p\u003e\n\u003cp\u003ePI: pulsatility index\u003c/p\u003e\n\u003cp\u003ePRL: prolactin\u003c/p\u003e\n\u003cp\u003eRR: relative risk\u003c/p\u003e\n\u003cp\u003eSC: sildenafil citrate\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWHO: World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the patients who agreed to participate in this study. We would like to thank Dr. KOSI Patrick, Dr. BURUBU Junior and Dr. DEMUPONDO Jean-Marie for their many contributions during the recruitment and follow-up of the patients. We would also like to thank Professor Dr. Batina Agasa, former Dean of the Faculty of Medicine and Pharmacy at Unikis, for helping us with all the administrative formalities and for his guidance at every stage of the study. We thank the nurses and technologists who participated in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.D.B.N. conceived the protocol, R.M.D. and J.J.SKV. revised it, A.M.O and G.K.B. validated it. J.D.B.N., J.J.SKV and A.M.O. supervised the entire study from realization to data collection and data treatment. J.D.B.N, N.L.O., and A.H.B.C. wrote the manuscript. A.M.O., R.M.D and G.K.B. checked the final version of the manuscript. All the authors approved its final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received financial support from the Faculty of Medicine and Pharmacy of the University of Kisangani and the Fondation des Anges. None of the authors has disclosed any financial relationship with any biotechnology manufacturer, pharmaceutical company, or other commercial entity with an interest in the subject matter or materials discussed in the manuscripts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study received ethical clearance from the research ethics committee of the University of Kisangani. Participation was free and anonymous, based on written consent. Refusal to participate in the study did not impact the infertile couple\u0026rsquo;s access to appropriate care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent signed by participating patients allowed us to disseminate anonymised study findings through publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSarhan R.M., Salem S.A.M., Elkomy M.H., Albuhayran R.M., Hussein P.R.S., Boshra M.S. Oral sildenafil citrate: A potential approach for improvement of endometrial thickness and treatment of unexplained infertility in women. \u003cem\u003eEur Rev Medic Pharm Sci 2023\u003c/em\u003e; 27\u0026nbsp;:4583-93\u003c/li\u003e\n \u003cli\u003eBegum MR, Ferdous J, Begum A, Quadir E. 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Predictive value of endometrial thickness, pattern and sub-endometrial blood flows on the day of hCG by 2D\u0026thinsp;doppler in in-vitro fertilization cycles: A prospective clinical study from a tertiary care unit.\u0026nbsp;\u003cem\u003eJ Hum Reprod Sci.\u0026nbsp;\u003c/em\u003e2011; 4:29-33\u003c/li\u003e\n \u003cli\u003eAli Dawood S, Ali Hussaini H., Ali M. Effect of Oral Estradiol Valerate versus Vaginal Sildenafil on Endometrial Receptivity Evaluated by Ultrasound and Pregnancy Rate in Iraqi Infertile females. \u003cem\u003eSys Rev Pharm 2020\u003c/em\u003e; vol. 11(6): 627-632\u003c/li\u003e\n \u003cli\u003eFetih A.N., Habib D.M., Abdelaal I.I., Hussein M., Fetih G.N., Othman E.R. Adding sildenafil vaginal gel to clomiphene citrate in infertile women with prior clomiphene citrate failure due to thin endometrium: a prospective self-controlled clinical trial.\u0026nbsp;\u003cem\u003eFacts Views Vis Obgyn\u003c/em\u003e. 2017; vol. 9(1): 21-27\u003c/li\u003e\n \u003cli\u003eKirkwood B, Sterne J. \u003cem\u003eEssential Medical Statistics\u003c/em\u003e. 2e \u0026eacute;dition, Blackwell Publishing; 2006. 413-438p\u003c/li\u003e\n \u003cli\u003eZegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R. \u003cem\u003eet al.\u003c/em\u003e The International Glossary on Infertility and Fertility Care, 2017. \u003cem\u003eHum Reprod\u003c/em\u003e.\u0026nbsp;2017; vol. 32(9):1786-1801\u003c/li\u003e\n \u003cli\u003eArora A., Goel JK, Goel R., Arya SB., Prajapati N. Ultrasonography and Doppler Study to Predict Uterine Receptivity in Infertile Patients Undergoing Embryo Transfer and its Correlation with Pregnancy Rate.\u0026nbsp;\u003cem\u003eJ South Asian Feder Obstetr Gynaecol.\u003c/em\u003e 2021; vol.13(3):146-150\u003c/li\u003e\n \u003cli\u003eKumar S., Amithra S., Anuthejaswi. Effect of sildenafil on endometrium in clomiphene citrate induced cycles\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003cem\u003eJ cardio Vasc Res\u0026nbsp;\u003c/em\u003e2023; vol. 14(7):1825-32\u003c/li\u003e\n \u003cli\u003eGerli S., Gholami H., Manna A., Scotto Di Frega A., Vitiello C. and Vittorio Unfer. Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study.\u0026nbsp;\u003cem\u003eFertil. Steril.\u003c/em\u003e 2000, vol. 73(1): 85-90\u003c/li\u003e\n \u003cli\u003eMassai MR, de Ziegler D, Lesobre V, Bergeron C, Frydman R, Bouchard P. Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment.\u0026nbsp;\u003cem\u003eFertil. Steril.\u003c/em\u003e 1993; vol. 59(6): 1179-86\u003c/li\u003e\n \u003cli\u003eAbdel Razik M, El‐Berry S, El‐Nezamy A, Saad A, Abdel Wahab A. Nitric oxide donors increase the pregnancy rate in patients with unexplained infertility undergoing clomiphene citrate stimulation and intrauterine insemination: a randomized controlled pilot study. \u003cem\u003eGynecol Endocrinol\u0026nbsp;\u003c/em\u003e2017; vol. 33(3):199‐202\u003c/li\u003e\n \u003cli\u003eMahran A, Abdelmeged A, Shawki A, Moheyelden A, Mohamed A. Nitric oxide donors improve the ovulation and pregnancy rates in anovulatory women with polycystic ovary syndrome treated with clomiphene citrate: an RCT. \u003cem\u003eInt. J Reprod Biomed\u0026nbsp;\u003c/em\u003e2016;14(1):9‐14\u003c/li\u003e\n \u003cli\u003eGoel T, Mahey R, Bhatla N, Kalaivani M, Pant S, Kriplani A. Pregnancy after endometrial scratching in infertile couples undergoing ovulation induction and intrauterine insemination cycles-a randomized controlled trial. \u003cem\u003eJ Assist Reprod Genet\u003c/em\u003e. 2017; vol. 34(8):1051-1058\u003c/li\u003e\n \u003cli\u003eCicek N, Eryilmaz OG, Sarikaya E, Gulerman C, Genc Y. Vitamin E effect on controlled ovarian stimulation of unexplained infertile women. \u003cem\u003eJ Assist Reprod Genet\u003c/em\u003e. 2012 Apr;29(4):325-8\u003c/li\u003e\n \u003cli\u003eMorsy AA, Sabri NA, Mourad AM, Mojahed EM, Shawki MA. Randomized controlled open-label study of the effect of vitamin E supplementation on fertility in clomiphene citrate-resistant polycystic ovary syndrome. \u003cem\u003eJ Obstet Gynaecol Res\u003c/em\u003e. 2020 Nov;46(11):2375-2382\u003c/li\u003e\n \u003cli\u003eMohamed HI, El-Noury, Soliman AS, Sadek MS and Abd-Elazim SM. Effect of Adding Sildenafil to Clomiphene Citrate Versus Clomiphene Citrate Alone on Endometrial Receptivity in un\u0026ndash;Ovulatory PCO Patients. \u003cem\u003eBenha J Appl Sci\u0026nbsp;\u003c/em\u003e2020; vol. 3(3):49-54\u003c/li\u003e\n \u003cli\u003eHeger A, Sator M, Pietrowski D. Endometrial Receptivity and its Predictive Value for IVF/ICSI-Outcome.\u0026nbsp;Geburtshilfe Frauenheilkd. 2012 Aug;72(8):710-715\u003c/li\u003e\n \u003cli\u003eHamid AMA, Elbiaa AMA, Saadoun RA, Rateb A, Madkour WAI. Effect of Adding Sildenafil to Clomiphene Citrate versus Clomiphene Citrate alone on Endometrium in Unexplained Infertility: Cross-Sectional, Non-Randomized Study. \u003cem\u003eObstet Gynecol Int J\u003c/em\u003e 2017; vol. 7(2): 00243 DOI: 10.15406/ogij.2017.07.00243\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWorld Health Organization. \u003cem\u003eWHO laboratory manual for the examination and processing of human semen\u003c/em\u003e, 6\u003csup\u003eth\u003c/sup\u003e edition. Geneva: World Health Organization; 2021, 292 pages\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Clomiphene, sildenafil, estradiol valerate, Applebaum score, unexplained infertility, Kisangani","lastPublishedDoi":"10.21203/rs.3.rs-3954559/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3954559/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e:\u003cstrong\u003e \u003c/strong\u003eOvarian stimulation with clomiphene is often associated with low pregnancy rates despite high ovulation rates in patients. Several approaches have been proposed to improve the results of clomiphene induction cycles, including the adjuvant use of sildenafil and estradiol. However, the efficacy of these adjuvants has been assessed in the majority of studies by measuring endometrial thickness, yet some evidence has reported a lack of correlation between endometrial thickness and clinical pregnancy rate. Our study therefore aims to compare the effects of sildenafil on the biophysical profile of the uterus (Applebaum score) and pregnancy rate, in comparison with valerate estradiol, among patients with unexplained infertility undergoing clomiphene induction cycles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This was a double-blinded, randomized controlled trial that compared two ovarian stimulation protocols in patients with unexplained infertility. Eligible patients who consented to this study were randomly assigned to one of two groups: clomiphene + sildenafil or clomiphene + estradiol valerate. The outcomes measured were clinical pregnancy rates and Applebaum scores.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The mean Applebaum scores of patients in the sildenafil group were significantly higher than those in the estradiol group (\u003cem\u003eP\u003c/em\u003e=0.000). The rate of biochemical pregnancy was comparable and not significantly different between both randomization groups (\u003cem\u003eP\u003c/em\u003e=0.385). However, the clinical pregnancy rate was significantly higher in the sildenafil group, at 28.92% versus 20.83% in the control group (\u003cem\u003eP\u003c/em\u003e=0.04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: As compared to estradiol valerate, the addition of sildenafil as an adjuvant during clomiphene ovulation induction cycles is associated with a high rate of clinical pregnancy and a good Applebaum score in patients with unexplained infertility.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e \u003cstrong\u003eregistration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegistry: Pan African Clinical Trials Registry\u003c/p\u003e\n\u003cp\u003eTrial n°: PACTR 202310849449401\u003c/p\u003e\n\u003cp\u003eDate of registration: October 12, 2023.\u003c/p\u003e","manuscriptTitle":"Sildenafil increased the Applebaum score and pregnancy rate in patients with unexplained infertility: a double-blind randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-15 15:58:31","doi":"10.21203/rs.3.rs-3954559/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fec0d277-6433-47d9-b255-b34e6312ade2","owner":[],"postedDate":"February 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-24T07:00:08+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-15 15:58:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3954559","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3954559","identity":"rs-3954559","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}