Endometrial injury for unexplained infertility: Arandomized case-control study
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 Endometrial injury for unexplained infertility: Arandomized case-control study Ayman M. Assaf, MD(1), Samy A.Saad, MD(1),Khaled M. Salama, MD (2 ),Ali Abdelnaby A. Morsy, M.Sc.(3) 1. Professor of Obstetrics and Gynecology, 2. Assistant professor of Obstetrics and Gynecology, 3..Assistant Lecturer of Obstetrics and Gynecology. Department of Obstetrics & Gynecology, Faculty of Medicine, Benha University, Banha, Egypt
Unexplained infertility, usually refers to a diagnosis (or lack of diagnosis) made in couples in whom all the standard investigations such as tests of ovulation, tubal patency and semen analysis are normal. Unexplained infertility is a term that has been applied to as many as, 30–40% of infertile couples (Smith et al., (2003). The potential causes of unexplained infertility was described as disturbances in endocrinological balance, immunology and genetic and reproductive physiology (Pellicer et al., 1998). None of these causes was solely able to explain all cases of reproductive failure. Empirically, interventions for managing unexplained infertility had been widely practiced. These interventions include expectant management, intrauterine insemination (IUI) with ovarian stimulation and in vitro fertilization (IVF)/ICSI, (El - Toukhy et al., 2008 ).Some ultrasonographic studies demonstrated that a substantial proportion of women with successful pregnancy had more optimal uterine blood flow and a thicker endometrium (Noyes et al., 1995) with more organized morphology (Serafini et al., 1994) compared with women without conception. In particular, increased uterine artery (UtA) vascular impedance (Zaidi et al., 1996) and low subendometrial or endometrial blood flow (Chien et al., 2002) have been associated with poor pregnancy rates. However, other studies did not revealed such associations (Puerto et al., 2003).The presence of both endometrial and subendometrial flow is indicative of good endometrial receptivity, (Chien et al., 2002).To improve blood flow to the uterus, some medications were suggested e.g low-dose aspirin (Weckstein et al., 1997) , vaginal sildenafil (Sher and Fisch, 2002), Vaginal micronized estradiol (Tourgeman et al., 2001),Antifibrotic as pentoxifylline (Trental) and high-dose vitamin E (Ledee-Bataille et al., 2002). Implantation requires synchronization between the developing embryo and endometrium. The dialogue between embryo and endometrium and the receptivity of the latter is under the control of the sex steroids, estrogen and progesterone as well as other hormones (Kodaman and Taylor, 2004).Implantation failure remains one of the major factors limiting success in in vitro fertilization (IVF) treatment. According to the ESHRE data on assisted reproductive technology outcomes across Europe in 2009, only 32% of fresh embryo transfers resulted in clinical pregnancies (Ferraretti et al., 2013).Recently, in order to improve outcomes in women with unexplained RIF, various studies have examined pregnancy rates after inducing local endometrial injury,(Almog et al., 2010 and Zhou et al., 2008). It has been shown that mechanical manipulation of the endometrium can enhance receptivity by modulating gene expression of factors required for implantation like glycodelin A (Mirkin et al., 2005), lamininalpha 4, integrin alpha 6 and matrix metalloproteinase 1 (Almog et al., 2010 and Zhou et al., 2008).
This randomized case-control study was performed at the Obstetrics and Gynecology Department of Benha University Hospital ,during the period between October 2013 till July 2015.One hundred and twenty women with unexplained infertility were included in the study ,these patients were recruited from Outpatient Clinic of Benha University, with the following criteria: age Between 20 - 35 years ,Body mass index 18-29 kg/m2, ,Complaining of primary infertility for more than two years, and planning for IVF/ICSI trial , All factors which may contribute to infertility were excluded .Normal ovulation confirmed by previous folliculometry, Normal hormonal profile FSH, LH, and prolactin ,Antimullerian hormone (AMH) more than 1 ng/ml ,Normal Hysterosalpingography,Normal laparoscoic finding. . All the male partners had normal semen analysis, according to WHO 2010. Primary exclusion Criteria:The patients with any of the following criteria were excluded from the study: Absence of inclusion criteria ,History of previous laparotomy ,Patients with history which may suggest endometriosis and Associated chronic medical conditions e.g. cardic disease, diabetes, renal disease … etc. Awritten, informed, consent, was taken from all women after explaining the nature and the aim of the study. The 120 patients were divided randomly into two groups (based on each alternate week referral to the clinic ).All the patients recieved Clomiphene citrate (CC) and, Human menopausal gonadotrophin ,according to the following protocol :Clomiphene Citrate(Clomiphene tablets, Clomiphene citrate 50 mg, The Arab Drug Company, ADCO, Egypt), 100 mg/day for 5 consecutive days, with therapy initiated on cycle day 3 . Human menopausal gonadotrophin (Merional 75IU, IBSA InstitutBiochimique SA, Switzerland), was injected intra-muscularly, in a dose of 150 iu/day, on the days 3, 5, 7, 9 of the menstrual cycle. Serial transvaginal ultra sound folliculometry was performed for all patients starting from day 10 and repeated every other day .Human menopausal gonadotrophin was continued daily, in the same dose, until follicles reached 18 -22 mm. When the dominant follicles reached 18 -22 mm, as measured by transvaginal ultrasound ,HCG(Choriomon 5000 IU, IBSA Institut Biochimique SA ,Switzerland) was injected intramuscularly , in a dose of 5,000 – 10,000 IU, and timed intercourse was advised, 36 h after HCG injection and the days after. Vaginal ultrasound was done about 60 h after HCG injection to confirm follicular rupure. On day 5 of the cycle, Doppler examination was performed to all patients. Also on day 5, but only for group II patients, local endometrial injury was performed. Doppler studies was repeated, for all our patients, on the same day of prescriping HCG. Technique of trans vaginal ultrasound:Trans vaginal sonography examination was performed with patient in the lithotomy position using a 7.5 -9 MHz, transvaginal transducer with color Doppler facility, using the Voluson 730 PRO V‐ G E, Health care USA.On ultrasound, a longitudinal view of the uterus was obtained then, the color Doppler mode was activated. The endometrial and subendometrial blood flow distribution pattern was determined by demonstrating pulsatile color signals in the sub endometrial and endometrial regions. Doppler sonography was performed on the vessels with the highest color intensity within the innermost endometrial and sub endometrial area. The insonation angle was kept at 0° to identify the course of the small spiral arteries .After confirming that waveforms were continuous, an average of three to five cardiac cycles were selected for calculation of resistance index (RI), pulsatility index (PI).The vessel with the lowest PI was considered for further statistical analysis. Uterine circulation was assessed simultaneously in each examination; bilateral uterine arteries were sampled lateral to the cervix near the internal os. Mean levels of both uterine RI and PI were used for analysis.on the day of HCG administration the endometrial thickness was measured ,and reported .on the same day The endometrial pattern was evaluated and described as a multilayered or a non-multilayered endometrium. A trilaminar endometrium presented as a triple-line pattern in which hyperechogenic outer lines and a well-defined central echogenic line with hypoechogenic or black areas between these lines. A non trilaminar endometrium consisted of homogeneous endometrial patterns, characterized by either hyperechogenic or isoechogenic endometrium. Technique of endometrial injury: Endometrial injury was done only for patient of the study group. It was done on day 5, under complete aseptic conditions, no anesthesia, was given in most of cases. Endometrial local injury was performed on the posterior wall, midline, and 10–15 mm from the fundus using pipelle endometrial sampling (Pipelle; Gynetics Medical Products, Hamont-Achel, Belgium). Statistical analysis: The clinical data were recorded on a report form. These data were tabulated and analyzed using the computer program SPSS (Statistical package for social science) version 16 to obtain: Descriptive data: Descriptive statistics were calculated for the data in the form of:
Analytical statistics: In the statistical comparison between the different groups, the significance of difference was tested using one of the following tests:-
A P value <0.05 was considered statistically significant (S) while >0.05 statistically insignificant P value <0.01 was considered highly significant (HS) in all analyses. Results: Table (1): patient's characteristics of the two groups.
This table shows no statistically significant differences between the two groups regarding the demographic characteristics, Age, BMI and duration of infertility. Table (2): Comparison between study and Control group, as regard uterine artery Doppler indices on day of HCG, administration.
This table shows no statistically significant differences between the two groups in uterine PI and RI in in day of HCG, administration. Table (3): Comparison of sub endometrial blood flow between study and control groups on the day of HCG, administration.
This table shows that on the day of HCG, administration,thesubendometrial blood flow was statistically higher in the study group compared to control grou Table (4): Spiral artery Doppler indices between study and control groups on the day of HCG, administration .
RI=resistance index, PI=pulsatility index. This table shows that, on the day of HCG, administration , the spiral artery Doppler indices (RI, PI) highly statistically significant differences ,Decrease (RI) and increase (PI) in study group,compared to control group. Table (5) shows comparison of pregnancy rate between the study and the control group .
All the parameters in this table are expressed in frequency, (%) with Chi-square test. *p-value less than 0.05 was considered statistically significant This table shows clinical pregnancy rate was significantly higher in the study group than in the control group (18.3 % and 6.7 % ,respectively,( P = 0.053) . DISCUSSION: In our study , endometrial injury was performed in the early follicular phase, in the same cycle of ovarian stimulation , this was the same as the study of Huang et al 2011 , who performed the endometrial injury day 4-7 of the cycle and Afsoon et al., 2014, was performed it day 6–8 of the menstrual cycle. Parsanezhad et al., 2013,performed endometrial local injury during the preovulatory days (the day of detecting urinary LH-surge) . Karimzade et al.( 2010 ) endometrial injury, was performed on the day of oocyte retrieval. The same study showed a negative impact on the pregnancy rate. Some studies investigated endometrial injury, in the cycle preceding ovarian stimulation in different phases of the cycle . Three studies performed intervention in the early proliferative phase (Demirol and Gurgan, 2004 and Makrakis et al., 2009; Rama Raju et al., 2006); Three studies performed in both the early proliferative and luteal phases (Barash et al., 2003 , Narvekar et al., 2010 and Leena et al ., 2015 ) and the remaining two performed only in the luteal phase (Karimzadeh et al., 2009; Raziel et al., 2007). There is some suggestion that injury induced in the luteal phase is likely to induce more decidualization; however, there is no conclusive evidence to suggest one is better than the other.In our study, we avoided injury in the preceeding cycle as regeneration of the endometrium may disrupt the effect induced by the injury. We did not perform the injury in the pre-ovulatory period to allow sufficient time for gene expression and cytokine production and other expected positive effect of the injury.In this study endometrial injury was done using a Pipelle endometrial catheter , which was also used in other studies, Barash et al., 2003, Raziel et al., 2007 , Karimzadeh et al., 2009 , Narvekar et al., 2010, Bonavita et al., 2011 ,Gibreel et al., 2012 and Parsanezhad et al., 2013 Endometrial biopsy catheter was used in other studies, Li et al., 2004 , Zhou et al., 2008 and Guven et al., 2011 . Salama et al.,2016 used neonatal feeding, tube No.8 for endometrial injury.Out patient hysteroscopy was used in many studies , Demirol and Gurgan, 2004, Rama Raju et al., 2006, and Makrakis et al., 2009.in this study we used Pipelle endometrial catheter ,because it simple procedure ,available ,cost effective ,can be done outpatient , no need for preparation. Although hysteroscopic injury might be more site specific but it add an extr cost of a relatively invasive procedure. After hysteroscopicinjury , a question may be raised about the effect of the injury or the effect of distending the uterine cavity. In this study endometrial injury, performed once , as many studies, Li et al., 2004 , Zhou et al., 2008 , Guven et al., 2011 ,Karimzadeh et al., 2009 and Bonavita et al., 2011 . This was to avoid the cost of multiple injury and the risk of infection. Narvekar et al., 2010 and Raziel et al., 2007, performed Endometrial injury, on two occasions .While Barash et al., 2003 , performed Endometrial injury, on four occasions. in this study Endometrial local injury was performed , site specific , on the posterior wall, midline, and 10–15 mm from the fundus . to avoid risk of bleeding and infection .In the above mentioned studies that using Pipelle endometrial biopsy ,the procedure was poorly described, but generally involved moving the catheter upwards and downwards in the endometrial cavity a few times or until the abnormal endometrial echoes had disappeared.in our study no complications were reported , except cramping and spotting , which was described by few patients. No complications were reported in most of other studies , either during or after the treatment cycle.In our study no prophylactic antibiotics were prescribed, to avoid its effect on pregnancy rate . Li et al., 2004, Zhou et al., 2008 and Narvekar et al., 2010 , prescribed Prophylactic antibiotics for 3–7 days after the intervention .In our study, endometrial injury, was performed without anesthesia except in 5 cases who recieved mild sedation due to difficulty in introducing the pipelle . To our knowledge, no previous studies have addressed uterine artery doppler, the endometrial and subendometrial blood flow following endometrial injury .As regard uterine artery dopplerindices , on day of HCG, adminstraion, there was no statistically significant difference (p value > 0.05 ) in uterine PI and RI, in Study group in comparison to control group . Our study, shows that on the day of HCG adminstration, after endometrial injury, thesubendometrial blood flow was statistically higher in the study group compared to control group, this may be due to the inflammatory response induced by endometrial injury. In this study, as regard, the spiral artery Doppler indices (RI, PI) , on the day of HCG, administration, there were highly statistically significant differences between study group, and control group . Decrease (RI) and increase (PI) in study group, compared to control group, may be due to increase blood flow ,due to inflammatory response induced by injury .Irrespective to endometrial injury, Raine-Fenning (2004) found that endometrial and subendometrial vascularity were significantly reduced in women with unexplained subfertility during the mid-late follicular phase, irrespective of estradiol or progesterone concentrations. In the present study, the patients underwent endometrial local injury had higher pregnancy rate compared to the control group (18.3 %vs. 6.7 %, p=0.053).In many studies ,pregnancy rate after endometrial injury, was statistically higher , but very variable. Raziel et al., (2007) , reported a pregnancy rate of 30% after endometrial injury , Karimzadeh et al., (2009), 27.1% , In Narvekar et al., (2010), 32.7% , Gibreel et al 2012, 25.9% , Parsanezhad et al.,2013. 14.9% ,Leena et al ., (2015 31.11% , while Salama et al.,2016 , reported 39% pregnancy rate after local endometrial injury. On the other hand , Afsoon et al.,( 2014) , reported no statistical significant difference in the pregnancy rate in patients underwent endometrial injury ( 23.6) compared to the control group (19.4%) . An explanation for their findings could be the longer interval between the endometrial injury and IUI. because injury was done within the follicular phase of the previous cycle of the IUI.
Local endometrial injury increase pregnancy rate in un explained infertility, Doppler study has an important role in evaluating sub endometrial blood flow before and after local endometrial injury. Based on our conclusions we may recommend local endometrial injury in un explained infertility. . Acknowledgements:The authors are grateful to all the team of work and the statistician, for their contribution to this work and data collection and analysis. REFERENCES:
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for quantitative data.