| BackgroundIntrauterine adhesions (IUA) refers to the mutual adhesion of uterine muscle wall and (or) cervical canals due to any event that causes damage to the basilar layer of the endometrium. It is also known as Asherman’s syndrome for that Asherman systematically described the etiology, symptoms and diagnosis of29cases of amenorrhea due to abortion or postpartum curettage for the first time in1948. IUA is a clinical common disease, the incidence of IUA presented a gradually rising trend with the increaseing of artificial abortion,the popularity of hysteroscopy and the increased awareness. As the difference of sites, area and degree of the IUA after the damage to the basilar layer of the endometrium, patients with intrauterine adhesions may present with hypomenorrhea, amenorrhea, infertility, the periodic hypogastralgia, abortion or obstetric complications and so on.With the development of endoscopic technology, hysteroscopy have been the gold standard of diagnosis for intrauterine adhesions, and transcervical resection of adhesions (TCRA) has become the preferred method in the treatment of IUA.The recurrence rate of intrauterine adhesions is3.1%to23.5%, especially20%to62.5% for severe adhesions. It is a difficult nature of the procedure to cure moderate to severe IUA. Repeated adhesions of uterine cavity is observed, which is seriously affect the reproductive function of patients with moderate to severe IUA.The treatment of moderate to severe intrauterine adhesions is a comprehensive methods. Separating adhesions is prerequisite, preventing adhesions is the important point, promoting endometrial repair is the key. The three portions complement each other, and the effect in treatment will be limited if each step is missing. The therapeutic regimen of IUA has not been unified, each regimen has its own characteristics. The effective therapeutic regimen universally adopted is the combined therapy based on TCRA, including the insertion of an intrauterine device (IUD) and oral estradiol valerate (E2V) postoperative. At present, many scholars have experimented with different doses of estradiol valerate to stimulate regeneration of the endometrium after surgical treatment of intrauterine adhesions.The treatment effect of high dose estradiol valerate is significantly better than that of normal dose.Absorbable adhesion barrier (Interceed) is the first product approved by the United States Food and Drug Administration (FDA) to prevent postoperative adhesion.It has been applied in a variety of Obstetrics and Gynecology operation and other surgical operation to prevent adhesions of abdominopelvic cavity, pleura, middle ear,muscle tendon,etc.There is no relevant reports about that Interceed was used on the intrauterine adhesions.In this study, Interceed which would be placed into uterine cavity was added based on the comprehensive treatment commonly used at present (TCRA+IUD+E2V),and various different regimens of E2V was received.We compared the therapeutic effect of each group to explore and analysis the clinical effect of different comprehensive methods on the treatment of moderate to severe intrauterine adhesions, hope to find more definitive and effective methods, reduce the recurrence of IUA, restore normal menstrual pattern and improve the pregnancy rate.MethodsSubjects1. Cases data:Between December,2010,and November,2012, patients who presented with secondary amenorrhea or secondary hypomenorrhea was diagnosed with moderate to severe intrauterine adhesions by hysteroscopy in Zhujiang Hospital. The study was divided into2stages:before January,2012,29patients (8moderate IUA,21severe IUA),5with secondary amenorrhea,24with secondary hypomenorrhea. After January,2012,20patients (3moderate IUA,17severe IUA),4with secondary amenorrhea,17with secondary hypomenorrhea.2. Classification:according to the classification and prognosis of intrauterine adhesions proposed by the American Fertility Society in1988:Extent of cavity involved:<1/3,1score;1/3-1/2,2scores;>2/3,4scores. Type of adhesions: Filmy,1score; Filmy and dense,2scores; Dense,4scores. Menstrual pattern: Normal,1score; Hypomenorrhea,2scores; Amenorrhea,4scores. Stage of disease is calculated from the criterion above, with stage1(mild) score of1～4, stage2(moderate) score of5～8, and stage3(severe) score of9～12.Determination of secondary hypomenorrhea:As previous menstrual bleeding time and bleeding volume in normal circumstances, menstrual blood volume is less than30ml or menstrual blood volume reduced more than1/3of previous menstrual quantity and menstrual duration less than3days.3. Exclusion criteria:①has a history of thromboembolic disease or family history of thromboembolic disease;②unexplained vaginal irregular bleeding;③uterine leiomyoma≥3cm;④abnormal nodules was found in breast by ultrasound;⑤serious abnormal liver function;⑥amenorrhea caused by dysfunction of ovary, pituitary, hypothalamus or endometrial tuberculosis;⑦endometriosis or adenomyosis.Procedure1. Grouping scheme:the totle patients were randomly divided into3groups:(1) Group of artificial cycle:15cases (5of moderate IUA,10of severe IUA), including1case of secondary amenorrhea and14cases of secondary menstruation, underwent TCRA and inserted IUD during the operation before January2012.(2) Group of sustained medication:14cases (3of moderate IUA,11of severe IUA), including4case of secondary amenorrhea and10cases of secondary menstruation, underwent TCRA and inserted IUD during the operation too before January2012.(3) Group with Interceed:20cases (3of moderate IUA,17of severe IUA), including4case of secondary amenorrhea and16cases of secondary menstruation, underwent TCRA and inserted IUD with Interceed during the operation after January2012.There were no significant difference of age, classification of IUA, changes of menstruation in the3groups.2. Prepare of preoperation:To get the detailed history of the patients before operation. Preoperative examination included blood coagulation function, liver function, blood serum lipids, breast ultrasound, ultrasound examination of uterus and uterine adnexa and so on.Cure various infections of reproductive tract. Eliminate the contraindication of operation and estrogen application and informed consent.Take orally misoprostol for600μg within6to8hours before operation to soften the cervix.Hysteroscopic surgery was scheduled in the early follicular phase just after menstruation (days5-7of the cycle) in the patients with secondary menstruation and at any time in the patients with secondary amenorrhea.3. Hysteroscopy and hysteroscopic adhesiolysisUnder the combined spinal-epidural anesthesia or intravenous anesthesia, the cervix was dilated to6.5mm with Hegar expanding uterus stick. The uterine cavity would be examed with the hysteroscopy, and then the patients would undergo TCRA if be diagnosed with moderate to severe IUA.Different ways of hysteroscopic adhesiolysis would be choosed according to the difference of the sites, the character and the compact degree of adhesions such as the mere touch of the endoscope, blunt separation with separator, resection with hysteroscopy needle electrode or electric cutting ring. The hysteroscopic adhesiolysis would be monitored by Laparoscopy or B ultrasound when necessary. The operation should be stopped if it is not possible to perform a hysteroscopy satisfactorily because of significant obliteration of the cavity. The adhesiolysis should be done for several times if it could not restore the size and shape of the uterine cavity during once operation.4. The specific therapeutical program and outcome measures(1) The therapeutical program and drug regimen in the3groups.①Group of artificial cycle:Insert IUD of different shape according to the different site of adhesions after TCRA. T shape IUD would be choosed if the adhesions located in the central or cornual areas of the uterine cavity, instead the O shape IUD would be choosed if the adhesions located in the sides wall. T shape IUD and O shape IUD both would be choosed if the adhesion area is large or the adhesion is complex.To take orally E2V (Bayer healthcare Co. Ltd,1mg/tablet)5mg every12hours for21days with the addition of medroxyprogesterone acetate (MPA) at a dose of10mg/day in the last10days as one cycle, and the treat would begin from the very next day after operation or the fifth day of the menstrual cycle. To recorde the Menstrual Blood Volume (MBV) according to the measurement method of unified provision in the periodic withdrawal bleeding time. To repeat hysteroscopy after3cycles.②Group of sustained medication:The patients in this group would undergo TCRA and insert IUD which is the same with group of artificial cycle, but with different drug regimen. To take orally E2V5mg every12hours from the very next day after operation or the fifth day of the menstruation also. And then receive transvaginal B ultrasound every2-3weeks to measure the endometrial thickness. The MPA, at a dose of10mg/day for10days, would be added when the endometrial thickness reach about6.5mm to7mm or above. Every cycle of the totle E2V would be no longer than90d. To recorde the MBV according to the measurement method of unified provision in the periodic withdrawal bleeding time too and to repeat hysteroscopy after3cycles.③Group with Interceed:After recover the uterine cavity shape through TCRA, insert IUD packaged with half a piece of absorbable adhesion barrier (Interceed, the United States of America Johnson company production,7.6cm×10.2cm) with hemostatic forceps slowly into the uterine cavity until reach the fundus of uterus. And then exam the uterine cavity with hysteroscopy, wash away bloodstains on the Interceed, smooth and fill plug the Interceed with the lens as far as possible.Fill the Interceed in the central of uterine cavity as central intrauterine adhesion and fill it around and bilateral uterine horn instead as peripheral intrauterine adhesion. As for the mixed adhesive or adhesive area is large, placed on half of the Interceed wire wrapped around the metal ring and put the other half of Interceed above or below the ring into the uterine cavity, placed the Interceed in the center of the metal ring and the middle of the uterine cavity. To take orally E2V5mg every12hours from the very next day after operation, and the patients would receive transvaginal B ultrasound every1-2weeks to monitor the absorption of Interceed for the first cycle, add MPA at a dose of10mg/day for10days at the time of3weeks after TCRA. It is the time that the Interceed is completely absorbed after be placed for30days. And then undergo the drug regimen as artificial menstrual cycle, the same with group of artificial cycle. To recorde the MBV according to the measurement method of unified provision in the periodic withdrawal bleeding time too and to repeat hysteroscopy after3cycles.(2) Measure of MBV and the comparison between before and after treatment: As the patients are enjoin to use unified ordinary daily sanitary napkin before the study, it will be regarded as a piece of sanitary napkin and be replaced when the bleeding area wet sanitary napkin about1/3area, which is about5cmx8cm, Calculate the totle number of the sanitary napkins of each period, and convert it to milliliter quantity according to the number of sanitary napkins and the area of the blood soaked.(3) Monitor the changes of endometrial thickness by transvaginal B ultrasound to compare the growth of endometrium with basilar layer severely impaired before and after administration of high dose of E2V.①Bfore TCRA in the three groups:to measure the endometrial thickness in the secretory phase of the patients with hypomenorrhea, and to measure the endometrial thickness for3times of the patients with secondary amenorrhea to get the average.②After TCRA:(a) Measure the endometrial thickness in the fifth day of the menstrual cycle of the3groups(i.e. prior to administration of E2V).(b) Measure the endometrial thickness in the twelfth day of take E2V again in group of artificial cycle (i.e. before add MPA).(c) Measure the endometrial thickness every2-3weeks until the endometrium thickened to about6.5mm-7mm in group of sustained medication.(d) In group with Interceed, measure the endometrial thickness in the twenty-first day of take E2V in the first cycle (i.e. before add MPA), and then monitor the endometrial thickness the same with group of artificial cycle in the later cycles.(4) In the first treatment cycle after TCRA, to monitor the absorption of Interceed inserted in the uterine cavity of the patients in group with Interceed through transvaginal B ultrasound:Patients receive ultrasonic exam and three-dimensional ultrasound reconstruction on the second day after TCRA, with Voluson7303D ultrasound diagnostic apparatus, made by General Electric Company, fixed doctor and fixed detection equipment, and then repeat every1to2weeks. Forecast the absorption time of Interceed by the time of the hyperecho of Interceed cannot be detected.(5) Repeat hysteroscopy:Repeat hysteroscopy after3treatment cycles (i.e.3times of withdrawal bleeding after TCRA) to evaluate the treatment effect of intrauterine adhesions in each group. If the adhesion appears again, the therapeutic regimen would be repeated in each group. If the uterine cavity without adhesion, the patients would keep to take high dose of estrogen and reduce the dose of estrogen until the withdrawal gradually after the MB V increased.(6) Exam the patients’ blood coagulation function, liver function, blood serum lipids and breast ultrasound every3months to contrast the changes before and after take orally high dose E2V.5. The judgment of therapeutic effect:①Excellent:no adhesion is found by second hysteroscopy;②Effective:the gradation of IUA is decreased1-2levels, but the uterine cavity still has adhesion;③Nullity:the gradation of IUA is indiscrimination or exacerbation contrast with preoperation.Statistical analysisTo analyse the datas with SPSS19.0statistical software. Measurement datas were described with the mean and standard deviation. To use paired t test analysed the treatment outcome in each group and used chi-square test to analyse the comparison of rate. Using nonparametric test to analyse ranked data.The multiple comparisons among groups with the normal distribution were analyzed by one-way ANOVA. there were significant differences as P<0.05Results1. The growth of the endometrium.(1) The endometrial thickness before TCRA:The endometrial thickness of the three groups were separately6.21±1.15mm,5.69±1.32mm and5.62±1.46mm. There was no statistical difference among the three groups (P=0.692).(2) The endometrial thickness prior to administration of E2V (i.e. the fifth day of the menstrual cycle):The endometrial thickness of the three groups were separately3.87±0.45mm,3.56±0.40mm and3.76±0.62mm. There was no statistical difference among the three groups (P=0.414).(3) The endometrial thickness before add MPA①Group of artificial cycle:The endometrial thickness was6.93±0.86mm. After taking progesterone,5patients with moderate IUA can appear withdrawal bleeding, instead2patients with severe IUA (accounting for13.3%in the group of artificial cycle) have no withdrawal bleeding after progestational challenge in the first artificial cycle.②Group of sustained medication:The endometrial thickness was7.46±0.77mm. The endometrial can thickening to8mm-9mm before withdrawal. The breakthrough bleeding would appear (3/14,21.4%) if the patients still not receive progesterone when the endometrial thickening to about7mm.③Group with Interceed:The duration and drug regimen of E2V in this group was similar to group of artificial cycle, and the growth of the endometrium was similar to group of artificial cycle too. The endometrial thickness can achieve6.96±0.99mm. All patients were successful withdrawal bleeding.There was no statistical difference in endometrial thickness among the three groups before add MPA. P=0.781for the comparison among the three groups.(4) Comparison of the endometrial thickness before TCRA and before added MPA in each group, P were0.017,0.000and0.001separately and the difference was statistically significant (P<0.05).2. Changes of menstrual blood volume before and after treatment.To recorde the menstrual blood volume (MBV) according to the measurement method of unified provision before the treatment.(1) The number of sanitary towel before treatment in3groups were separately3.07±2.46,1.64±1.55,2.30±1.92, converted into the blood volume were separately15.07±12.60ml,7.93±7.95ml,11.50±9.61ml. P=0.173for the comparison among the3groups of the number of sanitary towel before treatment, and P=0.182for the comparison among the3groups of the menstrual blood volume before treatment. There was no statistical difference among the three groups.(2) The number of sanitary towel after treatment in3groups were separately8.07±2.94,8.07±2.90,7.50±2.46, converted into the blood volume were separately40.33±14.70mh40.00±13.59ml.37.50±12.30ml. P=0.776for the comparison among the3groups of the number of sanitary towel after treatment, and P=0.790for the comparison among the3groups of the menstrual blood volume after treatment, there were no statistical difference among the three groups too. Compared the number of sanitary towel and the blood volume before and after treatment of each groups respectively, the difference was statistically significant (P<0.05).3. Effects on blood coagulation function, liver function and blood serum lipids, breast and the adverse reaction of oral administration of high dose estradiol valerate on women of reproductive age.All the49patients took orally estradiol valerate at a dose of10mg/d between9months at least and24months the longest. Detected the blood before took E2V and after took E2V for3months,6months,9months.(1) Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg):P>0.05for the the comparison among the4time point of each patients, the difference was not statistically significant. There was no one patient with thromboembolic disease, skin ecchymosis, bleeding and so on during the treatment.(2) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and total cholesterol (Chol):P>0.05for the the comparison among the4time point of all the49patients, and the difference was not statistically significant. After took orally the high dose of E2V, the mean of TG was a little higher than before, but the difference was not statistically significant still(P>0.05).(3) The49patients,who were all the women of reproductive age,in treatment duration ranged from9to24months, for the difference of withdrawal time for the patients after9months, the sample size in each group was different of each check time every3months. There was no comparison among the groups for more than9months, but there was no abnormal result of the monitoring indicators in all the patients received E2V. It prompted that there was no obvious adverse effect on blood coagulation function, liver function and blood serum lipids of oral high dose estradiol valerate (10mg/day) continuously on women of reproductive age within9to24months.(4) Effects on breast:Six patients (6/49,12.24%) feeled breast pain obviously before menstruation and it was disappeared after menstruation. There was no one patient with new primary breast tumor in all patients. (5) Other adverse reactions:The incidence of irregular bleeding of individual patients in the early stage due to missing drugs was6.12%(3/49cases). The similar situation did not appear again after the orders regular medication. There were no gastrointestinal symptoms such as nausea and vomiting during the medication.4. The recurrence of intrauterine adhesions.All patients in the3groups underwent the repeated hysteroscopy or TCRA after3cycles of treatment, partly underwent repeated hysteroscopy or TCRA for2to6times.(1)Repeated hysteroscopy in group of artificial cycle:The completely cure rate was13.3%(2/15).13patients appeared different degrees of IUA again,8(61.5%) of which had a less degree of IUA than preoperation.33.3%(5/15) of the patients were similar to preoperation. The total effective rate was66.7%(13/15). It was found through hysteroscopy for the second time that the adhesion was relatively looser than initial stage although the recurrence rate of IUA was high(recurrent rate was86.7%).Some of the adhesions was easily separated by the mere touch of the endoscope but a few of adhesions was separated with the electrode.(2) Repeated hysteroscopy in group of sustained medication:The completely cure rate was7.1%(1/14) and the recurrence rate of IUA was92.9%(13/14).38.5%(5/13) of the patients in this group had a less degree of IUA than preoperation and57.1%(8/14) were similar to preoperation. The total effective rate was42.6%(6/14).The length of time to each treatment cycle for E2V was during31to86days, with an average of53.11±14.78days. The length of time of3treatment cycles ranged from4months to7months. The second hysteroscopy found that the recurrence rate of IUA was still high (at a rate of92.9%) and the adhesions were thick and dense which was not easy to separate.The second hysteroscopy found that the cured patients with IUA in group of artificial cycle and group of sustained medication were all the patients with moderate endometrial adhesion, and the recurring adhesions were almost located around any shape IUD, such as the central intrauterine adhesion appeared in the middle of the O shape IUD and the peripheral intrauterine adhesion appeared around the trailing arm of the T shape IUD. If inserted both of O and T shape IUDs, the complexed intrauterine adhesion appeared at any space around them or even wrapped them.(3) Repeated hysteroscopy in group with Interceed:The completely cure rate was45%(9/20) and the recurrence rate of IUA was55%(11/20).11patients with moderate to severe intrauterine adhesions were recurrent with mild to moderate peripheral endometrial adhesion after only once TCRA, and most of the adhesion belt located at the surface of O shape IUD which was easily to separate directly by the tip of hysteroscope.The total effective rate of the therapy was100%(20/20). Repeat hysteroscopy found that there were5patients still with mild peripheral endometrial adhesion who received the comprehensive therapy including TCRA, inserting IUD and oral E2V.(4)Therapeutic effect analysis①The completely cure rate:P=0.591for the comparison between group of artificial cycle and group of sustained medication, there was no significant difference. Compared the completely cure rate of group with Interceed with group of artificial cycle and group of sustained medication, P were0.049、0.019seperately and the differences were statistically significant (P<0.05) in both comparison groups. There were significant differences among the3groups (P=0.022), the completely cure rate of group with Interceed was higher than that of group of artificial cycle or group of sustained medication.②The total effective rate:P=0.206for the comparison between group of artificial cycle and group of sustained medication, there was no significant difference. Compared the total effective rate of group with Interceed with group of artificial cycle and group of sustained medication, the P-value were0.006and0.000, the differences were statistically significant (P<0.05). There were significant differences among the3groups (P=0.001), the total effective rate of group with Interceed was higher than that of group of artificial cycle or group of sustained medication.5. To monitor the absorption of Interceed inserted in the uterine cavity through transvaginal B ultrasound.All the patients in group with Interceed received ultrasonic exam and three-dimensional ultrasound reconstruction from the second day after TCRA, with Voluson7303D ultrasound diagnostic apparatus, made by General Electric Company, fixed doctor and fixed detection equipment, to monitor the absorption of Interceed inserted in the uterine cavity and to forecast the absorption time of Interceed by the time of the hyperecho of Interceed cannot be detected.The transvaginal B ultrasound on the second day after TCRA indicated that all the patients had no IUD translocation, the shape of IUD was nomal and the hyperecho of Interceed could be detected. With postoperative time prolonged, Interceed began to gradually absorbed, and the hyperecho of Interceed gradually became smaller and weakened until disappeared. The absorption time of Interceed in the19cases Of the patients (19/20,95%) was within18～32days, average27.3±2.3days. Only1patient (1/20,5%) couldnot detect the hyperecho of Intercede at the7th day after TCRA.There was no Interceed be saw in uterine cavity of any patient when repeat hysteroscopy3months after TCRA.6. Repeat times of TCRAAll patients were followed up to now, repeat times of TCRA is in the following statistics: (1) Patients in group of artificial cycle underwent repeat hysteroscopic operation for1-4times, of which2patients for only once,8patients for twice,1patient for3times and4patients for4times, by a mean of2.27±1.01times for each patient.(2) Patients in group of sustained medication underwent repeat hysteroscopic operation for1-6times, of which1patient for only once,5patients for twice,4patients for3times,2patients for4times,1patient for5times and1patient for6times, by a mean of3.00±1.36times for each patient.(3) Patients in group with Interceed underwent repeat hysteroscopic operation for1-3times, of which9patients for only once,6patients for twice,5patients for3times, with an average of1.80±0.83times for each patient.(4) The comparation of repeat times of TCRA among3groups had no significant difference (P=0.016), the repeat times TCRA in group with Interceed was the least, followed by group of artificial cycle, and it was the most frequently in group of sustained medication.7. PregnancyAll patients were followed up to now in pregnancy in the following statistics:(1) There was2patients in group of artificial cycle in successful pregnancy, one was natural pregnancy and full-term normal delivered, another was pregnancy through in vitro fertilization and embryo transfer (IVF-ET), and delivered by cesarean section in October,2012.2patients are waiting for the IVF-ET due to the bilateral cornual tubal block,2patients are trying to get pregnant. The pregnancy rate is13.33%(2/15).The2patients who delivered already underwent2and3times TCRA separately.(2) There was1patient in group of sustained medication who had underwent TCRA for2times underwent abortion after natural conception due to personal and family reasons.3patients are waiting for IVF-ET and2patients are trying to get pregnant. The pregnancy rate is7.14%(1/14).(3) There were2patients in group with Interceed who only underwent TCRA for once in successful natural pregnancy and both full-term normal delivered in April,2013.4patients are waiting for IVF-ET and4patients are trying to get pregnant. The pregnancy rate is10.00%(2/20).There was no statistical difference in pregnancy rate among the three groups (P=0.531).Conclusions1. Oral administration of high dose estradiol valerate (10mg/d) is benefit to the growth of endometrium with the basal layers severely impaired and can increase the menstrual blood volume.2. The effect of taking high dose of estradiol valerate continuously for a long time in the treatment of moderate to severe intrauterine adhesions is similar to artificial cycle.3. It should not be a long time to undergo the reoperation of hysteroscopy after TCRA. The interval time should be within2or3months after TCRA. With the extension of interval, take estrogen also has little effect if the uterine cavity still have adhesion.4. There is no significant adverse effect on blood coagulation function, liver function and blood serum lipids of oral high dose estradiol valerate(10mg/d) continuously on women of reproductive age within9to24months.5. The Clinical effect of comprehensive treatment method of TCRA combined with IUD, Interceed and oral high dose of estrogen is significantly better than that without Interceed in preventing the recurrence of adhesions after operation in patients with moderate to severe intrauterine adhesions.6. It prompts that Interceed can prevent the recurrence of adhesions effectively, and reduce the degree of moderate to severe intrauterine adhesions, but the mechanism of action, action time and the effects on endometrium needs to be further discussed. Technology of place Interceed remains to be further improved.It also need a long time to observe the outcome of pregnancy. |
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