| Background:Intrauterine adhesions（IUA）refer to the formation of scar/fibrous tissue between the inner walls of the uterus.Patients with IUA are often associated with menstrual abnormalities,more commonly hypomenorrhea and amenorrhea.These symptoms may have adverse effects on subsequent fertility and pregnancy outcomes.The etiology of IUA is multifactorial and its prevalence is difficult to measure as it is increasing since last few decades,probably due to an increase in iatrogenic endometrial trauma and wide use of diagnostic hysteroscopy.The most common risk factor associated with IUA was pregnancy-associated,and more than 90%of IUA had been reported to be caused by pregnancy-associated curettage.Hooker et al.reported that curettage during pregnancy is a primary cause of IUA.Various studies have designated several factors that may affect the reproductive outcomes for instance,the extent,location and severity of the adhesions.But no specific feature is considered dominant till now.IUA is mainly diagnosed via hysteroscopy,ultrasound and hysterosalpingography（HSG）.Currently,hysteroscopy is the diagnostic gold standard of IUA.However,three-dimensional transvaginal ultrasound（3D-TVUS）has recently been adopted in the gynaecological sciences as it is handy,non-invasive,radiation-free,and relatively cheaper and has the possibility of displaying multi-sectional views.The management of IUA mainly focuses on two points:（i）to restore the physiological shape and size of the intrauterine cavity and（ii）is restoration of the endometrium.The gold standard for surgical treatment of IUA is hysteroscopic adhesiolysis（HA）,which aims to restore the shape and size of the cavity,at the same time when combined with“cold scissors ploughing technique”,it can improve the blood supply and thus enhance the fertility potential.For enhancing the fertility and implantation,the characteristics of the endometrium is equally important.Various studies have reported about the endometrial receptivity as an important component for successful blastocyst implantation.Endometrial receptivity is characterised as a momentary sole order of factors that make the endometrium receptive to the implantation of the embryo;the time frame when the uterine milieu is favourable to blastocyst acquisition and ensuing implantation.Dechaud et al.（2008）has reported that endometrial thickness,endometrial pattern and endometrial blood flow may influence endometrial receptivity.Other important features of the endometrium to consider are the endometrial echo,endometrial peristalsis,and endometrial-myometrial junctional zone.Uterine mobility and visibility of the fallopian tubal ostia are also believed to influence the pregnancy outcomes.Comprehensive management,like intrauterine devices（IUD）and/or Foley catheter balloon,hyaluronic acid gel,amnion grafts insertion,hormonal therapy or an early second-look hysteroscopy usually supplement HA in an aim to improve uterine morphology and reproductive outcomes.Early diagnosis and hysteroscopic treatment have undoubtedly been the key factors leading to such improvement.However,in severe cases of IUA,the results are still disappointing.While the prognosis for women suffering from IUA is steadily improving,it is still far from ideal.Outcome of present-day treatment is very good with regard to relief and correction of menstrual disorders,but far from satisfactory with regard to restoration of fertility.Successful treatment of IUA not only relies on complete separation of adhesive tissue but also on the prevention of adhesion reformation,because the reproductive outcome is adversely affected by the frequent recurrence of adhesions.IUAs became denser over time,and the larger the range of adhesions,the more likely they were to impact postoperative efficacy.Hormonal therapy like estrogen was further used post HA.Estrogen and progesterone were combined after HA which showed endometrial stability and improving pregnancy rates.However,for moderate-to-severe IUA,pregnancy rate and live birth rate is still not ideal.Even the currently employed anti-adhesion therapies in clinical practice like IUD and intrauterine balloons,as well as auxiliary measures such as biopolymers（hyaluronic acid and hydroxymethyl chitosan）,and estrogen;have all shown to be effective options,but they were not able to maximize the pregnancy rate in IUA patients and more research is needed.While some other less used adhesive therapies like amniotic membrane,stem cells,and traditional Chinese medicine are not widely studied.This brings us to study more about traditional Chinese medicine（TCM）“Humo-fang”.Zhaoling You et al.performed an experimental trial of Humo-fang in few patients of IUA with fertility requirements and it showed effective results on regenerating the endometrium as well as improving the fertility rate.However,to verify this clinically,whether the therapeutic efficacy of Humo-fang is helpful in treating the IUA and maximizing the pregnancy rate,we proposed this study.This study evaluates the role of Humo-fang in two parts,Chapter 1:To determine the efficacy of Humo-fang post hysteroscopic adhesiolysis for the treatment of intrauterine adhesion;Chapter 2:Efficacy of Humo-fang evaluated by 3D ultrasound.Objective:In this study,the main purpose is to determine the role of“Humo-fang”post HA,in the treatment of intrauterine adhesion;evaluate its effect on endometrium repair and improving the fertility rate so that it can be adopted as a routine practice for IUA patients who have fertility requirements.Methods:This study was designed as a prospective non-randomized controlled study（real world intervention）.From January 2021 to August 2021,patients aged between 20 and 45 years,with moderate to severe IUA who were admitted at the Third Xiangya Hospital of Central South University and Jiangwan hospital;and underwent HA were included in this study.A total of 427 participants were divided into four groups;group 1 included138 patients who were administered traditional Chinese medicine“Humo-fang”and silicon stent;group 2 were 137 patients who were administered Western medicine（sequential therapy of estrogen and progesterone）and silicon stent;group 3 included 75 patients who were given Humo-fang and uterine-shaped stainless steel IUD;while group 4 were 77 patients who were given Western medicine and uterine-shaped stainless steel IUD.The following basic information were collected prospectively for all the patients:age,parity,history of abortion,menstrual status and the cause of IUA,if it is dilation and curettage or other uterine cavity operation.Pre-operative and post-operative 3D-TVUS data（from the 16th to 24th day of menstrual cycle）was obtained for all these variables:endometrial thickness,intercornual distance,endometrial pattern,endometrial echo,the visibility of the fallopian tubal ostia,the endometrial-myometrial junction zone,uterine mobility,endometrial blood flow and endometrial peristalsis.HA was performed and IUA were scored by a senior surgeon during hysteroscopy,using the AFS scoring system which were as follows:1–4（mild）,5–8（moderate）,and 9–12（severe）.The AFS score and density of opening of endometrial glands during HA was recorded,and the AFS score reduction was evaluated after the end of the last HA.Post HA,silicon stent or stainless steel IUD was used and patients were given Humo-fang or estrogen&progesterone,based on the group classified.The first follow up hysteroscopy was performed after 1 month for severe IUA and 3 months from the date of 1st HA for moderate IUA.Second follow up hysteroscopy was done after 2-3 months from the date of 1st follow up HA for patients with severe IUA.Stent or IUD was removed once the endometrium was healthy and thereafter tubal catherization was done.Foley’s balloon catheter was placed for 3 days or 5 days based on the decline in AFS score.After each follow-up and at the end of treatment,3D-TVUS was performed in the late ovulation stage of the menstrual cycle（generally the 16th-24th day of the menstrual cycle）.The endometrial status was evaluated according to the 3D-TVUS data（endometrial thickness,intercornual distance,endometrial pattern,endometrial echo,the visibility of the fallopian tubal ostia,the endometrial-myometrial junction zone,uterine mobility,endometrial blood flow and endometrial peristalsis）and comprehensively analysed according to the intraoperative AFS score.At the end of the treatment when endometrium status was good,patients were advised to resume their conception efforts.Independent t-test and paired t-test were used to examine the nominal variables,and Pearson chi-square or Fisher’s Exact test was used to examine the association between categorical variables.A P-value<0.05 was considered statistically significant and all statistical tests were two-tailed.Results:There were no statistically significant differences between all the groups in terms of age,obstetric history,menstruation,pre-operative AFS scores and uterine cavity operations preoperatively（P>0.05）.For Humo-fang with stent（group 1）and estrogen&progesterone with stent（group 2）,there was significant difference in terms of post-operative menstruation（P=0.005）;post-operative AFS score（P=0.0001）;AFS score reduction（P=0.0001）;post-operative endometrial thickness（P=0.0001）and post-operative density of opening of endometrial gland（P=0.0001）.For Humo-fang with IUD（group 3）and estrogen&progesterone with IUD（group 4）,there was also a significant difference in terms of post-operative menstruation（P=0.049）;post-operative AFS score（P=0.0001）;AFS score reduction（P=0.0001）;post-operative endometrial thickness（P=0.0001）and post-operative density of endometrial gland（P=0.046）.The total fertility rate was 60%in group 1,46.4%in group 2,49.2%in group 3 and 40.4%in group 4.The live birth rate for group 1 was 4.1%,1.7%for group 2,4.4%for group 3 and no case of live birth in group 4.The rate of abortion for group 1 was 2.7%,13.2%for group 2,6%for group3 and 19.2%for group 4.The average time of conception after last HA for group 1 was 5.3±2.5 months,6.5±2.3 months for group 2,6±3.4 months for group 3 and 6.8±31 months for group 4.[Remark:The median time for the follow up of fertility rate for all the four group of patients was 10 months,since the shortest time for the follow up was 6 months whereas the longest duration was 14 months,until April2022.It should also be noted that 18/138 patients（13%）in group 1,23/137patients（16.7%）in group 2,8/75 patients（10.6%）in group 3 and 12/77patients（15.5%）in group 4,could not followed up for the pregnancy rate since their phone number was no more functional.]For group 1 and group 2:the total pregnancy rate was significantly different（P<0.05）.However,there was no significant difference in the live birth rate in these 2 groups（P>0.05）.There was significant difference in abortion rate as well（P>0.05）.For group 3 and group 4:there was significant difference in terms of total pregnancy rate（P<0.05）,the live birth rate（P<0.05）as well as the abortion rate（P<0.05）.3D-USG assessment:For group 1 and 2,endometrial echo was more homogeneous in group 1（P=0.018）,the number of visible fallopian tube ostia was more in the group 1（P=0.0003）.Endometrial blood flow,endometrial peristalsis,endometrial pattern（III-line sign）and uterine mobility were also better in the group 1（P=0.0001）.The intercornual distance was wider in group 1（P=0.016）.There was no statistical difference between both the groups in terms of endometrial-myometrial junction zone（P=0.057）but on doing the comparision with Chi-square test,we see that there is more of homogenous endometrial-myometrial junction zone in humo-fang group as compared to the estrogen group.For group 3 and group 4,the endometrial thickness in the humo-fang group was thicker than estrogen group（P=0.0001）.The number of visible fallopian tube ostia was more in the group 3（P=0.0003）,endometrial peristalsis was also better in the group 3（P<0.05）.The intercornual distance was also wider in group 3（P=0.0097）.Though there was not much statistical difference between both the groups for endometrial blood flow,endometrial echo and uterine mobility,but still these characteristics were better in humo-fang group as compared to the estrogen group.Conclusions:In conclusion,we demonstrated a TCM,Humo-fang,presenting a promising trend for IUA adjuvant therapies post HA.This is the first report that the Humo-fang has a better effect on menstruation restoration and endometrium regeneration than the widely accepted drug estrogen.This study strengthens the insight that certain TCM acts as an estrogen role and provides significant benefits to infertile patients.Exploring the potential effect of Humo-fang for IUA will contribute to the realization of novel therapeutic strategies and a promising target for clinical practice. |
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