Efficacy of high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation versus hysteroscopic cold knife separation alone in the treatment of infertility or amenorrhea caused by severe intrauterine adhesion: a retrospective cohort study.

There were no significant differences in age, number of pregnancies, frequency of curettage, proportion of balloon placement, infertility and low menstruation between the two groups ( P  > 0.05, Table  1 ). Table 1 Comparison of the baseline data between the two groups Baseline data The surgical group ( n  = 82) The combined group ( n  = 118) t/χ 2 P Age (Year) 30.68 ± 4.16 31.73 ± 4.24 1.736 0.084 Number of pregnancies (Time) 2.68 ± 0.42 2.61 ± 0.54 0.985 0.326 Frequency of curettage (Time) 2.95 ± 0.96 3.12 ± 1.07 1.152 0.251 Proportion of balloon placement 51 (62.20) 73 (61.86) 0.002 0.962 Infertility 65 (79.27) 92 (77.97) 0.049 0.826 Low menstruation 72 (87.80) 105 (88.98) 0.066 0.797 Note: The number of pregnancies and the number of uterine curettages in Table  1 were the baseline characteristics of the patients, and their potential association with intrauterine adhesion needed to be combined with multivariate analysis (see Table  3 ). All patients in this study were treated with hysteroscopy due to severe IUA combined with infertility or low menstrual cycle Comparison of the baseline data between the two groups Note: The number of pregnancies and the number of uterine curettages in Table  1 were the baseline characteristics of the patients, and their potential association with intrauterine adhesion needed to be combined with multivariate analysis (see Table  3 ). All patients in this study were treated with hysteroscopy due to severe IUA combined with infertility or low menstrual cycle Compared with the effective rate of 79.27% in the surgical group (Fig.  2 A), the effective rate of the combined group was 94.07% (Fig.  2 B), which was significantly higher ( χ 2  = 0.035, P  = 0.002, Table  2 ). The PBAC score of the combined group was significantly lower than that of the surgical group ( t  = 4.594, P  < 0.001, Table  2 ). Table 2 Comparison of clinical effects [Cases (%)] Clinical effects The surgical group ( n  = 82) The combined group ( n  = 118) χ 2 P Ineffective 17 (20.73) 7 (5.93) Effective 21 (25.61) 35 (29.66) Clinical cured 44 (53.66) 76 (64.41) Effective rate 65 (79.27) 111 (94.07) 10.035 0.002 PBAC (scores) 97.65 ± 12.59 90.03 ± 10.75 4.594 < 0.001 Note: Effective rate = Cases of (Effective + clinical cured) ÷ the total cases of each group×100% Comparison of clinical effects [Cases (%)] Note: Effective rate = Cases of (Effective + clinical cured) ÷ the total cases of each group×100% Fig. 2 Comparison of clinical effects. A : The surgical group; B : The combined group Comparison of clinical effects. A : The surgical group; B : The combined group Before intervention, there were no significant differences in endometrial thickness, capacity and volume between the two groups ( P  > 0.05). After intervention, the thickness, capacity and volume of the endometrium were significantly higher in the combined group than those of the surgical group ( t  = 7.608, P  < 0.001; t  = 8.044, P  < 0.001; t  = 11.372, P  < 0.001, Table  3 ). Table 3 Comparison of the recovery of uterine cavity morphology (‾ x  ±  s ) Uterine cavity morphology The surgical group ( n  = 82) The combined group ( n  = 118) t P The thickness of the endometrium (mm) Before intervention 4.30 ± 0.75 4.18 ± 0.88 1.007 0.315 After intervention 6.85 ± 1.02*** 8.27 ± 1.46*** 7.608 < 0.001 The capacity of the endometrium (cm 3 ) Before intervention 1.63 ± 0.61 1.49 ± 0.58 1.644 0.102 After intervention 3.63 ± 0.63*** 4.25 ± 0.46*** 8.044 < 0.001 The volume of the endometrium (mL) Before intervention 29.62 ± 4.85 31.02 ± 3.76 0.656 0.513 After intervention 35.53 ± 3.35*** 41.96 ± 4.29*** 11.372 < 0.001 Note: *** P  < 0.001 compared with the same group before intervention Comparison of the recovery of uterine cavity morphology (‾ x  ±  s ) Note: *** P  < 0.001 compared with the same group before intervention The re-adhesion rate of the combined group was 11.02%, which was significantly lower than 29.27% in the surgical group ( χ 2  = 10.689, P  = 0.002, Table  4 ). Table 4 Analysis of intrauterine re adhesion after intervention [Cases (%)] Clinical effects The surgical group ( n  = 82) The combined group ( n  = 118) χ 2 P Severe 5 (6.10) 0 (0.00) Moderate 8 (9.76) 4 (3.39) Mild 11 (13.41) 9 (7.63) No 58 (70.73) 105 (88.98) 10.689 0.001 Note: Re adhesion rate = cases (Severe + Moderate + Mild) ÷ total cases in each group ×100% Analysis of intrauterine re adhesion after intervention [Cases (%)] Note: Re adhesion rate = cases (Severe + Moderate + Mild) ÷ total cases in each group ×100% There was no significant difference in the incidence of adverse reactions between the surgical group and the combined group ( P  > 0.05). The pregnancy rate and satisfaction rate of the combined group were 20.34% and 97.46%, which were significantly higher than 6.10% and 89.02% in the surgery group ( χ 2  = 7.915, P  = 0.005; χ 2  = 6.101, P  = 0.014, Table  5 ). Among the 29 pregnant patients, 10 were conceived naturally and 19 were conceived by assisted reproductive technology. Table 5 Comparison of incidence of adverse reactions, pregnancy rate, and satisfaction [cases (%)] Clinical effects The surgical group ( n  = 82) The combined group ( n  = 118) χ 2 P Incidence of adverse reactions 10 (12.20) 12 (10.17) 0.203 0.652 Pregnancy rate 5 (6.10) 24 (20.34) 7.915 0.005 Satisfaction rate 73 (89.02) 115 (97.46) 6.101 0.014 Comparison of incidence of adverse reactions, pregnancy rate, and satisfaction [cases (%)] Univariate analysis showed that the proportion of patients with postoperative amenorrhea, miscarriage frequency (> 3 times), non-standard use of estrogen after surgery, uterine cavity operation frequency (> 2 times), no balloon placement, and only surgical treatment were significantly higher in the recurrence group than those in the non-recurrence group ( P  < 0.05, Table  6 ). Table 6 Univariate analysis of factors influencing the recurrence of IUA Factors Non recurrence group ( n  = 163) Recurrence group ( n  = 37) χ 2 P Age ≥ 35 years old 78 (47.85) 14 (37.84) 1.218 0.270 < 35 years old 85 (52.15) 23 (62.16) Postoperative amenorrhea present 19 (11.66) 14 (37.84) 15.003  3 times 48 (29.45) 21 (56.76) 9.952 0.002 ≤ 3 times 115 (70.55) 16 (43.24) Standard use of estrogen after surgery Yes 77 (47.24) 28 (75.68) 9.778 0.002 No 86 (52.76) 9 (24.32) History of pelvic inflammatory disease Yes 69 (42.33) 17 (45.95) 0.161 0.688 No 94 (57.67) 20 (54.05) Adhesion properties of uterine cavity Non muscular 120 (73.62) 22 (59.46) 2.937 0.087 Muscular 43 (26.38) 15 (40.54) Uterine cavity operation frequency > 2 times 54 (33.13) 23 (62.16) 10.735 0.001 ≤ 2 times 109 (66.87) 14 (37.84) Adhesion range ≥ 2/3 63 (38.65) 20 (54.05) 2.947 0.086 < 2/3 100 (61.35) 17 (45.95) Placement of the balloon Yes 94 (57.67) 30 (81.08) 7.016 0.008 No 69 (42.33) 7 (18.92) Treatment method Surgical group 58 (35.58) 24 (64.86) 10.689 0.001 The combined group 105 (64.52) 13 (35.14) Note: Standard use of estrogen after surgery in the table was only for patients in the combined group, indicating whether the treatment was completed according to the high-dose sequential regimen. No estrogen was used in the surgical group, and the “no” in this analysis represented nonstandard use in the combined group Univariate analysis of factors influencing the recurrence of IUA Note: Standard use of estrogen after surgery in the table was only for patients in the combined group, indicating whether the treatment was completed according to the high-dose sequential regimen. No estrogen was used in the surgical group, and the “no” in this analysis represented nonstandard use in the combined group Taking the recurrence of the patient after treatment as the dependent variable (1 = recurrence, 0 = non-recurrence), and the statistically different indicators in Table  7 as independent variables, the assignment was carried out for amenorrhea after curettage (1 = present, 0 = absent), miscarriages frequency (1 = > 3, 0 = ≤ 3), standardized use of estrogen after surgery (1 = no, 0 = yes), number of intrauterine procedures (1 = > 2, 0 = ≤ 2), placement of balloons (1 = no, 0 = yes), and treatment method (1 = combined treatment, 0 = surgical treatment). Multiple logistic regression analysis showed that postoperative amenorrhea, miscarriages frequency, standardized use of estrogen, intrauterine operations frequency, and placement of balloons were independent risk factors for recurrence after IUA treatment. Besides, combination therapy was a protective factor ( P  < 0.05, Table  7 ; Fig.  3 ). Table 7 Multivariate logistic regression analysis of factors affecting recurrence of IUA after treatment Indicator B SE Wald P OR 95% CI Postoperative amenorrhea 0.678 0.221 9.412 < 0.001 1.970 1.278 ~ 3.037 Miscarriages frequency 0.574 0.142 16.340 < 0.001 1.775 1.344 ~ 2.344 Standardized use of estrogen after surgery 0.418 0.156 7.180 0.029 1.519 1.119 ~ 2.063 Intrauterine operations frequency 0.569 0.214 7.070 0.032 1.766 1.162 ~ 2.686 Placement of balloons 1.183 0.307 14.849 < 0.001 3.264 1.788 ~ 5.960 Treatment methods -0.789 0.242 10.652 < 0.001 0.454 0.283 ~ 0.730 Multivariate logistic regression analysis of factors affecting recurrence of IUA after treatment Fig. 3 Forest plot of factors influencing recurrence of intrauterine adhesions after treatment using Multivariate logistic regression analysis. A : Postoperative amenorrhea; B : Miscarriages frequency; C : Standardized use of estrogen after surgery; D : Intrauterine operations frequency; E: Placement of balloons. F: Treatment methods Forest plot of factors influencing recurrence of intrauterine adhesions after treatment using Multivariate logistic regression analysis. A : Postoperative amenorrhea; B : Miscarriages frequency; C : Standardized use of estrogen after surgery; D : Intrauterine operations frequency; E: Placement of balloons. F: Treatment methods

A total of 200 patients with severe IUA from August 2020 to August 2023 were retrospectively selected as the study subjects. The sample size calculation formula was as follows: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$n = \frac{{{Z_{1 - \alpha /2}}\sqrt {2\overline p (1 - \overline p )} + {Z_{1 - \beta }}{{\sqrt {p1(1 - p1) + p2(1 - p2)} }^2}}}{{{{(p1 - p2)}^2}}}$$\end{document} Note: Z 1−α/2 is the two-sided quantile of standard normal distribution (when α = 0.05, Z 1−α/2 =1.96); Z 1−β is the one-sided quantile of standard normal distribution (when power 1-β = 0.8, Z 1−β =0.84); p̄ is the expected efficiency of the combination of the two groups; p1 and p2 are the expected efficiency of the surgery group and the combined group, respectively. Referring to previous studies, the effective rate was estimated to be 70% in the surgical group and 85% in the combined group. Considering the possible loss to follow-up, a certain proportion of the sample size was increased, and 200 patients were finally included (82 in the surgical group and 118 in the combined group). The inclusion process was shown in Fig.  1 . According to different treatment methods, they were divided into the surgical group (hysteroscopic cold knife separation, n  = 82) and the combined group (high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation, n  = 118). Fig. 1 The inclusion process of patients The inclusion process of patients Inclusion criteria: [ 1 ] According to the classification criteria of the American Society for Reproductive Medicine (ASRM, 1988) [ 11 ], the patient was diagnosed with severe IUA (The extent of IUA was ≥ 75%, accompanied by tubal opening and upper uterine atresia, and the adhesion tissue was dense muscular adhesion). Adhesion tissue was dense but not calcified (the adhesion tissue was dense, no obvious calcification was observed under hysteroscopy and sharp separation could be performed with a cold knife). Moreover, at least one of the following clinical features was present: secondary infertility (defined as the absence of pregnancy from regular, non-contraceptive sex for ≥ 1 year) or low menstruation (patients with ≥ 50% reduction in menstrual volume or PBAC score < 30) [ 2 ]. The patients had not used hormonal drugs (including but not limited to oral contraceptives, estrogen supplements, progestins, etc.) in the 3 months before the study; [ 3 ] There were no contraindications to the use of estrogen and progesterone (such as estrogen-dependent malignancies, unexplained uterine bleeding (after excluding common causes such as pregnancy-related bleeding, endometrial polyps and uterine fibroids, the cause of abnormal uterine bleeding could not be determined), serious cardiovascular disease (coronary heart disease and severe cardiomyopathy), thrombotic disease (deep vein thrombosis and pulmonary embolism), and breast cancer); [ 4 ] The case and follow-up data were complete (including the patient’s basic information, medical history, preoperative examination results, surgical records, postoperative treatment and review records). Exclusion criteria: [ 1 ] The patient who was allergic to drugs used in the study (Patients with allergic reactions to drugs used in studies such as mifepristone, estradiol valerate, medroxyprogesterone acetate, uterine cross-linked sodium hyaluronate gel (Gong Ankang), etc., confirmed by transdermal test or previous definite allergic history); [ 2 ] The patients who were combined with trichomonal vaginitis, mycotic vaginitis, bacterial vaginosis and other common reproductive tract infections, as well as vaginal septum, uterus didelphys, residual horn uterus and other reproductive tract malformations; [ 3 ] The patients with autoimmune diseases, abnormal liver and kidney function or heart disease; [ 4 ] The patients with mental disorders (including but not limited to schizophrenia, depression, bipolar disorder and other serious mental illnesses); [ 5 ] The patients with uterine fibroids, endometriosis and other diseases; [ 6 ] The patients with abnormal levels of endocrine hormones (if any one of the six sex hormones (follicle stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, prolactin) did not fall within the reference range of the corresponding stage of the normal menstrual cycle, and the changes of hormones caused by pregnancy, menopause and other physiological conditions were excluded, the endocrine hormone levels were determined to be abnormal); [ 7 ] The patients that could not be treated by cold knife (calcification of adhesion tissue, hard adhesion site, severe intimal injury) were excluded. This study was approved by the ethics committee of our hospital (approval number: FY2024-005). All patients signed informed consent, and the study complied with the requirements of the Declaration of Helsinki. The patients were orally given 100 mg mifepristone (Shanghai Xinhualian Pharmaceutical Co., Ltd., National Medical Products Administration Approval No. H1095022, specification: 25 mg) on the day before surgery, and fasted for at least 8 h before surgery. The surgical group: The patients were treated with hysteroscopic cold knife separation surgery. The patient was placed in the lithotomy position under general anesthesia. Sterile drapes were placed to ensure the surgical area was clean and sterile. Hysteroscopy was inserted, and the uterine cavity morphology and IUA were examined under direct vision. The patient’s uterine cavity was dilated until it could accommodate a Hegar 9 dilator. A HEOS hysteroscope (Produced by Karl Storz, Dr.-Karl-Storz-Straße 34, 78532 Tuttlingen, Germany) was inserted, and miniature scissors were inserted through the HEOS operating hole. A 3 mm single-cut scissor was used to treat adhesions on the lateral wall of the uterus, and a 3 mm double-cut curved scissor was used to treat adhesions on the bottom of the uterus. Adhesions in the uterine cavity were gradually removed from the body of the uterus to the bottom of the uterus. For IUA with large and hard adhesion range, sharp separation was performed slowly with miniature scissors. Then, the adhesion band was cut off with scissors until it was separated to the bottom of the cervix, and the scar tissue and adhesion band were removed (Cold knife dissection can accurately separate adhesions by sharp cutting with miniature scissors to avoid the risk of thermal damage to the resectoscope. In the preoperative evaluation, the research team confirmed that although the adhesion tissue of all patients was dense but not completely calcified, which was suitable for cold knife operation.). COOK uterine balloon stent was placed in the uterine cavity. Among the 82 patients, 51 patients were placed with the balloons, and 31 patients did not receive balloon placement. For patients with severe adhesion who were placed a balloon, the balloon was retained for 2 weeks. After surgery, the bleeding was stopped by compression according to the bleeding condition, and antibiotics were given for 3 consecutive days to prevent infection. One tube of Gong Ankang (generic name: cross-linked sodium hyaluronate gel for uterine cavity, Changzhou BRJ Biomedical Co., Ltd., Specification: 3 ml/tube/box) was injected into uterine cavity to prevent IUA after operation. The combined group: The patient was treated with high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation surgery, and one tube of Gongankang was injected into the uterine cavity to prevent IUA after surgery. Estradiol valerate (Bayer Vital GmbH, approval number: H20120369, specification: 1 mg) was given once a day, 4 mg each time, for 3 weeks. Then, medroxyprogesterone acetate (Southwest Pharmaceutical Co., Ltd., approval number: National Medical Products Administration H50020042, specification: 10 mg) was given once a day, 10 mg each time, continuous taking for 1 week, with an interval of 1 week between the two doses, for a total of 3 treatment courses. The treatment of hysteroscopic cold knife separation was the same as the surgical group. COOK uterine balloon stent was placed in the uterine cavity. Among the 118 patients, 73 patients were placed with the balloons, 45 patients did not receive balloon placement (There were 30 patients with acute inflammation of the genital tract, and 15 patients who were allergic to balloon materials and could not tolerate balloon placement). For patients with severe adhesion who were placed a balloon, the balloon was retained for 2 weeks. High-dose estrogen in this study was defined as estradiol valerate 4 mg daily, which was based on previous evidence [ 8 ]. The literature has shown that the 4 mg dose significantly increases endometrial thickness, promotes repair and reduces the risk of recurrence of adhesions compared with the standard dose (2 mg daily). The effectiveness of clinical outcomes [ 12 ]: The clinical efficacy of the treatment was evaluated, including ineffective (There was no significant improvement in menstrual flow and time, there was no significant change in uterine cavity detected by hysteroscopy 1 week after the end of menstrual period, and the PBAC score did not change significantly after treatment with the change of less than 10 points), effective (The amount and duration of menstruation were improved, hysteroscopy showed that the uterine cavity returned to normal, and the PBAC score was 10–30 points higher than that before treatment), and clinically cured (The menstrual volume and duration returned to normal, and the PBAC score evaluation reached the normal range. PBAC score < 100 was defined as the normal menstrual volume range. If the PBAC score was within this range and the menstrual cycle was regular after treatment, the menstrual symptoms were considered to be cured.). The effective rate of treatment was calculated. Total effective rate = (clinical cure + effective)/total cases ×100%. Recovery of uterine cavity morphology [ 13 ]: The recovery of uterine cavity morphology was judged by endometrial thickness, endometrial volume and volume change. The measurement time was selected in the late proliferative phase of the menstrual cycle. At this time, the endometrium is in the stage of rapid proliferation under the influence of estrogen, and the measurement results can better reflect the effect of treatment on endometrial growth. Normal uterine cavity morphology was characterized by uniform endometrial thickness that met the corresponding criteria in different stages of the menstrual cycle (e.g., thickness of about 3–8 mm in the proliferative phase and 8–14 mm in the secretory phase). The intimal volume and volume were moderate and regular in shape without adhesion, deformation, or other structural abnormalities. All patients were tested by VOLUSON S8 Doppler ultrasound diagnostic instrument (Shanghai Lingzeng Trading Co., Ltd.) before and after 2 months of treatment. For measurement of endometrial thickness, an ultrasound probe was placed transvaginally. On two-dimensional ultrasound images, the maximum thickness of the uterine sagittal section from the basal layer to the functional layer of the endometrium was measured, and the average of three measurements was taken. For the measurement of endometrial volume and volume, the three-dimensional imaging function of the ultrasound diagnostic instrument was used. The three-dimensional volume data of the uterus were collected, the boundary of the endometrium was automatically delineated by the analysis software of the instrument, and the endometrial volume and volume were calculated. At the same time, combined with the results of second exploration of hysteroscopy, the uterine cavity morphology, adhesion separation and endometrial repair were observed visually, and the recovery of uterine cavity morphology was comprehensively evaluated. Re-adhesion of the uterine cavity [ 14 ]: The degree of re-adhesion of uterine cavity was evaluated after 12 months of treatment. Intrauterine re-adhesion refers to the degree of re-adhesion in the uterine cavity after the separation of IUA, including no (There was no adhesions in uterine cavity, uterine horn and fallopian tubes, and the uterine cavity was normal in shape and the opening of the fallopian tubes was clearly visible on hysteroscopy), mild (There was a small amount of fibrous adhesion tissue in the uterine cavity, but the uterine horn and fallopian tube were not involved, with little effect on the morphology and function of the uterine cavity. Hysteroscopy showed a few adhesion bands, which did not affect the normal shape of uterine cavity and fallopian tube patency), moderate (Atresia occurred in part of the uterine cavity and one corner of the uterine horn, affecting the normal morphology and function of the uterine cavity. Hysteroscopy revealed partial intrauterine adhesions, partial atresia of the uterine horns, and partial obstruction of the fallopian tubes), and severe (Uterine cavity and both sides of the horn atresia, or uterine cavity completely disappeared, and seriously affected reproductive function and menstruation. Hysteroscopy showed severe adhesion of the uterine cavity, complete atresia of the uterine Angle and fallopian tube opening or disappearance of the uterine cavity structure). Adverse reaction incidence, pregnancy rate and satisfaction: The patients were followed up for 12 months to observe the occurrence of adverse reactions (such as bleeding, abdominal pain, etc.), and the total incidence was calculated. The pregnancy rate was observed during the follow-up period: It referred to the proportion of the total number of patients in whom an intrauterine gestational sac or fetal heart beat was observed by ultrasound during the follow-up period. Pregnancy was defined if a gestational sac was seen in the uterine cavity on transvaginal sonography or if fetal heart beat was observed after 6–7 weeks of gestation during follow-up. The pregnancy rate was calculated as the pregnancy rate = (number of patients with confirmed pregnancies ÷ total number of patients in each group) ×100%. The satisfaction with the treatment was recorded. The satisfaction of patients was scored on a Five-level rating system [ 15 ], including very satisfied (100 points), relatively satisfied (80 points), average (60 points), relatively dissatisfied (40 points) and very dissatisfied (20 points), with a total score of 100 points. Among them, very satisfied and relatively satisfied patients were included in the total satisfaction. Specific scoring was based on comprehensive consideration of the following aspects: Resumption of menstruation (40 points; Menstrual cycle returned to normal and menstrual volume returned to the normal range, scoring 30–40 points; The menstrual cycle was basically normal but the amount of menstruation was still small, scoring 15–29 points; Menstrual cycle and menstrual volume were not significantly improved, scoring 0–14 points), status of pregnancy (30 points; 25–30 points for successful pregnancy and delivery; 10–24 points for successful pregnancy with adverse outcomes such as abortion; 0–9 points for not pregnant), the ease of the treatment process (20 points, including whether the treatment process was convenient, and whether the treatment cycle was acceptable, etc., 15–20 points for good experience; 8–14 points for average experience; 0–7 points for poor experience), and effect on quality of life (10 points; Quality of life was significantly improved after treatment, scoring 8–10 points; Quality of life was some improvement after treatment, scoring 4–7 points; Quality of life was no significant improvement, scoring 0–3 points). Collection of data on recurrence: The re-adhesion of uterine cavity was evaluated after 12 months of treatment, and mild, moderate, and severe adhesions were considered as recurrence. General data of the two groups of patients were collected and compared, including age, number of miscarriages, timely and quantitative use of estrogen drugs after surgery, history of pelvic inflammatory disease, properties of IUA, number of intrauterine operations, preoperative amenorrhea, and adhesion range, etc. Statistical analysis was conducted using SPSS 23.0. Kolmogorov Smirnov test was used to test whether the measurement data were normal distribution. Measurement data conforming to normal distribution were expressed as‾ x  ±  s , and comparison between groups was analyzed by independent sample t test. Independent sample t test was used for inter group comparison. For the measurement data that did not obey the normal distribution, MannWhitney-U test was used, and the median (minimum value -maximum value) or median (25th to 75th percentile) was used to describe the data characteristics. The enumeration data including the effective rate, incidence of adverse reactions, satisfaction rate, recurrence rate, etc. were expressed as [cases (%)], and χ 2 test was used for comparison between groups. Multivariate Logistic regression analysis was used to analyze the influencing factors of recurrence after treatment of IUA. The level of statistical test was set at P  < 0.05.

In conclusion, in the treatment of severe IUA, high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation can significantly promote the recovery of uterine cavity morphology, reduce the incidence of postoperative intrauterine re-adhesion, and improve the postoperative pregnancy rate of patients. Clinicians can predict the risk of postoperative adhesion recurrence according to these factors, so as to develop targeted prevention strategies. At present, the long-term efficacy and prognosis of high-dose estrogen-progestin sequential therapy for IUA are not adequately evaluated. Future studies should focus on this and assess the stability of uterine cavity shape recovery, improvement of reproductive function, and changes in quality of life through long-term follow-up. In addition, it is necessary to pay attention to the possible effects of high-dose estrogen and progesterone sequential therapy on the cardiovascular system and endocrine system of patients to ensure the safety and feasibility of treatment. High dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation is effective in the treatment of severe IUA, which provides effective treatment for doctors. This method can promote the recovery of uterine cavity shape and improve the postoperative pregnancy rate, which is very important for patients with fertility needs. Doctors can prioritize this program to help patients restore reproductive function and improve the quality of life. Identifying the influencing factors of recurrence of IUA is helpful for doctors to manage patients with stratification. Patients with high risk factors, such as amenorrhea after curettage and history of multiple abortions, should be followed up closely, and the endometrium should be closely monitored to prevent re-adhesion. Preventive measures should be taken according to high-risk factors to reduce the risk of recurrence. The results of this study provide reference for future research. Sequential treatment with different doses and courses of estrogen and progestin can be explored to optimize the strategy. At the same time, the safety of long-term use of estrogen and progestin should be further studied to provide theoretical support and practical guidance for clinical practice and promote the development of the treatment field. Strengths of treatment regimen: In this study, high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation combined with the advantages of surgery and drug therapy can accurately separate adhesive tissue, promote endometrial repair, regulate endocrine, and effectively improve the treatment effect. Combined treatment is better in uterine cavity shape recovery, reducing re-adhesion rate and improving pregnancy rate, and provides an effective treatment for severe IUA. Strengths of study design: The study selected patients with severe IUA, focused on the effect of high-dose estrogen and progesterone sequential therapy, and the object was clear and targeted. A retrospective cohort design was used to include a large sample of patients. The patients were followed up for 12 months, and various clinical data were collected to provide solid evidence for the study conclusion. Strengths of influencing factors analysis: Multivariate Logistic regression analysis was used to explore the recurrence factors after treatment of IUA, and to identify the independent risk factors and protective factors. It is helpful for clinicians to understand the recurrence mechanism, conduct accurate risk assessment, develop personalized strategies, and improve the pertinence and effectiveness of treatment. Limitations of study design: The retrospective nature of this study has a risk of information bias, and some medical histories may be incomplete or inaccurate due to reliance on previous medical records. At the same time, confounding factors cannot be completely controlled, and the results may be affected by unconsidered factors and biased. Limitations of samples: The samples were obtained only from our hospital from a single source and may not be representative of all patients with severe IUA. There are differences in patients from different regions, races, and medical Settings, and the extrapolation of the study results is limited. Multi-center and large sample design should be considered in the future. Limitations of follow-up time: The follow-up period was 12 months, which was short. The long-term efficacy and safety of high-dose estrogen and progesterone sequential therapy are unclear. The follow-up time should be extended to observe the long-term uterine cavity morphology, reproductive function and long-term complications, so as to provide evidence for long-term application.

In this study, 200 patients with severe IUA were retrospectively analyzed, and it was found that high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation can significantly improve the therapeutic effect compared with simple hysteroscopic cold knife separation. The effective rate of the combined group was 94.07%, which was higher than 79.27% of the surgical group. After intervention, the thickness, capacity and volume of the endometrium of the combined group were significantly higher than those of the surgical group. The re-adhesion rate of the combined group was 11.02%, which was lower than 29.27% of the surgical group. The pregnancy rate and satisfaction rate of the combined group were 20.34% and 97.46%, which were significantly higher than 6.10% and 89.02% of the surgical group. Although the adhesive tissue of the patients included in this study was dense muscular, it did not reach the degree of complete calcification. The sharp separation of cold knife can avoid the thermal damage of resectoscope to the residual intima. In addition, multiple logistic regression analysis showed that postoperative amenorrhea, miscarriages frequency, standardized use of estrogen, intrauterine operations frequency, and placement of balloons were independent risk factors for recurrence after IUA treatment. Besides, combination therapy was a protective factor. IUA is a fibrotic adhesion of the endometrium caused by trauma, infection and other factors. The basic histological findings are endometrial tissue fibrosis, avascular fibrous tissue and spindle myofibroblast cells replace the normal matrix structure, making it difficult to distinguish the functional layer from the basal layer of the uterine cavity [ 16 ]. In this study, all patients had severe IUA combined with infertility or oligomenstruation and met clear indications for hysteroscopic treatment. The data in Table  1 showed that there was no significant difference in the number of pregnancies and the number of curettages between the two groups, which should be interpreted with caution in combination with literature evidence. The previous study has shown that repeated pregnancy termination or curettage may increase the risk of IUA by damaging the basal layer of the endometrium [ 17 ]. However, this study sample has certain limitations. Different patients have differences in the ability to repair surgical trauma and the regulation of their own hormone levels, which may affect the relationship between the number of pregnancies, the number of uterine curettage and intrauterine adhesion. Therefore, it is necessary to comprehensively consider the interaction of multiple factors through the multivariate analysis of this study (see Table  2 ) to further clarify the degree and direction of the influence of the number of pregnancies and the number of curettages on intrauterine adhesion under the specific sample of this study. Hysteroscopic adhesion resection can separate and remove the adhesion tissue, thereby improving the pregnancy rate. However, it has a greater damage to the endometrium and a longer postoperative recovery time. Hysteroscopic cold knife dissection can effectively separate and remove the intrauterine adhesion tissue, and restore the normal shape of the uterine cavity. However, the strength of the scissors is small, which requires the clinician to have rich clinical experience and surgical skills. In addition, most patients with severe IUA have severe endometrial damage, so drug treatment is needed to promote endometrial recovery and reduce the recurrence rate after uterine cavity morphology is restored [ 18 ]. Hypoestrogenic state can affect endometrial regeneration, while estrogen and progestin treatment can induce neointimal growth, thereby preventing recurrence of adhesions and increasing menstrual volume [ 19 ]. Siraj et al. [ 20 ] revealed that estrogen and progesterone activate phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway and mitogen-activated protein kinase (MAPK) pathway by binding to receptors on the surface of endometrial cells. The activation of PI3K/Akt pathway can promote the proliferation, survival and migration of endometrial cells, inhibit cell apoptosis, and contribute to the repair and regeneration of endometrium. The activation of MAPK pathway can regulate the synthesis and degradation of extracellular matrix, maintain the normal structure and function of endometrium, and thus prevent the recurrence of intrauterine adhesions. This study found that compared with patients treated with hysteroscopic cold knife separation alone, patients treated with high-dose estrogen and progesterone had higher clinical efficacy. Hysteroscopic cold knife dissection uses cold instruments without electric energy (such as pliers or scissors) to directly separate the adhesion tissue in the uterine cavity and restore the normal shape and structure of the uterine cavity. Compared with the hot knife separation method, the cold knife separation method can reduce the thermal injury during the operation, protect the surrounding normal tissues, and reduce the risk of postoperative complications [ 5 ]. Estrogen can promote the proliferation and differentiation of endometrial cells, and increase the thickness and receptivity of the endometrium. In high-dose estrogen-progestin sequential therapy, estrogen supplementation contributes to postoperative endometrial repair and regeneration. The combination of hysteroscopic cold knife separation and high-dose estrogen and progesterone sequential therapy can play a synergistic role in directly separating adhesions and restoring uterine cavity structure. High-dose estrogen-progestin sequential therapy can further consolidate the surgical effect and reduce the risk of postoperative re-adhesion by promoting endometrial repair, inhibiting inflammatory response and establishing an artificial cycle [ 21 ]. It is concluded that high dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation may be an effective method for the treatment of IUA. Endometrium is the main site of embryo implantation. Thin endometrium or decreased endometrial receptivity will affect the implantation of fertilized eggs and reduce the clinical pregnancy rate [ 22 ]. Normal uterine cavity shape, smooth peristalsis, normal buoyancy and uniform distribution of endometrium are the preconditions for maintaining normal function of endometrium [ 23 ]. Previous studies have found that hysteroscopic cold knife micro-shear separation can play an important role in improving the uterine cavity shape and increasing the pregnancy rate [ 24 ]. It has been reported that high-dose estrogen-progestin sequential therapy can significantly increase the endometrial thickness and reduce the recurrence rate of IUA in patients with moderate to severe IUA [ 25 ]. These findings were similar to the results of the present study. The results of the present study found that the thickness, capacity and volume of the endometrium of the patients in the combined group were significantly higher, and the incidence of intrauterine re-adhesion was significantly lower. It may be due to the decrease of endometrial layer in patients with IUA after operation, resulting in the disorder of estrogen and progesterone. However, high dose of estrogen and progestin can keep the body in a relatively balanced state after operation. They can specifically bind to estrogen and progesterone receptors in endometrium, accelerate the division and proliferation of endometrial stromal cells, and promote the diffusion of drugs to the endometrial layer, thereby promoting the repair of endometrium and reducing the incidence of re-adhesion [ 26 ]. The main direction of treatment is to restore the structure and volume of uterine cavity, prevent uterine wall adhesion, and improve the reproductive function of women of childbearing age. It has found that compared with hysteroscopic electrotomy and separation, hysteroscopic cold knife separation has higher cure rate and postoperative pregnancy rate, and lower complication rate and recurrence rate. This may be related to the ability of hysteroscopic cold knife separation to avoid endometrial damage caused by the thermal effect of energy instrument separation [ 27 ]. However, there was no significant difference in the incidence of adverse reactions between the two groups in this study, which was different from the above studies. This may be due to the fact that this study is a retrospective study, the sample size and the short follow-up time. In addition, the results of this study found that the combined group had higher satisfaction than the surgery group, which confirmed the feasibility of the sequential treatment of this dose of estrogen and progesterone for hysteroscopic cold knife separation to a certain extent. In addition, multiple logistic regression analysis showed that postoperative amenorrhea, miscarriages frequency, standardized use of estrogen, intrauterine operations frequency, and placement of balloons were independent risk factors for recurrence after IUA treatment. Besides, combination therapy was a protective factor. Patients with a history of uterine evacuation and amenorrhea have a high degree of endometrial damage, poor sensitivity to estrogen, and a long recovery time after separation operation, making them more prone to adhesions [ 28 ]. Excessive number of abortions is an important factor leading to IUA. Each abortion operation may cause different degrees of damage to the endometrium, especially when the operation is improper or the postoperative infection, the damage is more serious. With the increase of the number of abortions, the damage to the endometrium gradually accumulates, and the risk of intrauterine adhesion also increases. Qiao et al. [ 29 ] found that the incidence and severity of IUA increased significantly with the increase in the number of abortions. This is because each abortion operation may cause different degrees of damage to the endometrium, especially when the operation is improper or the postoperative infection, the damage is more serious. Multiple abortions lead to repeated damage to the basal layer of the endometrium, which is easy to form scar tissue during the repair process, thereby increasing the risk of intrauterine adhesion. This provides strong evidence to support the conclusion in this paper that the number of miscarriages is an independent risk factor for recurrence after treatment of IUA. The inflammatory response after miscarriage may also promote adhesion formation. Improper use of estrogen after surgery may result in insufficient dosage, which will lead to incomplete endometrial regeneration or poor healing and increase the risk of postoperative recurrence of adhesion [ 30 ]. Studies have shown that there is a clear correlation between the degree of IUA and the number of intrauterine manipulations. The more previous uterine cavity operations are, the larger and denser the adhesions in the uterine cavity may be. This may be due to more severe damage to the endometrial basal layer caused by multiple manipulations, thus increasing the likelihood and extent of adhesions [ 31 ]. In addition, this study found that the absence of balloon placement was a related factor affecting the recurrence of IUA in patients. The reason may be that the intrauterine balloon can effectively separate the adhesive surface and prevent the formation of new adhesions. At the same time, it can also play a role of compression hemostasis, reduce postoperative bleeding, thereby lowering inflammatory reactions, which is beneficial for the repair of the endometrium in the uterine cavity [ 32 ]. Vitale et al. [ 33 ] found that intrauterine balloon can effectively separate the adhesion surface and prevent the formation of new adhesion. The principle is that the balloon acts as a physical barrier in the uterine cavity, preventing the adhesion tissue from attaching again. At the same time, the balloon can also play the role of compression hemostasis, decrease postoperative bleeding, reduce inflammatory response, and create a good environment for the repair of uterine endometrium. This further explains the relationship between balloon placement and recurrence of IUA in the present study, making the discussion deeper and more convincing. This study found that combination therapy was a protective factor for postoperative recurrence of IUA, which further confirmed that high-dose estrogen and progestin sequential assisted hysteroscopic cold knife separation can effectively reduce postoperative recurrence. The unique contribution of this study is not only to further clarify the significant effect of high-dose estrogen and progesterone sequential therapy in promoting uterine cavity shape recovery, reducing re-adhesion rate and improving pregnancy rate in patients with severe IUA, but also to analyze the influence of different individual factors on the treatment effect. This study also found that postoperative amenorrhea, miscarriages frequency, standardized use of estrogen, intrauterine operations frequency, and placement of balloons were independent risk factors for recurrence after IUA treatment. This provides an important basis for clinicians to make risk assessment and individualized treatment plans according to the individual situation of patients. Compared with previous studies, the sample included patients with diverse characteristics such as age, pregnancy and number of curettages, making the findings more generalizable. In addition, although stem cells or platelet-rich plasma have shown certain potential in the treatment of IUA, they still face many technical and safety issues. Based on mature treatment methods, this study provides a practical reference for how to optimize the treatment strategy in current clinical practice, and has important practical significance for improving the prognosis of patients with severe IUA.

Intrauterine adhesions (IUA) are a common gynecological disease also known as Asherman syndrome. Its main cause is due to damage to the basal or superficial layer of the endometrium, which is usually caused by trauma of uterine surgery, infection, and other factors. These injuries lead to abnormal endometrial repair and the formation of scars or adhesive bands, thereby affecting uterine morphology and function. It will not only cause decreased menstrual volume, amenorrhea, infertility, dysmenorrhea, recurrent abortion and other symptoms to seriously affect women’s reproductive health, but also may have a negative impact on women’s mental health, reduce the quality of life, and bring heavy physical and mental burden to patients [ 1 , 2 ]. According to statistics, the incidence of IUA is 1.73-40% worldwide, and about 90% of IUA may be related to pregnancy [ 3 ]. According to data [ 4 ], the normal repair process of endometrium after injury involves the participation of a variety of cytokines and growth factors. For example, the transforming growth factor-β (TGF-β) family plays a key role in regulating the synthesis and degradation of extracellular matrix. When IUA occur, these repair mechanisms are abnormal, and overexpression of TGF-β may lead to excessive deposition of extracellular matrix, which in turn forms scar tissue and adhesive bands. Surgery is the main treatment for IUA. Hysteroscopic cold knife separation surgery is guided by hysteroscopy and uses a cold knife to cut the adhesive tissue, so as to promote the recovery of the uterus and reduce the damage of the endometrium caused by traditional electric resection and separation. It has the advantages of small trauma, quick recovery and few complications [ 5 ]. However, for patients with severe IUA, the efficacy of single hysteroscopic cold knife separation surgery is still not satisfactory, with a high recurrence rate after surgery. Moreover, the successful pregnancy rate of patients with severe IUA after surgery is low, only about 20-30% [ 6 ]. Maintaining the physical barrier of the uterine morphology and promoting endometrial growth are important factors to prevent the recurrence of IUA. Estrogen and progesterone belong to a group of steroid hormones. A study has found that estrogen and progesterone can promote the growth of endometrium, improve the intrauterine environment, and prevent the re-formation of adhesions. They can be used as an adjuvant treatment after intrauterine adhesion lysis, which plays an important role in promoting endometrial regeneration and preventing recurrent adhesions [ 7 ]. It has been reported that the combination of high-dose estrogen after separation of IUA has a better effect on endometrial repair in patients with severe IUA [ 8 ]. The study has found that laser separation is the use of laser energy to cut adhesive tissue, which has the characteristics of high accuracy and good hemostatic effect [ 9 ]. However, the study points out that laser separation may generate high heat during the procedure, causing thermal damage to the surrounding normal tissues, affecting the repair and regeneration of the endometrium, and increasing the risk of postoperative complications. In contrast, hysteroscopic cold knife separation uses cold instruments without electric energy to directly separate the adhesive tissue, which can reduce thermal damage during the operation, better protect the surrounding normal tissues, and reduce the incidence of postoperative complications. Although numerous studies have confirmed the effectiveness of estrogen for IUA after hysteroscopic surgery and the American Association of Gynecologic Laparoscopists (AAGL) guidelines for the management of intrauterine adhesions recommend estrogen, most of the existing studies focus on the general efficacy of estrogen [ 10 ]. This study differs from previous studies in that it focuses on high-dose estrogen-progesterone sequential therapy, a specific mode of administration and dose combination that has been less well studied in terms of uterine cavity morphology recovery. At the same time, there is a lack of in-depth discussion on the differences in the efficacy of high-dose estrogen and progestin-assisted hysteroscopic cold knife separation under different individual characteristics. Based on the actual clinical cases, this study studies the high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation, which can provide more targeted reference for clinicians to choose the treatment plan more accurately and improve the treatment effect of patients with severe IUA under the existing treatment methods. Based on this, this study aims to investigate the effect of high-dose estrogen and progesterone sequential assisted hysteroscopic cold knife separation on the recovery of uterine cavity morphology in patients with severe IUA.