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Estrogen in the Prevention of Adhesion Reformation

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ClinicalTrials.gov Identifier: NCT03620929
Recruitment Status : Enrolling by invitation
First Posted : August 8, 2018
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
Yang Ling Ling, Fu Xing Hospital, Capital Medical University

Brief Summary:

Asherman syndrome, which occurs after trauma to the basalis layer of the endometrium.It seems that the role of postoperative estrogen therapy in the prevention of recurrence of IU adhesions is still controversial. To investigate if estrogen therapy can prevent adhesion reformation after adhesiolysis.

After the completion of hysteroscopic adhesiolysis, recruited patients will be randomized to one of the two treatment groups by computer-generated numbers: having estrogen after hysteroscopic adhesiolysis three months, all patients in this group will be treated with hormone therapy for 3 cycles; each cycle consists of estradiol 4mg per day for 21 days with addition of progestogen in the form of dydrogesterone 10mg per day for the last 7 days; and the control group without estrogen treatment. A second-look hysteroscopy and ultrasound assessment of the endometrium will be carried out 4 weeks after the surgery, and again at 8 weeks after the surgery.


Condition or disease Intervention/treatment Phase
Asherman Syndrome Drug: Estradiol Valerate Phase 4

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Detailed Description:

Background information Asherman syndrome, which occurs after trauma to the basalis layer of the endometrium generally after endometrial curettage, may manifest as hypomenorrhea, amenorrhea, dysmenorrhea, infertility or recurrent miscarriage.

At present, hysteroscopic adhesiolysis is the recommended standard diagnostic method and treatment for IUA. Recurrence of uterine cavity adhesion post-operatively is frequently reported, especially in severe IUA patients. A number of strategies have been proposed to prevent recurrence of adhesion reformation, including the use of post-operative estrogen. However, it is still not known if estrogen therapy is indeed necessary or effective. In a prospective randomized study which evaluated the efficacy of estrogen in preventing IUA following hysteroscopic septal resection, it was found that estrogen did not have any benefit in reducing adhesion formation. In another RCT study on women with Asherman syndrome, there did not appear to be any difference in the recurrence of IUA and pregnancy rate between those who did or did not receive adjuvant hormonal medication. On the other hand, large doses of estrogen may result in endometrium fibrosis and inhibited endometrium receptivity.

It seems that the role of postoperative estrogen therapy in the prevention of recurrence of IU adhesions is still controversial. In this prospective, randomized, controlled study, we wish to determine if estrogen therapy is of benefit in preventing adhesion reformation after IUA for Asherman syndrome. As the effect may be different for subjects with different degrees of IUA, we propose to stratify the subjects into those with mild and severe IUAs.

Objectives To investigate if estrogen therapy can prevent adhesion reformation after adhesiolysis.

Patients The patients will be recruited from the hysteroscopy Center of the Fuxing Hospital, Beijing, China. Before the surgery all patients with suspected Asherman syndrome will undergo preoperative evaluations, including a detailed history of the menstrual pattern, any previous intrauterine surgery, reproductive history, as well as trans-vaginal ultrasonography. The severity and extent of intrauterine adhesions will be scored according to a classification system recommended by the American Fertility Society (AFS) (1988 version). The inclusion criteria include [1] women aged 18-40 years; written consent obtained; and agreement to have second-look hysteroscopy. The exclusion criteria included:1 has received estrogen therapy within 3 month of enrolment. 2 suffers from leiomyoma, endometrial polyps, cancer, or polycystic ovarian syndrome (PCOS). 3.History of genital tuberculosis; and 4. contraindications for estrogen therapy.

Study Design After the completion of hysteroscopic adhesiolysis, recruited patients will be randomized to one of the two treatment groups by computer-generated numbers: having estrogen after hysteroscopic adhesiolysis three months, all patients in this group will be treated with hormone therapy for 3 cycles; each cycle consists of estradiol 4mg per day for 21 days with addition of progestogen in the form of dydrogesterone 10mg per day for the last 7 days; and the control group without estrogen treatment. A second-look hysteroscopy and ultrasound assessment of the endometrium will be carried out 4 weeks after the surgery, and again at 8 weeks after the surgery.

Power Calculation On the basis of the results of the two published retrospective cohort studies comparing the balloon and hormone therapy group (control group) in the prevention of adhesion reformation, in the mild intrauterine adhesion (AFS score 1~6), we estimate that the adhesion reformation rate the hormone therapy group is 10% and control group is 30%. Accepting a type 1 error (a) of 0.05, and a type 2 error (b) of 0.10, the number of subjects in each arm of the randomized, controlled trial would be 39. Assuming that the dropout rate is 20%, the total number of subject to be recruited would be 49 in each arm. In the severe intrauterine adhesion (AFS score7~12) group, we estimate that the adhesion reformation rate the hormone therapy group is 25% and control group is 50%. Accepting a type 1 error (a) of 0.05, and a type 2 error (b) of 0.10, the number of subjects in each arm of the randomized, controlled trial would be 37. Assuming that the dropout rate is 20%, the total number of subject to be recruited would be 44 in each arm.

Procedure Surgical procedure The surgery will be carried out by one of three experienced hysteroscopic surgeons with the use of a 4.5-mm rigid hysteroscope (Olympus) with 5% saline perfusion under 100 mm Hg pressure. The primary procedure will be performed under general anesthesia in a day surgery unit. Ultrasonographic guidance will be routinely used. Once the extent and severity of uterine adhesion has been assessed, the adhesions will be divided with the use of mono-polar instrument until normal uterine anatomy is achieved.

Postoperative treatments All subjects will be treated with oral antibiotic for 5 days. In all cases hormone therapy will be started from the day of operation, consisting of estradiol valerate at a dose of 4mg/d for 21 days, with the addition of dydrogesterone at a dose of 10 mg/d for the last 7 days of the estrogen therapy. After the withdrawal bleed, the hormone therapy will be repeated for another cycle. Second-look hysteroscopy will be carried out in the early proliferative phase, 4 weeks after the initial operation; a third-look hysteroscopy will be carried out 8 weeks after the initial operation. After assessment of the extent and severity of any reformed adhesion, hysteroscopic adhesiolysis will be carried out at the time of the second-look or third-look procedure, if adhesion had recurred. The surgeon who later performs the second-look and third-look hysteroscopy will be blinded to the randomization. All patients will be treated with hormone therapy for a total of three cycles.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 186 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: The Effect of Estrogen in the Prevention of Adhesion Reformation After Hysteroscopic Adhesiolysis
Actual Study Start Date : August 13, 2018
Estimated Primary Completion Date : August 1, 2020
Estimated Study Completion Date : December 1, 2020


Arm Intervention/treatment
Experimental: Experiment group
Having estrogen(Estradiol Valerate) after hysteroscopic adhesiolysis three months, all patients in this group will be treated with hormone therapy for 3 cycles; each cycle consists of estradiol 4mg per day for 21 days with addition of progestogen in the form of dydrogesterone 10mg per day for the last 7 days;
Drug: Estradiol Valerate
In all cases hormone therapy will be started from the day of operation, consisting of estradiol valerate at a dose of 4mg/d for 21 days, with the addition of dydrogesterone at a dose of 10 mg/d for the last 7 days of the estrogen therapy. After the withdrawal bleed, the hormone therapy will be repeated for another cycle. Second-look hysteroscopy will be carried out in the early proliferative phase, 4 weeks after the initial operation; a third-look hysteroscopy will be carried out 8 weeks after the initial operation. After assessment of the extent and severity of any reformed adhesion, hysteroscopic adhesiolysis will be carried out at the time of the second-look or third-look procedure, if adhesion had recurred.
Other Name: dydrogesterone

No Intervention: Control group
Control group without estrogen treatment. A second-look hysteroscopy and ultrasound assessment of the endometrium will be carried out 4 weeks after the surgery, and again at 8 weeks after the surgery.



Primary Outcome Measures :
  1. AFS score [ Time Frame: 3 months ]
    The severity and extent of intrauterine adhesions will be scored according to a classification system recommended by the American Fertility Society (AFS) (1988 version).



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

patients with suspected Asherman syndrome

Exclusion Criteria:

  • 1 has received estrogen therapy within 3 month of enrolment. 2 suffers from leiomyoma, endometrial polyps, cancer, or polycystic ovarian syndrome (PCOS). 3.History of genital tuberculosis; and 4. contraindications for estrogen therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03620929


Locations
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China, Beijing
Fuxing hospital
Beijing, Beijing, China, 100073
Sponsors and Collaborators
Fu Xing Hospital, Capital Medical University

Publications:
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Responsible Party: Yang Ling Ling, principal investigator, Fu Xing Hospital, Capital Medical University
ClinicalTrials.gov Identifier: NCT03620929     History of Changes
Other Study ID Numbers: 2018FXHEC-KY025
First Posted: August 8, 2018    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yang Ling Ling, Fu Xing Hospital, Capital Medical University:
estradiol
Additional relevant MeSH terms:
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Gynatresia
Genital Diseases, Female
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Estradiol
Polyestradiol phosphate
Dydrogesterone
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Progestins