Title:
Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding.

Abstract:
Heavy menstrual bleeding is one of the most common reasons for referral of premenopausal women to a gynaecologist. Although medical therapy is generally first line, many women eventually will require further treatment. Endometrial ablation by hysteroscopic and more recent "second-generation" devices such as balloon, radiofrequency or microwave ablation offers a day-case surgical alternative to hysterectomy. Complete endometrial destruction is one of the main determinants of treatment success. Surgery is most effective if undertaken when endometrial thickness is less than four millimeters. One option is to perform the surgery in the immediate postmenstrual phase, which is not always practical. The other option is to use hormonal agents that induce endometrial thinning pre-operatively. The most commonly evaluated agents are goserelin (a gonadotrophin-releasing hormone analogue, or GnRHa) and danazol. Other GnRH analogues and progestogens have also been studied, although fewer data are available. It has been suggested that these agents will reduce operating time, improve the intrauterine operating environment and reduce absorption of fluid used for intraoperative uterine cavity distension. They may also improve long-term outcomes, including menstrual loss and dysmenorrhoea.
To investigate the effectiveness and safety of pre-operative endometrial thinning agents (GnRH agonists, danazol, estrogen-progestins and progestogens) versus another agent or placebo when given before endometrial destruction in premenopausal women with heavy menstrual bleeding.
The following electronic databases were searched to April 2013 for published and unpublished randomised controlled trials that met the inclusion criteria: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsycINFO.Other electronic sources of trials included trial registers for ongoing and registered trials; citation indexes; conference abstracts in the Web of Knowledge; the LILACS database for trials from the Portuguese- and Spanish-speaking world; PubMed; and the OpenSIGLE database and Google for grey literature.All searches were performed in consultation with the MDSG Trials Search Co-ordinator.
Randomised controlled trials (RCTs) were included if they compared the effects of these agents with one other, or with placebo or no treatment, on relevant intraoperative and postoperative treatment outcomes. Selection of trials was carried out independently by two review authors.
Two review authors independently assessed studies for risk of bias and extracted data on surgical outcomes, effectiveness outcomes, proportion of women requiring further surgical therapy during follow-up, endometrial outcome measures, acceptability of use outcomes and quality of life. Data were analysed on an intention-to-treat basis. Dichotomous data were combined for meta-analysis with RevMan software using the Mantel-Haenszel method to estimate pooled risk ratios (RRs). Continuous data were combined for meta-analysis with RevMan software using an inverse variance method to estimate the pooled mean difference (MD) with 95% confidence interval (CI). The overall quality of evidence for the main findings was assessed with the use of GRADE working group methods.
Twenty studies with 1969 women were included in this review. These studies compared GnRHa, danazol and progestogens versus placebo or no treatment; GnRHa versus danazol, progestogens, GnRH antagonists or dilatation & curettage; and danazol versus progestogens. Four studies performed more than one comparison.When compared with no treatment, GnRHa used before hysteroscopic resection were associated with a higher rate of postoperative amenorrhoea at 12 months (RR 1.6, 95% CI 1.2 to 2.0, 7 RCTs, 605 women, moderate heterogeneity; I(2) = 40%) and at 24 months (RR 1.62, 95% CI 1.04 to 2.52, 2 RCTs, 357 women, no heterogeneity; I(2) = 0%), a slightly shorter duration of surgery (-3.5 minutes, 95% CI -4.7 to -2.3, 5 RCTs, 156 women, substantial heterogeneity; I(2) = 72%) and greater ease of surgery (RR 0.32, 95% CI 0.22 to 0.46, 2 RCTs, 415 women, low heterogeneity; I(2) = 4%). Postoperative dysmenorrhoea was reduced (RR 0.59, 95% CI 0.40 to 0.87, 2 RCTs, 133 women, no heterogeneity; I(2) = 0%). The use of GnRHa had no effect on intraoperative complication rates (RR 1.47, 95% CI 0.35 to 6.06, 5 RCTs, 592 women, no heterogeneity; I(2) = 0%), and participant satisfaction with this surgery was high irrespective of the use of pre-operative endometrial thinning agents (RR 0.99, 95% CI 0.93 to 1.05, 6 RCTs, 599 women, low heterogeneity; I(2) = 11%). GnRHa produced more consistent endometrial atrophy than was produced by danazol (RR 1.84, 95% CI 1.23 to 2.75, 2 RCTs, 142 women, no heterogeneity; I(2) = 0%). For other intraoperative and postoperative outcomes, any differences were minimal, and no benefits of GnRHa pretreatment were noted in studies in which women underwent second-generation ablation techniques. Both GnRHa and danazol produced side effects in a significant proportion of women, although few studies reported these in detail. Few randomised data were available to allow assessment of the effectiveness of progestogens as endometrial thinning agents. When reported, the long-term effects of endometrial thinning agents on benefits such as postoperative amenorrhoea were reduced with time.The main study weaknesses were that most participants received no follow-up beyond 24 months and that the studies used a small sample size. Heterogeneity for outcomes reported ranged from none to substantial. More than half the trials had no blinding of participants or outcome assessment. Most of the trials were determined to have uncertain selection and reporting bias, as they did not report allocation concealment and evidence of selective reporting was noted. The quality of reporting of adverse events was generally poor, but, when described in the studies, they included menopausal symptoms such as hot flushes, vaginal dryness, hirsutism, decreased libido and voice changes, as well as other side effects such as headache and weight gain.
Low-quality evidence suggests that endometrial thinning with GnRHa and danazol before hysteroscopic surgery improves operating conditions and short-term postoperative outcomes. GnRHa produced slightly more consistent endometrial thinning than was produced by danazol, although both achieved satisfactory results. The effect of these agents on longer-term postoperative outcomes was reduced with time. No benefits of GnRHa pretreatment were apparent with second-generation ablation techniques. Also, side effects were more common when these agents were used.