Tan Yu Hwee, Lethaby Anne
Obstetrics and Gynaecology, ADHB, Auckland, New Zealand.
Cochrane Database Syst Rev. 2013 Nov 15;2013(11):CD010241. doi: 10.1002/14651858.CD010241.pub2.
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The following electronic databases were searched to April 2013 for published and unpublished randomised controlled trials that met the inclusion criteria: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials,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.
AUTHORS' CONCLUSIONS: 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.
月经过多是绝经前女性转诊至妇科医生处的最常见原因之一。尽管药物治疗通常是一线治疗方法，但许多女性最终仍需要进一步治疗。宫腔镜子宫内膜切除术以及最近的“第二代”设备，如球囊、射频或微波消融术，为子宫切除术提供了日间手术替代方案。子宫内膜完全破坏是治疗成功的主要决定因素之一。当子宫内膜厚度小于4毫米时进行手术最为有效。一种选择是在月经刚结束时进行手术，但这并不总是可行的。另一种选择是使用激素药物在术前使子宫内膜变薄。最常评估的药物是戈舍瑞林（一种促性腺激素释放激素类似物，或GnRHa）和达那唑。其他GnRH类似物和孕激素也已被研究，尽管可用数据较少。有人认为这些药物将减少手术时间，改善宫腔内手术环境，并减少术中用于扩张子宫腔的液体吸收。它们还可能改善长期疗效，包括经量减少和痛经。
研究术前子宫内膜变薄药物（GnRH激动剂、达那唑、雌激素 - 孕激素和孕激素）与另一种药物或安慰剂相比，在有月经过多的绝经前女性子宫内膜破坏术前使用时的有效性和安全性。
检索了以下电子数据库至2013年4月，以查找符合纳入标准的已发表和未发表的随机对照试验：月经紊乱与生育力低下组（MDSG）专门的对照试验注册库、Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、EMBASE、CINAHL和PsycINFO。试验的其他电子来源包括正在进行和已注册试验的试验注册库；引文索引；Web of Knowledge中的会议摘要；葡萄牙语和西班牙语世界试验的LILACS数据库；PubMed；以及OpenSIGLE数据库和Google中的灰色文献。所有检索均在与MDSG试验检索协调员协商后进行。
纳入随机对照试验（RCT），如果它们比较了这些药物与另一种药物、安慰剂或不治疗对相关术中及术后治疗结局的影响。试验的选择由两位综述作者独立进行。
两位综述作者独立评估研究的偏倚风险，并提取有关手术结局、有效性结局、随访期间需要进一步手术治疗的女性比例、子宫内膜结局指标、使用可接受性结局和生活质量的数据。数据按意向性分析原则进行分析。二分数据使用RevMan软件通过Mantel - Haenszel方法进行合并以进行Meta分析，以估计合并风险比（RRs）。连续数据使用RevMan软件通过逆方差方法进行合并以进行Meta分析，以估计合并平均差（MD）及其95%置信区间（CI）。主要研究结果的总体证据质量使用GRADE工作组方法进行评估。
本综述纳入了20项研究，共1969名女性。这些研究比较了GnRHa、达那唑和孕激素与安慰剂或不治疗；GnRHa与达那唑、孕激素、GnRH拮抗剂或刮宫术；以及达那唑与孕激素。四项研究进行了不止一项比较。与不治疗相比，宫腔镜切除术前使用GnRHa与术后12个月闭经率较高相关（RR 1.6，95% CI 1.2至2.0，7项RCT，605名女性，中度异质性；I² = 40%），在24个月时也是如此（RR 1.62，95% CI 1.04至2.52，2项RCT，357名女性，无异质性；I² = 0%），手术持续时间略短（-3.5分钟，95% CI -4.7至 -2.3，5项RCT，156名女性，高度异质性；I² = 72%），手术更轻松（RR 0.32，95% CI 0.22至0.46，2项RCT，415名女性，低异质性；I² = 4%）。术后痛经减轻（RR 0.59，95% CI 0.40至0.87，2项RCT，133名女性，无异质性；I² = 0%）。使用GnRHa对术中并发症发生率无影响（RR 1.47，95% CI 0.35至6.06，5项RCT，592名女性，无异质性；I² = 0%），无论术前是否使用子宫内膜变薄药物，参与者对该手术的满意度都很高（RR 0.99，95% CI 0.93至1.05，6项RCT，599名女性，低异质性；I² = 11%）。GnRHa比达那唑产生更一致的子宫内膜萎缩（RR 1.84，95% CI 1.23至2.75，2项RCT，142名女性，无异质性；I² = 0%）。对于其他术中及术后结局，任何差异都很小，在采用第二代消融技术的女性研究中未发现GnRHa预处理的益处。GnRHa和达那唑在相当比例的女性中都产生了副作用，尽管很少有研究详细报告这些情况。几乎没有随机数据可用于评估孕激素作为子宫内膜变薄药物的有效性。当报告时，子宫内膜变薄药物对术后闭经等益处的长期影响随时间而降低。主要研究的弱点是大多数参与者在24个月后没有随访，并且研究样本量较小。报告结局的异质性范围从无到高度。超过一半的试验没有对参与者或结局评估进行盲法处理。大多数试验被确定存在不确定的选择和报告偏倚，因为它们未报告分配隐藏情况且有选择性报告的证据。不良事件的报告质量普遍较差，但在研究中描述时，它们包括潮热、阴道干燥、多毛症、性欲减退和声音变化等绝经症状，以及头痛和体重增加等其他副作用。
低质量证据表明，宫腔镜手术前使用GnRHa和达那唑使子宫内膜变薄可改善手术条件和术后短期结局。GnRHa比达那唑产生的子宫内膜变薄更一致，尽管两者都取得了令人满意的结果。随着时间推移，这些药物对术后长期结局的影响降低。采用第二代消融技术时，GnRHa预处理没有明显益处。此外，使用这些药物时副作用更常见。
