Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC).
To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS.
We searched the following sources from inception to September 2014 to identify relevant randomised controlled trials (RCTs): the Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organisation (WHO) clinical trials register and Clinicaltrials.gov. Furthermore, we manually searched the references of relevant articles. The search was not restricted by language or publication status.
We included all RCTs of aromatase inhibitors used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS.
Data collection and analysis
Two review authors independently selected trials, extracted the data and assessed trial quality. Studies were pooled where appropriate using a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were pregnancy, miscarriage and multiple pregnancy. The quality of the evidence for each comparison was assessed using GRADE methods.
We included 26 RCTs (5560 women). In all studies the aromatase inhibitor was letrozole.
Live birth (12 RCTs)
One RCT compared letrozole with placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)
Nine RCTs compared letrozole with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.64, 95% CI 1.32 to 2.04, n=1783, I²=3%)
Two RCTs compared letrozole with laparoscopic ovarian drilling. There was no evidence of a difference between the groups in live birth rate (OR 1.19, 95% CI 0.76 to 1.86, n=407, I²=0%)
OHSS (16 RCTs)
There was no evidence of a difference in OHSS rates when letrozole (with or without adjuncts) was compared with placebo (one RCT, n=36), clomiphene citrate (with or without adjuncts) followed by timed intercourse (nine RCTs, n=2179) or intrauterine insemination (IUI) (two RCTs, n=1494), laparoscopic ovarian drilling (one RCT, n=260) or anastrozole (one RCT, n=220). Events were absent or very rare, and no study had more than 2 cases of OHSS.
Clinical pregnancy (25 RCTs)
One RCT compared letrozole versus placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)
Fifteen RCTs compared letrozole versus clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse. The pregnancy rate was higher in the letrozole group (OR 1.40, 95% CI 1.18 to 1.65, n=2816, I²=26%)
Three RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by IUI. The pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30 to 2.25, n=1597)
Three RCTs compared letrozole (with or without metformin) versus laparoscopic ovarian drilling. There was no evidence of a difference in the clinical pregnancy rate (OR 1.14, 95% CI 0.80 to 1.65, n=553, I²=0%)
Two RCTs compared letrozole versus anastrozole, one RCT compared a five day versus a 10 day administration protocol for letrozole and another RCT compared 5 mg of letrozole versus 7.5 mg of letrozole. There was no evidence of a difference in the clinical pregnancy rate in these comparisons.
The quality of the evidence was rated as low for live birth and pregnancy outcomes. The reasons for downgrading the evidence were poor reporting of study methods, possible publication bias and the tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth (suggesting that results might be somewhat less favourable to letrozole if all studies reported live birth).
Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. The quality of this evidence is low and findings should be regarded with some caution. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, though there were few relevant studies. OHSS was a very rare event, with no occurrences in most studies.
多囊性卵巢症候群 (polycystic ovary syndrome, PCOS) 是導致女性月經次數過少 (寡經症 [oligomenorrhoea]) 和無月經 (閉經 [amenorrhoea]) 的最常見原因。全球約有4%至8%的女性罹患PCOS，通常會造成無排卵型的低生育力。芳香環轉化酶抑制劑 (aromatase inhibitors, AIs) 是一種於2001年推出的新藥，可誘發排卵。過去10年所進行的臨床試驗，對於AI letrozole是否至少與第一線治療clomiphene citrate (CC) 同樣有效，所得到的結論不盡相同。
我們從頭開始搜尋下列來源，直至2013年10月24日為止，以找出相關的隨機對照試驗 (randomized controlled trial, RCT)：月經疾病及不孕症群組專業註冊 (Menstrual Disorders and Subfertility Group Specialised Register)、考科藍對照試驗中央註冊 (Cochrane Central Register of Controlled Trials)、MEDLINE、EMBASE、PsycINFO、Pubmed、LILACS、Web of Knowledge、世界衛生組織臨床試驗註冊 (World Health Organisation [WHO] clinical trials register) 和Clinicaltrials.gov.。此外也以人工方式搜尋相關論文的參考文獻。並未限制語言或發表狀態。
由2位文獻回顧作者獨立篩選試驗、萃取資料並評估試驗品質。我們適當匯集試驗，採用固定效果 (fixed effect) 模式，計算資料匯集後大部分結果的勝算比 (RO) 和95%信賴區間 (CI)，並計算卵巢過度刺激症候群 (ovarian hyperstimulation syndrome, OHSS) 的風險差 (RD)。主要結果為活產及OHSS，次要結果為懷孕、流產和多胞胎妊娠。使用GRADE法評估各項比較的證據品質。
有1篇試驗針對具clomiphene抗藥性 (clomiphene resistant) 的女性，比較letrozole和安慰劑的效果，結果並不明確 (OR為3.17，95% CI為0.12至83.17，n = 36)。
有9篇RCT比較於指定時間性交 (timed intercourse) 後，letrozole和clomiphene citrate (無論是否搭配輔助治療) 的效果，結果顯示letrozole組的出生率 (birth rate) 較高 (OR為1.63，95% CI為1.31至2.03，n = 1783，I2 = 3%)。
有2篇RCT比較letrozole和腹腔鏡卵巢燒灼術 (laparoscopic ovarian drilling) 的效果，結果發現2個治療組的活產率並無差異 (OR為1.19，95% CI為0.76至1.86，n = 407，I2 = 0%)。
當比較letrozole和安慰劑 (1篇RCT，n=36)、於指定時間性交後使用clomiphene citrate (無論是否搭配輔助治療) (9篇RCT，n=2179)、於人工授精 (intrauterine insemination, IUI) 後使用clomiphene citrate (無論是否搭配輔助治療) (2篇RCT，n=1494)、腹腔鏡卵巢燒灼術 (1篇 RCT，n=260) 或anastrozole (1篇RCT，n=220) 時，並無證據顯示OHSS的發生率具有組間差異。不是未發生事件就是發生的事件數極少，而且亦無試驗的OHSS病例超過2例。
有1篇RCT針對具clomiphene抗藥性的女性，比較letrozole和安慰劑的效果，結果並不明確 (OR為3.17，95% CI為0.12至83.17，n = 36)。
有15篇RCT比較於指定時間性交後，letrozole和clomiphene citrate (無論是否搭配輔助治療於一組或兩組) 的效果，結果顯示letrozole組的懷孕率較高 (OR為1.40，95% CI為1.18至1.65，n = 2816，I2 = 26%)。
有3篇RCT比較於IUI後，letrozole和clomiphene citrate (無論是否搭配輔助治療) 的效果，結果顯示letrozole組的懷孕率較高 (OR為1.71，95% CI為1.30至2.25，n = 1597)。
有3篇RCT比較letrozole和卵巢燒灼術的效果，結果發現2個治療組的臨床懷孕率並無差異 (OR為1.14，95% CI為0.80至1.65，n = 533，I ² = 0%)。
有2篇RCT比較letrozole和 anastrozole的效果，有1篇RCT比較5天和10天的letrozole治療計畫，另有1篇RCT比較5 mg和7.5 mg letrozole的效果，結果顯示各中比較的治療組間懷孕率並無差異。