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Clomiphene and anti-oestrogens for ovulation induction in PCOS

  • Review
  • Intervention

Authors


Abstract

Background

Subfertility due to anovulation is a common problem in women. First-line oral treatment is with anti-oestrogens, for example clomiphene citrate, but resistance (failure to ovulate) may be apparent with clomiphene. Alternative and adjunctive treatments have been developed such as tamoxifen, dexamethasone, and bromocriptine.

Objectives

To determine the relative effectiveness of anti-oestrogen agents alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome (PCOS).

Search methods

A search was conducted using the Cochrane Menstrual Disorders and Subfertility Group Trials Register (May 2009), CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to May 2009), and EMBASE (1980 to May 2009) for identification of relevant randomised controlled trials (RCTs). The United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs were searched.

Selection criteria

RCTs comparing oral anti-oestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility were considered. Insulin sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility were excluded.

Data collection and analysis

Data extraction and quality assessment were done independently by two review authors. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, overstimulation, ovarian hyperstimulation syndrome, and women reported adverse effects.

Main results

This is a substantive update of a previous review. Fifteen RCTs were included. One trial reported live birth. Miscarriage, multiple pregnancy rates and adverse events were poorly reported.

Clomiphene was effective in increasing pregnancy rate compared to placebo (OR 5.8, 95% CI 1.6 to 21.5) as was clomiphene plus dexamethasone treatment (OR 9.46, 95% CI 5.1 to 17.7) compared to clomiphene alone. No evidence of a difference in effect was found between clomiphene versus tamoxifen or clomiphene in conjunction with human chorionic gonadotrophin (hCG) versus clomiphene alone.

The remaining results had only one study in each comparison. A significant improvement in the pregnancy rate was reported for clomiphene plus combined oral contraceptives versus clomiphene alone. No evidence of a difference in effect on pregnancy rate was found with any of the other comparisons.

Authors' conclusions

This review shows evidence supporting the effectiveness of clomiphene citrate and clomiphene in combination with dexamethasone for pregnancy rate only. There is limited evidence on the effects of these drugs on outcomes such as miscarriage. Evidence in favour of these interventions is flawed due to the lack of evidence on live births.

摘要

背景

對於多囊性卵巢症候群而言,為了誘導排卵所使用的 Clomiphene與抗雌激素類的藥物

對於婦女們來說,因為排卵障礙而引起的次不孕症是1種常見的問題。第1線的口服治療方法是使用抗雌激素類的藥物,例如clomiphene的citrate,但是使用clomiphene之後可能會出現明顯的抗藥性(排卵失敗)。其他的以及輔助式的治療方法也已經被開發出來了,像是tamoxifen、dexamethasone,以及bromocriptine等等。

目標

對於患有次不孕症的婦女們而言,如果她們還同時遇到了可能是因為多囊性卵巢症候群(PCOS)而引起的排卵障礙時,不論是單獨使用抗雌激素類的藥物,或是將這類藥物與其他的醫學療法合併使用,都要確定它們的相對功效。

搜尋策略

搜尋 Cochrane Menstrual Disorders以及Subfertility Group Trials Register (May 2009) 、CENTRAL (Cochrane Library 2009, Issue 2) 、 MEDLINE (1966年2009年5月) 、以及EMBASE (1980年2009年5月) 以找出相關隨機對照試驗 (RCTs). 。此外還搜尋了The United Kingdom National Institute for Clinical Excellence (NICE) 指引以及相關文獻回顧的參考資料清單。

選擇標準

被考慮的隨機對照試驗是比較因排卵障礙而導致的次不孕症病人使用口服抗雌激素藥物而誘導排卵 (單獨或合併其他治療) 的情形。胰島素增敏劑、芳香環轉化?抑制劑,以及高泌乳素血症所引起的不孕症,則都被排除在外。

資料收集與分析

有2位審稿的作者獨立地完成了資料擷取與品質評估的工作。主要的結果為產下活胎的情況;次要的結果為懷孕、排卵、流產、多胞妊娠、過度刺激、卵巢過度刺激症候群,以及婦女們曾經反映過的不良作用。

主要結論

這是1份對於前次回顧所作的實質性更新。當中共收集了15份隨機對照試驗。有1份試驗曾經報告過產下活胎的情況。流產、懷上多胞胎的比率,以及不良事件等情形,則沒有妥善地加以報告。跟安慰劑比較起來,Clomiphene可以有效地提升懷孕的比率(OR 5.8,95% CI 1.6到21.5),至於跟單獨使用 clomiphene比較起來,clomiphene加上 dexamethasone的治療方法也可以達到同樣的提升效果(OR 9.46,95% CI 5.1到17.7)。若是將clomiphene與 tamoxifen比較起來,或是 將clomiphene加上人類的絨毛膜性腺激素(hCG)與單獨使用clomiphene比較起來,在這些比較之間,並沒有證據顯示出任何影響方面的差異。剩下的結果在每1項比較之中都只有1份研究。對於 clomiphene加上組合式的口服避孕藥與單獨使用clomiphene的比較而言,就懷孕比率方面的顯著改善狀況來看,都已經有人提出了報告。對於其他的比較項目而言,就懷孕比率方面的影響來看,在當中的任何1項之中都沒有發現到任何證據能夠顯示出其中的差異。

作者結論

若是僅就懷孕的比率來看,本篇回顧顯示了某些證據,能夠支持clomiphene的citrate以及clomiphene與dexamethasone合併使用時的功效。針對像是流產之類的結果而言,有關於這些藥物的結果方面,並沒有足夠的證據。因為欠缺在產下活胎方面的證據,所以對於偏好使用這些醫療介入行為方面的證據而言,就顯得有缺陷。

翻譯人

此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。

總結

對於同時具有排卵障礙的次不孕症而使用的Clomiphene與抗雌激素類的藥物。因為沒有排卵而造成的次不孕症,對於婦女們來說是很常見的。醫學治療方法或許可以當助這些婦女們進行排卵。例如clomiphene之類的口服抗雌激素,會造成對於卵巢方面的刺激增加,並且幫助排卵。對於clomiphene的功效而言,本篇研究的回顧發現了某些證據。在clomiphene與tamoxifen之間,並沒有發現到證據能夠顯示出任何差異,其中tamoxifen是1種類似的抗雌激素藥物。Dexamethasone(1種類固醇)以及組合型的口服避孕藥,這2種方式都被用來輔助clomiphene,並且顯示出了預期的成效。當我們已經知道有報告指出clomiphene的治療會帶來流產的風險時,在發生了早期的懷孕情況之外,只有少數幾篇研究曾經加以報告過,因此,關於有效的治療方面,並不能夠得到最終的結論。這些證據並沒有一致性,而且還需要有更深入的研究。

Plain language summary

Clomiphene and anti-oestrogens for subfertility associated with anovulation

Subfertility due to the absence of ovulation is common for women. Medical treatment may help these women ovulate. Oral anti-oestrogens, for example clomiphene, cause increased stimulation of the ovaries and aid ovulation. The review of studies found evidence for the effectiveness of clomiphene. No evidence of a difference between clomiphene and tamoxifen, a similar anti-oestrogen drug, was found. Dexamethasone (a steroid) and combined oral contraceptives are both used to supplement clomiphene and show promise. Few studies reported beyond the establishment of early pregnancy so that, given the reported risks of miscarriage with clomiphene treatment, no definitive conclusions can be drawn about effective treatment. Evidence was inconsistent and further research is needed.

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