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Meta-Analysis
. 2018 May 24;5(5):CD010287.
doi: 10.1002/14651858.CD010287.pub3.

Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome

Sebastian Franik  1 , Stephanie M Eltrop, Jan Am Kremer, Ludwig Kiesel, Cindy Farquhar
Affiliations
Meta-Analysis

Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome

Sebastian Franik et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: 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 class of drugs that were introduced for ovulation induction in 2001. Since about 2001 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).

Objectives: To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI).

Search methods: We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status.

Selection criteria: We included all RCTs of AIs 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 risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate 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 clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods.

Main results: This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary.

Authors' conclusions: Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

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Conflict of interest statement

No declarations of interest.

Figures

1
1
Study flow diagram for update 2018
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.1 Live birth rate.
5
5
Funnel plot of comparison: 2 Aromatase inhibitors compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.
6
6
Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.6 Ovarian hyperstimulation syndrome rate.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Abdellah 2011 {published data only}
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Chen 2016 {published data only}
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Davar 2011 {published data only}
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Dehbashi 2009 {published data only}
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Elgafor 2013 {published data only}
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El‐Gharib 2015 {published data only}
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El‐Khayat 2016 {published data only}
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Foroozanfard 2011 {published data only}
    1. Foroozanfard F, Mahdian M, Mousavi Gl, Pejmanmanesh M, Soleimani A. Use of letrozole versus clomiphene citrate combined with gonadotropins in patients with clomiphene resistant polycystic ovarian syndrome: A comparative study. Pakistan Journal of Medical Sciences 2011;27(5):967‐70.
Ganesh 2009 {published data only}
    1. Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B. Comparison of letrozole with continuous gonadotropins and clomiphene‐gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. Journal of Assisted Reproduction and Genetics 2009;26(1):19‐24. - PMC - PubMed
Ghahiri 2016 {published data only}
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Ghomian 2015 {published data only}
    1. Ghomian N, Khosravi A, Mousavifar N. A randomized clinical trial on comparing the cycle characteristics of two different initiation days of letrozole treatment in clomiphene citrate resistant PCOS patients in IUI cycles. International Journal of Fertility and Sterility 2015;9(1):17‐26. - PMC - PubMed
Hassan 2017 {published data only}
    1. Hassan A, Shehata N, Wahba A. Cost effectiveness of letrozole and purified urinary FSH in treating women with clomiphene citrate‐resistant polycystic ovarian syndrome: a randomized controlled trial. Human Fertility 2017;20(1):37‐42. - PubMed
Hendawy 2011 {published data only}
    1. Hendawy SF, Samaha HE, Elkholy MF. Letrozole versus clomiphene citrate for induction of ovulation in patients with polycystic ovarian syndrome undergoing intratuerine insemination. Clinical Medicine Insights: Reproductive Health 2011;5:11‐6. - PMC - PubMed
Ibrahim 2017 {published data only}
    1. Ibrahim MH, Tawfic M, Hassan MM, Sedky OH. Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate. Middle East Fertility Society Journal 2017;22(4):251‐4.
Kamath 2010 {published and unpublished data}
    1. Kamath MS, Aleyamma TK, Chandy A, George K. Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double‐blind, placebo‐controlled trial. Fertility and Sterility 2010;94(7):2857‐9. - PubMed
Kar 2012 {published data only}
    1. Kar S. Clomiphene citrate or letrozole as first‐line ovulation induction drug in infertile PCOS women: a prospective randomized trial. Journal of Human Reproductive Sciences 2012;5(3):262‐5. [DOI: 10.4103/0974-1208.106338] - DOI - PMC - PubMed
Legro 2014 {published and unpublished data}
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Liu 2015 {published data only}
    1. Liu W, Dong S, Li Y, Shi L, Zhou W, Liu Y, et al. Randomized controlled trial comparing letrozole with laparoscopic ovarian drilling in women with clomiphene citrate‐resistant polycstic ovary syndrome. Experimental and Therapeutic Medicine 2015;10(4):1297‐302. - PMC - PubMed
Liu 2017 {published data only}
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Moussa 2016 {published data only}
    1. Moussa AA, Torky H, Dief O, Elwahed AA, Senna HA. The effect of clomiphene citrate versus tamoxifen versus letrozol on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries. Acta Medica International 2016;3(2):88‐92.
Nazik 2012 {published data only}
    1. Nazik H, Kumtepe Y. Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction for women with polycystic ovarian syndrome. HealthMED Journal 2012;6(3):879‐83.
Ramezanzadeh 2011 {published data only}
    1. Ramezanzadeh F, Nasiri R, Yazdi MS, Baghrei M. A randomized trial of ovulation induction with two different doses of Letrozole in women with PCOS. Archives of Gynecology and Obstetrics 2011;284(4):1029‐34. - PubMed
Ray 2012 {published data only}
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Roy 2012 {published data only}
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Selim 2012 {published data only}
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Seyedoshohadaei 2016 {published data only}
    1. Seyedoshohadaei F, Tangestani L, Zandvakili F, Rashadmanesh N. Comparison of the effect of clomiphene‐ estradiol valerate vs letrozole on endometrial thickness, abortion and pregnancy rate in infertile women with polycystic ovarian syndrome. Journal of Clinical and Diagnostic Research 2016;10(8):QC10‐3. - PMC - PubMed
Sharief 2015 {published data only}
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Sh‐El‐Arab Elsedeek 2011 {published data only}
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Sohrabvand 2006 {published data only}
    1. Sohrabvand F, Ansari SH, Bagheri M. Efficacy of combined metformin‐letrozole in comparison with metformin‐clomiphene citrate in clomiphene‐resistant infertile women with polycystic ovarian disease. Human Reproduction 2006;21(6):1432‐5. - PubMed
Wu 2016 {published data only}
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Zarei 2015 {published data only}
    1. Zarei A, Shabahrami TB, Dadras N. Effects of letrozole in prevention of premature luteinizing hormone (LH) surge in infertile women with clomiphene citrate resistant polycystic ovary syndrome (PCOS) undergoing intrauterine insemination. Galen Medical Journal 2015;4(3):104‐11.
Zeinalzadeh 2010 {published data only}
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References to studies excluded from this review

Akbari 2012 {published data only}
    1. Akbari S, Ayazi Roozbahani M, Ayazi Roozbahani F. Comparing of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemation cycles. Iranian Journal of Reproductive Medicine 2012;10(1):29‐32. - PMC - PubMed
Al‐Hussaini 2014 {published data only}
    1. Al‐Hussaini T, Mohammed S, Abdellah M, Abdel Aleem A. Letrozole versus combined clomiphene citrate and metformin as a first line treatment in women with polycystic ovarian syndrome. British Journal of Obstetrics and Gynaecology 2014;E‐Posters:EP6.13.
Al‐Shaikh 2017 {published data only}
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Angel 2014 {published data only}
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Anwary 2012 {published data only}
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Azargoon 2012 {published data only}
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Azmoodeh 2015 {published data only}
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Badawy 2009c {published data only}
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Baruah 2009 {published data only}
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El Bigawy 2008 {published data only}
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Foroozanfard 2013 {published data only}
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Khanna 2013 {published data only}
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Li 2016 {published data only}
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Nahid 2012 {published data only}
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NCT00610077 {published data only}
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NCT01315912 {published data only}
    1. NCT01315912. Dosage optimization for letrozole treatment. clinicaltrials.gov/ct2/show/NCT01315912 (first posted 16 March 2011). [NCT01315912]
NCT01431352 {published data only}
    1. NCT01431352. Letrozole versus chinese herbal medicine on polycystic ovary syndrome (PCOS). clinicaltrials.gov/ct2/show/NCT01431352 (verified November 2013). [NCT01431352]
NCT01577017 {published data only}
    1. NCT01577017. The effects of letrozole and clomiphene citrate for induction of ovulation in polycystic ovarian syndrome (PCOS). clinicaltrials.gov/ct2/show/NCT01577017 (first posted 13 April 2012).
NCT01679574 {published data only}
    1. NCT01679574. Letrozole or combined clomiphene citrate metformin as a first line treatment in women with polycystic ovary syndrome. clinicaltrials.gov/ct2/show/NCT01679574 (first posted 96 September 2012). [NCT01679574]
NCT01793038 {published data only}
    1. NCT01793038. Clomiphene citrate plus uFSH versus aromatase inhibitor plus uFSH in clomiphene resistant infertile PCOS women. clinicaltrials.gov/ct2/show/NCT01793038 (verified March 2013). [NCT01793038]
Ozdemir 2013 {published data only}
    1. Ozdemir U, Ozaksit G, Cakir Gungor AN, Aydogan M. Letrozole usage adjuvant to gonadotropins for ovulation induction for patients with clomiphene citrate failure. Archives of Gynecology and Obstetrics 2013;288(2):445‐8. - PubMed
Pakrashi 2014 {published data only}
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Palihawadana 2015 {published data only}
    1. Palihawadana TS, Wijesinghe PS, Seneviratne HR. A comparison of endometrial thickness following augmentation of ovulation with clomifene citrate or letrozole in women with ovulatory infertility. Ceylon Medical Journal 2015;60(2):48‐52. - PubMed
Pourali 2017 {published data only}
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Sarvi 2010 {published data only}
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Sharma 2010 {published data only}
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Xi 2015 {published data only}
    1. Xi W, Liu S, Mao H, Yang Y, Xue X, Lu X. Use of letrozole and clomiphene citrate combined with gonadotropins in clomiphene‐resistant infertile women with polycystic ovary syndrome: a prospective study. Drug Design, Development and Therapy 2015;9:6001‐8. - PMC - PubMed
Yang 2008 {published data only}
    1. Yang M, Quan S, Li H, Song Y, Xing F. Effect of two different doses of letrozole in promoting ovulation in infertile women with polycystic ovarian syndrome. Journal of Southern Medical University 2008;28(11):2060‐2. - PubMed
Yun 2015 {published data only}
    1. Yun BH, Chon SJ, Park JH, Seo SK, Cho S, Choi YS, et al. Minimal stimulation using gonadotropin combined with clomiphene citrate or letrozole for intrauterine insemination. Yonsei Medical Journal 2015;56:490‐6. - PMC - PubMed

References to studies awaiting assessment

Aygen 2007 {published data only}
    1. Aygen EM, Guzel Z, Ozgun T, Atakul T, Sahin Y. The use of letrozole for ovulation induction in infertile women with polycystic ovarian syndrome. Erciyes Tip Dergisi 2007;29:195‐200.
Lorzadeh 2011 {published data only}
    1. Lorzadeh N, Kazemirad S, Mohammadi Z. Comparison of effects letrozole and clomiphene citrate for ovulation induction in women with polycystic ovary syndrome. Iranian Journal of Obstetrics, Gynecology and Infertility 2011;14(3):13‐9.
NCT02551367 {published data only}
    1. NCT02551367. Letrozole versus clomiphene citrate for ovulation induction in women with polycystic ovary syndrome ( PCOS). clinicaltrials.gov/ct2/show/NCT02551367 (verified September 2015). [NCT02551367]
Safdarian 2012 {published data only}
    1. Safdarian L, Dibazar NS, Ahmadzadeh A, Yekta BG. Comparing two ovulation induction methods by brachial artery ultrasonography in infertile women with polycystic ovary syndrome. Tehran University Medical Journal 2012;70:242‐9.
Shirin 2009 {published data only}
    1. Shirin G, Mehran A, Maryam B, Maryam G, Masoumeh M. Comparing the effects of clomiphene‐HMG and letrozole‐HMG on ovulation Induction in infertile women. Journal of Reproduction and Infertility 2009;10(2):109‐14.

References to ongoing studies

NCT03009838 {published data only}
    1. NCT03009838. Letrozole versus laparoscopic ovarian drilling in polycystic ovary syndrome. clinicaltrials.gov/ct2/show/NCT03009838 (first posted 04 January 2017).

Additional references

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