Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome

Sebastian Franik; Quang-Khoi Le; Jan AM Kremer; Ludwig Kiesel; Cindy Farquhar

doi:10.1002/14651858.CD010287.pub4

. 2022 Sep 27;2022(9):CD010287. doi: 10.1002/14651858.CD010287.pub4

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome

Sebastian Franik ^1,^✉, Quang-Khoi Le ¹, Jan AM Kremer ², Ludwig Kiesel ¹, Cindy Farquhar ³

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC9514207 PMID: 36165742

Abstract

Background

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 5% to 20% of women worldwide and often leads to anovulatory infertility. 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), a selective oestrogen receptor modulator (SERM).

Objectives

To evaluate the effectiveness and safety of AIs (letrozole) (with or without adjuncts) compared to SERMs (with or without adjuncts) for infertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination.

Search methods

We searched the following sources, from their inception to 4 November 2021, to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO. We also checked reference lists of relevant trials, searched the trial registers and contacted experts in the field for any additional trials. 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 using RoB 1. We pooled trials 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 rate and OHSS rate. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy rates. We assessed the certainty of the evidence for each comparison using GRADE methods.

Main results

This is a substantive update of a previous review; of six previously included trials, we excluded four from this update and moved two to 'awaiting classification' due to concerns about validity of trial data. We included five additional trials for this update that now includes a total of 41 RCTs (6522 women). The AI, letrozole, was used in all trials.

Letrozole compared to SERMs with or without adjuncts followed by timed intercourse

Live birth rates were higher with letrozole (with or without adjuncts) compared to SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40 to 2.11; I² = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high‐certainty evidence). This suggests that in women with a 20% chance of live birth using SERMs, the live birth rate in women using letrozole with or without adjuncts would be 27% to 35%. There is high‐certainty evidence that OHSS rates are similar with letrozole or SERMs (0.5% in both arms: risk difference (RD) −0.00, 95% CI −0.01 to 0.01; I² = 0%; 10 trials, 1848 participants; high‐certainty evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.69, 95% CI 1.45 to 1.98; I² = 0%; NNTB = 10; 23 trials, 3321 participants; high‐certainty evidence). This suggests that in women with a 24% chance of clinical pregnancy using SERMs, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 32% to 39%. There is little or no difference between treatment groups in the rate of miscarriage per pregnancy (25% with SERMs versus 24% with letrozole: OR 0.94, 95% CI 0.66 to 1.32; I² = 0%; 15 trials, 736 participants; high‐certainty evidence) and multiple pregnancy rate (2.2% with SERMs versus 1.6% with letrozole: OR 0.74, 95% CI 0.42 to 1.32; I² = 0%; 14 trials, 2247 participants; high‐certainty evidence). However, a funnel plot showed mild asymmetry, indicating that some trials in favour of SERMs might be missing.

Letrozole compared to laparoscopic ovarian drilling (LOD)

One trial reported very low‐certainty evidence that live birth rates may be higher with letrozole compared to LOD (OR 2.07, 95% CI 0.99 to 4.32; 1 trial, 141 participants; very low‐certainty evidence). This suggests that in women with a 22% chance of live birth using LOD with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 24% to 47%. No trial reported OHSS rates. Due to the low‐certainty evidence we are uncertain if letrozole improves pregnancy rates compared to LOD (OR 1.47, 95% CI 0.95 to 2.28; I² = 0%; 3 trials, 367 participants; low‐certainty evidence). This suggests that in women with a 29% chance of clinical pregnancy using LOD with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 28% to 45%. There seems to be no evidence of a difference in miscarriage rates per pregnancy comparing letrozole to LOD (OR 0.65, 95% CI 0.22 to 1.92; I² = 0%; 3 trials, 122 participants; low‐certainty evidence). This also applies to multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 1 trial, 141 participants; very low‐certainty evidence).

Authors' conclusions

Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high‐certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high‐certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

Keywords: Female; Humans; Pregnancy; Abortion, Spontaneous; Abortion, Spontaneous/epidemiology; Anovulation; Anovulation/complications; Anovulation/drug therapy; Aromatase Inhibitors; Aromatase Inhibitors/adverse effects; Clomiphene; Clomiphene/adverse effects; Fertility Agents, Female; Fertility Agents, Female/adverse effects; Infertility, Female; Infertility, Female/drug therapy; Infertility, Female/etiology; Letrozole; Letrozole/therapeutic use; Live Birth; Live Birth/epidemiology; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Ovulation Induction/methods; Polycystic Ovary Syndrome; Polycystic Ovary Syndrome/drug therapy; Pregnancy Rate; Selective Estrogen Receptor Modulators; Selective Estrogen Receptor Modulators/therapeutic use

Plain language summary

Aromatase inhibitors for infertility treatment in women with polycystic ovary syndrome

Review question: Cochrane authors examined the evidence about aromatase inhibitors for infertile women with polycystic ovary syndrome (PCOS).

Background: PCOS is the most common cause of infrequent or absent menstrual periods, and affects about 5% to 20% of women worldwide. It often causes anovulatory infertility (infertility related to inability to ovulate). Aromatase inhibitors (AIs) are used to make ovulation happen. Since about 2001 clinical trials have reached differing conclusions as to whether the AI, letrozole, is at least as effective for treating infertility as the most commonly used treatment, clomiphene citrate.

Trial characteristics: The review includes clinical trials where participants were randomly assigned to the intervention (letrozole) or to the comparison group (i.e. clomiphene citrate). These trials are called randomised controlled trials. Our review includes 41 randomised controlled trials with 6522 women. In all trials, the aromatase inhibitor used was letrozole. Comparators included clomiphene citrate, which was used in 26 of the randomised controlled trials, and laparoscopic ovarian drilling (a surgical technique used to trigger ovulation), which was used in four randomised controlled trials. Several trials included other treatments.

Key results: Letrozole appears to improve live birth rates and pregnancy rates compared to clomiphene citrate when used to cause ovulation, followed by timed intercourse. There appeared to be no difference for miscarriage rate or multiple pregnancy rate. Ovarian hyperstimulation syndrome, a serious adverse event of hormonal stimulation, was a very rare event and in most trials it did not occur. The certainty of the evidence for all these outcomes was high and seems to be reliable.

There appeared to be very low‐certainty evidence for higher live birth rates with letrozole compared to laparoscopic ovarian drilling, although there was only one relevant trial. The result for clinical pregnancy rate was uncertain. We are uncertain if letrozole decreases miscarriage and multiple pregnancy rates compared to laparoscopic ovarian drilling. No trials reported on ovarian hyperstimulation syndrome. The evidence is current to November 2021.

Certainty of the evidence: The overall certainty of the evidence ranged from very low to high. We downgraded evidence when we had small trials with few women or when methods were unclear.

Summary of findings

Summary of findings 1. Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome.

Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome
Patient or population: infertile women with polycystic ovary syndrome Setting: (fertility) clinics or outpatient settings Intervention: letrozole with or without adjuncts followed by timed intercourse Comparison: SERMs (clomiphene citrate) with or without adjuncts followed by timed intercourse
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with SERMs with or without adjuncts	Risk with letrozole with or without adjuncts	Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
Live birth rate	204 per 1000	307 per 1000 (265 to 352)	OR 1.72 (1.40 to 2.11)	2060 (11 RCTs)	⊕⊕⊕⊕ High
Ovarian hyperstimulation syndrome rate	7 per 1000	5 per 1000 (5 to 5)	RD −0.00 (−0.01 to 0.01)	1848 (10 RCTs)	⊕⊕⊕⊕ High
Clinical pregnancy rate	242 per 1000	350 per 1000 (316 to 387)	OR 1.69 (1.45 to 1.98)	3321 (23 RCTs)	⊕⊕⊕⊕ High
Miscarriage rate per pregnancy	252 per 1000	240 per 1000 (182 to 307)	OR 0.94 (0.66 to 1.32)	736 (15 RCTs)	⊕⊕⊕⊕ High
Multiple pregnancy rate	22 per 1000	16 per 1000 (9 to 28)	OR 0.74 (0.42 to 1.32)	2247 (14 RCTs)	⊕⊕⊕⊕ High
*The risk in the intervention group (and its 95% confidence interval) is based on the mean risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RD: risk difference; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Letrozole compared to laparoscopic ovarian drilling compared to placebo for infertile women with polycystic ovary syndrome
Patient or population: infertile women with polycystic ovary syndrome Setting: (fertility) clinics or outpatient settings Intervention: letrozole with or without adjuncts followed by timed intercourse Comparison: laparoscopic ovarian drilling (LOD) followed by timed intercourse
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with LOD	Risk with letrozole	Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
Live birth rate	229 per 1000	380 per 1000 (227 to 561)	OR 2.07 (0.99 to 4.32)	141 (1 RCT)	⊕⊝⊝⊝ Very Low^a,b,c
Ovarian hyperstimulation syndrome rate	No trials reported on this outcome
Clinical pregnancy rate	290 per 1000	375 per 1000 (279 to 482)	OR 1.47 (0.95 to 2.28)	376 (3 RCTs)	⊕⊕⊝⊝ Low^a,b
Miscarriage rate per pregnancy	151 per 1000	104 per 1000 (38 to 254)	OR 0.65 (0.22 to 1.92)	122 (3 RCTs)	⊕⊕⊝⊝ Low^a,b
Multiple pregnancy rate	0 per 1000	0 per 1000 (0 to 0)	OR 3.00 (0.12 to 74.90)	141 (1 RCT)	⊕⊝⊝⊝ Very Low^a,b,c
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
4 November 2021	New search has been performed	The review has been updated. We conducted a new search in November 2021. We include 5 new studies (Ashfaq 2018; Behnoud 2019; Najafi 2020; Salazar‐Ortiz 2016; Shi 2019). We added 6 new studies to awaiting classification (NCT03664050; NCT02703649; Jindal 2019; ,Ghoneim 2020; Kamel 2019; Rezk 2018). We added 5 studies as ongoing (CTRI/2018/04/013343; Cutler 2018; Huang 2020; IRCT2016030926962N2; Priest 2019). 4 studies that were included in the previous version have been excluded due to concerns about validity of the study data (study retraction or expression of concern) (Abu Hashim 2010; Badawy 2008; Badawy 2009a; Badawy 2009b). 2 studies that were included in the previous version have been moved to awaiting classification due to concerns about validity of the study data (Abdellah 2011; Abu Hashim 2010a).
4 November 2021	New citation required but conclusions have not changed	The addition of new studies has not led to a change in conclusions.

Date	Event	Description
6 November 2017	New search has been performed	The review has been updated. We conducted a new search on 6 November 2017. We included 16 new studies in the 2018 update ( Amer 2017; Chen 2016; El‐Gharib 2015; El‐Khayat 2016; Ghahiri 2016; Ghomian 2015; Hassan 2017; Hendawy 2011; Ibrahim 2017; Liu 2015; Liu 2017; Moussa 2016; Seyedoshohadaei 2016; Sharief 2015; Wu 2016; Zarei 2015). We added one study as ongoing (NCT03009838).
6 November 2017	New citation required but conclusions have not changed	There is no change to the conclusions of this review.
24 September 2014	Amended	This review has been amended. A new search was conducted on 18 September 2014 and new ongoing studies added.
17 July 2014	Amended	Addition of new data made available for Legro 2014. New secondary outcome has been added: miscarriage rate per pregnancy
26 February 2014	Amended	Correction of search date in Abstract and Methods sections

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Live birth rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.2 Ovarian hyperstimulation syndrome rate	2	167	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.05, 0.05]
1.3 Clinical pregnancy rate	2	167	Odds Ratio (M‐H, Fixed, 95% CI)	2.88 [1.08, 7.66]
1.4 Miscarriage rate per woman	2	167	Odds Ratio (M‐H, Fixed, 95% CI)	1.60 [0.26, 9.89]
1.5 Miscarriage rate per pregnancy	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.6 Multiple pregnancy rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Live birth rate	11	2060	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [1.40, 2.11]
2.1.1 AIs versus clomiphene citrate	8	1646	Odds Ratio (M‐H, Fixed, 95% CI)	1.79 [1.42, 2.25]
2.1.2 Aromatase inhibitor + metformin compared to clomiphene + metformin	2	194	Odds Ratio (M‐H, Fixed, 95% CI)	1.70 [0.89, 3.23]
2.1.3 Aromatase inhibitor + FSH compared to clomiphene + FSH	1	120	Odds Ratio (M‐H, Fixed, 95% CI)	1.18 [0.53, 2.61]
2.1.4 AIs versus clomiphene + estradiol valerate	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.54, 4.06]
2.2 Live birth rate by BMI	9	1880	Odds Ratio (M‐H, Fixed, 95% CI)	1.74 [1.41, 2.15]
2.2.1 BMI > 25	6	1428	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [1.44, 2.35]
2.2.2 BMI < 25	3	452	Odds Ratio (M‐H, Fixed, 95% CI)	1.49 [0.98, 2.25]
2.3 Live birth rate by first‐ or second‐line treatment	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.3.1 No previous ovulation induction	4	1089	Odds Ratio (M‐H, Fixed, 95% CI)	1.61 [1.22, 2.14]
2.3.2 CC‐resistant women	4	344	Odds Ratio (M‐H, Fixed, 95% CI)	1.78 [1.08, 2.93]
2.3.3 Unclear or mixed study cohort	3	627	Odds Ratio (M‐H, Fixed, 95% CI)	1.88 [1.31, 2.69]
2.4 Impact of allocation bias for live birth rate	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.4.1 Unclear risk of allocation	8	1031	Odds Ratio (M‐H, Fixed, 95% CI)	1.90 [1.42, 2.54]
2.4.2 Low risk of allocation	3	1029	Odds Ratio (M‐H, Fixed, 95% CI)	1.57 [1.18, 2.08]
2.5 Impact of detection bias for live birth rate	11	2060	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [1.40, 2.11]
2.5.1 High risk of detection	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	2.60 [0.83, 8.13]
2.5.2 Low risk of detection	5	1189	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [1.26, 2.16]
2.5.3 Unclear risk of detection	5	807	Odds Ratio (M‐H, Fixed, 95% CI)	1.76 [1.27, 2.44]
2.6 Impact of attrition bias for live birth rate	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.6.1 Unclear risk of attrition	1	147	Odds Ratio (M‐H, Fixed, 95% CI)	2.04 [0.93, 4.50]
2.6.2 Low risk of attrition	9	1645	Odds Ratio (M‐H, Fixed, 95% CI)	1.75 [1.39, 2.19]
2.6.3 High risk of attrition	1	268	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [0.85, 2.50]
2.7 Ovarian hyperstimulation syndrome rate	10	1848	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.7.1 AIs versus clomiphene citrate	8	1572	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.00]
2.7.2 Aromatase inhibitor + hMG versus clomiphene + hMG	2	276	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.04, 0.04]
2.8 Ovarian hyperstimulation syndrome rate by BMI	9		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
2.8.1 BMI > 25	4	1163	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.01, 0.00]
2.8.2 BMI < 25	5	605	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2.9 Clinical pregnancy rate	23	3321	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [1.45, 1.98]
2.9.1 Aromatase inhibitor versus clomiphene citrate	17	2516	Odds Ratio (M‐H, Fixed, 95% CI)	1.70 [1.42, 2.03]
2.9.2 Aromatase inhibitor + metformin versus clomiphene + metformin	3	294	Odds Ratio (M‐H, Fixed, 95% CI)	1.86 [1.05, 3.29]
2.9.3 Aromatase inhibitor + hMG versus clomiphene + hMG	2	276	Odds Ratio (M‐H, Fixed, 95% CI)	1.37 [0.82, 2.27]
2.9.4 AIs versus tamoxifen	2	135	Odds Ratio (M‐H, Fixed, 95% CI)	1.58 [0.64, 3.90]
2.9.5 AIs versus clomiphene + estradiol valerate	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	2.47 [0.94, 6.46]
2.10 Impact of allocation bias for clinical pregnancy rate	21		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.10.1 Unclear risk of allocation	17	1931	Odds Ratio (M‐H, Fixed, 95% CI)	1.74 [1.41, 2.14]
2.10.2 Low risk of allocation	4	580	Odds Ratio (M‐H, Fixed, 95% CI)	1.56 [1.10, 2.21]
2.11 Miscarriage rate per woman	15	2422	Odds Ratio (M‐H, Fixed, 95% CI)	1.37 [1.01, 1.87]
2.11.1 AIs versus clomiphene citrate	10	1752	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.98, 1.99]
2.11.2 Aromatase inhibitor + metformin versus clomiphene + metformin	3	294	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.52, 2.82]
2.11.3 Aromatase inhibitor + hMG versus clomiphene + hMG	2	276	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.31, 2.27]
2.11.4 AIs versus clomiphene + estradiol valerate	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	12.21 [0.66, 226.97]
2.12 Miscarriage rate per pregnancy	15	736	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.66, 1.32]
2.12.1 AIs versus clomiphene citrate	10	529	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.63, 1.42]
2.12.2 Aromatase inhibitor + metformin versus clomiphene + metformin	3	79	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.32, 2.02]
2.12.3 Aromatase inhibitor + hMG versus clomiphene + hMG	2	104	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.23, 1.96]
2.12.4 AIs versus clomiphene + estradiol valerate	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	8.13 [0.39, 167.90]
2.13 Multiple pregnancy rate	14	2247	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.42, 1.32]
2.13.1 Aromatase inhibitor versus clomiphene citrate	12	1971	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.35, 1.34]
2.13.2 Aromatase inhibitor + hMG versus clomiphene + hMG	2	276	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.29, 3.05]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Ovarian hyperstimulation syndrome rate	2	1494	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.00]
3.1.1 AI versus clomiphene	1	107	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.07, 0.03]
3.1.2 AI versus clomiphene + rFSH and rFSH only	1	1387	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.00]
3.2 Clinical pregnancy rate	3	1597	Odds Ratio (M‐H, Fixed, 95% CI)	1.71 [1.30, 2.25]
3.2.1 AI versus clomiphene	2	210	Odds Ratio (M‐H, Fixed, 95% CI)	2.09 [0.97, 4.53]
3.2.2 AI versus clomiphene + rFSH and rFSH only	1	1387	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [1.23, 2.22]
3.3 Miscarriage rate per woman	2	1490	Odds Ratio (M‐H, Fixed, 95% CI)	1.22 [0.62, 2.40]
3.3.1 AI versus clomiphene	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 8.06]
3.3.2 AI versus clomiphene + rFSH and rFSH only	1	1387	Odds Ratio (M‐H, Fixed, 95% CI)	1.32 [0.66, 2.65]
3.4 Miscarriage rate per pregnancy	2	260	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.37, 1.57]
3.4.1 AI versus clomiphene	1	15	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.00, 3.09]
3.4.2 AI versus clomiphene + rFSH and rFSH only	1	245	Odds Ratio (M‐H, Fixed, 95% CI)	0.85 [0.40, 1.79]
3.5 Multiple pregnancy rate	3	1597	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.49, 2.13]
3.5.1 AI versus clomiphene	2	210	Odds Ratio (M‐H, Fixed, 95% CI)	3.48 [0.14, 87.49]
3.5.2 AI versus clomiphene + rFSH and rFSH only	1	1387	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.44, 2.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Live birth rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.2 Clinical pregnancy rate	3	367	Odds Ratio (M‐H, Fixed, 95% CI)	1.47 [0.95, 2.28]
4.2.1 AI versus LOD	2	221	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [0.96, 2.97]
4.2.2 AI + metformin versus LOD	1	146	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.60, 2.39]
4.3 Miscarriage rate per woman	3	367	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.31, 2.44]
4.3.1 AI versus LOD	2	221	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.14, 2.50]
4.3.2 AI + metformin versus LOD	1	146	Odds Ratio (M‐H, Fixed, 95% CI)	1.35 [0.29, 6.27]
4.4 Miscarriage rate per pregnancy	3	122	Odds Ratio (M‐H, Fixed, 95% CI)	0.65 [0.22, 1.92]
4.4.1 AI versus LOD	2	73	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.72]
4.4.2 AI + metformin versus LOD	1	49	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.24, 6.09]
4.5 Multiple pregnancy rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Live birth	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.2 Ovarian hyperstimulation syndrome rate	2	236	Risk Difference (M‐H, Fixed, 95% CI)	‐0.03 [‐0.08, 0.01]
5.3 Clinical pregnancy rate	2	236	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.46, 1.43]
5.4 Miscarriage rate per woman	2	236	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.19, 1.92]
5.5 Miscarriage rate per pregnancy	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.6 Multiple pregnancy rate	2	236	Odds Ratio (M‐H, Fixed, 95% CI)	0.22 [0.04, 1.32]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Clinical pregnancy rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.2 Multiple pregnancy rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	Statistical method	Effect size
7.1 Live birth rate	1	Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.2 Clinical pregnancy rate	1	Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.3 Miscarriage rate per woman	1	Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.4 Miscarriage rate per pregnancy	1	Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.5 Multiple pregnancy rate	1	Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

*Study characteristics*
Methods	Randomised double‐blind clinical trial Duration and location of the trial: not stated
Participants	Inclusion criteria: non‐fertile clomiphene‐resistant women with PCOS Exclusion criteria: tubal, peritoneal and uterine causes of infertility were excluded by laparoscopic hysterosalpingogram or by ultrasonography. Specific endocrine abnormalities and male‐factor causes for infertility were also excluded. Participants had to end clomiphene treatment at least 2 months before enrolment. Number of centres: quote: "The study was done in the Baghdad teaching hospital/ Medical city which is a tertiary ref. hospital affiliated with Baghdad Med college/ University of Baghdad." (Email) Number of women randomised: 22 in the letrozole group and 18 in the anastrozole group Number of women analysed: 22 in the letrozole group and 18 in the anastrozole group Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 28.4 ± 5.18, group B anastrozole: 25.56 ± 6.26 BMI (kg/m²): group A letrozole: 29.95 ± 3.73, group B anastrozole: 27.90 ± 5.29 Duration of infertility (y): group A letrozole: 3.95 ± 2.70, group B anastrozole: 4.50 ± 3.61 Country: Iraq
Interventions	Group A: letrozole 2.5 mg/day orally given for 5 days during cycle days 3‐7 Group B: anastrozole 1 mg/day orally given for 5 days during cycle days 3‐7 Treatment was continued for 3 months. When ovulation or pregnancy did not occur, the same treatment protocol was used with the doubling of the first dose for a maximum of 2 treatment cycles.
Outcomes	Primary outcomes: ovulation rate/cycle, endometrial thickness (mm) measured on day of hCG administration Secondary outcomes: multiple pregnancy rate, pregnancy rate/cycle, E2 (pmoL/L), progesterone (nmoL/L), LH (U/l), number and size of follicles, pulsatility index, day of hCG administration
Notes	Ethical approval: quote: "Ethical approval was obtained from the Iraqi Board for medical specialization/Scientific committee" (email contact) Informed consent: quote: "written consent was obtained from all patients" (email contact) Source of funding: quote: "The study was partially funded by the Iraqi Board for medical specialization as well as the Drug Scientific Office of the Iraqi Ministry of Health." Power calculation: not reported We had email contact with Dr Al‐Omari, but there was no further information available about the outcomes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Actually, we just put all envelopes in a box, mixing them then the patient herself selected one." (email with Dr Al‐Omari)
Allocation concealment (selection bias)	Unclear risk	Quote: "My associate informed me that for randomisation we distributed blank envelops containing the medications at our Gyn.clinic on twice weekly basis." (email with Dr Al‐Omari)
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants were not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	It is not plausible that outcome assessors were blinded if participants were not
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts reported
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised double‐blind controlled clinical trial Duration and location of the trial: quote: "This study was conducted at the Fertility Unit, Derby Teaching Hospitals NHS Foundation Trust between April 2007 and June 2014.“
Participants	Inclusion criteria: quote: "eligible participants were women aged 18–39 years with BMI ≤ 35 kg/m2, anovulatory infertility, and a diagnosis of PCOS based on Rotterdam consensus (two of three criteria: oligo‐/anovulation, hyperandrogaenemia and sonographic appearance of polycystic ovaries) (Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group, 2004). Diagnosis of oligo‐/anovulation was based on a menstrual pattern of oligo‐/amenorrhoea (cycle > 35 days) and/or a low mid‐luteal serum progesterone concentration. Hyperandrogenaemia was diagnosed either clinically (acne/hirsutism) or biochemically (testosterone ≥ 2.5 nmoL/L or free androgen index [FAI] ≥ 5). Ultrasound criteria included ≥ 12 follicles (2 – 9 mm) and/or an ovarian volume of > 10 ml (Jonard et al., 2003). All participants had proven patency of at least one fallopian tube and normal semen analysis of their male partners (WHO, 1999)." Exclusion criteria: quote: "We excluded patients who have received OI within 6 months and those with uncontrolled thyroid disease or hyperprolactinaemia. Patients with marked hyperandrogaenemia were screened for adult onset congenital adrenal hyperplasia (by measuring serum 17‐ α ‐hydroxyl‐progesterone concentration) and Cushing syndrome (by measuring urinary free cortisol)." Number of women randomised: 159 women were randomised in total; 79 to CC, 80 to letrozole Number of women analysed: all women randomised were also analysed in the ITT analysis. Number of withdrawals/exclusions/loss to follow‐up and reasons: 3 women in the CC group discontinued treatment due to failing to attend; also 3 women discontinued treatment in the letrozole arm (1 due to social reasons, 1 failed to attend, 1 withdrew consent). Number of centres: this was a single‐centre, 2‐arm double‐blind RCT Age (y): letrozole: 28.3 (4.4) versus CC: 28.1 (4.2) BMI (kg/m²): letrozole: 27.5 (23.4‐32.2) versus CC: 27.7 (23.0‐31.0) Duration of infertility (y): 1.5 (1.0‐2.0) for both groups Country: UK
Interventions	Group A: letrozole was prescribed (by the senior investigator, SA) orally daily for 5 days starting on Days 2 – 4 of a menstrual period or a progestogen‐induced bleed (medroxy‐progesterone acetate 10 mg twice daily for 5 days). The starting dose was 1 tablet/day (letrozole 2.5 mg) and if ovulation was not achieved, the dose would be doubled in the second cycle. Group B: CC was prescribed daily for 5 days starting on days 2–4 of a menstrual period or a progestogen‐induced bleed (medroxy‐progesterone acetate 10 mg twice daily for 5 days). The starting dose was 1 tablet/day (50 mg) and if ovulation was not achieved, the dose would be doubled in the second cycle. Participants who failed to ovulate on the maximum dose (2 tablets) or to conceive after 6 ovulatory cycles were crossed over to the other drug (after a 6‐week washout period) following the same procedures as with the first drug.
Outcomes	Primary outcomes: clinical pregnancy (diagnosed by ultrasonographic visualisation of a gestational sac) rate per participant on primary treatment (before the cross‐over). Secondary outcomes: ovulation, live birth, pregnancy by ovulating participant, pregnancy by strata, mono‐ovulation, endometrial development (thickness and grades), pregnancy outcome and pregnancy complications. Other outcomes included pregnancy and live birth rates on secondary and overall (primary and secondary) treatments.
Notes	Ethical approval: the trial was approved by West Midlands Research Ethics Committee (Reference: 07/MRE07/5) and by the Medicines and Healthcare Products Regulatory Agency (MHRA). Informed consent: all participants gave written informed consent and the trial was monitored by the sponsor. Source of funding: sponsored by the University of Nottingham Power calculation: quote: "to detect a clinically significant difference of 20% between the previously reported pregnancy rate of CC (~35%) and letrozole with a two‐sided 5% significance level and power of 80%, a sample size of 212 participants (106 per arm) was required (Dickey and Holtkamp, 1996; Kousta et al., 1997; Imani et al., 2002)."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "An independent pharmacist randomly allocated participants to letrozole or CC, in 1:1 ratio according to a randomisation list created by the trial statistician using NQuery Advisor v6.0 software. Randomization was stratified by patients’ BMI (non‐obese < 30 kg/m² and obese 30 – 35 kg/m²) using mixed block sizes."
Allocation concealment (selection bias)	Low risk	Quote: "An independent pharmacist randomly allocated participants to letrozole or CC, in 1:1 ratio."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Investigators, patients, outcome assessors and the statistician were blinded to the allocation of participants."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Investigators, patients, outcome assessors and the statistician were blinded to the allocation of participants."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Intention‐to‐treat (ITT) analysis included all randomised subjects, regardless of whether or not they received the study drug. Per protocol (PP) analysis included all randomised subjects who received the study drug and were not lost to follow‐up. Participants who were lost to follow‐up were assumed neither to be pregnant nor to have given LB in the ITT analysis."
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised controlled clinical trial Duration and location of the trial: conducted in the Department of Obstetrics & Gynecology Unit‐I, Services Hospital, Lahore from January to December 2014
Participants	Inclusion criteria: age > 18 years but < 30 years; diagnosed PCOS assessed by presence of any two of the following finding (peripherally arranged 2‐9 follicles of 8 mm to 10 mm), increase LH and FCH ratio > 2; History of oligomenorrhea i.e. < 6 cycles/year; serum testosterone > 0.65 ng/mL Exclusion criteria: endocrine disorders like thyroid disorders assessed by TSH (0.5 IU/L to 5IU/L), T3 (4.3 pmol/L to 8.6 pmol/L) and T4 (9 Pmol/L to 22 Pmol/L), hyperprolactinemia assessed by serum prolectin levels (> 400 miu/L); other causes of anovulatory infertility (kalmann's syndrome, stress, exercise, anorexia nervosa) Number of centres: single‐centre trial Number of women randomised: 40 in the letrozole group and 40 in the CC group Number of women analysed: 40 in the letrozole group and 40 in the CC group Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): mean age overall group: 23.78 ± 2.41 years Mean BMI (kg/m²): BMI 23.58 ± 2.89 kg/m² Mean duration of infertility (y): 2.45 ± 0.62 years Country: Pakistan
Interventions	Group A: 40 women given letrozole, 5 mg for 5 days of menstrual cycle Group B: 40 women given CC, 100 mg for 5 days of menstrual cycle
Outcomes	Primary outcomes: ovulation rate Secondary outcomes: none
Notes	Ethical approval: not stated Informed consent: quote: "Informed consent was taken to include their data in study." Source of funding: not stated Power calculation: quote: "Eighty cases (40 in each group) is calculated using 95% confidence interval. 80% power of test with an expected percentage of efficacies of letrozole group is 63.3% and 29.4% in clomiphene citrate group. Non‐probability, purposive sampling technique was used."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported in detail, quote "patients were divided in two groups randomly by lottery method".
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants randomised were also analysed
Selective reporting (reporting bias)	Unclear risk	Protocol of the trial was not available
Other bias	High risk	The power calculation implies a very strong effect in favour of letrozole compared to CC and exactly reflects the results of the trial.

*Study characteristics*
Methods	Randomised controlled clinical trial Duration and location of the trial: not stated
Participants	Inclusion criteria: women with primary infertility and PCOS with no other known cause of infertility were enrolled in the trial. All participants had a history of oligo‐ or amenorrhoea and ovaries with at least 10 subcapsular cysts 2 mm to 10 mm in diameter and hyperechogenic stroma. Exclusion criteria: none declared Number of centres: setting unknown, tried to contact authors via email Number of women randomised: 51 in the letrozole group and 55 in the CC group Number of women analysed: 51 in the letrozole group and 55 in the CC group Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 27.1 ± 0.9, group B CC: 26.2 ± 1.1 BMI (kg/m²): group A letrozole: 26.1 ± 1.9, group B CC: 25.8 ± 1.8 Duration of infertility (y): group A letrozole: 2.2 ± 0.7, group B CC: 2.4 ± 0.9 Country: Turkey
Interventions	Group A: letrozole, 2.5 mg/day orally given for 5 days starting on cycle day 3 Group B: CC, 100 mg/day orally given for 5 days starting on cycle day 3
Outcomes	Outcomes: number of mature follicles, endometrial thickness (mm), day of hCG administration, ovulation rate, pregnancy rate, multiple pregnancies
Notes	Ethical approval: yes, the trial protocol was approved by the institutional ethics committee Informed consent: yes, informed consent was obtained from all trial participants Source of funding: not stated Conflicts of interest: quote: “Conflicts of interest: No conflicts of interest were declared in relation to this article” Power calculation: not stated We contacted Dr V Atay via email about the trial setting, about how randomisation and allocation were done, blinding and if data are available on OHSS, miscarriage rate and live birth rate, but no response.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear how it was done
Allocation concealment (selection bias)	Unclear risk	Unclear how it was done
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts reported
Selective reporting (reporting bias)	Unclear risk	Protocol of the trial was not available
Other bias	Low risk	None

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Clinical pregnancy rate	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.1 Letrozole day 3‐7 administration versus day 5‐9 administration	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
9.1 Ovarian hyperstimulation syndrome rate	1	Risk Difference (M‐H, Fixed, 95% CI)	Totals not selected
9.1.1 5 mg versus 7.5 mg letrozole	1	Risk Difference (M‐H, Fixed, 95% CI)	Totals not selected
9.2 Clinical pregnancy rate	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.2.1 5 mg versus 7.5 mg letrozole	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.3 Miscarriage rate per woman	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.3.1 5 mg versus 7.5 mg letrozole	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.4 Miscarriage rate per pregnancy	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.4.1 5 mg versus 7.5 mg letrozole	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.5 Multiple pregnancy rate	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.5.1 5 mg versus 7.5 mg letrozole	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

*Study characteristics*
Methods	Randomised controlled trial Duration and location of the trial: quote: "During the study period of 2004 through 2005, 80 patients with PCOS who attended the outpatient clinics of the Infertility and Reproductive Medicine Unit of the Zonguldak Karaelmas University Hospital (Zonguldak, Turkey) participated in this study.“
Participants	Inclusion criteria: women with anovulatory PCOS diagnosed using 2003 Rotterdam criteria Exclusion criteria: tubal, peritoneal and uterine cause of infertility. Male‐factor infertility. Specific endocrine abnormalities (Cushings disease/syndrome, hypothyroidism, hyperthyroidism, prolactinoma) Number of centres: 1, outpatient clinics of the Infertility and Reproductive Medicine Unit of the Zonguldak Karaelmas University Hospital (Zonguldak, Turkey) Number of women randomised: 80, 40 in group A letrozole and 40 in group B CC Number of women analysed: 38 in group A letrozole and 36 in group B CC Number of withdrawals/exclusions/loss to follow‐up and reasons: 6 lost to follow‐up, no reasons given Age (y): group A letrozole: 32.2 ± 3.9, group B CC: 30.6 ± 4.0 BMI (kg/m²): not stated Duration of infertility (y): group A letrozole: 5 (1‐10), group B CC: 3 (3‐11) Country: Turkey
Interventions	Group A: letrozole, 5 mg/day orally given for 5 days during cycle days 3‐7 Group B: CC, 100 mg/day orally given for 5 days during cycle days 3‐7
Outcomes	Outcomes: ovulation rate by cycle, pregnancy rate by cycle, delivery rate by cycle, miscarriage rate (abortion), multiple pregnancy rate, endometrial thickness on the day of hCG (mm), N of follicles sized > 15 mm in diameter on the day of hCG, E2 level on the day of hCG (pg/mL), E2 per follicle sized > 15 mm in diameter on the day of hCG (pg/mL)
Notes	Ethical approval: yes, the trial was approved by the institutional ethics committee of Karelmal university Informed consent: not stated Source of funding: no funding source or conflicts of interest stated Power calculation: sample‐size determination was based on the difference between the median number of follicles sized > 15 mm and E2 concentration on hCG day. A sample size of 60 participants (30 in each group) was targeted to be able to detect a difference of at least one follicle or of 200 pmol/L between the 2 groups, with alfa (type I error) set at 0.05 and 80% power. We contacted Dr Bayar by email for additional information, but he did not respond.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Simple randomisation performed by a computer
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was achieved by using central consultation for treatment of eligible participants.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Stated as double‐blind but it is not clear who was actually blinded and how this was achieved
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Stated as double‐blind but it is not clear who was actually blinded and how this was achieved
Incomplete outcome data (attrition bias) All outcomes	Low risk	6 participants lost to follow‐up, 4 and 2 respectively
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised non‐blinded controlled trial Duration and location of the trial: quote: "The study was conducted in a private infertility care setting as a randomized controlled trial between August 2004 and December 2005.“
Participants	Inclusion criteria: infertile women with PCOS diagnosed by the Rotterdam criteria 2003 who failed to ovulate by taking 100 mg of CC/day for 5 days in 2 consecutive cycles Exclusion criteria: women with hyperprolactinaemia, thyroid disorder, male‐factor infertility, known or suspicious tubal factor infertility (endometriosis and pelvic inflammatory disease), and unexplained infertility were excluded from the trial. Number of centres: 1, private infertility care setting Number of women randomised: 32 in each group Number of women analysed: 32 in each group Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 25.5 ± 4.0, group B CC: 26.1 ± 3.6 BMI (kg/m²): group A letrozole: 22.7 ± 2.8, group B CC: 23.6 ± 3.2 Duration of infertility (y): group A letrozole: 2.7 ± 1.1, group B CC: 2.6 ± 1.1 Country: India
Interventions	Group A: letrozole, 7.5 mg/day orally given for 5 days from cycle days 3‐7 Group B: CC, 150 mg/day orally given for 5 days from cycle days 3‐7
Outcomes	Primary outcomes: ovulation and pregnancy rate Secondary outcomes: follicular development by day 16 (mm), serum E2 on day of hCG (pg/mL), endometrial development by day 16 (mm), serum progesterone on day 21 (ng/mL), multiple pregnancies, OHSS cases. Live birth rate was provided by email contact.
Notes	Ethical approval: yes, the trial protocol was approved by the institutional review board (IRB) of Dhaka medical college. Informed consent: yes, participants were counselled and informed consent was obtained before recruitment. Source of funding: the trial was self‐funded. Power calculation: a trial population of 57 women was calculated, considering an average of 60% of PCOS women are associated with insulin resistance, allowing an alfa value of 0.05. Authors were contacted by email, and additional information was provided.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done by lottery method. They put the name of letrozole and CC in a sealed opaque envelope. By calculating sample size they made 64 pieces of paper, 32 for letrozole and 32 for CC.
Allocation concealment (selection bias)	Unclear risk	Quote: "All unleveled envelop were put together and the patients drew one piece of envelop from them. Then we opened the envelop to see the name of the drug." (by email contact with Prof Rashida)
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "There was no blinding" (by email contact with Prof Rashida)
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "There was no blinding" (email with Prof Rashida)
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Single‐blind randomised clinical trial Duration and location of the trial: quote: "In this single blind randomized trial, 148 ovarian cycles were studied in 100 clomiphene‐ resistance patients with PCOS who were chosen among 250 PCOS patients attending the Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran during the years 2007‐2008.“
Participants	Inclusion criteria: women who received 150 mg CC daily for 3 cycles and failed to become pregnant, and were diagnosed with anovulatory PCOS based on Rotterdam 2003. Exclusion criteria: quote: “We excluded patients with liver and kidney dysfunction, cardiovascular disease, diabetics, and those who use metformin or drugs affecting insulin secretion and CC in recent 2 cycles.” Number of centres: 1, research and clinical centre for infertility, Shahid Sadoughi University of Medical Sciences, Yazd Number of women randomised: 100 women, 50 in group A metformin‐letrozole, 50 in group B metformin‐CC Number of women analysed: 48 in group A metformin‐letrozole, 50 in group B metformin‐CC Number of withdrawals/exclusions/loss to follow‐up and reasons: 2, experienced side effects with metformin before letrozole was started Age (y): group A metformin‐letrozole: 28.5 ± 3.1, group B metformin‐CC: 29.6 ± 3.5 BMI (kg/m²): group A metformin‐letrozole: 29.0 ± 3.8, group B metformin‐CC: 29.2 ± 2.9 Duration of infertility (y): group A metformin‐letrozole: 3.8, group B metformin‐CC: 3.8 Country: Iran
Interventions	Group A: metformin 1500 mg daily for 6‐8 weeks, followed by 5 mg letrozole daily orally given for 5 days during cycle days 3‐7 if pregnancy did not occur Group B: metformin 1500 mg daily for 6‐8 weeks, followed by 100 mg CC daily orally given for 5 days during cycle days 3‐7 if pregnancy did not occur
Outcomes	E2 (pg/mL) on day of hCG administration, number of follicles > 18 mm in diameter, endometrial thickness on day of hCG administration (mm), clinical pregnancy rate, miscarriage rate (abortion)
Notes	Ethical approval: yes, the trial was approved by ethical board of Shahid Sagoughi University of Medical Sciences, Yazd. Informed consent: no, at least nothing written about it – authors contacted Source of funding: quote: “the study was fully supported and funded by Shahid Sadoughi University of Medical Sciences, Yazd, Iran” Power calculation: quote: "In this study, 50 cases were needed in each group so as to gain a significant difference of 22% in pregnancy rate at a significant level of 5% and a power of 80%" We contacted Dr Davar by email to get additional information, but we did not get a response.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done using a random‐numbers table
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated who was blinded in this single‐blinded trial
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated who was blinded in this single‐blinded trial
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 participants lost to follow‐up due to side effects experienced with metformin before letrozole was started.
Selective reporting (reporting bias)	Low risk	All outcomes reported stated in the protocol
Other bias	Low risk	None

*Study characteristics*
Methods	Double‐blind randomised trial Duration and location of the trial: quote: "During the period of February 2004 through November 2006, 100 patients with PCOS who attended the outpatient infertility clinics at Shiraz University of Medical Sciences participated in the present study.“
Participants	Inclusion criteria: infertility for at least 1 year, diagnosis of PCOS by the Rotterdam criteria 2003, having patent tubes on hysterosalpingogram, and normal semen analysis of the husband Exclusion criteria: participants must not have received any other medication for ovulation induction before enrolment into the trial. Number of centres: 1, outpatient infertility clinics at Shiraz University of Medical Sciences Number of women randomised: 100 women, 50 in each group Number of women analysed: 100 women, 50 in each group Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 23.6 ± 2.9, group B CC: 24.3 ± 3.4 BMI (kg/m²): group A letrozole: 27.5 ± 4.6, group B CC: 27.1 ± 3.6 Duration of infertility (y): group A letrozole: 2.0 ± 1.3, group B CC: 2.3 ± 1.9 Country: Iran
Interventions	Group A: letrozole, 5 mg/day orally given for 5 days during cycle days 3‐7 Group B: CC, 100 mg/day orally given for 5 days during cycle days 3‐7
Outcomes	Total number of follicles with diameter ≥ 14 mm, endometrial thickness on the day of hCG injection, pregnancy rate, miscarriage rate (abortion), multiple pregnancy rate, live birth rate
Notes	Ethical approval: yes, quote: “The study was approved by the Institutional Ethics Committee of the University.” Informed consent: yes, quote: “An informed written consent was obtained from each patient” Source of funding: not stated Conflicts of interest: quote: "Conflicts of interest: None declared" Power calculation: not stated Authors contacted about randomisation, allocation, and information about OHSS
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated how it was done
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Only the pharmacist knew the name of the medication that had been taken by the participants.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Only the pharmacist knew the name of the medication that had been taken by the participants.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants excluded or lost to follow‐up
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised double‐blind controlled trial Duration and location of the trial: quote: "A prospective double‐blind randomized controlled trial was conducted at the Teaching University Hospital of Cairo University, Cairo, Egypt, between August 1, 2013, and December 31, 2014.“
Participants	Inclusion criteria: quote: "eligible women were younger than 40 years, had primary or secondary infertility associated with PCOS, and had not ovulated in response to three cycles of 150 mg CC every day for 5 days from day 3 of the menstrual cycle. PCOS diagnoses were based on the revised 2003 Rotterdam consensus criteria. The presence of at least two of the following characteristics was considered diagnostic of PCOS: oligo ovulation or anovulation; hyperandrogenism; and polycystic ovaries detected using vaginal ultrasonography." Exclusion criteria: quote: "exclusion criteria were other factors of infertility, diabetes mellitus, hypertension, liver or kidney malfunction, heart disease, urinary symptoms, persistent hyperprolactinaemia, thyroid dysfunction, gonadotropin induction, and previous ovarian drilling. Male factor infertility was defined as a sperm count of less than 15 × 10^6/mL, a total motility of less than 40%, or normal morphology of less than 4%. Tubal factor infertility was confirmed by hysterosalpingography." Number of women randomised: 100 women were randomised. Number of women analysed: 100 women were analysed, 50 in each group Number of withdrawals/exclusions/loss to follow‐up and reasons: none Number of centres: single centre Age (y): CC 26.6 ± 2.9; letrozole 25.8 ± 3.6 BMI (kg/m²): CC 26.6 ± 2.7; letrozole 26.5 ± 2.8 Duration of infertility (y): CC 3.1 ± 1.4; letrozole 2.7 ± 1.6 Country: Egypt
Interventions	Group A: (control group) received 100 mg CC, given as 2 x 50 mg tablets daily for 5 days from the third day of the menstrual cycle. Group B: 5 mg letrozole, given as 2 x 2.5 mg tablets daily for 5 days from the third day of the menstrual cycle. Participants in both groups also received metformin and pioglitazone, which was taken daily as 1 tablet containing 850 mg metformin and 15 mg pioglitazone, for 10 days starting from the first day of the menstrual cycle.
Outcomes	Primary outcomemeasure: cumulative ovulation rate (proportion of cycles in which ovulation occurred in the whole follow‐up period). Other outcome measures: number of follicles ≥ 18 mm in size, endometrial thickness and serum estradiol levels on the day of hCG administration, serum progesterone level on day 21, and rate of clinical pregnancy (at least 1 intrauterine gestational sac detected)
Notes	Ethical approval: approved by the research ethics committee of the teaching University Hospital of Cairo University Informed consent: all participants signed a written informed consent form. Source of funding: Cairo University Power calculation: previous data indicated that the ovulation rate in group A would be 62%. If the ovulation rate for the letrozole, metformin, and pioglitazone (experimental) group was 87% (previous unpublished data from the trial unit), a total of 47 women would have to be recruited to each group to ensure a sufficiently powered trial. Assuming an attrition of 10%, the total number of patients to be recruited was 50 per group. ITT analyses were planned.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Enrolled women were randomly allocated using computer‐generated random number tables (block size four)"
Allocation concealment (selection bias)	Low risk	Quote: "Opaque sealed envelopes containing group allocations were prepared at a separate location every 24 hours. These envelopes were sent to an assigned nurse, who opened them before commencing ovulation induction"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Participants, the staff who conducted follow‐up, and data analysts were masked to the allocation to avoid bias"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Participants, the staff who conducted follow‐up, and data analysts were masked to the allocation to avoid bias"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were lost to follow‐up
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised controlled trial Duration of the trial: quote: "The study was conducted during the period from 1st August 2015 to 30th March 2016.“
Participants	Inclusion criteria: quote: "age >20 and <35 years old, patients were diagnosed to have PCOS criteria of diagnosis of PCO. Normal HSG and their partners had normal semen analysis according to WHO criteria (WHO, 2010) and CC‐resistant. If patients fail to respond to 150 mg/day for 5 days for 3 consecutive cycles, they are considered as CC‐resistant." Exclusion criteria: quote: "Age less than 20 yr or more than 35 yr, non‐PCOS, and those Patients with poor ovarian reserve i.e. hyperprolactinaemia, hypo and hyperthyroidism, diabetic patients and Cushing’s syndrome were excluded, non‐classical congenital adrenal hyperplasia, current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, antidiabetic or antiobesity drugs, or other hormonal drugs, any subject was affected by either neoplastic, metabolic, hepatic, or cardiovascular disorder or other concurrent medical illness (i.e. diabetes, renal disease, or malabsorptive disorders) were excluded, pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility, tubal infertility and male factor infertility were excluded with a hysterosalpingogram and with semen analysis, respectively." Number of women randomised: 80 women, 40 within each group Number of women analysed: 80 women, 40 within each group Number of withdrawals/exclusions/loss to follow‐up and reasons: none Number of centres: single‐centre trial Age (y): LOD group 28.8 ± 3.1 versus letrozole group 29.7 ± 3.7 BMI (kg/m²): LOD group 29.1 ± 1.6, letrozole group 29.2 ± 1.7 Duration of infertility (y): no mean ± SD reported Country: Egypt
Interventions	Group A: quote: "In group A, laparoscopy was performed under intravenous general anaesthesia with the patient in a supine position. A 5 mm incision was made in the navel, through which a long sheath punctured into the abdominal cavity, and the inflatable pneumoperitoneum was placed. Another two 5‐mm incisions were made on the right and left lower abdomen and the surgical instruments were inserted into the abdominal cavity. The patient was adjusted into a position with the head high up, the pelvic organs were exposed and a comprehensive exploration of the pelvic organs was made, focusing on the structure and position of the adjacent organs of the bilateral ovaries. Once immobilized, each ovary was cauterized at 4–6 points, using a monopolar electrosurgical needle, according to the size of each ovary. Following cauterization, a bilateral tubal hydrotubation with methylene blue was performed. During the procedure. The pelvis was irrigated using physiological saline. Ringer’s solution plus dexamethasone was added into the abdominal cavity to avoid adhesion. The total duration of the procedure, as well as any intra‐operative or post‐operative complications, was noted." Group B: quote: "In group B, 2.5 mg twice daily LE oral tablets were administered on the 3rd day of menses and then every day for 5 days. Treatment was repeated for up to six cycles if the patient failed to ovulate, the patients were followed‐up for 6 months after the treatment in both groups."
Outcomes	Pregnancy rate, abortion rate, ovulation, regular cycles, ovarian volume, antral follicle count
Notes	Ethical approval: trial was approved by Minia University Ethical Committee Informed consent: quote: “Informed consent was obtained from all participating women after the nature and purpose of the study had been explained to them and were fully understood” Source of funding: quote: “We have not received any funding from any corporate body or pharmaceutical company. “ Power calculation: none reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was achieved via the use of a randomisation number allocated prior to dosing, once eligibility had been determined, and a randomisation schedule was produced by an interactive voice response system vendor."
Allocation concealment (selection bias)	Low risk	Quote: "randomisation schedule was produced by an interactive voice response system vendor"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants were not blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Once the patients had been allocated to one of the two groups, the treatment was revealed to the investigator; however, the doctor responsible for performing the transvaginal ultrasound follow up assessment was blinded to the treatment groups."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All women randomised were also analysed.
Selective reporting (reporting bias)	Unclear risk	We found no reporting of outcomes in a trial protocol or Methods section
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised double‐blind placebo‐controlled trial Duration and location of the trial: quote: "This trial was conducted in a university teaching hospital between 2007 and 2009.“
Participants	Inclusion criteria: women with PCOS and clomiphene resistance who were being treated with ovulation induction. Additionally, women had to have a normal hormone profile and a male partner with normal semen parameters by WHO criteria. Normal hormone profile was defined as a FSH level of < 12 IU/L, serum prolactin level of < 25 ng/mL, and a TSH value between 0.3 µIU/mL and 4.5 µIU/mL. Exclusion criteria: women with other endocrine disorders such as Cushing syndrome, and congenital adrenal hyperplasia Number of centres: 1, Reproductive Medicine Unit, Christian Medical College, Vellore, Tamil Nadu, India Number of women randomised: 18 in each group Number of women analysed: 17 in each group Number of withdrawals/exclusions/loss to follow‐up and reasons: 2 lost to follow‐up before treatment started Age (y): group A letrozole: 25.6 ± 3.6, group B placebo: 25.7 ± 3.7 BMI (kg/m²): group A letrozole: 26.1 ± 3.7, group B placebo: 24.7 ± 4.2 Duration of infertility (y): group A letrozole: 5.2 ± 3.2, group B placebo: 3.6 ± 2.2 Country: India
Interventions	Group A: letrozole, orally given 2.5 mg/day for 5 days from cycle days 2‐6 Group B: placebo, also given for 5 days from cycle days 2‐6
Outcomes	Primary Outcome: ovulation rate Secondary Outcomes: live birth rate, OHSS rate, pregnancy rate, miscarriage rate, multiple pregnancy rate, endometrial thickness (mm), day 21 serum progesterone (nmoL/L), number of participants with mature follicle (%)
Notes	Ethical approval: yes, the protocol of the trial was approved by the institutional review board Informed consent: yes, written informed consent was obtained from each participant Source of funding: not stated Conflicts of interest: quote: "The Authors have nothing to disclose" Power calculation: quote: "Our literature pointed to a 75% ovulation rate when 2.5 mg of letrozole was used in women with PCOS who had clomiphene resistance. We hypothesized an ovulation rate of 60& with letrozole and 10% with placebo. On this basis, a sample size of 17 women in each arm (80% and alpha.05 for a two‐sided test) was calculated." Contacted authors about OHSS rate and how randomisation and allocation concealment were done in detail. All information provided
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly distributed using a computer‐generated randomisation sequence in blocks of 6, into 2 groups.
Allocation concealment (selection bias)	Low risk	Allocation concealment was done by using consecutively‐numbered sealed opaque envelopes containing the treatment packets.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The randomisation code was maintained by the pharmacy department, which revealed the group assignments at the end of the trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The code was revealed after the statistical analysis had been performed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	1 woman in each group was lost to follow‐up, after randomisation and before treatment started.
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised double‐blind multicentre trial Duration of the trial: quote: "Enrollment began in February 2009 and was completed in January 2012.“
Participants	Inclusion criteria: women with PCOS defined by the Rotterdam criteria and at least 1 patent fallopian tube and normal uterine cavity, and a male partner with sperm concentration of > 14 million/mL Exclusion criteria: quote: "We will exclude subjects with medical conditions that represent contraindications to CC, letrozole and/or pregnancy or who are unable to comply with the study procedures." Number of centres: multicentre trial Number of women randomised: 750, 374 in the letrozole group and 376 in the CC group Number of women analysed: 750, 374 in the letrozole group and 376 in the CC group Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 29 ± 5, group B CC: 28 ± 4 BMI (kg/m²): group A letrozole: 35 ± 10, group B CC: 35 ± 9 Duration of infertility (y): not reported Country: USA
Interventions	Group A: letrozole, orally given 2.5 mg/day for 5 days during cycle days 3‐7 Group B: CC, orally given 100 mg/day for 5 days during cycle days 3‐7
Outcomes	Live birth, ovulation rate, clinical pregnancy rate, miscarriage rate, multiple pregnancy rate
Notes	Ethical approval: quote: "The institutional review board at each centre approved the protocol, and all participants (women and their male partners) gave written informed consent." Informed consent: quote: "The institutional review board at each centre approved the protocol, and all participants (women and their male partners) gave written informed consent." Source of funding: quote: "The study is funded through a cooperative agreement by the Eunice Kennedy ShriverNational Institutes of Child Health and Human Development (NICHD)" Power calculation: a sample size of 300 subjects in each arm of the randomisation yields 81% statistical power to prospectively demonstrate a 0.10 absolute difference in live birth proportions between treatment arms (0.20 for CC and 0.30 for letrozole) using the Pearson’s Chi² test with a 2‐sided significance level of 0.05
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Almac statisticians will generate the randomisation scheme for the study."
Allocation concealment (selection bias)	Low risk	Third‐party allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "In order to maintain the double‐blind, CC and letrozole will be over encapsulated and packaged in identically appearing numbered study kits (using AlmacClinical Services, Durham NC) which will then be directly shipped to each clinical site."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "In order to maintain the double‐blind, CC and letrozole will be over encapsulated and packaged in identically appearing numbered study kits (using AlmacClinical Services, Durham NC) which will then be directly shipped to each clinical site. The randomisation scheme (including block size) will be disclosed to the DCC data manager, but not to any RMN investigators or staff, including the Protocol Lead Investigator."
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts were reported
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Low risk	None

PERMALINK

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome

Sebastian Franik

Quang-Khoi Le

Jan AM Kremer

Ludwig Kiesel

Cindy Farquhar

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Letrozole with or without adjuncts compared to SERMs with or without adjuncts followed by timed intercourse for infertile women with polycystic ovary syndrome.

Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for infertile women with polycystic ovary syndrome.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Effectiveness

Adverse events

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Study design and setting

Participants

Interventions

Outcomes

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

1. Letrozole compared to placebo

Primary outcomes

1.1 Live birth rate

1.1. Analysis.

1.2 OHSS rate

1.2. Analysis.

Secondary outcomes

*Study characteristics*
Methods	Double‐blind, randomised controlled clinical trial Duration and location of the trial: quote: "The double‐blind randomised clinical trial (RCT) study was conducted from September 22, 2012, to March 20, 2013, at the Islamic Azad University of Medical Sciences, 22 Bahman hospital in Mashhad, Iran."
Participants	Inclusion criteria: quote: "Those included were PCO infertile women aged 18‐40 years who had absence of ovulation (oligomenorrhea, amenorrhea), symptoms of increase in androgen in the blood (acne, hirsuitism) and the laboratory symptoms of androgen increasing (increase in testosterone (TST) and Dehydroepiandrosterone (DHEA),2 and with body mass index (BMI) less than 35." Exclusion criteria: quote: "Those with other infertility reasons, such as infertility in the partner, infertility duration more than 5 years, women with ovary cyst and internal pathology of the endometrium, active malignancy of the breast and the ovary, and individuals who avoided using aromatase inhibitor and oestrogen receptor modulator were excluded." Number of women randomised: 240 women Number of women analysed: 220 women were analysed, 110 within each group Number of withdrawals/exclusions/loss to follow‐up and reasons: 10 women in each group were lost to follow‐up Number of centres: single centre trial Age (y): group A: 27.5 ± 4.1, group B: 27.2 ± 3.9, group C: 27.5 ± 4.1 BMI (kg/m²): group A: 26.9 ± 1.7, group B: 26.8 ± 1.7, group C: 26.7 ± 1.5 Duration of infertility (y): group A: 1.9 ± 0.7, group B: 1.9 ± 0.7, group C: 2.2 ± 0.7 Country: Egypt
Interventions	Quote: "Patients who received Letrozole 5 mg tablets per night were in group A, and those who received CC 50 mg tablets per night were in group B. The medication lasted 3‐7 days in both groups."
Outcomes	Number of follicles, endometrial thickness, pregnancy rate by b‐hcg on day 16 after injection of hCG. Serum prolactin, DHEA, TSH, testosterone.
Notes	Ethical approval and informed consent: quote: "Approval was obtained from the institutional ethics committee, and written informed consent was taken from the subjects." Source of funding: quote: "none" conflicts of interest: quote: "none"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "At first, researchers drew a chart including 240 rows (001‐240). Then, we carried out an allocation to the control and sample group using the table random numbers."
Allocation concealment (selection bias)	Unclear risk	Quote: "Names and characteristics of patients were allocated to each group, and only the researchers were aware of this table, and the patients did not know about the drug."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Participants did not know about the drug"
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "researchers were aware of this table"
Incomplete outcome data (attrition bias) All outcomes	Low risk	20/240 women were lost to follow‐up, 10 in each group (9%)
Selective reporting (reporting bias)	Low risk	All outcomes were reported
Other bias	Low risk	None

*Study characteristics*
Methods	A partly‐randomised controlled clinical trial Duration and location of the trial: not stated
Participants	Inclusion criteria: infertile women with PCOS, diagnosis based on the 2003 Rotterdam criteria Exclusion criteria: women with ovarian or adnexal surgery, hypothyroidism, hyperprolactinaemia, bilateral tubal occlusion diagnosed with hysterosalpingography and unexplained infertility, and those with follicles greater than 10 mm Number of centres: 1, infertility polyclinic of Atatürk University Medical Faculty Erzurum Number of women randomised: 31 in group A, 33 in group B Number of women analysed: 31 in group A, 33 in group B Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 25.6 ± 4.5, group B CC: 27.8 ± 6.2 BMI (kg/m²): group A letrozole: 24.7 ± 3.6, group B CC: 24.9 ± 4.8 Duration of infertility (y): group A letrozole: 3.4 ± 3.0, group B CC: 4.4 ± 3.6 Country: Turkey
Interventions	Group A: letrozole, orally given 2.5 mg/day for 5 days during cycle days 3‐7 Group B: CC, orally given 100 mg/day for 5 days during cycle days 3‐7
Outcomes	Primary outcomes: ovulation rate and pregnancy rate Secondary outcomes: OHSS rate, miscarriage rate, multiple pregnancy rate, number of follicles on day of hCG (≥ 17 mm), E2 (pg/mL) on hCG day, endometrial thickness (mm), other side effects
Notes	Ethical approval: yes, quote: “Ethical approval was obtained from the institutional review board of Atatürk University Medical Faculty in order to conduct this study.” Informed consent: quote: "Instead of written consent verbal approval was obtained from the patients prior to study begin and treatment" ‐ correspondence with Dr Hakan Nazik Source of funding: quote: "This study was done by researchers without any funding" Power calculation: not stated All questions were answered by Dr Hakan Nazik
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The patients were randomly allocated using a computer random list into first and second groups”
Allocation concealment (selection bias)	Unclear risk	Quote: “The patients were randomly allocated using a computer random list into first and second groups”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "There was no blinding in our study" (email with Dr Hakan Nazik)
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "There was no blinding in our study" (email with Dr Hakan Nazik)
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts reported
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	High risk	Participants in group 2 letrozole were significantly younger and had a significantly shorter duration of infertility.

*Study characteristics*
Methods	Comparative randomised phase III open‐labelled trial Duration and location of the trial: quote: "A comparative, prospective, phase III, open labelled trial study was conducted in the Eden Hospital, Medical College Kolkata between January 2008 and December 2009.“
Participants	Inclusion criteria: infertile women aged 20‐35 with PCOS diagnosis based on the Rotterdam criteria 2003 Exclusion criteria: women with hyperprolactinaemia, thyroid disorder, male‐factor infertility, known or suspicious tubal‐factor infertility (endometriosis and pelvic inflammatory disease). Also women with a history of liver and kidney failure, cardiovascular diseases, diabetes, or women who consumed metformin or drugs affecting insulin secretion or CC in the previous 2 months Number of centres: 1, Eden Hopsital, Mecial College Kolkata Number of women randomised: 147; group A letrozole: 69, group B CC: 78 Number of women analysed: group A letrozole: 69, group B CC: 78 Number of withdrawals/exclusions/loss to follow‐up and reasons: 0 Age (y): group A letrozole: 28 (19‐35), group B CC: 29 (20‐35) BMI (kg/m²): group A letrozole: 28.8 (23.2‐34.6), group B CC: 28.5 (24.2‐33.6) Duration of infertility (y): group A letrozole: 2.2, group B CC: 2.4 (SD or range not given) Country: India
Interventions	Group A: letrozole, 2.5 mg/day given orally for 5 days from cycle day 3‐7 Group B: CC, 100 mg/day given orally for 5 days from cycle day 3‐7
Outcomes	Primary outcomes: ovulation rate, average follicular diameter on day 16, number of mature follicles produced by cycle, mean estradiol level on the day of hCG administration, mean endometrial thickness, pregnancy rate Secondary outcomes: miscarriage rate, live birth rate
Notes	Ethical approval: yes, the trial protocol was approved by the ethical committee of Medical College Kolkata Informed consent: yes, participants were counselled and informed consent was obtained before recruitment Source of funding: quote: “Conflict of interest: the authors hereby declare that they have not received any financial support for this study and there is no conflict of interest.” Power calculation: not stated We contacted Dr Ray by email about randomisation, allocation, blinding, multiple pregnancy rate, and OHSS, but he did not respond.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear how randomisation was done
Allocation concealment (selection bias)	Unclear risk	Unclear how allocation was done
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported if anyone was blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported if anyone was blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No participants stated as lost, but 147 participants is an odd number to start with, and so are the groups of 69 and 78 respectively; authors contacted for protocol
Selective reporting (reporting bias)	Unclear risk	All expected outcomes were reported, but contacted authors for protocol
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised clinical trial Duration and location of the trial: quote: "This prospective randomized controlled trial was performed at a tertiary care hospital from January 2005 to January 2010.“
Participants	Inclusion criteria: women aged 20‐35 years having infertility for > 1 year, BMI < 28, and with anovulatory PCOS based on the Rotterdam 2003 criteria Exclusion criteria: quote: "in all patients, a comprehensive infertility work‐up was done. This included a tubal patency test, pelvic ultrasonography, husband semen analysis, and serum hormone measurements (FSH, LH, prolactin, estradiol, progesterone, and testosterone) on the 2nd to 5th day of the cycle. Patients having abnormality in any of these tests, which may be responsible for reproductive failure, were excluded from the study." Number of centres: 1, a tertiary care hospital in India Number of women randomised: 212 women; group A letrozole: 104, group B CC: 108 Number of women analysed: letrozole group: 98, CC group: 106 Number of withdrawals/exclusions/loss to follow‐up and reasons: 8 lost to follow‐up Age (y): group A letrozole: 26.1 ± 1.8, group B CC: 26.5 ± 1.3 BMI (kg/m²): group A letrozole: 25.8 ± 2.1, group B CC: 25.4 ± 1.6 Duration of infertility (y): group A letrozole: 6.4 ± 3.8, group B CC: 5.8 ± 3.1 Country: India
Interventions	Group A: letrozole, orally given in doses of 2.5 mg/day and 5 mg/day for 5 days during cycle days 3‐7 Group B: CC, orally given in doses of 50 mg/day and 100 mg/day for 5 days during cycle days 3‐7 Treatment was continued for 3 months.
Outcomes	Mean number of follicles, endometrial thickness, ovulatory cycle rate, conception rate, pregnancy outcome, miscarriage rate, multiple pregnancies and OHSS rate
Notes	Ethical approval: yes, the necessary ethical approval was taken from Institutional Review Board to conduct this trial. Informed consent: yes, the participants were counselled, and informed consent was taken before randomisation. Source of funding: quote: “Source of support: Nil, Conflict of interest: None declared.” Power calculation: quote: "On basis of previous studies, to achieve a statistically valid comparison of pregnancy rates in the two groups, with a type I error of 0.05 and a power of 80%, a sample size of at least 40 women in each arm was required." We contacted Dr Roy by email to get additional information, but he did not respond.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Online software was used to generate a random‐number table (www.randomization.com).
Allocation concealment (selection bias)	Unclear risk	Quote: "Randomisation codes (A, B) were packed into sealed opaque envelopes by an individual not involved in enrolment, treatment and follow‐up of subjects to ensure concealment of allocation. One resident had the responsibility for dispensing the trial drugs to the patient based on the unique randomisation code. At the end of allocation, the resident provided us with a randomisation list."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	8 losses to follow‐up of 112 participants
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised controlled double‐blind trial Duration and location of the trial: not stated
Participants	Inclusion criteria: diagnosis of PCOS based on Rotterdam criteria provided that anovulation is 1 of the 2 required criteria Exclusion criteria: exclusion criteria were BMI > 35, presence of other causes of infertility, > 5 years infertility duration and known poor response to either drugs in previous cycles. Cases found to have baseline ovarian cysts or endometrial pathology were also excluded. Number of centres: 1, an infertility unit of a university hospital Number of women randomised: 124; group A letrozole: 62, group B CC: 62 Number of women analysed: group A letrozole: 59, group B CC: 57 Number of withdrawals/exclusions/loss to follow‐up and reasons: 3 in the letrozole and 5 in the CC group were reported as lost to follow‐up, but no further explanation given Age (y): group A letrozole: 25.0 ± 3.1, group B CC: 25.0 ± 3.6 BMI (kg/m²): group A letrozole: 27.7 ± 3.5, group B CC: 29.2 ± 3.5 Duration of infertility (y): not reported Country: India
Interventions	Group A: letrozole, 5 mg/day orally given for 5 days, cycle days not given Group B: CC, 100 mg/day orally given for 5 days, cycle days not given
Outcomes	Pregnancy rate, ovulation rate, endometrial thickness (mm), mid‐luteal progesterone level (ng/mL), number of follicles ≥ 12 mm
Notes	Ethical approval: yes, institutional review board (IRB) approval was obtained for the trial. Informed consent: yes, informed consent was taken from all included cases Source of funding: not reported, also no conflicts of interest given. Power calculation: not stated We contacted Dr Sheik‐el‐Arab Elsedeek by email about allocation concealment, blinding of outcome assessors, information on live birth, miscarriage rate, OHSS, multiple pregnancies and funding/COI, but he did not respond.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomised using computer generated tables to undergo one cycle of CC or let induction."
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated if personnel were blinded and how the participants were blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Both patients and sonographers were blinded to this allocation." Unclear if the other outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	8 participants lost to follow‐up, reasons unknown
Selective reporting (reporting bias)	Unclear risk	Only pregnancy was reported; we contacted the authors to get trial protocol
Other bias	Low risk	None

*Study characteristics*
Methods	Single‐blinded randomised clinical trial Duration and location of the trial: quote: "In this single‐blind randomized clinical trial, 120 ovarian cycles were studied in 60 clomiphene‐resistant patients with PCOS, who were chosen among 115 PCOS patients attending the infertility clinic of Vali‐e‐Asr Hospital (Tehran, Iran) during the years 2003–2004.“
Participants	Inclusion criteria: women with PCOS who had failed to become pregnant after 3 courses of 150 mg CC (considered as CC‐resistant), whereas the values of hormonal tests were normal. Tests: thyroid function, prolactin level, hysterosalpingography and husband’s sperm analysis Exclusion criteria: women with a history of liver and kidney failure, cardiovascular disease, diabetes (based on criteria set by the American Diabetic Association) or women who consumed metformin or drugs affecting insulin secretion or CC in the previous 2 months Number of centres: 1, infertility clinic of Vali‐e‐Asr Hospital, Tehran Number of women randomised: 60; group A metformin‐letrozole: 30, group B metformin‐CC: 30 Number of women analysed: group A metformin‐letrozole: 29, group B metformin‐CC: 30 Number of withdrawals/exclusions/loss to follow‐up and reasons: 1 because she got pregnant after metformin treatment before letrozole was started Age (y): group A metformin‐letrozole: 28.2 ± 3.1, group B metformin‐CC: 29.6 ± 3.5 BMI (kg/m²): group A metformin‐letrozole: 30.0 ± 4.8, group B metformin‐CC: 30.2 ± 3.9 Duration of infertility (y): group A metformin‐letrozole: 3.8, group B metformin‐CC: 3.8 Country: Iran
Interventions	Group A: metformin 500 mg x 3/d for 6 ‐ 8 weeks. If pregnancy did not occur, 2.5 mg letrozole from cycle days 3‐7 was given orally. Group B: metformin 500 mg x 3/d for 6‐8 weeks. If pregnancy did not occur, 100 mg CC from cycle days 3‐7 was given orally. Treatment was continued for 2 cycles.
Outcomes	Endometrial thickness on day of hCG administration (cm), number of follicles > 18 mm in diameter, mean total estradiol level on day of hCG administration (pM/L), mean estradiol level by mature follicle (pM/L), regular menses after metformin, adverse effects of metformin, live birth rate, pregnancy rate, miscarriage rate
Notes	Ethical approval: yes, consent from the deputy of research and the medical ethics committee of Tehran University of Medical Sciences Informed consent: not obtained because quote: “it was the routine treatment protocol and it was just put in the frame of a structured study” (email with Dr Farnaz Sohrabvand) Source of funding: quote: "No funding was necessary" (email with Dr Farnaz Sohrabvand) Power calculation: not stated Authors were contacted about live birth, multiple pregnancies, OHSS, informed consent, funding. No data available on live birth, multiple pregnancies and OHSS. Information retrieved about informed consent and funding (email with Dr Farnaz Sohrabvand)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A series of blind envelopes numbered from 1 to 60 had been prepared. Each patient was invited to pull out an envelope and was placed by the clinic secretary in either the metformin‐letrozole group (number 1‐30) or in the metformin‐CC group (31‐60)."
Allocation concealment (selection bias)	Unclear risk	Quote: "A series of blind envelopes numbered from 1 to 60 had been prepared. Each patient was invited to pull out an envelope and was placed by the clinic secretary in either the metformin‐letrozole group (number 1‐30) or in the metformin‐CC group (31‐60)."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants were not blinded.
Blinding of outcome assessment (detection bias) All outcomes	High risk	It is not plausible that outcome assessors were blinded if participants were not.
Incomplete outcome data (attrition bias) All outcomes	Low risk	One participant was excluded due to pregnancy after start of metformin treatment
Selective reporting (reporting bias)	Low risk	All outcomes were reported.
Other bias	Low risk	None

*Study characteristics*
Methods	Randomised clinical trial Duration of the trial: quote: "The trial was started on October 2009. Owing to the expiration of the study drug (berberine and matching placebo), the data safety and monitoring board decided to stop enrolment in November 2013“
Participants	Inclusion criteria: quote: "Chinese women with PCOS attempting to get pregnant were eligible if they fulfilled the following criteria: 1) age 20–40 years; 2) diagnosis of PCOS according to two of the three Rotterdam 2003 criteria, including oligo‐ovulation or anovulation, clinical and/or biochemical signs of hyperandrogenism, and/or polycystic ovaries; 3) at least one open fallopian tube and normal uterine cavity documented by hysterosalpingography, sonohysterography, or diagnostic laparoscopy within the past 3 years; 4) a male partner with sperm concentration of 15 million/mL and motility of 40% in at least one ejaculate; and 5) at least 1 year of infertility." Exclusion criteria: quote: "Subjects were excluded if they used hormonal drugs or other medications, including Chinese herbal prescriptions, in the past 3 months; had known severe organ dysfunction or mental illness; were pregnant, post‐miscarriage, postpartum, or breastfeeding within the past 6 weeks; or had congenital adrenal hyperplasia, clinically suspected Cushing syndrome, or an androgen‐secreting neoplasm." Number of women randomised: 644 women Number of women analysed: 644 women were analysed, 215 in group A, 214 in group B, 215 in group C. Number of withdrawals/exclusions/loss to follow‐up and reasons: 16/215 (7.4%) in the letrozole group, 25/214 (11.7%) in the berberine group, and 15/215 (7.0%) in the combination group (P = 0.16). Reasons for withdrawal were similar among the 3 groups (P = 0.16 for the 3 groups; P = 0.19 for lost to follow‐up; P = 0.88 for dropout; P = 1.0 for protocol violations; and P = 0.33 for adverse events). Number of centres: multicentre trial, 19 hospitals Age (y): group A 27.8 ± 3.6; group B 27.8 ± 3.7; group C 27.8 ± 3.6 BMI (kg/m²): group A 24.8 ± 4.5; group B 24.5 ± 4.1; group C 25.1 ± 5.0 Duration of infertility (months): group A 32.7 ± 24.0; group B 28.5 ± 21.6; group C 29.8 ± 21.3 Country: China
Interventions	Group A: 2.5 mg (1 tablet) of letrozole on days 3–7 of the first 3 treatment cycles. This dose was increased to 5 mg letrozole (2 tablets) or 2 tablets of letrozole placebo on days 3–7 of the last 3 treatment cycles if not pregnant Group B: berberine was administered orally at a daily dose of 1.5 g for 6 months. Group C: letrozole and berberine were administered in the same doses as reported above.
Outcomes	Cumulative live births, ovulation rate, conception rate, clinical pregnancy rate, multiple pregnancy rate, abortion rate, pregnancy complications, adverse events from trial medications
Notes	Ethical approval: the Institutional Review Boards at participating hospitals approved the protocol. Informed consent: every participant gave written informed consent. Source of funding: supported by National Public Welfare Projects for Chinese Medicine (200807021) of China, National Key Discipline of Chinese Medicine in Gynecolog, 2009–14, Heilongjiang Province Foundation for Outstanding Youths (JC200804), Intervention for Polycystic Ovary Syndrome Based on Traditional Chinese Medicine Theory–‘‘TianGui Shi Xu’’ (2011TD006), and National Clinical Research Base in Chinese Medicine, 2009–14, at First Affiliated Hospital, Heilongjiang University of Chinese Medicine. The funding sources had no involvement in the trial design, the collection, analysis, and interpretation of data, the writing of the report, or in the decision to submit the article for publication. Power calculation: the sample size calculation was based on anticipated live birth rate.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation was performed through a web‐based computer program (http://210.76.97.192:8080/cjbyj) operated by an independent data coordinating centre, the Institute of Basic Clinical Medicine of the China Academy of Chinese Medical Sciences. The randomisation was stratified by the participating sites."
Allocation concealment (selection bias)	Unclear risk	No further information about allocation after randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, investigators, physicians taking care of the participants, laboratory technicians, and data analysers were blinded to the assignments.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, investigators, physicians taking care of the participants, laboratory technicians, and data analysers were blinded to the assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	7% to 12% were lost to follow‐up, had protocol violations or adverse events. ITT analysis was performed.
Selective reporting (reporting bias)	Low risk	None, trial protocol was published prior to participant enrolment in the trial
Other bias	Low risk	None

Study	Reason for exclusion
Abu Hashim 2010	Trial had to be excluded due to retraction of the paper, concerns about validity of the data. Link to retraction notice: www.fertstert.org/article/S0015-0282(20)32164-6/fulltext
Akbari 2012	No PCOS
Al‐Hussaini 2014	Only short conference abstract; we did not find a published study article. We were unable to retrieve any information from trial authors.
Al‐Obaidi 2018	Pseudo‐randomization, poor responders were excluded from analysis
Al‐Shaikh 2017	Not a RCT
Angel 2014	RCT, but not about women with PCOS
Anwary 2012	Not a RCT
Azargoon 2012	Not a RCT
Azmoodeh 2015	No PCOS
Badawy 2008	Trial had to be excluded due to retraction of the paper, concerns about validity of the data. Link to retraction notice: www.fertstert.org/article/S0015-0282(07)01038-2/fulltext
Badawy 2009a	Trial had to be excluded due to an expression concern of the paper, concerns about validity of the data. Link to the expression of concern: doi.org/10.1016/j.fertnstert.2020.07.035
Badawy 2009b	Trial had to be excluded due to an expression of concern of the paper, concerns about validity of the data. Link to the expression of concern: www.sciencedirect.com/science/article/pii/S0015028220306889
Badawy 2009c	Not a RCT
Baruah 2009	Quasi‐randomised trial (quote: "Based on attendance order, patients with odd numbers were given letrozole and those with even numbers were given CC")
El Bigawy 2008	Quasi‐randomised trial
Foroozanfard 2013	Not randomised for clomiphene or letrozole
Huang 2019	Non‐PCOS
IRCT6517	Not randomised for letrozole
Khanna 2013	Not a RCT, no PCOS
Li 2016	Not randomised for letrozole
Mittal 2004	Not a RCT
Nahid 2012	Suspected quasi‐randomisation based on attendance order
NCT00610077	No published data found, last updated on clinicaltrials.gov in 2008. No response from trial authors
NCT01315912	Not a RCT
NCT01431352	For the 2018 update, there was no update on clinicaltrials.gov. No trial data available, and no response from authors.
NCT01577017	No trial results found, unable to obtain more information from trial authors
NCT01679574	Trial should be finished. We contacted authors by email found through Google because no contact information was written in the trial protocol: abd_ellah98@yahoo.com. For the 2018 update, there was no update on clinicaltrials.gov and still no response from the author.
NCT01793038	Unable to obtain information from trial authors. No trial data found, no update on clinicaltrials.gov.
NCT03135301	Letrozole in both arms
Ozdemir 2013	RCT, but not about women with PCOS
Pakrashi 2014	Not randomised for letrozole
Palihawadana 2015	Women with PCOS were excluded from the trial
Pourali 2017	Women with PCOS were excluded from the trial
Sharma 2010	Only conference abstract available, full article could not be found. Contact address of authors unknown
Wang 2019	Quasi‐randomised trial: participants excluded after randomisation when intervention was not successful (~30% of participants)
Xi 2015	Not a RCT
Yang 2008	Not a RCT (quote: "the allocation depended on the patients' choice" ‐ translated by Prof Taixiang Wu)
Yun 2015	Not a RCT

Methods	Randomised clinical trial
Participants	15 infertile women with PCOS
Interventions	Women were randomised into 3 treatment groups: Group 1: continuous metformin was used at the dose of 850 mg/tid/day for 6 months; afterwards, daily 2.5 mg letrozole between 3 and 7 days of the menstrual cycle was added to the metformin therapy. Group 2: participants received only daily 2.5 mg letrozole between days 3 and 7 of the menstrual cycle. Group 3: participants received daily 100 mg CC only between days 3 and 7 of the menstrual cycle.
Outcomes	Unclear
Notes	The article was written in Turkish, and we were not able to have it translated properly.

Methods	prospective clinical trial
Participants	236 infertile patients (2016‐2018) who were diagnosed as having anovulation due to PCOS
Interventions	Quote: "All patients were randomised by computer in two groups ‐Letrazole group (2.5‐5mg ) and CC group (50 mg to 100 mg) given for 5 days."
Outcomes	Ovulation rate
Notes	No trial data available, only conference abstract from ESHRE 2019 without any further information