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Efficacy and Safety of Letrozole Versus Clomiphene Citrate in Polyendocrine Metabolic Ovarian Syndrome: A Systematic Review, Meta-analysis, and GRADE Assessment of Randomized Controlled Trials
MBBS, MD, Krissheeven Mooroogiah1, Indraneel Banerjee2MS, DNB, MRCS, MCh, Vipul D Yagnik3MS, FMAS, FAIGES, FAIS, FISCP, PGDCN
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Received: ,
Accepted: ,
How to cite this article: Banerjee I, Mooroogiah K, Banerjee I, Yagnik VD. Efficacy and Safety of Letrozole Versus Clomiphene Citrate in Polyendocrine Metabolic Ovarian Syndrome: A Systematic Review, Meta-analysis, and GRADE Assessment of Randomized Controlled Trials. Glob J Med Pharm Biomed Update. 2026;21:22. doi: 10.25259/GJMPBU_73_2026
Abstract
Objectives:
Polycystic ovarian syndrome (PCOS) is a hormonal and metabolic disorder and a common cause of infertility among women. After multiple global consensus processes, the name was changed to polyendocrine metabolic ovarian syndrome (PMOS) in 2026.
Material and Methods:
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and was registered with PROSPERO (CRD420261426754). A thorough, systematic search was conducted across multiple databases from 2012 to 2026. The quality of the included studies was assessed using the Risk of Bias tool, and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Pooled effect estimates were calculated using a fixed-effect model; meta-analyses were performed, and forest plots were generated. The degree of heterogeneity was assessed by using the I2 statistic.
Results:
A pooled analysis using a fixed-effect model demonstrated that letrozole (LTZ) was associated with a significantly higher pregnancy rate than clomiphene citrate (CC) (risk ratio [RR] = 1.52, 95% confidence interval [CI] 1.29–1.78, Z = 5.10, p < 0.00001). There was no evidence of significant heterogeneity among included studies (χ2 = 3.59, df = 6, p = 0.73, I2 = 0%). Ovulation rates were higher in LTZ as compared with CC (RR = 1.13, 95% CI 1.07-1.19, Z = 4.70, p < 0.00001). There was low heterogeneity among the studies (χ2 = 8.48, df = 6, p = 0.24, I2 = 29%). The pooled data demonstrated that LTZ was associated with a significantly higher live birth rate than CC (RR = 1.42, 95% CI 1.14–1.77), Z = 3.16, p = 0.002). There was no evidence of heterogeneity between the included studies (χ2 = 0.004, df = 1, p = 0.85, I2 = 0%). LTZ significantly reduced hot flushes (RR = 0.60, 95% CI 0.47–0.78), but dizziness (RR = 1.52, 95% CI 0.98–2.3) and headache (RR = 1.80, 95% CI 0.39–8.21) were more frequent with LTZ than with CC.
Conclusion:
LTZ was more effective than CC in improving pregnancy, ovulation, and live birth rates in women with PMOS, with high to moderate certainty of evidence. Although LTZ was associated with fewer hot flushes, the certainty of evidence for adverse effects was very low. These findings support LTZ as the preferred first-line agent for ovulation induction, pregnancy, and live birth outcomes in women with PMOS and may guide future evidence-based clinical guidelines.
Keywords
Aromatase inhibitor
Clomiphene citrate
Letrozole
Polycystic ovarian disease
Polycystic ovarian syndrome
Polyendocrine metabolic ovarian syndrome
INTRODUCTION
Polycystic ovarian syndrome (PCOS) is a hormonal and metabolic disorder that affects around 10–13% of women in the reproductive age group. It is known as a common cause of infertility and accounts for about 80% of such cases.[1] The term PCOS has for a long time been recognized as inaccurate and misleading for both doctors and women living with PCOS, affecting the diagnosis, care, and treatment. For this reason, after multiple global consensus processes, the name was changed to polyendocrine metabolic ovarian syndrome (PMOS).[2] However, all randomized trials included in this review enrolled women diagnosed according to historical PCOS diagnostic criteria. The latter can be diagnosed if two of the following criteria are present: Clinical or biochemical hyperandrogenism, evidence of oligo-anovulation, polycystic-appearing ovarian morphology on ultrasound, with exclusion of other relevant disorders.[3]
The clinical features of PMOS include hirsutism and infertility, pregnancy complications, neonatal complications, obesity, impaired glucose tolerance, type 2 diabetes mellitus, depression, anxiety, panic attacks, and eating disorders.[4] Serious complications, such as an increase in the risk of developing endometrial hyperplasia and neoplasia, can also occur.[5] It was found that women suffering from PMOS have a lower ovulation rate as well as a lower pregnancy rate.[6] Based on the severity of metabolic and ovarian symptoms, PMOS can be classified into four main phenotypes (A, B, C, and D). Phenotype A is the most severe, and phenotype D is the least severe.[7]
A range of environmental factors, nutrition, and environmental pollutants contribute to the development of PMOS. Other factors include genetic predisposition, gut dysbiosis, diet, and lifestyle. Patients should adopt preventive behaviors to decrease the likelihood of developing associated diseases. Examples of preventive approaches are regular exercise and proper dietary habits.[7]
To treat this condition, drugs such as letrozole (LTZ) and clomiphene citrate (CC) have been proposed. LTZ is a widely used drug for reproductive disorders and neoplasia, namely breast carcinoma. It is a potent, selective aromatase inhibitor that reduces estrogen levels.[8] When the enzyme aromatase is inhibited, the level of estrogen drops, thus causing an increase in gonadotropin levels (luteinizing hormone level and follicle-stimulating hormone [FSH] level). This will, in turn, stimulate follicular growth, ultimately leading to ovulation. Many studies have shown that ovulation induction is about 70–80%.[9]
CC, on the other hand, has long been used as a 1st-line treatment. It is cost-effective and useful for inducing ovulation in PCOS.[10] It is a selective estrogen receptor modulator that competitively binds to estrogen receptors, thereby decreasing estrogen levels. This will trigger the release of FSH, which will stimulate follicle growth and maturation. Some antiestrogenic effects on the endometrium and cervical mucus, such as endometrial thinning and cervical mucus thickening, have been observed.[11,12]
Although both classes of drugs are used, their comparative effectiveness and safety remain uncertain and warrant evaluation, given their different mechanisms of action that can alter clinical outcomes and adverse effects. Several randomized controlled trials (RCTs) have found that LTZ is safer than CC. However, only the main adverse effects were considered, and the most effective drug for treatment still needs to be determined. This systematic review and meta-analysis aim to address this gap and provide evidence to inform clinical decision-making and update guidelines.
The primary objective of this systematic review and meta-analysis was to compare the efficacy and safety of LTZ and CC in women diagnosed with PMOS by evaluating pregnancy rate, ovulation rate, live birth rate, and incidence of adverse effects.
MATERIAL AND METHODS
Registration and protocol
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The research protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under ID number CRD420261426754. The full protocol is available in PROSPERO.[13]
Search strategy
A thorough search was conducted in PubMed, the Cochrane Central Register of Controlled Trials, Turning Research into Practice (TRIP), ScienceDirect, and Google Scholar to identify relevant manuscripts from 2012 to 2026. A combination of Medical Subject Headings terms/ keywords and Boolean operators was used for data extraction:
((Polyendocrine Metabolic Ovarian Syndrome) OR (PMOS) OR (Polycystic Ovary Syndrome) OR (PCOS)) AND ((Letrozole) OR (Aromatase Inhibitor)) AND (Clomiphene Citrate).
The strategy employed in the search, along with the total number of articles screened, is presented as shown in Table 1.
| Date and time of search | Database used | MeSH terms used | Filters used | Initial number | Omitted | Abstracts screened |
|---|---|---|---|---|---|---|
| July 03, 2026 at 20:53 |
PubMed | (Polyendocrine metabolic ovarian syndrome) OR (PMOS) OR (Polycystic Ovarian Syndrome) OR (PCOS) AND (Letrozole) OR (Aromatase Inhibitor) AND (Clomiphene Citrate) OR ((Polyendocrine metabolic ovarian[Title/ Abstract])) OR ((Polycystic Ovarian Syndrome[Title/Abstract])) OR ((Letrozole[Title/ Abstract])) OR ((Aromatase Inhibitor[Title/ Abstract])) OR ((Clomiphene Citrate[Title/ Abstract])) OR ((Polyendocrine metabolic ovarian syndrome[Title/Abstract])) OR ((PCOS[Title/ Abstract])) |
RCT, English, Humans, From 2012 to 2026 | 1247 | 1232 | 15 |
| July 03, 2026 at 21:44 |
Cochrane | MeSH descriptor:[Polycystic Ovary Syndrome] explode all trees OR MeSH descriptor:[clomiphene] explode all trees OR MeSH descriptor:[letrozole] explode all trees |
From 2012 to 2026 | 32 | 22 | 10 |
| July 03, 2026 at 22:05 |
TRIP | Polyendocrine metabolic ovarian syndrome OR PCOS OR Polycystic Ovarian Syndrome OR PCOS AND Letrozole OR Aromatase Inhibitor AND Clomiphene Citrate | From 2012 to 2026 | 34 | 22 | 12 |
| July 03, 2026 at 22:14 |
Google scholar | Polyendocrine metabolic ovarian syndrome OR PMOS OR Polycystic Ovarian Syndrome OR PCOS AND Letrozole AND Clomiphene Citrate | - | 53 | 45 | 8 |
| July 03, 2026 at 22:18 |
Science Direct | (Polyendocrine metabolic ovarian syndrome) OR (PCOS) OR (Polycystic Ovarian Syndrome) OR (PCOS) AND (Letrozole) OR (Aromatase Inhibitor) AND (Clomiphene Citrate) | From 2012 to 2026 | 51913 | 51841 | 72 |
| TOTAL | 53279 | 53162 | 117 | |||
MeSH: Medical Subject Headings, TRIP: Turning research into practice, RCT: Randomized controlled trial
Eligibility criteria
The eligibility criteria for this systematic review and meta-analysis were defined according to the PICOS framework (Population, Intervention, Comparison, Outcomes, Study design) to ensure a structured and reproducible study selection process. The population comprised women diagnosed with PCOS according to accepted diagnostic criteria; throughout the review, the updated PMOS terminology is used. The intervention evaluated was LTZ in the intervention group versus CC in the control group. The outcomes were ovulation rate, pregnancy rate, live birth, and adverse effects. The study design included RCTs comparing LTZ and CC in women with PMOS [Table 2].
| Population (P) | Patients diagnosed with polyendocrine metabolic ovarian syndrome |
|---|---|
| Intervention (I) | Letrozole |
| Comparison (C) | Clomiphene citrate |
| Outcome (O) | Ovulation rate, pregnancy rate, live birth, and adverse effects |
| Study design (S) | Randomized controlled trials |
Inclusion criteria
All RCTs published between 2012 and 2026 that evaluated women diagnosed with PCOS were assessed and considered for inclusion in this study. Only RCTs involving adult women diagnosed with PCOS and comparing either LTZ or CC were eligible. Full-text articles published in the English language were assessed and included in this systematic review and meta-analysis. Throughout this review, the updated terminology PMOS is used in accordance with the 2026 international consensus nomenclature.
Exclusion criteria
Non-RCTs, cohort studies, case–control studies, cross-sectional studies, case series, case reports, in vitro studies, animal experiments, commentaries, conference abstracts, editorials, letters to the editor, expert opinions, and review articles were excluded from the review.
Data synthesis
Data extraction was conducted on the titles. The titles were initially screened based on their abstracts. Thereafter, the full texts of the examined RCT titles that met the eligibility requirements were considered for the final selection. All articles were independently screened by KM and IB, and any discrepancies were resolved through discussion until consensus was reached. The extracted data included the study authors and year, type of study, sample size, body mass index (BMI), infertility duration, ovulation rate, pregnancy rate, live birth, and the adverse effects encountered.
Methodology quality assessment
The quality of the selected RCTs was independently assessed by two researchers, IB and KM. The Cochrane risk-of-bias tool for randomized trials (RoB2) was used to assess quality.[14]
The RoB2 tool is best suited for assessing domains at low, unclear, and high risk of bias. The Risk of Bias was assessed on five domains (D1–D5), which were as follows: D1 - Bias arising from the randomization process, D2 - Bias due to deviations from intended interventions, D3 - Bias due to missing outcome data, D4 - Bias in measurement of the outcome, and D5 - Bias in selection of the reported result.
The Risk-of-bias Visualization (ROBVIS) tool is a web-based application used to generate the traffic-light plots and the weighted bar plots.[15]
Data analysis and meta-analysis
The outcomes were analyzed as dichotomous variables and expressed as risk ratios (RRs) with 95% confidence intervals (CI). Pooled effect estimates were calculated using a fixed-effect model when included studies were statistically homogeneous. A fixed-effect model was used because heterogeneity across the pooled analyses was low (I2 ≤ 25%), indicating that the treatment effect was reasonably consistent across studies. Statistical heterogeneity among studies was assessed using the Chi-square test. The degree of heterogeneity was assessed using the I2 statistic. An I2 value of 0–25% was considered low heterogeneity, 26–50% moderate heterogeneity, 51–75% substantial heterogeneity, and >75% considerable heterogeneity. Statistical significance was determined using the Z-test, with a p < 0.05 considered statistically significant. Meta-analyses were performed, and forest plots were generated using the latest version of the Review Manager (RevMan Web) application (the Cochrane Collaboration, London, UK). The meta-analysis included all eligible RCTs identified through the predefined search strategy; therefore, a priori sample size estimation was not applicable.
Certainty of evidence
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the quality of evidence, and it was categorized as high, moderate, low, or very low certainty. It was graded across five domains: Risk of Bias, Inconsistency, Indirectness, Imprecision, and Publication Bias.[16]
RESULTS
An extensive literature search yielded a total of 53279 articles (PubMed – 1247, Cochrane – 32, TRIP – 34, ScienceDirect – 51913, Google Scholar – 53). Among these, 1287 were noted as duplicates and were excluded from the initial analysis by EndNote; 51803 records were marked as ineligible based on predetermined criteria, and 72 manuscripts were removed because of inadequate and unavailable information before screening. Thus 117 manuscripts were screened and 6 manuscripts were excluded based on inclusion and exclusion criteria. A total of 111 full-text articles were assessed for eligibility. 7 RCTs were finally assessed and included in the qualitative synthesis of the systematic review and meta-analysis. The PRISMA 2020 guidelines were followed and implemented throughout the production of this systematic review [Figure 1].
Table 3 shows the author, study year, study design, country, intervention, and doses of LTZ and CC. All the studies are RCTs in which LTZ was compared with CC. The studies have been conducted in India, USA, China, UK, and Iraq. The doses of LTZ used in the different studies were 2.5 mg. (Legro et al., 2014; Amer et al., 2017; Bansal et al., 2021; Wang et al., 2021; Al-Thuwaynee et al., 2023), 5 mg (Kar, 2012; Liu et al., 2017; Al-Thuwaynee et al., 2023), and 7.5 mg (Bansal et al., 2021; Al-Thuwaynee et al., 2023). The doses of CC ranged from 50 mg (Legro et al., 2014; Liu et al., 2017; Amer et al., 2017; Bansal et al., 2021; Al-Thuwaynee et al., 2023), 100 mg (Kar, 2012; Liu et al., 2017; Al-Thuwaynee et al., 2023) to a maximum of 150 mg (Liu et al., 2017; Bansal et al., 2021; Al-Thuwaynee et al., 2023). Table 4 compares age, BMI, and infertility duration between the Letrozole and Clomiphene Citrate groups.
| Author, Study year | Study design | Sample size | Country | Intervention | Dose of LTZ and CC |
|---|---|---|---|---|---|
| Kar, 2012[17] | RCT | 103 | India | CC and LTZ | LTZ 5 mg and 100 mg CC |
| Legro et al., 2014[18] | RCT | 750 | USA | CC and LTZ | CC 50 mg daily or LTZ 2.5 mg daily |
| Liu et al., 2017[19] | RCT | 268 | China | CC and LTZ | CC 50 mg for 5 days; and the daily dose gradually increased to 100 mg or 150 mg at maximum. LTZ 5mg for 5 days, maximum of three cycles. |
| Amer et al., 2017[20] | RCT | 159 | UK | CC and LTZ | CC 50 mg, LTZ 2.5 mg |
| Bansal et al., 2021[21] | RCT | 90 | India | CC and LTZ | LTZ 2.5 mg increased by 2.5 mg every cycle up to maximum of 7.5 mg; CC 50 mg increased by 50 mg every cycle up to a maximum of 150 mg maximum of three cycles. |
| Wang et al., 2021[22] | RCT | 270 | China | CC and LTZ | CC 50 mg daily or LTZ 2.5 mg daily. The dose was increased in subsequent cycles in both treatment groups in cases of non-response |
| Al-Thuwaynee et al., 2023[23] | RCT | 100 | Iraq | CC and LTZ | CC and LTZ CC in a stair step pattern (single dose of 50 mg, 100 mg, and 150 mg) LTZ single dose of 2.5, 5, and 7.5 mg |
RCT: Randomized controlled trial, LTZ: Letrozole, CC: Clomiphene citrate
| Author, Study year | Age for LTZ group/ years | Age for CC groups/ years | BMI for LTZ groups (kg/m2) | BMI for CC groups (kg/m2) | Infertility duration for LTZ groups/years | Infertility duration for CC groups/years |
|---|---|---|---|---|---|---|
| Kar, 2012[17] | 26.26±2.41 | 26.27±2.47 | 25.91±2.41 | 26.27±2.47 | 3.08±1.92 | 3.14±2.16 |
| Legro et al., 2014[18] | 28.8±4 | 28.9±4.5 | 35.1±9.0 | 35.2±9.5 | NA | NA |
| Liu et al., 2017[19] | 27.0±3.0 | 26.8±3.0 | 20.7±1.6 | 21.35±1.45 | 1±1 | 1±1 |
| Amer et al., 2017[20] | 28.3±4.4 | 28.1±4.2 | 27.8±4.4 | 27.0±3.0 | 1.5±0.5 | 1.5±0.5 |
| Bansal et al., 2021[21] | 27.0±3.56 | 26.0±3.97 | 23.90±3.57 | 23.10±3.64 | 3.9±2.3 | 3.4±2.5 |
| Wang et al., 2021[22] | 28.5±7.6 | 28.3±7.5 | 24.9±8.4 | 25.3±7.9 | 2.4±0.7 | 2.3±0.6 |
| Al-Thuwaynee et al., 2023[23] | 30.34±3.70 | 29.84±2.97 | 29.44±3.21 | 28.46±3.28 | NA | NA |
BMI: Body mass index, LTZ: Letrozole, CC: Clomiphene citrate
Table 5 shows author, study year, pregnancy rate for LTZ groups n (%), pregnancy rate for CC groups n (%), ovulation rate for LTZ groups n (%), ovulation rate for CC groups n (%), and live birth rate. Rate for LTZ groups n (%) and live birth rate for citrate groups n (%). The pregnancy rates for the LTZ group ranged between 20% and 62% compared to CC, which ranged between 7% and 44%. The ovulation rate for LTZ groups ranged from 62% to 87% compared to the ovulation rate for CC groups between 48% and 85%. The live birth rate for LTZ groups ranged between 26% and 50%, and live birth rate for citrate groups ranged from 19% to 36%.
| Author, Study year | Pregnancy rate for LTZ groups n (%) | Pregnancy rate for CC groups n (%) | Ovulation rate for LTZ groups n (%) | Ovulation rate for CC groups n (%) | Live birth rate for LTZ groups n (%) | Live birth rate for citrate groups n (%) |
|---|---|---|---|---|---|---|
| Kar, 2012[17] | 11/51 (21.6) | 4/52 (7.7) | 37/51 (72.5) | 32/52 (61.5) | NA | NA |
| Legro et al., 2014[18] | 117/374 (31.3) | 81/376 (21.5) | 331/374 (88.5) | 288/376 (76.6) | 103/374 (27.5) | 72/376 (19.1) |
| Liu et al., 2017[19] | 29/62 (46.8) | 22/63 (34.9) | 44/62 (71.5) | 31/63 (49.2) | NA | NA |
| Amer et al., 2017[20] | 49/80 (61.3) | 34/79 (43) | 67/80 (83.8%) | 63/79 (79.7%) | 39/80 (48.8) | 28/79 (35.4) |
| Bansal et al., 2021[21] | 19/45 (42.2) | 9/45 (20) | 85/98*(86.7) | 98/115 *(85.2) | NA | NA |
| Wang et al., 2021[22] | 23/90 (25.6) | 12/90 (13.3) | 57/90 (63.3) | 55/90 (61.1) | NA | NA |
| Al-Thuwaynee et al., 2023[23] | 11/50 (22) | 9/50 (18) | 43/50 (86) | 36/50 (72) | NA | NA |
Table 6 lists ADRs for CC and LTZ. CC was found to have more hot flushes 117/355 (33%), ovarian torsion 1/355 (0.3%), hospitalization 3/355 (0.8%), neonatal death (3%), hemorrhagic cysts 2/80 (2.5%), and blurred vision 1/50 (2%) compared to LTZ that was found to have more fatigue 78/359 (21.7%), dizziness 44/359 (12.3%), ectopic pregnancy 4/149 (2.7%), congenital anomaly 4/102 (3.9%), fetal death 4/102 (3.9%), and headache 3/50 (6%).*Ovulation rates are reported per treatment cycle rather than per participant.
| Author, Study year | Clomiphene | LTZ |
|---|---|---|
| Kar, 2012[17] | Endometrial thickness 7.61±1.96 mm (n=51) | Endometrial thickness 7.65±2.1 mm (n=52) |
| Legro et al., 2014[18] | Hot flushes 117/355 (33) Fatigue 53/355 (14.9) Dizziness 27/355 (7.6) Ovarian torsion 1/355 (0.3) Hospitalization 3/355 (0.8) Ectopic pregnancy 3/94 (3.2) Neonatal death 2/66 (3) Congenital anomaly 1/66 (1.5) Fetal death 1/66 (1.5) |
Hot flushes 73/359 (20.3) Fatigue78/359 (21.7) Dizziness 44/359 (12.3) Ovarian torsion 0/355 (0) Hospitalization 2/359 (0.6) Ectopic pregnancy 4/149 (2.7) Neonatal death 1/102 (1) Congenital anomaly 4/102 (3.9) Fetal death 4/102 (3.9) |
| Liu et al., 2017[19] | NA | NA |
| Amer et al., 2017[20] | Hemorrhagic cysts 2/80 (2.5) Acute cholecystitis 1/80 (1.3) Hospitalization 2/80 (2.5) Cyst formation 3/80 (3.8) Hot flushes 3/80 (3.8) Migraine 1/80 (1.3) Low mood 1/80 (1.3) Elevated liver enzyme 1/80 (1.3) Skin rash 1/80 (1.3) |
Hemorrhagic cystitis 1/80 (1.3) Hospitalization 1/80 (1.3) Cyst formation 3/80 (3.8) Diarrhea 2/80 (2.5) Nausea and vomiting 2/80 (2.5) Hot hands 1/80 (1.3) Heavy leg (1/80) Headache 1/80 (1.3) Neck pain 1/80 (1.3) Urinary tract infection 1/80 (1.3) Skin spot s1/80 (1.3) Hot flushes 0/80 (0) |
| Bansal et al., 2021[21] | NA | NA |
| Wang et al., 2021[22] | NA | NA |
| Al-Thuwaynee et al., 2023[23] | Nausea and vomiting 3/50 (6) Headache 2/50 (4) Dizziness 3/50 (6.0) Blurred vision 1/50 (2) |
Nausea and vomiting 2/50 (4) Headache3/50 (6) Dizziness 2/50 (4%) Blurred vision 0 (0%) |
LTZ: Letrozole, CC: Clomiphene citrate
The selected articles were critically appraised, with Figures 2 and 3 illustrating the results. The results of the assessment across the five domains were as follows: Bias from randomization process low risk and some concerns; bias from intended interventions low risk (100%); bias due to missing outcome data low risk (100%); bias due measurement of outcome low risk and some concerns, bias due to selection of reported results low risk, some concerns, and high risk; and overall risk of bias to be as follows: low risk, some concerns, high risk. The ROBVIS tool was used to generate the traffic light plot [Figure 2], and the summary/weighted bar plot [Figure 3] depicts the risk of bias.
A forest plot from a meta-analysis of seven RCTs, including 1507 women (752 in the LTZ group and 755 in the CC group), evaluated the effect of these drugs on pregnancy rate. A total of 259 pregnancies occurred in the LTZ group compared with 171 pregnancies in the CC group. The overall results show that LTZ increases pregnancy rates by 52% compared with CC. A pooled analysis using a fixed-effect model demonstrated that LTZ was associated with a significantly higher pregnancy rate than CC (RR = 1.52, 95% CI 1.29-1.78, Z = 5.10, p < 0.00001). There was no evidence of significant heterogeneity among the included studies (χ2 = 3.59, df = 6, p = 0.73, I2 = 0 %), supporting the consistency of the observed treatment effects across studies [Figure 4].
Figure 5 presents a forest plot of the ovulation rate, assessing the effects of LTZ and CC. The overall results show that LTZ increases ovulation by 13% as compared to CC. The pooled analysis demonstrated that LTZ was associated with a significantly higher ovulation rate compared to CC (RR = 1.13, 95% CI 1.07-1.19, Z = 4.70, p < 0.00001). There was low heterogeneity among the studies (χ2 = 8.48, df = 6, p = 0.24, I2 =29%), supporting consistent findings across studies.
A meta-analysis of two RCTs, including 909 participants (454 in the LTZ group and 455 in the CC group), assessed live birth outcomes. A total of 142 live births were observed in the LTZ group compared with 100 live births in the CC group. Overall, LTZ increased live birth rates by about 42% as compared to CC. The pooled fixed-effect analysis demonstrated that LTZ was associated with a significantly higher live birth rate than CC (RR = 1.42, 95% CI 1.14–1.77, Z = 3.16, p = 0.002). There was no evidence of heterogeneity between the included studies (χ2 = 0.004, df = 1, p = 0.85, I2 = 0 %), indicating consistent findings across studies [Figure 6].
Figure 7 presents a meta-analysis of adverse effects associated with LTZ and CC. A meta-analysis of two studies (n = 874) showed LTZ significantly reduced the risk of hot flushes compared to CC (RR = 0.60, 95% CI 0.47–0.78, p < 0.0001), (χ2 = 0.095, df = 1, p = 0.33, I2 = 0%), indicating consistent findings across studies [Figure 7a]. Figure 7b presents a meta-analysis of two studies on dizziness, including 814 participants (409 in the LTZ group and 405 in the CC group). The pooled analysis showed that LTZ was associated with a higher risk of dizziness compared with CC, but the difference was not statistically significant (RR = 1.52, 95% CI 0.98-2.35, Z = 1.86, p = 0.06). There was no evidence of heterogeneity among the included studies (χ2 = 0.092, df = 1, p = 0.34, I2 = 0 %), indicating consistent findings across studies. A meta-analysis of two studies including 260 participants showed no significant difference in the incidence of headache between LTZ and CC (RR = 1.80, 95% CI 0.39–8.21, Z = 0.76, p = 0.45). There was no evidence of heterogeneity among the included studies (χ2 = 0.14, df = 1, p = 0.71, I2 = 0 %), indicating consistent findings across studies [Figure 7c]. A meta-analysis of two studies including 874 participants found no statistically significant difference in hospitalization between LTZ and CC (RR = 0.60, 95% CI 0.14-2.47, Z = 0.71, p = 0.48). There was no heterogeneity between studies (I2 = 0%) [Figure 7d].
Table 7 presents the GRADE assessment of all RCTs, which provide a high-certainty starting level of evidence. For the primary outcomes, the certainty of the evidence for pregnancy and ovulation rates remained high, as no serious concerns were identified regarding risk of bias, inconsistency, indirectness, imprecision, or publication bias. The certainty of evidence for live birth was downgraded by 1 level to moderate due to concerns about risk of bias in the included studies, despite the significant benefit of LTZ over CC. For the adverse effects, including hot flushes, dizziness, and headache, the certainty of evidence was downgraded by 3 levels to very low due to serious limitations in study quality, imprecision arising from small sample sizes and wide CIs, and other methodological concerns. Overall GRADE assessment indicates high confidence in the evidence supporting the effectiveness of LTZ for improving pregnancy, ovulation outcome, and live births.
| Outcome | Risk of Bias | Inconsistency | Indirectness | Imprecision | Publication Bias | Final GRADE |
|---|---|---|---|---|---|---|
| Pregnancy rate | Not serious | Not serious | Not serious | Not serious | Undetected | High |
| Live birth | Serious | Not serious | Not serious | Not serious | Undetected | Moderate |
| Ovulation rate | Not serious | Not serious | Not serious | Not serious | Undetected | High |
| Adverse events | Serious | Not serious | Not serious | Serious | Suspected | Very low |
GRADE: Grading of Recommendations Assessment, Development, and Evaluation
Table 8 depicts a summary of findings (GRADE) for LTZ versus CC. GRADE assessment based on RCTs demonstrated high certainty of evidence for improved pregnancy (RR = 1.52, 95% CI 1.29–1.78) and ovulation rates (RR = 1.14, 95% CI 1.08–1.21) with LTZ compared with CC. The certainty of evidence for live birth was moderate (RR = 1.42, 95% CI 1.14–1.77). For adverse effects, LTZ significantly reduced hot flushes (RR = 0.60, 95% CI 0.47–0.78), but dizziness (RR = 1.52, 95% CI 0.98– 2.3) and headache (RR = 1.80, 95% CI 0.39–8.21) increased with LTZ. The certainty of evidence for all the adverse effects was very low.
| Outcome | Participants (studies) | Relative effect (RR) | Absolute effect LTZ versus CC (per thousand) |
Certainty (GRADE) |
|---|---|---|---|---|
| Pregnancy rate | 1507 women (7RCTs) | (RR=1.52, 95% CI 1.29–1.78) | +117 (344 vs. 227) | High |
| Live birth | 909 (2 RCTs) | (RR=1.42, 95% CI 1.14–1.77) | +93 (313 vs. 220) | Moderate |
| Ovulation rate | 1630 (7 RCTs) | (RR=1.13, 95 % CI 1.07 , 1.19) | +91 (791 vs 700) | High |
| Adverse events | ||||
| Hot flushes | 874 (2 RCTs) | (RR=0.60, 95% CI 0.47–0.78) | 60 fewer/1000 women* | Very low |
| Dizziness | 814 (2 RCTs) | (RR=1.52, 95% CI 0.98–2.3) | +42/1000 women* | Very low |
| Headache | 260 (2 RCTs) | (RR=1.80, 95% CI 0.39–8.21) | +40/1000 women* | Very low |
DISCUSSION
Pregnancy rate
This systematic review and meta-analysis showed that LTZ had a higher pregnancy rate and ovulation rate compared to CC: LTZ is significantly more effective than CC for improving the pregnancy rate, with a 52% higher chance of achieving the outcome (RR = 1.52, 95% CI 1.29–1.78, p < 0.00001). The studies are highly consistent (I2 = 0%).[17-23] A meta-analysis by Miller et al. also showed that LTZ was associated with a significantly higher pregnancy rate (RR = 1.57, 95% CI 1.39–1.76). The studies are highly consistent (I2 = 21%).[24] The pregnancy rate for the LTZ group ranged from 20% to 62%, compared with CC, which ranged from 7% to 44%. Another study by Banerjee Ray et al. also showed higher pregnancy rates in the LTZ group (28.9% vs. 17.9%, respectively).[25] Sakar et al. also found that the pregnancy rate was higher in the LTZ group than in the CC group (32.7% and 17.8%, respectively).[26] The superior efficacy of LTZ is likely attributable to its reversible inhibition of aromatase, which induces a physiological rise in follicle-stimulating hormone levels while avoiding the prolonged anti-estrogenic effects of CC on the endometrium and cervical mucus. Consequently, LTZ promotes monofollicular development, preserves endometrial receptivity, and creates a more favorable environment for conception, thereby translating improved ovulation into higher pregnancy rates.
Ovulation rate
LTZ is also significantly more effective than CC for improving the ovulation rate, with about a 16% higher chance of achieving the desired outcome (RR = 1.13, 95% CI 1.07-1.19, Z = 4.70, p <0.00001). The studies are highly consistent (I2 = 29%).[17-23] The ovulation rate for LTZ groups ranged from 62% to 87% compared to the ovulation rate for CC groups between 48% and 85%. The study by Banerjee Ray et al. also showed a higher ovulation rate in the LTZ group compared to the CC group (86.9% vs. 61.5%, respectively).[25] The 2021 study by Sakar et al. also found that ovulation lasted significantly longer in the LTZ group than in the CC group (17.3 ± 7.7 vs. 22.4 ± 8.1 days). The ovulation rate was higher in the LTZ group than in the CC group (83.6% and 64.2%).[26] This difference in pregnancy and ovulation rates was explained by Behnoud et al., who found that the 2 isomers of clomiphene (En Clomiphene and Zu Clomiphene) used in treatment had different excretion rates from the body. Zu Clomiphene takes a very long time to be excreted, thus causing unwanted adverse drug reactions (ADRs) and anti-estrogenic effects on cervical mucus and endometrium.[27]
Live births
Live birth rates were higher in the LTZ group than in the CC group (RR = 1.42, 95% CI 1.14–1.77, p < 0.002). The studies are highly consistent (I2 = 0%). A meta-analysis by Miller et al. also showed that LTZ has superior efficacy for this outcome (RR = 1.54, 95% CI 1.24–1.91). The studies are highly consistent (I2 = 35%).[18,20,24]
Legro et al. reported a higher live birth rate in the LTZ group than in the CC group, 103/374 (27.5%) versus 72/376 (19.1%), respectively.[18] Amer et al. also demonstrated that the live birth rate was higher in the LTZ group than in the CC group: 39/80 (48.8%) versus 28/79 (35.4%), respectively.[20] This finding can be further strengthened by another study by Amar et al., which found that LTZ resulted in a 40% increase in live birth rate compared to CC, which resulted in a 35% increase.[20] Wang et al. also showed better live birth rates with LTZ.[28] This difference in live birth rates is due to CC having a long half-life (about 2 weeks), which produces anti-estrogenic effects and thins the endometrium, affecting implantation. It was also found that an elevated BMI might be associated with a higher infertility rate.[20] Nevertheless, the beneficial effect of LTZ was consistently observed across studies despite differences in baseline BMI. Live birth is the most clinically relevant reproductive outcome because it reflects successful conception through delivery. Therefore, the improved live birth rate further supports the clinical benefit of LTZ.
ADR
This systematic review and meta-analysis found that LTZ significantly reduced hot flushes (RR = 0.60, 95% CI 0.47–0.78), but dizziness (RR = 1.52, 95% CI 0.98–2.3) and headache (RR = 1.80, 95% CI 0.39–8.21) increased with LTZ as compared to CC.[18,20,23] Even though CC resulted in more hospitalization and hot flushes than from LTZ, dizziness and headache were experienced more in LTZ. Sakar et al., however, showed that patients in the CC group experienced more ADRs compared to the LTZ group.[26] The cause of ADR in LTZ is due to the fact that the latter can cross the blood– brain barrier, thus inhibiting the synthesis of estrogen in the hippocampus and can thus cause cognitive dysfunction and other neurological symptoms.[29] According to the GRADE assessment, the certainty of evidence for adverse events was very low because only a limited number of randomized trials reported these outcomes, sample sizes were small, CIs were wide, and methodological limitations were present. Consequently, no firm conclusions can be drawn regarding the comparative safety profiles of the two agents, and larger well-designed randomized trials with standardized adverse event reporting are required.
The present findings are consistent with current international infertility guidelines, which recommend LTZ as the preferred first-line pharmacological agent for ovulation induction in women with PMOS/PCOS because of its superior ovulation, pregnancy, and live birth outcomes. The high certainty of evidence for pregnancy and ovulation outcomes observed in the present review further supports these recommendations.
Strengths
This study has several strengths. Only RCTss were included. A systematic search was conducted across multiple databases to synthesize the data. A meta-analysis was performed to generate pooled estimates. The quality of the included studies was assessed using the Cochrane Risk of Bias tool (RoB 2), and the certainty of the evidence for each outcome was evaluated using the GRADE approach. The inclusion of both RoB2 and GRADE provides a comprehensive assessment of methodological quality and certainty of evidence. Both efficacy (pregnancy, ovulation, and live birth) and safety outcomes were evaluated, providing clinically relevant evidence to improve decision-making. This study provides evidence to inform the development of future treatment guidelines for managing polyendocrine metabolic syndrome, with the aim of inducing ovulation and improving reproductive outcomes.
Limitations
This review has several limitations. Only English-language studies were included, which may introduce language bias. Publication bias was not formally assessed because of the limited number of included studies. Clinical heterogeneity existed due to variations in drug dosages, treatment protocols, participant characteristics, and historical diagnostic criteria for PCOS, although statistical heterogeneity was low. In addition, evidence for live birth was based on only two RCTs, and the certainty of evidence for adverse events was very low due to the limited number of studies and low event rates. Further large, well-designed multicenter RCTs are needed to strengthen the evidence.
CONCLUSION
LTZ was more effective than CC in improving pregnancy, ovulation, and live birth rates in women with PMOS, with high to moderate certainty of evidence. Although LTZ was associated with fewer hot flushes, the certainty of evidence for adverse effects was very low. These findings support current evidence favoring LTZ as the preferred first-line ovulation induction agent, pregnancy, and live birth outcomes in women with PMOS and may guide future evidence-based clinical guidelines.
What is already known about this topic
Both CC and LTZ are key therapeutic drugs used in the management of PMOS and have demonstrated improvements in ovulation and pregnancy rates.
LTZ is an aromatase inhibitor that inhibits estrogen by repressing the enzyme aromatase. It is an ovulation inducer used in women with infertility and endometrial thickness
CC is a Selective Estrogen Receptor Modulator that selectively binds to estrogen receptors in the hypothalamus, ovary, endometrium, and cervix, producing estrogenic and anti-estrogenic effects
What this study adds
LTZ is found to be better and improves pregnancy rate (RR = 1.13, 95% CI 1.07-1.19), ovulation rates (RR = 1.14, 95% CI 1.08–1.21), and live birth rates (RR = 1.42, 95% CI 1.14–1.77) compared with CC.
LTZ significantly reduced hot flushes (RR = 0.60, 95% CI 0.47–0.78), but dizziness (RR = 1.52, 95% CI 0.98–2.3) and headache (RR = 1.80, 95% CI 0.39–8.21) were more frequent with LTZ than with CC.
These findings support LTZ as the preferred first-line agent for ovulation induction, pregnancy, and live birth outcomes in women with PMOS (historically diagnosed as PCOS) and may guide future evidence-based clinical guidelines.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
Dr. Indrajit Banerjee and Prof. Vipul D. Yagnik is on the Editorial Board of the Journal.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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