Polycystic ovary syndrome (PCOS) is believed to be a common manifestation caused by multiple etiologies, which may be the result of the combined action of mental, psychological, environmental and drug factors. PCOS is a medical condition characterized by severe hormonal imbalance, abnormal follicular development, and thickened envelopes, leading to obstruction of follicular discharge which subsequently results in infertility (1) and even more negative impacts (e.g., teratogenesis, premature delivery, miscarriage, pregnancy-related complications) (2). Knowledge about the management of PCOS is evolving. However, it remains difficult to treat PCOS largely due to the complex etiology and heterogeneous clinical manifestations. Therefore, symptomatic therapy is mainly used. If PCOS patients are not adequately treated for a long period of time, both the reproductive system and other systems will be affected. Letrozole, a highly effective and selective aromatase inhibitor, is able to prevent the conversion of androgens into estrogen by effectively inhibiting aromatase activity. When the level of estrogen decreases, the ability to negatively inhibit the hypothalamus-pituitary-ovarian (HPO) axis is lost. Consequently, gonadotropin is elevated for better follicle development (3). When it comes to therapeutic agents, neither the effective rate nor the pregnancy success rate of the single use of letrozole for the treatment of PCOS combined with infertility is optimistic (4). However, it is promising that some clinical studies have achieved certain success in the treatment of PCOS with aspirin combined with letrozole, but there are only a relatively small number of single-center studies and the results of clinical reports are not consistent with each other. Therefore, this systematic review and meta-analysis aims to evaluate the efficacy and safety of aspirin combined with letrozole for PCOS and infertility, providing evidence for clinical treatment.
We present the following article in accordance with the PRISMA reporting checklist (available at http://dx.doi.org/10.21037/apm-21-606).
Criteria for inclusion and exclusion
We included randomized controlled trials (RCTs) with or without blinding. Studies were restricted to those published in Chinese and English.
We reviewed studies with participants who met the diagnostic criteria of PCOS (5), with restrictions on age, gender, and course of disease.
The experimental group was treated with aspirin combined with letrozole, and the control group was treated with letrozole alone, with no restrictions on the total daily dose and course of treatment.
(I) Endometrial thickness; (II) cervical mucus score; (III) ovulation rate; (IV) mature follicles; (V) pregnancy rate; (VI) abortion rate; (VII) adverse events (AEs).
(I) Non-RCT study; (II) studies published in non-Chinese and non-English languages; (III) duplicate studies, experience summaries, case studies, reviews, studies with incomplete outcome data, animal experiments, meeting minutes; (IV) studies evaluating less than 15 cases; (V) patients failed to take medicine regularly and quantitatively as prescribed by the doctor; (VI) the loss rate of the subjects was >20%.
We searched studies through the China National Knowledge Internet (CNKI), VIP database (VIP), the Wanfang database, the Chinese Biomedical Database (CBM), MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception to December 26, 2020 using Chinese and English search terms relevant to this review. The Chinese search terms used were aspirin, letrozole, polycystic ovary syndrome, and PCOS. The English search terms used were aspirin, letrozole, and polycystic ovary syndrome.
Data extraction and quality assessment
Two of the authors independently extracted general information (e.g., the first author, year of publication, research period, the number of cases, age, intervention and treatment), and outcome indicators (endometrial thickness, cervical mucus score, ovulation rate, mature follicles, pregnancy rate, miscarriage rate, adverse events). Disagreement was resolved by a third investigator. When relevant data was missed or unclear, we tried to contact the original author for accurate data, and we excluded studies without data available.
Two reviewers independently appraised studies in the search strategy for the inclusion and exclusion criteria. In case of disagreements, a third reviewer was consulted to resolve the discrepancies. The overall quality of studies included was evaluated by the improved Jadad scoring (6). The scoring includes 4 aspects: (I) generation of random sequences; (II) allocation concealment; (III) blinding method; (IV) follow up (withdrawal and quitting). Low quality studies: 1–3 points; high quality studies: 4–7 points.
The RevMan software package was used for meta-analyses and statistical tests. The mean difference (MD) was used for measurement of continuous variables. Odds ratio (OR) was used as the effect analysis statistic, and interval estimation was presented with 95% confidence intervals (CI). The assessment of heterogeneity between the included studies was performed using the χ2 test. When there was no significant heterogeneity between the results (P>0.10, I2≤50%), the fixed effects model was used for meta-analysis; otherwise, the random effects model was used. Repeated operation analysis was performed to estimate the same index. One study was deleted each time to show the impact of a particular study on the combined effect, and then the study was excluded for sensitivity analysis. At the same time, the heterogeneity between subgroups was assessed when there was heterogeneity. P value <0.05 was considered statistically significant.
Characteristics of articles
With the first search, we included 74 studies. Following the selection of studies according to the inclusion and exclusion criteria, 10 studies were eligible for final analysis (7-16). A total of 948 patients were included, of which 479 were in the experimental group and 469 were in the control group. The whole study selection process is depicted in Figure 1. The basic information of studies is shown in Table 1.
Methodological quality evaluation results
A total of 10 included randomized controlled articles were scored according to the modified Jadad scale (5 scored 3 marks and 5 scored 2 marks) (Table 2).
An improvement in endometrial thickness in patients with PCOS treated with aspirin combined with letrozole was reported in 5 studies (420 patients) (7,9,13,15,16). No significant heterogeneity was found among studies (P=0.44, I2=0%). The fixed effect model combined effect size was used for analysis. With aspirin combined with letrozole treatment, endometrial thickness was significantly higher than that of the single use letrozole group (MD=1.98, 95% CI: 1.63–2.34, P<0.00001) (Figure 2).
Cervical mucus score
The cervical mucus score in patients with PCOS treated with aspirin combined with letrozole was assessed in 3 studies (274 patients) (9,13,16). No significant heterogeneity was found among studies (P=0.60, I2=0%). The fixed effect model combined effect size was used for analysis. With aspirin combined with letrozole treatment, the cervical mucus score was significantly higher than that of the single use letrozole group (MD=1.65, 95% CI: 1.32–1.98, P<0.00001) (Figure 3).
The ovulation rate in patients with PCOS treated with aspirin combined with letrozole was assessed in 4 studies (366 patients) (7,8,10,14). No significant heterogeneity was found among studies (P=0.51, I2=0%). The fixed effect model combined effect size was used for analysis. With aspirin combined with letrozole treatment, the ovulation rate was significantly higher than that of the single use letrozole group (OR=3.50, 95% CI: 2.08–5.91, P<0.00001) (Figure 4).
Mature follicles in patients with PCOS treated with aspirin combined with letrozole were assessed in 3 studies (244 patients) (8,13,15). No significant heterogeneity was found among studies (P=0.41, I2=0%). The fixed effect model combined effect size was used for analysis. With aspirin combined with letrozole treatment, mature follicles were significantly higher than those of the single use letrozole group (MD=0.65, 95% CI: 0.51–0.78, P<0.00001) (Figure 5).
The pregnancy rate in patients with PCOS treated with aspirin combined with letrozole was assessed in 9 studies (896 patients) (7-14,16). No significant heterogeneity was found among studies (P=0.86, I2=0%). The fixed effect model combined effect size was used for analysis. With aspirin combined with letrozole treatment, the pregnancy rate was significantly higher than that of the single use letrozole group (OR=3.06, 95% CI: 2.28–4.12, P<0.00001) (Figure 6).
The abortion rate in patients with PCOS treated with aspirin combined with letrozole was assessed in 4 studies (366 patients) (7,10,11,16). No significant heterogeneity was found among studies (P=0.43, I2=0%). The fixed effect model combined effect size was used for analysis. With aspirin combined with letrozole treatment, the abortion rate was significantly lower than that of the single use letrozole group (OR=0.20, 95% CI: 0.11–0.38, P<0.00001) (Figure 7).
The AEs in patients with PCOS treated with aspirin combined with letrozole were assessed in 4 studies (400 patients) (9,10,12,15). No significant heterogeneity was found among studies (P=0.23, I2=30%). The fixed effect model combined effect size was used for analysis. There was no statistically significant difference in the incidence of AEs between the 2 groups (OR=0.76, 95% CI: 0.44–1.32, P=0.33) (Figure 8).
Publication bias analysis was carried out based on the pregnancy rate index (Figure 9). The symmetry of the skewed funnel plot indicates a publication bias.
PCOS is one of the most common endocrine and metabolic disorders, accounting for 30–60% of infertility in women of child-bearing age. It is characterized by menstrual disorders or amenorrhea, hirsutism, infertility, acne, and polycystic changes in the bilateral ovaries (17). Current studies have focused on PCOS in the treatment of infertility since clinical manifestations of this disease are extremely heterogeneous. PCOS is associated with high androgen, high estrogen, and low progesterone levels in the body, leading to infertility. Letrozole is an effective aromatase inhibitor that significantly reduces the negative feedback regulation caused by estrogen on the hypothalamic pituitary, stimulates follicular development, promotes the ovulation cycle, improves the responsiveness of the ovaries, restores the ovulation function of the ovaries, and has a good ovulation-stimulating effect (18,19). In addition, it improves the thickness of the endometrium (20,21). A previous study (22) indicated that letrozole could promote the secretion of cervical mucus for successful travel of sperm and could improve the endometrium to create a suitable environment for embryo implantation. However, the single use of letrozole for infertility of PCOS cannot effectively improve the pregnancy rate (4,23).
This meta-analysis of 10 RCTs and 948 patients with PCOS included 479 cases in the test group and 469 cases in the control group. Compared with the single use of letrozole, aspirin combined with letrozole can significantly increase endometrial thickness (MD=1.98, 95% CI: 1.63–2.34, P<0.00001), cervical mucus scores (MD=1.65, 95% CI: 1.32–1.98, P<0.00001), the ovulation rate (OR=3.50, 95% CI: 2.08–5.91, P<0.00001), the number of mature follicles (MD=0.65, 95% CI: 0.51–0.78, P<0.00001), and the pregnancy rate (OR=3.06, 95% CI: 2.28–4.12, P<0.00001), and can significantly decrease the abortion rate (OR=0.20, 95% CI: 0.11–0.38, P<0.00001). The hemodynamics of the reproductive organs are closely related to the functional status. Specifically, both blood perfusion and blood circulation are key factors that decide whether follicles develop normally or not. Aspirin has antiplatelet and anticoagulant effects, and is widely used in the clinical treatment of rheumatism. It also has anti-inflammatory, conventional antipyretic, and analgesic effects (24,25). In the treatment of PCOS, aspirin combined with letrozole achieves better therapeutic effects than letrozole alone. There are several possible explanations for the increased pregnancy rate with this combination: (I) aspirin promotes uterine artery blood flow that improves local tissue microcirculation in patients with PCOS. Additionally, it promotes endometrial development that creates better conditions for fertilized eggs to implant (26); (II) aspirin prevents platelet aggregation, promotes blood circulation in the uterus and ovaries of patients with PCOS, improves the disordered endocrine state, increases the content and concentration of progesterone, and increases the ovulation rate. Additionally, it reduces the excitability of the uterus and the sensitivity of the uterine muscle, protects the embryo, and improves the successful pregnancy rate (27); (III) aspirin significantly improves the morphology and thickness of the endometrium and increases the blood perfusion of local tissues. When combined with letrozole, aspirin maintains the balance of sex hormones, blocks the hypercoagulable reaction in the choriodecidual space, and reduces the abortion rate significantly (28,29). Therefore, aspirin combined with letrozole has better results in the treatment of infertility.
There are several limitations of this meta-analysis: (I) as for the overall quality of the included studies, most of them had small sample sizes, and treatment periods varied significantly among them, despite strict standards of inclusion and exclusion criteria; (II) as for the details of the study design, RCTs were not standardized enough. For example, some studies ignored the importance of allocation concealment and blinding methods in randomized controlled studies, and some studies failed to mention the specific randomization methods; (III) the follow-up time was different in various studies, and some studies did not report the follow-up time, while the follow-up time of some studies still needed to be extended. The issues mentioned above could have affected the accuracy of the meta-analysis.
In conclusion, the combination of aspirin and letrozole is safe and effective in the treatment of infertility in PCOS. Nevertheless, a large number of multi-center and high quality RCTs are still needed for verification to overcome the limitations of the studies included.
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/apm-21-606
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-21-606). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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(English Language Editor: C. Betlazar-Maseh)