Treatment of Polycystic Ovary Syndrome-Related Infertility Using a Combination of Compound Xuanju Capsules and Hormone Therapy: A Meta-Analysis

Objective To compare the therapeutic effects of compound Xuanju capsules combined with hormone therapy versus hormone therapy alone on polycystic ovary syndrome (PCOS)-related infertility using a meta-analysis. Methods Electronic databases including PubMed, The Cochrane Library, Web of science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP database were manually searched. The quality of included studies was evaluated based on the Cochrane systematic review standards, and the valid data were extracted for meta-analysis using Revman 5.3 software. Results A total of 14 randomized controlled trials accounting for 1249 patients were included. Meta-analysis showed that patients in the compound Xuanju capsule + hormone therapy group had higher estradiol levels and overall rates of effective treatment than those in the hormone therapy alone group. Moreover, they also exhibited lower levels of luteinizing hormone and follicle-stimulating hormone as well as lower Kupperman scores than the hormone therapy alone group. Fourteen studies were included in this meta-analysis, and although all reports mentioned the use of randomization, only eight described the specic method (e.g., randomization using a random number table). Concealment was not mentioned in most studies, and details of blinding, loss to follow-up, and withdrawal were not specically provided, affecting the strength of the evidence provided by the studies. In most studies, the measures of ecacy were the ovulation and pregnancy rates; LH, FSH, T, and E 2 levels; endometrial thickness; and overall rate of effective treatment. In contrast, few studies focused on the overall rate of effective Chinese medicine-based treatment, BBT, ovarian volume, maximum follicle diameter, follicle count, and HGF and VEGF levels. Future RCTs should not only be manner but should also include large sample sizes, strict randomization protocols, and a double-blind approach.


Introduction
In today's modern society, work-related stress has substantially increased, resulting in rising rates of female reproductive disorders such as polycystic ovary syndrome (PCOS), infertility, premature ovarian failure, and irregular menstruation. PCOS is a common condition associated with multimorbidity in women of reproductive age and is often accompanied by insulin resistance and obesity [1][2][3][4][5] . It is characterized by ovulatory disorders, hyperandrogenism, and polycystic ovarian changes, and its primary clinical manifestations are menstrual abnormalities, infertility, and acne. Infertility refers to a condition wherein women fail to achieve pregnancy after 1 year or more of regular unprotected sexual intercourse. In PCOS, ovulatory disorder is an important inducer of infertility. Currently, western allopathybased treatments for PCOS-related infertility use anti-androgens, aiming to regulate the menstrual cycle and induce ovulation. Hormone therapy with agents such as clomiphene, letrozole, tamoxifen, tripurelin, and progesterone is often the preferred modality for PCOS treatmen t [6][7][8][9][10] .
Although hormone therapy can improve hormone levels and the ovulation rate to a certain extent, it can cause several adverse effects and is less effective in improving clinical symptoms. Over the past few decades, the advantages of traditional Chinese medicine -which is gradually being applied for the treatment of PCOS-related infertility -are being highlighted. Some researchers have suggested that hormonal therapy combined with traditional Chinese medicine can improve therapeutic effects and pregnancy rates while exerting low toxicity and showing a good safety pro le. Therefore, in the present study, we aimed to conduct a meta-analysis of the current clinical ndings related to the effectiveness of compound Xuanju capsules combined with hormone therapy for the treatment of PCOS-related infertility in order to elucidate whether this combination provides more advantages than hormone therapy alone.

Inclusion and exclusion criteria
All randomized controlled trials (RCTs) examining the effect of compound Xuanju capsules combined with hormone therapy for treating PCOS-related infertility were retrieved. Duplicate publications and studies containing erroneous, incomplete, or unavailable data were excluded. In addition, studies wherein compound Xuanju capsules + hormone therapy was not adopted in the treatment arm and those wherein hormone therapy alone was not adopted in the control arm were excluded.

Intervention and outcome measures
The treatment arm included compound Xuanju capsules + hormone therapy, whereas the control arm included hormone therapy alone. The outcome measures were the overall rate of effective treatment, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, the LH/FSH ratio, estradiol (E 2 ) levels, testosterone (T) levels, overall rate of effective Chinese medicine-based treatment, ovarian volume, ovulation rate, pregnancy rate, basal body temperature (BBT), antral follicle count, endometrial thickness, maximum follicle diameter, follicle count, and hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels.

Data extraction and quality evaluation
Two evaluators read the title and abstract independently. After excluding studies that clearly did not meet the inclusion criteria, they reviewed the full text to determine whether the studies should be included. Any disagreements were resolved via discussions. Based on the quality evaluation standards described in the Cochrane Handbook for Systematic Reviews of Interventions, the following aspects were evaluated [11] : (1) What random sequence generation was adopted?; (2) Was allocation concealment adopted?; (3) Was blinding adopted?; (4) Was there any incomplete outcome data bias?; (5) Was there selection bias?; and (6) Was there any other bias?

Statistical analyses
All the statistical analyses were performed using Review Manager Version 5.3 provided by the Cochrane Collaboration Network. Chisquare (χ 2 ) analysis was performed to evaluate heterogeneity. At I 2 < 50%, studies were considered to have homogeneity, and the xed effects model was used for analysis. At I 2 > 50%, studies were considered to have high heterogeneity, and the random effects model was used. Sensitivity analysis was performed to identify the source of heterogeneity. The e cacy indexes were estimated based on intervals. Enumeration data were expressed as odds ratios (ORs) with 95% con dence interval (CIs), and measurement data were expressed as weighted mean difference (MDs) and 95% CIs. The Z(u) test was used to combine statistics, and the probability (P) was obtained according to the Z(u) value. At P ≤ 0.05, the combined results of multiple studies were considered statistically signi cant.

Literature search results
A total of 572 articles were obtained after searching the databases. Of them, 262 were retrieved from CNKI, 56 from Wanfang Data, 253 from VIP, and 1 from Medline. No articles were obtained from the Cochrane Library and Web of Science databases. Of the 572 articles, 550 (including inter-database duplications and irrelevant studies) were excluded, and 22 full texts were obtained. Eight articles that did not meet the inclusion criteria were excluded after full-text review, and 14 RCTs were nally included ( gure 1).

Methodological quality assessment of included studies
Fourteen RCTs performed in China, accounting for a total of 1,249 patients with comparable baseline characteristics, were included in this study. The characteristics of the included population are shown in Table 1. As for outcome measures, 6 studies reported the ovulation rate; 11 reported the pregnancy rate; 12 reported FSH levels; 7 reported E 2 levels; 12 reported LH levels; 2 reported the LH/FSH ratio; 9 reported T levels; 5 reported endometrial thickness; 6 reported the overall rate of effective treatment; 2 reported the overall rate of effective Chinese medicine-based treatment; 2 reported BBT; 2 reported ovarian volume; 2 reported the maximum follicle diameter; 2 reported follicle count; 2 reported HGF levels; 2 reported VEGF levels; and 2 reported adverse effects. The general characteristics of all included studies are summarized in Table 1.

Safety and publication bias
Adverse effects were reported in only 2 studies, and the descriptions were not detailed. Hence, we were unable to perform a safety evaluation. We performed an inverted funnel plot analysis of the reciprocal of the OR standard errors for ovulation and pregnancy rates; LH, FSH, T, and E 2 levels; endometrial thickness; and overall rate of effective treatment. We found asymmetric distributions, suggesting that the studies had a small sample size and possible publication bias. The plots are displayed in Figure 20-27.

Discussion
The results of our study showed that the combination of compound Xuanju capsules and hormone therapy was more effective than hormone therapy alone in improving LH, FSH, and E 2 levels; the overall rate of effective treatment; Kupperman score; ovulation rate; pregnancy rate; LH/FSH ratio; T levels; endometrial thickness; overall rate of effective Chinese medicine-based treatment; BBT; ovarian volume; maximum follicle diameter; follicle count; and HGF and VEGF levels in patients with PCOS-related infertility.
PCOS is the main cause of ovulatory disorder-related infertility in women of reproductive age. PCOS causes hyperandrogenism, polycystic changes in the ovaries, obesity, and hirsutism and eventually leads to infertility, leading to high physiological and psychological burden and affecting quality of life. Western allopathy-based hormone therapy -which relies on E 2 , progesterone, clomiphene, letrozole, tamoxifen, and tripurelin -is the most common method for treating PCOS-related infertility. Such treatment can improve sex hormone levels, promote ovulation, and regularize the menstrual cycle. However, hormone therapy also has several side effects, such as cervical mucosal thickening, luteal insu ciency, luteinized unruptured follicle syndrome, and endometrial thinning. Moreover, it also shows low e cacy in improving clinical symptoms.
Compound Xuanju capsules are mainly composed of Formica fusca L., Epimedium brevicornu, Fructus cnidii, and Fructus lycii. Monarch Formica fusca L. ants are sour, salty, and warm and can promote healthy energy, nourish the blood, and induce Yang Qi, thereby promoting ovulation. Epimedium brevicornu and Fructus cnidii can warm the kidney and invigorate Yang energy, as well as dispel wind and dampness. Among them, Epimedium brevicornu exhibits a hormone-like effect and can increase the weight of reproductive organs in animals. Fructus lycii can have good effects on the kidneys and negate emptiness, draw Yang from Yin, and prevent the aforementioned disadvantages. Studies have suggested that compound Xuanju capsules are effective in warming the kidneys and uterus. Therefore, the use of compound Xuanju capsules along with hormone therapy provides combinatorial bene ts and creates a more harmonious environment in the female reproductive system.
In the present study, methodological quality assessment showed that most included studies were of low quality, with methodological issues related to randomization, blinding, and follow-up. Such issues can lead to bias and affect the accuracy and reliability of the studies. Fourteen studies were included in this meta-analysis, and although all reports mentioned the use of randomization, only eight described the speci c method (e.g., randomization using a random number table). Concealment was not mentioned in most studies, and details of blinding, loss to follow-up, and withdrawal were not speci cally provided, affecting the strength of the evidence provided by the studies. In most studies, the measures of e cacy were the ovulation and pregnancy rates; LH, FSH, T, and E 2 levels; endometrial thickness; and overall rate of effective treatment. In contrast, few studies focused on the overall rate of effective Chinese medicine-based treatment, BBT, ovarian volume, maximum follicle diameter, follicle count, and HGF and VEGF levels. Future RCTs should not only be designed in a more systematic and robust manner but should also include large sample sizes, strict randomization protocols, and a double-blind approach.
In summary, our meta-analysis showed that the combination of compound Xuanju capsules and hormone therapy is more effective than hormone therapy alone in treating PCOS-related infertility. However, these ndings require validation via more rigorous double-blind RCTs with a large sample size. Such validation could increase the credibility of the results and provide more reliable evidence supporting the use of compound Xuanju capsules in combination with hormone therapy for treating PCOS-related infertility.

Abbreviations
PCOS, polycystic ovary syndrome; LH, luteinizing hormone; FSH, follicle-stimulating hormone; E 2, estradiol; T, testosterone; BBT, basal body temperature; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; OR, odds ratios; CI, con dence interval; MD, mean difference Declarations Ethics approval and consent to participate All experimental protocols involving animals were approved by the Ethics Committee of Zhenjiang Hospital of Traditional Chinese Medicine (Zhenjiang, China).

Consent to publish
All authors consent to publish this article.

Availability of data and materials
The analyzed datasets generated during the study are available from the corresponding author on reasonable request.   Comparison of FSH level Figure 6 Comparison of E2 level  Comparison of endometrial thickness  Comparison of overall rate of effective Chinese medicine-based treatment Comparison of right ovarian volume Figure 17 Comparison of follicle count Figure 18 Comparison of maximum follicle diameter Figure 19 Comparison of HGF        Funnel plot of overall rate of effective treatment