Acupuncture for oligospermia and asthenozoospermia

Abstract Background: Acupuncture is widely used for oligospermia and asthenozoospermia in China, but its effect is unclear. We aimed to determine the effectiveness and safety of acupuncture in treating oligospermia and asthenozoospermia. Methods: An electronic search for randomized controlled trials evaluating acupuncture treatment in patients with oligospermia and asthenozoospermia published from database inception to October 2018 was conducted in PubMed, EMBASE, the Chinese Biomedical Literature Database, the Chinese Scientific Journal Database (VIP Database), the Wan-Fang Database, the China National Knowledge Infrastructure and the Cochrane Library. We established search terms related to 3 areas (oligospermia, asthenozoospermia, and acupuncture). Two authors independently screened all identified citations and extracted the data. The methodological quality of the included trials was assessed using the Cochrane criteria. Results: Seven studies with a total of 527 subjects were screened according to inclusion and exclusion standards, and most of the studies had significant methodological weaknesses. Seven randomized controlled trials tested the effects of acupuncture compared with placebo acupuncture and conventional medications in patients with oligospermia and asthenozoospermia. The results of this study suggest that acupuncture alone has no clear superiority in improving sperm motility (standard mean difference [SMD] = 1.13, 95% confidence interval [CI]: −0.64 to 2.89), the sperm concentration (SMD = 0.32, 95% CI: 0.27–0.92) or semen volume compared with placebo acupuncture. No significant difference was found between acupuncture alone and conventional medications in improving sperm motility (SMD = −0.53, 95% CI: −2.54 to 1.48), the sperm concentration (SMD = −1.10, 95% CI: −1.48 to −0.72) or semen volume. However, adjuvant acupuncture may enhance the effect of medications on improving sperm motility (SMD = 4.10, 95% CI: 1.09–7.12) and the sperm concentration (SMD = 1.07, 95% CI: 0.739–1.40), but the study heterogeneity was too high to establish robust conclusions. Conclusion: These results suggest that the current evidence does not support acupuncture as an effective treatment for oligospermia and asthenozoospermia; therefore, acupuncture is not currently recommended as a treatment for these conditions. However, owing to the high risk of bias among the included studies, the evidence is limited, and more large-scale, high-quality clinical trials are needed in the future. Trial registration number: PROSPERO CRD42018083885


Introduction
Because of harmful factors such as life pressures, worsening environments, and food contamination, [1,2] the incidence of infertility has increased annually worldwide. [3] Statistical results show that the infertility rate has reached 15% among people of childbearing age, [3] with 50% of cases attributable to male infertility. [4] Oligospermia and asthenozoospermia are common causes of male infertility. The World Health Organization defines oligospermia and asthenozoospermia as "a state of impaired sperm production and motility". [5] The main therapeutic strategy is drug treatment, including androgens, gonadotropins, corticosteroids, follicle-stimulating hormone, and antioxidants. [6] Systematic reviews have shown that some treatments are effective, but others are not. [7,8] China announced that the iconic one-child policy had finally been replaced by a universal two-child policy in 2015, resulting in a large birth demand among Chinese parents. [9] However, the quality of sperm has been decreasing markedly in China. [2] Meanwhile, a global decline in human sperm quality including low sperm production, inferior morphology, and poor motility has been noted in recent decades, [10] and the causes vary and are complex. [11] To increase the probability of pregnancy, many people turn to complementary and alternative medicine therapies. [12] Acupuncture is an important component of complementary and alternative medicine, [13] and some studies have suggested that acupuncture is a promising treatment for oligospermia and asthenozoospermia. [14] A systematic review concluded that acupuncture might improve semen quality, but the evidence was insufficient because of the small number of studies. [15] However, the review did not comprehensively search research papers in Chinese databases and used improper control groups (such as patients receiving Chinese herbal medicine and Chinese patent medicine), complicating objective evaluation of the clinical efficacy and safety of acupuncture in oligospermia and asthenozoospermia, and the previous review was also outdated; consequently, the effectiveness and safety of acupuncture for oligospermia and asthenozoospermia have not been verified. Despite limited high-quality evidence for the clinical efficacy of acupuncture in oligospermia and asthenozoospermia, acupuncture has been widely used in an attempt to reduce clinical symptoms and improve the quality of semen in China; therefore, the current research evidence must be summarized and analysed.
Therefore, the aim of this study was to assess the evidence from randomized controlled trials (RCTs) for acupuncture as a treatment method for patients with oligospermia and asthenozoospermia.

Methods
This is a systematic review, and ethical approval was not necessary. The protocol of this review was registered in the International Prospective Register of Systematic Reviews, and the trial registration number was CRD42018083885.

Literature search
We searched PubMed, EMBASE, the Chinese Biomedical Literature Database, the Chinese Scientific Journal Database (VIP Database), the Wan-Fang Database, the China National Knowledge Infrastructure and the Cochrane Library for relevant studies published prior to October 30, 2019. Studies published in Chinese or English languages were retrieved using a combination of keywords and subject terms. We established search terms related to 3 areas (oligospermia, asthenozoospermia, and acupuncture). The search strategy used in the PubMed database is shown in Table 1. We identified additional relevant articles by manually searching the references.

Study selection
We included all RCTs that used acupuncture for oligospermia and asthenozoospermia. The patients conformed to the diagnostic criteria established in the management guidelines for male infertility issued by the authoritative diagnostic organizations. Any types of acupuncture were included, including manual acupuncture, scalp acupuncture, auricular acupuncture, electropuncture, three-edged needle acupuncture, warm acupuncture and dry needling. The control groups included patients receiving placebo acupuncture, no treatment controls, or patients receiving other conventional drugs, such as androgens, gonadotropins, corticosteroids, folliclestimulating hormone and antioxidants. Acupuncture with active medicine was also included if the medicine was also applied to the control group. The primary outcomes were the indicators of semen motility and sperm morphology). The secondary outcome was adverse events due to the treatments. We excluded the following studies: (1) non-RCTs; (2) duplicate studies; (3) studies lacking data integrity; (4) studies of acupuncture combined with Chinese medicine; and (5) studies without the information of interest.

Data extraction and management
Two investigators [Wen Jia and Chuan Wang] independently investigated the titles, abstracts and full texts of the papers identified through database searches to confirm that they contained eligible trials. The investigators extracted the data based on a standard data collection table. The main extracted information included the first author, publication year, country, age, gender, sample size, interventions, follow-up period, outcomes and adverse events. All disagreements were resolved by a third author [Ying Yin]. All retrieved studies were input into EndNote 7X (Thomson Reuters, New York, NY, USA) software to manage the data. Table 1 Search strategy used in PubMed.

Number
Search items

Assessment of risk of bias
Two investigators [Wen Jia and Chuan Wang] independently evaluated the risk of bias in the included RCTs according to the Cochrane Collaborations tool. [16] The following seven factors were evaluated: (1) random sequence generation; (2) allocation concealment; (3) blinding of the participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias. Each factor was categorized as low risk, high risk or unclear. Any disagreements were resolved by a third author [Ying Yin].

Statistical analysis
We conducted all statistical analyses with RevMan V.5.3.3 software. The indicators of semen quality were expressed as the standard mean difference (SMD) with 95% confidence intervals (CIs). We used a random-effects model or a fixed-effects model for the metaanalysis of the included studies based on the existence of heterogeneity between the study results. Heterogeneity was assessed using Cochrane's Q test and I2 statistics. [17] We used a funnel plot to assess publication bias when 10 or more trials were included in a meta-analysis, and approximately symmetrical funnel plots were considered indicative of a low risk of bias. [18] 3. Results

Study screening and characteristics of the included studies
A total of 253 records were identified from 7 electronic databases; after 122 duplicates were excluded, 131 records were considered for screening. A total of 92 irrelevant records were excluded after screening the titles and abstracts. Thirty-two records were excluded after the full-text screening. Finally, 7 RCTs involving 527 patients were eligible for inclusion. [19][20][21][22][23][24][25] Figure 1 shows the flow chart of the study searches. The characteristics of the included studies are shown in Table 2.

Study description
All studies were published from 2003 to 2017; 5 trials were performed in China, [21][22][23][24][25] 1 was performed in Brazil [19] and 1 was performed in Germany. [20] Five studies were two-arm trials, [19][20][21][22][23] and 2 were three-arm trials. [24,25]  3.2.2. Acupuncture intervention. All treatment protocols were based on traditional Chinese medicine theory and the clinical experience of the acupuncturists. Three trials used manual acupuncture alone, [20,22,23] 1 trial used the combination of manual acupuncture and moxa, [19] 1 trial used the combination of manual acupuncture and fire needle, [21] 1 trial used the combination of transcutaneous electrical acupoint stimulation and tamoxifen, [24] and another trial used the combination of moxa and L-carnitine. [25] The acupoints for each trial are shown in Table 3.

Discussion
This systematic review included 7 RCTs involving 527 patients. Five kinds of acupuncture were identified in the treatment of oligospermia and asthenozoospermia, including manual acupuncture, moxa, manual acupuncture plus fire needle, manual acupuncture plus moxa, and transcutaneous electrical acupoint stimulation. The results of the meta-analysis showed no difference in semen quality improvements between acupuncture alone and placebo acupuncture or conventional medications. Acupuncture plus conventional medications may be more effective than conventional medication alone in improving semen quality, but the methodological quality of the included studies was very low, and the heterogeneity was high; thus, the current evidence was insufficient to draw definitive conclusions. Some observational studies have suggested that acupuncture might have an effect on male infertility, [26] and some nonrandomized control studies found that the sperm concentrations and the percentage of ultramorphologically normal sperm were significantly higher after acupuncture compared with the waiting list group. [14,27] Acar et al [28] suggested that acupuncture might improve testicular perfusion by stimulating the nerve. Siterman et al [29] suggested that acupuncture might reduce genital inflammatory reactions by enhancing immune responses. However, the mechanism of acupuncture related to sperm quality is not clear.
In this systematic review, only 7 studies were included in the statistical analysis. Three studies reported no significant differences between acupuncture and placebo acupuncture in improving sperm motility (SMD = 1.13, 95% CI: À0.64 to 2.89), [20,22] the sperm concentration (SMD = 0.32, 95% CI: À0.27 to 0.92), [20,22] or semen volume (3.7 ± 1.4 versus 3.8 ± 1.6). [20] Four studies found no significant difference between acupuncture and conventional medication in improving sperm motility (SMD = À0.53, 95% CI: À2.54 to 1.48), [21,[23][24][25] while 3 studies reported that conventional medication might be more effective than acupuncture in improving the sperm concentration (SMD = À1.10, 95% CI: À1.48 to À0.72). [23][24][25] Therefore, the current evidence does not support acupuncture as an effective treatment for oligospermia and asthenozoospermia, which differs from the result of a previous systematic review. [15] The main reason for this phenomenon is that the previous systematic review included RCTs that applied acupuncture plus an herbal mixture for oligospermia and asthenozoospermia and used the same herbal mixture as the control groups; however, the herbal mixture was not recommended for the treatment of oligospermia and asthenozoospermia by the clinical practice guidelines on infertility. Therefore, the research design of the previous review was not appropriate, and the results of that review were not objective.
Two studies found that acupuncture plus conventional medication was significantly more effective than conventional medication alone in improving sperm motility (SMD = 4.10, 95% CI: 1.09-7.12), [24,25] which seems to imply that acupuncture can help to enhance the effects of conventional drugs, but the heterogeneity among these studies was too high to make robust conclusions. The only statistically significant improvement with a low level of heterogeneity (P = .24) seems to be the semen concentration (SMD = 1.07, 95% CI: 0.739-1.40), [24,25] and the result is same as the result of the previous study, [27] reflecting that acupuncture may have potential therapeutic value in sperm disorders. However, because of high statistical heterogeneity in other results, this does not support acupuncture as an effective treatment for oligospermia and asthenozoospermia.
One trial reported 1 case of fainting during acupuncture, [23] and another trial reported that all patients had no adverse events during treatment. [20] However, most trials did not report whether adverse events occurred during treatment; thus, whether acupuncture is a safe treatment for oligospermia and asthenozoospermia is uncertain.
The quality of the included trials was low, and the lack of blinding and randomization increased the selection bias and performance bias. Incomplete information and an unreasonable loss of patients led to a confounding bias in these results. Small sample sizes complicated determination of firm conclusions regarding the study outcomes, and the results of this study may change as more trials are conducted.

Conclusion
The results of this study suggest that acupuncture alone has no clear superiority in improving sperm quality compared with conventional medications or placebo acupuncture, so acupuncture is not recommended for improving the sperm quality and count of healthy individuals. Adjuvant acupuncture may enhance the effect of conventional medications, but the study heterogeneity was too high to make robust conclusions. The current evidence does not support acupuncture as an effective treatment for oligospermia and asthenozoospermia, more large-scale, highquality clinical trials will be needed in the future.