The role of N-acetyl-cysteine (NAC) orally daily on the sperm parameters and serum hormones in idiopathic infertile men: A systematic review and meta-analysis of randomised controlled trials

Zhongbao Zhou1, Yuanshan Cui1, 2, Xiaoyi Zhang3, Yong Zhang1

Abstract

The meta-analysis was performed to access the role of N-acetyl-cysteine (NAC) orally daily on the sperm parameters and serum hormones in idiopathic infertile men. Randomised controlled trials (RCTs) were retrieved using PubMed, EMBASE and Cochrane register databases. The references of included studies were also searched. Finally, three articles including 431 infertile men were analysed. The results indicated that the NAC group had a considerable improvement in sperm concentration (mean difference [MD], 3.80; p < .00001), ejaculate volume (MD, 0.69; p = .002), sperm motility (MD, 4.69; p < .0001) and normal morphology (MD, 1.68; p = .0002) compared with the placebo group. However, in terms of serum hormones, the NAC group did not show significant difference in increasing the serum levels of testosterone (MD, 1.35; p = .21), luteinising hormone (MD, 0.82; p = .40), follicle-stimulating hormone (MD, −7.48; p = .29) and prolactin (MD, −0.34; p = .32) compared with the placebo group. In conclusion, NAC orally daily produced a greater improvement in sperm concentration, ejaculate volume, sperm motility and normal morphology for idiopathic infertile men, whereas no significant influence in serum hormones, which required more high-quality RCTs with sufficient sample sizes and statistics to prove.

K E Y W O R D S
idiopathic infertile men, N-acetyl-cysteine, randomised controlled trials, sperm parameters and serum hormones, systematic review and meta-analysis

1 | INTRODUCTION

Infertility is a disease characterised by an inability to become pregnant for infertile couples after at least 1 year of unprotected intercourse, and male factors accounting for nearly half of the reported cases are considered to be secondary to testicular dysfunction or reproductive tract occlusion (Agarwal et al., 2015; Sharlip et al., 2002).
Oxidative stress (OS) and reactive oxygen species (ROS) are highly active oxidising agents that can be classified as endogenous or exogenous based on their origin, which may cause defective spermatogenesis and male infertility (Aitken et al., 2010). Additionally, many physiological and genetic factors may also related to the motility of spermatozoa and the occurrence of infertility (Hull et al., 1985). In particular, OS is considered to be an important factor affecting male fertility and sperm physiological function (Agarwal et al., 2008). Under physiological conditions, low levels of ROS generation are maintained, in order to support normal sperm functions such as sperm activation, capacitation and acrosome reaction (Ford et al., 1959). Increased pathological ROS production results in lipid peroxidation of male spermatozoa, reduces the quality of semen and damages sperm DNA by forming single and/or double(de Lamirande & Gagnon, 1992; Wathes et al., 2007). Reducing excess ROS production is very important for spermatozoa to maintain normal function and fertilisation ability (Agarwal et al., 2006).
N-acetyl-cysteine (NAC) is a derivative of L-cysteine, which mainly used as an antioxidant (Zafarullah et al., 2003). NAC conduces to the synthesis of glutathione (GSH) (Rushworth & Megson, 2014) and may help restore the depleted pool of GSH caused by OS and inflammation (Shimamoto et al., 2011; Wang et al., 2014). Some studies have reported that NAC had free radical scavenging activity both in vivo and in vitro (Ciftci et al., 2009; Erkkilä et al., 1998; Oeda et al., 1997). Safarinejad et al. indicated that NAC orally daily can significantly improve sperm motility compared with placebo (Safarinejad & Safarinejad, 2009). Comhaire et al. identified that NAC can not only increase sperm concentration and acrosome reaction, but also reduce ROS and sperm DNA oxidation (Comhaire et al., 2000). Evidence-based medicine is still lacking to prove the clinical effect of NAC orally daily. A meta-analysis was carried out to access the effect of NAC orally daily (600 mg) on the sperm parameters and serum hormones in idiopathic infertile men.

2 | METHODS

2.1 | Protocol

The preferred reporting items of the system review and meta-analysis (PRISMA) guidelines were used as the methodology for this metaanalysis (Moher et al., 2009). And, this research was registered on the PROSPERO website (registration number: CRD42020209000).

2.2 | Literature sources and retrieval strategies

Two authors searched independently for all randomised controlled trials (RCTs) published until 1 March 2020, regarding the effect of NAC orally daily in idiopathic infertile men. Researchers looked up PubMed, EMBASE, Cochrane Library databases and original references of the included studies, using various combinations of Medical Subject Headings (MeSH) terms. The search terms were as follows: “N-acetyl-cysteine”, “idiopathic infertility” and “men (or “male” or “patients”)”. There were no language restrictions on the inclusion of articles, and duplicate studies were excluded. If there was a dispute, it would be assessed by the third researcher.

2.3 | Inclusion and exclusion criteria

Inclusion criteria were as follows: (a) according to the history, physical examination and semen examination results, no cause or factor causing male infertility has been found. This study only included patients with idiopathic infertility, and there were no previous factors that could affect male fertility, failed attempts at conception and no female factors; (b) NAC orally daily in treating idiopathic infertile men was evaluated; (c) articles offered related data and full-text content, such as the number of patients and the variation of each indicator; and (d) trials must be RCT.
The following studies were excluded: not RCT, such as abstract, review or comment; patients with urogenital bacterial infection, smoking hypogonadism, varicocele, using drugs and other comorbidities, other treatment. If an identical experiment was published at various magazines or issued at diverse times, the latest study was included in the meta-analysis. Each study was included if an identical body of patients participated in multiple experiments. The search strategy according to the PICOS list was presented in Table 1. PRISMA flow chart was presented in Figure 1.

2.4 | Methods of assessing quality

Cochrane Handbook (Higgins and Green, 2011 [updated 2011 Mar; cited 2020 Jan]) was used to evaluate the quality of RCT. And the evaluation items were as follows: selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. Every RCT was evaluated by three quality classification criteria: (+) low possibility of bias, (?) secondary probability of bias and (-) high possibility of bias. All authors participated in the quality assessment of each article and agreed to the final results.

2.5 | Data extraction

Two researchers read all articles and extracted the following data: (a) characteristics of study; (b) name of authors; (c) study design and sample size; (d) interventions among the groups; and (e) evaluation index, such as sperm concentration, ejaculate volume, sperm motility, normal morphology, testosterone, luteinising hormone, folliclestimulating hormone and prolactin. Finally, all the extracted data were checked by another author. This research did not require ethical consent.

2.6 | Statistical analysis

Rev man 5.3.0 was used for the analysis and integration of data. Mean difference (MD) with 95% confidence intervals (CI) was applied to evaluate continuous index, and odds ratio (OR) with 95%CI was applied to evaluate dichotomous index. If the result was pvalue > .05 (DerSimonian & Laird, 1986), the fixed effect model was used for analysis. I2 reflected the ratio of heterogeneity across trials. Random effect model was adopted when the index showed p < .05 or I2 > 50%. If the result showed p < .05, the index suggested that there was statistically significant.

3 | RESULTS

3.1 | Basic characteristics and search process

We searched 146 studies in databases. Based on the inclusion criteria and exclusion criteria, 127 studies were deleted. Due to the lack of relevant information, 16 studies were excluded. Finally, three RCTs (Ciftci et al., 2009; Jannatifar et al., 2019; Safarinejad & Safarinejad, 2009) were used to analyse the effect of NAC orally daily (600 mg) on the sperm parameters and serum hormones in idiopathic infertile men. Figure 1 detailed selection PRISMA flow chart.

3.2 | The risk of bias

All included studies were randomised controlled design with specific randomised protocols and only one study described the calculation of sample size (Table 2). The outcomes of quality assessment are presented in Figures 2 and 3.

3.3 | Sperm parameters

3.3.1 | Sperm concentration

The analysis of sperm concentration was supplied by three RCTs including 431 patients, which showed heterogeneity p-value of .13 and I2 of 52%. Forest plots drew a MD of 3.80 and 95% CI of 2.36 to 5.24 (p < .00001), which indicated that NAC had a greater increase in sperm concentration for infertile men compared with placebo (Figure 4).

3.3.2 | Sperm volume

The analysis of sperm volume was supplied by three RCTs including 431 patients, which showed heterogeneity p-value of <.00001 and I2 of 92%. Forest plots drew a MD of 0.69 and 95% CI of 0.26 to 1.12 (p = .002), which indicated that NAC had a greater increase in sperm volume for infertile men compared with placebo (Figure 4).

3.3.3 | Sperm motility

The analysis of sperm motility was supplied by three RCTs including 431 patients, which showed heterogeneity p-value of <.00001 and I2 of 96%. Forest plots drew a MD of 4.69 and 95% CI of 2.45 to 6.94 (p < .0001), which indicated that NAC had a greater increase in sperm motility for infertile men compared with placebo (Figure 5).

3.3.4 | Normal morphology

The analysis of normal morphology was supplied by three RCTs including 431 patients, which showed heterogeneity p-value of <.00001 and I2 of 100%. Forest plots drew a MD of 1.68 and 95% CI of 0.79 to 2.58 (p = .0002), which indicated that NAC had a greater increase in normal morphology for infertile men compared with placebo (Figure 5).

3.4 | Hormonal analysis

A total of two RCTs including 311 patients (NAC: 155 infertile men; placebo: 156 infertile men) were used to estimate the level of testosterone, luteinising hormone, follicle-stimulating hormone and prolactin.

3.4.1 | Testosterone

High heterogeneity was found in forest plots (p = .04; I2 = 77%). Compared with placebo, NAC did not show a better effect in raising serum testosterone levels for infertile men (MD, 1.35; 95% CI, −0.75 to 3.45; p = .21; Figure 6).

3.4.2 | Luteinising hormone

High heterogeneity was found in forest plots (p < .00001; I2 = 98%). The random model did not show a significant difference between NAC and placebo in raising serum-luteinising hormone levels for infertile men (MD, 0.82; 95% CI, −1.07 to 2.71; p = .40; Figure 6).

3.4.3 | Follicle-stimulating hormone

Heterogeneity test was p < .00001 and I2 = 100%. The forest plots identified that there was not statistical significance between NAC and placebo in raising serum follicle-stimulating hormone levels for infertile men (MD, −7.48; 95% CI, −21.23 to 6.27; p = .29; Figure 6).

3.4.4 | Prolactin

High heterogeneity was found in forest plots (p < .0001; I2 = 94%). The forest plots identified that there was not statistical significance between NAC and placebo in raising serum prolactin levels (MD, −0.34; 95% CI, −1.02 to 0.33; p = .32; Figure 6).

4 | DISCUSSION

Infertility is an important medical and social problem, meanwhile, its severity and impact on well-being is huge. Despite the assisted reproductive technology has made a breakthrough in the last decade, the effective treatment for men with idiopathic infertile has not been determined. NAC is a derivative of amino acid L-cysteine and a precursor of GSH with antioxidant properties (Zafarullah et al., 2003), which increases the concentration of endogenous reductant in cells and/or directly acts as a free radical scavenger (Wang et al., 2014). Moreover, NAC plays an important role in the survival of the germ cells of human seminiferous tubules in vitro (Erkkilä et al., 1998; Oeda et al., 1997).
This study was a meta-analysis that aimed to confirm the role of NAC orally daily (600 mg) on the sperm parameters and serum hormones in idiopathic infertile men. The results demonstrated a greater improvement in sperm concentration, ejaculate volume, sperm motility and normal morphology in the NAC group compared with the placebo group. However, in terms of hormonal analysis, the NAC group did not show significant difference in increasing the serum levels of testosterone, luteinising hormone, follicle-stimulating hormone and prolactin compared with the placebo group.
NAC, as an N-acetyl derivative of the natural amino acid L-cysteine, is used to reduce the viscosity and elasticity of mucus because its impact to reduce disulphide bonds (Aitken et al., 1993). NAC also has the potential to act directly with oxidants. Like many thiols (such as GSH), NAC is a good scavenger of hydroxyl radicals (Orzechowski et al., 2002). A lot of evidence showed that NAC not only had the scavenger function, but also promoted the production of GSH, thus reducing or even preventing cell cultures or oxidant-mediated damage (Aruoma et al., 1989; Gillissen et al., 1997). In three RCT studies (Ciftci et al., 2009; Jannatifar et al., 2019; Safarinejad & Safarinejad, 2009), all patients were treated with NAC (600 mg/day orally) for at least 3 months, so we believed it to be a safe drug dose and it had a higher median lethal dose. Some animal experiments have confirmed that the drug is neither teratogenic nor gene mutation (Mokhtari et al., 2017). Excessive use of the drug may cause slight allergic reactions, especially after intravenous injection, no contraindications have been reported except for known allergic reactions to NAC (Tenenbein, 1984).
Over the past few years, the influence of NAC on semen parameters has been reported in some clinical trials of multiple countries (Mokhtari et al., 2017). Oeda et al. incubated human semen samples with and without NAC (1.0 mg/ml) at room temperature. The results showed that NAC could improve total sperm motility and significantly decrease ROS, suggesting that NAC can improve the function of damaged spermatozoa (Oeda et al., 1997). Akiyama (1999) tested the clearance of ROS in human semen, evaluated the generation of ROS and sperm function before and after NAC administration and concluded that although sperm density and sperm activity did not improve, the sperm function tended to improve and the level of ROS decreased significantly after NAC administration. In contrast to Akiyama's study, one RCT (Ciftci et al., 2009) identified that sperm motility improved after the treatment of NAC. Compared with the control group in this RCT, the NAC group's viscosity, liquefaction time and sperm volume were significantly improved.
Semen mucinosis is closely related to male infertility (ELzanety et al., 2004). Semen viscosity plays an important role in conception, because spermatozoa may adhere to semen fibres or mucus, hindering sperm migration from seminal plasma into the cervix and fertilisation site (Mokhtari et al., 2017). Siciliano et al. (2001) reported the serious damage of high-molecular-weight and low-molecular-weight antioxidant system in the semen of hyperviscosity. The proper viscosity of semen and cervical mucus is of great significance to fertility (Aruoma et al., 1989). Previous studies found that NAC had the activity of dissolving mucus and improving the properties of cervical mucus without the need of oestrogen supply (Badawy et al., 2006). In addition, NAC is actually nontoxic and widely used to reduce the viscosity and elasticity of mucus due to its ability to reduce disulphide bonds (Orzechowski et al., 2002). NAC can also reduce the effect of ROS activity in spermatozoa, which was a factor of reducing sperm viscosity (Orzechowski et al., 2002). Therefore, the decrease in viscosity may be the reason of the increase in semen volume.
Current research reported that the NAC group had no obvious differences in increasing the serum levels of luteinising hormone, prolactin, testosterone and follicle-stimulating hormone compared with the placebo group. However, Jannatifar et al. (2019) identified that serum-luteinising hormone and follicle-stimulating hormone decreased significantly and serum testosterone increased significantly after NAC treatment. For serum hormone, only two studies were included in the analysis, and the results still need to be demonstrated by RCT with sufficient sample sizes.
Spermatogenesis is highly controlled by hormonal environment, in addition to affecting the speed and quality of spermatogenesis, and any change in hormone profile may profoundly affect the chromosome ploidy and the integrity of sperm chromatin (Safarinejad & Safarinejad, 2009). The study found that the increase in testosterone has negative feedback to hypothalamus and pituitary, which leads to the decrease in GnRH pulse frequency and pituitary response to GnRH, and finally results in the decrease in gonadotropin release (Hayes et al., 2000). Khan et al. (2013) reported that the level of total antioxidant capacity (TAC) in seminal plasma of patients with asthenospermia was significantly lower than (that of) healthy men. Jannatifar et al. (2019) found that the concentration of seminal malondialdehyde (MDA) decreased significantly, and MDA was a specific marker of lipid peroxidation, while TAC increased significantly after NAC treatment. Therefore, NAC reduces the severity of oxidative stress, thus reducing lipid peroxidation and DNA fragmentation.
The meta-analysis demonstrated the positive effects of the use of the NAC orally daily for treating male infertility caused by OS on the semen parameters. And the latest report stated that their redox status prior to the treatment with a supplement of specific formulation. Notably, the treatment should be specifically personalised to achieve normal redox status. Finally, future researches should further describe the advantages, optimal dose and the risks about antioxidants (Henkel et al., 2019).
We need to acknowledge the limitations of this analysis. There are deficiencies in the quality of trials used for analysis, mainly including fewer trials and inconsistent indicators. However, the studies included in this study are all RCTs, which increases the strength of the research results. In addition, selection bias and subjective bias may affect the final results.

5 | CONCLUSIONS

The NAC orally daily produced a greater improvement in sperm concentration, ejaculate volume, sperm motility and normal morphology for idiopathic infertile men, whereas no significant influence in serum hormones, which required more high-quality RCTs with sufficient sample sizes and statistics to prove.

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