Among them, 44% of infertile men had no known disease that could explain infertility and these patients were assigned as idiopathic male infertility (Pierik et al., 2000). Conclusively, LC/LAC and NAC showed a greater improvement in sperm motility and normal morphology. Finally, seven articles including 621 patients were analyzed. We researched PubMed, EMBASE, and Cochrane Library databases and references to related articles. They may offer similar benefits in some cases but should not replace prescribed treatment without medical guidance. Overlapping mechanisms can increase the risk of hypoglycemia.
Study location, treatment duration and type of control were detected as sources of heterogeneity following subgroup analysis (Table 2). Thus, trim and fill analysis was conducted with five imputed studies. Sensitivity analysis determined that no particular study likely affected the pooled results. The type of control and study location were identified as sources of high heterogeneity following subgroup analysis.
Also, publication bias could change the effects of NAC on E2 levels and endometrial thickness. A comparison of two meta-analyses with the subjects of NAC and l-carnitine supplementation on inflammatory and oxidative stress biomarkers revealed that NAC had better effects than l-carnitine(Reference Faghfouri, Zarezadeh and Tavakoli-Rouzbehani6,Reference Fathizadeh, Milajerdi and Reiner44) . Other mechanisms proposed for the effects of l-carnitine on FSH and LH levels could be attributed to the regulation of lipid peroxidation and activity of antioxidant enzymes(Reference Rezaei, Mardanshahi and Shafaroudi43). Therefore, a definite interpretation of more decreasing effects of NAC on E2 levels than metformin needs more studies.
Eight studies 21,22,23,24,25,29,33,36 were assessed as being "excellent" and eight 26,27,28,30,31,32,34,35 were assessed as being "very good". Selected publications that met all the requirements proceeded to the next stage of data analysis and synthesis, supplemented by the review authors using the above criteria. This was carried out by two study investigators (D.F.-L., J.M.-A.) and disagreements were resolved by the intervention of another study investigator (C.D.-O.). In addition, two study investigators constructed a network graph using the Connected Papers website (, accessed on 19 April 2023) to ensure inclusion of publications through visual characterisation of records. No additional records of reference lists of relevant articles or grey literature were made. It consists of 8 items assessing selection bias (items 1 and 2), performance bias (item 3), detection bias (item 4), attrition bias (item 5), notification bias (item 6), publication bias (item 7), and observer bias (item 8).
It has been also revealed that levels of hormones and spermatogenesis were not different among adult male Wistar rats following NAC consumption(Reference Shahrzad, Shariati and Naimi15). In animal studies, E2 and progesterone levels were not changed after NAC supplementation in the serum of goats(Reference Luo, Ao and Duan14). Other potential effects of NAC for PCOS patients are lowering androgen levels, regulating menstrual cycles, increasing the follicle size, decreasing hirsutism, free testosterone and menstrual irregularity(Reference Oner and Muderris11). Also, NAC has other anti-inflammatory characteristics by increasing the cellular levels of glutathione (GSH) and promoting apoptosis in PCOS patients(Reference Teimouri, Mollashahi and Paracheh7).
Oestrogen levels also were increased after correcting publication bias. As well, NAC supplementation increased levels of GSH in individuals with low GSH levels and improved redox homoeostasis(Reference Paschalis, Theodorou and Margaritelis48). The risk of bias in one included study was low, in two was moderate and other included studies had a higher risk of bias. Due to the higher number of participants, this study was greatly weighted and influenced the overall results, so removing of mentioned study in sensitivity analysis changed the increasing effects of NAC on the FSH levels. Rinaldi et al. showed that intake of alcohol increased serum levels of dehydroepiandrosterone sulphate, testosterone, androstenedione and oestrone compared with non-consumers women(Reference Rinaldi, Peeters and Bezemer36,Reference Shafrir, Zhang and Poole37) . Performing subgroup analysis revealed that the effects of NAC on TT levels in studies with intervention duration ≥ 8 weeks were more robust than the entire sample (Table 2).
After NAC treatment, sperm motility correlated positively with TAC and negatively with MDA. Mean of seminal MDA decreased significantly after treatment with NAC compared to before treatment. Sperm parameters significantly improved after treatment with NAC compared to before treatment Inclusion criteria included the infertile couples with no previous report of pregnancy, normal female partner and male partner defined as having Asthenoteratozoospermia based on World Health Organization (WHO, 2010) criteria . In addition, daily treatment with NAC results in a significant improvement in sperm motility in comparison to placebo . NAC also contributes to glutathione (GSH) synthesis and may help restore the depleted pool of GSH often caused by oxidative stress and inflammation 17, 18. N-acetyl-cysteine (NAC), a derivative of amino acid L-cysteine, is currently used mainly as an antioxidant .
The peripheral blood sample was taken from each patient and was immediately centrifuged for 10 min at 3000 rpm (Hettich, EBA20, UK) and serum samples stored at − 70 °C for future evaluation and analysis. Sperm count was evaluated by a sperm counting chamber and expressed as million/ml. Normal morphology was assessed by Papanicolaou staining and subjects with less than 4% normal sperm morphology were considered as teratozospermic according to WHO criteria. Briefly, sperm motility was assessed by the Computer Aided Sperm Analysis (CASA) system (LABOMED, SDC313B, Germany), which defined sperm as progressive, non-progressive and immotile. Semen parameters (volume, sperm count, progressive and non-progressive motility and normal morphology) were evaluated according to WHO guidelines (2010). Variables including seminal parameters, DNA fragmentation index, chromatin maturity, total antioxidant capacity, lipid peroxidation and hormonal parameters (LH, FSH, Testosterone and Prolactin) were measured before and after the intervention. In addition, male height (m), weight (kg) and body mass index (BMI, kg/m3) were recorded and compared before and after intervention.
According to the bias assessment using the Cochrane Collaboration’s risk of bias tool, this study had a lower risk of bias; therefore, its results could be reliable. Nasr et al. reported that NAC supplementation increases the number of follicles in PCOS women(Reference Elgindy, El-Huseiny and Mostafa23). However, the effects of NAC on the number of follicles, endometrial thickness, LH and FSH levels were not markedly different. Recent studies showed that BMI and E2 levels have positive association. Subgroup analysis based on the country showed that the improving effects of NAC on the endometrial thickness are more significant in some countries. Previous studies showed that with different doses of NAC, different effects could be observed(Reference Cavallini, Ferraretti and Gianaroli32). However, due to the limited range of administered dosages of NAC, subgroup analysis based on the dosage was not performed on LH, FSH and TT levels.

Gender: Female

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