Meta-analysis: NAC has potential to improve fertility in PCOS

By Nikki Hancocks

- Last updated on GMT

Getty | champpixs
Getty | champpixs

Related tags NAC Fertility PCOS maternal health

Supplementation with the powerful antioxidant NAC (N-acetylcysteine) has the potential to contribute to a better function of the reproductive system in women with PCOS, according to a new systematic review and meta-analysis published in 'British Journal of Nutrition'.

Polycystic ovary syndrome (PCOS) is one of the most common hormonal, inflammatory, and oxidant disorders among women of reproductive age worldwide​ and approximately, 70% of women with PCOS have infertility. These patients may have missed, irregular, or prolonged menstrual cycles or high levels of androgens. Follicles cannot grow and mature due to hormonal imbalance meaning ovaries may store numerous immature follicles and fail to release an egg regularly.

NAC supplements are the synthetic form of the amino acid cysteine which can be found in high-protein foods, such as meat, fish, seafood, chicken or turkey. 

In subjects with PCOS, NAC has been said to reduce insulin and testosterone levels and facilitate serum levels of homocysteine and lipid profile​. NAC supplementation has also been said to increase the average number of ovulatory follicles >18mm and peak endometrial thickness in PCOS women​. Treatment with NAC induces ovulation, decreases miscarriage rates, and increases live birth rates​. 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​.

But findings have not been consistent. Results of a recent study ​showed no effect of NAC on levels of FSH, LH, and FSH /LH ratio among infertile PCOS women. In another study​, NAC supplementation had no significant effect on serum levels of SHBG, LH, FSH, LH/FSH, E2, and testosterone in PCOS patients after 12 weeks (5; 9; 13; 14)

Due to these inconsistency, the present meta-analysis aimed to evaluate the effects of NAC supplementation on ovulation biomarkers and serum levels of sex hormones in women with PCOS.

The authors say pooled analysis of 18 RCTs with a total population of 3,161 revealed that NAC supplementation had significant increasing and decreasing effects on FSH and TT levels, respectively. What's more, the elimination of publication bias using trim and fill analysis revealed that NAC also could decrease E2 levels and endometrial thickness. Country, type of control, and intervention duration were the possible sources of high heterogeneity in the pooled analyses.

However, the authors note this conclusion should be with precaution as the other sex hormones and ovulation parameters were not significantly influenced by NAC supplementation.

To the authors knowledge, this is the first comprehensive systematic review and meta-analysis addressing this issue, so far. 

The study search

A total of 931 articles were obtained from a systematic search of electronic databases. After removing duplicate papers and screening the articles carefully by the title and abstract, 35 papers were included. Seventeen articles after the full-text review were excluded. Overall, 18 articles met the inclusion criteria and enrolled in the meta-analysis

Limitations of this study are noted in the report. Firstly, only a limited number of the studies have assessed the effects of NAC on progesterone and SHBG levels so subgroup analysis could not be performed on these biomarkers. Second, due to this cause, the comprehensive subgroup analysis based on dosage or type of control in some biomarkers was not performed. Therefore, a definite interpretation on the on the effects of different dosages of NAC should be considered cautiously.

Third, in some cases, publication bias has changed the overall results. However, its impact was neutralised by performing trim and fill analysis.

Further studies are needed to compare the synergistic effects of NAC, metformin, and L-carnitine on reproductive biomarkers in patients with PCOS.

Mechanism of action

The authors note a number of different underlying mechanisms to explain how NAC could affect reproductive biomarkers.

NAC is the source of the sulfhydryl (SH) group that is essential for removing free radicals like H2O2, OH* , and O2 -*​. As well, NAC supplementation increased levels of glutathione (GSH) ​in individuals with low GSH levels and improved redox homeostasis. Moreover, ROS-induced mitogen-activated protein kinase (MAPK) activation could be inhibited by NAC​. Therefore, NAC, through decreasing lipid peroxidation, could have beneficial effects on reproductive biomarkers.

The authors note that the GSH levels might be effective in the relationship between NAC and reproductive biomarkers​. Therefore, measuring GSH levels to determine the availability of cysteine as the limiting step must be considered in future studies.

NAC increases the cellular levels of antioxidants and reduces glutathione at higher doses.​ Therefore, NAC can potentially improve insulin receptor activity in human erythrocytes and improve insulin secretion in response to glucose. Badawy et al. reported that NAC induced ovulation in PCOS patients through increasing insulin sensitivity​, similar to the effects of metformin on PCOS.

Source: British Journal of Nutrition


"The effects of N-acetylcysteine on ovulation and sex hormones profile in women with polycystic ovary syndrome: A systematic review and meta-analysis"

Shahveghar Asl, Z., Parastouei, K., & Eskandari, E. 

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