N-acetyl-cysteine to Treat Polycystic Ovarian Syndrome?

Review illuminates positive impact of NAC on PCOS

By Megan Chmelik

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Reference 

Thakker D, Raval A, Patel I, Walia R. N-acetylcysteine for polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Obstet Gynecol Int. 2015;2015:817849.

Study Design

A systematic review and meta-analysis were conducted to assess the risks and benefits of n-acetyl-cysteine (NAC) supplementation in women with polycystic ovarian syndrome (PCOS) compared to placebo or the diabetes medication metformin. The meta-analysis included 8 randomized controlled clinical trials involving 910 women (mean ages ranging 20-33 y) with a PCOS diagnosis confirmed by the Rotterdam criteria. 

Outcome Measures 

Primary outcome measures were live-birth rate and clinical pregnancy rate measured by the presence of a fetal heart rate. Secondary outcome measures included ovarian hyper-stimulation syndrome, miscarriage, and multiple pregnancy rates. Additional measures evaluated were resumption of menstrual regularity and spontaneous ovulation as well as improvements in body mass index (BMI); testosterone, fasting insulin, and glucose levels; glucose-to-insulin ratio; and homeostatic model of assessment-insulin resistance. 

Key Findings 

Live-birth rate was 3 times greater among the women receiving NAC supplementation compared to placebo (odds ratio [OR]:3.00; 95% confidence interval [CI]:1.05-8.60; P=0.04). Women in the group receiving NAC were 3.5 times more likely to become pregnant than women in the placebo group (OR:3.58; 95% CI:2.05-6.25; P<0.0001). Women with resistance to clomiphene citrate (CC), a common medication for treating PCOS, demonstrated a 5-times greater benefit in pregnancy rate when taking NAC (OR:4.83; 95% CI:2.30-10.13; P<0.0001) and an ovulation rate 9 times higher compared to placebo (OR:8.40; 95% CI:4.50-15.67; P=0.04). Women who were not CC-resistant still reported having a 3-times greater chance for ovulation with the use of NAC. Reductions in BMI, total testosterone, and fasting glucose levels were also reported among the NAC group. No differences were found in rates of miscarriage, menstrual regularity, hirsutism, or acne severity. In comparison to metformin, those receiving NAC were 60% less likely to achieve pregnancy (OR:0.40; 95% CI:0.23-0.71) and had an 87% lower ovulation rate (OR:0.13; 95% CI:0.08-0.22; P<0.001). 

Practice Implications

PCOS affects approximately 5% to 15% of women and is the leading cause of infertility due to chronic anovulation. Conventional approaches to treating ovulatory dysfunction typically include CC, followed by more invasive interventions as needed. Ovulatory success is achieved in only 15% to 40% of women treated with CC. Moreover, improved ovulation rates do not directly correlate with pregnancy outcomes.
Polycystic ovarian syndrome affects approximately 5% to 15% of women and is the leading cause of infertility due to chronic anovulation.
Metformin, another commonly used intervention for women with PCOS, reduces insulin resistance, which is said to play a significant role in the underlying pathophysiology of PCOS. Increasing insulin sensitization has been found to directly impact metabolic parameters and improve rates of ovulation. In the meta-analysis under review, metformin was clearly superior to NAC in both inducing ovulation and increasing successful pregnancy rates.
 
NAC, which is widely known for its mucolytic properties and is used as a therapeutic intervention for cystic fibrosis, is another treatment that has demonstrated improvement in both metabolic and hormonal parameters of PCOS. The supplement is often compared to metformin as it has demonstrated similar benefit in the management of PCOS.1
 
The first clinical trial to investigate the effect of NAC on metabolic parameters was published in 1998. It identified a correlation between elevated vascular cell adhesion molecule 1 (VCAM-1) plasma concentrations and depressed glutathione levels in untreated non‒insulin dependent diabetes patients. It was theorized that oxidative stress contributes to the upregulation of VCAM-1 expression. With that in mind, supplementation with NAC was found to reduce its expression and therefore offer protection against diabetes-related endothelial damage.2
 
Women with PCOS typically have upregulated expression of VCAM-1, which is positively correlated with elevated testosterone levels. Interventions like NAC that reduce VCAM-1 levels may consequentially reduce incidence of PCOS aggravation.3
 
In 2002, Fulghesu et al looked directly at the effect NAC had on PCOS. The study was the first of its kind and noted improvements in insulin sensitivity and androgen levels with NAC supplementation. Reductions in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels were also observed. Most notably, this study highlighted the fact that NAC was well tolerated, producing little to no adverse effect.4
 
Since 2002, multiple studies have examined the effect that NAC supplementation has on pathophysiology and symptomatology of the disorder. This current meta-analysis combines data from those studies and suggests that NAC supplementation is worth considering for patients with PCOS. On the other hand, it also suggests that metformin may be a superior treatment. Should patients take both? Perhaps not.
 
A 2014 study raised concern suggesting that coadministration of NAC with metformin negates some of the benefits found when either is given alone. Serum levels of luteinizing hormone, testosterone, cholesterol, and triglycerides did not drop in the experimental group receiving both, whereas these parameters did improve when either NAC or metformin was administered alone. As a result of these findings, the authors suggest that combining NAC and metformin may not be useful for patients who are undergoing ovulation stimulation by means of intra-cytoplasmic sperm injection.5
 
The bottom line for now is that NAC certainly appears beneficial for PCOS patients, but metformin may be superior. We may wish to hesitate recommending these therapies simultaneously until more research clarifies how the two work together. 

Editor's note: Megan Chmelik wrote this article under the guidance of Jacob Schor, ND, FABNO, an associate editor of this journal.

About the Author

Megan Chmelik is a third-year naturopathic medical student at National University of Natural Medicine in Portland, Oregon. Before moving to Portland, she worked for Rena Bloom, ND, and Jacob Schor, ND, FABNO, at the Denver Naturopathic Clinic. As part of a tradition of mentoring receptionists and preparing them for naturopathic school, Schor encouraged Chmelik to learn how to use PubMed and write review articles. Now years later, it is clear that this passion of his has been passed down as she continues to write for NMJ during her spare time.

References

  1. Oner G, Muderris II. Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2011;159(1):127-131.
  2. De Mattia G, Bravi MC, Laurenti O, et al. Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes. Diabetologia. 1998;41(11):1392-1396.
  3. Solano ME, Sander VA, Ho H, Motta AB, Arck PC. Systemic inflammation, cellular influx and up-regulation of ovarian VCAM-1 expression in a mouse model of polycystic ovary syndrome (PCOS). J Reprod Immunol. 2011;92(1-2):33-44. 
  4. Fulghesu AM, Ciampelli M, Muzj G, et al. N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Fertil Steril. 2002;77(6):1128-1135.
  5. Cheraghi E, Soleimani Mehranjani M, Shariatzadeh MA, Nasr Esfahni MH, Ebrahimi Z. Co-administration of metformin and N-acetyl cysteine fails to improve clinical manifestations in PCOS individual undergoing ICSI. Int J Fertil Steril. 2014;8(2):119-128.