N-Acetyl Cysteine (NAC)

What it is

• Powerful antioxidant
• Precursor of L-cysteine that results in an increase in the production of glutathione (antioxidant)
• It is not found in natural sources

What it does

• It is a powerful antioxidant and a penitential treatment option for diseases characterised by the generation of free oxygen radicals
• NAC stimulates glutathione biosynthesis, promotes detoxification, and acts directly as a scavenger of free radicals
• The critical antioxidant power of NAC is due to its role as a precursor of glutathione, which is one of the most important naturally occurring antioxidants
• Help restore the depleted pool of glutathione often caused by oxidative stress and inflammation
• Insulin sensitising effect and can improve levels of circulating insulin, this can help stabilise blood sugar balance – beneficial for PCOS (insulin resistance is commonly seen in patients with PCOS and can drive weight gain and impact fertility)
• Mucolytic - NAC can improve the character of the cervical mucous without additional oestrogen supply

Who it's recommended for

PCOS
IVF
Infertility
Poor sperm quality

Research

PCOS:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306416/
https://journals.sagepub.com/doi/full/10.1177/117739361000100002
https://www.hindawi.com/journals/ogi/2015/817849/

• NAC was found to significantly improve rates of live births and spontaneous ovulation compared to placebo in women with PCOS.

Outcome and conclusion: It can be concluded from the results of the present study that, NAC improves some of the clinical features, biochemical markers of insulin resistance, hormonal levels, anovulation, and consequently the long term health status of women with PCOS through inhibition of oxidative stress and improvement of peripheral insulin. Due to lack of adverse effects, NAC can be regarded as an appropriate substitute for insulin reducing medications in the treatment of PCOS patients.

NAC & Endometriosis:

https://www.mdpi.com/1660-4601/20/6/4686

• Endometriosis is a chronic, oestrogen-dependent, inflammatory disease, whose pivotal symptoms are dysmenorrhea, dyspareunia, and chronic pelvic pain (CPP). Besides the usual medical treatments, recent evidence suggests there are potential benefits of oral N-acetylcysteine (NAC) on endometriotic lesions and pain.

Objectives of the study carried out:

• Confirm the effectiveness of NAC in reducing endometriosis-related pain and the size of ovarian endometriomas.
• Assess if NAC may play a role in improving fertility and reducing the Ca125 serum levels.

Outcome and conclusion: Among the 52 patients with reproductive desire, 39 successfully achieved pregnancy within 6 months of starting therapy (p = 0.001). Conclusions: Oral NAC improves endometriosis-related pain and the size of endometriomas. Furthermore, it decreases Ca125 serum levels and may improve fertility in patients with endometriosis.

NAC & Clomiphene citrate (CC):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746301/
https://www.fertstert.org/article/S0015-0282%252804%252902849-3/abstract

• Clomiphene citrate (CC) is used for the induction of ovulation in PCOS women however resistance is seen in up to 40% of PCOS patients
• Recent studies have shown that a combination of CC and NAC considerably increased both ovulation and pregnancy rates in women with CC-resistant PCOS. 

Outcome and conclusion: NAC as an adjuvant to CC was more effective than placebo for CC-resistant patients with PCOS. It is safe and well tolerated.

NAC & Letrozole:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036781/

• PCOS patients receiving letrozole (ovulation induction) + NAC (1200mg) had bigger size follicles and ovulation and pregnancy rates were also significantly higher compared to those receiving letrozole alone.

Outcome and conclusion: NAC is an adjuvant to letrozole and can increase the pregnancy rates in PCOS patients.

Premature Birth:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451831/
https://pubmed.ncbi.nlm.nih.gov/18851855/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241507/

• Inflammation, foetal infection, and previous preterm delivery are significant risk factors for preterm birth and neonatal brain injury
• NAC by having an anti-inflammatory outcome can reduce the risk of preterm birth
• Women with previous preterm birth and bacterial vaginosis – 600mg of NAC daily can be taken orally along with progesterone after week 16 of pregnancy to protect against preterm birth recurrence and improve neonatal outcomes.

Outcome and conclusion: Antenatal and intrapartum administration of NAC has a beneficial effect on outcomes of premature newborns born in the context of intrauterine infection and/or inflammation.

Recurrent Pregnancy Loss:

https://pubmed.ncbi.nlm.nih.gov/18983759/
https://www.rbmojournal.com/article/S1472-6483(10)60322-7/pdf
https://www.sciencedirect.com/science/article/abs/pii/S1472648310603227
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241507/

• Administration of a combination of NAC and folic acid, in comparison with folic acid alone, results in prolongation of a living pregnancy up to 20 weeks.
• In addition, combination of NAC and folic acid were also associated with a significant increase in the full term pregnancy, as compared to folic acid alone

Outcome and conclusion: NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained recurrent pregnancy loss

Sperm Quality:

https://pubmed.ncbi.nlm.nih.gov/34933532/
https://onlinelibrary.wiley.com/doi/abs/10.1111/and.13953

• Infertile men have higher levels of semen reactive oxygen species (ROS) than fertile men. High levels of semen ROS can cause sperm dysfunction, sperm DNA damage and reduced male reproductive potential. 
• Three-month supplementation with NAC (600mg/day) significantly improved sperm parameters (count, motility and normal morphology) from pre-treatment baseline.

Outcome and conclusion: NAC consumption significantly improved sperm total motility, sperm morphology and sperm concentration

Assisted Fertility In Women Of Advanced Age:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9577027/#:~:text=Actually%2C%20NAC%20has%20been%20used,live%20birth%20rate%20(33)
https://rbej.biomedcentral.com/articles/10.1186/1477-7827-10-49

• Oocyte aging is closely related to mitochondrial dysfunction and oxidative stress. The mitochondrial function might be improved with the use of antioxidants (women aged 43 years+, the chance of getting a blastocyst with normal chromosomes is <5%)
• 600mg of NAC per day from the menstrual phase prior to the IVF/ICSI cycles for nearly 45 days – significantly increase the number high-quality blastocysts which can increase the chances of successful clinical pregnancy

Outcome and conclusion: NAC improves oocyte quality through antioxidant action, leading to high-quality blastocysts by improving the glutathione content. NAC pretreatment can improve the sensitivity of the ovary to exogenous gonadotropins in advanced age women, which may be helpful to promote oocyte development capacity.

Infertility:

https://rbej.biomedcentral.com/articles/10.1186/1477-7827-10-49
https://www.fertstert.org/article/S0015-0282%2804%2901904-1/fulltext

• NAC combination with vitamin E, or vitamins A+E, as well as essential fatty acids considerably reduced reactive oxygen species (ROS), leading to pregnancy rate improvement

Outcome and conclusion: NAC is an effective, cheap and safe adjuvant to clomiphene citrate in long standing unexplained infertility patients undergoing IUI. It improves pregnancy rate significantly in IUI cycles.

Safety

• Studies have shown no maternal or foetal harmful effects of NAC treatment.
• Safe and well-tolerated supplementary drug without any considerable side effects