Is N‑acetylcysteine (NAC) at 600 mg orally twice daily effective and safe for improving fertility in adults trying to conceive, including women with polycystic ovary syndrome (PCOS) or unexplained ovulatory dysfunction and men with abnormal semen parameters?

NAC for Fertility: Limited Evidence Does Not Support Routine Use

Current medical guidelines do not recommend N-acetylcysteine (NAC) for improving fertility outcomes in either men or women, as the benefits of supplements including NAC are of questionable clinical utility and lack sufficient high-quality evidence to support their use. 1, 2, 3

Male Infertility

Guideline Position on Supplements

• The AUA/ASRM 2021 guidelines explicitly state that clinicians should counsel patients that the benefits of supplements (including antioxidants and vitamins) are of questionable clinical utility in treating male infertility, with inadequate data to recommend specific agents 1
• The WHO guidelines (2017) strongly recommend that there are insufficient data to recommend supplemental antioxidant therapies for treatment of men with abnormal semen parameters and/or male infertility 1, 2

What Actually Works for Male Infertility

• For men with low testosterone and preserved fertility goals: aromatase inhibitors, hCG, or selective estrogen receptor modulators may be used (not NAC) 1
• For idiopathic infertility: FSH analogues may be considered, though SERMs have limited benefits relative to ART 1
• Critical pitfall: Testosterone monotherapy should never be prescribed for men interested in fertility, as it suppresses spermatogenesis 1, 3

Focus on Proven Interventions

• Weight loss in overweight/obese men to enhance sperm parameters 3
• Complete smoking cessation 3
• Avoidance of alcohol and recreational drugs 3
• Consider ART (IVF/ICSI) for definitive treatment when indicated 1

Female Infertility (PCOS and Unexplained)

Evidence Quality Assessment

The research evidence for NAC in women shows conflicting and inconsistent results:

• Most recent systematic review (2020): Found statistically insignificant improvements in clinical pregnancy rate (OR 1.55,95% CI 0.98-2.47), ovulation rate (OR 1.77,95% CI 0.76-4.14), and miscarriage rate (OR 0.76,95% CI 0.37-1.53) with high heterogeneity (I²=68-90%) 4
• NAC was found less efficacious than metformin in all outcomes 4

Divergent Individual Studies

While some older RCTs showed positive results:

• One 2005 study in CC-resistant PCOS showed improved ovulation (49.3% vs 1.3%) and pregnancy rates (21.3% vs 0%) when NAC was added to clomiphene 5
• Studies from 2012 and 2018 showed improved outcomes with NAC as adjuvant to CC or letrozole 6, 7

However, a 2017 RCT found NAC ineffective in PCOS patients undergoing IUI, with no significant differences in pregnancy rates 8

Critical Interpretation

The high heterogeneity (I²=68-90%) and inconsistent results across studies indicate:

• Study populations likely differed in important ways (BMI, insulin resistance, oxidative stress levels)
• Lack of standardized protocols makes robust conclusions impossible 2, 4
• No studies measured the outcomes that matter most: live birth rate and long-term quality of life 4

Safety Profile

NAC appears well-tolerated in fertility studies:

• No cases of ovarian hyperstimulation syndrome reported in NAC groups 5, 6, 7
• FDA labeling indicates NAC is generally safe but notes a slight non-dose-related reduction in fertility at high doses (500-1000 mg/kg/day) in animal studies 9
• Should only be used during pregnancy if clearly needed, as adequate human studies are lacking 9

Clinical Algorithm

For men with infertility:

1. Perform comprehensive semen analysis and hormonal evaluation 1
2. Address modifiable factors: weight loss, smoking cessation, avoid testosterone 1, 3
3. If low testosterone with preserved fertility goals: consider AIs, hCG, or SERMs 1
4. Do NOT recommend NAC or other supplements 1, 2
5. Refer for ART when appropriate 1

For women with PCOS or unexplained infertility:

1. First-line: clomiphene citrate or letrozole alone 5, 6, 7
2. If CC-resistant: consider metformin (superior to NAC) 4
3. Do NOT routinely add NAC given insufficient evidence and high heterogeneity 4
4. Focus on proven interventions: weight loss, lifestyle modification 3
5. Proceed to ART if first-line treatments fail 1

Bottom Line

The current evidence does not support prescribing NAC 600 mg twice daily for fertility in either men or women. While NAC appears safe, the lack of consistent benefit, high study heterogeneity, and absence of data on live birth rates means clinicians should focus on evidence-based interventions with proven efficacy rather than supplements of questionable utility. 1, 2, 3, 4