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Results of a randomized and controlled trial evaluating the use of N-acetylcysteine (NAC) on pregnancy outcomes and ovulation induction among women with polycystic ovarian syndrome (PCOS) were recently published in the Journal of Ovarian Research. NAC and other antioxidants have been evaluated in a number of PCOS trials, though it is not clear if its role as an antioxidant is NAC’s primary mechanism of action. While hyperandrogenism and hyperinsulinemia play critical roles, the cause of PCOS is not clearly established, despite affecting 7-12% of women.
This recent publication included results from both a clinical trial, as well as a report of NAC use in an animal model in which PCOS was induced with an aromatase inhibitor (letrozole). In the animal model, NAC normalized estrous cycles, improved LH and testosterone levels, and restored insulin sensitivity and glucose clearance compared to controls, with similar efficacy to metformin. NAC also boosted antioxidant enzymes in ovarian tissues, including superoxide dismutase, glutathione peroxidase, and catalase, as well as levels of the key cellular antioxidant glutathione, effects not observed with metformin.
The clinical trial portion of this publication included 230 women with PCOS, all of whom received a sequential letrozole and urinary follicle-stimulating hormone (uFSH) protocol to induce ovulation, and half of whom also received 1.8g oral NAC per day (divided into 3 equal doses), starting on the 2nd to 4th day of menstruation and continuing for 5 days. Follow-up for both groups was up to 3 ovulation induction cycles, with pregnancy as the primary outcome. While some of the technicians involved were blinded, the study participants and physicians were not.
The group of women receiving NAC had a higher clinical pregnancy rate per ovulation induction cycle compared to controls (31% vs. 23%), and they also had a higher cumulative pregnancy rate over the entire trial (78% vs. 58%), both found to be significantly higher. They also had a significantly higher ongoing pregnancy rate (continued pregnancy at 12 weeks) of 70% vs. 54%, with no differences in multiple pregnancy, early miscarriage, or ectopic pregnancy rates. A stratified analysis also found an even greater difference between groups among women with a BMI of 24 or higher, with a cumulative pregnancy rate of 73% vs. 44% in this population, suggesting that NAC may be more beneficial among women with overweight or obesity. Together, this provides more evidence that NAC may significantly improve the pregnancy rate of women with PCOS, and suggests possible mechanisms related to antioxidant protection of oocytes and ovarian tissues.
A review of NAC use among women with PCOS was recently published in Gynecological Endocrinology. This review concludes that the wide variety of doses, duration of treatment, and control groups makes definitive outcomes difficult to assess, yet NAC has a good safety profile, and often compares well, if somewhat inferior, to metformin. For example, one study cited in this review found that 1.8g per day NAC had significantly greater improvements in insulin sensitivity and testosterone reduction compared to metformin, along with fewer adverse effects, and at this same dose, more effectively improved lipid profiles, fasting blood sugar and insulin levels than metformin.
Systematic reviews have not reached uniform conclusions regarding NAC use to improve pregnancy rates among women with PCOS. A meta-analysis published in 2020, which included 15 randomized and controlled trials (RCTs) and over 2300 women, found increases in pregnancy and ovulation rates, yet these were not significant and were inferior to metformin’s effects. It’s worth noting that little interest exists in the United States to evaluate NAC’s efficacy; 14 of the 15 studies were conducted in Iran or Egypt, with a single study conducted in India, and most of the included studies had concerns about their quality. A previously published systematic review found that compared to placebo, NAC improved pregnancy and ovulation rates, but was inferior to metformin on both counts.
In addition to determining an optimal dosage for NAC, some women may benefit more than others; for example, it’s been suggested that women with a higher BMI and/or a greater degree of insulin resistance may be better candidates. Women who have a more resistance to clomiphene citrate (CC) may also be more likely to benefit. In a trial that enrolled 108 participants with PCOS and CC resistance, NAC had a significantly greater effect on fasting glucose and hirsutism compared to metformin, with slightly higher ovulation and pregnancy rates. In a previously published placebo-controlled trial conducted among women with CC resistance, NAC more than doubled the ovulation rate compared to placebo, and significantly increased the pregnancy rate, suggesting a clear advantage of NAC if metformin is not well tolerated.
It also remains an open question what other therapies work best with NAC; a recently published systematic review found that antioxidants have fairly broad benefits for the metabolic and endocrine anomalies that accompany PCOS, with some observational data to suggest that combination therapy with other agents, such as inositol, vitamin D, chromium, etc., may be more effective than single-therapy agents alone, a plausible hypothesis given the nature of PCOS. While NAC’s optimal role in PCOS is still vague, growing evidence suggests it should at least be considered as part of adjunctive therapy.
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