Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in reproductive aged women with multiple manifestations and consequences. It affects approximately 6-10% of reproductive aged women and the metabolic disturbances associated with it have immediate and long term potential outcomes including infertility, hyperandrogenism, type 2 diabetes, cardiovascular disease and even uterine cancer.
Insulin-sensitizing agents have emerged as an important strategy in addressing the fundamental underlying cause of PCOS, insulin resistance. In conventional medicine, the focus has been on metformin which is an insulin sensitizing agent and can decrease the levels of insulin, improve glucose tolerance, increase sex hormone binding globulin (SHBG), decrease circulating androgens and increase ovulation rates in women with PCOS. N-acetyl-cysteine (NAC) is used by many alternative practitioners as a mucolytic medication and for antioxidant effects. Lesser known is its role as an insulin regulatory agent. And previous studies have shown that it can improve circulating insulin levels and insulin sensitivity in hyperinsulinemic women with PCOS as well as being successful as an adjunct treatment with clomiphene citrate for ovulation in women with PCOS.
The purpose of the study reported on here was to evaluate the effects of metformin and NAC in patients with PCOS. This prospective trial randomly divided 100 women to receive either metformin, 500 mg three times daily or NAC, 600 mg three times daily for 24 weeks. Evaluations included hirsutism scoring, body mass index, serum samples for follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone-sulphate (DHEAS), 17 OH-progesterone, total testosterone, free testosterone, androstenedione, thyroid stimulating hormone (TSH), SHBG, prolactin, glucose tolerance tests (including glucose and insulin), tumor necrosis factor-alpha (TNF-alpha) and lipids.
Women were ages 17-38 and 75 of the 100 women with PCOS completed the study. All women in the NAC group completed the study and 5 of the 35 women in the metformin group did not complete the study. At baseline, there were no differences between the treatment groups. Following treatment, LH, total testosterone and free testosterone decreased significantly and SHBG increased significantly in both groups. Hirsutism improved significantly in both groups and the difference between the metformin group and NAC group was not significant. Menstrual regularity was restored in 9 patients in the metformin group and 11 patients in the NAC group (36% vs. 34 %) and both metformin and NAC women significantly improved menstrual irregularity. In the metformin group, total serum cholesterol levels were significantly lowered but no significant changes were observed in LDL, triglycerides and HDL. In the NAC group, total cholesterol and LDL decreased significantly but no changes were observed in triglycerides and HDL. The changes in lipid profiles between the two groups were not significant.
Both metformin and NAC had positive effects on reducing fasting insulin levels, without change in fasting glucose, but this means that glucose-insulin ratios were increased significantly following treatment with both medicines and in addition, both led to a significant improvement in the HOMA (homeostatic model assessment; a method used to quantify insulin resistance) and were considered comparable. TNF-alpha levels were increased in both groups but not significant from baseline and similar in both groups.
Commentary: Conventional medical treatments for PCOS have come to include a combination of hormonal contraceptives, progestins, statins and insulin-sensitizing agents, especially metformin. This combination of treatments have not clearly led to adequate prevention of consequences of PCOS such as cardiovascular disease and type 2 diabetes and insufficient treatment of anovulatory related infertility, hirsutism, and weight management in those PCOS women who are overweight/obese. In addition, these approaches are fraught with side effects, and for metformin this typically includes gastrointestinal symptoms that can lead to intolerance of the drug, as it did with the high dropout rate in the metformin group in the current study. However, metformin has been a very important addition to PCOS management and two systemic reviews have shown that metformin reduces menstrual irregularity, improves ovulation rates, although poor impact on hirsutism.
A treatment such as NAC is a welcomed addition to improve insulin sensitivity in the management of PCOS. It turns out to be very well tolerated with no adverse effects. In the current study, both metformin and NAC reduced menstrual irregularity, resulted in regression of hirsutism and reduced hyperinsulinemia in women with PCOS. Also in the current study, there were significant reductions in free testosterone and total testosterone in both groups, likely due to decreasing insulin levels and increasing SHBG levels, and decreases in total cholesterol and insulin which bodes well for long term prevention issues as they related to cardiovascular disease and type 2 diabetes.
Oner G, Muderris I. Clinical, endocrine and metabolic effects of metformin vs N-acteyl-cytseine in women with polycystic ovary syndrome. European Journal of Obstetrics and Gynecology and Reproductive Biology. 2011;159:127-131.