Salehpour S, Sene AA, Saharkhiz N, Sohrabi MR, Moghimian F. N-acetylecysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. J Obstet Gynaecol Res 2012 Sept; 39(9): 1182-1186.
Double-blind, placebo-controlled, randomized study
Study included 180 infertile women, age 20–35 years with polycystic ovarian syndrome (PCOS) based on Rotterdam criteria. Participants were included if they were infertile for less than 10 years, had a body mass index (BMI) < 35 kg/m2, had patent fallopian tubes confirmed by hysterosalpingography, and had a partner with a normal semen analysis. Participants were excluded if they had thyroid disease, hyperprolactinoma, hypercorticism, history of large ovarian cyst (> 6 cm), or history of visual disturbance caused by clomiphene citrate. Patients were also excluded if they were on any medications that affect glucose metabolism or ovulation for at least 3 months before the study.
Study Medication and Treatment Protocol
Study participants were randomly assigned to 2 treatment groups for ovulation induction. The 90 participants assigned to group 1 received 100 mg of clomiphene citrate (CC) on cycle day 3–7 along with 1,200 mg of N-acetylcysteine (NAC). The 90 participants assigned to group 2 received 100 mg of clomiphene citrate on cycle day 3–7 along with a placebo. Both NAC and the placebo were given in powdered form to be diluted in water in 2 daily divided doses. On cycle day 12, all participants were evaluated with transvaginal ultrasonography and, in the presence of at least 1 follicle with a diameter greater than 18 mm, an intramuscular injection of 10,000 units of human chorionic gonadotropin (hCG) was administered for timed intercourse 36 hours later.
Primary Outcome Measures
Participants were evaluated with transvaginal ultrasonography on cycle day 12 to determine the number of mature follicles (defined by a diameter greater than 18 mm) and to measure the thickness of the endometrial lining. In addition, serum β-hCG was measured 16 days after the hCG injection, and was repeated 2 days later for confirmation of a positive pregnancy test. A pelvic ultrasound was performed at 6 weeks gestation to assess the viability of the pregnancy.
When comparing the average number of mature follicles on cycle day 12, patients receiving CC+NAC had 1.5 + 0.89 follicles while patients receiving CC+placebo had 1 + 0.77 follicles (P=0.001). Endometrial thickness was also significantly greater in the patients receiving CC+NAC, with an average endometrial lining of 6.6 + 1.60 mm, compared to 5.4 + 1.61 mm in patients receiving CC+placebo (P=0.001). And lastly, the pregnancy rate was statistically higher in the CC+NAC group (20.73%) than the CC+placebo group (9.4%) (P=0.04). The differences between the groups were statistically significant for all outcome measures (number of follicles, endometrial thickness, and pregnancy rates). The only non-significant differences in the groups were for baseline demographics (age, number of years infertility, and body mass index). Furthermore, there was 1 case of twin pregnancy in the CC+NAC group compared to 1 twin pregnancy and 1 triplet pregnancy in the CC+placebo group. One cycle was canceled on the CC+placebo group when the participant developed a large 5 x 6 cm ovarian cyst. No other adverse events or cases of ovarian hyperstimulation syndrome were observed in any of the participants.
Several natural medicines have been shown to be beneficial as natural treatments for infertility secondary to anovulation in PCOS patients.
PCOS is one of the most common endocrine disorders, affecting up to 20% of women of reproductive age.1 The diagnostic criteria for PCOS include 2 of the following three factors: chronic oligomenorrhea or anovulation, hyperandrogenism, and polycystic ovarian morphology.2 Women with PCOS are more likely to be obese3 and have insulin resistance or impaired glucose tolerance.4 In fact, studies have shown that weight loss through dietary interventions and exercise can improve insulin resistance and hyperandrogenism, and also restore ovulation in women with PCOS who are obese or overweight. 5–7
Because not all patients with PCOS are overweight, it is important to understand the mechanism by which hyperinsulinemia impairs ovulatory function. Hyperinsulinemia plays a key role in the pathogenesis of PCOS by stimulating androgen production from the ovarian theca cells and also inhibiting the formation of sex hormone binding globulin, thereby increasing circulatory free androgens. Elevated insulin also alters the pulsatile secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn impairs ovulation.8 Therefore it should be no surprise that PCOS (and concomitant hyperinsulinemia) is diagnosed in 25% of women presenting with infertility.9
The first line of conventional treatment for ovulatory dysfunction attributed to PCOS is clomiphene citrate (CC), a triphenenylethylene derivative that predominately acts as an estrogen antagonist and has been used as an ovulation induction medication since 1967.10 The most common side effects of CC are vasomotor reaction, headache, nausea, and breast tenderness. Visual disturbances are experienced by 2% of CC users, which prompts immediate discontinuation of the medication because it can be permanent. The use of CC is also associated with an increased incidence of multiple gestations (5–8%). Another concerning effect of CC is thinning of the endometrial lining, which can result in implantation failure and lower pregnancy rates.
Despite its popularity, some patients with PCOS are resistant (do not ovulate) with the use of CC and require the use of adjunctive medication. Metformin, an oral antidiabetic drug in the biguanide class, has been used off label as an adjunctive treatment for ovulation induction, although this trend has been declining in recent years. The proposed benefits of metformin is to lower serum glucose, improve insulin resistance, and reduce androgen levels in PCOS patients, which would theoretically result in the resumption of ovulation;11 however randomized controlled trials show mixed benefit for the use of metformin as an adjunct to ovulation induction medication.12–14
Several natural medicines have been shown to be beneficial as natural treatments for infertility secondary to anovulation in PCOS patients. Myo-inositol (4 grams/day) has been shown to decrease serum androgens, improve insulin sensitivity, and help restore ovulatory function in PCOS patients.15 Vitamin D (100,000 IU/day) with calcium (1,000 mg/day) is associated with improvement in ovulatory function, follicular maturation and overall fertility in PCOS patients.16 While berberine (500 mg TID) has been shown to improve insulin sensitivity and decrease androgen levels,17 its effect on ovulation and infertility has yet to be elucidated.
While natural medicines can certainly support ovulatory function and improve fertility, none of these options are completely effective in all patients. Some patients may require prescriptions such as CC to ovulate. For these patients, co-treating with N-acetylcysteine (NAC) can improve the efficacy of CC while decreasing the side effects of thinning the endometrial lining. NAC has been shown in prior studies to improve insulin sensitivity and improve ovulatory function, particularly in women with treatment resistant anovulation.18–20 The antioxidant and antiapoptopic effects of NAC may improve folliculogenesis, and along with decreasing insulin and circulating androgens, improve ovulatory function.21 The antioxidant and protective effect against focal ischemia may play a role in preventing thinning of the endometrial lining.22
Although the authors chose to provide NAC in a powdered form to be diluted in water, NAC in an encapsulated form is widely available, equally effective, and more palatable. The low cost, safety, and tolerability of NAC make it a worthy adjunct to the treatment of anovulation in infertile patients with PCOS.
- Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998; 83(9):3078-3082.
- Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group, Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19(1)):41-47.
- Vrbikova J, Hainer V. Obesity and polycystic ovary syndrome. Obes Facts. 2009; 2(1):26-35.
- Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999; 84(1):165-169.
- Thomson RL, Buckley JD, Brinkworth GD. Exercise for the treatment and management of overweight women with polycystic ovary syndrome: a review of the literature. Obes Rev 2011; 12(5):e202-e210.
- Marsh KA, Steinbeck KS, Atkinson FS, et al. Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am J Clin Nutr. 2010; 92(1):83-92.
- Moran LJ, Noakes M, Clifton PM, et al. Short-term meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. Am J Clin Nutr. 2006; 84(1):77-87.
- JE Nestler. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008; 358(1):4754.
- ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists number 34, February 2002. Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002; 99(2):347-358.
- Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2006; 86(5 Suppl 1):S187-193.
- Barbieri RL. Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol. 2003;101(4):9.
- Siebert TI, ViolaMI, Steyn DW, Kruger TF. Is metformin indicated as primary ovulation induction agent in women with PCOS? A systematic review and meta-analysis. Gynecol Obstet Invest. 2012;73(4):304-313.
- Legro RS, Barnhart HX, Schlaff WE, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551-566.
- Morin-Papunen L, Rantala AS, Unkila-Kallio L, et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab. 2012;97(5): 1492-1500.
- Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of myo-inositol supplementation on oocyte’s quality in PCOS patients: a double blind trial. Eur Rev Med Pharmacol Sci. 2011;15(5):509-514.
- Firouzabadi RD, Aflatoonian A, Modarresi S, Sekhavat L, Mohammad-Taheri S. Therapeutic effects of calcium and vitamin D supplementation in women with PCOS. Complementary Ther Clin Practice. 2012;18(2):85-88.
- Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012; 166(1):99-105.
- 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.
- Rizk AY, Bedaiwy MA, Al-Inany HG. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate resistant patients with polycystic ovary syndrome. Fertil Steril. 2005; 83(2):367-370.
- Badawy A, State O, Abdelgawad S. N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: A cross-over trial. Acta Obstet Gynecol Scand. 2007; 86(2):218-222.
- 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.