Comparison of metformin and N-acetyl cysteine, as an adjuvant to clomiphene citrate, in clomiphene-resistant women with polycystic ovary syndrome

J Gynecol Obstet Hum Reprod. 2017 Sep;46(7):579-585. doi: 10.1016/j.jogoh.2017.07.004. Epub 2017 Jul 8.


Objective: To evaluate the effects of short- and long-term treatment with metformin and NAC, in an adjuvant to clomiphene citrate (CC), on the improvement of hormonal profile (SHBG, total testosterone, FBS, and fasting insulin) and fertility status in CC-resistant women with PCOS.

Materials and methods: One hundred and eight CC-resistant PCOS patients participated in the study and received either metformin (1500mg/day) or NAC (1800mg/day) with 100mg/day of CC for 8 and 12 weeks. Mean BMI, hirsutism score, LH/FSH ratio, endometrial thickness, mature follicle number, and serum concentrations of LH, FSH, E2, fasting insulin, total testosterone and FBS were evaluated before and after short- and long-term treatment. Furthermore, ovulation and pregnancy rates in the first and second cycles were also determined in treated patients.

Results: There was no significant difference in all variables before and 8 weeks after treatment with metformin and NAC. The BMI- and insulin-lowering effects of metformin were significantly higher than NAC after long-term treatment. However, the reducing-effect of NAC on hirsutism score and FBS levels was significantly more than metformin after 12 weeks. Treatment with metformin and NAC significantly increased ovulation and pregnancy rates in CC-resistant PCOS patients. In the first and second cycles, ovulation and pregnancy rates in patients treated with NAC were slightly higher than those received metformin.

Conclusions: Compared with metformin, administration of NAC in an adjuvant to CC is recommended for improving of hormonal profile and treatment of anovulatory infertility in hyperinsulinemic patients especially women with PCOS who are CC-resistant.

Keywords: Clomiphene resistance; Metformin; N-acetyl cysteine; PCOS.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Acetylcysteine / administration & dosage*
  • Adjuvants, Pharmaceutic / administration & dosage
  • Adult
  • Clomiphene / administration & dosage*
  • Drug Administration Schedule
  • Drug Resistance / drug effects
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Fertility Agents, Female / therapeutic use*
  • Follow-Up Studies
  • Humans
  • Infertility, Female / drug therapy*
  • Infertility, Female / etiology
  • Metformin / administration & dosage*
  • Ovulation Induction / methods*
  • Polycystic Ovary Syndrome / complications
  • Polycystic Ovary Syndrome / drug therapy*
  • Pregnancy
  • Pregnancy Rate


  • Adjuvants, Pharmaceutic
  • Fertility Agents, Female
  • Clomiphene
  • Metformin
  • Acetylcysteine