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Effects of Metformin on Ovulation and Pregnancy Rate in Women with Clomiphene Resistant Poly Cystic Ovary Syndrome Mahnaz Ashrafi, M.D.1, 2*, Fatemeh Zafarani, B.Sc.2, Ahmad Reza Baghestani, M.Sc.3 1. Endocrinology and Female Infertility Department, Royan Institute
2. Obstetrics and Gynecology Department, Faculty of Medicine, Iran University of
Medical Sciences, Akbar Abadi Hospital
3- Epidemiology Department, Royan Institute
Background: To evaluate the effect of metformin on ovulation and pregnancy rate in clomiphene citrate
resistant women with polycystic ovary syndrome (PCOS).
Material & Methods: In this clinical trial each patient, regarding her previous resistance to Clomiphene,
served as her own control. A total of 35 clomiphene citrate resistant PCOS patients, referring to Royan institute
were studied. Clomiphene citrate resistance was defined as having failure of ovulation during at least three
cycles using clomiphene citrate doses up to 200 mg/day on cycle days 3-7 after a withdrawal bleeding with
progesterone. Metformin was used alone or in combination with clomiphene citrate. First, the patients received
metformin up to 1500 mg/day for 8 weeks. During the next 2-3 cycle if the patients did not become pregnant,
clomiphene was added with increments of 100 mg (up to 150 mg/day). Follicular development and ovulation
were monitored by ultrasound scans and mid-luteal progesterone level. Menstrual pattern, ovulation, and
pregnancy rate were evaluated during the two stages of treatment.
Results: After 8 weeks of meformin monotherapy, ovulation occurred in 23 cases (65.7%) and 7 patients (20%)
became pregnant. Among other patients (28/35) who were treated with Clomiphene Ci\trate and metformin for
64 cycles, 19 patients (67.8%) had proper ovulation and five of them (17.8%) became pregnant. Totally,
metformin induced ovulation in 31 of 35 patients (88.6%) and twelve (34.3%) of them achieved pregnancy.
Conclusion: Metformin alone or in combination with clomiphene is a very effective treatment in inducing
ovulation and pregnancy in clomiphene resistant women with PCOS.

Keywords: PCOS, Clomiphene Citrate Resistant, Metformin, Ovulation


Introduction
ovulation induction in PCOS, but unfortunately Polycystic ovary syndrome (PCOS) is one of 10-20% of the women are clomiphene resistant approximately 5-10% of pre-menstrual women For CC resistant patients with PCOS, treatment (1, 2). It is a syndrome with unknown etiology with injectable gonadotropin is the usual modality for ovulation induction. However, chronic anovulation (2, 3). However, PCOS complications such as multiple pregnancy and ovarian hyperstimulation syndrome (7, 8). Recent studies have shown that women with PCOS are frequently insulin resistant and at clomiphene resistance in PCOSpatients (9-12). Hyperinsulinemia appears to lead to hyper intolerance or non insulin-dependant diabetes production of ovarian androgens and to an mellitus (NIDDM) in the third and fourth concentration and peripheral androgen action The anti-estrogen clomiphene citrate (CC) is by decreasing the serum sex-hormone-binding- widely accepted as a first line medication for
Received: 2 January 2007; Accepted: 12 April 2007
*Corresponding Address: P.O.Box: 19395-4644,
Endocrinology and Female Infertility Department, Royan
Royan Institute
Institute, Tehran, Iran
Iranian Journal of Fertility and Sterility
Vol 1, No 1, Spring 2007, Pages: 39-42
Email: info@royaninstitute.org
Ashrafi et al
Several insulin-sensitizing agents have shown to improve insulin resistance and therefore, Body weight and waist/hip ratio was checked reduce circulating insulin levels in women with before and during treatment cycles. Also FBS, PCOS (13). Among these, metformin cloridrate, OGTT, Fasting insulin, FSH, LH, and total an oral biguanide for type 2 diabetes mellitus, testosterone were measured on cycle day 3 is a safe and effective drug that is recently used for the treatment of PCOS patients (12-15). The administration of metformin improves (metformin hydrochloride, Tab; 500mg, Pars clinical and biochemical features of PCOS and minoo Co.) alone, 1500 mg/day for 8 weeks. induces ovulation cycles in anovulatory CC- During the next 2-3 cycles, clomiphene was resistant or nonresistant patients with PCOS added with increments of 100 mg (up to 150 mg/day) if the patients did not have successful monitored by transvaginal ultrasound scans dominant follicles (≥ 18mm), were seen, HCG 10,000 IU was injected intra muscularly. Ovulation was determined by mid-luteal serum This clinical trial study was conducted on 35 progesterone level (≥5 ng/ml).To confirm infertile patients with clomiphene resistant pregnancy β HCG test was done twice (12 and PCOS referring to Royan Institute (Infertility research center) from November 1999 up to pattern, ovulation, and pregnancy rate were evaluated during the two stages of treatment. The patients were healthy infertile women aged Data analysis was performed by SPSS software 20-35 years, with oligomenorrhia (interval utilizing student t-test (or Mann Whitney test if between menstrual periods from 35 days to 6 needing non parametric analysis), Levin test, months), normal serum FSH level (1-10 IU/L), χ 2, and logistic regression. P value ≤0.05 was considered as statistically significant. progesterone-induced withdrawal bleeding (19,20). All patients with hyperprolactinemia, diabetes and thyroid disorders were excluded. Demographic and laboratory results of the Male factor and tubal –uterine factor infertility Mean (±SD) age, duration of infertility, and ovulatory patients using students t-test (p>0.05). There were no statistically significant hyperandrogenaemia (NIH consensus criteria) changes in LH and total testosterone levels before and after treatment. A significant Clomiphene citrate resistance was defined as decrease in mean serum insulin level was having failure of ovulation during at least three detected after 8 weeks of Metformin treatment cycles using clomiphene citrate doses up to 200 mg/day on cycle days 3-7 after a withdrawal Table 1: Demographic, anthropometrics and laboratory findings of the studied patients
BMI Before
Insulin level
Treatment
level After
Testosterone Testosterone
Treatment
Treatment Treatment
Treatment
(mIU/ml)
(mIU/ml)
(mIU/ml)
(mIU/ml)
treatment
treatment
Mean±SD 25.8±4.06 29.89±5.17
19.20±7.55
16.18±7.97
9.78±8.65
8.1±6.45
1.3±1.11
0.98± 0.3
23-42.35
3.5-34.5
0.7-24.8
0.8-28.6
0.04 – 0.8
Metformin induces ovulation in CC resistant PCOS patients
Table 2: Ovulation and pregnancy rates of each phase of treatment
Type of treatment
Total Cycles
Cycles With
Cycles With
Ovulation No (%)
Pregnancy No.(%)
Metformin Alone
39(59.1%)
7(10.6%)
Metformin+CC
64 44(68.8%) 5(7.8%)
100+150mg
Total 130
83(63.8%)
12(9.2%)
CC=Clomiphene Citrate
Table 3: Number of patients who ovulated and conceived with different treatment conditions
Type of treatment
Cycles with
Cycles with
patients
ovulation
ovulation
Metformin alone
23(65.7%)
Metformin +CC (100-150g)
19(67.8%)
5(17.8%)
CC=Clomiphene Citrate
Table 2 demonstrates a summary of treatment In two studies, conducted by Acbay et al and Ehramann et al high dose of metformin (850 Metformin in combination with Clomiphene Citrate. Of 66 treatment cycles with Metformin administered and no significant change was alone, ovulation was documented in 39 cycles (59.1%) and pregnancy occurred in seven ycles resistant population of PCOS with previous Metformin and Clomiphene Citrate (100-150 mg), ovulation was recorded in 44 cycles In another study, Mitwally et al evaluated the (68.8%) and pregnancy occurred in five cycles effect of troglitazone on Clomiphene citrate (7.6%). Tables 3 showes the number of patients who ovulated and conceived with different Comparison of our results with the Mitwally ovulation in 31 of 35 patients (88.6%) and study showed no statistically significant twelve (9.2%) of them achieved pregnancy. pregnancy). But in some patients troglitazone leads to hepatic toxicity and liver function tests during treatment is required. Therefore, it correlation exists between, insulin resistance Several studies have demonstrated the effect of an insulin sensitizing agent like metformin and In this study, serum insulin level showed a troglitazone on PCOS patients. These agents significant reduction after 8-weeks of treatment. have been reported to result in restoration of This fact supports the hypothesis suggested by menstrual cycle, ovulation, and pregnancy (21). Several reports on treatment with insulin However we observed no significant reduction sensitizing agents suggest that metformin in BMI after treatment and therefore BMI has reduces LH/FSH, LH, free testosterone, and no effect on metformin response (p=0.1). It is well documented that metformin reduces We observed a high ovulation rate (88.6%) in a serum insulin level and results in ovulation series of 35 patients. In most of the patients ovulation was achieved with metformin alone Regarding the fact that the number of CC or in combination with low dose (100-150mg) resistant PCOS patients are considerable and clomiphene citrate. Metformin has been used in that usual treatments are expensive and have many recent studies. For example Nestler et al more serious documented complications, we metformin alone or metformin plus 50 mg/day combination with CC as a new therapeutic Ashrafi et al
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