Efficacy of metformin supplementation during ovarian stimulation of lean PCOS patients undergoing in vitro fertilization

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1 Acta Obstetricia et Gynecologica. 2009; 88: ORIGINAL ARTICLE Efficacy of metformin supplementation during ovarian stimulation of lean PCOS patients undergoing in vitro fertilization BANU KUMBAK 1 & SEMRA KAHRAMAN 2 1 Department of Obstetrics and Gynecology, Yeditepe University, Istanbul, Turkey and 2 ART and Genetics Center, Istanbul Memorial Hospital, Istanbul, Turkey Abstract Objective. To evaluate the effect of metformin addition during ovarian hyperstimulation on cycle parameters and outcome of in vitro fertilization (IVF) treatment in polycystic ovary syndrome (PCOS) patients with a body mass index (BMI) B28 kg/ m 2. Design. Retrospective review of patients records. Setting. Istanbul Memorial Hospital Assisted Reproductive Treatment Unit. Population. A total of 339 non-obese PCOS patients undergoing IVF were evaluated according to the supplementation of metformin. Methods. Cycle parameters and IVF outcomes of 220 patients given metformin were compared to those of 119 patients treated without metformin. Main outcome measures. Implantation and pregnancy rates. Results. Metformin cotreatment led to significantly lower peak E2 levels (3,481 pg/ml vs. 4,192 pg/ml; pb0.0001). However, gonadotropin consumption, stimulation duration, numbers of total and mature oocytes retrieved, fertilization rate, and ratio of grade I embryos developed were similar in both groups. In the metformin administered group, significantly higher implantation (25% vs. 18%; p0.003) and pregnancy rates (58% vs. 45%; p0.04) were achieved. Abortion and moderatesevere ovarian hyperstimulation syndrome rates were found to be similar in both groups. Conclusions. Although metformin use was especially and strongly recommended in obese PCOS cases, its supplementation during IVF in PCOS patients with a BMI B28 kg/m 2 was observed to be beneficial and efficacious. Key words: Polycystic ovary syndrome, metformin, in vitro fertilization, body mass index Abbreviations: ART: assisted reproductive treatment, BMI: body mass index, CC: clomiphene citrate, GnRH: gonadotropin-releasing hormone, HOMA: homeostasis assessment model, IR: insulin resistance, IVF: in vitro fertilization, OHSS: ovarian hyperstimulation syndrome, PCOS: polycystic ovary syndrome Introduction Ovulatory disorders give rise to approximately 30% of infertility cases, and polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility with a prevalence rate of approximately 20% in the infertile population (1,2). After the exclusion of other causes, patients are diagnosed with PCOS if they meet any two of the following three criteria: chronic oligoovulation or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries by ultrasound (3). Obesity and insulin resistance (IR) are also common features of the syndrome (4,5). IR with compensatory hyperinsulinemia is hypothesized to stimulate ovarian androgen synthesis and secretion and also decrease hepatic production of sex hormone-binding globulin, which leads to an increase in free androgen levels. Thus, IR may have a role in PCOS pathogenesis by worsening the already abnormal androgen signaling at the ovarian level (6). Although decreased insulin sensitivity was observed in both lean and obese PCOS patients, IR occurred more frequently in obese cases (6,7). Metformin is an agent that improves insulin sensitivity and lowers circulating insulin levels (8). It is an oral biguanide drug used in the treatment of type 2 diabetes mellitus. Metformin inhibits Correspondence: Banu Kumbak, Fahrettin Kerim Gokay cad. No:282 D:10, Erenkoy, Istanbul, Turkey. bkumbak@yahoo.com (Received 19 September 2008; accepted 17 February 2009) ISSN print/issn online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: /

2 564 B. Kumbak & S. Kahraman gluconeogenesis in the liver, which reduces hepatic glucose output and additionally augments insulinmediated glucose uptake in skeletal muscle (9,10). Metformin use in infertile PCOS women has been widely investigated, and the reported results have been controversial. Numerous studies have shown that metformin increased ovulatory rates and ameliorated hyperandrogenism. However, the efficacy of metformin use during in vitro fertilization (IVF) treatment has not been clearly established, and it is not justified to recommend metformin to all PCOS patients undergoing IVF treatment. Some PCOS patients have been suggested to benefit from metformin use during IVF; however, it is not yet clear which subgroup of women with PCOS should be recommended metformin. The objective of the present study was to determine whether metformin co-administration during IVF treatment in nonobese PCOS patients with a body mass index (BMI)B28 kg/m 2 was associated with favorable cycle characteristics and positive outcomes. Material and methods The records of a total of 339 infertile, PCOS patients with a BMI B28 kg/m 2, who were treated at the Istanbul Memorial Hospital Assisted Reproductive Treatment (ART) Unit between June 2003 and May 2005, were reviewed. We obtained approval from the hospital ethics committee, and informed consent was obtained from all patients. The PCOS diagnosis was established according to the revised Rotterdam consensus criteria, which are: oligo/ amenorrhea (fewer than six menses during the previous year), clinical and/or biochemical signs of hyperandrogenism (hirsutism with or without acne), and typical polycystic ovaries on a transvaginal ultrasound scan (presence of 12 or more follicles in each ovary measuring 29 mm in diameter and/or increased ovarian volume10 ml) (3). A patient was diagnosed with PCOS if she met any two of these three criteria. Of the 339 patients enrolled, 220 were treated with metformin (Glucophage ; Bristol-Myers Squibb, Turkey) at a dose of 850 mg twice a day when the gonadotropin-releasing hormone (GnRH) agonist was initiated for down-regulation. Metformin treatment continued throughout the ovarian stimulation with gonadotropins, and in cases where pregnancy was achieved, metformin treatment continued until the 12th gestational week. The remaining 119 patients did not receive metformin. All 339 patients were stimulated with a GnRH agonist long protocol. In patients who had regular cycles, the GnRH agonist was initiated on the 21st day of the preceding cycle. Patients with irregular cycles were treated with an oral contraceptive pill (Ginera ; Schering, Turkey) from the third day of the preceding cycle, and the GnRH agonist was initiated on the 21st day of the pill. Patients were stimulated with recombinant follicle-stimulating hormone (rfsh; Puregon ; Organon or Gonal-F ; Serono) at a dose of IU daily according to their BMI, age, and previous cycles, if present. The doses were adjusted according to the serial sonographic follicular sizes and serum estradiol (E2) measurements. When the leading follicle reached 20 mm in diameter, human chorionic gonadotropin (HCG) was administered at a dose of 5,00010,000 IU, depending on the serum E2 concentration. Oocyte pick-up was arranged 36 hours after HCG injection. All the patients received luteal phase support of progesterone in oil (75 mg daily) starting the day after oocyte retrieval. Embryo transfer was performed on days three to five under ultrasound guidance, followed 12 days later by a serum b-hcg measurement. An ultrasound was performed three weeks after a positive pregnancy test date. Patient characteristics recorded included age, infertility duration, day three FSH, day three luteal hormone (LH), BMI, plasma insulin, and glucose levels. The cycle characteristics measured included the total gonadotropins used, days of stimulation, serum E2 on the day of HCG administration, endometrial thickness on the day of HCG administration, numbers of total and mature oocytes retrieved, fertilization rate, embryo grade, and the day of transfer. As outcome measures, we determined the implantation rate (number of gestational sacs per number of embryos transferred), the b-hcg positive pregnancy rate per embryo transfer, the spontaneous abortion rate (pregnancy loss before 12 weeks including biochemical and anembryonic gestations per number of b-hcg positive pregnancies), and the moderate to severe ovarian hyperstimulation syndrome (OHSS) rate. Data were analyzed using SPSS version 13.0 for Windows (SPSS Inc., Chicago, IL). The Student s t- test and chi-squared test were used for statistical analyses, when appropriate. The level of significance was pb0.05. Results A total of 339 cycles were evaluated. The demographic characteristics of the patients were similar in the two groups except for the BMI, which was significantly higher in the group given metformin (Table I). The two groups were similar in terms of the following stimulation characteristics: stimulation

3 Metformin in lean PCOS women undergoing IVF 565 Table I. Demographic characteristics of PCOS patients with a BMIB28 kg/m 2 according to the supplementation of metformin. Metformin positive (n220) Metformin negative (n119) p Age (years) NS Infertility duration (years) NS BMI (kg/m 2 ) Day 3 FSH (miu/ml) NS Day 3 LH (miu/ml) NS Fasting glucose (mg/dl) NS Fasting insulin (miu/ml) NS Note: Values are means9standard deviation (SD). FSH, follicle-stimulating hormone; LH, luteinizing hormone; BMI, body mass index; NS, not significant; p0.05. Student s t-test. duration, total amounts of gonadotropins used, number of total and mature oocytes obtained, fertilization rates, number of eight-cell embryos per number of total embryos present on day three, number of grade I embryos transferred, and embryo transfer day (Table II). Significantly lower peak serum E2 levels were observed in the group administered metformin (3,481 pg/ml vs. 4,192 pg/ml; pb0.0001, Table II). When the treatment outcomes were compared, the implantation rate (25.4% vs. 17.8%; p 0.003) and the b-hcg positive pregnancy rate per embryo transfer (57.7% vs. 45.3%; p 0.04) were significantly higher in the metformin-administered group vs. the patients who did not receive metformin (Table II). In contrast, the rates of spontaneous abortion and moderate to severe OHSS did not differ significantly between the two groups (Table II). Discussion This study demonstrated that treatment with metformin during ovarian stimulation increased implantation and pregnancy rates in PCOS patients undergoing IVF with a BMIB28 kg/m 2. We suggest that metformin has beneficial effects in non-obese PCOS patients when administered during IVF. PCOS is a heterogeneous disorder with different characteristic features in different subgroups of patients. Since IR and the accompanying hyperinsulinemia appear to be central in the PCOS pathogenesis, treatment with insulin sensitizers, mainly metformin, has gained increasing popularity since the first case series published in 1994 (1113). In a study by Caliskan et al. (14), IR was observed in 24% women with PCOS in a Turkish population. For lean women with PCOS, the prevalence of IR was reported to be 622% (1517). Table II. IVF cycle characteristics and outcomes of PCOS patients with a BMIB28 kg/m 2 according to the supplementation of metformin. Metformin positive (n220) Metformin negative (n119) p Total gonadotropins used (IU) 1, , NS HCG day NS HCG E2 (pg/ml) 3,48191,258 4,19291,335 B HCG endometrium (mm) NS Total oocyte (n) NS MII oocyte (n) NS Fertilization (%) NS Grade I embryos transferred (n) NS Eight-cell emb. no./total emb NS no. on Day 3 (%) ET day NS Cleavage stage ET (%) NS Blastocyst stage ET (%) NS IR (%) PR/ET (%) Abortion (%) NS OHSS (moderatesevere) (%) NS Note: Values are means9standard deviation (SD) or percentages. HCG, human chorionic gonadotropin; E2, estradiole; ET, embryo transfer; IR, implantation rate; PR, pregnancy rate; OHSS, ovarian hyperstimulation syndrome; NS, not significant; p0.05. Student s t- test and chi-squared test.

4 566 B. Kumbak & S. Kahraman Although metformin is not a fertility drug, it has been reported to affect metabolism and induce ovulation indirectly by reducing the circulating concentration of insulin. In PCOS patients, metformin was shown to reduce insulin, testosterone, and LH concentrations (1820). Although, the indiscriminate recommendation of metformin to all PCOS patients was not supported, metformin has been specifically suggested for PCOS patients with IR and/or obesity (21). It remained unclear whether metformin was also beneficial for lean PCOS women. A previous study showed that metformin improved hirsutism scores and ovulation and decreased dehydroepiandrosterone sulfate (DHEAS) levels in lean PCOS women (22). Similarly, in a recent study performed in lean PCOS patients without pretreatment IR, metformin improved hyperandrogenemia and anovulation (23). On the contrary, another study reported no metabolic benefits of metformin treatment in non-obese PCOS women (24). In our study, we aimed to investigate whether metformin use during IVF treatment improved outcome parameters, rather than the metabolic aspects, in lean PCOS women. Our results demonstrate a beneficial effect of metformin co-administration during IVF in non-obese PCOS patients. In our study, we observed that the women treated with metformin were significantly heavier than those who were not treated with metformin; however, the plasma glucose and insulin levels were similar in the two groups, implying that the IR states were similar. Recently, it was suggested that metformin use in PCOS patients should be restricted to women with glucose intolerance (25), but others disagreed with this suggestion (26). Furthermore, there is no consensus on the most accurate way to measure insulin sensitivity. Insulin sensitivity has been measured by the fasting glucose to insulin ratio, the intravenous glucose tolerance test, and the homeostasis assessment model (HOMA), but there has been no comparison of the sensitivities and specificities of these methods. Moreover, there are inconsistencies among studies on when and how IR was documented in the PCOS patients (27). We did not document IR in every PCOS patient, and metformin was administered to lean PCOS patients according to the physician s recommendations. Two large randomized studies examined the effect of metformin on the reproductive aspects of PCOS (28,29). These studies showed that metformin treatment in addition to clomiphene citrate (CC) did not improve ovulation, ongoing pregnancy, and live-birth rates in PCOS women. However, those two studies were performed in PCOS patients who had undergone ovulation induction and not IVF. Our aim was to investigate the influence of metformin on the outcome parameters of IVF treatment in lean PCOS patients. A number of previous studies have reported on metformin use in PCOS patients undergoing IVF. In a retrospective study of 46 non-obese PCOS patients undergoing IVF, fertilization and clinical pregnancy rates were higher in the metformin-treated patients, and the investigators concluded that metformin use improved oocyte quality (30). Similarly, other investigators reported that metformin use in PCOS patients undergoing IVF improved pregnancy rates (3133). Our results are in agreement with these findings. In contrast, a meta-analysis reported that metformin co-administration during IVF treatment in PCOS patients did not improve pregnancy rates (34). As shown in the aforementioned studies, the benefits of metformin use during IVF have not yet been clearly established, which may be because of the wide range of characteristics in women with PCOS. Additionally, the differences in the lengths of the metformin treatments before and during IVF make it difficult to compare the results of the studies. Our study is the first to report the effects of metformin use in a large, non-obese, PCOS patient group undergoing IVF. We analyzed the IVF cycles in specifically non-obese women with PCOS and evaluated the effect of metformin administered during the treatment period on the outcome parameters. In two meta-analyses, metformin was suggested to result in fewer cases of OHSS during IVF (34,35). Although we observed significantly lower E2 levels in the metformin-administered group, we did not observe a lower rate of OHSS, as might be expected. However, the mechanism of OHSS development is controversial; therefore, high E2 levels may be only one of the factors involved in OHSS pathophysiology. We further evaluated the abortion rate during metformin treatment, and we observed no significant difference between the two groups. Similarly, a meta-analysis reported that metformin co-administration during IVF treatment did not improve the live birth rate (34). In contrast, numerous studies have suggested that metformin administration during pregnancy reduced first-trimester pregnancy loss in women with PCOS (3638). However, these studies included all PCOS patients without BMI discrimination. In contrast, we evaluated pregnancy outcomes in lean PCOS women only. Presently, reports on the efficacy of metformin cotreatment before and during IVF treatment in all PCOS patients are controversial and inconclusive.

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