Assisted Reproduction and Infertility


response to metformin is related to a direct action of the drug on the ovary in addition to its systemic insulin-sensitising effects.


Metformin is available in two oral formulations: immediate- and extended-release tablets. Even though no dose-finding study is currently available, metformin administration at incremental doses from 500 to 2,500mg/day has been proposed.17


differences in terms of pregnancies24,25


Second-line Treatments Alternative Clomiphene Citrate Regimens Novel protocols of CC administration have been proposed in patients with known CC resistance in order to evaluate treatment schedules more effectively. In a recent RCT, Badawy et al.43


proposed an Compared with


placebo or no therapy, the efficacy of metformin in inducing ovulatory cycles was demonstrated24,25,29


even though there were no significant and live births.25


Several studies have compared metformin and/or CC for inducing ovulation in therapy-naïve infertile PCOS patients. Contrasting data have been found. In a study by Palomba et al.,30


extended CC regimen and compared it with more expensive and sophisticated alternatives, i.e. gonadotropins. Interestingly, data obtained in this RCT43


showed significantly higher ovulation and a similar ovulation rate


between women receiving CC and those receiving metformin was shown. A significant increase in pregnancy rate and a trend in favour of metformin treatment for an increased live birth rate were described.30 Conversely, advantages of using CC rather than metformin on ovulation,22,31


pregnancy and live birth22 rates have been reported.


Lastly, a higher frequency of multiple pregnancy was observed in patients taking CC compared with metformin.22


Pooling data available in the literature, metformin resulted in no significant advantage over CC regarding cumulative ovulation, pregnancy and live birth rates.32


The meta-analysis32


heterogeneity in terms of dosage and modality of drug administration,22,30,31,33,34


mass index distribution22,30,31,33,34 of ovulation.22


A recent meta-analysis29


regimens, have recently been proposed in an RCT and a retrospective analysis, respectively. Compared with the standard protocol, the administration of 100mg/day of CC in the luteal phase resulted in improved ovulation and pregnancy rates, even if no significant difference was observed, whereas the total number of follicles during stimulation was significantly higher.44


pregnancy rates after the extended CC regimen than after gonadotropin administration. This suggests that in CC-resistant PCOS patients a further period of CC administration might be preferable. Alternative protocols for CC administration, such as luteal phase44 stair-step45


and On the other reported high


criteria adopted for PCOS diagnosis,22,33,34 and previous treatment for induction


body confirmed that metformin is of benefit in


improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates, whether used alone, in combination with CC or compared with CC monotherapy.


Aromatase Inhibitors Several experiments35–38


have evaluated the efficacy of aromatase


no significant difference was detected in ovulation and pregnancy rates per cycle. Contrary to this, Begum et al.36


rate in letrozole-treated women was higher than in patients treated with CC, even if statistical significance was not reached. With the exception of Polyzos et al.,37


in a meta-analysis of RCTs38


inhibitors – in particular letrozole – as a first-line therapy for inducing ovulation in infertile patients affected by PCOS. Letrozole was usually administered at a dose of 2.5mg/day for four days from day three to day seven of the menstrual cycle.39,40 Badawy et al.,35


In the study by showed that


letrozole administration resulted in higher ovulation and pregnancy rates than CC. Similarly, a recent trial41


demonstrated that the pregnancy a significantly higher


rate of pregnancies and live births was demonstrated in women with PCOS treated with letrozole compared with those treated with CC. However, no definitive conclusions are yet available.


the effectiveness of laparascopic ovarian diatermy (LOD) as a first-line method of ovulation induction in infertile women with PCOS was evaluated by comparing it with CC. Although LOD is theoretically superior to CC, this study failed to demonstrate any advantage in using LOD.42


Laparoscopic Ovarian Diathermy In a recent RCT,42


CC administration resulted in more


pregnancies and live births than LOD, although the difference was not statistically significant due to the relatively small sample size.


14


hand, the stair-step protocol consisted of giving the patient 50mg/day CC for five days and immediately following this by increasing the dose weekly, if there is no ovarian response, by 50mg/day CC, up to a maximum of 150mg/day. Stair-step cycles were less time-consuming and demonstrated greater efficacy in terms of ovulation rate compared with published historical CC outcomes for women who were non-responsive to the drug.


Clomiphene-citrate-sensitising Treatments Lifestyle Modifications


Lifestyle interventions have demonstrated reproductive benefits not only in therapy-naïve infertile PCOS patients but also in patients who were not responsive to first-line therapies. It has been hypothesised that lifestyle interventions should help to sensitise the ovary to subsequent CC administration.8


Clinical data46


showed that in CC-resistant PCOS patients a very short-term intervention consisting of structured exercise training plus a hypocaloric diet is effective in improving ovarian sensitivity to CC.


Metformin


Metformin is a widely studied second-line therapy in PCOS patients in combination with other drugs and/or in a pre-treatment regimen.


Two meta-analyses considering metformin plus CC,47,48 although


having heterogeneous results, demonstrated significant benefits with metformin co-treatment in CC-resistant PCOS women in terms of ovulations and pregnancies. The benefits on ovulation were also successively confirmed,27


even if significant heterogeneity was


demonstrated across the studies. No data were provided on the effect of this regimen on pregnancy and live birth rates. More recently, metformin plus CC was confirmed to improve ovulation and pregnancy rates compared with CC alone, especially in CC-resistant and obese PCOS patients.49


When metformin and CC in combination


was compared with LOD, higher ovulation and pregnancy rates were observed even if no significant benefit was demonstrated in terms of miscarriage and live birth rates.50


The ovulation and pregnancy rates in subjects treated with metformin plus CC were similar to those receiving metformin plus letrozole, even if endometrial thickness and full-term pregnancies were significantly higher after this last treatment.51


EUROPEAN OBSTETRICS & GYNAECOLOGY


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