Article
Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial

https://doi.org/10.1016/j.rbmo.2011.05.012Get rights and content

Abstract

Sequential use of letrozole and human menopausal gonadotrophin (HMG) was compared with HMG only in poor ovarian responders undergoing IVF. Patients (n = 53) with less than four oocytes retrieved in previous IVF cycles or less than five antral follicles were randomized to either letrozole for 5 days followed by HMG or HMG alone. The letrozole group had lower dosage of HMG (P < 0.001), shorter duration of HMG (P < 0.001) and fewer oocytes (P = 0.001) when compared with controls. Live-birth rate was comparable with a lower miscarriage rate in the letrozole group (P = 0.038). Serum FSH concentrations were comparable in both groups except on day 8, while oestradiol concentrations were all lower in the letrozole group from day 4 (all P < 0.001). Follicular fluid concentrations of testosterone, androstenedione, FSH and anti-Müllerian hormone were higher in the letrozole group (P = 0.009, P = 0.001, P = 0.046 and P = 0.034, respectively). Compared with HMG alone, sequential use of letrozole and HMG in poor responders resulted in significantly lower total dosage and shorter duration of HMG, a comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment of follicular fluid.

The management of poor ovarian responders or women with poor ovarian reserve in IVF is controversial. The use of letrozole has been studied; however, results are inconsistent. This randomized trial studied the sequential use of letrozole and gonadotrophin compared with gonadotrophin alone in poor responders undergoing IVF. The sequential use of letrozole and gonadotrophin led to a significantly lower dosage and shorter duration of gonadotrophin use, significantly fewer oocytes, comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment at a lower cost.

Introduction

IVF is an effective treatment for various causes of subfertility. It involves ovarian stimulation for multiple follicular development, oocyte retrieval and embryo transfer after fertilization. Multiple embryos are usually transferred to compensate for their low implantation potential, which has remained steady at 20–25% despite recent advances in ovarian stimulation, gamete handling, assisted fertilization and embryo culture. The success of embryo cryopreservation also makes it desirable to obtain multiple embryos to allow an increased number of embryo transfers, thus increasing the cumulative pregnancy rates (Wang et al., 1994).

Therefore, the development of multiple follicles in response to gonadotrophin stimulation is usually considered as one of the key factors leading to a successful outcome. Poor ovarian response has usually been associated with low pregnancy rates and many of these cycles are cancelled without proceeding to oocyte retrieval (Keay et al., 1997). The management of poor ovarian responders has been extensively reviewed (Fasouliotis et al., 2000, Karande and Gleicher, 1999, Keay et al., 1997, Mahutte and Arici, 2002, Surrey and Schoolcraft, 2000, Tarlatzis et al., 2003) but remains a great challenge in assisted reproduction technology.

Letrozole, a third-generation reversible aromatase inhibitor, has been tried in poor responders undergoing IVF treatment. It inhibits the aromatization of androgen into oestrogen, which in turn reduces the negative feedback and results in an increase in gonadotrophins, which is the underlying mechanism of its use in ovulation induction (Mitwally and Casper, 2001). The sequential use of letrozole and gonadotrophins was reported to induce more mature follicles in intrauterine insemination cycles (Mitwally and Casper, 2002). A few studies (Davar et al., 2010, Garcia-Velasco et al., 2005, Goswami et al., 2004, Ozmen et al., 2009, Schoolcraft et al., 2008, Verpoest et al., 2006, Yarali et al., 2009) on the use of letrozole in poor ovarian responders undergoing IVF treatment have been reported but their results are not consistent.

This randomized trial was conducted to compare the sequential use of letrozole and human menopausal gonadotrophin (HMG) with HMG only in poor ovarian responders or women with poor ovarian reserve undergoing IVF treatment.

Section snippets

Study population

Subfertile patients attending the Centre of Assisted Reproduction and Embryology, The University of Hong Kong–Queen Mary Hospital were recruited if they had less than four oocytes retrieved in their previous failed IVF cycles or were found to have less than five antral follicles as assessed during early follicular phase within 2 months preceding the IVF treatment cycle. Those aged above 40 or having major medical illness, such as severe hepatic or renal impairments, were excluded.

Consecutive

Study population

During the study period between 1 September 2005 and 30 September 2009, 65 consecutive eligible patients were approached and 53 patients were recruited. The study was prematurely terminated before reaching the pre-defined sample size due to recruitment difficulties. Twenty-six subjects were randomized to the letrozole group while 27 subjects were in the control group (Figure 1). There was no adverse event in both groups leading to cessation of treatment cycles.

The demographic data are shown in

Discussion

Results of this randomized study confirmed that sequential use of letrozole and HMG in poor ovarian responders significantly reduced the total dosage and duration of HMG used. Although the number of oocytes retrieved was significantly lower in the letrozole group, the live-birth rate was similar for both groups. It was also shown that serum FSH concentrations were comparable in both groups on the majority of the days during ovarian stimulation. Follicular fluid concentrations of testosterone,

Acknowledgements

This study was supported by the Hong Kong OG Trust Fund. The authors thank all women who participated in this study and Ms Jane Chan for the co-ordination of the study.

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    Dr Vivian Lee is a resident specialist in the Reproductive Medicine team in the Department of Obstetrics and Gynaecology, Queen Mary Hospital. Her main research interest includes the use of letrozole in assisted reproduction technology and medical abortion.

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