ArticleSequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial
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.
References (41)
- et al.
A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation
Fertil. Steril.
(2004) - et al.
Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial
Fertil. Steril.
(2009) - et al.
Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial
Fertil. Steril.
(2009) - et al.
Comparisons of follicular levels of sex steroids, gonadotropins and insulin like growth factor-1 (IGF-1) and epidermal growth factor (EGF) in poor responder and normoresponder patients undergoing ovarian stimulation with GnRH antagonist
Eur. J. Obstet. Gynecol. Reprod. Biol.
(2007) - et al.
GnRH antagonist/letrozole versus microdose GnRH agonist flare protocol in poor responders undergoing in vitro fertilization
Taiwan J. Obstet. Gynecol.
(2010) - et al.
Reproductive biology and IVF: ovarian stimulation and endometrial receptivity
Trends Endocrinol. Metab.
(2004) - et al.
Intrafollicular antimullerian hormone levels predict follicle responsiveness to follicle-stimulating hormone (FSH) in normoandrogenic ovulatory women undergoing gonadotropin releasing-hormone analog/recombinant human FSH therapy for in vitro fertilization and embryo transfer
Fertil. Steril.
(2009) - et al.
The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study
Fertil. Steril.
(2005) - et al.
High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome
Fertil. Steril.
(1996) - et al.
Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders
Fertil. Steril.
(2002)
Follicular fluid concentrations of vascular endothelial growth factor, inhibin A and inhibin B in IVF cycles: are they markers for ovarian response and pregnancy outcome?
Eur. J. Obstet. Gynecol. Reprod. Biol.
Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols
Reprod. Biomed. Online
Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol?
Fertil. Steril.
Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques
Fertil. Steril.
Anti-Mullerian hormone substance from follicular fluid is positively associated with success in oocyte fertilization during in vitro fertilization
Fertil. Steril.
Differential regulation of aromatase and androgen receptor in granulosa cells
J. Steroid Biochem. Mol. Biol.
Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate
Fertil. Steril.
Aromatase inhibitors in ovarian stimulation for IVF/ICSI: a pilot study
Reprod. Biomed. Online
Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte’s ability to fertilize
Fertil. Steril.
Anti-Mullerian hormone and inhibin B as predictors of pregnancy after treatment by in vitro fertilization/intracytoplasmic sperm injection
Fertil. Steril.
Cited by (38)
Stimulation for low responder patients: adjuvants during stimulation
2022, Fertility and SterilityCo-treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis
2022, Reproductive BioMedicine OnlineCitation Excerpt :In the studies (n = 6) (Garcia-Velasco et al., 2005; Verpoest et al., 2006; Mohsen and El-Din, 2013; Yucel et al., 2014; Ebrahimi et al., 2017; Moini et al., 2019), without significantly reduced oestradiol levels, no association was found between oestradiol level, number of oocytes or expected ovarian response. Three of the included studies did not report oestradiol levels at trigger day (Lee et al., 2011; Bastu et al., 2016). A stimulation protocol with a minimum of 5 mg letrozole per day for at least 5 days seems appropriate to ensure a significant suppression of oestradiol in most of the women.
Effects of using letrozole in combination with the GnRH antagonist protocol for patients with poor ovarian response: A meta-analysis
2021, Journal of Gynecology Obstetrics and Human ReproductionLow dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis
2018, Fertility and SterilityCitation Excerpt :Midluteal long GnRH-a regimen was used in both arms in one study (30). Ovarian stimulation was performed by daily injections of recombinant FSH in four studies (19, 29, 30, 37), Highly purified/purified-FSH in one study (36), hMG in four studies (31, 33–35), whereas both FSH and hMG were applied in three studies (27, 28, 32). The onset of administration of gonadotropins in the low doses arm was early (cycle days, 2–3) in five studies (27-30, 38), and initiated late (cycle days, 5–7) for the other nine studies (19, 31–38).
In vitro fertilization treatments with the use of clomiphene citrate or letrozole
2017, Fertility and SterilityThe effect of letrozole as an adjunct in GnRH-antagonist protocol on IVF/ICSI outcome in women with endometriosis: a randomized clinical trial
2023, Middle East Fertility Society Journal
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.