NEWS: Inclusion of Letrozole in GnRH Antagonist Multiple Dose Protocol Improves IVF Outcomes in Poor Responders

Management of diminished ovarian reserve is challenging, despite the ongoing extensive research to develop an effective method of controlled ovarian stimulation (COS). Although various COS regimens such as GnRH agonist flare-up, GnRH agonist low dose long, and GnRH antagonist protocols have been developed, an efficient protocol for improving the outcomes in poor responders still remains elusive. A recent retrospective study highlights that letrozole cotreatment with GnRH antagonist multiple dose protocol (MDP) yields similar pregnancy outcomes with lesser dosage and shorter duration of rhFSH, compared to standard GnRH MDP protocol in IVF poor responders. The study results are published in Obstetrics and Gynecology Science.

Kyung-Hee Lee, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Seoul, Korea, and coworkers conducted the retrospective cohort study on 103 poor responders in consecutive IVF cycles to evaluate the impact of incorporating letrozole in GnRH antagonist MDP protocol. The researchers compared the COS and IVF outcomes between the letrozole (n=46) and the standard GnRH antagonist MDP (n=57) groups. The following were noted in the group administered with letrozole, when compared to the controls:

  • Lower dose (2549.4±392.9 vs. 3012.8±431.5) and fewer days of rhFSH administration (9.5±1 vs.10.6±1.5)
  • Lesser duration of GnRH antagonist administration (4.6±1.0 vs. 5.4±1.5 days)
  • Higher number of oocytes retrieved (5.3±2.0 vs. 4.3±1.9)
  • Similar rates of clinical pregnancy per embryo transfer (31.1% vs. 25.5%), clinical pregnancy per cycle initiated (30.4% vs. 24.6%), and embryo implantation (13.5% vs. 11%)

Based on the findings, the scientists concluded that letrozole as an adjuvant to gonadotropins may serve as a more effective method than the standard GnRH antagonist MDP protocol in poor responders, who undergo IVF/ICSI cycles.

Similar results were reported in an earlier study by Ozmen et al (Reproductive BioMedicine Online, 2009), wherein the adjunctive administration of letrozole to GnRH antagonist protocols reduced the cycle cancellation rates and total gonadotropin dose, thereby decreasing the cost. The poor responders (n=70) were randomized into two subsets: group A received 5mg/day of letrozole along with 450 IU/day of rFSH, while group B was administered only rFSH. Both the groups received a flexible GnRH antagonist regimen. The study observed that group A had significantly lesser serum estradiol levels on the day of hCG administration (1870±159 vs. 2015±175 pg/mL; P< 0.05) and mean total rFSH dose (2980±435 versus 3850±580 IU; P< 0.05), when compared to group B. Lower rate of cycle cancellation owing to poor response was found in group A than in the controls (8.6% vs.28.6%; P< 0.05). The corresponding rates of clinical pregnancy per embryo transfer were 25.8% and 20%, and the cost of attaining the clinical pregnancy were US $11560 and US $17584, respectively.

Letrozole boosts intraovarian androgens by blocking the conversion of androgen to estrogen, leading to an increase in early follicular growth, thereby having the potential to improve IVF outcomes. Several trials have evaluated the use of aromatase inhibitors for ovulation induction in patients with polycystic ovarian syndrome and in those who are resistant to clomiphene citrate treatment; however, there is limited evidence to support its effectiveness in stimulated IVF cycles. In a review on the use of aromatase inhibitors in IVF, Papanikolaou et al (Reprouctive Biology and Endocrinology, 2011) indicated that letrozole may serve as a promising option in stimulated IVF cycles, especially in women with poor ovarian response. Further, considering the fact that there are not many trials that have compared the effectiveness of letrozole/GnRH antagonist protocol with the standard GnRH antagonist regimen, the findings from the current study are encouraging for poor responders. However, the researchers highlighted the need for further large, prospective randomized studies to validate the safety and efficacy of letrozole before advocating it as an effective therapeutic option for infertile women.

References

  • Lee KH, Kim CH, Suk HJ, et al. The effect of aromatase inhibitor letrozole incorporated in gonadotrophin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization. Obstet Gynecol Sci. 2014 May;57(3):216-22.
  • Ozmen B, Sönmezer M, Atabekoglu CS, Olmus H. Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols. Reprod Biomed Online. 2009 Oct;19(4):478-85.
  • Papanikolaou EG, Polyzos NP, Humaidan P. Aromatase inhibitors in stimulated IVF cycles. Reprod Biol Endocrinol. 2011 Jun 21;9:85

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