Extended High Dose Letrozole Regimen Versus Short Low Dose Letrozole Regimen as an Adjuvant to GnRH Antagonist Protocol in the Management of Poor Responders Undergoing IVF-ET
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 2

Summary: 
      The aim of this randomized controlled trial is to compare the efficacy of extended high dose
      letrozole regimen (5 mg /day for the first 5 days of cycle and 2.5 mg/day for the subsequent
      3 days ) with short low dose letrozole regimen (2,5 mg/day from cycle day 3 to 7 ) as an
      adjuvant to GnRH antagonist protocol in the management of patients with poor ovarian response
      undergoing IVF-ET.
    

Detailed description: 
      Poor response to controlled ovarian stimulation (COH) is estimated to occur in 9-24 % of all
      IVF cycles. Although there is no consensus on the definition of poor response to COH,
      inability to produce adequate number of mature follicles( ≤ 2-5) or to recruit adequate
      number of oocytes ( ≤ 3 oocytes ) in response to standard stimulation protocols are the main
      criteria used for diagnosis of poor responders .

      Patients with poor response to COH usually have higher cyclical cancelation rate , poor
      embryo quality and less number of embryos suitable for transfer or cryopreservation .

      During the past decade gonadotropin releasing hormone antagonists (GnRHant) were widely used
      in the treatment of patients with poor response to standard gonadotropin releasing hormone
      agonist (GnRHa) protocols .In contrast to GnRHa, GnRHant is administered at the late
      follicular phase and therefore don't suppress the early follicular phase endogenous
      gonadotropins and has no suppressive effect on ovarian function at the stage of follicular
      recruitment.Several studies comparing GnRHant protocol with the standard GnRHa long protocol
      revealed a reduction in the duration of stimulation , dose of required gonadotropins , and
      the costs of IVF cycle with GnRHant as well as equivalent pregnancy rates .

      In 2001, Mitwally and Casper introduced letrozole ( a third generation non steroidal
      aromatase inhibitor licensed for treatment of hormonally-responsive breast cancer after
      surgery ) as new ovulation induction agent in clomiphene citrate resistant patients with
      polycystic ovary syndrome (PCOS) . Subsequent studies confirmed the effectiveness of
      letrozole in induction of ovulation in women with PCOS and in superovulation (either alone or
      in combination with gonadotropins ) .

      In patients with poor response undergoing IVF, several studies revealed that the combination
      of letrozole ( 2.5 mg or 5 mg/day for 5 consecutive days in early follicular phase ) with
      GnRHant protocol improved the ovarian response and reduced the gonadotrophin dose required.
      On the other hand , Schoolcraft et al reported that letrozole(2.5 mg/day from cycle day 3 to
      7)/GnRHant protocol has no advantages over microdose flare GnRHa protocol.

      The ideal dose and duration of letrozole administration for ovulation and superovulation is
      still not clear. Several studies comparing two doses of letrozole (2.5 mg or 5 mg) in
      superovulation suggested that the higher dose might be associated with more follicles
      developing.

      In almost all studies to date , letrozole was administered for five consecutive days in early
      follicular phase . In only one study , letrozole (2.5 mg/day) was administered for ten
      consecutive days starting on day 1 of menstrual cycle . In that study , prolonged
      administration of letrozole produced more mature follicles and pregnancies than short
      letrozole therapy regimen in patients with clomiphene citrate resistant polycystic ovary
      syndrome .

      The investigators designed this randomized controlled trial to compare the efficacy of
      extended high dose letrozole regimen (5 mg /day for the first 5 days of cycle and 2.5 mg/day
      for the subsequent 3 days ) with conventional short low dose letrozole regimen (2,5 mg/day
      from cycle day 3 to 7 ) as an adjuvant to GnRHant protocol in the management of patients with
      poor ovarian response undergoing IVF-ET.
    

Intervention name(s): Extended high dose letrozole regimen /GnRH antagonist protocol; Short low dose letrozole regimen /GnRH antagonist protocol
Intervention type(s): Drug; Drug
Intervention description(s): Letrozole (Femara; Novertis pharma AG, Basle, Switzerland) is administered starting on cycle day one for 8 consecutive days . The dose of letrozole is 5mg /day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days .
Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.
GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .; Letrozole (Femara; Novertis pharma AG, Basle, Switzerland)2.5 mg /daily is administered for 5 consecutive days starting on cycle day 3.
Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 3 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.
GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .
Other intervention name(s): Extended letrozole/GnRHant; Short Letrozole/GnRHant
Intervention MeSH terms: Letrozole; LHRH, N-acetyl-(4-chlorophenylalanyl)(1)-(4-chlorophenylalanyl)(2)-tryptophyl(3)-arginyl(6)-alanine(10)-; Prolactin Release-Inhibiting Factors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Letrozole ,IVF, poor responders , GnRH antagonist