A Comparison of the Microdose Leuprolide Protocol vs. Luteal Phase Ganirelix Protocol in Women Who Are or Who Are Predicted to be Low Responders
Condition: Infertility
MeSH terms: Infertility
Study type: Observational

Summary: 
      Patients who have undergone in vitro fertilization (IVF) and produced four or less follicles
      or had four or less oocytes (eggs) retrieved are often referred to as poor responders. We
      will refer to these patients from this point forward as "low responders" to avoid using a
      potentially offensive label. We are currently using 2 different IVF medication protocols in
      our practice to treat low responder patients with infertility: the "Microdose Leuprolide"
      protocol and the "Luteal Phase Ganirelix" protocol. We would like to conduct a
      randomized-controlled trial and randomize patients to one treatment group or the other to
      determine which medication protocol is more effective in treating infertility in this group
      of patients.
    

Detailed description: 
      Women who demonstrate a suboptimal response to controlled ovarian hyperstimulation (COH) are
      a challenge to treat with assisted reproductive technologies such as in vitro fertilization
      (IVF). Such patients are often referred to clinically and in the medical literature as poor
      responders. A variety of different protocols have been studied and used to treat these
      patients. One protocol used to treat poor responders is the microdose leuprolide flare
      protocol 1,2. This widely-used protocol was first described in 1997 by Schoolcraft et al. 1
      The microdose leuprolide flare protocol is so named because the administration of a
      gonadotropin-releasing hormone agonist (GnRH-a) in the early follicular phase causes an
      initial rise in endogenous gonadotropins called a "flare" before it causes downregulation and
      suppression of gonadotropins. Use of oral contraceptive pills (OCPs) in the preceding cycle
      prevents corpus luteum formation which could be supported by exogenous GnRH-a in the
      subsequent cycle. The microdose leuprolide flare protocol has been shown to be a safe and
      effective protocol which may lead to decreased cycle cancellation rates and increased
      clinical and ongoing pregnancy rates in poor responders 2,3.

      The development of GnRH antagonists led to additional treatment options for poor responders
      4. With GnRH antagonist use, suppression in the early follicular phase may be avoided. The
      GnRH antagonist is then added in the late follicular phase to prevent an LH surge. This
      protocol may enable a poor responder to recruit more follicles in the early follicular phase
      and thus have a more optimal response to stimulation. A randomized-controlled multicenter
      trial comparing the GnRH antagonist ganirelix to a GnRH agonist (Buserelin, intranasal
      preparation) in patients using recombinant FSH (rFSH) showed that ganirelix was safe and
      well-tolerated 5. They found that the mean duration of stimulation was 1 day shorter in the
      ganirelix group and that this group used significantly less rFSH. A randomized-controlled
      clinical trial of poor responders comparing the use of ganirelix to microdose leuprolide
      acetate (GnRH-a) in patients undergoing COH for IVF found that the outcomes were similar in
      both groups 6. There were no differences in total number of days of stimulation, amount of
      rFSH used, peak estradiol levels, number of oocytes retrieved, fertilization rate,
      implantation rate, or pregnancy rate. However, this study was limited by a small sample size.
      Another randomized-controlled trial by Akman et al. 7 compared the use of microdose
      leuprolide to GnRH antagonist (Cetrotide) in poor responders undergoing IVF. They found no
      difference in implantation rates and clinical pregnancy rates but were also limited by a
      small sample size.

      In IVF cycles, poor responders often develop a dominant follicle and multiple small follicles
      rather than multiple large follicles which is the goal of such treatment. In such cases, the
      IVF cycle is often cancelled. The physiology behind such asynchronous follicular growth
      during COH is poorly understood. Such discrepant growth may be the result of size differences
      in early antral follicles 8. It is also possible that the premature FSH elevation that occurs
      in the late luteal phase of the menstrual cycle plays a role in this process 9. FSH prevents
      follicular atresia at the end of the luteal phase10. Some follicles are intrinsically more
      sensitive to FSH and able to respond to low levels of this hormone than others. Given the
      fact that larger follicles are often more FSH-responsive than small follicles, it makes sense
      that exogenous gonadotropins may lead to worsening follicular asynchrony during COH 11.

      It has recently been shown that the use of estradiol in the luteal phase of the preceding
      menstrual cycle may facilitate growth of follicles in a coordinated fashion 8, 11. Fanchin et
      al.11 prospectively studied 90 women who were undergoing IVF cycles using GnRH antagonists
      and randomly assigned them to receive either 4 mg of oral micronized estradiol from cycle day
      20 until day 2 of the next cycle or to serve as controls and receive no estradiol treatment.
      They found that the group that received estradiol had significantly smaller follicles on day
      8 of their cycle and had less of a discrepancy in follicle size.. The group that received
      estradiol also had more follicles that were 16 mm or greater, more mature oocytes, and more
      embryos than the control group. The clinical pregnancy rate was greater in the estradiol
      group although this finding was not statistically significant (34 vs. 25%).

      Recently, GnRH antagonists have also been shown to coordinate follicular size and subsequent
      growth when used in the luteal phase of the preceding menstrual cycle 12,13. Dragesic et al.
      13 developed a novel protocol for poor responders which incorporated both transdermal
      estradiol (E2)and GnRH antagonist use in the luteal phase, followed by gonadotropin
      stimulation in the follicular phase and the addition of a GnRH antagonist in the late
      follicular phase. From this point on, this protocol will be referred to as the Luteal Phase
      Ganirelix (LPG) Protocol. During the LPG protocol, subjects applied a 0.1 mg transdermal
      estradiol patch on the 10th day after the LH surge and replaced this patch with a fresh 0.1
      mg patch every other day. On the second day of patch use, subjects began taking daily
      ganirelix acetate 0.25 mg subcutaneously for 3 days. Subjects presented for ultrasound on day
      2 of menses for FSH, LH, E2 and an ultrasound and stimulation was started per protocol with
      gonadotropins (rFSH and human menopausal gonadotropin (HMG)). Ganirelix was started when a
      13mm follicle was measured on ultrasound, E2 exceeded 300 pg/mL, or on cycle day 7. Human
      chorionic gonadotropin (hCG) was given for final oocyte maturation and oocyte retrieval was
      performed 35-36 hours later. All embryo transfers were performed 72 hours after oocyte
      retrieval. This retrospective study of 68 subjects compared their responses to the LPG
      protocol with their responses to a prior IVF cycle protocol, which included microdose
      leuprolide, low-dose leuprolide, and coflare protocols. They found that when patients used
      the LPG Protocol they had significantly lower cycle cancellation rates, more oocytes
      retrieved, more mature oocytes, more normally fertilized oocytes, and more embryos available
      for transfer compared to their prior cycles. Patients did use more gonadotropins during the
      LPG protocol and had more days of stimulation, although the latter was not statistically
      significant.

      Our goal in our proposed study is to determine whether the Microdose Leuprolide and LPG
      Protocols are equally efficacious in treating poor responders.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Women ages 21-44 who are currently undergoing In Vitro Fertilization treatment at our
        center.