| Study summary: |
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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. |
| Criteria: |
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Inclusion Criteria:
- Women ages 21-44 undergoing IVF for infertility
- Prior IVF cycle with poor response (≤4 follicles on ultrasound,≤ 4 oocytes retrieved,
peak estradiol <1000 pg/mL, prior IVF cycle cancelled for poor response)
OR
- Predicted poor response (age >40, basal FSH ≥10 mIU/mL, prior poor response to
gonadotropin (peak estradiol <500 pg/mL))
Exclusion Criteria:
- Medical contraindications for oral contraceptive pills, injectable gonadotropin
medications, estradiol, or progesterone in oil use.
- Medical contraindications to pregnancy
- Prior IVF cycle with Microdose Protocol or Luteal Phase Ganirelix Protocol |