This article was of interest to me. I work with poor responders and they are not just “older” women. I have treated women in their early 30’s with “poor responder” diagnosis. They have normal FSH, E2 and regular cycles, but respond very poorly to fertility drugs and produce limited follicles. The article rethinks the traditional IVF stimulation cycle for poor responders and raises some interesting thoughts about how hormones can effect more than one part of the cycle.
The authors developed a protocol to lengthen the follicular phase of the IVF cycle. By increasing the number of days during the follicular phase, it allows the body to recruit and mature more follicles. It was theorized that increasing the number of days of stimulation also allows each follicle to mature its’ corpus luteum. From my perspective some poor responders are truly not “poor responders” but react to stimulation differently then other women, something the article indicates.
My biggest concern, as an acupuncturist, is how hormones from a failed cycle could affect the next IVF cycle. Often couples decide to enter the next IVF cycle right after a failed one. The author postulates that the corpus luteum might have some negative effects in the follicle phase by suppressing follicular growth. This would make sense in a healthy regular cycle. The body only wants one follicle for the fertilization, since multi pregnancies are more demanding on a women’s physical health. Yet the theory raises interesting questions about the effect of hormones given in much larger doses during an IVF cycle. How do hormones affect the success of the next cycle? Most doctors believe drugs have limited side effects to follicular growth in repetitive cycles. From my experience multiple cycle given back to back are generally not successful and the number of follicles retrieved decrease with each cycle. Plus these follicles are poorer in quality and result in decreased fertilization. My theory: women (especially poor responders) need to rest between cycles, since it is important to allow the body to eliminate circulating hormones from the previous cycle.
Novel follicular-phase gonadotropin-releasing hormone antagonist stimulation protocol for in vitro fertilization in the poor responder
Fertility and Sterility – Vol 88, No 5, November 2007
Poor responders possess guarded prognoses and continue to challenge current treatments. Current stimulation regimens afford little benefit for those exhibiting either an age-appropriate or age-inappropriate poor response. Although not entirely understood, this poor response may be partly a result of either a shortened follicular phase with limited ability to recruit a sizable cohort or a potential increased sensitivity to the lingering suppressive effects of the recent corpus luteum. Ovarian stimulation protocols aim to enhance follicular recruitment and avoid spontaneous ovulation. Oral contraceptive pills and GnRH agonists (GnRH-a) can also prevent corpus luteum formation and provide sufficient time for luteolysis. While inducing pituitary suppression, these adjuvants may throttle the ovarian response. Similarly, so-called flare protocols can undermine the cycle by leading to premature luteinization (15) Luteal suppression with GnRH-a can prove dire for the poor responder. We propose that rapidly acting GnRH antagonists afford an opportunity to extend the follicular phase and prevent corpus luteum formation without adversely impacting ovarian responsiveness. As such, we present the impact of a follicular–phase GnRH-antagonist protocol on zygote yield in patients who previously had exhibited a poor response to traditional stimulation protocols. This case series involves patients who underwent two IVF cycles between May 15, 2003 and August 30, 2004. In the first cycle, subjects exhibited a peak E2 level of <1,000 pg/mL or had fewer than five oocytes retrieved in response to a conventional long or short protocol (cycle A) and were stimulated in the next IVF attempt by a novel follicular antagonist protocol (cycle B). Cycle A was performed by using standard long and short protocol. For long protocols, pituitary desensitization was achieved with SC leuprolide acetate (Lupron) during the luteal phase of the preceding. Ovarian stimulation was then achieved with SC administration of recombinant FSH (either follitropin alpha [Serono] or follitropin beta [Organon]). For conventional GnRH-antagonist cycles, daily GnRH-antagonist (ganirelix, Organon) injections were initiated when a lead follicle measured 13 mm or when E2 level reached 600 pg/mL and were continued until hCG injection. For short protocols, Lupron was started within the first 3 days of menses, and FSH injections were initiated 1–3 days after that Cycle B stimulation involved an initial injection of cetrorelix acetate on cycle day 5–8, followed by a second injection of cetrorelix acetate 4 days later. With cetrorelix start, medroxyprogesterone acetate was given and was continued until ovarian suppression was confirmed. With ovarian suppression demonstrated, a combination of recombinant FSH (225 IU SC, 2 times per day) and recombinant hCG (2.5 μg, SC, 4 times per day) was initiated, and medroxyprogesterone acetate was discontinued to allow for vaginal bleeding. Dilute recombinant hCG was given to provide LH activity and compensate for the decline in LH activity that has been seen by some investigators with the use of GnRH antagonists. When a lead follicle size of 13 mm was observed, cetrorelix (0.25 mg SC, 4 times per day) was started and continued until the triggering hCG injection.We administered hCG (10,000 IU SC) when the lead follicle was ≥18 mm and the majority of the cohort was >15 mm. Embryos were transferred on post retrieval day 2 or 3 under transabdominal ultrasound guidance.
Findings – Summary the characteristics and outcome measures of cycles A and B.
*A total of 12 patients, with a median age of 39.5 years (range, 31–41 y), were included.
*Median duration of infertility and day 3 FSH were 2.0 years and 6.25 IU/L.
*Cycle A, one was luteal GnRH-a suppression and three were antagonist and eight were flare protocols.
*The median peak E2 was 1,262 pg/mL in cycle B and was 658 pg/mL in cycle A.
*The median number of recruited follicles sized >10 mm at the time of hCG was 6.5 in cycle B, compared with 3.5 in cycle A.
*This is consistent with the higher oocyte, zygote, and cleavage-stage embryo yield seen in cycle B compared with in cycle A.
*The implantation rate, number of pregnancies, and number of ongoing pregnancies were higher in cycle B compared with in cycle A. The development of a rapidly acting GnRH antagonist enabled us to design a stimulation protocol that does not compromise the ovarian stimulatory response of poor responders. By using a GnRH antagonist in the follicular phase before ovarian stimulation, we demonstrated a significant improvement in oocyte, zygote, and embryo yield. A trend toward improved implantation, clinical-pregnancy, and ongoing-pregnancy rates in the follicular GnRH-antagonist cycle was noted. Local and systemic factors play a role in the follicular response. These culminate with the pituitary gland triggering ovulation and subsequent corpus luteum formation. Luteinizing hormone may serve to support corpus luteum activity, and corpus luteum factors such as inhibin A, prostaglandin F2α, and endothelin-1 may negatively affect ovarian steroidogenesis and oocyte maturation. Individuals with diminished ovarian reserve exhibit early ovulation and corpus luteum formation. Such patients appear especially susceptible to the suppressive ovarian effects of pituitary desensitizers and must walk a tight balance between an excitatory ovarian response and suppressive pituitary response. Gonadotropin-releasing hormone agonists initially elicit a stimulatory pituitary flare response, followed by ovarian suppression. Although this flare effect enhances follicular recruitment, it can result in premature luteinization and thus compromise the cycle. Luteal GnRH-a protocols can overly suppress the ovarian response and lead to low oocyte yield in poor responders. To our knowledge, we are the first to use a GnRH antagonist before ovarian stimulation in an attempt to lengthen the follicular phase. Our aim was to lengthen the recruitment phase of the cycle to allow for the rescue of more follicles once gonadotropin stimulation was initiated. With an ovarian response demonstrated, conventional use of a GnRH antagonist was initiated to prevent ovulation. Thus, more oocytes and zygotes were attained. The protocol described combines effective pituitary suppression with aggressive ovarian stimulation and results in improved oocyte and embryo yield. How it enhances cycle performance remains unknown. It is possible that administering a GnRH antagonist during the follicular and preventing ovulation extends the follicular phase, lengthens the oocyte recruitment interval, and allows for the maturation of more oocytes. This protocol may more closely mirror the normal follicular phase. It is also possible that extending the follicular phase temporally distances the ovary from the residual negative influence of the corpus luteum, affording greater ovarian sensitivity to exogenous FSH.