A new approach for luteal support in ART by exploiting the LH stimulatory property of GnRH analogs

Luteal phase support or supplementation is a mandatory therapeutic intervention following controlled ovarian hyperstimulation. Indeed, stimulation of multiple follicular development for the purposes of assisted reproductive technologie (ART) has been shown to consistently result in an aborted luteal phase, associated with low pregnancy and high miscarriage rate (Pritts and Atwood 2002). The cause of this luteal deficiency is not fully understood. In physiologically normal, menstrual cycles, secretion of progesterone and estrogens by corpus luteum is controlled by ample LH pulses. In ART, the endogenous pulsatile secretion of LH is suppressed or severely disturbed during the luteal phase, resulting from controlled ovarian hyperstimulation (Tavaniotou et al. 2001). Luteal support has been routinely used and is performed by administering either exogenous progesterone or repeated injections of hCG. Both approaches have been shown to be effective, but hCG use is limited by the increased risk of OHSS. Progesterone administration (i.m. or vaginal) is therefore the mainstay of luteal support. (Pritts and Atwood 2002) We developed the hypothesis that use of repeated small doses of GnRH agonist instead of progesterone could provide improved luteal support, being (1) convenient for the patient (nasal route preferred to the vaginal route), (2) more physiological, hence potentially more effective and safer (restoring endogenous LH pulses), and (3) capable of reversing any residual activity of GnRH antagonist by competing at the GnRH receptor level. The initial challenge was to define the dose and frequency of GnRH agonist (intranasal buserelin) administration, which would be convenient for patients and maintain the agonist effect, while avoiding progressive desensitization of pituitary GnRH receptors. This was achieved in two pilot studies, which concluded that i.n. administration of buserelin once a day was effective for mild stimulation (Pirard et al. 2005), and three time a day was the optimal frequency for ART (Pirard et al. 2006). Our prospective, randomized, comparative, trial compared 40 IVF/ICSI patients pre-treated with a GnRH antagonist, in whom buserelin was used to trigger final maturation and provide luteal support, with 20 IVF/ICSI patients pre-treated with a GnRH agonist, in whom hCG was used to trigger final follicular maturation and vaginal progesterone (3 x 200 mg/day) was used for luteal support. This trial demonstrated a normal luteal phase duration in all patients, and a trend toward a better pregnancy rate in the buserelin group (31.4% v.s 22.2 and 25.7% vs. 16.7% respectively for a positive pregnancy test and ongoing pregnancy rate). An additional open study (32 patients) was also conducted using buserelin only for luteal support (with hCG to trigger final maturation). The pregnancy rate per embryo transfer was 45.2%, and the implantation rate was 31.5%. Regarding patient preference, a retrospective survey indicated that, compared to vaginal capsules, i.n. buserelin administration took less time (78.9%) and was less painful (57.9%), easier (84.2%) and less stressful (68.4%). Patients reported a strong (85%) preference for i.n. luteal support versus vaginal progesterone (n= 19). In conclusion, these results support the hypothesis that i.n. administration of buserelin as luteal support is potentially a patient-friendly method, which may improve outcomes of GnRH antagonist-treated cycles.(MED 3) -- UCL, 201