ABSTRACT: Gonadotropin-releasing hormone (GnRH) antagonists offer a number of advantages compared with GnRH agonists in patients undergoing the controlled ovarian hyperstimulation protocol for in vitro fertilization (IVF) cycles. A major drawback of the GnRH-antagonist protocol used with gonadotropin administration is the need for weekend oocyte retrieval because of the limitation for programming cycles, as when it is started on day 2 or day 3 of menses, an unpredictable event.
This article is an editorial describing several approaches using GnRH-antagonist protocols that may avoid the need for weekend oocyte retrieval. The first of these is administration of an oral contraceptive in the cycle before stimulation with subsequent starting of gonadotropin stimulation.
It has been reported that pretreatment with an oral contraceptive markedly suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels and results in a better synchronized response and a scheduled cycle compared with GnRH-antagonist–only protocols. With pretreatment, some studies also found similar pregnancy rates compared with the long protocol. An updated meta-analysis challenged these findings.
The pooled data in that meta-analysis showed that oral contraceptive pretreatment was associated with a significant decrease in the ongoing pregnancy rate per randomized patient, compared with GnRH-antagonist cycles without any pretreatment. However, all pooled studies included used recombinant FSH alone for stimulation. The detrimental effect of oral contraceptive pretreatment on pregnancy rates could be related to the induced low endogenous LH levels or the impact of the gestagen component on the endometrium. It is unclear whether the addition of LH or the use of human menopausal gonadotropin for stimulation would overcome the negative effect of low LH.
An alternative approach to pretreatment with an oral contraceptive for programming GnRH-antagonist cycles is the use of an estrogen during the previous luteal phase. A prospective, randomized, multicenter study (Ceerdrin-Durnerin et al, Fertil Steril 2012:97) in the current issue of the journal compared the outcome of estradiol pretreatment versus direct initiation of stimulation on cycle day 2 among 472 patients. To avoid weekend oocyte retrieval, study group patients received estradiol daily from 7 days before the expected day of menses to the next Thursday after menstrual bleeding, and gonadotropin administration–recombinant FSH was started on a Friday. The main finding of this study was that the oocyte yield was comparable between both groups. Moreover, there were no differences in the fertilization rate and the proportion of good-quality embryos, and the delivery rates per cycle were similar. Because the prognosis was good, and there was normal ovarian function in all patients, it is unknown whether this protocol would be efficient for scheduling the cycle in a different population, such as poor responders or polycystic ovary patients.
Modulation of the days of initiation of the stimulation and of human chorionic gonadotropin triggering is another approach that may allow skipping of weekend retrievals. A recent study reported that starting gonadotropin administration either on day 2 or day 3 of the cycle had a similar effect in the ongoing pregnancy rate. Advancing or delaying human chorionic gonadotropin triggering for 1 day may not affect the outcome in normal responders, but as with use of estrogens, it may not be applicable for a different population of patients.
In summary, there is strong evidence suggesting a detrimental effect of the most extended approach of oral contraceptive pretreatment in GnRH-antagonist cycles if FSH stimulation alone is performed. Luteal phase administration of estrogen is a possible alternative. Programming of GnRH-antagonist cycles to improve the final outcome continues to be a challenge.