Gonadotropin-Releasing Hormone Agonist Protocols Some of the more commonly used ART medications and protocols are summarized in Fig. 32.6 and Table 32.8. In the long protocol, a GnRH agonist is started in the luteal phase (day 21) of the previous cycle. This diminishes the GnRH agonists ﬂare effect and suppresses endogenous FSH and dominant follicle selection to promote synchronous follicular growth (317). After 10 to 14 days of GnRH agonist administration, a pelvic ultrasound and estradiol level are used to confirm suppression and gonadotropin stimulation begins. The GnRH agonist is continued (the dose may be halved or unchanged) throughout the cycle until the hCG trigger (317,324). Mean serum progesterone levels on the day of hCG administration using the long protocol are reportedly 0.84 ng/mL (320). The long protocol provides for better oocyte yields and pregnancy rates in normal responders when compared with shorter protocols that use later administration or early cessation of agonists (317). Shorter protocols using lower GnRH agonist doses have been advocated for poor responders in whom excessive suppression may be undesirable, perhaps from direct negative effects of the agonist on the ovary (324). However, long protocols, particularly those using single-dose depot rather than daily GnRH agonist formulations, are associated with higher gonadotropin dose and duration, which themselves have been associated with lower pregnancy rates (327–329). Alternatively, GnRH microdose ﬂare protocols have been developed that may improve oocyte yield in poor responders. Microdose ﬂare regimens involve pretreatment with 14 to 21 days of combination oral contraceptives. Four days following the
Figure 32.6 In vitro fertilization protocols using gonadotropin-releasing hormone (GnRH) agonist or antagonist with gonadotropins in controlled ovarian hyperstimulation. hCG, human chorionic gonadotropin.
cessation of the oral contraceptive pills, a microdose (leuprolide 25 μg) of agonist is added in the early follicular phase to take advantage of the agonist ﬂare effect. Gonadotropin stimulation is initiated 1 to 2 days later while continuing the agonist (324).
lix) were developed by modifying the GnRH decapeptide at six positions. They compete with endogenous GnRH for binding to pituitary GnRH receptors. Because they have no agonistic activity, GnRH antagonists lead to almost immediate suppression of FSH and LH and do not require the additional time for pituitary down-regulation that characterizes the GnRH agonists. With prolonged use, GnRH antagonists down-regulate GnRH receptors (323). At this time, the only delivery method available for GnRH antagonist is subcutaneous injection, although orally active agents are in development. GnRH antagonists can be given as 0.25 mg daily doses or as a single 3 mg dose with no difference in outcome (325). The time between daily injections should not exceed 30 hours (301). With single dose regimens, avoidance of multiple injections is attractive, but additional small doses starting 4 days after initial dose are required in 10% of cycles (325). Use of GnRH antagonists in ART protocols is typically begun on day 4 to 7 of stimulation. This timing balances the risk for premature LH surges with the need for initiation of endogenous FSH-mediated follicular recruitment and endogenous estradiol production prior to administration (301,317,325).