Luteinizing Hormone surge and Premature Luteinization Without GnRH agonist or antagonist suppression, LH surges occur in IVF cycles resulting from high estradiol levels in the early follicular phase. This, in turn, results in a lower oocyte yield and reduced pregnancy rates (317). Spontaneous ovulation prior to oocyte retrieval is reported to occur in 16% of nonsuppressed IVF cycles (318). The premature LH rise typically occurs after 5 to 7 days of stimulation (317). In contrast, premature luteinization is a somewhat misleading term that refers to a rise in serum progesterone (cutoffs vary from 0.8 to 2 ng/mL) observed on the day of hCG administration and occurs in the setting of low LH levels secondary to gonadotropin-suppressive medications (319). The incidence of premature luteinization has been estimated at 6% to 7% when the progesterone cutoff level is set at greater than 1.5 ng/mL, but it may be as high as 35%. Mechanisms underlying premature luteinization may include incomplete pituitary desensitization, increased granulosa cell receptor sensitivity to LH secondary to aggressive COH or innately poor responders, and/or the presence of multiple follicles each producing a normal amount of progesterone consistent with the late follicular phase (319,320). Although the literature on this subject remains inconsistent, the negative effects of premature luteinization have been attributed to endometrial advancement rather than oocyte or embryonic dysfunction (319–321). Methods proposed to address premature luteinization have included earlier triggering with hCG, less aggressive stimulation protocols, cryopreservation of embryos (freeze-all), and administration of the antiprogestin mifepristone at the time of hCG (320,322).
GnRH Agonists Native GnRH is rapidly degraded in the circulation. Commercial preparations of GnRH agonists consist of decapeptides similar to GnRH but for modification at two amino acid residues, which increase both the half-life and the receptor binding affinities (323).
Over the course of 10 to 14 days, agonists initially bind to and upregulate pituitary GnRH receptor activity, leading to a ﬂare response of increased gonadotropin secretion. This is followed by receptor desensitization (depleted gonadotropin pools along with rapid uncoupling of the GnRH receptor from its regulatory protein and loss of signal transduction) that suppresses circulating levels of pituitary gonadotropins and, with high doses and prolonged use, eventually decreases GnRH receptor numbers (301,317,323–325). Therefore, prolonged use of GnRH agonists induces a menopause-like state characterized by low estradiol levels and accompanied by common side effects such as hot ﬂashes and moodiness. The ﬂare effect may cause ovarian cyst formation as described in the “Unexplained Infertility” section of this chapter (301). GnRH agonists are commercially available for either depot or daily use and can be administered intranasally (buserelin and nafarelin) or by intramuscular or subcutaneous injection (leuprolide, triptorelin, or buserelin). Intranasal preparations have lower absorption rates when compared to injectable agonists and are associated with milder suppression (326). Typical starting daily doses of leuprolide are 1 mg, 0.5 mg, or 25 μg (microdose) (324).