shows the hormonal and follicular growth profile
shows the hormonal and follicular growth profile of the woman who ovulated in both cycles. In cycle 1, an LH surge occurred on day 17, when serum oestradiol concentration was 210.5 pg/ml and follicle diameter 17 mm. In cycle 2, ganirelix administration was continued until day 19 instead of until the onset of the LH surge in cycle 1 (day 17), because follicular growth was observed by transvaginal ultrasound, despite the administration of the antagonist. On day 19, a dominant follicle of 16.7 mm diameter was detected, while serum oestradiol was 205 pg/ml. An LH surge started on day 20 (44.0 mIU/ml), when the diameter of the follicle was 20.7 mm. A week after the LH surge onset, serum progesterone concentration was high (21.1 ng/ml).
Menstruation in cycle 2 was delayed by 11.0 ± 0.85 days (n = 8). In the volunteer who ovulated in both cycles only a 3-day delay was observed.
Discussion The present study demonstrates that treatment of normal women with the GnRH antagonist ganirelix, at a daily dose of 0.25 mg during the follicular phase of the normal menstrual cycle, affects the secretion of LH and disrupts follicle maturation. Although serum LH concentrations decreased significantly compared with untreated control cycles, there was no significant within-cycle variation, in Calpeptin to previous studies (Fugimoto et al., 1997; ). The apparent disparity between the present and the previous studies in terms of LH secretion can be explained by the frequency of blood sampling. In particular, in a previous study the nadir LH, FSH and oestradiol concentration was seen at 4, 16 and 16 h, respectively after the last injection of ganirelix, but hormone values returned to the pre-treatment concentration at 24 h (). It is likely, therefore, that in the present study a temporal decrease in hormone concentrations was missed. According to previous data, the GnRH antagonist cetrorelix seems to perform similarly to ganirelix (Christin-Maitre et al., 2000, Gonzalez-Barcena et al., 1994, Griesinger et al., 2006, Leroy et al., 1994, Sommer et al., 1994). In the present study, only the dosage of 0.25 mg/day ganirelix was investigated, as this is the dose currently used in ovarian stimulation protocols for the prevention of a premature LH surge. This dose, however, seems to be insufficient to prevent the LH surge in ovarian stimulation cycles because several LH peaks have been reported, varying from 8 to 35%, a rate that is not far from the 20% chance of occurrence of an endogenous LH surge in such cycles without the use of an antagonist or an agonist (Borm and Mannaerts, 2000, Engel et al., 2002, Messinis et al., 2005, Wang et al., 2016). In addition ganirelix, given to normal women in the follicular phase at a daily dose of 0.25 mg for 5 days, has been unable to block the positive feedback effect of exogenous oestradiol (). Whether the same can happen with endogenous oestrogen was not possible to test in the present study, as oestradiol never reached pre-ovulatory concentrations that could provoke gonadotrophin release, except in one case in which an endogenous LH surge occurred despite the administration of the antagonist. In the literature, two such cases have been previously reported on treatment with cetrorelix, suggesting that the antagonist may not always be effective in preventing the endogenous LH surge (). The mechanism via which follicle selection failed during treatment with ganirelix is not known. Deficiency in gonadotrophin secretion seems to be excluded for the following reasons. Serum FSH concentrations remained stable throughout the whole period of antagonist administration and were similar to those in cycle 1. On the other hand, there was no significant within-cycle variation in LH concentrations during the administration of ganirelix, while on cycle day 8, serum FSH, LH and oestradiol values were similar in the two cycles (). Therefore, despite the fact that the pattern of blood sampling might have impacted in particular on LH concentrations, it is evident that overall there was an adequate amount of this gonadotrophin in the circulation for normal steroidogenesis. In particular, the variation in LH concentrations between the two cycles before day 8 did not affect steroidogenesis and did not impact on follicle growth as follicle size on that day did not differ significantly between the two cycles. It was after day 8 that oestradiol concentrations started to increase only in the control cycles, indicating that, despite a similar gonadotrophin profile in the two cycles, selection of a dominant follicle occurred in the control, but not in the ganirelix cycles. After day 10, especially during the last 4 days before the LH surge onset in the control cycles – it started on average on day 15 – follicle selection still did not happen in the ganirelix cycles, while treatment with the antagonist continued. During that period, the hormonal differences between the two cycles () can be attributed to the growth of the dominant follicle in the control cycles (suppression of FSH – negative feedback, gradual rise of LH in late follicular until LH surge onset – positive feedback) and not to the action of ganirelix. In particular, in the ganirelix cycles (), daily FSH and LH concentrations were still in the normal range for the early follicular phase (FSH average 6–7 mIU/ml; LH average 6.5 mIU/ml), indicating that even after many days of ganirelix treatment there was a state of normal gonadotrophin secretion and not deprivation. It is interesting to note that earlier studies with the use of GnRH agonists or more potent antagonists in men or women had shown a significant reduction in FSH and LH bioactivity, which in some cases was disproportionately greater relative to the reduction in the immunoreactivity of these hormones (Cedars et al., 1990, Dahl et al., 1986, Meldrum et al., 1984, Pavlou et al., 1988). Whether the same applies to the currently used preparations of GnRH analogues needs investigation.