GnRH agonist and GnRH antagonist protocols in ovarian stimulation: differential regulation pathway of aromatase expression in human granulosa cells

Abstract

Gonadotrophin-releasing hormone (GnRH) agonists and antagonists have been widely used to prevent premature LH surge during ovarian stimulation. However, studies have shown a significantly lower serum oestradiol concentration on the day of human chorionic gonadotrophin administration for cycles using GnRH antagonist. This study compared aromatase gene expression in granulosa lutein cells from 50 women randomly assigned to receive either GnRH agonist (group 1, n=28) or GnRH antagonist (group 2, n=22). The cellular mechanism involved in the observed effects was also investigated. GnRH antagonist treatment significantly affected serum oestradiol concentration (1894+/-138 versus 1074+/-63 pg/ml; P < or = 0.001), follicular-fluid oestradiol concentration in large follicles (18,565+/-2467 versus 10,184+/-1993 pg/ml; P < or = 0.05), aromatase activity (9600+/-1179 versus 5376+/-997 fmol/10(6) cells/h; P < or = 0.05) and mRNA aromatase/mRNA glyceraldehyde 3-phosphate dehydrogenase (15+/-3 versus 6+/-1; P < 0.05). Protein kinase C (PKC) activity in granulosa lutein cells from the GnRH antagonist group was 2.5-fold higher than in the GnRH agonist group. In-vitro experiments showed that selective down-regulation of PKC was only observed in GnRH-desensitized granulosa lutein cells. This report suggests that, in granulosa lutein cells, the modulation of the FSH-induced protein kinase A pathway by PKC was different in agonist versus antagonist cycles.

Extrapituitary Actions of GnRH Antagonists: Prospects for in vitro Fertilization Programs

“…Accumulating evidence indicates that GnRH-ant can inhibit dose-dependently aromatase expression and activity in human granulosa cell [33,34]. Remarkably, these findings correlate well with the clinical evidence that GnRhant are associated with lower estradiol levels in both serum and follicular fluid.…”

“…These data lead to the suggestion that both analogues do not substantially affect gonadotropin receptor status of granulosa cells, but that GnRH-ant can induce inhibitory effects on granulosa lutein cell aromatase activity. In line with the concept that ovarian steroidogenesis can be affected by GnRH-ant, Kalaf et al [33] found a significant reduction in serum estradiol concentrations in patients treated with GnRH-ant in comparison with those receiving GnRHa. The decrease in circulating concentrations of estradiol observable in the GnRH-ant patients, according to authors, could reflect a lower estradiol synthesizing capability of the GnRH-ant-exposed follicles.…”

Assisted Reproduction

“…162 When follicular dynamics were compared between GnRHa and GnRH-antagonist cycles, it was found that the modulation of the FSH-induced protein kinase A pathway by protein kinase C was different in agonist versus antagonist cycles. 163 The changed modulation of this pathway results in lower levels of serum and follicular estradiol via lower levels of aromatase activity. It does not appear, however, that low levels of estradiol are, in fact, detrimental to pregnancy rates in these IVF cycles.…”

Successful Pregnancy Following Dual Triggering Concept (rhCG + GnRH Agonist) in a Patient Showing Repetitive Inmature Oocytes and Empty Follicle Syndrome: Case Report

“…The same happened in our case, the fourth initial attempts were conducted under the long agonist protocol. At the biochemical level, granulose lutein cells have showed a different pathway modulation of the FHS-induced kinases in agonist versus antagonist cycles [27]; hence it is logical to assume that the type of protocol may influence intrafollicular environment and oocyte maturation pathways and may contribute in some cases to abnormal oocyte development. However, other findings challenge this hypothesis, for example EFS cases are described in both agonist and antagonist protocols and also when GnRHa are used for triggering [3].…”