Association between FSH dose and AMH level on oocyte quantity and quality in GnRH antagonist cycles

Abstract

Accumulating data suggest that high FSH doses during IVF may impair follicular number and function, as well as oocyte and embryo quality. It is unknown whether this detrimental relationship holds true for all patients regardless of AMH level. The objective of this study was to test the hypothesis that high FSH dosing has a detrimental effect on oocyte quantity and quality in patients with low and normal AMH, but may be necessary for patients with a high AMH to overcome the inhibitory effect of AMH on gonadotropin receptor expression and action in granulosa cells. Retrospective cohort study All first GnRH antagonist IVF/ICSI cycles between 1/2013 and 5/2016 (n=994) in patients with a documented AMH at a single academic institution were included. The cohort was stratified by AMH (ng/mL) into tertiles (<1.8, 1.8-4.2, >4.2). The primary exposure was daily FSH dose on cycle days 2-7: <225IU, 225-449IU, and >450IU. Primary outcomes were total and mature (MII) oocyte yield. Secondary outcomes were 2PN and usable (transferred plus frozen) embryo yield, as well as % cycles with at least 1 degenerating oocyte or embryo, and/or arrested embryo. Poisson regression adjusted a priori for age and AMH was used to model the association between FSH dosing and stimulation outcomes across AMH tertiles. Other covariates, including diagnosis, donor status, BMI, day 3 FSH, antral follicle count, use of hMG, trigger type, and length of OCP lead-in were tested for confounding. High FSH dosing was associated with a significantly lower yield of MII and total oocytes for both low and medium AMH tertiles, but the opposite was observed for the high AMH tertile (Table). In contrast to the lack of association between high FSH dose and usable embryos in the low AMH tertile, a significant association was observed in the high AMH tertile. There was no significant association between FSH dose and 2PN yield, or % cycles with oocyte/embryo degeneration or arrested embryos. These findings support the hypothesis that early high FSH doses in GnRH antagonist cycles have a negative effect on total and mature oocyte yield in patients with an expected low or normal response. However, in patients with a high AMH (>4.2 ng/mL), the effect is opposite, suggesting that high gonadotropin dosing may be necessary to overcome the inhibitory effect of AMH on early folliculogenesis.Tabled 1Ovarian stimulation outcomes as a function of day 2-7 FSH dosing (daily IU) and AMH (ng/mL) tertilesAMH<1.8AMH 1.8-4.2AMH>4.2N=323N=337N=334Mean no. MII oocytesFSH dose <225 IU9.2 (6.2)12.2 (6.1)14.2 (8.1)225-449 IU7.5 (4.1)11.5 (6.5)15.9 (9.5)>450 IU5.3 (3.0)7.2 (4.0)16.7 (10.2)aRR (95% CI)1.00 (Ref)1.00 (Ref)1.00 (Ref)aRR (95% CI)0.95 (0.81-1.12)1.11 (1.04-1.20)1.17 (1.07-1.27)aRR (95% CI)0.80 (0.67-0.96)0.73 (0.60-0.89)1.21 (0.99-1.48)P-value<0.0001<0.00010.01Mean no. oocytes retrievedFSH dose <225 IU11.6 (6.8)15.1 (7.2)18.8 (10.2)225-449 IU9.6 (5.0)14.8 (7.6)20.8 (10.8)>450 IU7.2 (3.8)11.4 (4.7)26.7 (16.5)aRR (95% CI)1.00 (Ref)1.00 (Ref)1.00 (Ref)aRR (95% CI)0.96 (0.83-1.11)1.15 (1.08-1.23)1.18 (1.09-1.27)aRR (95% CI)0.86 (0.73-1.01)0.91 (0.78-1.07)1.49 (1.27-1.75)P-value0.02<0.0001<0.0001Mean no. usable embryosFSH dose <225 IU4.1 (2.7)5.0 (3.1)5.8 (4.0)225-449 IU3.2 (2.0)4.9 (3.9)6.3 (4.5)>450 IU2.9 (1.9)4.5 (2.8)7.0 (3.4)aRR (95% CI)1.00 (Ref)1.00 (Ref)1.00 (Ref)aRR (95% CI)0.88 (0.68-1.14)1.17 (1.04-1.31)1.25 (1.09-1.43)aRR (95% CI)0.91 (0.69-1.21)1.10 (0.83-1.47)1.43 (1.01-2.02)P-value0.600.030.001Values represent mean +/- SD Open table in a new tab