The VEGF and PEDF levels in the follicular fluid of patients co- treated with LETROZOLE and gonadotropins during the stimulation cycle

Abstract

BackgroundPrevious studies have shown that androgens, in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. Recent studies have shown that aromatase inhibitor, letrozole, improves ovarian response to FSH in normal and poor responder patients, possibly by increasing intraovarian androgen levels. Studies in mice also showed an effect of letrozole to increase pigment epithelium-derived factor (PEDF) and to lower vascular epithelial growth factor (VEGF), which might be expected to reduce the risk of ovarian hyperstimulation syndrome (OHSS) with stimulation. The aim of this study was to compare the VEGF and PEDF levels in the follicular fluids of normal responders treated with letrozole and gonadotropins during the ovarian stimulation with patients treated with gonadotropins only.MethodsA single center, prospective clinical trial. We collected follicular fluid from 26 patients, on a GnRH antagonist protocol, dual triggered with hCG and GnRH agonist. The patients in one group were co-treated with letrozole and gonadotropins during the ovarian stimulation and the patients in the other group were treated with gonadotropins only. VEGF, PEDF, estrogen, progesterone and testosterone levels were measured by ELISA kits.ResultsThe age of the patients, the total dose of gonadotropins and the number of oocytes were comparable between the two groups. In the follicular fluid, the estrogen levels (2209 nmol/l vs. 3280 nmol/l, p = 0.02) were significantly decreased, and the testosterone levels (246.5 nmol/l vs. 40.7 nmol/l, p < 0.001) were significantly increased in the letrozole group compared to the gonadotropin only group. The progesterone levels (21.4 μmol/l vs. 17.5 p = NS) were comparable between the two groups.The VEGF levels (2992 pg/ml vs. 1812 pg/ml p = 0.02) were significantly increased and the PEDF levels (9.7 ng/ml vs 17.3 ng/ml p < 0.001) were significantly decreased in the letrozole group.ConclusionsOpposite to observations in the mouse, we found that VEGF levels were increased and PEDF levels were decreased in the follicular fluid in patients treated with letrozole during the stimulation cycles. Further investigation is required to determine if patients treated with letrozole during the IVF stimulation protocol are at increased risk for developing OHSS as a result of these findings.

Letrozole-associated controlled ovarian hyperstimulation in breast cancer patients versus conventional controlled ovarian hyperstimulation in infertile patients: assessment of oocyte quality related biomarkers

“…Our results are also in accordance with a recent study that showed comparable pregnancy rates in normal responder infertile patients undergoing Let-COH or conventional COH. The authors observed significantly lower E2 and significantly higher T levels in the FF [38].…”

Letrozole supplementation during controlled ovarian stimulation in expected high responders: a pilot randomized controlled study

“…Considering the fact that high progesterone levels were positively related to the number of mature follicles, it was possible that low responders with a lower expression of FSH receptor in the granulosa cells were demonstrated [33]. Contrary to this situation, high responders showed the overexpression of FSH receptors in their follicular granulosa cell population [34, 35] and might be the reason why letrozole could not reduce the total gonadotropin dose needed for ovarian stimulation in hyper-responders.…”

A review of the physiology behind letrozole applications in infertility: are current protocols optimal?

“…There was no difference in the cumulative pregnancy rate at the time of publication, but the influence of embryo cryopreservation made this difficult to evaluate. Since vascular endothelial growth factor (VEGF), strongly implicated as a possible cause of OHSS, is increased with the use of letrozole in humans [ 71 ], the potential for OHSS in patients with a high ovarian reserve may be a concern for women with normal or high ovarian reserve.…”

“…Garcia-Velasco et al [ 8 ] and Hass et al [ 71 ] both showed that letrozole taken during the first 5 days of gonadotropins or until ovulation triggering during IVF increased androgen levels in follicular fluid of pre-ovulatory follicles. However, at this time in follicular development, virtually no androgen receptors are present in granulosa cells [ 18 , 19 ].…”