Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles

Abstract

Progesterone elevation (PE) during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF)/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i) Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii) Is PE on the day of human chorionic gonadotropin (hCG) associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI) cycles outcomes in all patient subgroups? (iii) Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv) Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle-stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the limitations of the currently available assays to measure progesterone at low ranges, caution should be applied to adopt specific cutoff values above which the effect of progesterone rise could be considered detrimental and to recommend “freeze-all” based solely on pre-defined cutoff points.

Flexible Low-Dose GnRH Antagonist Protocol Is Effective in Patients With Sufficient Ovarian Reserve in IVF

“…Embryo transfer was conducted on day 3 after oocyte retrieval. All the patients received embryo transfer on day 3, except in the following cases: (a) serum estrogen >7,000 pg/mL on the trigger day, (b) more than 15 oocytes were retrieved, (d) the presence of uterine or endometrial abnormalities such as endometriosis, uterine myoma, endometrial polyps, or intrauterine adhesion, (e) an initial increase of progesterone over 1.5 ng/mL before the trigger day (18), or (f) the patient refused fresh embryo transfer. A maximum of two embryos were transferred.…”

Stop GnRH-Agonist Combined with Multiple-Dose GnRH-Antagonist for Patients with Elevated Peak Serum Progesterone Levels Undergoing Ovarian Stimulation for IVF: A Proof of Concept

“…Multiple studies have examining the subtle elevation in serum progesterone during the follicular phase of OS and its effect on cycle outcome have yielded conflicting results regarding pregnancy rate (summarized in [2][3][4][5]). Orvieto Kolibianakis et al [3] have demonstrated in their metaanalysis that progesterone elevation on the day of hCG administration was associated with a significantly decreased probability of clinical pregnancy in patients undergoing OS for IVF using GnRH antagonists (-ant).…”

“…Moreover, recent evidence suggests that progesterone elevation affects not only implantation but also embryo quality [4]. On the other hand, Esteves et al [5] have recently reviewed the existing evidence regarding late follicular phase progesterone rise and showed that progesterone elevation was mainly caused by the supraphysiological stimulation during OS and is not influenced by the type of gonadotropin used. Moreover, its detrimental effect on IVF outcome does not affect all patient populations equally and might be overcome by the availability of good-quality embryo.…”

A retrospective study in Chinese infertility patients to investigate pregnancy outcomes of gonadotropin-releasing hormone antagonist in in vitro fertilization/intracytoplasmic sperm injection cycles: The FASSION study

“…However, a meta-analysis comprising 63 eligible studies (55,199 fresh IVF cycles using either agonist or antagonist protocols) found that a high progesterone level (defined as progesterone levels ≥ 0.8 ng/mL) on the day of triggering is associated with a decreased probability of pregnancy [22]. In contrast, a recent review of the available evidence suggested that debate remains regarding the impact of late follicular phase progesterone elevation on fresh ET IVF/ICSI outcomes [23]. To further validate this prediction model, we performed a sensitivity analysis.…”