Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles

Lawrenz, Barbara; Beligotti, F.; Engelmann, N.; Gates, Davis; Fatemi, Human M.

doi:10.1093/humrep/dew213

Cited by 42 publications

(31 citation statements)

References 25 publications

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“…PE is rather dependent on the overall GC output and is, therefore, associated with the number of follicles, oocytes, and E2 levels. Notwithstanding, some evidence suggests that the use of rFSH may be associated with higher P output than urinary gonadotropin normal and high responders, due to the higher potency of rFSH than urinary products ( 35 , 40 ).…”

Section: Resultsmentioning

confidence: 99%

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

Esteves¹,

Khastgir²,

Shah

et al. 2018

Front. Endocrinol.

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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.

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Section: Resultsmentioning

confidence: 99%

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

Esteves¹,

Khastgir²,

Shah

et al. 2018

Front. Endocrinol.

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“…Nevertheless, in patients treated with corifollitropin alfa mimicking a step-down protocol by releasing gradually decreasing doses in the follicular phase, P 4 E (>1.5 ng/mL) was less frequent than in patients given 200 or 300 IU of daily FSH in the secondary analysis of ENGAGE and PURSUE studies. 37 Although overall pregnancy rates were comparable among all of these studies, these findings might highlight the importance of refraining from aggressive stimulation with FSH, but also the need to add LH or LH-like activity when a high dose of FSH is planned to decrease P 4 concentration on the day of triggering. In this context, a head-to-head RCT is urgently needed to determine the value of adding LH to FSH by taking P 4 E as the primary outcome.…”

Section: What Are the Preventive And Rescue Strategies For Progesteromentioning

confidence: 85%

Progesterone Elevation and Preventive Strategies to Avoid Implantation Failure

et al. 2019

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Despite the wide utilization of gonadotropin-releasing hormone analogs, progesterone elevation (P4E) in the late follicular phase occurs in 5 to 30% of all ovarian stimulation (OS) cycles. Although the detrimental effect of P4E on pregnancy rates in fresh in vitro fertilization cycles is valid in all subsets of cases, higher levels of P4 and a longer duration of P4E may be needed in patients with a hyper-ovarian response in order for a negative impact on pregnancy rates to occur. Available preclinical and clinical data suggest that aggressive OS with high doses of follicle-stimulating hormone might increase 3β-hydroxy steroid dehydrogenase and 17β-hydroxy steroid dehydrogenase enzyme activity in human granulosa cells, which leads to high P4 production and hence a higher amount of leakage to the systemic circulation due to a lack of 17α-hydroxylase enzyme expression in human species. High P4 concentrations appear to alter gene expression in the endometrium; however, caution is necessary regarding its potential effect on oocyte/embryo quality with respect to the role of inherent follicular disruption in some women. In terms of the mechanism of overproduction in P4 synthesis, the main preventive strategy should be avoiding aggressive stimulation. Unfortunately, there is lack of large-scale randomized controlled trials for other approaches, including deferred embryo transfer in the thaw cycle. Since there is a significant inter-assay variability for P4 measurement, it may be wise to recommend that every center should define their own P4E and the level needed for harm to occur based on their own assays and datasets before deciding the best approach.

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“…This approach is especially important in lower progesterone ranges, as the detection of early progesterone rise will enable the clinician to adjust the ovarian stimulation regimen, e.g. reduction of the stimulation dosage [ 22 ] or shorten the stimulation duration [ 23 ], as these are strategies proven to prevent a possible progesterone elevation [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Inter-assay variation and reproducibility of progesterone measurements during ovarian stimulation for IVF

et al. 2018

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In recent years there is increasing evidence that elevated progesterone levels during ovarian stimulation for IVF / ICSI have a negative impact on the ART-outcome. However, different progesterone assays were used in the previous studies and different assays might produce varying results. This retrospective study evaluated the reproducibility and reliability of different progesterone assays with a special focus on progesterone levels below 1.5 ng/ml, as this range is crucial for early detection of progesterone rise during ovarian stimulation for IVF. A total of 413 blood samples were categorized in different progesterone ranges and whether they were retrieved on the day of final oocyte maturation and the results were compared regarding their reproducibility and reliability. To compare the reproducibility between the different progesterone assays, the Intraclass Correlation Coefficient (ICC) was calculated and interpretation of the ICC results was done according to Cicchetti, ranging from poor to excellent. The correlation of the assays was excellent when all samples were compared including samples retrieved on day of final oocyte maturation, however in the ranges of progesterone levels 1.0 ng/ml to < 1.5 ng/ml, 0.8 ng/ml to < 1.0 ng/ml and < 0.8 ng/ml, the ICC varied between poor and excellent. The assays “gen III” and “Architect” showed an excellent reproducibility of progesterone results throughout all ranges of progesterone levels.This analysis demonstrates, that different progesterone assays have a limited reproducibility and that the results depend on the assay used and the range of progesterone level. This fact leads to two important conclusions. Firstly the limited reproducibility might lead to substantially different treatment decisions in ovarian stimulation treatment for IVF and secondly critical interpretation of thresholds, provided by meta-analysis, is crucial despite the risk that the so far gained clinical experience might become irrelevant and has to be adjusted to the results, obtained by each assay.

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Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles

Abstract: ENGAGE study: ClinicalTrials.gov identifier NTC00696800. PURSUE-study: NCT01144416.

Cited by 42 publications

References 25 publications

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

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

Progesterone Elevation and Preventive Strategies to Avoid Implantation Failure

Inter-assay variation and reproducibility of progesterone measurements during ovarian stimulation for IVF

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