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Progesterone serum concentration in late follicular and in luteal phase in Group A (with GnRH antagonist) and in Group B (without GnRH antagonist). Day 0 day of HCG administration.
Source publication
The aim of our study was to explore luteal phase hormone profiles in gonadotrophin-stimulated cycles with or without gonadotrophin-releasing hormone (GnRH) antagonist therapy during intrauterine insemination (IUI). Forty-one infertile couples were recruited in this randomized clinical study.
The 19 patients included in group A were treated for 21 c...
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Citations
... However, there are very little published data on the very early luteal steroid profile following hCG trigger and the limited data available are constrained due to limited serial blood sampling post hCG trigger ( [9,10,17,18]. The current study will advance our understanding of the very early luteal steroid profile following hCG trigger which is the cornerstone of follicular maturation in IVF/ICSI cycles. ...
Background
Studies have suggested that controlled ovarian hyperstimulation adversely affects endometrial receptivity due to advanced endometrial maturation. This adverse effect is mainly attributed to supraphysiological levels of both estrogen and progesterone identified in stimulated cycles. There is a paucity of published data investigating the very early luteal steroid profile following hCG trigger.
Aim of the study
This prospective, observational study was undertaken to determine the increase in serum progesterone levels after human chorionic gonadotrophin (hCG) trigger in stimulated IVF/ICSI cycles.
Materials and methods
This proof-of-concept study included 11 patients requiring ovarian stimulation for IVF/ICSI and who planned to avail of pre-implantation genetic screening with embryo vitrification of their biopsied embryos at blastocyst stage. For each study participant, five additional blood samples were drawn at the following specific times in the stimulation cycle, on the morning (10.00–12.00) of the assigned day to induce final oocyte maturation with hCG trigger, immediately prior to administration of hCG for final oocyte maturation, 1 h, 2 h, and 36 h post hCG trigger. A prediction model, the Gompertz curve, was used to determine serum progesterone levels at intervals between the 2 h post hCG trigger sample and the day of oocyte retrieval.
Results
Statistically significant increases in serum progesterone levels were identified following hCG administration as early as 1 h following trigger (P4 0.57 ng/ml, p < 0.05), 2 h following trigger (P4 0.88 ng/ml, p < 0.001) and on the day of oocyte retrieval (P4 9.68 ng/ml, p < 0.001). According to our prediction model, the Gompertz curve, the projected serum progesterone level at 4 h post trigger would have achieved a level of 1.45 ng/ml, 8 h post trigger of 3.04 ng/ml, and 12 h post trigger of 4.8 ng/ml. The very early and significant increases in serum progesterone following hCG trigger are clearly demonstrated in this study.
Conclusion
The endometrium is undoubtedly exposed to rapidly increasing serum progesterone levels post hCG trigger that would not be identified until much later in natural menstrual cycles.
Trial registration number: This study is registered with clinicaltrials.gov under the identifier NCT04417569.
... However, women undergoing ovarian stimulation during IUI cycles are not hypogonadotropic, and the half-life of hCG is relatively long. Therefore, the use of at least 5000IU hCG is biologically enough to persist for at least ten days, by which time the cytotrophoblast would have resumed secreting hCG in adequate amounts 40 . ...
Intrauterine insemination is a simple, non-invasive and safe initial treatment option, especially in low resource settings for selected group of patients before initiating assisted reproduction technology treatment. A wise selection of patients and timing are key to its success. Detailed assessment of the infertile couple, controlled ovarian stimulation with follicular development monitoring, appropriate processing the seminal fluid, trigger with hCG at a correct time, single IUI in strict aseptic condition followed by 10-15 minutes of immobilization are currently considered vital elements of Intrauterine insemination to improve its outcome. Intrauterine insemination can be considered as a bridge between basic and advanced fertility treatment for selected infertile couples especially in countries with limited resources for assisted reproductive technologies.
... However, data on hormone levels in the early luteal phase are rare in women receiving an hCG bolus trigger. In addition, initial studies evaluating the early luteal phase steroid profile after hCG trigger have been limited by small patient populations (33)(34)(35). However, the speed by which progesterone rises after ovulation induction is nicely illustrated by recent data from Vuong et al. (21), which included a total of 160 women receiving 6,500 IU for final maturation of follicles and no exogenous luteal phase support (Table 1). ...
Final maturation of follicles has, in connection with ovarian stimulation and infertility treatment, traditionally been achieved by the administration of a human chorionic gonadotropin (hCG) bolus trigger of 5,000 to 10,000 IU. This trigger serves two purposes: induce oocyte maturation; and serve as luteal phase support owing to its long half-life. It now appears that the hCG bolus trigger is unable to support both these two purposes optimally. In particular, after an hCG trigger, the early luteal phase is hormonally abnormal and different from conditions observed in the natural menstrual cycle: the timing of the initiation of hCG and progesterone rise is much faster after an hCG trigger than in a natural menstrual cycle; the maximal concentrations of hCG and progesterone considerably exceed those naturally observed; and the timing of the peak progesterone concentration after an hCG trigger is advanced several days compared with the natural cycle. Furthermore, the hCG trigger without any follicle-stimulating hormone activity may induce oocyte maturation less efficiently than the combined luteinizing hormone and follicle-stimulating hormone surge normally seen. Collectively, the endometrium is likely to be advanced after an hCG trigger, and the implantation potential is probably not optimal. The precise effect on pregnancy rates after the different progressions of hCG and progesterone concentrations during the early luteal phase has not yet been determined, but more individualized methods using more physiological approaches are likely to improve reproductive outcomes.
... In general, there is a limited amount of published data about the early luteal steroid profile after hCG trigger (Ragni et al., 2001;Fauser et al., 2002;Beckers et al., 2003). This information is important to allow provision of the most optimal luteal phase support strategies during IVF, with the goal of increasing live birth rates. ...
... This information is important to allow provision of the most optimal luteal phase support strategies during IVF, with the goal of increasing live birth rates. However, existing studies have been limited by small patient populations and a low number of blood samples for steroid level determination during the early luteal phase (Ragni et al., 2001;Fauser et al., 2002;Beckers et al., 2003). ...
Study question:
What is the early luteal phase hormonal profile in patients undergoing ovarian stimulation for IVF/ICSI followed by hCG trigger and a freeze-all strategy without luteal phase support?
Summary answer:
The peak concentration of progesterone occurred 4 days after oocyte pick-up (OPU + 4), with an average 35% fall from OPU + 4 to OPU + 6, and progesterone levels before and 12 h after hCG administration predicted levels during the early luteal phase.
What is known already:
The luteal phase during IVF differs from that during normal cycles, particularly with respect to the serum progesterone level profile. This can cause asynchrony between the embryo and the endometrium, potentially resulting in implantation failure and poor reproductive outcomes.
Study design, size, duration:
This prospective study included 161 women with normal ovarian reserve receiving GnRH antagonist co-treatment during ovarian stimulation with FSH who were followed up to 6 days after OPU in a single IVF cycle.
Participants/materials, setting, methods:
Women aged 18-42 years undergoing IVF with ovarian stimulation using FSH were included. Ovulation was triggered with recombinant hCG 250 μg. Hormone levels were determined from blood samples taken on the day of trigger, before hCG, at 12, 24 and 36 h after hCG and at 1, 2, 3, 4, 5 and 6 days after OPU. The primary endpoint was early luteal phase serum concentrations of progesterone, LH, estradiol and hCG.
Main results and the role of chance:
One outlier with a pre-hCG serum progesterone level of 11.42 ng/mL was excluded, so all analyses included 160 subjects. Progesterone levels began to increase 1 day after OPU, peaked 4 days after OPU (114 ng/mL), then declined from OPU + 5 onwards. Peak progesterone levels were at OPU + 4, OPU + 5 or OPU + 6 in 38.8, 29.4 and 13.8% of patients, respectively. Approximately two-thirds of patients had a fall in serum progesterone from OPU + 4 to OPU + 6. Pre-hCG progesterone levels correlated significantly with those at 24 h after hCG (r2 = 0.28; P < 0.001), which in turn correlated significantly with progesterone at OPU + 4 (r2 = 0.32; P < 0.001). LH peaked (4.4 IU/L) 12 h after hCG trigger, persisting for 24 h but was barely elevated compared with physiological levels. Serum estradiol peaked twice: at 24 h post-trigger and at OPU + 4. Highest hCG levels (130 mIU/mL) occurred at 24 h post-injection. The best correlations between the number of follicles ≥11 mm and serum progesterone level were seen at 24 and 36 h after hCG and OPU + 1.
Limitations, reasons for caution:
The influence of different profiles of serum progesterone on reproductive outcomes could not be determined because a freeze-all strategy was used in all patients. In addition, data were not available to relate serum hormone level findings with endometrial histology or endometrial receptivity analysis to clearly identify the relationship between serum hormones and the window of implantation.
Wider implications of the findings:
Detailed information about early luteal phase hormone levels could be used to optimize and individualize luteal phase support to improve reproductive outcomes.
Study funding/competing interest(s):
This study was funded by My Duc Hospital, Ho Chi Minh City, Vietnam. All authors state that they have no conflicts of interest to disclose.
Trial registration number:
NCT02798146; NCT03174691.
... Pour notre analyse, nous avons retenu les protocoles de stimulation ovarienne par FSH [29][30][31][32][33][34] avec introduction d'un antagoniste de la GnRH si besoin [33,34]. Les critè res d'exclusion de l'analyse é taient la pré sence d'une malformation uté rine [35,36] ou de polype uté rin [37], la pré sence d'un ovaire unique, une impermé abilité tubaire même unilaté rale [38] ou la pré sence d'un hydrosalpinx [39]. ...
... Pour notre analyse, nous avons retenu les protocoles de stimulation ovarienne par FSH [29][30][31][32][33][34] avec introduction d'un antagoniste de la GnRH si besoin [33,34]. Les critè res d'exclusion de l'analyse é taient la pré sence d'une malformation uté rine [35,36] ou de polype uté rin [37], la pré sence d'un ovaire unique, une impermé abilité tubaire même unilaté rale [38] ou la pré sence d'un hydrosalpinx [39]. ...
... Pour notre analyse, nous avons retenu les protocoles de stimulation ovarienne par FSH [29][30][31][32][33][34] avec introduction d'un antagoniste de la GnRH si besoin [33,34]. Les critè res d'exclusion de l'analyse é taient la pré sence d'une malformation uté rine [35,36] ou de polype uté rin [37], la pré sence d'un ovaire unique, une impermé abilité tubaire même unilaté rale [38] ou la pré sence d'un hydrosalpinx [39]. ...
... Pour notre analyse, nous avons retenu les protocoles de stimulation ovarienne par FSH [29][30][31][32][33][34] avec introduction d'un antagoniste de la GnRH si besoin [33,34]. Les critè res d'exclusion de l'analyse é taient la pré sence d'une malformation uté rine [35,36] ou de polype uté rin [37], la pré sence d'un ovaire unique, une impermé abilité tubaire même unilaté rale [38] ou la pré sence d'un hydrosalpinx [39]. ...
Introduction: The objective of our study is to evaluate the impact of luteal phase support by hCG in intrauterine inseminations preceded by ovarian gonadotropin stimulation.
Patients and Methods: A retrospective study was conducted at the CHU of Nice between March 1, 2016 and October 31, 2017. During this period, 300 intrauterine inseminations were included in data analysis. Ovarian stimulation was performed by gonadotropins and a GnRH antagonist was added, if needed. Following a modification of standard operative procedure in the department, patients who performed an intrauterine insemination from December 1, 2016 received luteal phase support with two injections of hCG 1500 IU, performed at three days of interval. Pregnancy and ovarian hyperstimulation syndrome were the primary and secondary study endpoints, respectively.
Results: Out of 300 inseminations included in the analysis, 144 were performed with luteal phase support and 156 without support. No statistically significant difference in pregnancy rate was observed between these two groups (19.4% of pregnancy in the luteal phase support group and 15.38 % in the group without luteal phase support, p = 0.353). No ovarian hyperstimulation syndrome occured over the course of the study.
Conclusion: Our study shows a slight improvement of pregnancy rate in the group subjected to luteal phase support by hCG after intrauterine insemination, but the benefit was not significant. A randomised prospective study based on a large cohort could help to assess the effect of luteal phase support during intrauterine inseminations.
... As more FSH would be needed in antagonist cycles, owing to the suppression of endogen gonadotrophin production, in accordance with other studies [17,20], the total r-FSH dose required was higher in the GnRH-ant group, but the difference was not statistically significant. Interestingly, Allegra et al. [21] and Lambalk et al. [18] reported a lower total r-FSH dose used in women receiving antagonists, but the authors stated that the explanation of the reasoning for this observation was difficult. ...
Objective
To evaluate the effect of the GnRH antagonist on gonadotropin ovulation induction in women with PCOS.
Materials and methods
A total of 175 intrauterine insemination (IUI) cycles in women with polycystic ovary syndrome (PCOS) were included in the study. Women in the control group (n = 87) underwent controlled ovarian stimulation (COS) with recombinant follicle stimulating hormone (r-FSH) only, while women in the study group (n = 88) were administered r-FSH plus cetrorelix.
Results
As expected, the mean value of luteinizing hormone and progesterone, on the day of human chorionic gonadotropin administration were statistically significantly lower in patients receiving GnRH antagonist than the control group (p = 0.002). Premature luteinization occurred in only one of the patients in the GnRH antagonist group (1.1%) and in 15 of the 88 cycles in the control group (17.2%), showing a significant difference between the two groups (P = 0.001). The clinical pregnancy rate per cycle was higher in GnRH-antagonist group compared to the control group but the difference did not reach to a statistical significance (25% vs 14.9%, P = 0.096).
Conclusions
Adding GnRH-antagonist in COS/IUI cycles in women with PCOS resulted in a lower incidence of premature luteinization but did not improve pregnancy rates. However, owing to some benefits, antagonist therapy could be considered as a reasonable alternative to IVF in order to reduce PCOS patients'emotional distress.
... Предварительные наблюдения в циклах искусственной внутриматочной инсеминации подтверждали эту гипотезу. Однако позднее обнаружено, что профили гормонов лютеино-вой фазы в циклах овариальной стимуляции и инсеминации с применением и без антГнРГ не отличались по концентрации прогестерона и продолжительности лютеиновой фазы [22]. Тем не менее продолжающийся анализ использования антГнРГ в циклах ЭКО укреплял исследователей во мнении о влиянии этих препаратов на лютеолиз и соответственно на снижение шансов на беременность [23,24]. ...
... [8][9][10] The introduction of GnRH-ant during IUI-stimulated cycles may prevent spontaneous ovulation and premature luteinisation, and may improve clinical pregnancy rate. 11,12 However, since their first use in 2001, 13 the effectiveness of this strategy remains a subject of debate. ...
... Eight studies were subsequently excluded after the examination of full-text: two studies were not RCT. 16,17 Ragni et al. 13 aimed to evaluate the luteal phase profile in women undergoing IUI-stimulated cycles with/without GnRH-ant. Two studies evaluated the effectiveness of different stimulation protocols in women receiving gonadotrophins plus GnRH-ant before IUI. ...
Background:
Several randomised controlled trials (RCTs) have investigated the usefulness of pituitary block with gonadotrophin-releasing hormone (GnRH) antagonists during intrauterine insemination (IUI) cycles, with conflicting results.
Objective:
The aim of the present systematic review and meta-analysis of RCTs was to evaluate the effectiveness of GnRH antagonist administration as an intervention to improve the success of IUI cycles.
Search strategy:
Electronic databases (MEDLINE, Scopus, EMBASE, Sciencedirect) and clinical registers were searched from their inception until October 2017.
Selection criteria:
Randomised controlled trials of infertile women undergoing one or more IUI stimulated cycles with GnRH antagonists compared with a control group.
Data collection and analysis:
The primary outcomes were ongoing pregnancy/live birth rate (OPR/LBR) and clinical pregnancy rate (CPR). Pooled results were expressed as odds ratio (OR) or mean differences with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroups analysis. The body of evidence was rated using GRADE methodology. Publication bias was assessed with funnel plot, Begg's and Egger's tests.
Main results:
Fifteen RCTs were included (3253 IUI cycles, 2345 participants). No differences in OPR/LBR (OR 1.14, 95% CI 0.82-1.57, P = 0.44) and CPR (OR 1.28, 95% CI 0.97-1.69, P = 0.08) were found. Sensitivity and subgroup analyses did not provide statistical changes in pooled results. The body of evidence was rated as low (GRADE 2/4). No publication bias was detected.
Conclusion:
Pituitary block with GnRH antagonists does not improve OPR/LBR and CPR in women undergoing IUI cycles.
Tweetable abstract:
Pituitary block with GnRH antagonists does not improve the success of IUI cycles.
... We followed the usual time of IUI after hCG, as there is no consensus about the best time suggested, although it has been mentioned to be anywhere between 12 hours and 60 hours [14]. Although luteal phase support benefit in cycles using antagonist protocol is a matter of unproven research [15][16][17][18], we chose to implement luteal support, as it might increase the pregnancy rate [19,20]. Other studies showed that routine luteal-phase support by vaginal suppositories did not improve pregnancy results in clomiphene citrate induced cycles in IUI trials [21], but an evidence-based review recommended to apply luteal-phase support in stimulated IUI cycles only when proven cost-effective [22]. ...
p> Objective: The primary goal of this study was to compare the ovulation and pregnancy rates in women with unexplained infertility undergoing intrauterine insemination utilizing an antagonist (cetrolix) protocol versus the commonly used clomiphene citrate regimen.
Patients and Methods: This was a randomized controlled study performed at Assisted Reproductive Techniques Center of Ain Shams University Maternity Hospital, over a 2-year period, between Jan 2014 and Jan 2016, and included 80 women,with unexplained infertility undergoing intrauterine insemination (IUI), were randomised into two groups. Group I (n=40) received the antagonist protocol: human menopausal gonadotropins were given from Day 2 to reach a dominant follicle of 18-22 mm, intramuscularly. Then, cetrolix (0.25 mg) was subcutaneously started from Day 6 or Day 7 until the day of human chorionic gonadotropins (hCG; that was given in the dose of 10,000 IU, intramuscularly) when follicles reached 18-22 mm. Group II (n=40) receivd the clomiphene citrate protocol: clomiphene citrate given 100 mg/d from Day 2 to Day 6 and then human menopausal gonadotropin (hMG) to reach a dominant follicle of 18-22 mm, intramuscularly. Follow up until day of hCG, afterward, the IUI of 0.5mL was done from 34 hours to 36 hours using IUI catheter without guidance of ultrasonography and with an empty urinary bladder. The primary outcome was clinical pregnancy rate defined as the presence of intrauterine gestational sac detected by ultrasound at 5-weeks’ gestation . The number of dominant follicles, level of serum estradiol, and luteinizing hormone at the day of hCG injection and the incidence of twin or triplet pregnancies in both groups were secondary outcome measures.
Results: In this study
Conclusions: It seems that clinical pregnancy rates were significantly higher by cetrolix protocol
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