Daily low-dose hCG stimulation during the luteal phase combined with GnRHa triggered IVF cycles without exogenous progesterone: a proof of concept trial.

Can the luteal phase support be improved in terms of efficacy, hormonal profiles and convenience as compared with today's standard care? Daily low-dose rhCG supplementation in GnRHa triggered IVF cycles can replace the traditional used luteal phase support with exogenous progesterone. A bolus of hCG for final maturation of follicles in connection with COS may induce the risk of OHSS and the luteal phase progesterone levels rise very abruptly in the early luteal phase. This is a proof-of-concept study conducted as a three arm RCT with a total of 93 patients. First patient enrolled in January 2012 and the study finished in January 2014. Normal responder women undergoing IVF/ICSI treatment in a university hospital. One arm served as control, where women followed a standard antagonist protocol. Two study arms were included both having 125 IU hCG daily for luteal phase support without exogenous progesterone after using a GnRHa trigger for ovulation induction. In both study arms exogenous FSH was stopped on stimulation day 6 and replaced by exogenous hCG that was initiated on either stimulation day 2 or day 6. Blood samples were obtained on the day of ovulation induction, on the day of oocyte pickup (OPU) and day OPU + 7. The mean serum levels of hCG did not exceeded the normal physiological range of LH activity in any samples. Mid-luteal progesterone levels were significantly higher in the two study groups receiving daily low-dose hCG for luteal phase support as compared with the control group (control group: 177 ± 27 nmol/l; study group 1: 334 ± 42 nmol/l; study group 2: 277 ± 27 nmol/l; (mean ± SEM). No differences in reproductive outcome were seen between groups. The number of patients included is limited and conclusions need to be verified in a larger RCT. Endogenous production of progesterone may become more attractive as the luteal phase support with levels of LH-like activity only in the physiological range and may, from the patients' point of view, replace inconvenient exogenous progesterone preparation. Further hCG may reduce the cost of stimulation and may collectively be used for stimulation of the follicular phase, ovulation induction and for luteal phase support. An unrestricted grant from ARTS Biologics made this study possible. None of the authors has any competing interests to declare. ClinicalTrial.gov number: NCT01504139. 28 December 2011.

Andersen CY ，Elbaek HO ，Alsbjerg B ，Laursen RJ ，Povlsen BB ，Thomsen L ，Humaidan P ... -  《-》

GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.

Humaidan P ，Polyzos NP ，Alsbjerg B ，Erb K ，Mikkelsen AL ，Elbaek HO ，Papanikolaou EG ，Andersen CY ... -  《-》

Response to ovulation trigger is correlated to late follicular phase progesterone levels: A hypothesis explaining reduced reproductive outcomes caused by increased late follicular progesterone rise.

Is there an association between progesterone (P4) levels on the day of hCG or GnRH trigger and on the day of oocyte retrieval in IVF/ICSI cycles? A significant positive correlation between P4 levels on the day of trigger and the day of oocyte retrieval is seen; HCG trigger induces a steeper P4 increase than GnRHa trigger. FSH induces LH receptor (LHR) expression on granulosa cells, and LHR produces progesterone when exposed to LH-like activity. FSH per se also to some extent induces P4 secretion. Late follicular phase progesterone rise has been associated with reduced reproductive outcomes. This study is based on data from a previously published RCT conducted from 2009 to 2011. A total of 384 participants were enrolled; 199 received 5000 IU hCG and 185 received buserelin 0.5 mg for triggering ovulation. P4 was measured on the day of ovulation induction and on the day of oocyte retrieval. FSH consumption and number of retrieved follicles were recorded. A significant linear relationship between P4 on the day of ovulation induction and oocyte retrieval was seen in the hCG trigger group (P < 0.00001) as well as in the GnRHa trigger group (P < 0.00001). The P4 ratio (the increase in P4 between ovulation induction and oocyte retrieval) was significantly higher in the group of patients with <5 follicles compared to those with 5-15 and >15 follicles (P < 0.0001). The FSH consumption per follicle was significantly higher in the group of patients with <5 follicles compared to those with 5-15 and >15 follicles (P < 0.0001). Although the study demonstrates a significant correlation between P4 levels before and after ovulation trigger, it does not demonstrate a causal relation to the number of LHRs present on granulosa cells. The findings of this study support the proposed hypothesis that follicles exposed to high levels of FSH during ovarian stimulation will respond with an inappropriately high LHR expression. This in turn causes a high P4 output in response to the trigger. This study further expands our understanding of the underlying mechanisms affecting reproductive outcomes in relation to ovarian stimulation. The authors received no specific funding for this work and disclose no conflicts of interest. N/A.

Friis Wang N ，Skouby SO ，Humaidan P ，Andersen CY ... -  《-》

Towards an optimal luteal support modality in agonist triggered cycles: a randomized clinical trial.

Elgindy EA ，Sibai H ，Mostafa MI ，Gibreel A ，Darwish E ，Maghraby H ... -  《-》

The early luteal hormonal profile in IVF patients triggered with hCG.

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? 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. 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. 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. 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. 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. 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. Detailed information about early luteal phase hormone levels could be used to optimize and individualize luteal phase support to improve reproductive outcomes. 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. NCT02798146; NCT03174691.

Vuong LN ，Ho TM ，Pham TD ，Ho VNA ，Andersen CY ，Humaidan P ... -  《-》