Study question Does eight weeks of low dose hCG priming improve the outcome of ovarian stimulation for IVF/ICSI in women with low ovarian reserve. Summary answer Significantly more oocytes were retrieved following eight weeks of low dose hCG priming, when compared to an identical IVF/ICSI treatment immediately before the priming period. What is known already Administration of androgens prior to ovarian stimulation for IVF might upregulate the FSH receptor level on granulosa cells making the follicles more responsive to exogenous FSH. LH and hCG stimulate the follicular androgen synthesis, acting through LH receptors on the theca cells, enabling their use as an intra-ovarian androgen priming method. Exogenous testosterone and DHEA priming have been shown to increase the number of retrieved oocytes and the live birth rate, but systemic androgen administration is associated with side effects. Long term ‘intra-ovarian’ priming with hCG without systemic effects in women with low ovarian reserve has not previously been investigated. Study design, size, duration A prospective, paired, non-blinded study including 20 women serving as their own controls conducted between January 2021 and July 2021 at The University Hospital Copenhagen Rigshospitalet, Denmark. Participants underwent two identical consecutive IVF/ICSI treatments, a Control cycle including elective freezing of all blastocysts and a Study cycle with fresh blastocyst transfer. The Control and Study cycle were separated by approximately eight weeks (two menstrual cycles) of androgen priming by daily injections of 260 IE hCG. Participants/materials, setting, methods Inclusion criteria were age 18-40 years, regular menstrual cycle 23-35 days and AMH <6.29 pmol/L. Control and Study IVF/ICSI cycles were performed in a fixed GnRH-antagonist protocol using a daily dose of 300 IU rFSH and GnRH antagonist 0.25 mg from stimulation day 5-6. Primary endpoint was the follicular output rate defined as the pre-ovulatory follicle count (>16 mm) on hCG trigger day divided by the antral follicle count (2-10 mm) on cycle day 2-3. Main results and the role of chance 20 women with a mean (SD) age of 36.8 (3.2) years and an AMH level of 3.7 (1.5) pmol/L were included and completed the study. The number of oocytes retrieved was significantly higher in the Study compared to Control Cycle: 4.7 (2.8) vs. 3.2 (1.7), (P = 0.007), and the number of blastocysts was 1.2 (1.6) vs. 0.6 (0.7) in the Study compared to Control cycle, (P = 0.11). The follicular output rate was 0.4 (0.4) in the Study cycle initiated immediately after eight weeks of hCG priming, which was similar to the follicular output rate of 0.38 (0.2) in the Control cycle performed just before initiating the priming period (P = 0.81). The number of follicles above 10 mm on trigger day was 7.3 (5.0) in the Study and 5.3 (2.9) in the Control cycle (P = 0.018). Although the duration of stimulation seemed longer in the Study compared to Control cycle, 10.1 (1.5) and 8.9 (2.7) days respectively (P = 0.05), the same trigger criterion was defined and used in the two cycles confirmed by a similar mean diameter of the two biggest follicles on trigger day: 18.5 (1.1) vs. 18.3 (1.1) mm in the Study and Control cycle, respectively (P = 0.91). Limitations, reasons for caution The sample size calculation was based on the follicular output rate, and the study was not powered to look at oocyte retrieval rates. Bigger studies are needed to confirm this finding. Wider implications of the findings Although no increase in the follicular output rate was demonstrated, significantly more oocytes were retrieved after eight weeks of hCG priming, which is an important finding in a population of women with low ovarian reserve. Benefits of long term low dose hCG priming must be confirmed in a larger study. Trial registration number NCT04643925
Study question Does ovarian morphology and length of the follicular phase differ between immediate and postponed mNC-FET cycles? Summary answer More cystic follicular residue after oocyte pick-up was observed at cycle day 2-5 in immediate vs postponed mNC-FET. The immediate follicular phase was longer. What is known already Whether the optimal timing for treatment with mNC-FET is in the cycle immediately following ovarian stimulation (OS) and oocyte pick-up, or in a subsequent cycle, has been much debated. Recent evidence suggests that reproductive outcomes after immediate vs postponed FET are comparable or even better in programmed-cycle FET. Due to concerns about suboptimal ovarian and endocrinological conditions in the natural cycle immediately following an OS/IVF cycle, postponed FET has become the standard treatment in most settings. However, studies describing attributes of the immediate NC-FET are lacking and little is known about cycle characteristics and ovarian morphology shortly after oocyte pick-up. Study design, size, duration The present descriptive sub-study is based on data from an ongoing Danish, multicentre, randomised controlled trial (RCT), investigating if mNC-FET can be performed in the cycle immediately following OS and oocyte pick-up, without compromising pregnancy and live birth rates. Participants were randomized 1:1 to mNC-FET in the immediate vs a subsequent cycle. The first 102 participants were included in the present sub-study. Data was collected between April 2021 and December 2022. Participants/materials, setting, methods Women with a regular menstrual cycle, aged 18-40 years, undergoing single blastocyst mNC-FET were eligible for inclusion. Ovarian morphology and cycle length were compared between immediate and postponed mNC-FET using Chi-squared test for categorical variables, and independent sample T-test or Mann Whitney U-test for continuous variables. Categorical variables were reported as numbers and percentages, continuous variables as mean and standard deviation or median and range. Main results and the role of chance Background characteristics including age, BMI, AMH and normal cycle length were similar for women in the immediate and postponed group, apart from a lower rate of elective freeze all-transfers (30.2% vs 55.1%, p = 0.011) in the OS cycle preceding FET, in the immediate vs the postponed group. The total number of cystic follicular structures (hypo- and non-hypodense) >10 mm (2 (range 0-11) vs 0 (range0-3), p = <0.001) were higher in the immediate vs the postponed group on cycle day (CD) 2-5 of the treatment cycle. On the day of hCG-trigger, there was no significant difference in the total number of cystic follicular structures between the groups, but a higher number of non-hypodense structures was found in the immediate group (p = 0.021). Endometrial thickness was greater in the immediate vs postponed group (8.6 vs 7.8 mm, p = 0.031) while the mean size of the dominant follicle was similar 17.1 vs 17.3 mm between groups (p = 0.410). The average day of hCG-trigger was CD15 (range 9-24) in the immediate group compared to CD12 (range 5-28) in the postponed group (p = 0.001). More ultrasound scans of follicular development were needed in the immediate vs postponed group (3 vs 2, p = 0.012). Limitations, reasons for caution The proportion of elective freeze-all in the OS cycle preceding FET differed between the immediate and postponed group which may bias the results. The sample size limits stratified analyses. Wider implications of the findings The findings of this study indicate that cystic follicular ovarian structures shortly after oocyte pick-up are commonly occurring. However, most of these structures seems to regress before the time of ovulation. The follicular phase was longer in immediate cycles, and whether this effects pregnancy outcomes is yet unknown. Trial registration number NCT04748874
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