Random start protocols are commonly used for oocytes cryopreservation in women with cancer. However, evidence to support their effectiveness is yet modest. This study aims to compare the quality of ovarian response between the ovary carrying the dominant follicle or the corpus luteum (active ovary) and the contralateral ovary (resting ovary). Women with a diagnosis of malignancy who underwent oocytes cryopreservation were reviewed. The main inclusion criterion was the presence of a unilateral dominant follicle or a unilateral corpus luteum on the first day of ovarian hyperstimulation. The primary outcome was the number of mature oocytes retrieved. Intra-patient comparisons between the two ovaries were made using the nonparametric Wilcoxon test for paired data. Forty-three women were included. The number of mature oocytes retrieved from the active and the resting ovaries did not differ, the median [interquartile range—IQR] being 4 [2–7] and 5 [2–8], respectively (p = 0.09). The rate [IQR] of mature oocytes per developed follicle was 58% [40–80%] and 65% [33–87%], respectively (p = 0.42). In addition, no significant difference emerged when repeating the analyses separately for women carrying dominant follicles and for those carrying corpora lutea. This study failed to detect any detrimental effect of the presence of a dominant follicle or a corpus luteus on the ovarian response to hyperstimulation, thus supporting the validity of random start protocols.
Study question Is the use of conventional-IVF (c-IVF) a viable option in single oocyte retrieved cycles? Summary answer The use of c-IVF on single oocyte seems to be a successful strategy in terms of laboratory performance indicators outlined in the Vienna Consensus. What is known already Intracytoplasmic Sperm Injection (ICSI) has greatly improved the chances of reproductive success in cases of male factor infertility, but it is often used without strong evidence, such as in cases of low numbers of retrieved oocytes, assuming it will avoid unexpected total fertilization failure (TFF). On these bases, several ART centers irrationally opt for ICSI when few oocytes are retrieved. This approach is due to the fear of facing TFF the following day. This situation is boosted when only one oocyte is available. Available studies on c-IVF in these circumstances are generally reassuring, but evidence is limited and inconclusive. Study design, size, duration This is a monocentric retrospective observational study performed at the Infertility Unit of the Fondazione Ca' Granda Ospedale Maggiore Policlinico between 2014 and 2021. The primary outcome of the study is normal fertilization rate, which is expected to be ≥ 60% according to the Vienna Consensus. The study sample (about 300 cycles) was calculated to obtain a 95% CI within the range of ± 5%. A binomial distribution model was used to determine the 95%CI of proportions. Participants/materials, setting, methods Only women who had recovered one oocyte at the oocyte retrieval were included in the study. Collected data included age of both partners, previous pregnancies, female BMI, antral follicle count, total motile sperm count. A multivariate analysis was performed to identify predictive factors for fertilization. Based on the policy of our Center, c-IVF was performed only in case of normal sperm variables according to WHO 2010 manual and in the absence of history of TFF. Main results and the role of chance Out of 700 cycles with single oocyte retrievals, 304 were treated with c-IVF, which resulted in normal fertilization (2PN) in 209 cases, corresponding to a fertilization rate of 69% (95%CI: 63-74%). In 13 cycles, oocytes were shown to be immature (germinal vesicle or metaphase I) at the time of fertilization check. In these cases, fertilization could not occur. If we exclude them, the fertilization rate raised to 72% (209/291) (95%CI: 66-77%). This fertilization rate was within the Vienna Consensus KPI for competency range and was no more than 5% lower compared to the benchmark value. Clinical pregnancy and live birth rates per cycle were 14% and 11%, respectively. Finally, we compared baseline characteristics of cycles with normal fertilization to those with failed fertilization. Both univariate and multivariate analyses failed to identify predictive factors of fertilization. Limitations, reasons for caution The retrospective nature and the absence of a control group do not allow us to draw robust and definitive conclusions. However, the large sample sized allowed us a precise estimation of the fertilization rate. Wider implications of the findings Fear about TFF is not a valid reason to opt for ICSI in women retrieving only one oocyte. The use of ICSI increases costs without providing benefits. We also failed di identify predictive factors of fertilization, hampering the possibility to select a subgroup of women who may benefit from ICSI. Trial registration number Not applicable
Study question Is follicular steroidogenesis impaired in women undergoing random start protocols for fertility preservation? Summary answer The phase of menstrual cycle at initiation of ovarian stimulation does not influence the endocrine microenvironment surrounding oocytes. What is known already Cryopreservation of oocytes is the gold standard for fertility preservation in women with cancer. Random start protocols have been introduced for oocytes cryopreservation in these patients to shorten the duration of ovarian stimulation. However, albeit generally reassuring, available evidence is still insufficient to rule out a sub-optimal cycle outcome of random start protocols. Study design, size, duration The present study was conducted to provide evidence on the validity of random start protocols by exploring the quality of ovarian steroidogenesis. The primary outcome was comparing levels of steroids in the follicular fluid between women initiating the random start protocol in the luteal phase and those initiating in the follicular phase (considered as controls since equivalent to the conventional protocols). We excluded those requiring concomitant letrozole assumption. Participants/materials, setting, methods Seventy-one women with cancer were prospectively recruited during a 24-month period. Thirty-three initiated in luteal phase while 38 in follicular phase. All women were stimulated with recombinant FSH and GnRH antagonists. At the time of oocytes retrieval, follicular fluids were pooled, and a sample was frozen at -80 °C. All samples were assayed concomitantly after thawing, by liquid chromatography tandem mass spectrometry. The concentration of 15 different steroid hormones was determined. Main results and the role of chance Baseline characteristics of the two groups were similar. No differences emerged in anamnestic data and ovarian reserve variables. Cycle outcome did not also differ, the two study groups being similar in terms of total dose of gonadotropins, duration of stimulation, number of developed follicles and number of oocytes retrieved. The median [interquartile range] number of frozen mature oocytes was 9 [5-14] and 10 [5-21] in women who initiated in the luteal and the follicular phase, respectively (p = 0.42). None of the 15 tested steroid hormones differed. Two subgroup secondary analyses were performed to rule out confounders. First, we excluded women who were on estroprogestins at the time of recruitment (leaving 31 women initiating in the follicular phase and 32 in the luteal phase). Levels of steroids in the follicular fluids were still mainly similar. We observed a significant difference only for androstenedione, levels being higher for women initiating stimulation in the follicular phase. Second, we compared women in the early (up to day 5) and late follicular phase (26 and 12 cases, respectively). Levels of steroids in the follicular fluids did not differ except for cortisone, the concentration being higher in the early follicular phase. Limitations, reasons for caution Our study is not randomized, inevitably exposing our results to confounders. Assessment of intraovarian steroidogenesis is an indirect evidence of oocyte quality. Multiple comparisons were done, exposing our findings to type I errors (such as, in our opinion, the differences that emerged in the secondary analyses). Wider implications of the findings Random start protocols have become the standard of care for fertility preservation in women with cancer in the absence of robust evidence. Our data supports the validity of random start protocols in terms of quality of ovarian response since none of the tested hormones differed. Trial registration number Not applicable
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