D. Stoop

Fertility preservation for age-related fertility decline

Cryopreservation of eggs or ovarian tissue to preserve fertility for patients with cancer has been studied since 1994 with R G Gosdens paper describing restoration of fertility in oophorectomised sheep, and for decades previously by others in smaller mammals. Clinically this approach has shown great success. Many healthy children have been born from eggs cryopreserved with the Kuwayama egg vitrification technique for non-medical (social) indications, but until now very few patients with cancer have achieved pregnancy with cryopreserved eggs. Often, oncologists do not wish to delay cancer treatment while the patient goes through multiple ovarian stimulation cycles to retrieve eggs, and the patient can only start using the oocytes after full recovery from cancer. Ovarian stimulation and egg retrieval is not a barrier for patients without cancer who wish to delay childbearing, which makes oocyte cryopreservation increasingly popular to overcome an age-related decline in fertility. Cryopreservation of ovarian tissue is an option if egg cryopreservation is ruled out. More than 35 babies have been born so far with cryopreserved ovarian tissue in patients with cancer who have had a complete return of hormonal function, and fertility to baseline. Both egg and ovarian tissue cryopreservation might be ready for application to the preservation of fertility not only in patients with cancer but also in countering the increasing incidence of age-related decline in female fertility.

Live birth rates following natural cycle IVF in women with poor ovarian response according to the Bologna criteria

STUDY QUESTION What is the effect of natural cycle IVF in women with poor ovarian response according to the new ESHRE definition for poor ovarian responders: the Bologna criteria? SUMMARY ANSWER Although natural cycle IVF is a promising treatment option for normal responders, poor ovarian responders, as described by the Bologna criteria, have a very poor prognosis and do not appear to experience substantial benefits with natural cycle IVF. WHAT IS KNOWN ALREADY Previous trials have shown that natural cycle IVF is an effective treatment for the general infertile population and might be an option for poor ovarian responders. However, none of the trials have examined the effect of natural cycle IVF in poor responders according to the Bologna criteria, the newly introduced definition by the ESHRE Working Group on Poor Ovarian Response Definition. In this trial, we examined the effect of natural cycle IVF in poor ovarian responders fulfilling the Bologna criteria. STUDY DESIGN, SIZE, DURATION In this retrospective cohort trial, 164 consecutive patients, undergoing 469 natural cycle IVFs between 2008 and 2011 were included. Patients were stratified as poor and normal responders: 136 (390 cycles) were poor ovarian responders according to the Bologna criteria, whereas 28 women (79 treatment cycles) did not fulfil the criteria and were considered as normal responders. PARTICIPANTS/MATERIALS, SETTING, METHODS All patients were monitored with hormonal analysis and ultrasound scan every second day, from Day 7 or 8 of the cycle onwards. When a follicle of >16 mm was observed, ovulation was triggered with 5000 IU of i.m. hCG and oocyte retrieval was performed 32 h later. MAIN RESULTS AND THE ROLE OF CHANCE Live birth rates in poor responders according to the Bologna criteria were significantly lower compared with the control group of women; the live birth rate per cycle was 2.6 versus 8.9%, P = 0.006 and the live birth rate per treated patient was 7.4 versus 25%, P = 0.005. In poor responders according to the Bologna criteria, live birth rates were consistently low and did not differ among different age groups (≤ 35 years, 36-39 years and ≥ 40 years), with a range from 6.8 to 7.9%. LIMITATIONS, REASONS FOR CAUTION A limitation of our analysis is its retrospective design; however, taking into account that we included only consecutive patients treated with exactly the same protocol, the likelihood of selection bias might be considerably limited. In addition, the control group in our study refers to women of younger age and therefore the promising results among patients who did not fulfil the Bologna criteria apply only to women of younger age. WIDER IMPLICATIONS OF THE FINDINGS Our trial suggests that although natural cycle IVF is a promising treatment option for younger normal responders, its potential is very limited to poor ovarian responders as described by the Bologna criteria, irrespective of patients age. This highlights the very poor prognosis of these women and therefore the urgent need for future trials to examine the effect of ovarian stimulation protocols in women with poor ovarian response as described by the Bologna criteria. STUDY FUNDING/COMPETING INTEREST(S) No funding was used. There are no competing interests to declare.

Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos?

STUDY QUESTION What is the impact of ovarian response on cumulative live birth rates (LBR) following utilization of all fresh and frozen embryos in women undergoing their first ovarian stimulation cycle, planned to undergo single embryo transfer (SET). SUMMARY ANSWER Cumulative LBR significantly increases with the number of oocytes retrieved. WHAT IS KNOWN ALREADY Several studies have addressed the issue of the optimal number of oocytes retrieved following controlled ovarian stimulation (COS) for IVF/ICSI and demonstrated that ovarian response is independently related to LBR following IVF/ICSI. The vast majority of studies pertained only to the outcome of the fresh IVF cycle and did not evaluate the cumulative LBR following the transfer of all fresh and frozen-thawed embryos after a single ovarian stimulation, which is the most meaningful outcome for the infertile patient. STUDY DESIGN, SIZE, DURATION This study is a large cohort analysis of retrospective data from January 2009 to December 2013 in a tertiary medical centre, at the Centre for Reproductive Medicine at the University Hospital of Brussels. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included 1099 eligible consecutive women 18-40 years old undergoing their first IVF cycle and planned to undergo SET in their fresh cycle. All patients were treated with a conventional starting gonadotrophin dose of 150-225 IU recombinant FSH (rFSH) in a fixed GnRH antagonist protocol. Vitrification was used as cryopreservation method. To evaluate the impact of oocyte yield on fresh LBR and on cumulative LBR after utilization of all cryopreserved embryos, patients were categorized into four groups according to the number of oocytes retrieved: 1-3 (Group A), 4-9 (Group B), 10-15 (Group C) or >15 oocytes (Group D). MAIN RESULTS AND THE ROLE OF CHANCE Regarding LBR in the fresh IVF/ICSI cycles, unadjusted results did not show any significant difference when comparing either high (>15 oocytes) versus normal (10-15 oocytes) (P = 0.65), or normal (10-15) versus suboptimal (4-9 oocytes) responders (P = 0.2). LBR in the fresh cycles were significantly higher (P < 0.05) in high, normal and suboptimal responders when compared with the low ovarian responder group (1-3 oocytes). Moderate-severe ovarian hyperstimulation syndrome occurred in 11 out of 1099 patients (1%). The cumulative LBR significantly increased with the number of oocytes retrieved (χ(2) test for trend P < 0.001). High responders (>15 oocytes) demonstrated a significantly higher LBR not only versus poor (0-3 oocytes) (P < 0.001) and suboptimal (4-9) responders (P < 0.001), but also versus women with normal (10-15) ovarian response (P = 0.014). Finally, although suboptimal responders had a better outcome compared with poor ovarian responders (P = 0.002), this group had a significantly lower cumulative LBR compared with normal ovarian responders (P = 0.02). Multivariate logistic regression analysis showed that the ovarian response category remained an independent predictive factor (P < 0.001) for cumulative LBR. LIMITATIONS, REASONS FOR CAUTION This is a cohort analysis based on retrospective data collection. Despite our robust methodological approach, the presence of biases related to retrospective design cannot be excluded. High responders may inherently have had a better prognosis. In addition, we cannot provide any guidance for patients undergoing either multiple embryo transfers or treated with higher gonadotrophin doses. WIDER IMPLICATIONS OF THE FINDINGS Women undergoing COS for their first IVF/ICSI cycle and SET should be informed that, although the number of oocytes retrieved does not affect LBR in the fresh cycle, the higher the oocyte yield, the higher the probability to achieve a live birth after utilization of all cryopreserved embryos. Large cohort studies are needed in order to confirm our results of cumulative LBR in different ovarian stimulation settings with higher stimulation doses. STUDY FUNDING/COMPETING INTERESTS No external funding was used for this study. No conflicts of interest are declared.

Obstetric outcome in donor oocyte pregnancies: a matched-pair analysis

BackgroundTo investigate the obstetrical and perinatal impact of oocyte donation, a cohort of women who conceived after OD was compared with a matched control group of women who became pregnant through in vitro fertilisation with autologous oocytes (AO).MethodsA matched-pair analysis has been performed at the Centre for Reproductive Medicine of the UZ Brussel, Dutch speaking Free University of Brussel. A total of 410 pregnancies resulted in birth beyond 20 weeks of gestation occurring over a period of 10 years, including 205 oocyte donation pregnancies and 205 ICSI pregnancies with autologous oocytes (AO). Patients in the OD group were matched on a one-to-one basis with the AO group in terms of age, ethnicity, parity and plurality. Matched groups were compared using paired t-tests for continuous variables and McNemar test for categorical variables. A conditional logistic regression analyses was performed adjusting for paternal age, age of the oocyte donor, number of embryos transferred, and singleton/twin pregnancy.ResultsOocyte donation was associated with an increased risk of pregnancy induced hypertension (PIH) (matched OR: 1.502 CI: 1.024-2.204), and first trimester bleeding (matched OR: 1.493 CI: 1.036-2.15). No differences were observed between the two matched groups with regard to gestational age, mean birth weight and length, head circumference and Apgar scores.ConclusionsOocyte donation is associated with an increased risk for PIH and first trimester bleeding independent of the recipients’ age, parity and plurality, and independent of the age of the donor or the partner. However, oocyte donation has no impact on the overall perinatal outcome.

Clinical validation of a closed vitrification system in an oocyte-donation programme

Controversy exists about the risk of microbiological contamination from direct contact with unsterile liquid nitrogen during oocyte vitrification. The aim of this observational study was to evaluate the effectiveness of oocyte vitrification using a high-security closed vitrification system in a donation programme. Oocyte vitrification was performed using CBS High Security closed straws (Cryo Bio System) with DMSO/ethylene glycol/sucrose as the cryoprotectant (Irvine Scientific freeze kit). A total of 123 vitrified metaphase-II oocytes were warmed in 20 recipient cycles (6.2 warmed oocytes per recipient); of these, 111 oocytes (90.2%) survived vitrification and warming. All surviving oocytes were microinjected and 86 (77.5%) were normally fertilized, of which 53 (61.6%) developed up to good-quality day 3. Ten embryo transfers resulted in a clinical pregnancy (50.0%) and an ongoing clinical pregnancy rate of 45%. Five revitrified embryos were warmed in three warming cycles (survival rate 100%). These transfers resulted in an additional ongoing twin pregnancy, leading to a cumulative ongoing pregnancy rate per patient of 50% (10/20). The ongoing implantation rate per warmed oocyte and per injected oocyte was 10.6% (13/123) and 11.7% (13/111). The present data demonstrate that oocyte vitrification using a closed vitrification device yields excellent oocyte survival, fertilization and embryo development.

Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI

This retrospective study determined the efficacy of ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) in poor ovarian responders fulfilling the Bologna criteria for poor ovarian response and identified predictors of live birth rates. Overall, 485 patients undergoing 823 ovarian stimulation cycles for IVF/ICSI with maximum gonadotrophin dose (≥ 300 IU) between January 2009 and December 2011 were included. Patients were considered eligible, irrespective of the treatment protocol, if they were classified as poor responders based on the recently developed definition for poor ovarian response by the European Society of Human Reproduction and Embryology, the Bologna criteria. Live birth rates did not significantly differ between women aged <40 and women aged ≥ 40 years either per cycle (7.1 versus 5.2%, OR 1.38, 95% CI 0.77-2.46) or per patient (11.6 versus 8.8%, OR 1.36, 95% CI 0.75-2.46). In logistic regression analysis, the number of oocytes retrieved was the only variable significantly associated with live births (OR 1.92, 95% CI 1.03-3.55 for >3 versus 1-3 oocytes). Bologna poor responders demonstrate very low live birth rates, irrespective of age and treatment protocol used. An increase in the number of oocytes retrieved is an independent variable related to live birth rates.

Reproductive potential of a metaphase II oocyte retrieved after ovarian stimulation: an analysis of 23 354 ICSI cycles

BACKGROUND Live birth per cycle and live birth per embryo transfer are commonly used outcome measures for IVF treatment. In contrast, the assessment of the reproductive efficiency of human oocytes fertilized in vitro is seldom performed on an egg-to-egg basis. This approach may however gain importance owing to the increasingly widespread use of oocyte cryopreservation, as the technique is becoming more established. The aim of the current study is to quantify the reproductive efficiency of the oocyte according to ovarian ageing and ovarian response. METHODS We performed a retrospective analysis of the outcome of all consecutive patients attending for treatment between 1992 and 2009. The outcome in terms of live birth after fresh and cryopreserved embryo transfer per mature oocyte was calculated for 207 267 oocytes retrieved in 23 354 ovarian stimulation cycles. The oocyte utilization rate (number of live births per mature oocyte) was further analysed in relation to the ovarian response. RESULTS The oocyte utilization rate in women in the age of ≤ 37 years remains constant with a mean of 4.47% live birth per mature oocyte [95% confidence interval (CI): 4.32-4.61]. From the age of 38 years onwards, a significantly lower oocyte utilization rate was noted, declining from 3.80% at the age of 38 years to 0.78% at 43 years (P < 0.001). In this 38-43 years age group, oocyte utilization rate was no longer dependent on ovarian response (P = 0.87). CONCLUSIONS The major strength of the study, which is also its weakness, is the fact that we included a large number of cycles performed over a long period of time. According to our results, the oocyte utilization rate between 23 and 37 years of age depends largely on ovarian response and to a much lesser extent on age. From the age of 38 years onwards, the utilization rate depends largely on age and to a much lesser extent on ovarian response. Considering the increased use of oocyte freezing for fertility preservation, these data are extremely valuable as they provide an estimate of the number of oocytes needed to achieve a live birth.

Does oocyte banking for anticipated gamete exhaustion influence future relational and reproductive choices? A follow-up of bankers and non-bankers

STUDY QUESTION What is the nature of the relational status, reproductive choices and possible regret of a pioneer cohort of women that either considered or actually performed oocyte banking for anticipated gamete exhaustion (AGE)? SUMMARY ANSWER Only half of the women who banked oocytes anticipate using them in the future but the experience with oocyte banking is overwhelmingly positive, with the majority of AGE bankers preferring to have it performed at a younger age. WHAT IS KNOWN ALREADY Most women who choose to cryopreserve oocytes for the prevention of age-related fertility decline are single and are hoping to buy time in their search for a suitable partner. The question of why some candidates actually embark on such treatment while others eventually prefer not to freeze remains unclear. There are no follow-up data available either on post-freezing changes in relational status, or on attitude towards the undergone treatment and the reproductive outcome. STUDY DESIGN, SIZE, DURATION A retrospective cohort study was performed with 140 women who visited the outpatient clinic between 2009 and 2011. All women (mean age 36.7 ± SD 2.62) considered oocyte preservation for age-related infertility. At least 1 year after their initial visit (range 12-45 months), women were contacted by phone to participate in a standardized questionnaire developed to evaluate their actual relational and reproductive situation, their attitude towards banking and future reproductive plan. PARTICIPANTS/MATERIALS, SETTING, METHODS Eighty-six women (61.4%) completed at least one cryopreservation cycle. The non-bankers included 54 women who either preferred no treatment (n = 51) or attempted stimulation but cancelled because of poor response (n = 3). The response rate among bankers was 75.4% (65/86) while 55.8% (29/52) of the non-bankers were reached for interview. MAIN RESULTS AND THE ROLE OF CHANCE Among bankers, 50.8% of women think they will use the oocytes at some point, while 29.2% indicated that they currently consider the use of frozen oocytes less likely than anticipated at time of oocyte retrieval. However, although 95.4% would decide to do it again, the majority (76.0%) would prefer to do it at a younger age. Among bankers, 96.1% would recommend the treatment to others. Women who banked accept a higher maximum age for motherhood when compared with non-bankers (43.6 versus 42.5 years; P < 0.05). Almost all bankers and 89.6% of the non-bankers still have a desire for a child. Bankers and non-bankers did not differ in terms of experiencing steady relations (47.7 versus 55.2%), attempting conception (35.4 versus 44.8%) and not conceiving within 1 year (17.4 versus 15.4%). LIMITATIONS, REASONS FOR CAUTION The study has a limited follow-up of 1-3 years and therefore does not provide information on the reproductive outcome of the cryopreserved oocytes. Although most women appear to be realistic about their chances of pregnancy, the outcome of such treatment could affect the attitude of women towards the treatment. Furthermore, the findings of non-bankers cannot be generalized to the general population because the control group of non-bankers in this study actually visited a centre as a potential candidate for banking. WIDER IMPLICATIONS OF THE FINDINGS Bankers and non-bankers have a surprising congruent relational status and reproductive choices, indicating that freezing oocytes does not appear to influence the life choices of the women. The study provides insights into the important psychological aspect of reassurance associated with preventive oocyte banking, expressed by high satisfaction after banking in combination with a decreased intention of ever using the eggs.

Can 200 IU of hCG replace recombinant FSH in the late follicular phase in a GnRH-antagonist cycle? A pilot study

BACKGROUND GnRH-antagonist protocols shorten the treatment period and reduce inconvenience for IVF patients. This randomised controlled trial (RCT) further explored whether low-dose hCG can be used clinically to replace recombinant FSH (rFSH) during the late follicular phase in a GnRH-antagonist protocol. METHODS Seventy ICSI patients undergoing controlled ovarian stimulation (COS) in a GnRH-antagonist protocol was randomized into two groups. The control group received a standard treatment with rFSH (Puregon) plus a GnRH-antagonist, daily from Day 6 of stimulation. In the study group, rFSH was discontinued when six follicles >or=12 mm were observed and estradiol levels were >600 ng/l; rFSH was subsequently replaced by low-dose hCG (200 IU/l daily). RESULTS Mean values (SD) for dose and duration of rFSH treatment in the control versus low-dose hCG group were 1617 (280) versus 1273 (260) IU rFSH [between-group difference -344, 95% confidence interval (CI) -483 to -205; P < 0.001], and 8.2 (1.6) versus 6.4 (1.3) days (-1.8, -2.6 to -1.1; P < 0.001), respectively. The mean number of metaphase II oocytes of 10.1 versus 8.9 (between-group difference -1.2, 95% CI -3.9 to 1.5) and the ongoing pregnancy rates of 10/35 (29%) versus 13/35 (37%) (between-group difference 8.6%; 95% CI -13.0 to 29.1%; P = 0.45) for control versus hCG, respectively, did not differ. CONCLUSION In this pilot trial, substitution of rFSH by low-dose hCG in the final days of COS leads to a reduction of FSH consumption whereas ICSI outcome, in terms of oocyte yield and ongoing pregnancy rate, remains comparable to the traditional regimen (ClinicalTrials.gov, trial number: NCT00750100).

Shorter CAG repeats in the androgen receptor gene may enhance hyperandrogenicity in polycystic ovary syndrome

Background. The main goal of the present study was to assess the influence of the androgen receptor gene CAG repeat polymorphism on hyperandrogenism and its phenotypical features in patients with polycystic ovary syndrome (PCOS). Methods. CAG repeat lengths were analyzed in 97 oligo-anovulatory women with ultrasound features of PCOS. All individuals were assessed for endocrine parameters and their phenotypical features were recorded. These parameters were correlated with the CAG repeat lengths. Results. PCOS patients with a bi-allelic mean lower than 21 repeats had lower dihydrotestosterone levels (p = 0.007), lower androstenedione levels (p = 0.023), lower luteinizing hormone levels (p = 0.023), a lower luteinizing hormone/follicle-stimulating hormone ratio (p = 0.021) and the highest percentage of patients with acne and/or hirsutism (p = 0.021). Conclusions. Our findings support the hypothesis that the PCOS phenotype may result from either elevated androgen levels or an enhanced sensitivity to androgens caused by a more active androgen receptor.