Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes.

OBJECTIVE: To assess the clinical pregnancy rate per transfer in recipients of embryos from donor oocytes obtained after ovarian stimulation initiated on day 2 (D2) or day 15 (D15) of the menstrual cycle with a secondary end point of comparing the response to stimulation. DESIGN: Prospective observational comparative study. SETTING: Private in vitro fertilization (IVF) program. PATIENT(S): Oocyte donors (OD) and recipients. INTERVENTION(S): Donors stimulated within 3 months, starting on day 2 or day 15 after bleeding, with recombinant follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH) antagonist, and GnRH agonist trigger, and oocytes vitrified and later assigned to recipients, followed by routine IVF procedures one to two embryos transferred. MAIN OUTCOME MEASURE(S): Primary outcome pregnancy rate, and secondary outcome number of mature oocytes retrieved. RESULT(S): Nine D2 and nine D15 cycles were performed in nine donors. There were no differences between D2 and D15 in the number of mature oocytes obtained (14.0±6.96 vs. 16.89±7.52). To date, 20 recipients have received vitrified oocytes (8 recipients received D2 oocytes and 12 recipients received D15 oocytes). There were no differences between the groups of recipients in fertilization rate (77.3% vs. 76.5%) or number of embryos transferred (1.50±0.53 vs. 1.67±0.65). Twelve clinical pregnancies were obtained. No differences were noted in pregnancy rates (62.5% vs. 58.3%) or implantation rates (41.67% vs. 45%) between recipients of D2 oocytes and recipients of D15 oocytes. CONCLUSION(S): Donor oocytes obtained after ovarian stimulation initiated on day 15 of the cycle achieve good pregnancy rates. This information is useful for patients with cancer undergoing fertility preservation. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01645241.

Live birth using vitrified--warmed oocytes in invasive ovarian cancer: case report and literature review.

This article reports the live birth of a healthy newborn using vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after insemination of warmed oocytes. Eighteen days after the transfer, she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. As far as is known, this is the first live birth reported through vitrified-warmed oocytes in a patient with invasive ovarian cancer. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, controversial issues are discussed. Fertility preservation is a proven possibility in some cancer patients according to their age, disease and time available until the beginning of their oncological treatment. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, no live birth has been reported. We report the live birth of a healthy newborn through vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after the insemination of the warmed oocytes. Eighteen days after the transfer she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. To our knowledge, this is the first live birth reported using vitrified-warmed oocytes in invasive ovarian cancer. Controversial issues are reviewed and discussed.

Investigations into implantation failure in oocyte-donation recipients.

In recent decades, the Western world has been experiencing a societal trend to prioritize the professional careers of women who postpone motherhood to about 40 years of age, when, unfortunately, natural reproductive potential declines. This is the reason why these women increasingly find it necessary to resort to oocyte donation to have a child. Thanks to the young age of the donors, the efficacy of oocyte donation is the highest of all assisted reproduction treatments and pregnancy rates achieved with this technique exceed 50%. Moreover, the large registries from ESHRE and ASRM show live birth rates close to this figure. However, there are patients who experience repeated failures in several oocyte-donation cycles, and so far oocyte-donation repeated implantation failure has not been clearly defined. This study analysed the results obtained from 2531 oocyte-donation cycles carried out in 1990 patients and defines oocyte-donation repeated implantation failure as failure to implant with more than two embryo transfers and more than four high-grade embryos transferred. This study observed this condition in 140 oocyte recipients (7%). Also, oocyte cohort size, uterine factors and systemic thrombophilias as important aetiological factors were identified were to offer new therapeutic strategies to patients.

Endometriosis and IVF: are agonists really better? Analysis of 1180 cycles with the propensity score matching.

OBJECTIVE: To compare the outcomes of patients with confirmed endometriosis undergoing in vitro fertilization (IVF)-embryo transfer (ET) treated with either gonadotropin-releasing hormone agonist (GnRHa) or gonadotropin-releasing hormone antagonist (GnRHant) using the propensity score (PS) matching. DESIGN: Observational, retrospective analysis from January 2000 to December 2010. SETTING: Private tertiary fertility clinic. PATIENT(S): Patients with endometriosis confirmed by ultrasound or surgery (American Fertility Society; AFS grades I-IV) that underwent an IVF-ET, stimulated with standard controlled ovarian hyperstimulation (COH) and GnRHa or GnRHant. INTERVENTION(S): A PS was assigned to all patients, which calculates the conditional probability of receiving a certain treatment; a higher PS (1) meant a higher probability of receiving treatment with GnRHa, and a lower PS (0) meant a higher probability of receiving GnRHant. The PS was calculated with a logistic regression model adjusted specifically for age, follicle stimulating hormone, antral follicle count and previous IVF cycles. All patients were divided into three groups according to their PS. MAIN OUTCOME MEASURE(S): pregnancy rate (PR) per cycle. RESULTS: 1180 patients were analyzed. Raw PR per cycle was 41.8% and 23.4%, and PR per ET was 44.3 and 27%, respectively. PR per cycle: 41.9 versus 30% in group A; in group B, 39.7% versus 36.4% and in group C, 15.4% versus 18.9%. The overall odds ratio for PR adjusted by PS was 1.10 [0.58-2.19]. CONCLUSIONS: After matching patients by PS, PR after COH with either GnRHa or GnRHant may be equally effective.

Is AMH useful to reduce low ovarian response to GnRH antagonist protocol in oocyte donors?

We aimed to establish the reference values of Anti-Müllerian hormone (AMH) in our oocyte donor population and correlate them with the ovarian response to an antagonist stimulation protocol and to study the predictive capacity of AMH for poor response (PR). Normal AMH curves were obtained for 172 candidates. AMH levels decreased with age although they showed great heterogeneity and spread in absolute values at any age range. AMH levels showed a positive correlation, statistically significant, with the Antral Follicle Count (r = 0,705), and number of oocytes retrieved (r = 0,356). In receiver operating characteristic curve analysis a threshold value of AMH = 2.31 ng/ml predictive for retrieval <6 MII (area under the curve (AUC) 0.675) was identified. This cut-off predicted PR with a sensitivity of 70.4% and a specificity of 61.8%, (PPV = 39.6%; NPV = 85.5%, p = 0.004). When performing a multiple logistic regression analysis including age, AFC and FSH, an AUC = 0.668 for PR was obtained whereas if AMH was added to the model it resulted in an AUC = 0.713. In oocyte donors aged 18 to 35 with an AFC ≥ 10 and basal FSH <10 mIU/ml, measuring AMH levels improved just slightly the prediction for PR.

Cancer and fertility preservation: Barcelona consensus meeting.

Improvements in early diagnosis and treatment strategies in cancer patients have enabled younger women with cancer to survive. In addition to the stressful event of the diagnosis, patients with malignant diseases face the potential loss of the opportunity to have children. Preservation of fertility has become a challenging issue and it is still surrounded by controversies. On the basis of available evidence, a group of experts reached a consensus regarding the options for trying to preserve fertility in women with cancer: among established methods, in postpubertal women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Combining several strategies on an individual basis may improve the chances of success. Realistic information should be provided before any intervention is initiated. Counseling should offer support for patients and provide better care by understanding emotional needs, psychological predictors of distress and methods of coping. Early referral to the fertility specialist is essential as fertility preservation (FP) may improve quality of life in these patients. The information summarized here is intended to help specialists involved in the treatment of cancer and reproductive medicine to improve their understanding of procedures available for FP in young cancer patients.

GnRH antagonist rescue of a long-protocol IVF cycle and GnRH agonist trigger to avoid ovarian hyperstimulation syndrome: three case reports.

OBJECTIVE: To describe three clinical cases involving patients at high risk of severe ovarian hyperstimulation syndrome (OHSS) during IVF stimulation. DESIGN: Description of clinical management of IVF cycles and outcomes in patients at risk of developing OHSS. SETTING: Reproductive medicine unit, private hospital. PATIENT(S): Three infertile patients undergoing stimulation for IVF/intracytoplasmic sperm injection presenting high risk of OHSS. INTERVENTION(S): IVF patients treated under long protocol presenting high risk of OHSS had their cycles rescued by withdrawing the agonist and replacing it with an antagonist and triggering ovulation with an agonist bolus. MAIN OUTCOME MEASURE(S): OHSS symptoms, pregnancy. RESULT(S): None of the three patients developed OHSS. One patient got pregnant after fresh embryo transfer, one patient got pregnant after frozen embryo transfer, and one patient had no oocytes retrieved despite the detection of LH in urine after the GnRH bolus. CONCLUSION(S): When a patient undergoing an IVF cycle with long protocol is at high risk of severe OHSS, rescuing the cycle by withdrawing the agonist and replacing it with an antagonist and triggering ovulation with an agonist bolus could be considered without jeopardizing the safety of the patient while retaining the opportunity for success of the cycle. Further broader studies are needed.

Gonadotrophin-releasing hormone-antagonists vs long agonist in in-vitro fertilization patients with polycystic ovary syndrome: a meta-analysis.

AIM: This article is a systematic review of the literature to establish whether there is an advantage in the use of GnRH antagonists (Ant) compared to the long agonist protocol (Ago) in patients with polycystic ovarian syndrome (PCOS). MATERIAL AND METHODS: The meta-analysis was conducted using the MIX software with Mantel?Haenszel weighting method and the fixed effect model. RESULTS: Five studies were identified. We analyzed 269 Ant and 303 Ago cycles. Pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS) were analyzed in all five studies, abortion rates were analyzed on three. Pregnancy rates did not differ between the groups: 137/269 (Ant Group) versus 172/303 (Ago Group) (OR: 0.80 CI: [0.57-1.11]). The incidence of OHSS per Ant (13/269) was significantly lower compared to the Ago (35/303) (OR: 0.47 CI: [0.24-0.92]). No difference was found between the two groups in the abortion rate: 10/77 (Ant Group) versus 9/88 (Ago Group) (OR: 1.29 CI: [0.49-3.36]). CONCLUSION: The limited evidence present in literature suggests that in patients with PCOS there is no difference between a long Ago and an Ant protocol in terms of pregnancy and abortion rates. It seems more likely that the use of the Ant may reduce the incidence of OHSS.

Endometriosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach.

Infertility is a common problem presented by patients with endometriosis. At present, whichever treatment is chosen, half of patients with advanced stages of the disease will remain infertile afterwards. This observational study looked at the reproductive outcome achieved after treating a group of 825 patients aged between 20 and 40 years with endometriosis-associated infertility during the period 2001-2008. Of the 483 patients who had surgery as the primary option, 262 became pregnant (54.2%). Among the patients who did not become pregnant, 144 underwent 184 IVF cycles and 56 additional pregnancies were obtained (30.4% clinical pregnancy rate per retrieval). It is notable that, before any treatment, patients with endometriosis had a poorer ovarian reserve than the control group. The combined strategy of endoscopic surgery and subsequent IVF led to a total of 318 pregnancies, which represents a combined clinical pregnancy rate of 65.8%. This percentage is significantly higher than that obtained with surgery alone (P < 0.0001), with 173 patients who were not operated on and who went to IVF as the primary option (P < 0.0001) and with 169 patients who had no treatment and achieved 20 spontaneous pregnancies (P < 0.0001).

Poor prognosis for ovarian response to stimulation: results of a randomised trial comparing the flare-up GnRH agonist protocol vs. the antagonist protocol.

OBJECTIVE: To determine the efficacy of the flare-up agonist and the antagonist protocols in patients with poor prognosis for ovarian response. METHODS: A randomised trial was conducted on two hundred and twenty-one women considered as having poor prognosis for ovarian response to stimulation, based on previous cycles or clinical criteria. All women were prospectively randomised into two groups of treatment (flare-up group and antagonist group) by computer-assisted randomisation in a 1:1 ratio. The main outcome measure was clinical pregnancy rate. RESULTS: Groups were homogeneous in age and baseline characteristics. Duration of stimulation, gonadotropin consumption, number of oocytes retrieved and number and quality of embryos transferred did not differ significantly between the groups. E(2) level the day of hCG administration was significantly higher in the flare-up group. Pregnancy rates per started cycle were 15% in the flare-up group and 14.1% in the antagonist group. Cancellation rates were 12.5% in the flare-up group and 16.3% in the antagonist group. None of these differences reached statistical significance. CONCLUSIONS: No statistically significant differences were observed between the two protocols regarding clinical pregnancy rates. In patients with poor prognosis for ovarian response, the flare-up agonist and the antagonist protocols were comparable regarding clinical pregnancy rates.

Use of letrozole in assisted reproduction: a systematic review and meta-analysis.

BACKGROUND: Letrozole is the third-generation aromatase inhibitor (AI) most widely used in assisted reproduction. AIs induce ovulation by inhibiting estrogen production; the consequent hypoestrogenic state increases GnRH release and pituitary follicle-stimulating hormone (FSH) synthesis. METHODS: A systematic search of the literature was performed for both prospective and retrospective studies. Meta-analyses of randomized clinical trials (RCTs) were performed for three comparisons: letrozole versus clomiphene citrate (CC), letrozole + FSH versus FSH in intrauterine insemination (IUI) and letrozole + FSH versus FSH in IVF. In the absence of RCTs, non-randomized studies were pooled. RESULTS: Nine studies were included in the meta-analysis. Four RCTs compared the overall effect of letrozole with CC in patients with polycystic ovary syndrome. The pooled result was not significant for ovulatory cycles (OR = 1.17; 95% CI 0.66-2.09), or for pregnancy rate per cycle (OR = 1.47; 95% CI 0.73-2.96) or for pregnancy rate per patient (OR = 1.37; 95% CI 0.70-2.71). In three retrospective studies which compared L + FSH with FSH in ovarian stimulation for IUI, the pooled OR was 1.15 (95% CI 0.78-1.71). A final meta-analysis included one RCT and one cohort study that compared letrozole + gonadotrophin versus gonadotrophin alone: the pooled pregnancy rate per patient was not significantly different (OR = 1.40; 95% CI 0.67-2.91). CONCLUSIONS: Letrozole is as effective as other methods of ovulation induction. Further randomized-controlled studies are warranted to define more clearly the efficacy and safety of letrozole in human reproduction.

Sonographic assessment of ovarian reserve. Its correlation with outcome of in vitro fertilization cycles.

Ovarian reserve is a crucial factor for normal ovarian response and the achievement of pregnancy after in vitro fertilization (IVF). Recently, the study of morphological markers by means of ultrasonographic counting of antral follicles (AFC) has proved useful. The present prospective study included 327 consecutive IVF patients who had a basal ultrasound scan of their ovarian reserve during the early follicular phase and had a first IVF cycle between 1 and 3 months later. We performed 313 ovum pick-ups with a mean of 11.1 +/- 7.9 oocytes retrieved. The pregnancy rate per aspiration was 34.5%. Clear and significant differences were observed between normal and low response with respect to AFC, follicle-stimulating hormone (FSH) level and age. We also found that AFC correlated negatively and significantly with age, FSH and LH, and positively and also significantly with the total number of follicles, estradiol level and the number of oocytes retrieved. Using receiver operating characteristic curves, the cut-off value of AFC for poor response was 7 follicles. The value of AFC for predicting pregnancy was lower, although patients with AFC of 8 or more follicles obtained significantly higher pregnancy rates. We consider that AFC should be included in the study of the infertile patient.

Use of a prediction model for high-order multiple implantation after ovarian stimulation with gonadotropins.

OBJECTIVE: To determine prospectively the effectiveness in clinical practice of a prediction model for high-order multiple pregnancies (HOMP) (triplets or more). DESIGN: Prospective study. SETTING: University teaching hospital. PATIENT(S): Eight hundred forty-nine consecutive infertile patients undergoing a total of 1,542 treatment cycles. INTERVENTION(S): Gonadotropin ovarian stimulation or induction of ovulation without IVF MAIN OUTCOME MEASURE(S): Observed and predicted overall pregnancy rates and the incidence of HOMP. RESULT(S): The use of the prediction model (implying cancellation of all cycles at high risk for HOMP) would result in an 8% (95% confidence interval, 6.8%-9.2%) reduction of overall pregnancy rate but also in a 285% (95% CI, 279%-291%) reduction of HOMP. CONCLUSION(S): By using our prediction model, it was possible to maintain a low risk of HOMP with a good pregnancy rate in patients receiving gonadotropin ovarian stimulation or induction of ovulation without IVF.

Serum progesterone concentrations on the day of HCG administration cannot predict pregnancy in assisted reproduction cycles.

The effect of subtle rises of progesterone in the late follicular phase of cycles of ovarian stimulation with gonadotrophin-releasing hormone (GnRH) agonists on pregnancy outcome is controversial. This study used receiver-operating characteristic (ROC) analysis to gain further insight into the predictive value of serum progesterone concentrations on the day of human chorionic gonadotrophin (HCG) injection in normally responding patients receiving the long protocol of GnRH agonist (group L; n = 218) and in low responders receiving the short ('flare-up') protocol (group S; n = 159). ROC analysis showed that serum progesterone concentration on the HCG day was not indicative of conception and non-conception cycles in the whole population studied, in group L or in group S. To further assess the potential impact of 'high' concentrations of circulating progesterone on the day of HCG administration on pregnancy rates and outcome, the threshold value (<0.9 ng/ml) to discriminate between women with 'high' (group H; n = 197) and 'normal' (group N; n = 180) progesterone was applied. No significant differences were found with respect to pregnancy and miscarriage rates between these two groups. Serum progesterone concentrations on the day of HCG administration therefore cannot predict pregnancy in assisted reproduction cycles using GnRH agonists and gonadotrophins.

The role of GnRH antagonists in assisted reproduction.

The different schemes of application of gonadotrophin-releasing hormone (GnRH) antagonists in ovarian stimulation protocols for assisted reproduction are reviewed. Starting from the initial schemes of single and/or multiple doses, the efficacy of GnRH antagonists in 'soft' protocols of ovarian stimulation has been evaluated in natural cycles, and the possibility of inducing the final oocyte maturation under antagonists either with native luteinizing hormone-releasing hormone or with GnRH agonists. The largest clinical studies carried out with cetrorelix or with ganirelix and published to date were analysed. Apart from the benefits of reducing the duration of the treatment, gonadotrophin requirements and ovarian hyperstimulation syndrome incidence, there is still a serious debate on the potential deleterious effect of GnRH antagonists on implantation and pregnancy rates. More specific aspects such as cycle programming, application of GnRH antagonists in protocols for poor responders etc., were also reviewed in this survey.