Rosa Tur

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.

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).

Triggering of ovulation by a gonadotropin releasing hormone agonist in gonadotropin-stimulated cycles for prevention of ovarian hyperstimulation syndrome and multiple pregnancy.

Ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies are the two main complications of ovulation induction using gonadotropins. Withholding an ovulatory dose of human chorionic gonadotropin (hCG) remains the safest option for prevention of both complications. However, this policy frustrates both patient and physician, wastes time and money due to cancelled treatment, and results in cancellation of a high proportion of cycles that would not have progressed to clinical OHSS. As gonadotropin releasing hormone analogs (GnRH-a) may elicit surges of endogenous luteinizing hormone and follicle stimulating hormone, we investigated the usefullness of a single s.c. injection of leuprolide acetate (0.5 mg) to trigger ovulation, without inducing OHSS or multiple pregnancy, in 23 consecutive gonadotropin-stimulated cycles which would otherwise have been cancelled. All patients had at least 4 mature follicles (> or = 14 mm in diameter) and plasma estradiol levels > 1000 pg/ml on the day of GnRH-a injection. No luteal support was given. Seventeen of the 23 (74%) cycles were ovulatory and four singleton pregnancies resulted, giving a pregnancy rate of 17.4% per cycle. The remaining six patients (26%) clearly had defective or short luteal phases. No patient developed OHSS. It is concluded that GnRH-a may be an acceptable substitute for hCG to salvage treatment cycles in patients thought to be at risk for OHSS or multiple pregnancy. However, further studies are necessary for optimization of this approach in order to improve ovulatory and conceptional results.

Elective single-embryo transfer in oocyte donation programmes: should it be the rule?

The aim of this study is to compare the cumulative clinical pregnancy and live birth rates (fresh embryo transfers followed by frozen-thawed embryo transfers from the same stimulated cycle) between single-embryo transfer (SET) and double-embryo transfer (DET) in an oocyte donation programme. A retrospective analysis of the outcome in 1139 recipient fresh cycles (1073 from DET and 66 from SET) with at least three available embryos for transfer was performed. The clinical pregnancy rates were similar after SET (45.5%, 30/66) and DET (57.1%, 613/1073), whereas the multiple pregnancy rate was 0% and 39.5% for SET and DET, respectively. After evaluating the results using the Kaplan-Meier survival analysis in a period of 1 year, no statistically significant differences were observed in the cumulative clinical pregnancy and live birth rates (SET 82.8% and 76.4% versus DET 77.2% and 63.7%). The results indicate that for women who have at least three available embryos in oocyte donation programmes, one single embryo should be transferred as no significant decrease in the success rate is observed and multiple pregnancy can be avoided. Clinical pregnancy rate is higher when transferring two embryos compared with one. However, this also results in a higher incidence of twin pregnancy, which is associated with increased obstetric and perinatal risks. The aim of this study was to compare the cumulative clinical pregnancy and live birth rates (fresh embryo transfers followed by frozen-thawed embryo transfers from the same stimulated cycle) between single-embryo transfer (SET) and double-embryo transfer (DET) cycles in our oocyte donation programme. A retrospective analysis of the outcome in 1139 recipient fresh cycles (1076 from DET and 66 from SET) with at least three available embryos for transfer was performed. The clinical pregnancy rates were similar after SET (45.5%, 30/66) and DET (57.1%, 613/1073), whereas the multiple pregnancy rate was 0% and 39.5% for SET and DET, respectively. The cumulative clinical pregnancy and live birth rates were similar between the two strategies (SET 82.8% versus DET 77.2%) and the same was found for the cumulative live birth rates (SET 76.4% versus DET 63.7%). Our results indicate that for women who have at least three available embryos in OD programmes, one single embryo should be transferred as no significant decrease in the success rate is observed while multiple pregnancy is avoided.

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.

Analysis of factors associated with multiple pregnancy in an oocyte donation programme

The aim of this study is to identify the factors associated with multiple pregnancy in an oocyte donation programme. A retrospective study (2000-2007) of 945 synchronous cycles was performed. Two embryos were transferred in all cycles on day 2 after oocyte retrieval. All variables (egg donor and recipient age, number of inseminated oocytes, fertilized oocytes, cleaved embryos, good-quality embryos available, good-quality embryos transferred and frozen embryos) were analysed in relation to the clinical pregnancy rate per transfer (PR) and the multiple pregnancy rate (MPR). The donor age was 26.8±4.5 years and recipient age was 41.0±5.4. The number of good-quality embryos per recipient was 3.1±2.5. The PR was 55.1% and the MPR 36.5%. The number of good-quality embryos transferred (2 versus 0) was significantly associated (P<0.05) with the PR (60.6% versus 43.5%). The relationship between the MPR and the number of good-quality embryos transferred was adjusted by donor and recipients age. For those patients who received 2 versus 0 good-quality embryos, the odds ratio of a multiple pregnancy was 2.1 (95% CI 1.121-3.876). The only predictive factor for multiple pregnancies in an oocyte donation programme is the quality of the transferred embryos. Since the development of assisted reproduction techniques, most countries have witnessed increased rates of multiple pregnancy. In IVF/intracytoplasmic sperm injection, effective strategies must be established to prevent multiple pregnancy without reducing overall pregnancy rates. In oocyte donation programmes, there is less awareness about the related risks. Actually, a minimum of two embryos are still transferred in most centres. The patients age is higher and this fact implies more obstetric and perinatal complications. The aim of this study is to identify the factors associated with multiple pregnancy to contribute to establish future guidelines to avoid those risks.

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.

Cancer and fertility preservation: Barcelona consensus meeting

Abstract 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.

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.

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.