Ernesto Bosch

Obesity and the risk of spontaneous abortion after oocyte donation.

OBJECTIVE To determine whether obesity increases the risk of spontaneous abortion. DESIGN Retrospective study. SETTING Oocyte donation program at the Instituto Valenciano de Infertilidad in Spain. PATIENT(S) Seven hundred twelve cycles of recipients of ovum donation with known body mass index (BMI), good-quality embryo transfer, and absence of uterine pathology or clinical history of antiphospholipid antibodies or recurrent abortion. INTERVENTION(S) Recipients were divided in four BMI (kg/m(2)) groups: lean, with BMI <20 (n = 92; 12.9%); normal, with BMI = 20-24.9 (n = 398; 55.9%); overweight, with BMI = 25-29.9 (n = 172; 24.2%); and obese, with BMI >/=30 (n = 50; 7%). Clinical parameters were compared among the groups. MAIN OUTCOME MEASURE(S) Spontaneous abortion rates according to BMI. RESULT(S) No difference was found among the four BMI groups in any of the parameters of the cycle analyzed. The overall abortion rate was 15.8% (57 of 360). There were significant differences in abortion rates between the obese (38.1%), and the normal (13.3%) and overweight (15.5%) groups. When several cutoff BMI values were established (20, 25, and 30), only the obese women demonstrated a greater risk of abortion. Compared with the normal population, the obese group showed a significant fourfold increase in the risk of spontaneous abortion. CONCLUSION(S) Our findings confirm that obesity (BMI >/=30) is an independent risk factor for spontaneous abortion. Therefore, it would be advisable for obese patients to reduce weight before becoming pregnant.

Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis

BACKGROUND Elevated serum progesterone levels at the end of the follicular phase in controlled ovarian stimulation (COS) leads to a poorer ongoing pregnancy rate in IVF cycles due to reduced endometrial receptivity. The objective of this study was to use microarray technology to compare endometrial gene expression profiles at the window of implantation according to the levels of circulating progesterone. METHODS For this prospective cohort study, microarray data were obtained from endometrial biopsies from 12 young healthy oocyte donors undergoing COS with pituitary suppression by either gonadotrophin-releasing hormone (GnRH) agonists or antagonists, and recombinant FSH. On the day of recombinant chorionic gonadotrophin (rCG) administration, six women had serum progesterone levels (P) >1.5 ng/ml (study group) and six had serum P levels <1.5 ng/ml (control group). Endometrial samples were collected using a Pipelle catheter 7 days after the rCG injection. RESULTS Using the parametric test, we identified 140 genes significantly dysregulated (64 up- and 76 down-regulated) in the study group endometria compared with the control endometria, regardless of the GnRH analogue employed. These genes are related to cell adhesion, developmental processes, the immune system and others, which are all required for normal endometrial function development. Of the 25 gene targets previously proposed as markers for endometrial receptivity, 13 appeared over-regulated in the study group. CONCLUSIONS Our results reveal that elevated progesterone levels on the day of rCG administration can induce significant alterations in the gene expression profile of the endometrium.

Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis

OBJECTIVE To analyze the impact of LH administration on cycle outcome in ovarian stimulation with GnRH antagonists. DESIGN Randomized, open-label, controlled trial performed in two age subgroups. Recombinant (r) FSH versus rFSH + rLH administration was compared. SETTING University-affiliated private infertility clinic. PATIENT(S) Up to 35 years old (n = 380) and aged 36 to 39 years (n = 340), undergoing their first or second IVF cycle. INTERVENTION(S) Recombinant LH administration since stimulation day 1. MAIN OUTCOME MEASURE(S) Implantation rate, ongoing pregnancy rate. RESULT(S) In the young population, implantation rates were similar: 27.8% versus 28.6%, odds ratio (OR) 1.03 (95% confidence interval [CI] 0.73-1.47), as was the ongoing pregnancy rate per started cycle: 37.4% versus 37.4%, OR 1.0 (95% CI 0.66-1.52). In older patients, the implantation rate was significantly higher in the rFSH + rLH group: 26.7% versus 18.6%, OR 1.56 (95% CI 1.04-2.33). Ongoing pregnancy rates per started cycle were 33.5% versus 25.3%, OR 1.49 (95% CI 0.93-2.38). CONCLUSION(S) Recombinant LH administration significantly increased the implantation rate in patients aged 36 to 39 years. A clinically relevant better ongoing pregnancy rate per started cycle was observed, although the difference was not statistically significant. Patients younger than 36 years do not obtain any benefit from rLH administration.

Highly purified hMG versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists—a randomized study

BACKGROUND Highly purified hMG (hp-hMG) has recently shown better cycle outcome than the recombinant FSH (rFSH) when compared in GnRH agonist long protocol cycles. However, they have not yet been compared in GnRH antagonist cycles. METHODS A RCT comparing the ongoing pregnancy rate (primary end-point) in 280 patients undergoing IVF/ICSI after stimulation with hp-hMG or rFSH controlled with a GnRH antagonist. RESULTS No significant differences were observed between hp-hMG and rFSH in terms of the ongoing pregnancy rate per started cycle (35.0 versus 32.1%, respectively; P = 0.61); relative risk: 1.09 (95% confidence interval: 0.78-1.51; risk difference: 2.9%). No differences were observed for implantation, clinical pregnancy and pregnancy loss rates. More oocytes were obtained from patients receiving rFSH then hMG (14.4 +/- 8.1 versus 11.3 +/- 6.0, respectively; P = 0.001). Estradiol was higher at the end of stimulation in the hp-hMG group (P = 0.02), whereas progesterone was higher in patients stimulated with rFSH (P < 0.001). CONCLUSIONS A similar outcome was observed for hp-hMG and rFSH when used for stimulation in GnRH antagonist cycles. However, some differences were found in ovarian response in terms of oocyte yield and hormonal profile. Clinical Trials.gov TRIAL REGISTRATION NUMBER NCT00669786.

Endometrial quality in infertile women with endometriosis.

Several analyses in our infertility (IVF) and oocyte donation programs were carried out to gain clinical knowledge of the factors involved in the etiology of endometriosis‐associated infertility. We first compared the IVF outcomes in women with tubal infertility and endometriosis. The results indicated that patients with endometriosis had a poorer IVF outcome in terms of reduced pregnancy rate per cycle, per transfer, and reduced implantation rate per embryo replaced. We then evaluated embryo development in vitro in women with and without endometriosis who underwent IVF and embryo replacement 72 hours after oocyte retrieval. We observed that compared to controls, patients with endometriosis had a significantly reduced number of blastomeres per embryo as well as an increased incidence of arrested embryos in vitro. In subsequent studies we compared fertility parameters in patients receiving donor oocytes. We noted that when donor oocytes came from patients without known endometriosis, embryo development and implantation rates were similar in patients with and without endometriosis. However, when the results of oocyte donation were classified according to the nature of the oocytes donated, patients who received embryos derived from oocytes from women with endometriotic ovaries showed a significantly reduced implantation rate compared to the controls. Taken together, these observations suggest that IVF in patients with endometriosis may be related to alterations within the oocyte, which, in turn, result in embryos of lower quality with a reduced ability to implant.

Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone–stratified, dose–response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection

OBJECTIVE To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrations. DESIGN Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-<2.1 ng/mL]; high: 15.0-44.9 pmol/L [2.1-6.3 ng/mL]) trial. SETTING Seven infertility centers in four countries. PATIENT(S) Two hundred sixty-five women aged ≤37 years. INTERVENTION(S) Controlled ovarian stimulation with either 5.2, 6.9, 8.6, 10.3, or 12.1 μg of rhFSH, or 11 μg (150 IU) of follitropin alfa in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S) Number of oocytes retrieved. RESULT(S) The number of oocytes retrieved increased in an rhFSH dose-dependent manner, from 5.2 ± 3.3 oocytes with 5.2 μg/d to 12.2 ± 5.9 with 12.1 μg/d. The slopes of the rhFSH dose-response curves differed significantly between the two AMH strata, demonstrating that a 10% increase in dose resulted in 0.5 (95% confidence interval 0.2-0.7) and 1.0 (95% confidence interval 0.7-1.3) more oocytes in the low and high AMH stratum, respectively. Fertilization rate and blastocyst/oocyte ratio decreased significantly with increasing rhFSH doses in both AMH strata. No linear relationship was observed between rhFSH dose and number of blastocysts overall or by AMH strata. Five cases of ovarian hyperstimulation syndrome were reported for the three highest rhFSH doses and in the high AMH stratum. CONCLUSION(S) Increasing rhFSH doses results in a linear increase in number of oocytes retrieved in an AMH-dependent manner. The availability of blastocysts is less influenced by the rhFSH dose and AMH level. CLINICAL TRIAL REGISTRATION NUMBER NCT01426386.

Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients

BackgroundIn the last two decades, pregnancy rates for patients undergoing in-vitro fertilisation (IVF) have significantly increased. Some of the major advances responsible for this improvement were the introduction of controlled ovarian stimulation (COS) for the induction of multiple follicle development, and the utilisation of mid-luteal gonadotropin-releasing hormone agonists to achieve pituitary down-regulation and full control of the cycle. As a result, a combination of a gonadotropin-releasing hormone agonist with high doses (150-450 IU/day) of recombinant follicle-stimulating hormone has become the current standard approach for ovarian stimulation. However, given the heterogeneity of patients embarking on IVF, and the fact that many different drugs can be used alone or in different combinations (generating multiple potential protocols of controlled ovarian stimulation), we consider the need to identify special populations of patients and adapt treatment protocols accordingly, and to implement a more individualised approach to COS.DiscussionStudies on mild, minimal and natural IVF cycles have yielded promising results, but have focused on fresh embryo transfers and included relatively young patient populations who generally have the potential for more favourable outcomes. The efficacy of these protocols in patients with a poorer prognosis remains to be tested. When comparing protocols for COS, it is important to think beyond current primary endpoints, and to consider the ideal quality and quantity of oocytes and embryos being produced per stimulated patient, in order to achieve a pregnancy. We should also focus on the cumulative pregnancy rate, which is based on outcomes from fresh and frozen embryos from the same cycle of stimulation. Individualised COS (iCOS) determined by the use of biomarkers to test ovarian reserve has the potential to optimise outcomes and reduce safety issues by adapting treatment protocols according to each patients specific characteristics. As new objective endocrine, paracrine, functional and/or genetic biomarkers of response are developed, iCOS can be refined further still, and this will be a significant step towards a personalised approach for IVF.ConclusionsA variety of COS protocols have been adopted, with mixed success, but no single approach is appropriate for all patients within a given population. We suggest that treatment protocols should be adapted for individual patients through iCOS; this approach promises to be one of the first steps towards implementing personalised medicine in reproductive science.

Clinical factors affecting endometrial receptiveness in oocyte donation cycles.

OBJECTIVE To provide a summary of the actual knowledge about the clinical factors affecting the oocyte recipient (other than those associated with uterine cavity abnormalities) on the outcome of oocyte donation cycles. DESIGN Review of the literature. SETTING Information regarding the association between age, body mass index (BMI), endometrial priming, tobacco consumption, hydrosalpinx, and endometriosis/adenomyosis in oocyte recipients and the results of oocyte donation cycles. RESULT(S) Recipient age and the presence of hydrosalpinx are clearly associated with a poorer outcome in oocyte donation cycles. The negative impact of tobacco consumption has recently been confirmed. The exact relevance of an elevated BMI is under debate but it is likely that it determines a lower ongoing pregnancy rate (PR). Endometriosis may be significant for endometrial receptiveness in the context of a natural cycle, but no negative impact is detected when standard endometrial priming protocols are used in oocyte donation. The same may be true for adenomyosis, although its relevance to endometrial receptiveness is less clear. CONCLUSION(S) Accumulated knowledge in the field of oocyte donation has led to the recognition of clinical variables that affect cycle outcome by impairing endometrial receptiveness. Many studies are being carried out on endometrial molecular and gene expression changes taking place in these circumstances. In the near future a comprehensive understanding of these processes should be achieved, from a genetic, molecular, and clinical perspective. These advances in the collective knowledge will lead to an improvement in the diagnosis and treatment of infertile patients.

Prospective study into the value of the automated Elecsys antimüllerian hormone assay for the assessment of the ovarian growing follicle pool

OBJECTIVE To evaluate a new fully automated assay measuring antimüllerian hormone (AMH; Roche Elecsys) against antral follicle count in women of reproductive age. DESIGN Prospective cohort study. SETTING Hospital infertility clinics and academic centers. PATIENT(S) Four hundred fifty-one women aged 18 to 44 years, with regular menstrual cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) AMH and antral follicle count (AFC) determined at a single visit on day 2-4 of the menstrual cycle. RESULT(S) There was a statistically significant variance in AFC but not in AMH between centers. Both AFC and AMH varied by age (overall Spearman rho -0.50 for AFC and -0.47 for AMH), but there was also significant between-center variation in the relationship between AFC and age but not for AMH. There was a strong positive correlation between AMH and AFC (overall spearman rho 0.68), which varied from 0.49 to 0.87 between centers. An agreement table using AFC cutoffs of 7 and 15 showed classification agreement in 63.2%, 56.9% and 74.5% of women for low, medium, and high groups, respectively. CONCLUSION(S) The novel fully automated Elecsys AMH assay shows good correlations with age and AFC in women of reproductive age, providing a reproducible measure of the growing follicle pool.

Moderate Ovarian Stimulation Does Not Increase the Incidence of Human Embryo Chromosomal Abnormalities in in Vitro Fertilization Cycles

CONTEXT A high chromosomal abnormalities rate has been observed in human embryos derived from in vitro fertilization (IVF) treatments. The real incidence in natural cycles has been poorly studied, so whether this frequency may be induced by external factors, such as use of gonadotropins for ovarian stimulation, remains unknown. DESIGN We conducted a prospective cohort study in a University-affiliated private infertility clinic with a comparison between unstimulated and stimulated ovarian cycles in the same women. Preimplantation genetic screening by fluorescence in situ hybridization was performed in all viable d 3 embryos. OBJECTIVE The primary objective was to compare the incidence of embryo chromosomal abnormalities in an unstimulated cycle and in an ulterior moderate ovarian stimulated cycle. Secondary outcome measures were embryo quality, blastocyst rate of biopsied embryos, number of normal blastocysts per donor, type of chromosomal abnormalities, and clinical outcome. RESULTS One hundred eighty-five oocyte donors were initially recruited for the unstimulated cycle, and preimplantation genetic screening could be performed in 51 of them, showing 35.3% of embryo chromosomal abnormalities. Forty-six of them later completed a stimulated cycle. The sperm donor sample was the same for both cycles. The proportion of embryos displaying abnormalities in the unstimulated cycle was 34.8% (16 of 46), whereas it was 40.6% (123 of 303) in the stimulated cycle with risk difference=5.8 [95% confidence interval (CI)=-20.6-9.0], and relative risk=1.17 (95% CI=0.77-1.77) (P=0.45). When an intrasubject comparison was made, the abnormalities rate was 34.8% (95% CI=20.5-49.1) in the unstimulated cycle and 38.2% (95% CI=30.5-45.8) in the stimulated cycle [risk difference=3.4 (95% CI=-17.9-11.2); P=0.64]. No differences were observed for embryo quality and type of chromosomal abnormalities. CONCLUSIONS Moderate ovarian stimulation in young normo-ovulatory women does not significantly increase the embryo aneuploidies rate in in vitro fertilization-derived human embryos as compared with an unstimulated cycle. Whether these results can be extrapolated to infertile patients is still unknown.