Usability and utility of the CONSORT calculator for FSH starting doses: a prospective observational study.

This prospective, multicentre, observational study assessed usability and utility (co-primary endpoints) of the consistency in r-hFSH starting doses for individualized treatment (CONSORT) calculator in French routine clinical practice. Physicians first planned their recombinant human follicle-stimulating hormone (r-hFSH) starting dose. The CONSORT calculator was then used to recommend a starting dose. Data were collected for 197 women aged 18-35 years undergoing ovarian stimulation. The usability rate was high: 44/45 (97.8%) physicians found CONSORT user-friendly and easy to use for ≥75% of patients. Utility data showed that physicians followed the CONSORT recommendation for 89/197 (45.2%) patients. Reasons given for not following the CONSORT-calculated dose (N = 108) included: the CONSORT-calculated dose was too divergent from the planned dose (48.1%; 52/108) and/or the CONSORT-calculated dose did not correspond to the patient profile (46.3%; 50/108). The mean ± SD starting dose of r-hFSH planned by physicians was 163.9 ± 51.2 IU; the mean (SD) starting dose recommended by the CONSORT calculator was 119.7 ± 20.9 IU and the mean (SD) dose actually prescribed to patients was 151.7 ± 51.1 IU. Despite low physician-reported utility in this study, post-hoc analyses suggest the CONSORT calculator has potential for use in routine clinical practice.

Psychological assessment of mothers and their assisted reproduction triplets at age 3 years.

The aim of this study was to examine the psychological well-being of mothers and the psychological development of their 3-year-old triplet children conceived by in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Comparisons were carried out between a sample of 10 families with IVF/ICSI triplets and matched groups of 15 families with IVF/ICSI twins and 30 families with IVF/ICSI singletons. The families were recruited from Follow-Up, a national organization in France that was established to study children conceived by assisted reproduction. Standardized measures of the mother's emotional well-being and of the children's psychological development were administered. Mothers with a multiple birth were found to experience greater difficulties in parenting than mothers of singletons, with no differences between mothers of triplets and mothers of twins. Regarding the children, there were no differences in emotional or behavioural problems between triplets, twins and singletons. However, the triplets and twins showed a delay in some aspects of language development in comparison with the singleton children.

[Ovulation induction]. / La stimulation de l'ovulation.

Ovulation induction, indicated in anovulatory women, is nowadays a major treatment in any cause of infertility. Ovulation induction can be designed to obtained one or two follicles or to obtain a controlled ovarian hyperstimulation. Mild stimulations are used for anovulatory patients or patient with dysovulation, or for intrauterine insemination. Controlled ovarian hyperstimulation aimed at obtaining high number of follicle in In Vitro Fertilization procedure. All ovulation induction should be strictly monitored to prevent complication and mainly multiple pregnancies and the ovarian hyperstimulation syndrome. All ovulation induction should take place after a careful work up of the couple to determine the cause of infertility. This allows to select the best treatment and to avoid complications.

Mifepristone is an effective oral alternative for the prevention of premature luteinizing hormone surges and/or premature luteinization in women undergoing controlled ovarian hyperstimulation for in vitro fertilization.

The present clinical study was conducted to investigate the effectiveness of a daily dose of 40 mg mifepristone in preventing premature LH surges in women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization and to study the effect of this antiprogestin cotreatment on endometrial receptivity. This was a prospective, open-label, randomized, exploratory study in 15 healthy volunteer oocyte donors who were randomly allocated to the experimental COH group, including mifepristone (group 1), or the control group, using a long protocol with GnRH agonists (group 2), in a ratio of 2:1, i.e. 10 and five subjects, respectively. In group 1, human chorionic gonadotropin (hCG) was randomly administered (group 1A) or was withheld (group 1B) at the end of stimulation, so that two subgroups of five subjects each were formed, differing in the final oocyte maturation trigger. In all patients receiving mifepristone, 50 mg progesterone were administered im at the time of hCG administration to counteract residual antiprogestogenic activity of mifepristone. Serum estradiol, progesterone (P), LH, and FSH levels were monitored in each patient on d 3 and 6 and every 48 h thereafter. Endometrial biopsies were taken 2 and 7 d after hCG or P administration. Endometrial tissue was processed and evaluated in a blinded fashion for endometrial dating and quantitative PCR of at least four genes known to be up-regulated in receptive endometrium. The total FSH dose and duration of treatment in the two arms of the study were similar. The mean LH levels on d 6 of stimulation and the day of hCG/P treatment in the mifepristone group were 0.8 +/- 0.7 and 0.5 +/- 0.6 mIU/ml, and those in control subjects were 2.4 +/- 3.8 and 2.0 +/- 1.7 mIU/ml, respectively. No LH surges were observed in any subject treated with mifepristone. Serum P levels on the day of hCG/P were below the cut-off level (1.2 ng/ml) in all subjects of the mifepristone group (range, <0.5 to 1.05 ng/ml). The mean numbers of cumulus-oocyte complexes retrieved were 11.6 +/- 6.6 and 19.6 +/- 11.8 in the subgroup treated with mifepristone and hCG and in the control group, respectively. The mean percentages of metaphase II, metaphase I, and germinal vesicle stage oocytes were 86.2, 6.9, and 3.4% in the mifepristone group and 68.4, 6.1, and 11.2% in the control group. In the mifepristone group that did not receive hCG and received P only at the end of stimulation, an endogenous LH surge was not observed nor were oocytes obtained. Histological evaluation of endometrial samples in patients treated with mifepristone and hCG (group 1A) confirmed normal development, whereas in patients treated with mifepristone only (group 1B), there was a complete arrest of the endometrial maturation. The expression patterns of glycodelin, IGF-binding protein-7, glutathione peroxidase-3, and solute carrier family 1 member 1 show a striking absence of up-regulation in patients treated with mifepristone (groups 1A and 1B) compared with controls (group 2). The results of this exploratory study provide evidence that mifepristone is effective for the prevention of premature LH surges and/or premature luteinization in women undergoing COH for in vitro fertilization. However, endometrial receptivity status requires additional evaluation after decreasing RU-486 doses before this strategy can be considered as a new alternative to GnRH agonist/antagonist treatment.

Evidence of early placental vascular anastomosis during selective embryo reduction in monozygotic twins.

OBJECTIVE: To describe selective embryo reduction of two triplet pregnancies with a monozygotic twin. DESIGN: Case reports. SETTING: Infertility unit of a Department of Obstetrics and Gynecology. PATIENT(S): Two patients treated with IVF-ET who had triplet pregnancies. INTERVENTION(S): Selective embryo reduction of monozygotic twins. MAIN OUTCOME MEASURE(S): Fetal heart beat. RESULT(S): During intracardiac injection of potassium chloride plus midazolam in one of the monozygotic twin fetuses, we observed an immediate diminution of the cardiac pulse rate of the second twin. This phenomenon was observed in both patients. CONCLUSION(S): These observations clearly indicate the presence of vascular anastomosis between the two fetuses of these monozygotic twins. Thus, use of toxic substance to reduce one of the two fetuses of a monozygotic twin pregnancy is contraindicated. In cases of triplets that include a monozygotic twin, it is safest to interrupt the evolution of the twin if selective reduction is desired.

Assessment of leukemia inhibitory factor levels by uterine flushing at the time of egg retrieval does not adversely affect pregnancy rates with in vitro fertilization.

OBJECTIVE: To assess intrauterine levels of leukemia inhibitory factor (LIF) by uterine flushing at the time of egg retrieval and to confirm that the procedure has no detrimental effect on pregnancy rates. DESIGN: Prospective study. SETTING: Assisted reproductive unit of a university hospital. PATIENT(S): Uterine flushing was performed in 148 IVF patients. The first 100 patients were compared with a matched control group. INTERVENTION(S): Uterine flushing at the time of egg retrieval. MAIN OUTCOME MEASURE(S): IVP-ET results, pregnancy rates, and intrauterine LIF levels. RESULT(S): Pregnancy rates were not different in the group of patients with (27%) or without uterine flushing (28%). Leukemia inhibitory factor was detected in 60 patients (46%). Pregnancy rates did not differ between patients' detectable LIF and those in whom LIF was undetectable. Mean levels of LIF were 30.1 +/- 49.3 pg/mL and 28.6 +/- 51.2 pg/mL in pregnant and nonpregnant patients respectively. CONCLUSION(S): The flushing procedure at the time of egg retrieval did not adversely affect pregnancy rates. Leukemia inhibitory factor was detected in 46% of patients at the time of egg retrieval, but no correlation were observed with better pregnancy rates in patients with detectable LIF. Mean LIF levels did not differ in pregnant and nonpregnant women. Access to endoluminal secretions of the endometrium during IVF-ET may represent a new research in human implantation.

How can chemical compounds alter human fertility?

The effects of environmental toxins, such as pesticides, solvents and industrial waste, on human and animal health have caused much public fear. The suggested mechanism of action for these xenobiotics is their capacity to interact with steroid hormones receptors, in particular those for estrogens and androgens. Concern was reinforced by the "historical" example of diethylstilbestrol, an estradiol mimetic causing genital cancer in girls exposed in utero. The real harm of these environmental xenobiotics is controversial. Some authors estimate that they do not reach sufficiently high concentrations to do damage and much experimental work has been done. In this review, we summarise the latest findings on the molecular mechanisms of action of three environmental toxicants, xenohormones, dioxin and glycol ethers and compare animal and cell experimental model data with epidemiological studies.

[Treatment of cancer in women and fertility preservation]. / Traitement du cancer chez la femme et préservation de la fertilité.

The progress observed in the treatment of cancer have increased the survival rate of patients. Therefore, the different aspects of quality of life are considered as more and more important. Fertility is one of the major concern of women surviving cancer. Chemotherapy and radiotherapy can alter gametes and reproductive function. For some patients, a method to preserve fertility potential can be proposed. In the patient who have a partner, embryo freezing is the most reliable method, but give a limited chance of pregnancy. Recent interesting data has been obtained with oocyte freezing but the teams succeeding in the method and the number of pregnancies obtained remains limited. Moreover these methods request the time to perform ovarian stimulation. Freezing of ovarian tissue is giving us lots of hopes. Ovarian stimulation is not necessary and allow the conservation of a large number of eggs. However it is requesting a surgical procedure and no pregnancy was obtained so far in the human species. If the different methods to preverve fertility were not possible to propose or failed, oocyte donation give a good chance of success. It is important to state that no matter which method is used, the success rate will be correlated to the integrity of the uterus which can be altered by the different treatments of cancer and especially by radiotherapy. Collaboration between the teams of oncology and reproductive medicine is a progress in the management of young cancer patients. The technical progress in the technique of ovarian tissue freezing and in vitro maturation of follicle could be determinant in the choices proposed to the patients.

Ovarian hyperstimulation syndrome prevention strategies: individualizing gonadotropin dose.

The choice of the gonadotropin starting dose is an important parameter to prevent the onset of ovarian hyperstimulation syndrome (OHSS). The vast majority of studies available propose decreasing the gonadotropin starting dose, but conflicting results confirm that simply reducing the dose is not sufficient to prevent OHSS. True and dependable individualization of the gonadotropin starting dose is not yet possible. Attempts have been made to select parameters that predict ovarian response and to model them in a scoring system or algorithm that would result in a recommended gonadotropin starting dose. The CONSORT (CONsistency in r-FSH Starting dOses for individualized tReatmenT) dosing algorithm individualizes recombinant human follicle-stimulating hormone doses for assisted reproduction technologies, assigning 37.5-IU increments according to easily available patient characteristics (basal follicle-stimulating hormone, body mass index, age, and antral follicle count) that have been proven to accurately predict ovarian response to ovarian stimulation. The use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in a preliminary study. Results of a prospective randomized study are awaited to see if this tool would allow individualization of the gonadotropin starting dose.

The antral follicle count: practical recommendations for better standardization.

OBJECTIVE: To provide recommendations for the standardized use of the Antral follicle count (AFC) which is used to predict ovarian response to gonadotrophin stimulation during assisted reproductive technology treatment. However, the nature of the follicles that are visualized by ultrasound and the competence of the oocytes held within are largely unknown. In addition, there is considerable variability in the clinical definitions and technical methods used to count and measure antral follicles in both published studies and clinical practice. DESIGN AND SETTING: In December 2007, specialist reproductive medicine clinicians and scientists attended a workshop in an effort to address these issues. Literature concerning the physiology and measurement of ovarian antral follicles was reviewed, clinical and technical considerations regarding antral follicle measurement were discussed, and an operational definition of AFC was developed. PATIENT(S): None. INTERVENTION(S): None. OUTCOME MEASURES: Simple recommendations were established for the standardization of AFC assessment in routine clinical practice. The basic clinical and technical requirements required for AFC evaluation were agreed upon, and a systematic method of measuring and counting antral follicles in routine practice was proposed. CONCLUSION(S): The use of a standardized approach according to the practical recommendations for antral follicle counting as presented is encouraged in future clinical trials and routine practice. The authors also advocate a systematic evaluation of these recommendations as standardized study data become available.

Women's views on Friendly IVF: a qualitative preliminary study.

OBJECTIVE: To study in the French Context women's experiences with a low-stimulation regimen of in vitro fertilisation (Friendly IVF) and to compare them with those of women undergoing standard IVF (S-IVF). POPULATION AND METHODS: Two assisted reproduction technology centers participated in this preliminary study. Patients'views were explored qualitatively. In-depth interviews were conducted at the end of the second monitored cycle. Twelve friendly IVF patients and 13 S-IVF patients participated in the study. RESULTS: The respondents indicated that the most positive aspect of Friendly IVF was the low doses of hormones used. Cancellation of cycles and failure of oocyte retrieval were perceived the most negatively. Women in the Friendly IVF group reported fewer side effects and expressed emotional distress less acutely than women in the S-IVF group. The Friendly IVF treatment was percieved as a first step, sustaining the hope of success with a standard treatment. CONCLUSION: Friendly IVF, as practiced in the center studied, represents a valuable alternative for most respondents as a first step in IVF treatment.

Pregnancy after in vitro fertilization-intracytoplasmic sperm injection obtained with a modified natural cycle in a BRCA1 mutation carrier.

OBJECTIVE: To report a successful pregnancy after a semi-natural IVF cycle for a BRCA1 gene mutation carrier. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 26-year-old patient with BRCA1 gene mutation. INTERVENTION(S): Semi-natural IVF cycle and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Pregnancy rate. RESULT(S): A modified natural IVF cycle was performed, resulting in pregnancy and delivery. CONCLUSION(S): A modified natural IVF cycle is an effective and safe solution for BRCA1 or BRCA2 mutation gene carrier women with couple infertility.

Artificial versus stimulated cycles for endometrial preparation prior to frozen-thawed embryo transfer.

The objective of this study was to compare the implantation rate, pregnancy rate and endometrial thickness of frozen-thawed embryo transfers using endometrial preparation with either an artificial cycle or stimulated cycle. This was a prospective randomized trial at a single academic IVF centre. Seventy-seven patients undergoing artificial cycles received oral oestradiol; patients with endometrium < 7 mm on day 9-10 were switched to vaginal oestradiol. Eighty-six patients undergoing stimulated cycles received recombinant FSH followed by human gonadotrophin hormone injection. Vaginal progesterone was begun 2 or 3 days prior to embryo transfer. There was no difference in implantation rate (8.5% versus 7.3%), pregnancy rate (16% versus 13%), cancellation rate (both 23%) or endometrium thickness (8.7 +/- 1.1 mm versus 8.7 +/- 1.0 mm) between artificial and stimulated cycles. Stimulated cycles had a higher incidence of thin endometrium (27% versus 5%, P < 0.01). In artificial cycles, patients switched to vaginal oestradiol had improved pregnancy rate (31%) versus patients who received oral oestradiol alone (13%) (P = 0.05). It is concluded that artificial and stimulated cycles produce comparable pregnancy rates, implantation rates, cancellation rates and endometrial thickness, although stimulated cycles have a higher incidence of thin endometrium. Vaginal oestradiol supplementation improved implantation rates.

Impact of gonadotrophins and steroid hormones on tumour cells derived from borderline ovarian tumours.

BACKGROUND: Conservative surgery is currently proposed for young patients with borderline ovarian tumours (BOT). For those experiencing infertility, the question of medically assisted procreation is raised. We have evaluated in vitro the proliferation of cultured BOT cells in response to FSH or estradiol (E(2)). METHODS: Primary cell cultures were prepared from BOT. The presence of FSH and E(2) receptors was evaluated by immunochemistry. Cultures in vitro were stimulated with FSH (40 and 200 mUI/ml) or E(2) (300 and 2000 pg/ml) for 96 h and proliferation was evaluated with the WST-1 test. RESULTS: Four primary cultures were obtained that expressed FSH and E(2) receptors to different extents. Growth was generally similar to controls when treated with either FSH or E(2) although 300 pg/ml E(2) caused a significant inhibitory effect on cell proliferation (P = 0.035). CONCLUSION: No stimulatory effect of FSH or E(2) on cultured BOT cells was found, despite the presence of receptors. Although preliminary, these results suggest that gonadotrophins and E(2) could be used in patients experiencing infertility after conservative surgery.

Do children born after assisted reproductive technology have a higher incidence of birth defects?

Recent studies seem to find a significant increase in the incidence of birth defects among children conceived with assisted reproductive technologies. Those data should lead to proper counseling of couples treated with these techniques.

Behavioral and cognitive development as well as family functioning of twins conceived by assisted reproduction: findings from a large population study.

OBJECTIVE: To establish the nature and extent of difficulties in parenting and child development in families with twins conceived by assisted reproduction. DESIGN: Comparisons were carried out between a representative sample of 344 families with 2- to 5-year-old twins conceived by IVF/intracytoplasmic sperm injection (ICSI) and a matched comparison group of 344 families with singletons from IVF/ICSI. One twin was randomly selected for data analysis to avoid the bias associated with nonindependence of measures. SETTING: A general population sample of IVF/ICSI families. PATIENT(S): Mothers and children. INTERVENTION(S): Mothers completed a questionnaire booklet. MAIN OUTCOME MEASURE(S): Standardized measures of the mother's psychological well-being (parenting stress, depression, and quality of marriage) and standardized measures of the child's psychological development (emotional/behavioral problems and cognitive development). RESULT(S): Mothers of twins showed significantly higher levels of parenting stress and depression than mothers of singletons and were significantly more likely to find parenting difficult and significantly less likely to obtain pleasure from their child. Regarding the children, there was no difference in the level of emotional or behavioral problems between twins and singletons. However, twins showed significantly lower levels of cognitive functioning. CONCLUSION(S): Greater difficulties in parenting and child development were experienced by IVF/ICSI families with twins than by IVF/ICSI families with singletons.

Patient-friendly ovarian stimulation.

The ultimate goal of successful IVF is the birth of a healthy child with no maternal complications. Advances in ovarian stimulation protocols using gonadotrophin-releasing hormone agonists (GnRHa) and high doses of gonadotrophins have resulted in increased oocyte numbers with improved pregnancy and birth rates. However, the efficacy of such therapy is controversial when measured against the potential side effects. These side effects include those arising from oestrogen deprivation during desensitization, complications associated with an increased risk of ovarian hyperstimulation syndrome (OHSS), and an increased possibility of multiple births. Additionally, the increased cost due to more frequent monitoring and increased drug dosage negatively impacts on patient care. Thus, refinements in drug regimens are needed not only to address these side effects, but also to target the quality, not the quantity, of oocytes. In studies comparing GnRH antagonist (GnRHnt) to GnRHa, patients receiving GnRHnt underwent a shorter induction using less gonadotrophin, the incidence of OHSS was reduced and they reported a better quality of life. While larger studies are needed to confirm these promising findings, it appears that milder stimulation protocols could represent an interesting option, at least for selected patients.

Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists.

BACKGROUND: The purpose of this study was to investigate whether luteal estradiol (E(2)) administration reduces follicular size discrepancies and enhances ovarian response in recombinant FSH (r-FSH)/GnRH antagonist protocols. METHODS: We studied prospectively 90 IVF-embryo transfer (ET) candidates who were randomly pre-treated with 17beta-E(2) (4 mg/day) from day 20 until next cycle day 2 (E(2) group, n = 47) or served as controls (control group, n = 43). On day 3, all women started r-FSH treatment. A single 3 mg dose of GnRH antagonist was administered eventually according to follicular maturation. Outcome measures were magnitude of size discrepancy of growing follicles on day 8 of r-FSH treatment and number of follicles >or=16 mm in diameter on the day of HCG. RESULTS: On day 8, follicles were smaller (9.9 +/- 2.5 versus 10.9 +/- 3.4 mm, P < 0.001) and their size discrepancies attenuated (P < 0.001) in the E(2) group compared with the control group. This was associated with more >or=16 mm follicles, mature oocytes and embryos in the E(2) group. CONCLUSIONS: Luteal E(2) administration reduces the pace of growth, improves size homogeneity of antral follicles on day 8 of r-FSH treatment and increases the number of follicles reaching maturation at once. Coordination of follicular development optimizes ovarian response to r-FSH/GnRH antagonist protocols and may constitute an attractive approach to improving their outcome.

Premature LH and progesterone rise in intrauterine insemination cycles: analysis of related factors.

Premature LH and progesterone surges are associated with different factors and hormonal modulators. The aim of the present study was (i) to investigate the clinical and laboratory factors and (ii) to highlight the importance of different stimulation protocols in associated premature LH and progesterone surges in intrauterine insemination (IUI) cycles. The study involved a retrospective investigation of 75 patients undergoing IUI for infertility treatment (135 IUI cycles) between 1996 and 2000, with initial serum LH concentrations >10 mIU/ml during ovarian stimulation. Ultrasound characteristics, follicular sizes, serum oestradiol, progesterone and LH concentrations and ovarian stimulation protocols were measured. There was a wide range of oestradiol serum concentrations (93-2245 pg/ml) and follicular size (12-25 mm). In 49.6% of cycles, the dominant follicle was <16.5 mm. Patients with >2 follicles measuring <15 mm had higher oestradiol serum concentrations (P = 0.008). Multiple regression analyses revealed no association between these variables and premature LH/progesterone surge. In conclusion, LH/progesterone surges cannot be predicted utilizing clinical parameters normally employed, e.g. ultrasound serum oestradiol assay or ovarian stimulation protocol. Patients with follicles >14 mm or more and with high numbers of small follicles and high oestradiol are at risk of a spontaneous LH surge. These variables can be used to time the administration of GnRH antagonist administration until better predictive factors are demonstrated.

Should diagnostic hysteroscopy be a routine procedure during diagnostic laparoscopy in women with normal hysterosalpingography?

The advantage of hysteroscopy (HSC) over hysterosalpingography (HSG) in the accuracy of the diagnosis of uterine cavity abnormalities that may cause or contribute to infertility has been shown by numerous studies. The aim of this study was to analyse the results obtained from diagnostic HSC performed routinely during diagnostic laparoscopy in the investigation of the infertile women, to evaluate the effectiveness of the procedure in the diagnosis of uterine causes of female infertility. Ninety-three infertile patients with normal uterine cavity as demonstrated in HSG underwent diagnostic laparoscopy and hysteroscopy in this infertility unit. The hysteroscopy showed a normal cavity in 80 cases (88%), giving a false-negative rate of 12% for HSG. The pathologies found included small adhesions (two cases), an arcuate fundus (two cases), an endometrial polyp (three cases), and endometrial hyperplasia was diagnosed in four cases. In the absence of a positive history or a radiographical suggestion of endometrial abnormalities, or both, HSC made little diagnostic contribution towards elucidating the cause of female infertility or to finding a pathology that could affect the chances of achieving a normal pregnancy. However, in view of the low complication rates, minimal time requirement, and a negligible effect on the post-operative course, HSC could be performed on all infertile patients undergoing diagnostic laparoscopy.