Long-term outcome of patients undergoing in-vitro fertilisation in France: The outcome study.

The Outcome study examines the fate of 4083 patients beginning IVF in 41 IVF centres, between January 2010 and December 2013. Cumulative live birth rate per patient (CLBR), the best reflection of IVF efficacy, is rarely presented in publications as it requires long-term follow-up, including all successive cycles, and pregnancies outcome. Analysis of international publications shows an average CLBR of 41.6 % and a drop-out rate of 49.5 %, both greatly varying by country and IVF centres. Because of the frequency with which patients change centre (8%), the Outcome study distinguishes patients with a past history of IVF in another centre (CLBR=47.2 %) and patients undergoing their first true cycle (CLBR=56.4 %). Survival techniques by Competing Risk, intended to take account of drop-out and lost to follow-up, assessed the overall CLBR as being 65.4 %. Differences in performance between centres are considerable for both CLBR (32-64%) and Performance Index, taking account of the number of cycles required to achieve a pregnancy (2-5). Multiple variance logistic regression analysis shows that the indicators influencing performance are age, parity, number of oocytes, smoking habit and overweight. These indicators are independent each other and are influencing performance in a high significant way. After adjusting for these indicators, the differences between centres are reduced but remain large and very significant. No centre appears to have specific expertise in the management of patients with adverse indicators. The Outcome study therefore confirms that the large differences in performance between centres are not explained by a difference in the treated population.

Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol.

BACKGROUND: Steroid pre-treatments may be useful to program GnRH antagonist IVF/ICSI cycles. This prospective study assessed hormonal and ultrasound data collected during the free period after the discontinuation of three different pre-treatments to provide information on the optimal time interval required before starting stimulation. METHODS: Women were randomized to receive oral contraceptive pill (OCP) [ethinyl estradiol (E(2)) 30 microg + desogestrel 150 microg] (n = 21) or norethisterone 10 mg/day (n = 23) or 17-betaE(2) 4 mg/day (n = 25) or no pre-treatment (n = 24) for one cycle before IVF. Assessments were performed on post-treatment day (PD) 1, 3 and 5, or on spontaneous cycle day (CD) 1 and 3. RESULTS: After OCP and progestogen administration, FSH and LH concentrations shifted from strongly suppressed PD1 levels to PD5 values similar to those observed on CD1. Meanwhile, follicle sizes remained small up to PD5. In contrast, estrogen pre-treatment poorly reduced FSH levels on PD1 compared with OCP or progestogen. Consequently, follicle size was more heterogeneous. FSH rebound was maximal on PD3, whereas LH levels were slightly increased up to PD5. CONCLUSIONS: A 5-day free interval after OCP or progestogen offers the advantages of gonadotrophin recovery and homogeneous follicular cohort, whereas early FSH rebound occurring after estrogen pre-treatment argues for a short free period.

Luteal phase defects following agonist-triggered ovulation: a patient-dependent response.

The luteal phase (LP) of patients receiving triptorelin 0.1 mg to trigger ovulation was studied. Patients not pregnant in the first cycle with 0.1 mg were randomized into different groups for a second cycle: 0.1 mg again for patients who experienced a normal LP (group 1); patients affected with LP disorders were randomized into the following groups: 0.1 mg again (group 2); increasing dosage of triptorelin 0.5 mg once (group 3) or 0.1 mg three times (group 4); luteal support either with oral micronized progesterone (group 5) or human chorionic gonadotrophin (HCG) 1500 IU (group 6). Ovulation occurred in all cycles, but an inadequate LP was observed in 34.4% of the non-conceptional cycles. Patients demonstrating a normal LP as well as those affected with luteal disorders in their first cycle showed the same luteal pattern in their consecutive cycles triggered in the same way. In defective LP patients, increasing or repeating triptorelin doses did not restore the luteal phase or the pregnancy rate, both returning closer to normal after luteal support. Defective LP observed after agonist-triggered ovulation do not occur at random; therefore this patient-dependent response may be related to the personal characteristics of each patient's pre-ovulatory physiological surge profile.

Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study.

BACKGROUND: When administered in the late follicular phase to prevent an LH surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be detrimental for assisted reproductive technology cycle outcome. Therefore, a prospective study was designed to assess the effects of recombinant human (r)LH supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The protocol consisted of cycle programming with oral contraceptive pill, ovarian stimulation with rFSH and flexible administration of a single dose of cetrorelix (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed envelopes or according to woman's birth date) to receive (n = 114) or not (n = 104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG injection. RESULTS: The only significant difference was a higher serum peak E2 level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P < 0.001) whereas the numbers of oocytes and embryos as well as the delivery rate (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were similar in both groups. CONCLUSIONS: These results show that in an unselected group of patients, there is no evident benefit to supplement GnRH antagonist-treated cycles with rLH.

[Revisiting the clomifene-gonadotropin protocol in IVF with the use of a GnRH antagonist]. / Réhabilitation du protocole clomiphène-gonadotrophines en FIV par l'utilisation d'un antagoniste du GnRH.

OBJECTIVE: To assess the ability of GnRH antagonists to prevent LH surges during superovulation for IVF in classical stimulation protocols with clomiphene and gonadotropins. PATIENTS AND METHODS: Fifty-eight patients were treated with clomiphene (100 mg daily for 5 days starting on cycle day 2) and gonadotropins (225 UI HMG on cycle days 5, 7 and 9), with monitoring starting on cycle day 10. Cetrorelix, 0.25 mg, was administered daily when dominant follicle diameter reached 18 mm and/or plasma estradiol levels 800 pg/ml. RESULTS: No premature LH surge was observed during the 48 stimulation cycles completed. The pregnancy rate was 20.8% per punction and 25.6% per transfer, and there was no clinical ovarian hyperstimulation syndrome in these series. CONCLUSIONS: Cetrorelix, 0.25 mg, optimizes the classical stimulation with clomiphene and gonadotropins by preventing LH surges; the so-completed protocol yields acceptable pregnancy rates with lower hormone quantities and reduced risks of ovarian hyperstimulation, and becomes a convenient choice when "softer" treatments for IVF are considered.

[Comparison of different protocols of ovulation induction, by GnRH agonists and chorionic gonadotropin]. / Comparaison de différents protocoles de déclenchement de l'ovulation, par agonistes du GnRH et gonadotrophine chorionique.

OBJECTIVE: The aim of this study was to determine the best way of using a gonadotropin-releasing hormone agonist (GnRHa) for triggering ovulation and to analyse the reasons for short luteal phases. MATERIALS AND METHODS: Thirteen different regimens of GnRH-a administration were used to trigger ovulation using different dosages and either one, two or three administrations: triptorelin, buserelin spray, buserelin subcutaneously, leuprolide and nafarelin in 231 treatment cycles. Pregnancy rate and luteal phase duration were compared with those of a control group for whom ovulation was triggered with hCG. RESULTS: Ovulation with supraphysiologic elevation of both FSH and LH was achieved in the 13 GnRHa groups. For the five main groups analysed, GnRHa produced shorter and inadequate luteal phases than did hCG but no difference was found between agonists. Pregnancy rates were not statistically different between the agonist groups or in comparison with the hCG group. CONCLUSION: The use of GnRHa to trigger ovulation is efficient, despite short luteal phases, and has proven its utility in comparison with hCG. As the different modes of stimulation appear to yield comparable results, the cost of treatment should be a significant element to take into consideration.

[Difficult embryo transfers: contribution of echography]. / Transferts d'embryons difficiles: l'apport de l'échographie.

The aim of this retrospective study is to compare the results of embryo transfer in IVF without or after cervical dilatation, and trans-myometrial trans-vaginal transfer and after ultrasound-guided transfer. From 1989 to 1996 we have performed 4,355 embryo transfers to obtain 1,115 pregnancies. The results were 25.6% pregnancy by transfer and 10.9 embryos to start a pregnancy. During this time 281 transfers were appreciated as difficult or impossible and a cervical dilatation was done. We obtain 17.4% pregnancies by transfer with 16.5 embryos per pregnancy. We also practiced for the same indication 50 transmyometrial-transvaginal transfers. The result was 18% pregnancy by transfer and 16 embryos to start a pregnancy. In 1997 we have stopped cervical dilatations to prefer in these indications ultrasound-guided embryo transfer. 74 transfer were performed with this method to obtain 28.4% pregnancies per transfer and 9.9 embryos to start one pregnancy. This results are compared to a subgroup of women 38 years old or less, with a normal partner's sperm and in witch two embryos or more were transferred. At the end we think that the use of ultrasonography for embryo transfer is benefit in IVF program.

[Problems posed by oocyte donation organization]. / Problèmes posés par l'organisation du don d'ovocytes.

Ten years after the first pregnancy in France and 3 years after the setting of the law of Bioethic oocyte donation procedure is coming up against many difficulties (search of donors, cost, efficacy). We will try to consider all of them to prepare the way for an official recognition of this specific procedure of AMP.

Ongoing pregnancies after intracytoplasmic injection using cryopreserved testicular spermatozoa.

We report two clinical pregnancies occurring after intracytoplasmic sperm injection (ICSI) using cryopreserved spermatozoa obtained from testicular biopsy, made in two different infertility situations in our clinic. The first patient showed a secretory azoospermia associated with elevated serum follicular stimulating hormone (FSH) level and spermiogenesis maturation arrest. The second patient was affected by azoospermia resulting from bilateral epididymal obstruction. Spermatozoa present in the wet preparation of testicular biopsy made on the day of scrotal exploration were cryopreserved within the testicular tissue for both men. Intracytoplasmic injections were performed at a later date, using spermatozoa prepared from frozen-thawed tissues. In each case, three embryos were obtained and transferred in utero. The transfers resulted in a twin pregnancy for the first case, and in a singleton pregnancy for the second. Living foetuses were seen in the ultrasound scan at the 7th week and both pregnancies are proceeding to date beyond 30 weeks without complications.

[Age and fertility: value of endometrial co-cultures]. / Age et fertilité: apport des cocultures sur cellules endométriales.

Embryo coculture system may contribute to understand the mechanisms underlying the decrease of fertility with aging. We report here our experience of coculture on maternal endometrial cells and histology of endometrial biopsy in 90 patients with repeated failures of implantation. Histology dating failed to find any age related changes. In coculture system, it is obvious that embryo viability diminishes with aging, but for equal embryonic quality, the maternal age does not interfere significantly on pregnancy rate. Anyway the number of first trimester abortions seems higher in older women. Coculture system emphasizes the major role of oocyte aging in the decrease of fertility and may be useful to establish a prognostic in IVF for older patients.

Coculture of embryos on homologous endometrial cells in patients with repeated failures of implantation.

OBJECTIVE: To evaluate the value of coculture of embryos on endometrial cells in patients with repeated failures of implantation. DESIGN: A retrospective comparison of pregnancy rates between IVF-ET with coculture and standard culture methods. PATIENTS: Ninety patients with repeated failures of transfer (range 4 to 11) underwent IVF-ET for a variety of disorders. METHOD: Embryos were cocultured on homologous endometrial cells and transferred on day 4 after retrieval of oocytes. RESULTS: The overall pregnancy rate for these patients was 21% per transfer versus 8% in previous IVF-ET cycles. A higher percentage (28%) was obtained for women < 39 years of age or on transfer of at least one morula (32.5% pregnancy per transfer). CONCLUSION: Coculture of embryos on homologous endometrial cells is both safe and ethical. It appears to be a valuable approach for the selection of a good quality embryo before transfer. The technique should prove to be of benefit to patients with repeated failures of implantation and also may be of value for assessing the respective responsibility of endometrium and embryo in these repeated failures. However, the mechanisms underlying this improvement need to be determined to simplify the procedure.

Comparison between flare up and down regulation effects of luteinizing hormone-releasing hormone agonists in an in vitro fertilization program.

Luteinizing hormone-releasing hormone (LH-RH) agonists are being increasingly used in ovulation stimulation protocols in IVF programs. The results of two methods of utilization of LH-RH agonists are compared. In the long protocol, gonadotropin stimulation was commenced only after a preliminary period of pituitary desensitization with LH-RH agonist. In the short protocol, exogenous gonadotropins were administered shortly after the start of LH-RH agonist therapy, benefiting from the gonadotropin flare up effect. One hundred eighty-six patients were equally divided between the two treatments. There was no difference in the ovarian response on the day of human chorionic gonadotropin (hCG) or the number of mature oocytes recovered. The cleavage rate of mature oocytes was higher in the short protocol (70% versus 56% P less than 0.01). The ongoing pregnancy rate per treatment cycle was similar in both groups (18% in the long protocol and 16% in the short protocol). Analysis of the luteal phases revealed a trend for higher progesterone values in the long protocol although this was only significant on the 2nd day following oocyte retrieval. As the clinical results were similar, other factors should be taken into account when deciding therapy. These include patient convenience, cost, and side effects. Other schedules of ovulation stimulation with LH-RH agonists are discussed.

LHRH agonists in IVF: different methods of utilization and comparison with previous ovulation stimulation treatments.

LHRH agonists are being increasingly used in ovulation stimulation protocols in IVF programmes. We have compared the results of two methods of utilization of LHRH agonists. In the long protocol, gonadotrophin stimulation was only commenced after a preliminary period of pituitary desensitization with LHRH agonist. In the short protocol, exogenous gonadotrophins were administered shortly after the start of LHRH agonist therapy, benefiting from the gonadotrophin flare-up effect. One-hundred-and-eighty-six patients were divided equally between the two treatments. There was no difference in the ovarian response on the day of HCG or the number of mature oocytes recovered. The cleavage rate of mature oocytes was higher in the short protocol (70, versus 56, P less than 0.01). The ongoing pregnancy rate per treatment cycle was similar in both groups (18, in the long protocol and 16, in the short protocol). Analysis of the luteal phases revealed a trend for higher progesterone values in the long protocol although this was only significant on the second day following oocyte retrieval. As the clinical results were similar other factors should be taken into account when deciding therapy. These include patient convenience, cost and side-effects. Other schedules of ovulation stimulation using LHRH agonists are discussed.

[Gonadoblastoma. Review of the literature. Apropos of a case]. / Le gonadoblastome. Revue de la littérature. A propos d'une observation.

Gonadoblastoma, which was described for the first time by Scully in 1953, is a rare tumour of the gonads. Only about 150 cases have been reported. Anatomo-pathologically it shows itself by a combination of large primitive germinal cells, small cells which resemble the immature cells found in the granulosa and in the Sertoli and sometimes Leydig-theco interstitial cells. Calcification is suggestive. Gonadoblastomas usually develop in a dysgenetic gonad. Pure gonadic dysgenesis is more commonly found. The subjects usually are of feminine phenotype and can demonstrate somatic or sexual abnormalities. The caryotypes most frequently found are 46 XY or 45 XO/46 XY. It is rare for the Y chromosome to be absent. All patients with gonadoblastomas should be HY antigen positive. The tumour is benign but the germinal epithelium can change towards a seminoma type. Because of this it is wise to carry out laparotomy with removal of both adnexae if there is a gonadoblastoma present. The case we have studied illustrates the typical profile of a gonadoblastoma. It occurred in a young woman who had pure gonadic dysgenesis with a caryotype 46 XY (Swyer's syndrome). It was bilateral associated on the left side with a seminoma, and for this reason we carried out bilateral extirpation of the adnexae followed up by therapy with cobalt.