Comparison of early versus late initiation of GnRH antagonist co-treatment for controlled ovarian stimulation in IVF: a randomized controlled trial.

STUDY QUESTION: What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? SUMMARY ANSWER: Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. WHAT IS KNOWN ALREADY: During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. STUDY DESIGN, SIZE, DURATION: This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). LIMITATIONS, REASONS FOR CAUTION: The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. STUDY FUNDING/COMPETING INTEREST(S): This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov, no. NCT00866034.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort.

BACKGROUND: Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS: We identified a nationwide historic cohort of 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997-1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS: After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16-2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62-6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25-14.33 and 2.14; 95% CI = 1.07-4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS: Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

Determinants of the choice for single or double embryo transfer in twin prone couples.

BACKGROUND: Some 84% of all European in vitro fertilisation (IVF) and intracytoplasmatic sperm injection (ICSI) cycles is performed with the transfer of more than 1 embryo, with 22% resulting in twin pregnancies. At many centres, the choice for one or more embryos is made through a shared decision-making process. To reduce the twin rate in a twin prone population by increasing the use of elective single embryo transfer (eSET), it is important to identify which objective patient factors are related to the choice for double embryo transfer (DET) and eSET. Therefore, the aim of this study was to identify determinants related to the choice for the transfer of eSET or DET in a twin prone population. METHODS: A retrospective study was performed on 477 twin prone couples at 2 Dutch IVF centres. We collected data on possible objective patient determinants, and a multivariate logistic regression analysis was performed to determine the impact of these determinants on the decision for DET. RESULTS: Of the twin prone couples, 61% opted for DET in their first IVF/ICSI cycle. Within the multivariate analysis, two objective patient determinants acted as a risk factor for the choice of DET - a lower number of available embryos (p=0.03) and a previous ongoing pregnancy after IVF/ICSI (p=0.04). The explained variance of the determinants was 3%. CONCLUSIONS: In twin prone couples, 61% still opted for DET in their first IVF/ICSI cycle. We identified 2 objective patient determinants for DET, but with an explained variance of only 3%. Therefore, further research is necessary to identify barriers and facilitators for eSET at both the level of the couples and clinicians.

[Ten years of results of in-vitro fertilisation in the Netherlands 1996-2005]. / Tien jaar resultaten van in-vitrofertilisatie in Nederland, 1996-2005.

OBJECTIVE: To present the numbers and results of Dutch IVF treatment from 1996-2005 and to describe trends and differences between centres. DESIGN: Retrospective data-collection, description and analysis. METHOD: The annual statistics from all Dutch IVF centres covering the years 1996-2005 were collected, described and analysed. RESULTS: During this period 138,217 IVF or intracytoplasmic sperm injection (ICSI) cycles were started and 14,881 transfers of frozen-thawed embryos (cryo transfers) were performed. The number of ICSI treatments, in particular, increased to more than 6000 cycles during this period. These treatments resulted in 30,488 ongoing pregnancies (22.1% per cycle started; 19.1% for IVF and 23.4% for ICSI). The ongoing pregnancy rate per cycle increased from 17.6% in 1996 to 24.4% in 2005. The increase after cryo transfers was remarkable (from 9.4% to 17.6%). It is estimated that during this period, about 1 in 52 newborns in the Netherlands was an IVF or ICSI child (1996: 1 in 77, 2005: 1 in 43). There were differences between the individual centres regarding the ongoing pregnancy rate per cycle (range: 15.0-26.4%), the percentage of ICSI (range 20-58%), the percentage of cryo transfers per cycle (range: 4-22%) and the multiple pregnancy rate (range 5-27% in 2005). CONCLUSIONS: In the Netherlands the pregnancy rate has increased over the last 10 years as has the number of IVF treatments. Cryo transfers have become increasingly important and the multiple pregnancy rate has decreased. Although thanks to the collaboration of all centres, the current registry produces important data and works well, there are a number of limitations e.g. the retrospective nature with no validation, which must be tackled over the coming years.

Pulsatile luteinizing hormone patterns in the follicular phase of the menstrual cycle, polycystic ovarian disease (PCOD) and non-PCOD secondary amenorrhea.

To characterize the oscillations of plasma LH in normally cycling and amenorrheic women, three groups of women were studied: I, normal women during the follicular phase of the cycle (n = 9); II, women with polycystic ovarian disease (PCOD; n = 11); and III, women with non-PCOD secondary amenorrhea (n = 12). Blood samples were obtained at 10-min intervals for 6 h on 2 separate days. A pulse was defined as an increase in LH at least 20% over the preceding lowest value (nadir). Since LHRH release immediately follows the nadir of the LH levels, the nadir interval (NI) was used for analysis. For analysis, the results from 1 day were selected at random from each subject, and from each day, the same number of NIs also were randomly selected. When two NIs from each patient were selected, the median NI was 75 min in group I, 45 min in group II, and 45 min in group III. When three or four NIs were chosen, the median NI was 60 min in group I, 50 min in group II, and 40 min in group III. The differences between the groups were statistically significant. When three NIs were selected, the mean of the corresponding LH amplitudes was 2.8 U/liter in group I, 6.0 U/liter in group II, and 1.5 U/liter in group III. The differences between these groups were statistically significant. Thus, the NI in PCOD patients was shorter than that during the follicular phase of the cycle, but this short NI is not unique for PCOD, since the NI in non-PCOD secondary amenorrhea patients was even smaller. The LH amplitude was higher in PCOD and lower in non-PCOD secondary amenorrhea compared to that during the follicular phase of the cycle. The decrease in NI in PCOD and/or non-PCOD secondary amenorrhea vs. the NI of the follicular phase could be explained by either a higher frequency of LHRH pulses from the hypothalamus or an increased sensitivity of the pituitary leading to a greater response of the pituitary to LHRH pulses.

The staging of peritoneal endometriosis by the type of active lesion in addition to the revised American Fertility Society classification.

OBJECTIVE: To evaluate changes in peritoneal endometriosis by the type of lesion in comparison with the scoring system of the revised American Fertility Society (AFS) classification. DESIGN: Prospective evaluation at laparoscopy before and 6 months after discontinuance of a 3-month medical therapy with either dydrogesterone or danazol. SETTING: A general hospital. PATIENTS: Forty cycling women with endometriosis and infertility. Fourteen patients could be fully evaluated by their revised AFS score and type of peritoneal lesion. INTERVENTIONS: Laparoscopy before and 6 months after discontinuance of medical therapy. MAIN OUTCOME MEASURE: Revised AFS score and type of peritoneal lesions. RESULTS: The revised AFS score decreased or remained unchanged in 13 of 14 patients, whereas red papular or vesicular lesions were present at both laparoscopies in 5, absent in 4, disappeared in 3, and appeared de novo in 2. A changing pattern also was seen in other types of small peritoneal lesions. CONCLUSION: In contrast with the revised AFS score, the study of the type of peritoneal lesions shows a changing pattern of activity. The significance in pathophysiological and clinical studies should be investigated further.

A randomized controlled study comparing the endocrine effects of pulsatile intravenous gonadotropin-releasing hormone after gonadotropin-releasing hormone agonist pretreatment versus clomiphene citrate in patients with polycystic ovary syndrome.

OBJECTIVE: To compare the endocrine changes in the follicular phase in infertile patients with polycystic ovary syndrome (PCOS) treated with either pulsatile IV GnRH after GnRH-agonist (GnRH-a) down-regulation or clomiphene citrate (CC). DESIGN: Subgroup analysis within a randomized, controlled, multicenter study. SETTING: Women referred to the Infertility Clinic, Catharina Hospital Eindhoven, The Netherlands. PATIENT(S): Twenty-eight infertile patients with PCOS. INTERVENTIONs): Patients were randomly assigned to pulsatile IV GnRH (10-20 microgram/90 min) after GnRH-a down-regulation or CC (50-150 mg; cycle days 3-7). Patients were monitored on alternate days with ovarian sonography and serum concentrations of E(2), LH, and FSH. Serum P and sonography confirmed ovulation. MAIN OUTCOME MEASURE(S): Serum concentrations of E(2), LH, and FSH were assessed before treatment was started and after each ovarian sonography. RESULT(S): In ovulatory cycles, no statistically significant differences were observed during the follicular phase comparing serum concentrations of E(2), LH, and FSH between the treatments. However, a significant increase in LH occurred in the GnRH group. CONCLUSION(S): No significant endocrine differences were observed between GnRH and CC treatment. However, there was a significant increase in the serum LH concentration during the follicular phase in the GnRH group. Increments of LH in the GnRH group may be due to recovery of endogenous LH secretion.

Ovarian hyperstimulation syndrome: facts and fallacies.

Severe or critical ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian hyperstimulation for assisted reproduction techniques (ART). The syndrome is characterized by cystic enlargement of the ovaries and fluid shifts from the intravascular to the third space. The morbidity in OHSS is mainly determined by the hemodynamic changes caused by increased capillary permeability. The incidence of OHSS depends on definitions, risk factors, ovarian stimulation protocols, luteal support and conception. Currently, research on the pathogenesis of OHSS is focused on increased capillary permeability. Several theories are reviewed. Until the pathogenesis of OHSS becomes clear, treatment is restricted to supportive therapy. The various proposals for management of OHSS are discussed and, based on the available data, directions for the management of various grades of OHSS are summarized. However, prevention and early recognition are still the most important tools to handle OHSS. A flowchart with preventive measures for OHSS is presented derived from the available literature.

Angiotensin sensitivity test revisited.

OBJECTIVE: To determine the validity of a single angiotensin sensitivity test as predictor of pregnancy-induced hypertension with special reference to the dietary sodium intake at the time of testing. METHODS: The angiotensin sensitivity test was successfully performed at 32 weeks' gestation in 104 women. In 90 of these women, the 24-h urinary sodium-creatinine ratio was known. Using an effective pressure dose of 10 ng/kg/min as the cutoff level, test characteristics were assessed in both the total population and after subdivision into a sodium restricted (n = 23) and an unrestricted diet group (n = 67). RESULTS: The incidence of pregnancy-induced hypertension was 13.4%. The number of positive angiotensin sensitivity tests was 7.5%. Test characteristics showed poor sensitivity (22.2%) and high specificity (94.8%); positive and negative predictive values were 40.0% and 88.7%, respectively. None of the sodium-restricted women was angiotensin sensitive. Sodium restriction did not have a significant influence on sensitivity, specificity, and predictive values of the test. CONCLUSION: The angiotensin sensitivity test is not an appropriate screening test to predict hypertensive disorders of pregnancy. No significant effect of dietary sodium restriction was found.

Initiation of spermatogenesis and successful in vitro fertilization in an infertile male with panhypopituitarism; superiority of pulsatile LH-RH over gonadotropins? A case report.

This case report describes an infertile male patient with panhypopituitarism, presumably caused by traumatic breech delivery. Previous hMG/hCG treatment had failed to induce spermatogenesis. Initiation of the production of motile and morphological normal sperm, despite persisting significant oligozoospermia was established with s.c. pulsatile LH-RH treatment. Spermatogenesis could be maintained with i.m. hCG injections bi-weekly. Later, fruitful in vitro fertilization (IVF) resulted in the birth of a healthy daughter.

Dynamics of immunoreactive endothelin plasma levels during ovarian stimulation for in vitro fertilization with and without dietary sodium restriction.

OBJECTIVE: To investigate the correlation between immunoreactive endothelin plasma levels and both the number and size of follicles and its relationship with the development of ovarian hyperstimulation syndrome, in in vitro fertilization cycles, with and without dietary sodium restriction. STUDY DESIGN: Randomized study in an assisted reproduction unit of a large teaching hospital. Data of 88 women form the basis of this report (45 ad libitum sodium intake and 43 dietary sodium restriction). Non-parametric tests were used for statistical analysis. RESULTS: Immunoreactive endothelin plasma levels neither correlate with the number of follicles, independent of their size, nor with the grade of ovarian hyperstimulation syndrome. Immunoreactive endothelin plasma levels decrease significantly in the luteal phase. These results are the same in both sodium diet groups. CONCLUSIONS: Immunoreactive endothelin plasma levels do not correlate with the number and size of follicles and they are not related to the development of ovarian hyperstimulation syndrome. These findings are independent of sodium intake.

[Pregnancy course and outcome in 2956 pregnancies after in-vitro fertilization in Netherlands]. / Beloop en uitkomst van 2956 zwangerschappen na in-vitrofertilisatie in Nederland.

OBJECTIVE: Description of the outcome of pregnancies after in vitro fertilisation (IVF) in Dutch IVF centers. DESIGN: Descriptive, retrospective. METHOD: Data were collected on IVF pregnancies in the period 1984-1992 from seven Dutch IVF centers. RESULTS: The study comprised 2956 pregnancies. Five centres provided data on 2133 ongoing and non-ongoing pregnancies. More than 25% ended in a spontaneous abortion (22.3%) or ectopic pregnancy (3.6%). From the seven centres there were data available on 2311 ongoing pregnancies. Of these, 30.8% were multiple; preterm delivery occurred in 29.2%. The birth weight of 40.6% of 3173 neonates was lower than 2500 g and that of 10.1% lower than 1500 g. A birth weight under the 10th percentile of the national reference curve was found in 16.7% and under the 2.3rd percentile in 4.3% of cases. Perinatal mortality was 31.3 pro mille. In 1588 singleton pregnancies preterm birth occurred in 15.6%; 41.3% of the singletons weighed less than 2500 g, of which 3.6% less than 1500 g while 12.3% had a birth weight below the 10th percentile. The results of our study are similar to those of other major studies in the literature and are unfavourable compared with to Dutch reference values. This is mainly due to the high proportion of multiple pregnancies. However, we found indications of a slight disturbance of pregnancy in IVF singleton and twin pregnancies.

[Results of in vitro fertilization in the Netherlands, 1996-2000]. / Resultaten van in-vitrofertilisatie in Nederland, 1996-2000.

OBJECTIVE: To describe the annual results in all 13 Dutch in vitro fertilisation (IVF) centres in the period 1996-2000, and to look for possible differences between individual centres and years. DESIGN: Retrospective data collection, description and analysis. METHOD: The results collected on the website of the Dutch Society of Obstetrics and Gynaecology (Dutch acronym: NVOG; www.nvog.nl) in the period 1996-2000 were integrated and described, with special attention to possible differences between centres and years. RESULTS: In 1996-2000 (5 years), 63,414 IVF or ICSI treatment cycles were started in the Netherlands, and 5,884 transfers of cryopreserved embryos were performed. The number of treatment cycles increased over the years, particularly the number of ICSI cycles. The total number of ongoing pregnancies was 12,991 (20.5% per started cycle; 22.5% for ICSI and 18.3% for IVF). Particularly during the first 3 years, there was an increase in these percentages (IVF: from 16.4% (1996) to 19.2% (1998); ICSI: from 18.3% (1996) to 23.9% (1998)). There were differences between the centres in both the percentage of ongoing pregnancies per started IVF/ICSI cycle (range 13.7-25.1%) and the percentage ICSI (14-61%) and cryo-transfers per total number of treatment cycles (0-26%). It was estimated that, during this 5-year period, 1 out of every 61 Dutch neonates resulted from IVF or ICSI. CONCLUSION: The pregnancy-rates after IVF and ICSI increased during the study period, and were comparable with the rates in other European countries. Some important data are still missing from the inventory, for example regarding the number of embryos per transfer, multiple pregnancies, live births, congenital malformations and complications.

A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility.

BACKGROUND: Controlled ovarian hyperstimulation with intrauterine insemination (IUI) is a widely accepted treatment for unexplained and male subfertility. No consensus exists about the drug of first choice to be used as hyperstimulation. This randomized multicentre trial using a parallel design compares the efficacy of clomiphene citrate (CC) with that of recombinant FSH (rFSH). METHODS: Couples with primary unexplained or male subfertility were randomized to receive CC or rFSH for ovarian hyperstimulation. The treatment was continued for up to four cycles unless pregnancy occurred. Cycles with more than three follicles were cancelled. Cumulative pregnancy rates and live birth rates were primary outcomes. Cancellation during treatment and multiple birth rates are secondary outcomes. Results were analysed following the intention-to-treat principle. RESULTS: Seventy couples with male subfertility and 68 couples with unexplained subfertility were included. Seventy-one women received CC, and 67 received rFSH. Twenty-seven pregnancies were observed in the CC group (38%) and 23 in the rFSH group (34.3%) relative risk (RR) 1.11 [95% confidence interval (95% CI) 0.71-1.73]. The live birth rate was 28.2% (20/71) and 26.9% (18/67) for CC and rFSH, respectively, RR 1.05 (95% CI 0.61-1.80). Overall, the live birth rates per cycle were 10% for CC-stimulated and 8.7% for rFSH stimulated cycles. The total multiple pregnancy rate was 6.0%. Thirty-five cycles (8.6%) were cancelled because of four or more follicles (CC, n = 17; rFSH, n = 18). CONCLUSIONS: In couples with primary unexplained or male subfertility participating in an IUI program, ovarian hyperstimulation can be achieved by CC or rFSH. No significant difference in live birth rates between CC and rFSH was observed. Being less expensive, CC seems the more cost-effective drug and therefore, can be offered as drug of first choice.

Two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia: Boucher-Neuhäuser syndrome.

We describe two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia, Boucher-Neuhäuser syndrome, a rare but distinct pleiotropic single gene disorder with an autosomal recessive pattern of inheritance. The cases presented illustrate that this syndrome is still poorly recognised. We provide a review and analysis of previously reported cases and the differential diagnosis, which might aid in the identification of additional cases.

The influence of dietary sodium restriction on renal and ovarian renin and prorenin production during ovarian stimulation.

In a prospective study, the effect of dietary sodium restriction on plasma and follicular fluid renin and prorenin concentrations and on fertilization measures was investigated during ovarian stimulation. In all, 18 women undergoing ovarian stimulation for in-vitro fertilization and embryo transfer were randomly divided into groups with and without sodium restriction. Plasma renin and prorenin concentrations were higher in the low sodium than in the normal sodium group. Plasma renin concentrations showed a mid-luteal rise. Plasma prorenin concentrations increased 4-fold on the day of oocyte retrieval, followed by a gradual decline to basal values. The low sodium group had more follicles than the normal sodium group. Neither follicular fluid renin and prorenin concentrations, nor the total amount of follicular fluid renin and prorenin per ovary differed significantly between the two groups. Oocyte yield and fertilization rates were similar in both groups. These rates were correlated with neither renin nor prorenin concentrations in follicular fluid. We conclude that sodium restriction did not influence cyclic plasma variation of renin or prorenin or follicular fluid renin and prorenin concentrations. In addition, fertilization rates were not affected by sodium restriction.

A quantitative structural model of the testis of fertile males with normal sperm counts.

The morphology of testicular biopsies of 8 healthy fertile men with proven normal sperm counts was studied using stereological techniques. Quantitative estimations were made of different cellular compartments in the testicular biopsies. The experimental errors of observation, homogeneity of the section, accuracy of the measurements and errors caused during the preparation of the sections were studied. A stereological model of the human testis comprising all compartments was designed. The present observations on the stereological parameters were compared with the results in literature; generally a good agreement was found. This stereological model enabled the authors to establish the quantitative correlations that exist between the separate compartments of the human testis. The tubular length density was positively correlated with the tubular surface density. The tubular surface density showed a negative correlation with the volume density of the germinal cell nuclei. The tubular volume density showed a negative correlation with the volume density of the Leydig cells. The intra-tubular volume density correlated negatively with the volume density of the Leydig cells and with the volume density of the remaining extra-tubular tissue. The intra-tubular tissue density correlated negatively with the volume density of the intra-tubular space.