Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.

STUDY QUESTION: Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older? SUMMARY ANSWER: Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles. WHAT IS KNOWN ALREADY: In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting. STUDY DESIGN, SIZE, DURATION: A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the 'r-FSH and r-LH' and 'r-FSH only' groups respectively. LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment. WIDER IMPLICATIONS OF THE FINDINGS: Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older. STUDY FUNDING/COMPETING INTEREST(S): Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare. TRIAL REGISTRATION NUMBER: The trial was registered in the Dutch trial register (ISRCTN10841210).

Reproducibility of saline contrast sonohysterography for the detection of intracavitary abnormalities in women with abnormal uterine bleeding.

OBJECTIVES: Saline contrast sonohysterography (SCSH) is a diagnostic test for the examination of intracavitary abnormalities. The objective of this study was to calculate interobserver and intraobserver agreement for the interpretation of video recordings of SCSH procedures according to different levels of experience. METHODS: SCSH examinations were carried out by an operator experienced at performing SCSH and were recorded on video. To assess interobserver and intraobserver agreement, video material was scored by observers allocated to different groups according to their level of experience. Observers who had performed 25 or more SCSH procedures were defined as experienced (Group A), those who had carried out 1-24 as less experienced (Group B), and those with no experience of performing SCSH as inexperienced (Group C). All observers were blinded to the case histories of the patients. RESULTS: There was a significant difference in kappa values for interobserver agreement between the most experienced group and the less experienced observers. Group A, with the highest level of experience, had a mean kappa value of 0.62 (95% CI, 0.56-0.67), compared with 0.38 (95% CI, 0.33-0.43) in Group B and 0.47 (95% CI, 0.43-0.52) in Group C. The interobserver agreement in Group A was significantly higher than that in Groups B and C (P < 0.001 and P = 0.023, respectively), and Group C performed better than Group B (P = 0.024). Intraobserver agreement (n = 7) was good, with a mean kappa value of 0.66 (Group A, 0.63; Group C, 0.71). CONCLUSIONS: Interobserver agreement in interpretation of video recordings of SCSH by inexperienced sonographers is poor, whereas the intraobserver agreement is good. We consider the poor interobserver agreement to be due to non-uniform diagnostic criteria. Uniform diagnostic criteria for SCSH should be incorporated into the training of residents and other physicians performing these examinations.

The paradox of declining fertility but increasing twinning rates with advancing maternal age.

BACKGROUND: Advancing female age is associated with declining fertility potential due to decreasing numbers and quality of oocytes but also with a distinct increase in dizygotic twinning rates, a phenomenon that has never been explained. METHOD: An analysis of follicle development was made in 959 spontaneous ovulatory cycles of 507 women. RESULTS: Multiple ovarian follicular development (>1 follicle >14 mm) and, by implication, multiple rather than single ovulations occurred in 105 women whose mean age (36.1 versus 34.6 years) and mean basal FSH concentrations (10.3 versus 7.7 IU/l) were significantly greater than those with monofollicular development (P < 0.01). The prevalence of multifollicular development increased with age. CONCLUSIONS: Dizygotic twinning must be associated with the development of >1 large follicle, which we found to be a significantly more frequent occurrence in older women. It is hypothesized that the response of pituitary release of FSH to the decreased negative feedback induced by impending ovarian failure often 'overshoots', causing multiple follicular development. In the presence of two good-quality oocytes, a twin pregnancy may result.