Individualization of the starting dose of follitropin delta reduces the overall OHSS risk and/or the need for additional preventive interventions: cumulative data over three stimulation cycles.

RESEARCH QUESTION: Is individualization of dosing with follitropin delta in sequential ovarian stimulation cycles an effective preventive strategy for ovarian hyperstimulation syndrome risk? If so, for which patients does an individualized strategy provide the greatest OHSS risk reduction and/or the need for additional preventive interventions? DESIGN: A secondary analysis of three ovarian stimulation cycles in IVF/intracytoplasmic sperm injection patients included in one randomized, assessor-blinded trial comparing two recombinant FSH preparations (ESTHER-1, NCT01956110), and a second trial in women undergoing up to two additional cycles (ESTHER-2, NCT01956123). Of 1326 women (aged 18-40 years) randomized and treated with follitropin delta or alfa in cycle 1, 513 continued to cycle 2 and 188 to cycle 3. Follitropin delta and alfa doses were maintained/adjusted according to ovarian response in the previous cycle. RESULTS: Individualized dosing with follitropin delta significantly reduced moderate/severe OHSS and/or preventive interventions (P=0.018) versus conventional dosing with follitropin alfa in patients undergoing up to three ovarian stimulation cycles. The greatest benefit was observed in patients in the highest anti-Müllerian hormone (AMH) quartile (P=0.012). On evaluating separately, individualized dosing with follitropin delta significantly lowered the incidences of moderate/severe OHSS (P=0.036) and preventive interventions (P=0.044) versus follitropin alfa. CONCLUSION: An individualized follitropin delta dosing regimen decreased the risk of moderate/severe OHSS as well as the incidence of preventive interventions versus a conventional follitropin alfa regimen. An analysis per AMH quartile indicated that these statistically significant differences are driven mainly by patients with the highest pretreatment AMH levels.

Follitropin delta in repeated ovarian stimulation for IVF: a controlled, assessor-blind Phase 3 safety trial.

RESEARCH QUESTION: To evaluate the immunogenicity of follitropin delta in repeated ovarian stimulation. DESIGN: Controlled, assessor-blind trial in IVF/intracytoplasmic sperm injection patients undergoing repeated cycles of ovarian stimulation (cycles 2 and 3), following initial stimulation with follitropin delta or follitropin alfa (cycle 1) in a preceding randomized trial. In cycles 2 and 3, 513 and 188 women, respectively, were treated as randomized in cycle 1, with dosing based on ovarian response in the previous cycle. RESULTS: The incidence of treatment-induced anti-FSH antibodies with follitropin delta was 0.8% and 1.1% in cycles 2 and 3, respectively, which was similar to the incidence in cycle 1 (1.1%). No antibodies were of neutralizing capacity. Women with pre-existing anti-FSH antibodies were safely treated with follitropin delta without boosting an immune response. Treatment with follitropin delta and follitropin alfa gave similar outcomes for mean number of oocytes retrieved (9.2 versus 8.6 [cycle 2]; 8.3 versus 8.9 [cycle 3]), ongoing pregnancy (27.8% versus 25.7%; 27.4% versus 28.0%) and live birth rates (27.4% versus 25.3%; 26.3% versus 26.9%). The presence of anti-FSH antibodies did not affect the ovarian response. CONCLUSIONS: The trial demonstrated the low immunogenicity potential of follitropin delta in repeated ovarian stimulation, and confirmed the appropriateness of the follitropin delta dosing regimen in repeated cycles, with documented efficacy and safety.

Luteal phase progesterone and oestradiol after ovarian stimulation: relation to response and prediction of pregnancy.

Research has focused on optimizing luteal phase support and endometrial receptivity in ovarian stimulation cycles. In this study, serial endocrine measurements were taken in 600 patients after a gonadotrophin-releasing hormone antagonist stimulation protocol. On the day of blastocyst transfer, serum progesterone and oestradiol were similar irrespective of a subsequent positive or negative pregnancy test (median 99 ng/ml versus 103 ng/ml for progesterone, respectively) or a subsequent live birth or pregnancy loss. Serum progesterone was significantly correlated to each ovarian response parameter (total number of follicles, number of oocytes retrieved and oestradiol concentration; r = 0.45, 0.57 and 0.54 respectively, all P < 0.0001). These correlations were consistent irrespective of clinical outcome. On the day of the pregnancy test, these correlations had vanished except in the live birth subgroup showing a weaker correlation (r = 0.22, 0.27 and 0.32 respectively, all P < 0.005). The lowest HCG and progesterone levels associated with live birth were 59.3 IU/l and 12.3 ng/ml, respectively. Fourteen out of 92 patients (15.2%) with pregnancy loss had normal HCG but low progesterone levels (above and below their respective 5th percentile), and miscarried before the end of the 7th week, when the luteal-placental shift occurs.

Association between blastocyst morphology and outcome of single-blastocyst transfer.

The aim of this study was to assess the ability of three individual blastocyst morphology parameters - expansion and hatching (EH) stage, inner cell mass (ICM) grade and trophectoderm grade - to predict outcome of a cycle with single-blastocyst transfer. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 intracytoplasmic sperm injection patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist cycle with compulsory single-blastocyst transfer on day 5 were included. In the simple logistic regression analysis, all three blastocyst morphology parameters were statistically significantly (P<0.005 for each) associated with positive human chorionic gonadotrophin, clinical and ongoing pregnancy rates and live birth rates, while only the ICM grade was significantly (P=0.033) associated with early pregnancy loss rate. Blastocyst EH stage was the only significant predictor of live birth (P=0.002) in the multiple logistic regression. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the EH stage. Transfer of a blastocyst with ICM grade A may reduce the risk of early pregnancy loss. Choosing the embryo(s) with the best implantation potential is essential for securing each couple the highest chance of achieving pregnancy after assisted reproduction. The selection of embryo(s) for transfer at the blastocyst stage is based on morphology parameters of expansion and hatching stage, inner cell mass grade and trophectoderm grade. The aim of this study was to assess the relative impact of each parameter in predicting the probability of a successful outcome. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 patients who underwent single-blastocyst transfer on day 5 were included. Statistical analysis showed that all three blastocyst morphology parameters were significantly associated with positive human chorionic gonadotrophin (ßHCG), clinical and ongoing pregnancy rates and live birth rates. Only the inner cell mass grade was significantly associated with early pregnancy loss between the positive ßHCG test and confirmation of ongoing pregnancy 10-11weeks after transfer. The expansion and hatching stage was the only significant predictor of live birth in the multiple logistic regression analysis. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the expansion and hatching stage. Transfer of a blastocyst with inner cell mass grade A may reduce the risk of early pregnancy loss.

Gender difference in antidiuretic response to desmopressin.

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(C(max)) (P = 0.0183) and borderline significant for log(AUC) (P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 µg than for men. The ED(50) for men was modeled to be 43.2 µg and 16.1 µg for women, with the ED(50) men/women estimated to be 2.7 (1.3-8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 µg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-µg melt is an efficacious and safe dose, while for women a dose of 25 µg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.

Levamisole inhibits angiogenesis in vitro and tumor growth in vivo.

The synthetic anthelmintic compound Levamisole has previously been used in cancer treatment as an adjuvant in combination with 5-fluorouracil. Its mode of action remains unclear, but an immune-stimulatory effect has been suggested. Here, we show that Levamisole inhibits angiogenesis in vitro and tumor growth in vivo. In vitro, Levamisole specifically inhibits proliferation and differentiation of endothelial cells propagated in co-culture with fibroblasts. In vivo, Levamisole inhibits the growth in nude mice of a transplanted human tumor. The use of nude mice as tumor hosts permits the discrimination between the angiogenesis inhibitory effect of Levamisole and its assumed immune-stimulatory effect. Our findings support a possible therapeutic effect of angiogenesis inhibitors in the treatment of cancer and call for further investigations of the mechanism(s) underlying the anti-angiogenic effect of Levamisole.

[Disease outbreak monitoring system based on ambulance transport data]. / Monitorering af sygdomsudbrud på basis af akutte medicinske ambulancekørsler.

INTRODUCTION: Disease outbreak monitoring is relevant not only for naturally occurring diseases but also for detecting a biological terror event. Surveillance systems are already operational in Denmark, but none of these has the high update frequencies necessary for early warning, and the majority monitor specific infectious diseases. MATERIALS AND METHODS: An early-warning system for detection of disease outbreaks in Denmark based on ambulance transport frequency was developed and tested employing a biological outbreak scenario. RESULTS: The system, termed "Bioalarm", demonstrated an ability to adapt to minor statistical variations due to, e.g., mild influenza epidemics and at the same time to elicit an early warning in the event of a outbreak consistent with a bioterrorist attack. CONCLUSION: Bioalarm not only is relevant for early warning of a disease outbreak as a result of a biological attack but also facilitates early detection of naturally occurring outbreaks.