Abstract Background Small randomized clinical trials have found that patients with heart failure (HF) and atrial fibrillation (AF) randomized to an ablation strategy for AF experienced improved cardiovascular outcomes. We examined the relation in routine clinical practice. Purpose We aimed to assess if first-time pulmonary vein isolation ablation (PVI) for AF among patients with HF was associated with decrease in HF hospital admissions rates and furosemide dosage in the year after PVI compared with the year before. Methods We identified patients with HF and available left ventricular ejection fraction (LVEF) treated with a first-time PVI using the Danish Ablation Registry, and alive at 1-year follow-up. Patient comorbidities and concomitant pharmacotherapy (including furosemide dosage and HF hospital admissions) were identified utilizing Danish nationwide registries. For inclusion, patients were required to have been diagnosed with HF in an in- or outpatient setting <10 years of first-time PVI or have a LVEF at the time of PVI ≤45%. Patients were grouped according to LVEF at time of PVI: ≤35%, 36–45%, and >45%. For comparison of HF hospital admission and furosemide usage before and after PVI, McNemars test were used. Wilcox signed-rank test were used to test difference in furosemide dosage before and after PVI. Results We identified 668/3450 patients with HF treated with first-time PVI for AF between 2010–2017 (median age 62 years [Q1,Q3=56,69 years], 81% male, and median LVEF 45% [Q1,Q3=40,60%]). Of these, 13 patients (2%) died during one-year follow-up. Overall, 36% of patients with HF had one or more HF hospital admissions the year before PVI compared with 7% in the year after PVI (p<0.0001) (Figure 1). Patients with LVEF ≤35% had the highest proportion of HF hospital admissions the year before PVI (53%) and was reduced more than 4-fold (13%) in the year after first-time PVI, with consistent findings in all LVEF groups (Figure 1). At the time of PVI, 36% of patients with HF were treated with furosemide compared with 30% in the year after PVI (p<0.0001) (Figure 2). Moreover, we identified significant reductions in furosemide dose in the year after PVI compared with the year before (median dose 60 mg [Q1,Q3=30,80 mg] and 20 mg [Q1,Q3=0,60 mg], respectively, p=0.001). Here, reductions in furosemide requirements were consistent across LVEF subgroups. Conclusion Patients with HF treated with a first-time PVI strategy for AF had a 5-fold decrease in HF hospital admissions in the following year compared with the year before PVI. Among patients treated with furosemide at time of PVI, significant reductions in dose one year after PVI was identified but also significant reductions in proportion of patients requiring any furosemide at all. Funding Acknowledgement Type of funding sources: None.

This study investigated the combination of an unstimulated IVF cycle with in-vitro maturation (IVM) of additional immature cumulus–oocyte–complexes (COC) from the same cycle collected at the same time as the spontaneous preovulatory follicle. This could potentially improve rates of embryo transfer and pregnancy/live births compared with conventional unstimulated IVF treatment and at the same time eliminate the risk of ovarian hyperstimulation syndrome. This prospective trial included 77 women with regular menstrual cycles. Age at inclusion was between 20 and 37 years. Results showed a retrieval rate of mature oocytes of 50/80 (62.5%) per cycle started and immature COC were collected in 74/80 (92.5%) cycles. The embryo transfer rate was 28/80 (35.0%) with mature oocytes and increased in total to 43/80 (53.8%) with IVM oocytes. Corresponding birth rates per transfer were 3/28 (10.7%) and 4/43 (9.3%). Birth rates per aspiration were 3/76 (3.9%) and 4/76 (5.3%). It is concluded that the protocol described here shows proof of concept, but the impact of the IVM procedure only reached a significant level regarding embryo transfer, not with live births. The reason for this is yet unclear, but asynchrony between endometrial factors and IVM oocytes together with unknown competence of IVM embryos is suspected.For some time, there has been an increasing interest in mild approaches for fertility treatment, in particular IVF. In-vitro maturation (IVM) of immature eggs outside the ovaries followed by IVF is one of the potential treatments which eliminates the risk of ovarian hyperstimulation syndrome and minimizes the side-effects of medication. At the same time, natural-cycle IVF without hormonal stimulation is also experiencing a revival. By combining IVM and natural-cycle IVF, we aimed for to improve success rates in terms of more fertilized eggs to transfer and higher number of pregnancies and live births compared with sole natural-cycle IVF. At the same time, this project was a pilot study of eggs retrieved at this particular stage of the spontaneous menstrual cycle. Their reproductive capacity might be different from eggs retrieved in an earlier phase regarding maturation and fertilization capacity. The results showed that outcome was not better in the protocol combining IVM and natural-cycle IVF compared with natural-cycle IVF only. The reproductive capacity of the retrieved immature eggs seems less than reported in other IVM protocols. Though the combined concept of IVM and natural-cycle IVF is possible and there are ongoing pregnancies from both IVM and in-vivo matured eggs, we recommend either optimizing an IVM programme or using natural-cycle IVF rather than our original approach.

Objective: To detect differences in follicular fluid (FF) levels of amphiregulin (AR), depending on mode of triggering final oocyte maturation.Design: Prospective randomized trial.Setting: Three IVF units.Patient(s): Ninety-six patients undergoing IVF-intracytoplasmic sperm injection.Intervention(s): Ovulation triggered with either urinary hCG or GnRH agonist (GnRH-a). Controls: 15 FF samples from small antral follicles (3-9 mm) and 12 FF samples from natural cycle.Main Outcome Measure(s): Follicular fluid concentration of AR, P(4), E(2), vascular endothelial growth factor, and inhibin B.Result(s): Significantly lower levels of AR were found in FF from the GnRH-a group versus the hCG group, 51 +/- 3.5 versus 71 +/- 6.0 ng/mL. In FF from natural cycles, levels of AR were significantly higher than those of GnRHa triggering but significantly lower than those of urinary hCG triggering. In small antral follicles only 5 out of 15 follicles contained measurable amounts of AR. When urinary hCG and GnRH-a triggering were compared, FF P4 was significantly higher after urinary hCG triggering, whereas no difference was seen regarding E2, vascular endothelial growth factor, and inhibin B. A total of 14% more metaphase II oocytes and 11% more transferable embryos were obtained after GnRH-a triggering.Conclusion(s): This study suggests that oocyte competence is linked to granulosa cell AR secretion. (Fertil Steril (R) 2011; 95:2034-8. (C) 2011 by American Society for Reproductive Medicine.)

Objective: To prospectively assess the reproductive Outcome with a small bolus of hCG administered on the day of oocyte retrieval after ovulation induction with a GnRH agonist (GnRHa).Design: Prospective, randomized trial.Setting: Three hospital-based IVF clinics.Patient(s): Three hundred five WF/intracytoplasmic sperm injection patients after a GnRH antagonist protocol.Intervention(s): Ovulation induction was performed with either 10,000 IU hCG or 0.5 mg GnRHa (buserelin) supplemented with 1,500 IU hCG on the day of oocyte retrieval.Main Outcome Measure(s): Reproductive outcome in the two groups.Result(s): No significant differences were seen regarding positive hCG/ET rate (48% and 48%), ongoing pregnancy rate (26% and 33%), delivery rate (24% and 31%), and rate of early pregnancy loss (21% and 17%) between the GnRHa and 10,000 IU hCG groups, respectively.Conclusion(s): A small bolus of hCG in the GnRHa group secured the luteal phase, resulting in a comparable reproductive Outcome in the two groups. However, a nonsignificant difference of 7% in delivery rates justifies further studies to refine the use of GnRHa for Ovulation induction. (Fertil Steril (R) 2010:93:847-54. (C)2010 by American Society for Reproductive Medicine.)

We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(ε-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake.

Fragestellung: Bei Erwachsenen mit Typ-1-Diabetes konnte gezeigt werden, dass Insulindetemir im Vergleich zu anderen Basalinsulinen mit einer geringeren intraindividuellen Variabilität assoziiert ist. Diese randomisierte, doppelblinde, Crossover-Studie verglich die intraindividuelle Variabilität der pharmakokinetischen Profile von Insulindetemir und Insulinglargin bei Kindern und Jugendlichen mit Typ-1-Diabetes.

BACKGROUNDThe role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist.METHODSWe employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration.RESULTSThe LH treatment was associated with increased small antral follicles prior to FSH stimulation (P = 0.007), and an increased yield of normally fertilized (2 PN) embryos (P = 0.03). There was no influence of the r-hLH pretreatment upon hormone profiles or ultrasound assessments during the FSH phase. Anti-mullerian hormone increased in both groups during the week prior to FSH stimulation (P = 0.002).CONCLUSIONSThis sequential approach to the use of r-hLH in standard IVF showed a possible modest clinical benefit. The results support other recent work exploring up-regulated androgen drive upon follicular metabolism indicating that clinical benefit may be obtainable after further practical explorations of the concept.

The present data corroborate previous studies demonstrating a significant beneficial effect of acupuncture in IVF. A final proof of this effect, however, requires larger, prospective, placebo-controlled trials.

BACKGROUND: We aimed to determine the efficacy of ovarian hyperstimulation protocols employing a GnRH antagonist to prevent a premature LH rise allowing final oocyte maturation and ovulation to be induced by a single bolus of either a GnRH agonist or hCG. METHODS: A total of 122 normogonadotrophic patients following a flexible antagonist protocol was stimulated with recombinant human FSH and prospectively randomized (sealed envelopes) to ovulation induction with a single bolus of either 0.5 mg buserelin s.c. (n=55) or 10 000 IU of hCG (n=67). A maximum of two embryos was transferred. Luteal support consisted of micronized progesterone vaginally, 90 mg a day, and estradiol, 4 mg a day per os. RESULTS: Ovulation was induced with GnRH agonist in 55 patients and hCG in 67 patients. Significantly more metaphase II (MII) oocytes were retrieved in the GnRH agonist group (P < 0.02). Significantly higher levels of LH and FSH (P < 0.001) and significantly lower levels of progesterone and estradiol (P < 0.001) were seen in the GnRH agonist group during the luteal phase. The implantation rate, 33/97 versus 3/89 (P < 0.001), clinical pregnancy rate, 36 versus 6% (P=0.002), and rate of early pregnancy loss, 4% versus 79% (P=0.005), were significantly in favour of hCG. CONCLUSIONS: Ovulation induction with a GnRH agonist resulted in significantly more MII oocytes. However, a significantly lower implantation rate and clinical pregnancy rate in addition to a significantly higher rate of early pregnancy loss was seen in the GnRH agonist group, most probably due to a luteal phase deficiency.

Objective. To identify prognostic factors influencing the outcome of infertility treatment using homologous intrauterine inseminations (IUI-H). Design. Retrospective study of all patients undergoing IUI-H at the Fertility Clinic, Odense University Hospital from August 1st, 1990 to July 31st, 1998. Setting. University-affiliated infertility clinic. Patients. Eight hundred and ninety-three couples undergoing 2473 IUI-H treatment cycles. Infertility diagnosis, female age, number of follicles, type of hormonal treatment, length of follicular phase, endometrial pattern, and semen quality related to clinical pregnancy rate, cumulative birth rate and multiple gestations. Results . Throughout the nine year period the overall clinical pregnancy rate per IUI-H cycle was 11.9% with a significant increase from 8.7% in 1990 to 14.8% in 1998. The multiple birth rate was 18.1%. The birth rate per couple was 27.2% after a mean of 2.8 treatment cycles. The pregnancy rate was highest in the first treatment cycle and the cumulative birth rate rose only slightly after the fourth treatment cycle. Of the main outcome measures the following were positively and significantly related to a successful outcome of IUI: i) The first treatment cycle – compared to the following up to six treatment cycles; ii) number of mature follicles – up to five – at the time of insemination, however, with an unacceptable high rate of multiple pregnancies with more than 4 mature follicles; iii) use of CC/hMG-FSH as compared to CC only for ovarian stimulation; iv) number of motile sperms inseminated exceeding 5 million; v) time of insemination between the 13th and the 16th day in the cycle and vi) anovulatory or idiopathic infertility . Conclusions. IUI-H is a simple and inexpensive treatment giving acceptable pregnancy rates for up to four treatment cycles providing that at least 3 to 4 mature follicles have developed at the time of insemination, which implies that hormonal ovarian stimulation and induction of ovulation is used, that insemination occurs between cycle day 13 and 16 and that at least 5 million motile sperms are available for insemination. Our results indicate that in the presence of tubal pathology or less than 5 million motile sperms, the couples should be referred directly to IVF-treatment.

Objective. To identify prognostic factors influencing the outcome of infertility treatment using intrauterine insemination with donor semen (IUI-D). Design. Retrospective study of all patients undergoing IUI-D between August 1st, 1990 and July 31st, 1998. Setting. University-affiliated infertility clinic. Patients. Three hundred and five couples undergoing 1131 IUI-D treatment cycles. Main outcome measures. Type of hormonal treatment, number of follicles, length of follicular phase, endometrial pattern, female age, infertility diagnosis and semen quality related to clinical pregnancy rate, cumulative birth rate and multiple gestations. Results. Throughout the nine year period the overall clinical pregnancy rate per cycle was 22.3%, with an increase from 12.9% in 1990 to 34.6% in 1998. The multiple birth rate was 20.6%. The birth rate per couple was 61.1% after a mean of 3.2 treatment cycles. The pregnancy rate was highest in the first treatment cycle and the cumulative birth rate rose only slightly after the sixth treatment cycle. The following parameters were positively and significantly correlated to a successful outcome of IUI-D: i) the first treatment cycle – compared to the following up to six treatment cycles; ii) number of mature follicles – more than one – at the time of insemination, however, with an unacceptable high rate of multiple pregnancies when more than 3 mature follicles were present; iii) time of insemination after the 12th day in the cycle; iv) insemination after ovulation has occurred and; v) female age under 30 years . Conclusions. IUI-D is a simple and inexpensive treatment giving acceptable pregnancy rates for up to six treatment cycles if at least 2 mature follicles have developed at the time of insemination, which implies that hormonal ovarian stimulation and induction of ovulation is used, and ovulation has occurred at the time of insemination, which ought to take place after cycle day (cd) 12 with at least two million motile spermatozoa.

This prospective randomised study comprising 57 women undergoing IVF treatment evaluate the effect of exposure of oocytes to follicle stimulating hormone (FSH) and epidermal growth factor (EGF) during fertilisation and the first 24 hours of culture. Half of the oocytes (every other) were cultured in standard medium, while the other half received standard medium enriched with 25 IU/1 FSH and 2 ng/ml EGF. Thereby each woman served as her own control. The pre-embryo with the over all best morphology decided the group from which the maximal two pre-embryos for transfer was selected. The two groups were comparable with regard to all clinical parameters monitored. The number of oocytes, fertilisation rate, rate of pre-embryo formation and quality assessment of the pre-embryos was similar between the two groups. In contrast, the rate of positive hCG tests and the implantation rate were significantly augmented in the FSH/EGF group. It is suggested that FSH and EG-F may enhance nuclear and cytoplasmatic maturation of oocytes during conventional IVF treatment.

A multicentre, double-blind, randomized dose-finding study of Org 37462 (ganirelix) was conducted in 333 women undergoing ovarian stimulation with recombinant follicle stimulating hormone (rFSH; Puregon(R)) to establish the minimal effective dose preventing premature luteinizing hormone (LH) surges during ovarian stimulation. For ovarian stimulation, rFSH was given in a fixed daily dose of 150 IU for 5 days from days 2 to 6 of the menstrual cycle. From cycle day 7 onward, up to and including the day of human chorionic gonadotrophin (HCG), Org 37462 (dosages 0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/0.5 ml) was administered once daily by s.c. injection, and the rFSH dose was adjusted depending on ovarian response. The lowest (0.0625 mg) and highest (2.0 mg) dose groups were terminated prematurely on the advice of an external independent advisory committee. Serum Org 37462 concentrations increased in a linear dose-proportional manner, whereas serum LH and increases of oestradiol fell with increasing Org 37462 dose. During Org 37462 treatment, serum LH concentrations greater than or equal to 10 IU/l were observed in the lowest dose groups with incidences of 16% (0.0625 mg), 9% (0.125 mg) and 1.4 % (0.25 mg), On the day of HCG, the number of follicles greater than or equal to 11, greater than or equal to 15 and greater than or equal to 17 mm were similar in the six dose groups, whereas serum oestradiol concentrations were highest in the 0.0625 mg group (1475 pg/ml) and lowest in the 2 mg group (430 pg/ml), The median daily dose of rFSH was between 150 and 183 IU and the overall median duration of Org 37462 treatment was similar to 5 days in the six treatment groups. Overall, Org 37462 treatment appeared to be safe and well tolerated. The mean number of recovered oocytes and good-quality embryos was similar in all dose groups and ranged from 8.6 to 10.0 and 2.5 to 3.8, respectively. The mean number of replaced embryos in the different dose groups ranged from 2.3 to 2.7, The implantation rate was highest in the 0.25 mg group (21.9%) and lowest in the 2 mg group (1.5%). The early miscarriage rates (first 6 weeks after embryo transfer) were 11.9 and 13% in the 1 and 2 mg group respectively, whereas in the other dose groups this incidence was zero (0.0625%) up to a maximum of 3.7% (0.5 mg group). The vital pregnancy rate (with heart activity) at 5-6 weeks after embryo transfer was highest in the 0.25 mg group, i.e. 36.8% per attempt and 40.3% per transfer, and resulted in an ongoing pregnancy rate 12-16 weeks after embryo transfer of 33.8% per attempt and 37.1% per transfer. In conclusion, a daily dose of 0.25 mg Org 37462 prevented LH surges during ovarian stimulation and resulted in a good clinical outcome.

InhaltFlow‐cytometrische DNA‐Analyse von Granulosazellen aus superovulierten, bovinen, präovulatorischen FollikelnIn 68 Aspiraten aus präovulatorischen Follikeln von 14 superovulierten Kühen wurde der Anteil der Granulosazellen in der DNA‐S‐Phase des mitotischen Zyklus (“S‐Fraktion”) sowie die Konzentrationen von Progesteron und Östradiol‐17β in der Follikelflüssigkeit bestimmt. Zwischen der S‐Fraktion und den Konzentrationen der gemessenen Steroidhormone in der Follikelflüssigkeit ergaben sich signifikante Zusammenhänge. Die mitotische Aktivität der Granulosazellen, d.h. die S‐Fraktion, blieb bis zu 17 Stunden nach dem präovulatorischen LH‐Peak unverändert. Anschließend erfolgte ein signifikanter Abfall bis zur 21.—23. Stunde. Diese Befunde konnen zur Beurteilung der präovulatorischen Periode herangezogen werden. Die S‐Fraktion läuft sowohl mit den präovulatorischen follikulären Veränderungen als auch mit den Steroidkonzentrationelz der Follikelflüssigkeit parallel. Sie bietet dadurch eine Möglichkeit, das follikulare Stadium individuell ansprechen zu können. Indirekt ist damit auch eine Aussage über den Reifezustand der Oozyten möglich.