Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of Ovaleap® (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART)

Background: Pharmacokinetic studies with XM17 (Ovaleap®), a recombinant human follicle-stimulating hormone (r-hFSH, follitropin alfa), have demonstrated good safety and tolerability in healthy women whose endogenous FSH levels were down-regulated with a long agonist protocol. In these studies, Ovaleap® pharmacokinetics were dose-proportional and bioequivalent to the reference follitropin alfa product (Gonal-f®). The objective of the present study is to determine whether Ovaleap® is equivalent to Gonal-f® with respect to the number of oocytes retrieved in infertile but ovulatory women undergoing assisted reproductive technology (ART) therapy. Methods: This multinational, multicenter, randomized (1:1), active-controlled, assessor-blind, comparative study included infertile normally gonadotrophic women 18 to 37 years old with a body mass index of 18 to 29 kg/m2 and regular menstrual cycles of 21 to 35 days undergoing ART therapy. During a 5-day fixed-dose phase, women received 150 IU/day of Ovaleap® (n = 153) or Gonal-f® (n = 146), followed by an up to 15-day dose-adaptation phase during which doses could be adjusted every 3 to 5 days, up to a maximum of 450 IU/day. Ovaleap® was to be deemed equivalent to Gonal-f® if the two-sided 0.95 confidence interval (CI) for the difference in the number of oocytes retrieved fell within the equivalence range of ±3 oocytes. Results: Similar numbers of oocytes were retrieved in the 2 treatment groups. The mean ± SD number of oocytes retrieved was 12.2 ± 6.7 in the Ovaleap® group and 12.1 ± 6.7 in the Gonal-f® group (intent-to-treat [ITT] population). Regression analysis estimated a mean difference of 0.03 oocytes between the treatment groups (95 % CI: −0.76-0.82), which was well within the prespecified equivalence range of ±3 oocytes. Ovaleap® and Gonal-f® showed favorable and comparable safety profiles, with no unexpected safety findings. Conclusions: Ovaleap® has shown the same efficacy and safety as Gonal-f® for stimulation of follicular development in infertile women (up to 37 years of age) who are undergoing ART therapy. Trial Registration EudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901. Date of trial registration: 19 March 2010

Spermiogramm und Seminalplasma: Der andrologische Faktor

Zusammenfassung: Das Spermiogramm liefert als wenig standardisierte Methode nur grobe Informationen zur Diagnostik männlicher Subfertilität. Daher sollte außer bei hoch pathologischen Werten das Spermiogramm nicht als alleinige Entscheidungsgrundlage für die Therapie dienen. Therapeutisch können neben der ICSI (intrazytoplasmatische Spermieninjektion) bei einer männlichen Infertilität auch mit intrauterinen Inseminationen gute Ergebnisse erzielt werden. In Fällen, bei denen selbst die ICSI-Methode versagt, scheint die IMSI-Technik (intrazytoplasmatische, morphologische selektierte Spermieninjektion) vielversprechend zu sein. Unabhängig von der Behandlungsmethode ist es von entscheidender Bedeutung, eine möglichst gute Samenprobe zu gewinnen. Dabei ist es möglich, mit einfachen Methoden wie einer Verkürzung der Abstinenzzeit oder einer Probengewinnung zu Hause die Samenqualität entscheidend zu verbessern. Neueste Erkenntnisse zeigen, dass die Anwendung von Seminalplasma in der Reproduktionsmedizin das Endometrium rezeptiver macht und somit die Implantation des Embryos unterstützen kann. Auch Geschlechtsverkehr um den Zeitpunkt des Embryotransfers scheint die Behandlung positiv zu beeinflusse

Variations of Steroid Hormone Metabolites in Serum and Urine in Polycystic Ovary Syndrome after Nafarelin Stimulation: Evidence for an Altered Corticoid Excretion.

To evaluate the clinical relevance of testing pituitary-ovarian responses in patients suffering from polycystic ovary syndrome (PCOS) with the GnRH agonist nafarelin, a 1.2-mg dose of nafarelin was given intranasally to 19 women with PCOS and 15 healthy premenopausal women. The subsequent analysis of steroids in both serum and urine during the test was carried out at several time points for up to 24 h. Serum levels of 17 alpha-hydroxyprogesterone were elevated at all time points of the test in PCOS patients vs. controls [at baseline, 3.5 +/- 0.2 vs. 1.8 +/- 0.1 nmol/L (P < 0.001); at 24 h, 9.9 +/- 0.9 vs. 4.9 +/- 0.3 nmol/L (P < 0.001)]. Basal levels of androstenedione were higher in the patient group, but there was no significant change during the test in either group. Serum testosterone levels were also found to differ in PCOS patients compared with the control values at baseline (2.2 +/- 0.2 vs. 1.5 +/- 0.1 nmol/L; P < 0.05) and after nafarelin treatment (at 24 h, 3.2 +/- 0.4 vs. 1.8 +/- 0.2 nmol/L; P < 0.05). Serum estradiol levels rose significantly in both groups during the test; the posttest levels were significantly higher in PCOS than in controls. The PCOS patients displayed a significant increase in androgen and gestagen metabolites as well as in glucocorticoid metabolites excreted in the urine during the 24 h. In the control subjects, except for 17 alpha-hydroxypregnanolone, which rose significantly, none of the urinary steroids investigated showed relevant changes during the nafarelin test. The posttest excretion of allo-tetrahydrocortisol (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) and the increase in 17 alpha-hydroxypregnanolone excretion (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) were distinctly higher in PCOS patients than in the controls; the diagnostic sensitivity of the combination of both parameters was 89% at a 93% specificity. Thus, measurements of 17 alpha-hydroxyprogesterone levels in serum and of urinary allo-tetrahydrocortisol and 17 alpha-hydroxypregnanolone after nafarelin treatment make this stimulation test a valuable diagnostic tool for identifying PCOS patients. The significant changes in the excretion of urinary androgen and gestagen metabolites, unmasked by GnRH agonist stimulation, suggest a functional alteration of the pituitary-ovarian axis. The reason for the increased excretion of glucocorticoid metabolites after nafarelin stimulation remains to be clarified

Fertility preservation in >1,000 patients: patient's characteristics, spectrum, efficacy and risks of applied preservation techniques

Introduction: Data on the characteristics of female patients counselled for fertility preservation and the efficacy and risk of the applied procedures are still poor. We therefore analysed the registry of a network of 70 infertility centers which are involved in fertility preservation in Germany, Switzerland and Austria, called FertiPROTEKT (hhtp://www.fertiprotekt.eu). Materials and methods: 1,280 counselled patients (15-40years) were analysed regarding characteristics and different fertility preservation treatments before cytotoxic therapy in 2007-2009. Results: 34.8% of the counselled patients were diagnosed with breast cancer, 30.5% with Hodgkin's lymphoma, 25.4% with other malignancies and 9.3% with non-malignant diseases. 89.6% of the treated breast cancer patients were 25-40years of age, and 87.5% of the lymphoma patients were 15-30years of age. At the time of counselling, 85.3% of the breast cancer patients and 92.7% of the lymphoma patients were childless. 1,080 patients received a single or combined therapy such as GnRH agonists (n=823), cryopreservation of ovarian tissue (n=500), ovarian stimulation (n=221) and transposition of the ovaries (n=24). Only one severe complication, requiring postponement of the chemotherapy, was documented. In stimulated patients, 2,417 oocytes (mean n=11.6, SD±7.7) were received. Fertilisation rate per received oocyte was 61.3%. Conclusions: Fertility preservation programmes mainly involve women without children, diagnosed with breast cancer or Hodgkin's lymphoma. Fertility preservation techniques can be applied with low risk. The limited and age-dependant success rate of the different therapies require individualised approaches of single or combined fertility preservation technique

Cross-cultural comparison of fertility specific quality of life in German, Hungarian and Jordanian couples attending a fertility center

Background: Only a few studies have reported cross-cultural comparisons regarding psychosocial consequences of infertility. Differences between societies with different cultural backgrounds were revealed and seemed to be based on the importance of pronatalism. Our aim was to measure cross-cultural differences in fertility specific quality of life of infertile couples in Germany, Hungary and Jordan who attend a fertility center in a cross-sectional study. Methods: A cross-sectional study was conducted in one fertility clinic in Germany, in five fertility clinics in Hungary and in one fertility clinic in Jordan. Overall 750 couples (252 couples in Jordan, 246 couples in Germany and 252 couples in Hungary) attending the first medical infertility consultation were asked to fill out our questionnaire set. Fertility specific quality of life (FertiQoL) and sociodemographic differences were measured between couples from three countries. Results: Jordanian couples had the shortest relationship (5.8 ± 4.3 yrs.), though they reported the longest duration of child wish (4.2 ± 3.6 yrs.) and fertility treatments (3.0 ± 3.3 yrs.). The proportion of high education was considerably higher in Jordanian women and men (60 % and 66 %, respectively) compared to the other two samples. First, marked cross-country differences were obtained on Emotional, Mind/Body and Relational subscales of the FertiQoL, indicating that Jordanian couples reported poorer fertility-related quality of life than Germans and Hungarians (p < 0.001). After controlling for the sociodemographic and medical variables, a significant difference only in the Emotional domain was observed (p < 0.001). Conclusions: The study revealed only a few cultural based differences in fertility specific quality of life between the couples of the three countries. Thus, infertility counselors should pay attention to psychosocial problems rooted in individual sociocultural aspects of the infertile couple regardless of cultural stereotypes. Further studies should identify sociocultural factors within different subgroups of infertile patients instead of focusing different societies as a whole because intra-cultural psychosocial differences in experiencing infertility seem to be more important for the individual patient than intercultural differences

GnRH analogs do not protect ovaries from chemotherapy-induced ultrastructural injury in Hodgkin's lymphoma patients

Purpose: To determine the protective effect of gonadotropin-releasing hormone analogs (GnRHa) using several ultrasound and endocrine markers to detect ultrastructural ovarian damage in Hodgkin's lymphoma patients. Methods: Ten patients who had been treated for Hodgkin's lymphoma and had received GnRHa to protect ovarian function were matched with patients at similar age, who had received the same chemotherapy regimens without GnRHa. In addition, ten healthy women at the same age were matched to the study groups to compare ovarian markers. Blood samples were drawn to determine anti-Müllerian hormone, Inhibin B, follicle-stimulating hormone and transvaginal ultrasound scans were performed to determine antral follicle count and ovarian volume. All women were asked about their menstrual cycle pattern. Results: No difference was found when comparing the ovarian parameters of both study groups. Compared with healthy women, all ovarian parameters in the Hodgkin's lymphoma patients were significantly different. Conclusions: The results of this study demonstrate ultrastructural ovarian damage in Hodgkin's lymphoma patients irrespective of GnRHa co-treatment. These findings do not support previous studies, showing GnRHa to protect ovarian functio

ПРОБЛЕМИ ФОРМУВАННЯ ЕФЕКТИВНОГО ІМІДЖУ В СУЧАСНІЙ ПОЛІТОЛОГІЇ

Проаналізовані поняття та структура політичного іміджу, визначені компоненти ефективного іміджу політика, виділені складові елементи та закономірності побудови сучасної іміджевої стратегії.Analyzed the concept and structure of political image, the image identified components of effective policy, special elements and patterns of modern image strategy

Serum periostin levels in early in pregnancy are significantly altered in women with miscarriage

Background: Miscarriage is a common complication in pregnancy and there is still a lack of biomarkers usable in asymptomatic patients before the event occurs. Periostin (PER), whose levels rise particularly during injury or inflammation, has been shown to play an important local role in implantation and early embryonic development. As PER has been described as a biomarker in various medical conditions we intended to evaluate if changes in PER serum levels may help to identify women at risk for spontaneous abortion in the first trimester. Methods: Women between 18 and 42 years without confounding comorbidities who conceived by IVF/ICSI and ovarian hyperstimulation were analysed in the study after informed consent. Maternal serum samples from 41 patients were assessed at the time of pregnancy testing (PT) and the following first ultrasound checkup (US). Patients were subsequently divided in two groups: (1) patients with subsequent miscarriage in the first trimester (n = 18) and (2) patients with ongoing pregnancy (n = 23), allowing for statistical analysis and investigating the change of PER levels per individual. PER levels were measured using enzyme-linked immunosorbent assay. Statistical analysis was performed using the Fisher exact and Student’s t test. p ≤ 0.05 was considered to be significant. Results: There was no significant difference concerning possible confounders between the two groups. We did not find any significant difference in PER levels at the time point of PT or US. By investigating the interindividual changes of PER between the two time points however, we observed that patients with a following miscarriage showed increasing levels of PER at the time point of PT compared to US in contrast to patients with an ongoing pregnancy who demonstrated a decrease in PER levels. These alterations were significant in the absolute as well as in the relative comparison. Conclusion: The relative expression of PER between PT and US is significantly altered in asymptomatic women with subsequent miscarriage compared to women with ongoing pregnancy. Therefore systemic PER levels might represent a potential promising biomarker for the assessment of pregnancy outcome. Trial registration Not applicable

Concentration of rocuronium in cerebrospinal fluid of patients undergoing cerebral aneurysm clipping†

Background. This study assessed the concentration of rocuronium in the cerebrospinal fluid (CSF) of patients undergoing cerebral aneurysm clipping, and investigated whether the mode of administration (single bolus vs continuous infusion) influenced the CSF concentration. Methods. Twenty patients with subarachnoid haemorrhage were randomly allocated to receive a bolus dose (bolus group), or a bolus followed by a continuous infusion of rocuronium (infusion group) (n=10 for each group). Arterial blood and ventricular CSF were sampled 2 h after the rocuronium bolus. Samples were analysed by liquid chromatography electrospray ionization‐tandem mass spectrometry. Results. Rocuronium could be detected in all the CSF samples. The mean (range) CSF concentration was 2.2 (0.9-4.6) ng ml-1 in the bolus group and 12.4 (2.4-34.6) ng ml-1 in the infusion group; P<0.01. Conclusions. This study demonstrated that rocuronium, normally not considered to cross the blood-brain barrier, is regularly found in the CSF of patients undergoing cerebral clipping; continuous infusion of the drug led to higher plasma and CSF concentrations than after a single bolus dose. Br J Anaesth 2004; 92: 419-2