Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders.

STUDY QUESTION: Does the gonadotropin (GN) starting dose and the addition of clomiphene citrate (CC) during the early follicular phase influence oocyte yield in poor responders undergoing ovarian stimulation for IVF treatment? SUMMARY ANSWER: The number of retrieved oocytes was similar regardless of the starting dose of GN (150 versus 450 IU) with or without the addition of CC (100 mg from Day 3 to 7 versus placebo). WHAT IS KNOWN ALREADY: ART in poor responders is a challenge for patients and clinicians. So far, randomised controlled studies addressing interventions have shown that neither the GN dose nor the addition of oral medication has any significant effect on the clinical outcome of ART in poor responders. There is limited knowledge about the effect of GN starting dose in combination with CC during the early follicular phase of ovarian stimulation on ovarian response markers and ART outcome. STUDY DESIGN, SIZE, DURATION: This single-centre randomised double-blinded clinical trial was conducted from August 2013 until November 2017. Using the Bologna criteria, 220 of 2288 patients (9.6%) were identified as poor responders and 114 eligible participants underwent ovarian stimulation in a GnRH-antagonist protocol for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were equally randomised to one of four treatment arms: Group A (n = 28) received 100 mg CC (Day 3-7) and a starting dose of 450 IU HMG, Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG, Group C (n = 30) received placebo and a starting dose of 450 IU HMG and Group D (n = 27) received placebo and a starting dose of 150 IU HMG. Serum levels of FSH, LH, estradiol and progesterone were measured on Day 1 and 5 and on the day of ovulation induction. Available embryos were cultured up to the blastocyst stage and were always transferred in the same cycle. The primary outcome was the number of oocytes collected after ovarian stimulation. Other outcome measures were response to ovarian stimulation, embryo development and obstetrical outcome. MAIN RESULTS AND THE ROLE OF CHANCE: All study participants (n = 114) fulfilled at least two of the Bologna criteria for poor responders. Median age of the study population was 38.5 years. There were 109 patients who underwent oocyte retrieval. The number of oocytes retrieved was similar among the groups (±SD; 95% confidence intervals); A: 2.85 (±0.48; 2.04-3.98), B: 4.32 (±0.59; 3.31-5.64); C: 3.33 (±0.52; 2.45-4.54); D: 3.22 (±0.51; 2.36-4.41); P overall = 0.246. However, ovarian stimulation with 150 IU plus CC resulted in a higher number of blastocysts compared to ovarian stimulation with 450 IU plus CC (±SD; 95% confidence intervals); A: 0.83 (±0.15; 0.58-1.2), B: 1.77 (±0.21; 1.42-2.22); P overall = 0.006. Mean FSH serum levels were lower in the groups with a starting dose of 150 IU. Adding CC did not affect mean serum FSH levels. There were no differences in estradiol concentrations among the groups. Endometrial thickness was lower in the groups receiving CC. The overall live birth rate (LBR) was 12.3%, and the cumulative LBR was 14.7%. LIMITATIONS, REASONS FOR CAUTION: The trial was powered to detect differences in neither the number of blastocysts nor the LBR, which would be the preferable primary outcome of interventional trials in ART. WIDER IMPLICATIONS OF THE FINDINGS: We found that ovarian stimulation with 150 IU gonadotrophin in combination with 100 mg CC produced more blastocysts. The effect of adding CC to GN on LBR in poor responders remains to be proven in randomised trials. High GN doses (450 IU) resulted in high FSH serum levels but increased neither the estradiol levels nor the number of retrieved oocytes, implying that granulosa cell function is not improved by high FSH serum levels. Lower starting doses of GN lead to a reduction of costs of medication. The small but significant difference in blastocyst formation and the lower FSH levels in the treatment groups receiving less GN may be an indication of better oocyte quality with higher developmental competence. STUDY FUNDING/COMPETING INTEREST(S): The costs for the HMG used for ovarian stimulation were provided by IBSA Switzerland. The study was also supported by the Repronatal Foundation, Basel, Switzerland. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01577472. TRIAL REGISTRATION DATE: 13 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: August 2013.

[Extracorporeal shock wave therapy for delayed union of long bone fractures - preliminary results of a prospective cohort study]. / Die extrakorporale Stosswellentherapie (ESWT) in der Behandlung von Pseudarthrosen des Röhrenknochens. Erste Ergebnisse einer prospektivenklinischen Untersuchung.

Extracorporal shock wave therapy (ESWT) has been postulated as an additional therapeutic option in nonunion after fracture treatment. We have reexamined patients with nonunions treated at our institution to evaluate the efficacy of the method. In a prospective nonrandomized study patients were investigated with a minimum duration of nonunion of 6 months. Following 2 cycles of ESWT with 2000 impulses/18 kV, the reevaluation was performed at 1, 3 and 6 months after treatment. A total of 27 pseudarthroses was reevaluated, in 11 one or more reosteosyntheses had been performed prior to ESWT. Following ESWT we found a success rate of 41 % (n = 11). The clinical evidence of subjective, clinical improvement was found in 5 of these patients within 1 month, in all of these patients within a period of 3 months. Radiologic evidence of improvement occurred in none of these patients within 1 month, in all of these patients within 6 months. ESWT appears to represent an additional treatment option in patients with longstanding nonunion. If no improvement occurs, the maximum delay of reosteosynthesis is three months.

Xanthomatosis resembling scleroderma in multiple myeloma.

A patient with multiple myeloma had severe cutaneous and gastrointestinal xanthomatization and symptoms characteristic of systemic sclerosis. Clinical findings included thickened sclerotic skin, dysphagia associated with an akinetic esophagus, and abnormal findings on roentgenograms of the upper and lower gastrointestinal tract. Biopsy specimens obtained from the skin and the gastrointestinal tract studied by light and electron microscopy showed thickening, hyalinization, and xanthomatization of the subepithelial connective tissue. Macrophages containing lipid vacuoles were shown to assume a perivascular orientation on ultrastructural study. Our case appears to be unique since this combination of findings has not been reported previuosly. In addition, our electron micrographs may help to define better the pathogenetic process involved in the association between myeloma and plane xanthomata.

Myocardial rupture. Major left ventricular infarct rupture treated by infarctectomy.

A myocardial rupture that occurred during anesthesia induction for infarctectomy was successfully repaired, and the patient is well and free of symptoms 10 1/2 months later.

Cardiac rupture--challenge in diagnosis and management.

Previous studies of the incidence, natural history, pathogenesis and diagnosis of cardiac rupture are presented, and 20 additional cases described. Progressive cardiorrhexis after myocardial infarction causes death in possibly more than 25,000 persons a year in the United States, and more frequent antemortem diagnosis is needed. Suggestions for future clinical and experimental studies are described and possible means of early diagnosis and therapy are outlined.