Abstract
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
Fertility preservation is an urgent challenge in the transplant setting. A panel of transplanters and fertility specialists within the Pediatric Diseases Working Party of the European Society for ...Blood and Marrow Transplantation (EBMT) and the International BFM Study Group provides specific guidelines. Patients and families should be informed of possible gender- and age-specific cryopreservation strategies that should be tailored according to the underlying disease, clinical condition and previous exposure to chemotherapy. Semen collection should be routinely offered to all postpubertal boys at the diagnosis of any disease requiring therapy that could potentially impair fertility. Testicular tissue collection might be offered to postpubertal boys; nevertheless, its use has been unsuccessful to date. Oocyte collection after hormonal hyperstimulation should be offered to postpubertal girls facing gonadotoxic therapies that could be delayed for the 2 weeks required for the procedure. Ovarian tissue collection could be offered to pre-/post-pubertal girls. Pregnancies have been reported after postpubertal ovarian tissue reimplantation; however, to date, no pregnancy has been reported after the reimplantation of prepubertal ovarian tissue or in vitro maturation of pre-/post-pubertal ovarian tissue. Possible future advances in reproductive medicine could change this scenario. Health authorities should prioritize fertility preservation projects in pediatric transplantation to improve patient care and quality of life.
Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant ...diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT.
The fluting of Folsom points is an elegant technological solution to several problems faced by highly mobile hunters focused on bison procurement. The symmetrical, bifluted form allowed a split, ...facial-contact haft to extend nearly to the tip, thereby controlling both location and extent of fracture and allowing many cycles of point reworking. Extreme thinness achieved by fluting facilitated leading edge sharpness for enhanced penetration. The near-constant cross- section from tip to base meant no loss of leading edge acuteness upon resharpening and inter-changeability of broken segments. The high-friction, forwardly adjustable haft assured firm mounting even with shortened, reused point segments. This efficient design was critical for groups who spent weeks and maybe months away from raw material sources in pursuit of game. Short, exhausted Folsom points or “slugs” are what archaeologists most commonly find and study. In contrast, a quite long, fully fluted point made from a yet longer preform was the intended product of the Folsom knapper. The model presented here can be tested through study of preform length, finished point proportions, fracture patterns, haft element features, and use-wear analysis in archaeological specimens, as well as actualistic hunting experiments. The engine driving persistent use of snap blade, full fluted projectile technology was focused commitment to a single, highly mobile game species (bison). This specific technofunctional element in Folsom culture reveals a weapon system designed to mitigate against extreme risk regarding access to raw material. Continuing research should demonstrate that the appearance, geographic distribution, persistence, and disappearance of the Folsom fluted point relate closely to juxtapositions of climatic change, biotic change, and human population movements that occurred near the end of the Pleistocene.
Alfred W. Bowers’ work epitomized the direct historical approach in Plains anthropology. Bowers integrated archaeology, ethnohistory, and ethnology in his studies of the tribes of the Middle Missouri ...subarea. Yet his archaeological and historical research and interpretations have not been widely recognized. Bowers’ 1948 dissertation, A History of the Mandan and Hidatsa, and associated collections, have only recently become easily accessible. Bowers’ dissertation employed oral history and tradition, ethnohistoric accounts, and archaeological data to develop accounts of Mandan and Hidatsa history supported by independent lines of evidence. The culture-historical system he developed for Mandan and Hidatsa prehistory and history is a valuable framework for structuring and understanding Middle Missouri archaeology and cultural sequences and relationships. We review Bowers’ career, assess the significance of his work, and discuss the associated collections and their research potential.
A four-year program of remote sensing at the Double Ditch State Historic Site (32BL8) demonstrates the utility of combined prospecting methods for understanding complex settlements when combined with ...traditional excavation methods. Magnetic gradiometry revealed countless subterranean storage pits, hearths, and two previously unknown fortification systems that vastly increase the settlement's area and projected population to perhaps 2,000 individuals. Electrical resistance surveys helped define middens, other depositional areas, houses, and earth-borrowing pits. Ground-penetrating radar yielded details about ditch, house, and mounded midden interior forms. Aerial survey from a powered parachute acquired high-resolution digital color and thermal infrared imagery. The former distinguished houses, borrow pits, and ditches from middens and fill areas by changes in vegetation; the latter did the same through temperature variations that also highlighted historic excavations. High-resolution topographic survey allowed documentation of topographic expressions caused by ditches, houses, borrow pits, and mounds. The remote sensing program reduced excavation costs by targeting features. Excavations confirmed anomaly identifications and established a chronology that documents late-fifteenth-century origins to an ultimate contraction in the eighteenth century, with abandonment after a smallpox outbreak about A.D. 1785. Evidence suggests that large mounds formed integral components of the village"s defenses. Excavations also reveal extensive earth moving for mound building, earthlodge coverings, and other reasons still unclear. This practice caused the truncation or obliteration of many earlier archaeological features and forces realization that long-occupied settlements were fluid through time with continual reworking of deposits, and complex depositional, use, and formation histories.
Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant ...diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT. Bone Marrow Transplantation (2017) 52, 1029-1035; doi: 10.1038/bmt.2017.21; published online 13 March 2017
Mutations in the human cationic trypsinogen are associated with hereditary pancreatitis. The cDNA coding for human cationic trypsinogen was subcloned into the expression vector pcDNA3. The mutations ...R122H, N29I, A16V, D22G, and K23R were introduced by site directed mutagenesis. We constructed an expression vector coding for active trypsin by subcloning the cDNA of trypsin lacking the coding region for the trypsin activating peptide behind an appropriate signal peptide. Expression of protein was verified by Western blot and measurement of enzymatic activity. AR4-2J cells were transiently transfected with the different expression vectors and cell viability and intracellular caspase-3 activity were quantified. In contrast to wild-type trypsinogen, expression of active trypsin and mutated trypsinogens reduced cell viability of AR4-2J cells. Expression of trypsin and R122H trypsinogen induced caspase-3 activity. Acinar cells might react to intracellular trypsin activity by triggering apoptosis.
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