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Biomedical subjects

R F Casper

Publications and source records attributed to R F Casper.

At least 37 records · Page 2Linked to original sources
PubMed2000

Estrogen with interrupted progestin HRT: a review of experimental and clinical studies.

This review outlines the basic principles of a novel interrupted progestin HRT regimen in which estrogen is administered continuously, and progestin is given in a 3-days on, 3-days off pulsed fashion. The rationale for this regimen is to prevent receptor down-regulation and allow increased estrogen and progestin sensitivity during the progestin-free periods. Background information is provided including the reasons for poor patient acceptance of HRT, and the concerns of the potential association of HRT with breast and endometrial cancer. Experimental studies in the rat are described which provide evidence in support of the rationale for the interrupted progestin regimen. Clinically, two pilot studies examining symptom control, bleeding rates and safety of the interrupted progestin regimen, as well as preliminary results of a third study examining the usefulness of this regimen for addback therapy in GnRH agonist treated patients, are outlined. The preliminary results of phase III trials are presented. These clinical studies all demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate an advantage of this new regimen compared to continuous combined HRT.

Animals↗
PubMed2000

Use of the internet by infertile couples.

OBJECTIVE: To evaluate and compare the extent of Internet use by infertile couples attending a government-funded and a private assisted reproductive technology clinic. DESIGN: A prospective study. SETTING: One private and one public tertiary care fertility clinic in Toronto. PATIENT(S): 250 patients were approached, and 150 (60%) responded. INTERVENTION(S): A self-administered questionnaire on socioeconomic status, fertility history, and computer and Internet use. MAIN OUTCOME MEASURE(S): The extent of Internet use on fertility-related issues was determined, correlated with socioeconomic status and fertility history, and compared between the two clinics. RESULT(S): Higher levels of education, employment, and combined family income characterized patients at the private clinic. A similarly high proportion of patients at both clinics had previous experience with the Internet (mean, 75.3%). Overall, 42% of the total study population and 55.8% of current Internet users had used the Internet for fertility-related issues. Using a logistic regression model, none of the patients' socioeconomic or clinical variables predicted Internet use. Thirty percent of the patients found the Internet helpful in their decision making process. CONCLUSION(S): A considerable proportion of infertile couples from all socioeconomic levels is actively using the Internet with regard to their fertility problems. Health care providers should consider the Internet an important tool for all aspects of their interaction with infertile persons.

Adult↗
PubMed2000

The choice of embryo transfer catheter affects embryo implantation after IVF.

OBJECTIVE: Comparison of two transfer catheters in an IVF program. DESIGN: Prospective, randomized clinical study. SETTING: A private tertiary care center for ART. PATIENT(S): 66 patients < 38 years of age undergoing IVF and/or ICSI. INTERVENTION(S): Patients were randomly assigned to undergo ET using the Tomcat catheter (n = 32) or the TDT catheter (n = 34). MAIN OUTCOME MEASURE(S): Primary outcome measures were implantation and pregnancy rates. Secondary outcome measures were contamination with blood and/or mucus on the tip of the catheter, cramping or patient discomfort, and time required to complete ET. RESULT(S): Use of the Tomcat catheter resulted in significantly higher implantation (25.2% vs. 8.4%) and clinical pregnancy rates (47% vs. 14.7%) compared with the TDT catheter. All secondary outcome measures were similar for both catheters. CONCLUSION(S): The choice of ET catheter may affect the success of IVF-ET cycles. Use of the Tomcat catheter compared with the TDT catheter seems to result in significantly better efficiency of the ET procedure and is more cost effective.

Adult↗
PubMed2000

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol.

Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution. The prototypical compound is TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), also known as dioxin. There is an increasing body of knowledge linking cigarette smoking to osteoporosis and periodontal disease, but the direct effects of smoke-associated aryl hydrocarbons on bone are not well understood. Through the use of resveratrol (3,5,4'-trihydroxystilbene), a plant antifungal compound that we have recently demonstrated to be a pure AhR antagonist, we have investigated the effects of TCDD on osteogenesis. It was postulated that TCDD would inhibit osteogenesis in bone-forming cultures and that this inhibition would be antagonized by resveratrol. We employed the chicken periosteal osteogenesis (CPO) model, which has been shown to form bone in vitro in a pattern morphologically and biochemically similar to that seen in vivo, as well as a rat stromal cell bone nodule formation model. In the CPO model, alkaline phosphatase (AP) activity was reduced by up to 50% (P<0.01 vs control) in the presence of 10(-9) M TCDD and these effects were reversed by 10(-6) M resveratrol (P<0.05 vs TCDD alone). TCDD-mediated inhibition of osteogenesis was restricted primarily to the osteoblastic differentiation phase (days 0-2) as later addition did not appear to have any effects. Message levels for important bone-associated proteins (in the CPO model) such as collagen type I, osteopontin, bone sialoprotein and AP were inhibited by TCDD, an effect that was antagonized by resveratrol. Similar findings were obtained using the rat stromal bone cell line. TCDD (at concentrations as low as 10(-10)M) caused an approximately 33% reduction in AP activity, which was abrogated by 3. 5x10(-7) M resveratrol. TCDD also induced a marked reduction in mineralization ( approximately 75%) which was completely antagonized by resveratrol. These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol. Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease. If so, resveratrol could prove to be a promising preventive or therapeutic agent for smoking-related bone loss.

Alkaline Phosphatase↗
PubMed1999

The detrimental effect of increased endometrial thickness on implantation and pregnancy rates and outcome in an in vitro fertilization program.

OBJECTIVE: To determine whether there is a maximal value for endometrial thickness, as measured on the day of hCG administration, above which implantation and pregnancy are unlikely to occur. DESIGN: Retrospective analysis. SETTING: A university-based tertiary care center for assisted reproductive technology. PATIENT(S): A total of 809 IVF cycles in 623 patients resulting in ET. INTERVENTION(S): Endometrial thickness was measured by means of transvaginal ultrasound on the day of hCG administration. Cycles were divided into two groups based on endometrial thickness. Group A consisted of 680 cycles with "normal" endometrial thickness (7-14 mm), and group B included 37 cycles with "increased endometrial thickness" (>14 mm). MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy and miscarriage rates. RESULT(S): Group B cycles had significantly lower implantation and pregnancy rates compared with group A (3% versus 15% and 8.1% versus 29.7%, respectively). Two of 3 pregnancies (66.6%) from group B miscarried, compared with 44 of 202 (21.8%) pregnancies in group A. CONCLUSION(S): Patients with endometrial thickness of > 14 mm on the day of hCG administration comprise approximately 5% of the patients who undergo ET in our program. Our experience suggests that implantation and pregnancy rates are significantly reduced, and miscarriage rates may be increased in this group.

Adult↗
PubMed1999

Intracytoplasmic sperm injection after follicle stimulation with highly purified human follicle-stimulating hormone compared with human menopausal gonadotropin.

PURPOSE: Our purpose was to compare oocyte nuclear maturation and embryo quality after pituitary down-regulation and ovarian stimulation with highly purified follicle-stimulating hormone (FSH) or human menopausal gonadotropin (HMG). METHODS: Fifty-five patients 37 years of age or younger who were undergoing in vitro fertilization (IVF)-intracytoplasmic sperm injection (ICSI) were evaluated retrospectively. In all cases, male factor was the only indication for treatment, with no female-related factors identified. Following pituitary down-regulation, patients were stimulated with hMG (n = 20) or highly purified FSH (n = 35). Main outcome measures included ovarian response to stimulation, oocyte maturity, and ICSI fertilization results. Secondary outcome measures included pregnancy rates and outcome. RESULTS: The ovarian response to stimulation was similar for the two groups, as were the percentage of metaphase II oocytes, fertilization and cleavage rates, and number and quality of transferred and cryopreserved embryos. Cycle outcome was comparable. CONCLUSIONS: In normogonadotropic subjects, monocomponent therapy with highly purified FSH is as effective as hMG in stimulating ovarian follicular development, synchronization of oocyte maturation, and IVF-ICSI outcome. Our findings support the conclusion that the luteinizing hormone component in the stimulation protocol is unnecessary.

Adolescent↗
PubMed1999

Variability in the expression of trophectodermal markers beta-human chorionic gonadotrophin, human leukocyte antigen-G and pregnancy specific beta-1 glycoprotein by the human blastocyst.

Improved culture conditions that support the development of human embryos to the blastocyst stage in vitro led to the prospect of blastocyst transfer to increase pregnancy rates. Thus, there is a need for characterization of possible biochemical markers able to predict the implantation potential of human blastocysts. In this study, the expression of three placental markers that are expressed prior to implantation, beta-human chorionic gonadotrophin (HCG), human leukocyte antigen (HLA)-G and pregnancy specific beta-1 glycoprotein (SP-1), was investigated. beta-HCG transcript could be detected as early as the two-cell stage, which is one to two cleavage divisions earlier than previously reported. Both beta-HCG and HLA-G transcripts could be detected in the majority of blastocysts, but their levels were highly variable. No association could be found between the amount of transcript for these genes, total cell number or cell death rate. Interestingly, there was a highly positive correlation between accumulation of beta-HCG and HLA-G transcripts. SP-1 protein concentrations were assessed in the culture medium of blastocysts using enzyme-linked immunosorbent assay. There was a significant positive correlation between SP-1 concentrations and blastocyst cell numbers. Moreover, synthetic oviductal medium enriched with potassium resulted in an SP-1 concentration twice as high as that observed using human tubal fluid medium. These data suggest that SP-1 may be used to select blastocysts with higher cell number, possibly resulting in higher pregnancy rates.

Apoptosis↗
PubMed1999

DNA damage in round spermatids of mice with a targeted disruption of the Pp1cgamma gene and in testicular biopsies of patients with non-obstructive azoospermia.

Non-obstructive azoospermia accounts for a considerable proportion of male factor infertility. Current therapies for treatment of this kind of infertility include procedures such as intracytoplasmic sperm injection (ICSI), round spermatid injection (ROSI), round spermatid nucleus injection (ROSNI) and elongated spermatid injection (ELSI). All involve injection of haploid germ cells retrieved from testicular biopsies into recipient oocytes. We have investigated a mouse model of azoospermia for quality of haploid germ cell genomes, based on 4,6-diamidino-2-phenylindole (DAPI)/TdT-mediated dUTP nick-end labelling (TUNEL) labelling. The mouse model, a targeted mutation in the protein phosphatase 1cg gene, results in severe depletion of haploid germ cells from the round spermatid stage on. Mice homozygous for the mutation are completely infertile, and produce only the occasional spermatozoon. Spermatozoa and round spermatids retrieved from either the epididymides or the testes of mutant mice displayed very high rates of DNA fragmentation. In contrast, similar cells retrieved from heterozygous or wild-type littermates displayed low levels of DNA fragmentation. In some cases, the high rates of DNA fragmentation in mutant cells could be lowered by inclusion of antioxidants in the retrieval media. High rates of DNA fragmentation were also observed in round spermatids retrieved from testicular biospies of human patients with non-obstructive azoospermia. These results suggest that one of the features of the pathology associated with azoospermia is fragmented DNA in haploid germ cells. This raises questions about the suitability of using these cells for fertility treatment.

Adult↗
PubMed1999

Preliminary experience with subcutaneous human ovarian cortex transplantation in the NOD-SCID mouse.

Xenogeneic transplantation of ovarian cortex into an immunodeficient animal host may be an approach toward fertility preservation for young female patients undergoing cancer therapy. Our objective was to evaluate the development of follicles in human ovarian cortex placed s.c. in non-obese diabetic-severe combined immune deficiency (NOD-SCID) mice (n = 54). The following variables were compared: 1) male versus female mice as hosts, 2) intact versus pituitary down-regulated mice, and 3) warm versus cold tissue transport. After 2 wk, 37 of 50 (74%) of the human xenografts contained follicles. At 12 wk after transplantation, exogenous gonadotropin stimulation resulted in follicle growth in 19 of 37 (51%) of the grafts, including the development of antral follicles, which could be palpated and visualized through the mouse skin. Significantly more developing follicles were identified in male versus female mice (13 of 17 vs. 6 of 20, respectively; p = 0.013) after stimulation. No difference was found between intact and pituitary down-regulated mice as hosts. Follicular survival was significantly increased by warm versus cold tissue transport. Our results suggest that s.c. ovarian cortex xenografting into NOD-SCID mice is feasible. Primordial follicles in ovarian xenografts retain their developmental potential and form antral follicles following gonadotropin stimulation.

Animals↗
PubMed1999

Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity.

Aryl hydrocarbon receptor (AhR) ligands such as dioxin and benzo[a]pyrene are environmental contaminants with many adverse health effects, including immunosuppression, carcinogenesis, and endothelial cell damage. We show here that a wine component, resveratrol (3,5,4'-trihydroxystilbene), is a competitive antagonist of dioxin and other AhR ligands. Resveratrol promotes AhR translocation to the nucleus and binding to DNA at dioxin-responsive elements but subsequent transactivation does not take place. Resveratrol inhibits the transactivation of several dioxin-inducible genes including cytochrome P-450 1A1 and interleukin-1beta, both ex vivo and in vivo. Resveratrol has adequate potency and nontoxicity to warrant clinical testing as a prophylactic agent against aryl hydrocarbon-induced pathology.

Anticarcinogenic Agents↗
PubMed1998

Expression and regulation of genes associated with cell death during murine preimplantation embryo development.

The newly fertilized preimplantation embryo depends entirely on maternal mRNAs and proteins deposited and stored in the oocyte prior to its ovulation. If the oocyte is not sufficiently equipped with maternally stored products, or if zygotic gene expression does not commence at the correct time, the embryo will die. One of the major abnormalities observed during early development is cellular fragmentation. We showed previously that cellular fragmentation in human embryos can be attributed to programmed cell death (PCD). Here, we demonstrate that the PCD that occurs during the 1-cell stage of mouse embryogenesis is likely to be regulated by many cell death genes either maternally inherited or transcribed from the embryonic genome. We have demonstrated for the first time the temporal expression patterns of nine cell death regulatory genes, and our preliminary experiments show that the expression of these genes is altered in embryos undergoing fragmentation. The expression of genes involved in cell death (MA-3, p53, Bad, and Bcl-xS) seems to be elevated, whereas the expression of genes involved in cell survival (Bcl-2) is reduced. We propose that PCD may occur by default in embryos that fail to execute essential developmental events during the first cell cycle.

Animals↗
PubMed1998

Sperm deoxyribonucleic acid fragmentation is increased in poor-quality semen samples and correlates with failed fertilization in intracytoplasmic sperm injection.

OBJECTIVE: To determine the incidence of DNA fragmentation in human sperm used for intracytoplasmic sperm injection (ICSI) and to correlate any detected DNA damage with semen analysis parameters and fertilization rates in ICSI. DESIGN: Descriptive and correlational clinical study. SETTING: Tertiary care fertility clinic. PATIENT(S): A total of 150 semen samples was collected from men in the ICSI program. INTERVENTION(S): For each sample, sperm wash and swim-up were performed, and the percentage of recovered sperm with DNA fragmentation was determined with the use of terminal transferase-mediated deoxyuridine triphosphate-biotin end labeling. MAIN OUTCOME MEASURE(S): The percentage of sperm with DNA fragmentation was correlated with semen analysis parameters and ICSI fertilization rates. RESULTS(S): The mean (+/- SD) percentage of sperm with fragmented DNA was 14.5% +/- 1.5% and ranged from 0.5% to 75%. A significant negative association was found between the percentage of sperm with DNA fragmentation and the ICSI fertilization rate. We also observed that the motility and morphology of the ejaculated sperm were correlated negatively with the percentage of DNA fragmentation in the washed sperm recovered by the swim-up technique. CONCLUSION(S): Our results suggest that when poor-quality semen samples are used for ICSI, there is a greater likelihood that some sperm selected for injection, despite appearing normal, contain fragmented DNA. Whether sperm DNA damage may contribute to failure of pronuclear formation and embryo development in some apparently unfertilized ICSI oocytes is unclear.

Cleavage Stage, Ovum↗
PubMed1998

Historical prospective cohort study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasing hormone agonist.

OBJECTIVE: To determine the duration of time to the recurrence of pain attributable to endometriosis after the discontinuation of treatment with danazol or a GnRH agonist (GnRH-a) in patients who have had a satisfactory response to the treatment. DESIGN: Retrospective study. SETTING: Nine academic medical centers in three countries. PATIENT(S): Three hundred twenty-seven women with diagnosed and staged endometriosis who were treated with at least 6 months of danazol or a GnRH-a and who experienced significant pain relief with therapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Duration of pain relief after completion of treatment as determined by a patient-initiated report of pain recurrence or increase in pain severity requiring intervention. RESULT(S): The median time to the recurrence of pain was 6.1 months for patients treated with danazol and 5.2 months for patients treated with a GnRH-a. CONCLUSION(S): Although there was a lack of uniformity in treatment effects across sites, the analyses have taken into account major covariant effects. The time to the recurrence of endometriosis-associated pain after danazol treatment was slightly longer than that after GnRH-a treatment.

Adult↗
PubMed1998

Case-based reasoning in IVF: prediction and knowledge mining.

In vitro fertilization (IVF) is a medically-assisted reproduction technique, enabling infertile couples to achieve successful pregnancy. Given the unpredictability of the task, we propose to use a case-based reasoning system that exploits past experiences to suggest possible modifications to an IVF treatment plan in order to improve overall success rates. Once the system's knowledge base is populated with a sufficient number of past cases, it can be used to explore and discover interesting relationships among data, thereby achieving a form of knowledge mining. The article describes the TA3IVF system--a case-based reasoning system which relies on context-based relevance assessment to assist in knowledge visualization, interactive data exploration and discovery in this domain. The system can be used as an advisor to the physician during clinical work and during research to help determine what knowledge sources are relevant for a treatment plan.

Artificial Intelligence↗
PubMed1998

Ovarian hyperstimulation following the sole administration of agonistic analogues of gonadotrophin releasing hormone.

Ovarian hyperstimulation following the sole administration of gonadotrophin-releasing hormone agonists (GnRHa) is exceedingly rare. We hereby report on two infertile patients undergoing in-vitro fertilization-embryo transfer who developed ovarian hyperstimulation under such circumstances. In both patients, GnRHa were administered using the 'long protocol' regimen. The first patient developed ovarian hyperstimulation on two occasions, with mid-luteal depot administration of triptorelin and with early follicular triptorelin, administered as daily subcutaneous injections. In both cycles, within 2 weeks of triptorelin therapy, massive ovarian multifollicular enlargement occurred, concomitant with high serum oestradiol concentrations, which resolved spontaneously following expectant management. The second patient developed ovarian hyperstimulation following daily injections of leuprolide acetate starting at the mid-luteal phase. The final stage of ovulation was triggered by human chorionic gonadotrophin (HCG) and 11 oocytes were retrieved. In-vitro fertilization resulted in embryo formation, but failed to result in pregnancy. The same phenomenon recurred in a subsequent cycle despite preventive pretreatment with an oral contraceptive. A negative GnRH test, performed just before HCG administration, suggested than an ongoing 'flare-up effect' was unlikely to cause ovarian stimulation. Ovarian hyperstimulation can occur following the sole administration of GnRHa irrespective of the preparation used and the administration protocol. Although spontaneous resolution is the rule, once this condition has developed, HCG administration and oocyte retrieval are feasible. This rare entity probably represents an exaggerated form of ovarian cyst formation following GnRHa administration, the underlying pathophysiology of which remains unresolved.

Administration, Cutaneous↗
PubMed1998

Gamete-specific DNA fragmentation in unfertilized human oocytes after intracytoplasmic sperm injection.

The objective of the present study was to assess the integrity of maternal and/or paternal chromatin in injected oocytes that remained unfertilized after intracytoplasmic sperm injection (ICSI). The study was performed on 102 oocytes that failed to show pronuclear formation 18-20 h after ICSI. We used chromatin labelling with 4,6-diamidino-2-phenylindole (DAPI) to identify maternal and paternal chromatin, coupled with biotin-mediated end-labelling to assess DNA fragmentation in each gamete. It was shown that 50% of oocytes without pronuclear formation following ICSI contained chromatin with damaged DNA, and that the source of the DNA fragmentation was equally divided between the spermatozoon (25.8%) and the oocyte (24.4%). A significantly greater proportion of condensed spermatozoa in human oocytes had damaged DNA, compared to decondensed spermatozoa (24.7 compared to 5.9%, P=0.002). There was a significant increase in the incidence of DNA fragmentation in oocytes from patients older than 35 years (65+/-1.2%) compared to those from younger patients (36+/-1.0%) (P < 0.05). Further, 17% of unfertilized oocytes contained no paternal chromatin. Thus, DNA fragmentation in both spermatozoa and oocytes is associated with failure of fertilization in ICSI. In some cases of severe male factor infertility, a significant proportion of spermatozoa injected into oocytes may contain fragmented DNA. Injection of oocytes with spermatozoa containing abnormal chromatin will probably result in failure of sperm decondensation and fertilization. In older women, a significant proportion of oocytes injected may contain fragmented DNA. These observations may explain the consistent inability of most clinics to achieve fertilization rates higher than 65% with ICSI.

Adult↗