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Biomedical subjects

Robert F Casper

Publications and source records attributed to Robert F Casper.

At least 37 records · Page 2Linked to original sources
PubMed2005

Live birth of healthy triplets after in vitro fertilization and embryo transfer in an acromegalic woman with elevated growth hormone.

OBJECTIVE: To report a case of successful triplet pregnancy in an acromegaly patient with IVF and embryo transfer. DESIGN: Case report. SETTING: Tertiary center for assisted reproductive technologies. PATIENT(S): A 33-year-old woman with acromegaly and primary infertility. INTERVENTION(S): Controlled ovulation hyperstimulation and IVF/embryo-transfer treatment using gonadotropins. MAIN OUTCOME MEASURE(S): Uncomplicated pregnancy course and successful take-home triplet infant girls. RESULT(S): Successful ovarian stimulation and IVF is possible in acromegalic patients. CONCLUSION(S): There may be an effect of elevated growth hormone resulting in increased ovarian response to gonadotropin, inducing hyperstimulation and high-order multiple pregnancies in these patients.

Acromegaly↗
PubMed2005

Are recombinant gonadotrophins safer, purer and more effective than urinary gonadotrophins?

Recombinant gonadotrophins have been proposed as the gold standard for current infertility treatment. However, there is little difference between the various available urinary or recombinant gonadotrophins in terms of safety, purity or clinical efficacy. Resources committed to determining an advantage of one gonadotrophin preparation over another would be better spent on research for new treatments.

Female↗
PubMed2005

Successful pregnancy following transfer of embryos from oocytes with abnormal zona pellucida and cytoplasm morphology.

The failed or impaired fertilization in an IVF cycle may be a result of undetected abnormalities in sperm function, poor oocyte quality, or impaired spermatozoon-oocyte interaction. Whether oocyte dysmorphisms have an impact on intracytoplasmic sperm injection (ICSI) outcome, fertilization, and implantation is controversial. A 33-year-old nulligravida female with a 2-year history of primary infertility was referred to the Toronto Centre for Advanced Reproductive Technology for infertility management. The patient underwent several cycles of ovulation induction followed by timed intercourse or intrauterine insemination without a resulting pregnancy. Following the failed insemination cycles, she proceeded to IVF. Six morphologically abnormal oocytes (including three that were cucumber-shaped) were retrieved and all injected with a single spermatozoon. Four oocytes showed normal fertilization and developed to day-3 embryos with abnormal morphology and were transferred. Two weeks after the embryo transfer, the patient had a positive beta-human chorionic gonadotrophin (beta-HCG). The pregnancy was uneventful, and a healthy baby boy was delivered at 41 weeks of age by Caesarean section. Since fertilization, embryo development, and successful pregnancy was achieved in this case, it is recommend that oocytes with extreme morphological abnormalities should not be discarded as ICSI may overcome the barriers to fertilization and cleavage.

Adult↗
PubMed2004

Human chorionic gonadotropin administration is associated with high pregnancy rates during ovarian stimulation and timed intercourse or intrauterine insemination.

BACKGROUND: There are different factors that influence treatment outcome after ovarian stimulation and timed-intercourse or intrauterine insemination (IUI). After patient age, it has been suggested that timing of insemination in relation to ovulation is probably the most important variable affecting the success of treatment. The objective of this study is to study the value of human chorionic gonadotropin (hCG) administration and occurrence of luteinizing hormone (LH) surge in timing insemination on the treatment outcome after follicular monitoring with timed-intercourse or intrauterine insemination, with or without ovarian stimulation. METHODS: Retrospective analysis of 2000 consecutive completed treatment cycles (637 timed-intercourse and 1363 intrauterine insemination cycles). Stimulation protocols included clomiphene alone or with FSH injection, letrozole (an aromatase inhibitor) alone or with FSH, and FSH alone. LH-surge was defined as an increase in LH level > or =200% over mean of preceding two days. When given, hCG was administered at a dose of 10,000 IU. The main outcome was clinical pregnancy rate per cycle. RESULTS: Higher pregnancy rates occurred in cycles in which hCG was given. Occurrence of an LH-surge was associated with a higher pregnancy rate with clomiphene treatment, but a lower pregnancy rate with FSH treatment. CONCLUSIONS: hCG administration is associated with a favorable outcome during ovarian stimulation. Awaiting occurrence of LH-surge is associated with a better outcome with CC but not with FSH treatment.

Adult↗
PubMed2004

Umbilical cord blood stem cells.

The umbilical cord contains a rich source of haematopoietic stem cells that can be used to reconstitute the blood system and can easily be extracted and cryopreserved, thus allowing for the establishment of HLA-typed stem cell banks. Recently, it has been demonstrated that umbilical cord stem cells have the potential to give rise to non-haematopoietic cells, such as bone, neural and endothelial cells. It is not clear whether these multipotential cells are mesenchymal-like cells or blood cells. Currently, the number of these specialized cells capable of undergoing the differentiation process into non-haematopoietic cells is low and remains a block to the clinical development of umbilical cord stem cells for non-haematopoietic cell therapy. Further research will allow us to overcome these hurdles. This expanded potential for umbilical cord stem cells might replace embryonic stem cells and other fetal cells for some cell and tissue therapies.

Adult↗
PubMed2004

Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation.

OBJECTIVE: To compare the use of the aromatase inhibitor, letrozole, in conjunction with follicle-stimulating hormone (FSH) injection, and FSH alone for controlled ovarian hyperstimulation (COH) in patients with polycystic ovarian syndrome (PCOS) or ovulatory infertility. METHODS: This nonrandomized study included two study groups: 26 patients with PCOS and 63 with ovulatory infertility (unexplained infertility [41 patients], male factor infertility [17 patients], and endometriosis [5 patients]), who received letrozole in addition to FSH; and two control groups: 46 PCOS patients and 308 with ovulatory infertility (unexplained infertility [250 patients], male factor infertility [42 patients], and endometriosis [16 patients], who received FSH only. All patients had intrauterine insemination (IUI). Main outcome measures included dose of FSH used per cycle, number of preovulatory follicles greater than 16 mm in diameter, cancellation rate, and pregnancy rate. RESULTS: The FSH dose required for ovarian stimulation was significantly lower when letrozole was used in both study groups compared to the control groups without a significant difference in number of follicles greater than 16 mm. IUI cancellation rate was significantly lower with letrozole treatment in PCOS patients. In women with PCOS, clinical pregnancy rate per completed IUI cycle was 26.5% in the letrozole plus FSH group versus 18.5% in the FSH-only group. In ovulatory infertility patients, the pregnancy rate was similar in both study and control groups (11%). CONCLUSION: We believe that inhibition of estrogen synthesis by aromatase inhibition will release the estrogenic negative feedback, resulting in an increase in endogenous FSH secretion. Moreover, by inhibiting conversion of androgens into estrogens, accumulating androgens may increase follicular sensitivity to FSH. Such a protocol has the potential to lower FSH treatment cost and may improve response for low responders who require high FSH doses during ovarian stimulation.

Adult↗
PubMed2004

Aromatase inhibitors in ovulation induction.

The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.

Anovulation↗
PubMed2003

Three-dimensional in vitro culture of endometrial explants mimics the early stages of endometriosis.

OBJECTIVE: To reproduce the earliest phases of endometriosis using a new in vitro model in which cells from a cultured endometrial fragment can proliferate, invade, reconstitute new endometrial-like tissue, and generate blood vessels. DESIGN: Experimental in vitro study. SETTING: A hospital-based academic research institute. PATIENT(S): Five normal ovulating women undergoing surgery for various benign gynecological indications. INTERVENTION(S): Endometrial samples obtained from the fundus of the uterine cavity were placed in a three-dimensional fibrin matrix culture system. MAIN OUTCOME MEASURE(S): Degree of proliferation of stromal cells and invasion of the fibrin matrix, gland, and stroma formation, vessel sprouting, and immunohistochemical characterization of various cellular components. RESULT(S): During the first week of culture, an endometrial cell outgrowth was observed from the original fragments in 120 of 144 wells (83.3%). Subsequently, cell outgrowths could be quantified in 132 (91.6%), 129 (89.5%), and 127 (88.1%) of the wells after 15, 60, and 90 days, respectively. An invasion of the matrix by the human endometrial cells led to the formation of tubular structures that coalesced into tissue, architecturally resembling endometrium and in which the glands were immunohistochemically positive for cytokeratin. New capillaries, immunohistochemically positive for CD31 and vimentin, sprouted from the endometrial outgrowths at the beginning of the fifth week of culture. CONCLUSION(S): These data show that cells from endometrial explants can proliferate and invade a fibrin matrix in vitro generating new glands, stroma, and vessels consistent with endometriosis. The three-dimensional fibrin matrix used in the present study provides an opportunity to observe the earliest biological events of endometriosis in a quantifiable way.

Cell Division↗
PubMed2003

Expression of apoptosis-related genes during human preimplantation embryo development: potential roles for the Harakiri gene product and Caspase-3 in blastomere fragmentation.

In order to resolve the mechanisms and reasons of cellular fragmentation it is crucial to understand what genes may be responsible for regulation of this process. We report herein that human oocytes and preimplantation embryos possess abundant levels of transcripts encoding cell death suppressors, Mcl-1, Bcl-x and Bag-1, and the cell death inducer genes, Bax and Caspase-2. Lower but detectable levels of mRNA expression for the Bfl-1/a1, Bcl-w, Harakiri (Hrk) and Caspase-3 genes were also detected during all developmental stages. We also performed analysis of gene expression in single human embryos exhibiting various degrees of fragmentation at the 2-, 4- and 8-cell stages. At the 4-cell stage, embryos displaying 30-50% fragmentation showed a significant increase in Hrk mRNA levels (P = 0.016). Immunostaining with anti-Hrk antibody confirmed increased staining in some, but not all, fragmented embryos. While Caspase-3 transcripts were elevated in both 4- and 8-cell embryos exhibiting a severe degree of fragmentation, this difference did not reach statistical significance. However, accumulation of Caspase-3 mRNA in fragmented embryos was paralleled by an induction of Caspase-3-like activity. These findings suggest that cellular fragmentation in a subset of human preimplantation embryos could be regulated by certain components of a genetic programme of cell death.

Alternative Splicing↗
PubMed2003

Aromatase inhibitors for the treatment of infertility.

Ovarian stimulation during infertility treatment is used either alone or in conjunction with intrauterine insemination and assisted reproductive technologies. At the present time, the two main medications used for ovarian stimulation include an oral antioestrogen, clomiphene citrate and injectable gonadotrophins. In spite of the high ovulation rate, the use of clomiphene citrate is associated with adverse side effects and low pregnancy rates. In clomiphene citrate failures, gonadotrophin injections are generally the next treatment option but, especially in polycystic ovarian syndrome, are associated with increased risk of severe ovarian hyperstimulation syndrome and high multiple pregnancies. Therefore, an effective oral treatment that could be used without risk of ovarian hyperstimulation syndrome and with minimal monitoring is preferred. It was hypothesised that aromatase inhibitors can be administered early in the follicular phase to induce ovulation by releasing the hypothalamus and/or pituitary from oestrogen negative feedback. The success of aromatase inhibitors in induction and augmentation of ovulation has been reported. In addition, increased intraovarian androgen levels may synergise with central effects of decreased oestrogen to enhance ovarian response to gonadotrophin stimulation. This increased sensitivity to follicle-stimulating hormone may be especially useful in poor responders. The potential future applications for aromatase inhibitors in infertility management are also discussed.

Aromatase↗
PubMed2002

Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic helix-loop-helix period aryl hydrocarbon nuclear translocator single-minded (PAS) transcription factor family. This receptor has been shown to be important in various aspects of growth and development as demonstrated by AhR-null mice. A yeast two-hybrid screen of a mouse embryonic day 11 library for AhR-interacting proteins revealed Nedd8 as a candidate. The interaction was confirmed in a cell-free system and in mammalian cells by co-immunoprecipitation; however, in vitro neddylation assays showed that Nedd8 does not covalently modify AhR. Transfection of Nedd8 into a cell line stably transfected with a dioxin response element linked to a chloramphenicol acetyltransferase reporter gene demonstrated that Nedd8 amplified ligand-induced transcription. Deletion of the Gly-76 residue in the carboxyl terminus of Nedd8 abolished this effect and prevented AhR-Nedd8 interaction. Nedd8 overexpression also resulted in accumulation of AhR protein in the nucleus, independent of exogenous ligand. These studies demonstrate that the AhR interacts with Nedd8 and suggest that this interaction enhances the transcriptional activity of the receptor, perhaps involving increased nuclear accumulation or retention. Immunohistochemistry performed on embryonic day 11.5 mouse sections indicated Nedd8 and AhR localize to overlapping areas in the heart and spinal ganglia, raising the possibility that this interaction may play a role in organogenesis.

Animals↗
PubMed2002

Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders.

OBJECTIVE: To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI. DESIGN: Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH. SETTING: Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto. PATIENT(S): Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles). INTERVENTION(S): Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were >/=2 cm followed by IUI. MAIN OUTCOME MEASURE(S): Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate. RESULT(S): Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%). CONCLUSION(S): In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.

Aromatase Inhibitors↗
PubMed2002

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.

Adolescent↗
PubMed2002

Effect of in vivo GnRH agonist and GnRH antagonist on hCG and insulin-stimulated progesterone production by human granulosa-lutein cells in vitro.

PURPOSE: To investigate hCG and insulin-stimulated progesterone (P) production by human granulosa-lutein cells (hGLC) in vitro. METHODS: hGLCs were isolated from patients undergoing IVF-ET cycles in which GnRH agonist or GnRH antagonist was used to prevent a midcycle gonadotropin surge. The cells were cultured for 3 days, and then treated with hCG 0.5, 1, and 10 IU/I, and insulin 0.01, 0.1, and 1 microM in serum free conditions. In vitro P production was measured by enzyme immunoassay. RESULTS: hCG stimulated P production by hGLCs from cycles in which GnRH antagonist was used, but a blunted response was seen in GnRH-agonist treated cycles. Insulin-stimulated P production was similar in cells from cycles in which GnRH-agonist or GnRH-antagonist treatment was used. CONCLUSIONS: Because insulin and hCG may share common pathways beyond the level of receptor activation, we hypothesize that GnRH agonist, but not GnRH antagonist, may affect the expression and/or activation of LH receptors in the hGLCs.

Adult↗
PubMed2002

Expression of cystic fibrosis transmembrane conductance regulator during early human embryo development.

Formation of the blastocyst is one of the first morphological changes in early embryonic development. Ion transport has been shown to be crucial for blastocoele cavity formation and expansion, although the mechanisms that underlie this process are presently unknown. As a transmembrane Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR) may participate in ion transport and early blastocoele formation. CFTR mRNA was detected throughout preimplantation embryo development and in the unfertilized oocyte. Immunocytochemistry disclosed the presence of CFTR protein from the 8-cell stage, reaching maximum immunoreactivity at early blastocyst stage embryos. Patch clamp electrophysiology of morulae and blastocysts demonstrated typical CFTR Cl(-) channel activities in the apical membrane of trophectoderm cells. Thus CFTR is expressed both at mRNA and protein levels in human morulae and blastocysts, and functions as a cAMP-regulated apical membrane Cl(-) channel. These data suggest that CFTR may contribute to blastocoele formation in the early human embryo.

Blastocyst↗
PubMed2002

Aromatase inhibition for ovarian stimulation: future avenues for infertility management.

Ovarian stimulation is applied during infertility management either alone or in conjunction with intrauterine insemination and assisted reproductive technologies. At the present time, the two main medications used for ovarian stimulation include an oral antiestrogen, clomiphene citrate, and injectable gonadotropins. In spite of the high ovulation rate with the use of clomiphene citrate, the pregnancy rate is much lower. In clomiphene citrate failures, gonadotropin injections have generally been used as the next treatment option. Treatment with gonadotropins is difficult to control and characteristically associated with increased risk of severe ovarian hyperstimulation syndrome and high multiple pregnancies. Therefore, an effective oral treatment that could be used without risk of hyperstimulation and with minimal monitoring is the preferred therapy. We hypothesize that aromatase inhibitors can be administered early in the follicular phase to induce ovulation by releasing the hypothalamus or pituitary from estrogen negative feedback. Based on this hypothesis, we have reported the success of aromatase inhibitors in induction and augmentation of ovulation in addition to improving ovarian response to gonadotropin stimulation. Moreover, there are other potential applications for aromatase inhibitors in infertility management, including improving implantation in assisted reproduction and in-vitro maturation.

Anastrozole↗