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Biomedical subjects

Robert F Casper

Publications and source records attributed to Robert F Casper.

At least 19 recordsLinked to original sources
PubMed2007

The presence of pinopodes in the human endometrium does not delineate the implantation window.

OBJECTIVE: To assess pinopode formation in human endometrium during the luteal phase of the menstrual cycle and in the first trimester of pregnancy. DESIGN: Prospective clinical study. SETTING: Outpatient infertility clinics and outpatient family planning clinic. PATIENT(S): Thirty-two regularly cycling infertile women, 15 regularly cycling fertile women, 9 women receiving elective termination of pregnancy, and 1 woman receiving GnRH agonist and hormone therapy addback. INTERVENTION(S): Endometrial tissue was collected by suction pipelle and examined by scanning electron microscopy for pinopode formation. MAIN OUTCOME MEASURE(S): Endometrial tissue was scored (0, 1, 2, 3, or 4) depending on the percentage of the surface covered in pinopodes (from 0% to >20% of 100 fields). RESULT(S): Pinopodes were present throughout the luteal phase of the menstrual cycle, up to the 11th week of pregnancy, and in the endometrium of the woman on GnRH agonist and hormone therapy. CONCLUSION(S): Pinopodes can be detected in the progesterone-exposed endometrium for an extended period of time, in contradistinction to the perception that they are markers for the implantation window in the human endometrium.

Adult↗
PubMed2007

Expression of glycodelin and cyclooxygenase-2 in human endometrial tissue following three-dimensional culture.

PROBLEM: Our previous study showed that in vitro culture of human endometrial tissue in a three-dimensional (3D) fibrin matrix could mimic the early stages of endometriosis with invasion, gland and stroma formation and sprouting of new vessels. The objective of the present study was to evaluate the expression of glycodelin (Gd) and cyclooxygenase-2 (COX-2), two angiogenic factors, to further validate the 3D culture model of endometriosis. METHOD OF STUDY: Human endometrial fragments were obtained from endometrial biopsies and placed in a 3D fibrin matrix culture. Immunohistochemistry with specific antibodies to Gd and COX-2 was used to examine endometrial epithelium and blood vessels, and 4, 6-diamidino-2-phenylindole staining was used for nuclear identification. RESULTS: Three-dimensional culture of human endometrial tissue in the fibrin matrix resulted in the proliferation of endometrial stromal cells, glandular epithelium and angiogenesis. Gd positive glandular epithelium was seen in 85% of wells with developing endometrial glands and COX-2 positive new vessels were seen in 80% of wells with angiogenesis-like structures after 4 weeks of culture. CONCLUSION: Our findings confirm that angiogenesis occurs following the culture of endometrial tissue in the 3D fibrin matrix, and suggests that Gd and COX-2 might play important roles in promoting neovascularization and cell proliferation in the establishment of endometriosis.

Adult↗
PubMed2006

Follicular phase dynamics with combined aromatase inhibitor and follicle stimulating hormone treatment.

OBJECTIVE: The objective of this study was to evaluate follicular phase parameters during ovarian stimulation with FSH alone or with the aromatase inhibitor letrozole. METHODS: Two groups of women undergoing intrauterine insemination (IUI): group I (389 patients; mean age 35 +/- 4.3 yr) underwent 630 IUI cycles stimulated with letrozole and FSH; and group II (134 patients; mean age 36.0 +/- 4.6 yr) underwent 166 IUI cycles stimulated with FSH only. Each group was stratified into ovulatory and anovulatory cycles. Patients were monitored by ultrasound for folliculometry and blood sampling for hormonal assay on d 3, 7, 9, or 10 of the cycle, and on the day of human chorionic gonadotropin administration. RESULTS: Group I had a significantly lower follicular count greater than 10 mm on d 7, greater than 12 mm on d 9 or 10, and greater than 15 mm on the day of human chorionic gonadotropin administration compared to group II (P = 0.006, <0.001, and <0.001, respectively). After stratifying patients by diagnosis, this relationship was maintained only for patients with ovulatory infertility (P = 0.003, <0.001, and <0.001, respectively). Serum estradiol (E2) was significantly lower in the group I ovulatory and anovulatory at the last three monitoring visits (P < 0.001). However, the difference in E2 levels decreased in the preovulatory period with similar E2 levels per mature follicle. No premature preovulatory progesterone rise was observed in either group. However, significantly lower progesterone levels were observed in the second half of the follicular phase in group I (P = 0.02 and <0.001). Endometrial thickness was significantly lower in group I at the second and third visits (P < 0.001, 0.01) but was comparable to group II at the last monitoring visit. Although, the pregnancy rates were similar between the two groups, the multiple pregnancy rate was significantly higher in the FSH-only group (P = 0.039). CONCLUSION: The addition of letrozole modifies the follicular, hormonal, and endometrial dynamics of FSH-stimulated cycles with possible positive effects on the overall cycle outcome.

Adult↗
PubMed2006

Effect of a statin on an in vitro model of endometriosis.

OBJECTIVE: To determine the inhibitory effect of a statin on angiogenesis in a three-dimensional (3-D) culture of human endometrial fragments in vitro. Angiogenesis has been proposed as an important mechanism in the pathogenesis of endometriosis, and statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have been shown to have anti-inflammatory and anti-angiogenic activity. DESIGN: Experimental in vitro study of human endometrial biopsies and 3-D culture in fibrin matrix. SETTING: Research laboratory at a university-affiliated infertility center. PATIENT(S): Forty-six normal ovulating women undergoing infertility treatment. INTERVENTION(S): Endometrial samples obtained from the fundus of the uterine cavity were minced, and the fragments were placed in a three-dimensional fibrin matrix culture system. MAIN OUTCOME MEASURE(S): Presence or absence of proliferation of stromal cells and invasion of the fibrin matrix, presence or absence of vessel sprouting, and immunohistochemical characterization of cellular components. RESULT(S): During the 1st week of culture, invasion of stromal cells into the fibrin matrix occurred in the control group and in some wells outgrowths were observed. After 2 weeks, endometrial glands were observed in the outgrowths at a distance from the main tissue and were growing in conjunction with new vessel formation until the end of culture period. A concentration-dependent effect of lovostatin was seen on cell growth and angiogenesis in the experimental groups. In the presence of 5 and 10 microM of statin, angiogenesis was abolished, and cell proliferation was inhibited. In the presence of 1 microM of lovastatin, angiogenesis was reduced, but cell proliferation was not affected. CONCLUSION(S): The statins were shown to be effective in inhibiting the mechanisms of cell proliferation and angiogenesis in an experimental model for the development of endometriosis-like tissue.

Adult↗
PubMed2006

Brown oocytes: implications for assisted reproductive technology.

Fertilization, embryo development, and successful pregnancy can be achieved after transfer of embryos derived from brown oocytes at the same rate as embryos from morphologically normal oocytes. Therefore, brown oocytes are probably normal and this morphological criterion does not seem to be indicative of any adverse outcome in IVF.

Adult↗
PubMed2006

Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation.

BACKGROUND: To compare the clinical results and the cost-effectiveness of using the aromatase inhibitor, letrozole, in conjunction with FSH and FSH alone for controlled ovarian stimulation (COS) in patients undergoing intrauterine insemination (IUI) for a variety of indications. METHODS: Four hundred and thirty-two consecutive patients who underwent 872 IUI cycles were included. The study population was composed of two groups. Group I included 308 patients who underwent 589 IUI cycles with letrozole and FSH for the following indications: anovulation (143 cycles), male factor infertility (147 cycles), unexplained infertility (250 cycles), endometriosis (18 cycles) and combined indications (31 cycles). Group II included 124 patients who underwent 283 IUI cycles who received FSH only for the following indications: ovarian factor infertility (82 cycles), male factor infertility (66 cycles), unexplained infertility (114 cycles), endometriosis (13 cycles) and other indications (8 cycles). Main outcome measures included number of mature follicles >16 mm in diameter, dose of FSH used per cycle, clinical pregnancy rate and cost-effectiveness ratio per pregnancy. RESULTS: FSH dose required for ovarian stimulation was significantly lower when letrozole was used (P < 0.0001). Although a significantly higher number of follicles >16 mm and endometrial thickness at the day of hCG administration (P < 0.0001) were observed in Group II, pregnancy rate per started (14.4 versus 15.9%) and per completed cycles (15.77 versus 18.07%) was the same in Group I and Group II, respectively. IUI cancellation rate was significantly lower with letrozole treatment (P = 0.05%). The cost per cycle was significantly lower in Group I versus Group II (468.93 Can dollars +/- 418.18 versus 1067.28 +/- 921.43; P < 0.0001). The cost-effectiveness ratio was 3249.42 dollars in the letrozole group and 6712.00 dollars in the FSH-only group. CONCLUSION: A letrozole-FSH combination could be an effective ovarian stimulation protocol in IUI cycles. Such a protocol may be more cost-effective than FSH alone because of the difference of FSH dose and cost. A randomized controlled trial is needed to further substantiate this finding.

Aromatase Inhibitors↗
PubMed2006

Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain.

This pilot study examined the effect of a low-dose E and pulsed progestogen hormone therapy (HT) regimen for add-back during long-term GnRH-agonist therapy on bone mineral density (BMD) in five patients with stage IV endometriosis. Bone mineral density was stable after initiation of HT for the entire follow-up period (up to 10 years). One patient stopped her treatment on two occasions to conceive and was successful each time with delivery of a normal baby. No patient had return of pelvic pain after HT add-back.

Adult↗
PubMed2006

Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate.

OBJECTIVE: To evaluate the incidence of congenital malformations among offspring of mothers who conceived with clomiphene citrate (CC) or with letrozole treatment for infertility. DESIGN: Retrospective study. SETTING: 5 fertility centers in Canada. PATIENTS: 911 newborns from women who conceived following CC or letrozole treatment. INTERVENTIONS: Examination of medical files of both mother and newborn, and cross-checked with the parents by telephone calls. MAIN OUTCOME MEASURES: Identified major and minor congenital malformations, birth weight, age of the mother, and type of treatment that led to the conception. RESULTS: Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%). In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the letrozole group (0.2%). CONCLUSION: There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments. However, it appears that congenital cardiac anomaly is less frequent in the letrozole group. The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on our data.

Adult↗
PubMed2006

Clinically relevant expansion of hematopoietic stem cells with conserved function in a single-use, closed-system bioprocess.

The clinical potential of umbilical cord blood-derived stem and progenitor cells has been demonstrated in various animal and human transplantation studies. However, the need for increased numbers of appropriate umbilical cord blood-derived cells continues to limit the development and success of these therapies. Ex vivo expansion has been widely studied as a method to overcome this limitation. We describe the use of a clinically relevant single-use, closed-system bioprocess capable of generating greater numbers of hematopoietic stem and progenitor cells that maintain in vivo and in vitro developmental potential. In addition to expanded numbers of CD34+ cells, CD34(+)CD38(-) cells, colony-forming cells, and long-term culture-initiating cells, the bioprocess generated > or =3.3-fold more long-term nonobese diabetic/severe combined immunodeficient repopulating cells (quantitatively determined using limiting dilution analysis) than present at input. Interestingly, these cells were also capable of multilineage engraftment and were shown to maintain their engraftment potency on a per long-term nonobese diabetic/severe combined immunodeficient repopulating cell basis compared with input noncultured cells. The developmental capacity of bioprocess-generated cells was further demonstrated by their ability to repopulate secondary nonobese diabetic/severe combined immunodeficient recipients. In vitro lineage analysis confirmed that bioprocess-generated cells could differentiate into myeloid and natural killer, B, and T cell lymphoid lineages. This in-depth analysis describes a bioprocess that generates human hematopoietic stem and progenitor cells with conserved hematopoietic activity, establishes analysis criteria for in vitro hematopoietic stem cell expansion studies, and serves as a foundation to test the therapeutic utility of cultured hematopoietic stem cells in large animals and humans.

Animals↗
PubMed2006

Genetic polymorphism in the fibrinolytic system and endometriosis.

OBJECTIVE: Although most women experience retrograde menses during their reproductive life, endometriosis develops only in a small percentage. We hypothesized that persistence of a fibrin matrix in peritoneal pockets, as a result of hypofibrinolysis, could allow menstrually deposited endometrial fragments to initiate endometriosis. Fibrinolysis is modulated by several factors, and polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) gene are considered to be one of the important determinants. The objective of this study was to evaluate PAI-1 genotypes in a group of women with or without endometriosis. METHODS: In 118 women (75 with laparoscopically confirmed endometriosis and 43 controls), genomic DNA was extracted from blood and the PAI-1 promoter genotype was determined by polymerase chain reaction amplification of DNA using specific primers for the 4G or 5G allele followed by gel electrophoresis. A portion of the polymerase chain reaction product was purified and sequenced to confirm the gel electrophoresis results. RESULTS: Endometriosis was more likely in patients with 4G/5G (odds ratio 38; 95% confidence interval [CI] 6-229) or 4G/4G (odds ratio 441; 95% CI 53-3,694) compared with 5G/5G PAI-1 genotype. Fifty-two of 75 women with endometriosis (69 %, 95% CI 58-79%) had the 4G/4G genotype compared with only 5 of 43 (12%; 95% CI 4-25%) controls. In contrast, the 5G/5G genotype associated with normal fibrinolysis was found in 2 of 75 (3%; 95% CI 0-9%) women with endometriosis compared with 24 of 43 (56%; 95% CI 40-71%) controls. CONCLUSION: Hypofibrinolysis, associated with the 4G allele of the PAI-1 gene, was found significantly more often in women with endometriosis compared with controls. Persistence of fibrin matrix could support the initiation of endometriotic lesions in the peritoneal cavity, explaining why some women with retrograde menstruation develop endometriosis while others do not. LEVEL OF EVIDENCE: II-2.

Adult↗
PubMed2006

Potential of aromatase inhibitors for ovulation and superovulation induction in infertile women.

For almost half a century, the first-line treatment for ovulation induction in cases of anovulation, unexplained infertility, or mild male factor has been clomifene (clomiphene citrate). Clomifene is an effective and safely used oral agent, but is known to have relatively common antiestrogenic endometrial and cervical mucous adverse effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancies with clomifene compared with natural cycles. These drawbacks are mainly a result of the extended antiestrogenic effect of clomifene as a result of its accumulation in the body (clomifene isomers have a half-life of several days up to few weeks). Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of clomifene. Over the last few years several published studies, both controlled and noncontrolled, compared clomifene and treatment with aromatase inhibitors (AIs), either alone or in combination with gonadotropins, for ovulation induction or augmentation. These studies found AIs as effective as clomifene in inducing ovulation, with the major advantage of absence of any antiestrogenic adverse effects. Several other major advantages of AIs include the lower serum estrogen production per developing follicle resulting in more physiological estrogen levels around the time of ovulation and good pregnancy rates with a lower incidence of multiple pregnancy than with clomifene. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of gonadotropins required for optimal follicle recruitment and improve the response to gonadotropin stimulation in poor responders. Such preliminary evidence suggests that AIs may replace clomifene in the future because of similar efficacy with a reduced adverse-effect profile. However, we believe that definitive studies in the form of randomised controlled trials comparing clomifene with AIs are needed.

Anovulation↗
PubMed2005

Review: aromatase inhibitors for ovulation induction.

CONTEXT: For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. EVIDENCE ACQUISITION: We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. EVIDENCE SYNTHESIS: Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. CONCLUSIONS: Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.

Anovulation↗
PubMed2005

The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment.

Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use of aromatase inhibitors reduces hyperestrogenism inevitably attained during ovarian stimulation. In addition, the adjunct use of aromatase inhibitors during ovarian stimulation reduces amount of gonadotropins required for optimum stimulation. The unique approach of reducing hyperestrogenism, as well as lowering amount of gonadotropins without affecting the number of mature ovarian follicles is an exciting strategy that could result in improvement in the treatment outcome by ameliorating the deleterious effects of the ovarian stimulation on follicular development, endometrial receptivity, as well as oocyte and embryo quality.

Animals↗
PubMed2005

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work.

Decreases in melatonin production in human and animals are known to be caused by environmental lighting, especially short-wavelength lighting (between 470 and 525 nm). We investigated the novel hypothesis that the use of goggles with selective exclusion of all wavelengths less than 530 nm could prevent the suppression of melatonin in bright-light conditions during a simulated shift-work experiment. Salivary melatonin levels were measured under dim (<5 lux), bright (800 lux), and filtered (800 lux) light at hourly intervals between 2000 and 0800 h in 11 healthy young males and eight females (mean age, 24.7 +/- 4.6 yr). The measurements were performed during three nonconsecutive nights over a 2-wk period. Subjective sleepiness was measured by self-report scales, whereas objective performance was assessed with the Continuous Performance Test. All subjects demonstrated preserved melatonin levels in filtered light similar to their dim-light secretion profile. Unfiltered bright light drastically suppressed melatonin production. Normalization of endogenous melatonin production while wearing goggles did not impair measures of performance, subjective sleepiness, or alertness.

Adult↗
PubMed2005

Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation.

OBJECTIVE: This study was undertaken to report the outcome of pregnancies achieved after ovarian stimulation, including the use of the aromatase inhibitor, letrozole, for ovarian stimulation. STUDY DESIGN: A cohort study comparing the outcome of pregnancies achieved after letrozole and other ovarian stimulation treatments with a control group of pregnancies spontaneously conceived without ovarian stimulation. RESULTS: In 3 tertiary referral centers, there were 394 pregnancy cycles in 345 infertile couples (63 pregnancies with 2.5 mg of letrozole alone or with gonadotropins, 70 pregnancies with 5.0 mg of letrozole, 113 pregnancies with clomiphene alone or with gonadotropins, 110 pregnancies with gonadotropins alone, and 38 pregnancies achieved without ovarian stimulation). Pregnancies conceived after letrozole treatments were associated with similar miscarriage and ectopic pregnancy rates compared with all other groups. In addition, letrozole use was associated with a significantly lower rate of multiple gestation compared with clomiphene citrate. CONCLUSION: The favorable pregnancy outcome and low multiple gestation rate of aromatase inhibitors for ovarian stimulation is encouraging for the development of these agents as first-line ovulation induction agents.

Abortion, Spontaneous↗
PubMed2005

Dynamic changes in cellular and microenvironmental composition can be controlled to elicit in vitro human hematopoietic stem cell expansion.

OBJECTIVE: The absence of effective strategies for the ex vivo expansion of human hematopoietic stem cells (HSCs) limits the development of many cell-based therapies. Prior attempts to stimulate HSC expansion have focused on media supplementation using cytokines and growth factors. In these cultures, cellular and microenvironmental compositions change with time. In this study, the impact of controlling these dynamic changes on HSC output is determined. MATERIALS AND METHODS: Cord blood-derived lin(-) cells were cultured for 8 days in serum-free medium supplemented with stem cell factor, Flt3 ligand, and thrombopoietin. Functional, phenotypic, and molecular (gene and protein) analyses were used to characterize dynamic changes in cellular and microenvironmental composition. The effects of these changes and the mechanism behind their effects on HSC expansion were assessed using a selection/media exchange-based global culture manipulation (GCM) technique. RESULTS: We show that the direct secretion of negative regulators by culture-generated lin(+) cells, and the indirect stimulation of cells to secrete negative regulators by culture-conditioned media, limits in vitro HSC generation. The GCM strategy was able to abrogate these effects to produce elevated numbers of LTC-ICs (14.6-fold relative to input), migrating rapid NOD/SCID repopulating cells (12.1-fold), and long-term NOD/SCID repopulating cells (5.2-fold). CONCLUSIONS: Cellular and microenvironmental changes that occur during all in vitro HSC cultures can significantly affect HSC output through the direct or indirect secretion of negative regulators. This study provides insight into the mechanisms regulating HSC fate in vitro and describes a novel methodology to regulate overall in vitro microenvironmental dynamics to enable the generation of clinically relevant numbers of HSCs.

Animals↗
PubMed2005

Single-dose administration of an aromatase inhibitor for ovarian stimulation.

Recently, the success of a 5-day administration of an aromatase inhibitor for ovarian stimulation has been shown. In this report, a convenient simple regimen of administering an aromatase inhibitor as a single dose has been found to have comparable success to a 5-day regimen for ovarian stimulation.

Aromatase Inhibitors↗