Supervised administration of methadone by pharmacists.
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Community Pharmacy Services↗
Biomedical subjects
R T Scott
Publications and source records attributed to R T Scott.
Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation.
OBJECTIVE: To evaluate the contribution of the uterus to age-related reproductive failure in women. PATIENTS: Thirty-eight ovum donors (30.2 +/- 4.9 years [mean +/- SD]) donating oocytes throughout 102 ovum donations. Fifty-one cycles were documented in "younger" recipients (35.8 +/- 3.1 years) and 51 in "older" recipients (44.0 +/- 3.1 years). The study was prospectively designed; same-cohort oocytes obtained from one young donor during a specific cycle were evenly distributed between "young" and "old" ovum recipients. Use of oocytes from a single source and a unique ovulatory cohort provides strict control over oocyte quality. Uterine age is varied by design, according to the age of the recipient at the time of ET. The role of the aging uterus in the decline of female fertility can be thus isolated and scrutinized. RESULTS: No significant (NS) difference in the number of ova received (7.9 +/- 3.4 versus 7.0 +/- 3.5), ova fertilized (4.4 +/- 1.5 versus 4.5 +/- 2.3), or embryos transferred (4.1 +/- 1.5 versus 4.1 +/- 1.6) was observed between the < 40 and > or = 40 recipient age groups. A total of 23 pregnancies occurred among the 102 ETs (22.6%). Eleven clinical pregnancies (21.6%) resulting in 10 deliveries were observed in the < 40 recipient age group, and 12 clinical pregnancies (23.5%) leading to 10 deliveries occurred in the > or = 40 recipient age group (NS). The pregnancy loss rates were 9.1% (1 of 11) and 16.7% (2 of 12) for the two recipient age groups, respectively, (NS). CONCLUSION: The capacity to conceive and to gestate a conception to term when oocyte quality is controlled appears to be independent of uterine aging through the fifth decade of life.
Adult↗
Comparison of leuprolide acetate and human chorionic gonadotropin for the induction of ovulation in clomiphene citrate-stimulated cycles.
OBJECTIVE: To examine the relative efficacies of leuprolide acetate (LA) and hCG in inducing ovulation and a normal luteal phase during clomiphene citrate (CC)-stimulated superovulation cycles. DESIGN: Prospective, randomized, blinded, and cross-controlled in consecutive cycles. SETTING: Large military tertiary care center. PATIENTS: Twenty-one ovulatory patients undergoing superovulation with CC and IUIs for the treatment of unexplained or male factor infertility. INTERVENTIONS: Clomiphene citrate (100 mg/d) on cycle days 5 through 9 in both of the study cycles. Administration of 2 mg SC LA in one cycle and 10,000 IU IM hCG in another cycle for induction of the midcycle surge. MAIN OUTCOME MEASURES: Serum LH, FSH, E2, and P levels every 12 hours for 36 hours after administration of either LA or hCG to characterize the midcycle hormonal dynamics. Luteal phase duration and serum P levels during the midluteal phase were used to estimate the adequacy of the luteal phase. Serial ultrasounds also were done to determine the incidence of luteinized unruptured follicle syndrome. RESULTS: Serum FSH levels in the periovulatory interval were significantly higher after the administration of LA. There were no differences in the periovulatory E2 or P levels or the incidence of sonographic evidence of ovulation after administration of either LA or hCG. Although midluteal serum P levels were higher in the cycles in which hCG was administered, all 42 treatment cycles had adequate luteal phases as assessed by luteal phase duration and three midluteal P levels. Ongoing pregnancies occurred after both LA- and hCG-stimulated cycles. CONCLUSION: Leuprolide acetate and hCG were equivalent in their abilities to induce ovulation. Further evaluation of the adequacy of the luteal phase and the ensuing pregnancy rates after LA induction of an endogenous gonadotropin surge are indicated.
Adult↗
Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization.
OBJECTIVE: To determine if women who previously had demonstrated poor ovarian responsiveness during ovulation induction for IVF would obtain an improved follicular response by the administration of microdoses of GnRH agonist (GnRH-a). DESIGN: Prospective evaluation using the same patients' previous assisted reproductive technology cycles as historic controls. SETTING: Large military tertiary care center. PATIENTS: Thirty four patients who were low responders (peak E2 < 500 pg/mL [conversion factor to SI unit, 3.67]) during ovulation induction with luteal phase GnRH-a suppression followed by exogenous gonadotropins. INTERVENTIONS: Follicular phase administration of 20 micrograms leuprolide acetate every 12 hours beginning on cycle day 3 and supplemented with exogenous gonadotropins beginning on cycle day 5. MAIN OUTCOME MEASURES: Paired analysis of initial E2 response, peak E2 level attained, number of follicles > or = 16 mm, duration of stimulation, ampules of gonadotropins required, late follicular LH levels, number of mature oocytes retrieved, and fertilization rates. RESULTS: Ovarian responsiveness was enhanced during the microdose GnRH-a stimulation cycle when compared with the previous stimulation cycle. Specifically, the patients had a more rapid rise in E2 levels, much higher peak E2 levels, the development of more mature follicles, and the recovery of larger numbers of mature oocytes at the time of retrieval. None of the patients had premature LH surges as evidenced by a significant rise in LH levels or a significant decline in E2 levels. There were no differences in the fertilization rates. CONCLUSION: Microdose GnRH-a administration beginning in the early follicular phase may result in an augmented ovarian response when compared with traditional GnRH-a-exogenous gonadotropin stimulations. Additionally, it may decrease gonadotropin requirements while effectively preventing premature LH surges.
Adult↗
Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test.
OBJECTIVE: To test whether the reduced fecundity in women who smoke cigarettes may be attributed to the accelerated development of diminished ovarian reserve. DESIGN: Retrospective evaluation of clomiphene citrate (CC) challenge tests in women from a general infertility population who did and did not smoke cigarettes (part 1) and retrospective evaluation of the impact of smoking on pregnancy rates (PRs) in IVF among women with normal ovarian reserve (part 2). SETTING: Large military tertiary care center. PATIENTS: Sixty-five women who smoked cigarettes and 145 women who did not smoke cigarettes in the general infertility population (part 1) and women undergoing IVF for strict tubal factor infertility with normal ovarian reserve who did (n = 29) and did not (n = 73) smoke (part 2). INTERVENTIONS: Clomiphene citrate challenge tests, composed of FSH levels on cycle days 3 and 10 with 100 mg of CC administered on cycle days 5 through 9. MAIN OUTCOME MEASURES: Comparison of the incidence of abnormal CC challenge test results between women who did and did not smoke, and comparison of peak E2 levels, number of mature follicles, number of mature oocytes retrieved, fertilization rates, and total and ongoing PRs. RESULTS: The incidence of diminished ovarian reserve was increased in women who smoked (8 of 65 [12.31%]) when compared with age-matched controls who did not smoke (7 of 145 [4.83%]). Among women with normal CC challenge tests who were undergoing IVF, there were no differences in peak E2 levels, the number of mature follicles, the number of mature oocytes retrieved, fertilization rates, or total and ongoing PRs. CONCLUSION: Women who smoke have an accelerated development of clinically detectable diminished ovarian reserve. Additionally, the fact that women who smoke cigarettes with normal ovarian reserve have ovarian responses and PRs that are equivalent to age-matched nonsmoking controls suggests that diminished ovarian reserve may be a principal mechanism reducing fecundity among women who smoke cigarettes.
Adult↗
Characterization of Tru-Trax in-vitro penetration testing of cervical mucus.
To determine the distribution of results of an in-vitro cervical mucus penetration system employing both human and bovine mucus (Tru-Trax) in a general infertility population, 133 couples prospectively underwent in-vitro and post-coital testing of cervical mucus. The distribution of Tru-Trax results in couples with normal semen analyses and Insler scores showed significantly greater penetration in bovine (22.3 +/- 6.0 mm) than in human mucus (20.3 +/- 5.4 mm) (P < 0.001). However, the lower limit of the 95% confidence interval of the normal population with either type of mucus was approximately 10 mm. This limit was significantly lower than that described by the kit manufacturer. The predictive value for post-coital tests using human mucus in the Tru-Trax system was good (> 90%) in all groups. The overall penetration into either human or bovine mucus was significantly correlated with the percentage of motile spermatozoa in the semen sample (P < 0.001). In conclusion, in-vitro cervical mucus penetration tests with the Tru-Trax system are related to in-vivo post-coital tests, although the lower limit of the range of anticipated results in the normal population was significantly lower than that described by the manufacturer. The ultimate value of this type of testing will await clinical trials which evaluate clinical end-points such as pregnancy rates.
Adult↗
Immunohistochemical localization of transforming growth factor-beta in human implantation sites.
Transforming growth factor-beta (TGF beta), a protein known to antagonize many of the functions of the epidermal growth factor-receptor system, was localized immunohistochemically in unruptured ectopic pregnancies (EP) removed by salpingectomy (n = 8), uterine decidua from EP (n = 4), and decidua and trophoblast from electively terminated first trimester pregnancies (ETP; n = 8). Two rabbit polyclonal antisera that recognize both TGF beta 1 and beta 2 were used. Immunostaining for TGF beta was identified in all three forms of trophoblast, cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblasts, which were differentiated histologically and immunohistochemically. Moderate cytoplasmic immunostaining was found in villous cytotrophoblasts in both EP and ETP. Nonvillous (anchoring) cytotrophoblasts in these same tissues demonstrated moderate immunostaining adjacent to the villous and light immunostaining distal to the villous. In intermediate trophoblasts, moderate to intense immunostaining was seen in EP and ETP. Syncytiotrophoblasts demonstrated moderate cytoplasmic immunostaining in EP and ETP as well as moderate to intense staining of plasma membranes and microvilli. Nuclear staining was not evident in any form of trophoblast. TGF beta immunostaining was demonstrated in both glands and stroma of decidua from both EP and ETP; however, staining was more intense in decidua from ETP. With the known presence of TGF beta receptors and mRNA in placenta, these results suggest an autocrine/paracrine role for TGF beta regulation of endometrial-trophoblast function during human implantation.
Decidua↗
Gonadotropin-releasing hormone antagonist administration enhances gonadotrope responsiveness at doses inadequate to suppress immunoassayable gonadotropin levels.
Chronic GnRH antagonist therapy produces enhanced gonadotrope responsiveness to supraphysiologic stimuli despite the lack of any measurable suppression of gonadotropin levels. This indicates that GnRH antagonists fundamentally alter gonadotrope response mechanisms without inhibiting gonadotropin release. Beyond the physiologic implications, these data may eventually impact the development of clinical protocols. Benefits could include enhancements in the endogenous gonadotropin flare during controlled ovarian hyperstimulation cycles. Additionally, proposed contraceptive protocols where GnRH antagonists are used to produce the initial inhibition in gonadotropin release and are then followed by a GnRH-a (to avoid the gonadotropin flare) may in fact produce paradoxical results.
Animals↗
Gonadotropin responsiveness to ultralow-dose leuprolide acetate administration in baboons.
OBJECTIVE: To evaluate the gonadotropin response to ultralow doses of a GnRH agonist, leuprolide acetate (LA). DESIGN: Prospective and cross-controlled. SETTING: Primate research center. SUBJECTS: Four reproductive age cycling baboons (Papio cyanocephalus). INTERVENTIONS: Three different doses of LA were given intravenously to each animal followed by serial sampling. MAIN OUTCOME MEASURES: Response patterns of circulating serum gonadotropin levels. RESULTS: All four animals responded to each of the three doses of LA in a dose-dependent fashion. Levels of LH and FSH peaked at 49.5 +/- 2.6 mIU/mL and 72.5 +/- 3.4 mIU/mL, respectively, for the highest dose studied (0.17 microgram/kg). Levels of LH peaked earlier but were lower than the FSH peak levels. CONCLUSIONS: Supraphysiological levels of gonadotropins are attained after the administration of ultralow doses of LA. The level of the response is dose-dependent and is in the range that is required to attain controlled ovarian hyperstimulation.
Analysis of Variance↗
Evaluation of the significance of the estradiol response during the clomiphene citrate challenge test.
OBJECTIVE: To evaluate the relationship between the E2 response during the clomiphene citrate (CC) challenge test and ovarian responsiveness to exogenous gonadotropins. DESIGN: Performance of a CC challenge test followed by ovulation induction with exogenous gonadotropins as part of participation in an assisted reproduction program. SETTING: Assisted reproduction program in a large military tertiary care center. PATIENTS: Two hundred forty-seven women between the ages of 24 and 39 years with normal CC challenge tests within 1 year of their assisted reproduction cycle. INTERVENTIONS: Performance of CC challenge tests and ovulation induction with exogenous gonadotropins as a component of an assisted reproduction cycle. MAIN OUTCOME MEASURES: Correlation of the E2 response during the CC challenge test and peak E2, the duration of stimulation, number of ampules of exogenous gonadotropins, number of mature follicles, number of mature oocytes recovered, and fertilization and pregnancy rates in an assisted reproduction program. RESULTS: No correlation exists between the E2 response during the CC challenge test and any of the parameters evaluated. CONCLUSION: Monitoring of the E2 response during the CC challenge test did not predict ovarian responsiveness or pregnancy rates in patients participating in an assisted reproduction program and one may choose not to include it in routine testing.
Adult↗
The duration of leuprolide acetate administration prior to ovulation induction does not impact ovarian responsiveness to exogenous gonadotropins.
OBJECTIVE: To evaluate the possible impact that the duration of GnRH agonist (GnRH-a) suppression has on subsequent ovarian responsiveness to exogenous gonadotropins. DESIGN: Prospective evaluation of the relationship between the duration of GnRH-a and multiple parameters of ovarian responsiveness. SETTING: Assisted reproduction program in a large military tertiary care center. PATIENTS: One hundred sixty-five women being pretreated with leuprolide acetate (LA) before ovulation induction with exogenous gonadotropins. INTERVENTIONS: Variable duration of LA administration before stimulation. MAIN OUTCOME MEASURES: Outcome measures include duration of stimulation, days until doubling of basal E2, number of ampules of exogenous gonadotropins, peak E2, number of mature follicles, and number of mature oocytes. RESULTS: The duration of LA pretreatment had no effect on any of the parameters of ovarian responsiveness analyzed. CONCLUSION: Once complete suppression of gonadal function is attained, the duration of GnRH-a suppression has no impact on subsequent ovarian responsiveness to exogenous gonadotropins.
Adult↗
Evaluation of the impact of intraobserver variability on endometrial dating and the diagnosis of luteal phase defects.
OBJECTIVE: To determine the magnitude of intraobserver variation in dating endometrial biopsies and its impact on clinical management. DESIGN: Blinded histopathologic interpretation of endometrial biopsy specimens 1 year apart by five pathologists. SETTING: Large military tertiary care center. PATIENTS: Endometrial biopsy specimens from 51 patients undergoing evaluation for potential luteal phase defects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Calculation of the magnitude of the individual and overall intraobserver variation in endometrial dating for the five pathologists and estimation of its potential impact on clinical management. RESULTS: The intraobserver variation was 0.69 +/- 0.05 days (means +/- SE). There was no significant difference in the magnitude of the variation for 1-day or 2-day dating ranges. The theoretical probability of altering clinical management by having the same pathologist redate a given specimen ranged from 15% to 28%. CONCLUSION: Histologic dating of endometrial biopsies is subject to a small but highly clinically significant intraobserver variability that may have a major impact on clinical management.
Biopsy↗
Transforming growth factor-alpha in human implantation trophoblast: immunohistochemical evidence for autocrine/paracrine function.
Epidermal growth factor (EGF) and its receptor (EGF-R) have been demonstrated in human implantation sites. Transforming growth factor-alpha (TGF-alpha), a protein with extensive sequence homology to EGF and with equal affinity for the EGF-R, was localized immunohistochemically in early intrauterine and ectopic pregnancies. Within the same experiments, TGF-alpha immunostaining was more intense in ectopic than intrauterine pregnancies. In both groups, TGF-alpha immunostaining was moderate to intense in the syncytiotrophoblast (ST), light to moderate in the cytotrophoblast (CT), and moderate to intense in intermediate trophoblast (IT). In ST, TGF-alpha immunostaining localized to the cytoplasm and plasma membranes, including microvilli. No nuclear associated TGF-alpha was noted in ST. In CT, differential TGF-alpha immunostaining was noted between the villous and nonvillous CT. Villous CT demonstrated light to absent cytoplasmic TGF-alpha immunostaining with intense nuclear staining. In contrast, nonvillous CT revealed moderate to intense cytoplasmic staining without demonstrable nuclear staining. These results demonstrate the presence of immunoreactive TGF-alpha in all forms of trophoblast. The known presence of the EGF-R suggests an autocrine/paracrine role for TGF-alpha during human implantation.
Embryo Implantation↗
Immunohistochemical localization of transforming growth factor-alpha in human endometrium, decidua, and trophoblast.
Transforming growth factor-alpha (TGF-alpha) was localized immunohistochemically in human proliferative and secretory endometrium, decidua, and trophoblast from first, second, and third trimester pregnancies. In proliferative endometrium, TGF-alpha immunostaining was moderate to intense and localized predominantly to stromal cells, whereas glandular staining was absent to light. After ovulation, TGF-alpha staining was light within the stroma, but moderate to intense around spiral arterioles. Moderate to intense staining was also detected in glandular and surface epithelium in secretory endometrium, with no staining noted in subnuclear vacuoles. In hypersecretory endometrium, staining was predominantly epithelial. In decidua, TGF-alpha was detected in intermediate trophoblast and on the surface epithelium. In first trimester trophoblast, TGF-alpha was detected in both cytotrophoblast (CT) and syncytiotrophoblast. Cytoplasmic staining was light in CT and moderate to intense in ST, with particular staining of plasma membranes. Intense TGF-alpha staining of nuclear membranes in CT was noted. TGF-alpha staining was light to absent in second and absent in third trimester trophoblast. This study demonstrates immunoreactive TGF-alpha in tissues known to be responsive to epidermal growth factor, and also demonstrates the presence of immunoreactive TGF-alpha associated with nuclear membranes. Thus, TGF-alpha may play an autocrine/paracrine role in endometrial development and trophoblast function.
Decidua↗
A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population.
OBJECTIVE: To assess the results of screening an unselected general infertility population for diminished ovarian reserve with the clomiphene citrate challenge test. METHODS: Two hundred thirty-six couples were followed prospectively and studied for the relationship between clomiphene citrate challenge test screening and final diagnoses and long-term fertility rates. RESULTS: Abnormal clomiphene citrate challenge tests were found in two of 61 (3%) of the patients younger than 30 years, in five of 72 (7%) aged 30-34, in seven of 68 (10%) aged 35-39, and in nine of 35 (26%) aged 40 or older. An abnormal test predicted lower pregnancy rates; conception occurred in 92 of 213 (43%) of patients with normal results, but only two of 23 (9%) of patients with abnormal results (P < .004). Unexplained infertility (not considering the clomiphene citrate challenge test) was a common finding in patients with abnormal clomiphene citrate challenge test results (12 of 23). This incidence was significantly higher than that in patients with normal clomiphene citrate challenge test results (20 of 213) (P < .001). CONCLUSIONS: Approximately 10% of the patients in the general infertility population had abnormal clomiphene citrate challenge tests. The incidence of abnormal results increases with age beginning in the early 30s, occurs with a higher frequency in patients who would otherwise be diagnosed with unexplained infertility, and prognosticates decreased long-term pregnancy rates.
Adult↗
Establishment of an assisted reproduction program in the Armed Forces.
Approximately one in seven couples are infertile. Half of these couples fail to conceive following conventional therapies. Recently, technologies have evolved which provide hope to these couples and lead to cumulative pregnancy rates of 65%. An assisted reproduction (AR) program has recently been established at Wilford Hall Medical Center. The reproductive endocrinologists, on-service residents, and clinic support staff are responsible for all aspects of care including stimulation, retrieval, andrology, embryology, and transfer. To date, there have been 104 transfers with 28 pregnancies. In summary, AR is available in the Armed Forces and allows infertile couples to receive state-of-the-art health care.
Appointments and Schedules↗
Epidermal growth factor and its receptor in human implantation trophoblast: immunohistochemical evidence for autocrine/paracrine function.
Epidermal growth factor (EGF) and its receptor (EGF-R) were immunohistochemically localized in trophoblast during human implantation from intrauterine and ectopic pregnancies. EGF immunostaining was absent to light in the cytotrophoblast (CT), light to moderate in intermediate trophoblast (IT), and intense in the syncytiotrophoblast (ST). In ST, EGF immunostaining was found mostly in the cytoplasm; however, staining of the plasma membrane was also noted. Immunostaining for the EGF-R was absent to light in the CT and moderate to intense in the IT. Immunostaining for the EGF-R was intense in the ST, with moderate staining in the cytoplasm and intense staining in the plasma membrane. Staining was most intense on the microvilli of the ST. Additionally, EGF-R immunostaining could be demonstrated on nuclear membranes. The increase in the intensity of the immunostaining for both EGF and EGF-R noted in CT, IT, and ST suggests a differentiated expression of this receptor-ligand system in human trophoblast and provides evidence for an autocrine/paracrine role for EGF in trophoblast function. The presence of this receptor-ligand system during early human implantation strongly supports a role for EGF and the EGF-R in embryo-uterine signalling and the implantation process.
Embryo Implantation↗
The window of embryo transfer and the efficiency of human conception in vitro.
Women with ovarian failure transferred with donated oocytes provide a unique in vivo model for the elucidation of the window of implantation and efficiency of reproduction in the human. Throughout 52 ovum donation cycles, the temporal window of endometrial receptivity was tested by replacing 2- to 12-cell embryos between days 16 and 24 of hormonally and histologically defined cycles. Of 37 transfers within days 17 to 19, 15 (40.5%) conceptions occurred. Twelve (32.4%) have reached viability. Of 11 patients transferred on days greater than or equal to 20, none conceived. Likewise, no pregnancies were achieved with 4 transfers on cycle day 16. Analysis of multiple embryo transfers within the suggested window of endometrial receptivity (days 17 to 19) revealed 14 of 24 (58.3%) to be conception cycles. considering only transfers with two or more embryos, at least one of which is of high quality (grades 1 to 2), yielded a 63.2% pregnancy rate. The results indicate a very high efficiency for in vitro fecundity provided optimal conditions are attained. The concepts leading to success in the ovum donation model should set the course for continued research toward improving results in other forms of assisted reproduction.
Abortion, Spontaneous↗