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Circulating levels of Ang-2 and sTie-2 receptor were detectable but invariant in women during COS cycles. During the postimplantation period, the rise in Ang-2 (but not sTie-2) levels probably reflects placental rather than luteal production.

Previous reports showed that 17beta-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca2+ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin + the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by >72 h in 17beta-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-beta (ER-beta) binding activity, estriol (E3), suppresses in vivo and in vitro CH. E3 treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin + U-46619 challenge. In vitro treatment of rhesus coronary VMC for >72 h with nanomolar E3 attenuated late Ca2+ signals. This reduction of late Ca2+ signals also appeared after >72 h of treatment with subnanomolar 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an endogenous dihydrotestosterone metabolite with ER-beta binding activity. R,R-tetrahydrochrysene, a selective ER-beta antagonist, significantly blocked the E3- and 3beta-Adiol-mediated attenuation of late Ca2+ signal increases. ER-beta and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E3 treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E3 or 3beta-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E3- and 3beta-Adiol-mediated reduction in persistent Ca2+ signals is associated with ER-beta-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle.

Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A(2) analog U46619 stimulated brief vasoconstriction (for 1-3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.

Objective: Preimplantation genetic diagnosis is an established technique that provides an alternative to prenatal diagnosis for patients who are at risk of transmitting a serious genetic disorder to their offspring. Preimplantation genetic diagnosis has been used for couples who have been at risk for having offspring with single gene or X-linked disorders and for screening for common age-related aneuploidy and in couples who themselves carry balanced chromosomal rearrangements. The aim of this study was to summarize our experience using preimplantation genetic diagnosis after the identification of a parental balanced translocation, specifically as it relates to the number of embryos that are suitable for transfer after preimplantation genetic diagnosis for a known translocation and aneuploidy screening., Study Design: This is a retrospective review of data from a single center that involved 6 couples that initiated the process of preimplantation genetic diagnosis for translocation and aneuploidy screening by fluorescent in situ hybridization., Results: A total of 65 embryos were obtained, of which 56 embryos (86%) were suitable for fluorescent in situ hybridization analysis. After fluorescent in situ hybridization, 1 embryo was diagnosed as normal or balanced (1.7%). Forty-three embryos (76.8%) were unbalanced for the translocation; 8 embryos (14.3%) were aneuploid, and 4 embryos (7.1%) were uninformative. There were no clinical pregnancies., Conclusion: In our experience, there are very few embryos that are available for transfer from these patients after translocation and aneuploidy screening because of multiple unbalanced segregation products and a high rate of aneuploidy. Factors that contributed to this may be related to which parent carries the translocation, methods that were used for in vitro fertilization, and advanced maternal age. Although preimplantation genetic diagnosis for translocation carriers theoretically can enhance the pregnancy rate for a couple, there are limitations. This information should be shared with couples who are contemplating preimplantation genetic diagnosis for translocation, and the options of sperm or egg donor should be considered.

Objective: To test if transdermal progesterone (P) confers coronary vascular protection in surgically menopausal preatherosclerotic rhesus monkeys., Methods and Results: Ovariectomized rhesus monkeys fed an atherogenic diet (AD) for 19 months were treated with an investigational transdermal P cream (n=7) or identical placebo cream (n=5) for 4 weeks. Aorta and carotids showed fatty streaks and Oil Red O staining demonstrated lipid deposition. Serum P levels in P-treated rhesus monkeys (0.6 ng/mL) were significantly greater than placebo (0.2 ng/mL). Significant elevation of cholesterol, LDL cholesterol, and HDL cholesterol, was noted in all animals. Lp(a) was significantly attenuated in the AD-fed P-treated monkeys. Coronary angiographic experiments stimulating vasoconstriction by intracoronary injections of serotonin plus U46619 showed exaggerated prolonged actions amplified by AD, but significant protection against severe prolonged vasoconstriction in P-treated monkeys. Immunocytochemistry confirmed co-expression of P and thromboxane prostanoid (TP) receptors in coronaries and aorta. Western blotting demonstrated TP receptor attenuation in vascular muscle after P treatment., Conclusions: Coronary hyperreactivity, a putative component of coronary artery disease mediated via increased vascular muscle thromboxane prostanoid receptors, can be prevented by subphysiological levels of P, not only in nonatherosclerotic (previously shown) but also in preatherosclerotic primates.

Background: In a prospective study we measured circulating levels of vasoactive factors and their soluble receptors in women undergoing controlled ovarian stimulation (COS) for IVF who were at risk for ovarian hyperstimulation syndrome (OHSS), and compared them to those in a primate model, the rhesus monkey., Methods: A total of 23 women were enrolled in the study and serum vascular endothelial growth factor (VEGF)-A (free and total), soluble (s)VEGF-R1 and -R2, and angiogenin levels were compared in pregnant and non-pregnant women, and in monkeys, during follicular stimulation, the luteal phase and early pregnancy., Results: VEGF levels were similar during the period of follicular stimulation in pregnant and non-pregnant women, but a significant rise in both free and total VEGF occurred in pregnant women during the luteal phase (P < 0.05). The level of sVEGF-R1 (but not -R2) increased (P < 0.05) following implantation, and the rise in sVEGF-R1 corresponded to an abrupt fall in free (but not total) VEGF. In contrast, total VEGF levels remained similar to those observed on the day of hCG injection. Angiogenin levels tended to decline during follicular stimulation, then increased marginally during the luteal phase and were unchanged in early pregnancy. In contrast to women, free VEGF levels were non-detectable and total levels remained constant through the natural menstrual cycle and COS protocols in monkeys., Conclusions: The levels of circulating angiogenic factors and soluble receptors demonstrate significant changes during COS cycles and early pregnancy in women. Thus, the systemic effect of these agents is influenced by ligand-receptor protein-binding interactions, and these relationships may exhibit dynamic changes during COS cycles and early pregnancy, and could contribute to the development of OHSS.

Objective: To evaluate alternatives for couples with severe male factor infertility who fail to conceive with IVF-intracytoplasmic sperm injection (ICSI)., Design: Outcomes of couples using artificial insemination with donor sperm (AID) after failed IVF-ICSI, assessing multiple risk factors affecting prognosis., Setting: University infertility service., Patient(s): Nineteen patients with complex infertility disorders who failed IVF-ICSI and subsequently used AID (1 to 7 cycles)., Intervention(s): Artificial insemination with donor sperm was performed 36 hours after detection of an LH surge or hCG injection., Main Outcome Measure(s): Pregnancy outcomes were determined., Result(s): Seventeen pregnancies occurred in 16 women associated with AID for a pregnancy rate per cycle of 27.9% within a mean of 3.2 +/- 18 cycles. Live birth rate per cycle was 24.6%., Conclusion(s): A high pregnancy rate was achieved with AID in women who failed IVF-ICSI. Given the low cost and effectiveness of AID in this series, consideration of AID is a reasonable and effective option even in couples with poor prognosis who fail to conceive with IVF-ICSI.

Objective: To compare fecundity rates following intrauterine insemination (IUI) with donor sperm frozen conventionally versus an IUI-ready preparation., Design: Both retrospective results and a prospective, randomized study where recipients were assigned to one of two sperm cryopreservation methods in each cycle of intrauterine insemination are reported., Setting: University-based infertility practice, affiliated private practices, and andrology laboratory., Patient(s): Women desiring therapeutic insemination in an effort to establish pregnancy., Intervention(s): Intrauterine insemination with donor sperm frozen conventionally or by an IUI-ready protocol., Main Outcome Measure(s): Cycle fecundity in donor IUI recipients., Result(s): In a retrospective analysis involving 642 inseminations in 209 recipients, 79 pregnancies were recorded for an overall pregnancy rate of 12.3% per insemination (or cycle): 11.3% with IUI-ready sperm and 13.9% with conventionally preserved sperm. In a follow-up prospective, randomized study, the pregnancy rate for IUI-ready sperm preparations was 36% per cycle (14 of 39) whereas that for conventionally preserved sperm was 19.6% per cycle (9 of 46). Thirteen of the 23 pregnancies occurred in the first study cycle of insemination; only two pregnancies were observed in patients undergoing more than four cycles of insemination., Conclusion(s): Cycle fecundity for IUI-ready donor sperm is equivalent to conventional cryopreserved sperm based on both prospective and retrospective assessments.

Objective: Blastocysts are advanced-stage embryos with high implantation potential; theoretically, limited numbers of blastocysts can be used for embryo transfer to achieve good pregnancy rates with low multiple pregnancy rates. Clinical outcomes of a newly implemented blastocyst transfer program were evaluated., Study Design: This study is a retrospective analysis of 553 blastocyst transfer cycles performed by a university-based in vitro fertilization program; risk factors associated with multiple gestations were analyzed., Results: An average of 2.2 embryos were used for embryo transfer. The overall clinical pregnancy rate per embryo transfer was 45.1%; multiple gestation, twin, and triplet rates were 40.9%, 36.5%, and 4.3%, respectively. Multiple gestations increased significantly (1) when embryo transfer was done on day 5, (2) when > or =2 blastocysts were present on day 5, and (3) when maternal age was < or =30 years., Conclusion: In spite of a conservative approach to the number of blastocysts used for embryo transfer, the overall multiple pregnancy rate was high, and triplet pregnancies did occur.

Objective: To evaluate the selection process and cost of screening oocyte donors., Design: Retrospective analysis., Setting: University-based IVF program., Patient(s): Potential oocyte donors., Intervention(s): Outcomes of all inquiries by individuals responding to recruitment advertisements for oocyte donors over a 10-month period were assessed. Recruitment and screening costs to bring a single donor into the program were calculated., Main Outcome Measure(s): The attrition rate for each step of the oocyte donor screening process was determined. The costs assessed over the study period included the following: advertisement, administrative, professional, ultrasound, and blood screening. The total cost to bring a single donor into the program was calculated., Result(s): Advertisements led to 315 phone inquiries from potential oocyte donors. Of these, a total of 223 (71%) voluntarily withdrew from the screening process, 54 (17%) were screened out for medical or psychological reasons, and 38 (12%) entered the active donor pool. The total cost to bring a single donor into the program was approximately 1,869 dollars., Conclusion(s): There was significant attrition in the screening process for oocyte donation that needs to be taken into account in determining the costs of managing the program.

Objective: To study and evaluate a sequential, extended embryo culture system., Design: Prospective study., Setting: University-affiliated IVF clinic., Patient(s): All couples who were treated between October 1997 and July 1998., Intervention(s): A standard human tubal fluid plus 10% serum substitute supplement (SSS) culture medium was used. The embryos were transferred to extended culture medium (S2 or G2) on day 3., Main Outcome Measure(s): Blastocyst formation and implantation and pregnancy rates., Result(s): Forty percent of the 20 donated cryopreserved embryos progressed to the blastocyst stage by day 6. Clinically, 7 (5.6%) of the 125 cycles did not result in a transfer. Blastocyst formation rates ranged from 33%-63% in the five study groups. Implantation rates ranged from 15%-52% and pregnancy rates ranged from 37%-75%., Conclusion(s): Extended culture to day 5 or 6 results in acceptable blastocyst formation rates, implantation rates, and pregnancy rates.

Objective: Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms., Study Design: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch., Results: The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo (P <.05) from week 2 onward in the Esclim 50 and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity was also reduced. Estrogen-related adverse events, particularly metrorrhagia and endometrial hyperplasia, were less frequent in the Esclim 25 group than in the higher-dosage groups., Conclusion: All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio.

Objective: The objective of this study was to evaluate the serum levels of progesterone resulting from the application of a progesterone cream to the skin., Study Design: Six postmenopausal women were evaluated at a university clinic over a 4-week period., Results: Transdermal estradiol 0.05 mg was applied 2 days before the first application of progesterone (30 mg/d) and was continued throughout the study. Patches were changed twice a week. Progesterone cream was applied once a day for 2 weeks. On day 15 and for the next 2 weeks, the progesterone cream was applied twice daily (60 mg/d). Serum 17beta-estradiol and progesterone were measured at 9 different times over a 24-hour period on day 1 and at weekly intervals for the 4-week duration of the study. Serum 17beta-estradiol concentrations varied among women, with mean concentrations of 40 to 64 pg/mL observed. Consistency in 17beta-estradiol concentrations was found within individual persons throughout the study. Serum progesterone concentrations also varied among women, with mean concentrations ranging from 1.6 to 3.3 ng/mL. After 2 weeks of percutaneous dosing, progesterone concentrations were sustained for at least 8 hours and were consistent within a given person. An appropriate increase in progesterone concentration occurred after 4 weeks compared with 2 weeks of application. Individually, a 0.53 correlation, significant at P <.0001, was seen between the absorption of 17beta-estradiol and progesterone., Conclusion: Significant increases in serum concentrations of progesterone were observed in all of the women studied. The percutaneous absorption of progesterone correlates strongly with the absorption of transdermal 17beta-estradiol. There is variance in absorption of progesterone just as with 17beta-estradiol, and the 2 measures are closely correlated. The percutaneous application of progesterone cream appears to be a safe and effective route of administration.

Objective: Our purpose was to evaluate the viability and transfer efficiency of cryopreserved embryos allowed to develop into blastocysts in extended culture for in vitro fertilization., Study Design: The embryos for in vitro fertilization that had been cryopreserved at either 2 PN (pronuclear) or cleaving stage (day 1-3) were thawed and cultured for uterine transfer on day 5. Outcome for day 5 embryo transfer was prospectively compared with previous outcomes from embryos transferred on day 2 or 3., Results: For embryos thawed and transferred on day 2 or 3 (n = 99), the pregnancy rate was 33%, the implantation rate per embryo transferred was 15.2%, and the rate of multiple gestations was 42.4% (14/33) with 35.7% of pregnancies having >/=3 gestational sacs. For extended culture embryos transferred on day 5 (n = 25), the pregnancy rate was 36%, the implantation rate per embryo transferred was 16.7%, and the rate of multiple gestations was 33.3% (3/9) with all of these being twins. For embryo transfers performed on day 5 in which only blastocysts were transferred (n = 9), the pregnancy rate was 66.7%, the implantation rate per blastocyst was 44.4% (greater than the rate for the day 2 or 3 embryos, P =.0043), and the rate of multiple gestations was 33.3% (2/6) with all of these being twins. In extended culture 29.8% of cryopreserved embryos progressed to the blastocyst stage. In this series 4 subjects (15.4%) did not have blastocysts by day 5., Conclusion: Acceptable pregnancy rates can be obtained from cryopreserved embryos cultured to the blastocyst stage with a significantly higher implantation rate. Transfer of embryos that have "self-selected" to blastocysts results in reduced risk of higher-order (>2) multiple gestations, because only 1 or 2 embryos are transferred.

Objective: To examine fecundability trends among sperm donors., Design: Retrospective analysis., Setting: University-based sperm bank and donor insemination program., Patient(s): Sperm donors and recipients., Intervention(s): A group of recipients underwent IUI with cryopreserved donor sperm. Fecundability was calculated for 20 sperm donors over 800 insemination cycles., Main Outcome Measure(s): Average fecundability per donor was compared for the first 40 cycles of a donor's use and for those donors within a group of more fertile recipients. Sperm parameters, recipient ages, and number of unique recipients for each donor were analyzed., Result(s): Average donor fecundability is constant; however, individual donors demonstrated differences among their fecundabilities (overall mean, 0.09; range, 0.01-0.26). These differences persisted for donors among a group of more fertile recipients (overall mean, 0.12; range, 0.02-0.35). A donor's fecundability at 15 cycles is predictive of his future performance., Conclusion(s): Differences in fecundability exist among sperm donors which cannot be discerned through routine semen parameters. Sperm donor fecundability should be analyzed periodically, and directors of sperm banks should consider discontinuing use of a donor whose outcome is substandard.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) originating from the follicle or corpus luteum may be a physiological regulator of ovulation and neovascularization of luteinizing tissue, as well as a pathological factor in the development of ovarian hyperstimulation syndrome (OHSS). The objective of this study was to quantify VEGF production by human luteinized granulosa cells in vitro and to determine if gonadotrophin stimulates VEGF production directly and/or indirectly via enhanced synthesis of progesterone. In study 1, luteinized granulosa cells collected from women undergoing ovarian stimulation for in-vitro fertilization were cultured in the presence and absence of human chorionic gonadotrophin (HCG; 100 ng/ml) and/or low density lipoprotein (LDL; 100 microg protein/ml). In study 2, the progesterone synthesis inhibitor trilostane (250 ng/ml) and/or a progesterone receptor antagonist ZK137.316 (3.2 microM) were also added. Medium was harvested on days 1, 3, 5, 7 and 9 of culture and assayed for VEGF and progesterone. Results of study 1 were divided into two categories based on control concentrations of VEGF on day 1: 'low producers' (n = 6; <750 pg VEGF/ml) and 'high producers' (n = 5; >1000 pg VEGF/ml; P < 0.01). VEGF concentrations in cultures of both low and high producers increased (P < 0.01) from day 1 to maximal values on day 3, then steadily declined through to day 9. Chronic exposure to LDL or HCG increased (P < 0.05) VEGF concentrations in cultures of low producers by day 3 and day 5 respectively. In contrast, LDL did not alter VEGF concentrations in cultures of high producers and HCG did not increase VEGF concentrations until day 7. Nevertheless, acute exposure to HCG beginning on day 7 increased (P < 0.05) VEGF concentrations 3-fold in cultures of low or high producers. In study 2, trilostane treatment decreased (P < 0.05) progesterone concentrations by 91% on day 1 of culture but had no effect on VEGF concentrations on any day. ZK137.316 alone or with trilostane did not affect VEGF synthesis. These results suggest that VEGF production by luteinized granulosa cells is enhanced by gonadotrophin (HCG) independent of gonadotrophin-stimulated progesterone synthesis. These data are consistent with the hypothesis that the exacerbation of OHSS in early pregnancy is mediated by the CG stimulation of luteal VEGF production.

Objective: To study the differential effects of subcutaneous E2 alone or in combination with P on the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation in naturally postmenopausal diet-controlled rhesus monkeys., Design: Prospective, longitudinal controlled study., Setting: Oregon Health Sciences University, Portland, Oregon, and Oregon Regional Primate Research Center, Beaverton, Oregon., Patient(s): Five naturally postmenopausal rhesus monkeys., Intervention(s): Estradiol was administered subcutaneously for the first 4 weeks, followed by E2 plus P for 4 weeks, followed by a third 4-week washout period., Main Outcome Measure(s): Changes in plasma lipoprotein levels and oxidation of LDL and serum concentrations of E2 and P., Result(s): Levels of LDL cholesterol fell after 4 weeks of treatment with E2, compared with baseline. The lag time to half maximal light absorbancy after 4 weeks of E2 treatment was significantly increased compared with baseline. The maximal absorbance values and the slope of the propagation phase after 4 weeks of treatment with E2 were decreased compared with baseline. After 4 weeks of combined E2 and P treatment, all values were comparable to baseline., Conclusion(s): These results suggest that subcutaneous E2 therapy appears to enhance LDL resistance to oxidation and that this effect is attenuated by the addition of the P.

Objective: To define the relationship between serum and follicular fluid (FF) levels of vascular endothelial growth factor (VEGF), E2, and P in patients undergoing IVF; to quantify the effects of hCG on serum levels of VEGF during early pregnancy, and to report serial measurements of serum and ascites fluid levels of VEGF in a patient with severe ovarian hyperstimulation syndrome (OHSS)., Design: Prospective observational study., Setting: University IVF program., Patients(s): Women undergoing conventional IVF, receiving donated oocytes or spontaneously conceiving. One patient hospitalized with severe OHSS., Main Outcome Measure(s): Concentrations of VEGF, E2, and P in serum, FF, or peritoneal fluid., Result(s): At the time of egg retrieval, FF VEGF concentrations were positively correlated with serum and FF P concentrations and with patient age. At 11 to 14 days after ET, pregnant recipients of autologous fresh embryos had higher serum VEGF levels than both nonpregnant recipients of autologous fresh embryos and pregnant recipients of donor eggs. Elevated serum VEGF levels in a patient with severe OHSS coincided with the clinical onset and recurrence of symptoms., Conclusion(s): In patients undergoing IVF, FF VEGF levels at the time of egg retrieval correlated with the degree of follicular luteinization. There is a significant ovarian contribution to circulating VEGF levels during early gestation. Elevated serum VEGF levels may be a factor in the etiology of OHSS symptoms.

Objective: To test a sucrose-glycerol cryoprotectant for IUI-ready sperm preparation., Design: Semen aliquots from normozoospermic donors either were subjected to conventional semen freezing (TES and Tris yolk buffer in 7.4% final glycerol) with post-thaw processing or were preprocessed and frozen in HEPES-buffered human tubal fluid with 1% human serum albumin, 4% sucrose, and 6% glycerol. All aliquots were cooled to 4 degrees C, exposed to liquid nitrogen vapors, and stored in liquid nitrogen. Aliquots from each were processed by centrifugation resuspension or by centrifugation in Percoll (Pharmacia, Alameda, CA) before sperm parameters were analyzed., Setting: University-based andrology laboratory., Main Outcome Measure(s): Recovery of motile sperm., Result(s): Percoll processing produced preparations with higher percentages of motile cells; however, cryopreserved sperm had a lower recovery of motile sperm compared with Percoll-processed fresh semen or centrifugation/resuspension-processed fresh or frozen samples. The percentages of sperm with normal morphologies were significantly increased in the IUI-ready samples compared with samples frozen conventionally. The IUI-ready Percoll-processed sample produced the best results, with a final mean motility of 36% and an overall yield of motile sperm of 17.4%., Conclusion(s): The sucrose-glycerol-based cryoprotectant produced an IUI-ready preparation with motile sperm recovery comparable to that of conventional semen cryopreservation but with improved percent morphology.

Objective: Our purpose was to determine whether aortic size and compliance are altered by an exogenously induced rise in estrogen., Study Design: Magnetic resonance imaging was used to determine the aortic cross-sectional area/aortic pressure relationship in nine premenopausal women before and after menotropin therapy. Simultaneous electrocardiograms, carotid pulse tracings, phonocardiograms, and brachial artery pressures were obtained before each magnetic resonance imaging acquisition. Ascending thoracic aorta cross-sectional area was obtained every 32 msec and aligned with brachial artery pressures extrapolated from the carotid pulse tracing, allowing construction of the ascending thoracic aorta cross-sectional area/aortic pressure relationships. Aortic cross-sectional area was normalized to body surface area, and the shifts in the position for the ascending thoracic aorta cross-sectional area/aortic pressure relationship were determined with use of analysis of covariance., Results: Heart rate and aortic pressure were unchanged before and after menotropin treatment. Initial estradiol levels were < 20 pg/ml. After menotropin treatment (7.4 +/- 1.0 days) estradiol levels rose to 905 +/- 371 pg/ml (p < 0.0001). Ascending thoracic aorta cross-sectional area/body surface area was not significantly increased, adjusted y mean of 389 +/- 7 mm2/m2 before and 403 +/- 7 mm2/m2 after menotropin treatment (p < 0.24). The slope of the ascending aorta cross-sectional area/aortic pressure relationship, an index of aortic compliance, increased from 1.4 +/- 0.6 mm2/m2/mm Hg before to 1.7 +/- 0.6 mm2/m2/mm Hg after menotropin treatment (p < 0.001)., Conclusion: In premenopausal women a short-term rise in estrogen induced by menotropin treatment is associated with an increase in aortic compliance. Aorta size is not significantly increased within this time frame.

Oestrogen and progesterone are promoters of uterine leiomyoma growth: oestrogen receptors (ER) and progesterone receptors (PR) are over-expressed in these tumours. Paradoxically, there is a heterogeneity in responsiveness of leiomyoma growth to oestrogen and progesterone in culture. In this study, leiomyoma and adjacent myometrium were obtained at hysterectomy. The effect of oestrogen and progesterone on steroid receptor maintenance was examined using minced explants. Quantitative enzyme-linked immunoassay and Northern analysis were performed to assess ER and PR protein and mRNA content respectively. There was an approximately 75% decrease in ER and PR protein content within 8 h of incubation in both leiomyoma and myometrium. The presence or absence of oestrogen and/or progesterone had no effect on receptor protein loss. Northern analysis indicated a parallel loss of ER and PR mRNA transcripts. These findings suggest that the ER and PR expression in leiomyoma may require other extracellular factors. In-vitro studies designed to test the effects of sex steroids and their respective inhibitors on growth and function of leiomyoma and myometrial cells should consider this phenomenon.

Objective: Our purpose was to determine whether sex steroids alter aortic size and compliance in postmenopausal women., Study Design: Twenty-six postmenopausal women were randomized to receive either conjugated estrogens 0.625 mg per day (group 1) or conjugated estrogens 0.625 mg per day and medroxyprogesterone 2.5 mg per day (group 2). Aortic cross-sectional area was measured by magnetic resonance imaging before and after 3 months of hormone therapy., Results: Estradiol levels increased in both group 1 and group 2 (p < 0.0001). Ascending aortic cross-sectional area increased from 439 +/- 7 mm2 to 466 +/- 7 mm2 in group 1 (p < 0.008) but was unchanged in group 2. Within the range of aortic pressures studied, no change in aortic compliance could be detected., Conclusion: Estrogen therapy in postmenopausal women was associated with an increase in aortic size; but this effect was not detectable with the addition of progestin. The potential antagonistic effect of progestin on estrogen-induced aortic enlargement suggests that the favorable cardiovascular effects of postmenopausal estrogen therapy cannot be automatically extended to the combination estrogen-progestin.

Objective: Our purpose was to determine whether insulin-like growth factors I and II preferentially stimulate uterine leiomyoma cells versus myometrial cells in monolayer culture., Study Design: Leiomyomas and normal myometrium were obtained at hysterectomy from five premenopausal women. Specimens were enzymatically digested for use in primary monolayer cell cultures. By use of serum-free media, insulin-like growth factor I or II was added in 1, 10, and 100 ng/ml concentrations to both cell types with the patient serving as her own control. Cell number, prolactin production, and proliferative index values were measured on day 15 of cell culture., Results: Significant increases in cell number were found in the leiomyoma cultures (p < 0.05) treated with 10 and 100 ng/ml insulin-like growth factors I but not with insulin-like growth factors II. Neither factor exerted a stimulatory effect on myometrial cells., Conclusion: Insulin-like growth factors I preferentially stimulates leiomyoma cells in monolayer culture. These results suggest an autocrine-paracrine role in vivo for this factor in conjunction with gonadal steroids in promoting leiomyoma growth.

Objective: This study was designed to compare the results of preliminary evaluation, ovarian hyperstimulation, and monitoring of patients at a distant in vitro fertilization satellite center with those treated at the main campus of the program., Study Design: Fifty-four patients completing oocyte retrieval cycles at the Eugene satellite Oregon Health Sciences University in vitro fertilization program for the period Jan. 1, 1991, through Dec. 31, 1993, were compared with 222 patients at the main campus for age, peak estradiol level, number of oocytes retrieved, number of embryos, clinical pregnancy rate, and pregnancy outcome., Results: There were no statistically significant differences between the Eugene in vitro fertilization satellite center and the main campus for any of the factors analyzed with the exception of clinical pregnancy rate. The clinical pregnancy rate per cycle at the Eugene satellite center was 39% while the Portland main campus rate was 23% (p = 0.027), presumably because of a larger number of couples with severe male factor infertility at the central site., Conclusion: A distant in vitro fertilization satellite program was highly successful in the Oregon experience. In addition to greater convenience to the patients, the program was highly comparable to the main campus program in measured parameter of ovarian hyperstimulation, oocyte retrieval, number of embryos, and pregnancy rate.

Estrogen and progestin are believed to be important physiological regulators of uterine leiomyoma growth. We recently showed that progesterone receptor messenger ribonucleic acid (mRNA) and protein levels are increased in human uterine leiomyomas compared with those in myometrial biopsy tissue obtained from the same patient. To further characterize the molecular mechanisms underlying abnormal growth of uterine leiomyomas, we analyzed biopsy samples of tumor and adjacent normal myometrium for estrogen receptor (ER) gene expression. Northern analysis indicated that ER mRNA levels were increased 1.4-to 12.6-fold in leiomyoma compared with myometrium in all patients examined (n = 11), whereas beta-actin mRNA was not different between the two groups. The size of the primary ER mRNA transcript was 6.2 kilobases in both leiomyoma and myometrium, indicating no gross mutation of the ER gene. An ER protein of 66 kilodaltons was detected by Western blot analysis, and quantitative immunoassay of ER revealed 9448 +/- 1955 fmol/mg DNA in leiomyoma compared to 2827 +/- 979 fmol/mg DNA in myometrial tissue. Scatchard analysis of 17 beta-estradiol binding to cell-free extracts revealed enhanced binding capacity (per mg DNA) in leiomyoma tissue (n = 6) of about 6-fold, whereas ER binding affinity was not substantially different between the leiomyoma and adjacent myometrial tissues. We propose that increased expression of progesterone receptor in leiomyoma is most likely a consequence of overexpression of functional ER that results in increased end-organ sensitivity to estradiol.

Objectives: To determine the effectiveness of a 3-month course of nafarelin and, furthermore, to determine the long-term efficacy in patients treated for 3 and 6 months with nafarelin for symptoms associated with endometriosis., Design: Double-blind, prospective, multicenter, clinical trial., Setting: Fifteen reproductive endocrine clinics throughout the United States., Patients: One hundred seventy-nine women with pelvic pain and endometriosis., Interventions: Patients were assigned randomly to 3 months nafarelin followed by 3 months of placebo (n = 91) or to 6 months nafarelin (n = 88) in a prospective, randomized, double-blind multicenter trial. Patients were followed for 12 months after cessation of therapy., Main Outcome Measures: Patient-reported pain scores and physician-reported physical exam findings., Results: Pain scores dropped significantly by the end of treatment in both groups. Symptoms recurred in both groups, and pain scores gradually increased during the follow-up period but always remained below baseline in both groups. No significant difference in efficacy was noted between the groups. A total of 26% of patients in each group underwent retreatment for recurrent symptoms., Conclusions: A 3-month course of nafarelin provided effective symptom relief for endometriosis. One year follow-up demonstrated continued pain relief but with gradual return of symptoms.

Objective: To investigate the role of transcervical tubal catheterization in diagnosis and treatment of proximal tubal obstruction associated with salpingitis isthmica nodosa., Design: Retrospective case study., Setting: University hospital and outpatient radiology practice., Patients: Fifty-two women with proximal tubal obstruction associated with salpingitis isthmica nodosa., Intervention: Selective salpingography and catheter recanalization using fluoroscopic guidance., Main Outcome Measures: The number of tubes visualized to the fimbria as a percentage of the tubes with proximal tubal obstruction on the initial hysterosalpingogram was determined as a measure of diagnostic efficacy. To evaluate the treatment potential of catheter recanalization, the patients were grouped according to tubal status at the conclusion of the procedure and subsequent pregnancies were evaluated., Results: Forty-seven of 65 tubes (72%) with proximal tubal obstruction were recanalized successfully. Among the 19 women who were able to conceive only via a recanalized salpingitis isthmica nodosa tube, there were 6 live births (32%) and two tubal pregnancies (10%)., Conclusion: Selective salpingography allows complete tubal diagnosis in almost three fourths of patients with proximal tubal obstruction and salpingitis isthmica nodosa. The radiographic diagnosis of salpingitis isthmica nodosa may be pressure dependent. Intrauterine pregnancies occur via recanalized salpingitis isthmica nodosa tubes, therefore catheter recanalization may be attempted before tubal microsurgery or IVF in patients with proximal tubal obstruction and associated salpingitis isthmica nodosa.

Objective: The study intent was to examine long-term effects on bone mass of 3 or 6 months of nafarelin therapy for endometriosis., Study Design: Women with established endometriosis (N = 173) were randomized to receive nafarelin (200 micrograms intranasally twice a day) for either 3 or 6 months in a double-blind fashion. Bone mineral density was measured by dual energy x-ray absorptiometry at lumbar spine and proximal femoral sites for 18 months., Results: Bone mineral density declined at spinal and femoral sites similarly in both 3- and 6-month treatment groups. There was a partial, but incomplete, return to baseline levels after 12 to 15 months of follow-up. The recovery of bone mass was more complete in subjects with higher dietary calcium intakes., Conclusion: Nafarelin therapy for endometriosis results in a sustained loss of spinal and femoral bone density, particularly in women with lower calcium intakes.

Objective: Our purpose was to identify molecular mechanisms underlying abnormal growth of uterine leiomyomas., Study Design: Biopsy samples of tumor and adjacent "normal" myometrium from nine patients were analyzed for progesterone receptor gene expression and for proliferation-associated antigen Ki-67., Results: Northern analysis indicated that progesterone receptor messenger ribonucleic acid levels were increased twofold to 15-fold in leiomyoma compared with adjacent myometrial biopsy tissue from all patients (n = 9), whereas beta-actin messenger ribonucleic acid was at similar levels in these samples. Quantitative immunoassay, immunohistochemistry studies, and Western blot analyses revealed increased amounts of progesterone receptor protein in the tumor tissue. Both the progesterone receptor A and B forms were expressed in the leiomyoma and adjacent myometrium. Corresponding to increased progesterone receptor gene expression, the proliferation-associated antigen Ki-67 was also significantly elevated in the leiomyoma tissue., Conclusion: These data provide the first evidence that progesterone receptor messenger ribonucleic acid is overexpressed in uterine leiomyomas, suggesting that amplified progesterone-mediated signaling is instrumental in the abnormal growth of these tumors.

Objective: Our purpose was to evaluate transvaginal ultrasonographic findings in ectopic pregnancies for positive ultrasonographic sign(s)., Study Design: Eighty-nine patients admitted with an ectopic pregnancy from September 1987 through September 1989 were retrospectively reviewed. Sixty-nine had undergone transvaginal ultrasonography within 10 days before surgery. The ultrasonographic examinations were reviewed by four radiologists., Results: Ultrasonography revealed adnexal masses in 54 patients (78%). Thirty-six masses had an appearance consistent with an adnexal ring. Twenty-four adnexal rings demonstrated a thin sonolucent area surrounding the ring, a "halo sign" (67%). A control group of 116 intrauterine pregnancies were evaluated by ultrasonography. Forty-one women had adnexal cysts. Twenty-seven of these had an adnexal ring; only two of these had halos., Conclusion: The halo sign is presumptive evidence of a living ectopic pregnancy and, when identified, may allow earlier diagnosis and intervention.

Objective: To assess the efficacy of intrauterine insemination (IUI) in a donor insemination program., Design: Prospective randomized clinical trial., Setting: Donor insemination program., Patients, Participants: Women undergoing insemination were randomly assigned to receive either IUI or intracervical insemination for a maximum of six cycles., Interventions: None., Main Outcome Measure(s): Cycle fecundity rates between the two routes were compared., Results: The monthly fecundity rate for intracervical insemination was 5.1% compared with 23% by IUI. By life table analysis, pregnancy rates for IUI were significantly higher than intracervical insemination (P = 0.02)., Conclusions: Intrauterine insemination with quarantined donor sperm is superior to intracervical insemination.

Quality of life is important when comparing the relative advantages of nafarelin versus danazol for the treatment of endometriosis. Recent studies have investigated the potential differences between the safety profiles of nafarelin and danazol and the impact of these profiles on the patient's quality of life. Results show that although these drugs have similar efficacy, they are associated with very different safety profiles. Most notable are the androgenic effects such as weight gain associated with danazol. With nafarelin, hypoestrogenic side effects, such as hot flashes, are more common. More important, these differences in safety profiles may prove to be relevant to patient satisfaction and compliance with therapy.

Objective: Patients with endometriosis were studied to investigate hormonal suppression by the gonadotropin-releasing hormone against nafarelin acetate compared with danazol. We hypothesized that the pattern, time course, and degree of gonadotropin and ovarian suppression would be different., Design: The study included 16 patients who were randomized into one of three 6-month treatment protocols., Setting: Patients were recruited from a university hospital setting., Patients: Eligible candidates were 18 to 45 years of age, with regular menses and documented pelvic endometriosis., Intervention: Six-month treatment protocols included nafarelin 800 or 400 micrograms/d, or danazol 800 mg/d., Main Outcome Measures: Serum estradiol (E2), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone were determined before treatment and then monthly. Thirteen patients consented to a 12-hour hospital admission during the 5th and 6th month of treatment to determine LH pulse frequency and amplitude., Results: Estradiol and P were suppressed in all groups, but E2 significantly more by nafarelin than danazol (P less than or equal to 0.01). Nafarelin, 800 micrograms, significantly depressed LH pulse amplitude compared with danazol (P less than or equal to 0.05). Two patients in the nafarelin group had the administration of their medication observed, and both demonstrated single, high-amplitude pulses immediately after administration., Conclusion: Nafarelin is a more potent LH and E2 suppressor than danazol, and the agonist effect of nafarelin may continue to provoke transient gonadotropin responses despite long-term therapeutic suppression.

The endocrine response to controlled ovarian hyperstimulation was reviewed in 94 women undergoing in vitro fertilization during 114 cycles. The purpose of this review was to evaluate the effect of short-term oral contraceptive suppression on the recovery of pituitary gonadotropin function and subsequent controlled ovarian hyperstimulation. Seventy-three cycles (64%) were adequate for oocyte retrieval. In 41 cycles (36%) hyperstimulation was discontinued. The serum 17 beta-estradiol value in women with a poor response was 57 +/- 50 pg/ml on day 8 compared with 376 +/- 334 pg/ml in the women who completed in vitro fertilization (p less than 0.05). The majority of women (84.2%) had a prompt response to controlled ovarian hyperstimulation after short-term oral contraceptive suppression. Most discontinuations were due to dominant follicle selection or luteinizing hormone surge and not to oversuppression by short-term oral contraceptives. Clinical pregnancies occurred in 15 women (20.5% of harvests).

We investigated the use of a gonadotropin-releasing hormone agonist (GnRH-a) to assist in the synchronous entry of a fixed number of subjects into in vitro fertilization (IVF) and gamete intrafallopian tube transfer cycle. Using a protocol in which a GnRH-a was given in the follicular or luteal phase, the clinical pregnancy rate per procedure was 27%. We conclude that the use of a GnRH-a for synchronous cycles in IVF-embryo transfer is efficacious and results in acceptable pregnancy rates.

The relative efficiency of intrauterine insemination with washed spermatozoa versus intracervical deposition of semen was examined in donor insemination for therapeutic reasons. Fecundability in a group of 26 women who desired insemination as a treatment for azoospermia or severe astheno-oligozoospermia in their partner was comparable, despite the 10-fold higher numbers employed using the intracervical route.

We investigated the sensitivity and specificity of serial serum hCG assays to diagnose early ectopic pregnancy in 50 asymptomatic women at risk. The initial two hCG values obtained at 2-5-day intervals were used to calculate doubling time and percentage increase. Twenty-five women had a viable intrauterine pregnancy, 14 an ectopic gestation, ten a spontaneous abortion, and one a molar pregnancy. A normal percentage increase and/or doubling time was observed in 64% of women who eventually proved to have an ectopic pregnancy. Ultimately, 85% of our patients demonstrated abnormal values when subsequent hCG pairs were analyzed. The sensitivity of these tests to diagnose asymptomatic ectopic pregnancy was 36%, with a specificity of 63-71%. We conclude that a normal rise in hCG production does not reliably differentiate an ectopic from an intrauterine pregnancy in the asymptomatic patient.

Fragmentation on removal of an effective and asymptomatic Lippes Loop is reported. The etiology of this event is hypothesized and the patient's managment is discussed. It is likely that fragmentation occurred as a result of material fatigue secondary to movement about the fixed, embedded tip. Surgical removal was effected.

Several studies on artificial insemination by donor (AID) semen have suggested that the gender of infants can be influenced by treatment of the women with clomiphene citrate (CC) and by the type of semen used (fresh versus cryopreserved). We conducted a 3-year prospective clinical trial to test these hypotheses. Two groups of pregnant women were evaluated. Group I (n = 130) comprised women whose ovulation was induced by CC; group II (n = 190) comprised those who conceived during spontaneous ovulatory cycles. In a total of 320 pregnancies, 55 spontaneous abortions occurred, 23.1% in group I and 13.2% in group II (P less than or equal to 0.05). Two tubal ectopic pregnancies occurred in group I. Of the 100 and 165 pregnancies carried to term in the treated and control groups, respectively, 11% and 1.8% involved twins (P less than or equal to 0.005). When only single births were considered, group I had 46.1% males in 89 term pregnancies, and group II had 60.5% males in 162 term pregnancies. Significantly more female offspring occurred in the group treated with CC (P less than or equal to 0.05). Because it is possible that a portion of the effects observed in this study were a function of cryopreservation of the AID semen, we compared data on frozen sperm with data on fresh sperm in terms of abortion, gender, and incidence of multiple births; there were no significant differences. Fertil Steril 40:481, 1983.

Eighty-five normal women underwent external cephalic version (ECV) for breech presentation in the late 3rd trimester. The protocol included real time ultrasonic scanning and pre- and post-procedure electronic fetal monitoring. Subcutaneous terbutaline sulfate (0.25 mg.) was administered to (43/85 or 50.5%) of ECV candidates and rendered the procedure easier for patient and operator. A single operator, head-over-heels technique assisted by supine Trendelenberg's position was used. Rh negative women were routinely administered 300 mcg of immune globulin. Successful ECV (53/85, 62.5%) was related to maternal parity, but not to gestational age nor eventual delivery weight. In this series only engagement of the breech was reliable in predicting ECV failure. Fifty of 51 (98.1%) successfully verted women delivered a cephalic presentation infant at term. Cesarean section was performed in 5/51 of these patients (9.8%) for routine obstetrical indications. In one case, compound presentation at term resulting in dystocia and eventual cesarean section was believed related to prior successful version. In contrast, 15/30 (50%) of the ECV failure patients went on to operative delivery despite a liberal institutional policy toward term vaginal breech trials. In addition, the only serious fetal complication in this series, meconium aspiration, occurred in a vaginally delivered breech infant. It is unlikely that late 3rd trimester ECV will impact on out overall rate of cesarean delivery. In North America prematurity is the greatest risk factor in malpresentation and our policy increasingly is to permit attempts at term breech vaginal delivery. Nonetheless, ECV deserves serious consideration. When successful, ECV avoids the costs and/or risks of either cesarean section or vaginal trial of breech.(ABSTRACT TRUNCATED AT 250 WORDS)

In this double-blind study of changes in plasma lipid and lipoprotein concentrations during 6-month medical treatment of endometriosis, 53 patients were randomly assigned to one of four treatment schedules: danazol, 800 mg/day (n = 10); danazol, 600 mg/day (n = 8); intranasal nafarelin acetate, 800 micrograms/day (n = 10); or intranasal nafarelin acetate, 400 micrograms/day (n = 25). Plasma levels of triglycerides, cholesterol, and low-density lipoprotein, very low-density lipoprotein, and high-density lipoprotein cholesterol fractions were obtained before, during, and 1 month after treatment. High-density lipoprotein2 and high-density lipoprotein3 cholesterol concentrations were measured in selected patients. Body weight was also followed. The drugs were equally effective in achieving symptomatic relief and laparoscopically demonstrated resolution of endometriosis but differed significantly in their effects on lipid concentrations. Nafarelin acetate had no adverse effects on serum lipoprotein concentrations, whereas danazol significantly decreased high-density lipoprotein cholesterol (p less than 0.01), as well as the high-density lipoprotein2 subfraction (p less than 0.05), and increased low-density lipoprotein cholesterol (p less than 0.01). Danazol significantly increased body weight (p less than 0.01), whereas nafarelin did not.

The evaluation of patients complaining of amenorrhea with or without galactorrhea has been greatly enhanced by the availability of serum prolactin determinations and advances in diagnostic radiology. Likewise, the treatment of these patients with ergot derivative has resulted in the return of normal menses, and many pregnancies have been reported. The present report is of a patient with hyperprolactinemic amenorrhea-galactorrhea successfully treated with bromocriptine. A pregnancy followed resumption of menses, and a suprasellar cromophobeadenoma became manifest by producing blindness of the patient. The case is presented with recommendations for diagnosis and treatment.

The described technique simplifies the diagnosis of fallopian tube disease and has promising potential for nonsurgical treatment of female infertility caused by fallopian tube obstruction.

Several species of primates have sex differences in sex steroid-binding protein (SBP), female adults having higher serum binding capacities (micrograms of dihydrotestosterone bound per deciliter) than male adults, e.g., male humans, 1.28 +/- 0.4; human females, 2.86 +4- 0.9; Macaca nemestrina male animals, 5.62 +/- 1.24; Macaca nemestrina female animals, 11.07 +/- 1.85 (means +/- standard deviations). SBP correlates inversely with metabolic clearance rates of testosterone (T). The sex difference was identified in rhesus monkeys, six per group, evaluated 4 years after postpubertal castration: male animals 3.95 +/- 1.14; female animals 5.85 +/- 0.98 (p less than 0.05). Estradiol-17 beta (E2) pellets producing physiologic levels of E2 in female monkeys obliterated the sex difference by increasing SBP in male animals. After withdrawal of E2, physiologic levels of T in male monkeys produced a marked decrease in SBP levels (p less than 0.01), and the sex difference reappeared; castrated female animals and prenatally androgenized female animals responded similarly to T (2.81 +/- 0.81 and 2.64 +/- 0.49, respectively). Both values were greater (p less than 0.05) than that of the male group (2.02 +/- 0.33). These data suggest that the sex steroid milieu influences the binding capacity of SBP for potent androgens in adulthood but that the differentiation of the SBP sex in rhesus monkeys is determined by factors other than prenatal androgen exposure.

This study was designed to determine the efficacy of using OCs prior to ovulation induction in an IVF-ET program. A total of 26 cycles were initiated after gonadotropin suppression with OCs and 22 laparoscopies (84.6%) were performed. A pregnancy rate of 22.7% per laparoscopy and 23.8% per ET was achieved. The results suggest that the use of OCs to regulate oocyte retrieval can result in acceptable pregnancy rates and facilitate efficient time use of IVF-ET personnel.