An extremely luminous panchromatic outburst from the nucleus of a distant galaxy.

Variable x-ray and γ-ray emission is characteristic of the most extreme physical processes in the universe. We present multiwavelength observations of a unique γ-ray-selected transient detected by the Swift satellite, accompanied by bright emission across the electromagnetic spectrum, and whose properties are unlike any previously observed source. We pinpoint the event to the center of a small, star-forming galaxy at redshift z = 0.3534. Its high-energy emission has lasted much longer than any γ-ray burst, whereas its peak luminosity was ∼100 times higher than bright active galactic nuclei. The association of the outburst with the center of its host galaxy suggests that this phenomenon has its origin in a rare mechanism involving the massive black hole in the nucleus of that galaxy.

A comparison of post-thaw results between cryopreserved embryos derived from intracytoplasmic sperm injection and those from conventional IVF.

OBJECTIVE: To study the effect of freezing on early stage embryos derived from intracytoplasmic sperm injection (ICSI) or from IVF. DESIGN: Prospective, controlled clinical study. SETTING: Private IVF center. PATIENT(S): Sixty-seven consecutive patients undergoing frozen-thawed embryo transfer cycles. INTERVENTION(S): Early stage embryos were frozen, thawed, and transferred. MAIN OUTCOME MEASURE(S): Post-thaw survival, implantation and pregnancy rates. RESULT(S): We noted an 88% post-thaw survival rate, an 18% implantation rate, and a 52% pregnancy rate in the ICSI group and 81%, 11%, and 25%, respectively, with conventional fertilization. CONCLUSION(S): Early stage embryos (either zygote or 2-4 cells) derived from ICSI can be frozen with confidence and higher post-thaw survival and pregnancy rates can be achieved when compared with those from conventional IVF.

Clinical application of intracytoplasmic sperm injection using in vitro cultured testicular spermatozoa obtained the day before egg retrieval.

OBJECTIVE: To study the effect of in vitro culture on the quality of human testicular sperm and the efficiency of intracytoplasmic sperm injection with in vitro cultured testicular sperm. DESIGN: Clinical study. SETTING: A private IVF center. PATIENT(S): Twenty consecutively seen IVF patients undergoing testicular biopsies for ICSI. INTERVENTION(S): The testicular specimens were cultured in vitro for 24 hours and the isolated spermatozoa were microinjected. MAIN OUTCOME MEASURE(S): Preincubation and postculture sperm motility, and fertilization, implantation, and pregnancy rates after intracytoplasmic sperm injection. RESULT(S): Motility increased from initial nonmotile or twitching sperm to free motile sperm in 18 of 20 cases. The injection of in vitro cultured testicular sperm resulted in a fertilization rate of 58%, an implantation rate of 20%, and a pregnancy rate of 45%. CONCLUSION(S): A testicular biopsy procedure can be performed the day before egg retrieval. Despite the low initial sperm quality, a high percentage of the prepared testicular sperm showed increased motility after 24 hours of culture. The injection of in vitro cultured testicular sperm into matured oocytes resulted in fertilization, implantation, and pregnancy rates comparable to those obtained with ejaculated sperm.

Maximizing pregnancy rates and limiting higher-order multiple conceptions by determining the optimal number of embryos to transfer based on quality.

OBJECTIVE: To define statistical thresholds for the number of embryos to be transferred to achieve an optimal pregnancy rate and keep higher-order multiple conceptions (pregnancy with more than two fetal sacs with cardiac activity) within an acceptable limit. DESIGN: A retrospective review of patient records. SETTING: Private practice assisted reproductive technology (ART) facility. PATIENT(S): Seven hundred fifty-four consecutive patients who underwent IVF-ET from 1994-1996. INTERVENTION(S): Embryo grading and score system used on day 3 of embryo transfer. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and multiple conception rates. RESULT(S): For women < or =35 years old, transfer of up to four poor-quality, two fair-quality, or two good-quality embryos is optimal to eliminate any risk of higher-order multiple pregnancies. Transfer of four poor-quality, three fair-quality, or two good-quality embryos is recommended for women 36 to 39 years old. In women who are > or =40 years old, five embryos need to be transferred regardless of embryo quality. CONCLUSION(S): The mean cumulative embryo score can be used as a reference to determine an optimal number of embryos to transfer and to predict pregnancy outcome.

Coculture of human embryos with buffalo rat liver cells for women with decreased prognosis in in vitro fertilization.

OBJECTIVE: The coculture of human embryos with epithelial cells may improve both embryo quality and pregnancy rates. In this current study we tested the efficacy of coculture with the buffalo rat liver cell line on pregnancy rates in women with a potentially poor prognosis for success with in vitro fertilization (previous in vitro fertilization failure, advanced maternal age, increased early follicular follicle-stimulating hormone levels, and anovulation). STUDY DESIGN: This prospective controlled study evaluated a total of 203 women (135 coculture, 68 controls) undergoing in vitro fertilization. Implantation rates per embryo, clinical pregnancy rates, and continuing/delivered pregnancy rates were analyzed. RESULTS: Buffalo rat liver cells, which are commercially available, are stable in coculture. Implantation rates (number of sacs with fetal heart motion per embryos transferred) were similar for coculture (19%) and control (18%) embryos. No difference in the rate of continuing/delivered pregnancies per retrieval was noted (17% coculture vs 14% control) in the group with advanced maternal age, but coculture caused a trend toward improved pregnancy rates in the group with ovulatory dysfunction (43% coculture vs 14% control) and the group with previous in vitro fertilization failure (34% coculture vs 28% control). CONCLUSION: This is the first published controlled study to our knowledge that reports the use of the buffalo rat liver cell coculture for human in vitro fertilization in a large number of patients. Our data support consideration of buffalo rat liver coculture for in vitro fertilization for women with previous in vitro fertilization failure and possibly for patients with oocyte or ovulatory dysfunction.

Clinical application of nonselective assisted hatching of human embryos.

OBJECTIVE: To evaluate the effect of nonselective assisted hatching on pregnancy rate (PR) and to provide an alternative and simplified method for clinical application of assisted hatching. DESIGN: Retrospective analysis of clinical data. SETTING: Private infertility practice. PATIENT(S): Women from 258 consecutive stimulated IVF cycles. INTERVENTION(S): Assisted hatching was performed on each transferred embryo regardless of patient history, embryo morphology, or other selection criteria routinely applied to many IVF programs. MAIN OUTCOME MEASURE(S): Pregnancy, live birth, and implantation rates. RESULT(S): Of 258 consecutive patients who had nonselective assisted hatching, 109 (42%) had clinical pregnancies, with 93 (36%) live births and 178 (20%) embryos implanted. CONCLUSION(S): Nonselective assisted hatching resulted in an acceptable PR and provided an alternative and simplified method for clinical application of assisted hatching.

Blastocyst development in co-culture: development and morphological aspects.

A retrospective study was undertaken to determine if initial culture conditions and embryo quality had an effect on subsequent blastocyst development in co-culture for cryopreservation. The apparent effects of freeze-thawing on blastocysts at the ultrastructure level were also observed. On day 3 of culture, embryos were categorized into two groups based on their morphological attributes. Results suggest that the initial culture environment of embryos up to day 3 (5- to 8-cell stage) did not affect the subsequent rate of blastocyst formation in co-culture. However, the initial embryo quality had an impact on blastocyst formation and quality. On day 5.5, 90% (60/67) of the optimal quality embryos (six to eight blastomeres with minimal or no fragmentation on day 3) had attained the blastocyst stage, which was greater (P < 0.01) than the 55% (31/56) observed with the sub-optimal embryos (five to eight blastomeres with 30-50% fragmentation on day 3). Furthermore, 66% (44/67) of embryos initially graded as optimal were suitable for cryopreservation, which was greater (P < 0.01) than attained with embryos of lesser quality (22/56; 39%). At the ultrastructural level, the polarized distribution of plasma membrane microvilli was retained, as was the integrity of the nuclear membrane following thawing.

Embryonic morphology and rate of implantation of human embryos following co-culture on bovine oviductal epithelial cells.

A study was undertaken to evaluate embryonic development and establish pregnancies with human embryos after in-vitro culture in two different systems. Treatment A consisted of culturing zygotes in serum-supplemented human tubal fluid culture medium (HTF). Treatment B consisted of culturing zygotes on a monolayer of bovine oviductal epithelial cells with HTF. At the time of embryo replacement, embryos in treatment B had 4.11 blastomeres present, which was greater (P < 0.05) than the 3.81 present for embryos in treatment A. In addition, the cellular fragmentation rate for treatment A embryos was 1.10, which was greater (P < 0.05) than the fragmentation rate of 0.38 for embryos within treatment B. The incidence of ongoing pregnancy was higher after replacement of co-cultured embryos (treatment B) (43%) than replacement of conventionally cultured embryos (treatment A) (29%). The implantation rate per embryo increased (P < 0.05) from 11.5 to 18.4% after co-culture. In treatment B the proportion of 'spare' embryos developing to expanded blastocysts was 58.5%, which was greater (P < 0.05) than the blastocyst development rate of 29.3% observed for embryos within treatment A.

Gonadotropin dynamics in women receiving immediate or delayed transdermal estradiol after oophorectomy.

A prospective study was performed in 24 premenopausal women to evaluate the gonadotropin dynamics of pharmacologic doses of transdermal estradiol-17 beta (E2) administered after bilateral oophorectomy. Patients were given 0.2-mg transdermal E2 patches for 2 weeks, followed by 0.1-mg patches for 4 weeks either immediately postoperatively (immediate estrogen replacement therapy [ERT]) or beginning 12-14 days after surgery (delayed ERT). Serum gonadotropins and E2 levels were measured serially, and postmenopausal symptoms were prospectively recorded. Administration of 0.2 mg transdermal E2 immediately after surgery suppressed the post-castration rise in gonadotropins for at least 4 days, but LH and FSH levels did increase to the menopausal range after 2 weeks despite continued therapy. Sustained circulating levels of E2 with transdermal E2 therapy were comparable to follicular phase values. Vasomotor symptoms were well controlled by 0.2 mg of transdermal E2 in the majority of patients during the clinical trial. There was no significant estrogen-related morbidity despite the large doses used. Two patients had skin irritation at the patch site causing discontinuation of therapy. These data suggest that large doses of transdermal E2 can suppress gonadotropin levels only for a brief interval. We were unable to demonstrate any long-term alteration in the hypothalamic-pituitary set point for sensitivity to exogenous E2.

Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group.

The purpose of this study was to evaluate efficacy and safety parameters in women with leiomyomata uteri treated with the GnRH agonist leuprolide acetate depot, 3.75 mg intramuscularly every 4 weeks for 24 weeks. One hundred twenty-eight patients were enrolled in a randomized, double-blind, placebo-controlled multicenter study involving 13 investigative centers. Mean uterine volume decreased by 36% at 12 weeks and 45% at 24 weeks of leuprolide therapy. Patients treated with placebo had increased in mean uterine volume of 16% at 12 weeks and 5% at 24 weeks. Seventy-seven percent of leuprolide-treated patients had a more than 25% reduction in uterine volume, compared with 9% of placebo-treated controls. Mean uterine volume returned to pre-treatment size 24 weeks after cessation of leuprolide treatment. The majority of patients had resolution or improvement of their fibroid-related symptoms after 24 weeks of leuprolide treatment. Of 38 leuprolide-treated patients presenting with menorrhagia, 37 (97%) had resolution of this symptom at the time of the final visit. Although 95% of women treated with leuprolide acetate experienced some side effects related to hypoestrogenism, only five patients (8%) terminated treatment prematurely. We conclude that leuprolide acetate depot treatment of leiomyomata uteri is safe and causes significant but temporary reductions in uterine size and fibroid-related symptoms.

Comparison of endometrial biopsy and urinary pregnanediol glucuronide concentration in the diagnosis of luteal phase defect.

To determine if pregnanediol glucuronide (PG) excretion is useful in luteal phase assessment, we compared daily first morning urinary PG concentrations during the luteal phase in nine normal and nine deficient cycles. Total luteal pregnanediol excretion (44.1 +/- 11.3 versus 64.0 +/- 11.6 area units +/- SEM) was not different. However, significantly less pregnanediol was excreted by the abnormal group during the 1st 5 days of the luteal phase (12.7 +/- 1.2 versus 18.0 +/- 1.7 area units +/- SEM, respectively). Thus, delayed PG excretion may be characteristic of luteal phase defect and measurement of urinary PG may be useful only if daily samples during the early luteal phase are obtained.

Insulin resistance and abnormal ovarian responses to human chorionic gonadotropin in chronically anovulatory women.

We studied the interrelationships between insulin resistance, obesity, and abnormal ovarian androgen secretion in chronically anovulatory women with clinical or biochemical evidence of hyperandrogenism. Four groups of six subjects each were studied: (1) normal weight (within 10% ideal body weight) anovulatory, (2) obese (greater than 120% ideal body weight) anovulatory, (3) normal weight eumenorrheic, and (4) obese eumenorrheic. After dexamethasone suppression, human chorionic gonadotropin (2000 IU/1.5m2 body surface area intramuscularly) was administered to each subject. Serum testosterone levels were subsequently determined hourly for 17 hours. On a separate occasion, an oral glucose tolerance test was administered to five subjects from each group. Serum glucose and immunoreactive insulin levels were determined before and after the ingestion of a standard 100 gm glucose load. As a group, the anovulatory women had higher (p less than 0.05) basal testosterone levels (1005 +/- 97 pg/ml) than did the ovulatory women (241 +/- 21 pg/ml) (values +/- SE). Obesity per se was not associated with increased basal testosterone levels. Testosterone levels rose in response to human chorionic gonadotropin (p less than 0.005) only in obese anovulatory women, reached maximal levels after 3 hours, and subsequently remained stable. Basal immunoreactive insulin levels were elevated (p less than 0.05) only in obese anovulatory women (52.4 +/- 20 microU/ml) compared with obese eumenorrheic (8.7 +/- 1.0 microU/ml), normal weight anovulatory (5.8 +/- 2.4 microU/ml), and normal weight eumenorrheic (4.6 +/- 0.4 microU/ml) women. Similarly, maximal increases in immunoreactive insulin levels after glucose ingestion were significantly greater (p less than 0.01) in obese anovulatory women compared with other groups. Of note is the observation that maximal changes in testosterone observed within the first 3 hours after human chorionic gonadotropin and maximal changes in insulin were correlated (r = 0.91, p less than 0.01). These data suggest that (1) both insulin resistance and an abnormal acute response to human chorionic gonadotropin are seen only in obese anovulatory women and (2) the degree to which these two abnormalities are manifested is clearly correlated. The mechanism(s) responsible for this interrelationship, as well as the underlying cause(s) of these biochemical defects, remain to be elucidated.

Underestimation of gestational age by conventional crown-rump length dating curves.

Inaccuracies in gestational age assignment based on published crown-rump length data were noted in patients with known ovulation dates. In this study, we tested the hypothesis that crown-rump length data derived from pregnancies with known ovulation dates differ from those of menstrually timed pregnancies. Seventy-two previously infertile women with known dates of ovulation had crown-rump length measurements from 35-79 days postovulation. We transformed the data to menstrual age (gestational age) by adding 14 days to the date of ovulation and compared our crown-rump length values with those of two previous reports. At corresponding crown-rump length values, the gestational ages from our data differed from those in the previous studies. We suggest using crown-rump length dating curves based on ovulation-timed pregnancies because crown-rump length data derived from menstrually dated pregnancies underestimate true gestational age.

Increased cortisol production in women runners.

Because we previously found increased basal serum cortisol levels in women runners, we examined adrenocortical function in amenorrheic running women (AR), eumenorrheic running women (R), and normal nonexercising women (NC) in further detail. Mean 24-h urinary cortisol levels were significantly elevated (P less than 0.001) in six AR [45.1 +/- 7.2 (+/- SEM) micrograms/24 h] and eight R (38.5 +/- 6.9 micrograms/24 h) compared to four NC (13.9 +/- 2.8 micrograms/24 h). After adrenal suppression with 2 mg dexamethasone, integrated responses and absolute maximal elevations in serum cortisol levels in response to 10 micrograms/m2 exogenous ACTH (1-24) administered as an iv bolus dose, were not significantly different among six AR, six R, and six NC. This dose of ACTH results in maximal steroid release. The disappearance rates of cortisol (5 mg, iv) after dexamethasone suppression were similar in four AR, five R, and four NC and corresponded to a two-compartment model with mean half-lives of 4.9 and 93.8 min, respectively. Cortisol-binding globulin levels were also similar among the groups. These data document higher cortisol secretion and suggest increased ACTH secretion in running women.

Ovulation induction in clomiphene-resistant anovulatory women: differential follicular response to purified urinary follicle-stimulating hormone (FSH) versus purified urinary FSH and luteinizing hormone.

We studied 15 anovulatory women undergoing ovulation induction with purified human urinary FSH or purified human urinary FSH and LH [human menopausal gonadotropins (hMG)]. All patients had either sporadic or no vaginal bleeding after progesterone therapy and failed to ovulate after receiving clomiphene (250 mg for 5 days) plus hCG. Other causes of infertility were ruled out. Sixteen cycles of FSH and 12 cycles of hMG were administered according to a standard protocol. Estradiol, progesterone, androstenedione, testosterone, LH, and FSH concentrations were quantitated by RIA. Follicular diameter was determined using ultrasound. There was no significant difference in the amount of FSH or hMG used per patient, in the duration of therapy before hCG administration, or in the length of the luteal phase in any patient. There was a difference in the number of follicles greater than 1000 mm3 per cycle in those patients receiving FSH compared to the number in those receiving hMG [2.8 +/- 1.3 (+/- SEM) vs. 4.4 +/- 1.5 follicles; P = 0.026). The maximum follicular phase serum estradiol (18.3 vs. 34.8 ng/ml) and maximum luteal phase progesterone concentrations (1289 vs. 2808 pg/ml; P = 0.026) were also different between the FSH and hMG groups. Linear regression analysis revealed a significant correlation between the peripheral serum estradiol levels and the total follicular volume of follicles in the hMG-treated group which was not apparent in the FSH-treated group. These findings suggest that exogenous LH may not be required to induce folliculogenesis in anovulatory patients.

Plasma beta-endorphin concentrations prior to and during pregnancy, in labor, and after delivery.

Beta-Endorphin was measured by radioimmunoassay in peripheral plasma of nonpregnant women (58 +/- 2.4 pg/ml, n = 17, mean +/- SE), during the first trimester (47 +/- 2.4 pg/ml, n = 11), the second trimester (33 +/- 1.9, n = 11), and the third trimester (49 +/- 2.7 pg/ml, n = 10) of pregnancy, during early (202 +/- 32 pg/ml, n = 12) and advanced labor (389 +/- 78 pg/ml, n = 10), and 30 to 60 minutes post partum (177 +/- 22 pg/ml, n = 12). Mean plasma levels of beta-endorphin were significantly lower in each trimester of gestation than the levels in nonpregnant control subjects. During labor and the early postpartum period, maternal plasma levels of beta-endorphin were significantly elevated. Furthermore, peripheral plasma levels of beta-endorphin during labor fell from 189 +/- 31 to 97.6 +/- 12 pg/ml (n = 13, p = 0.015) in response to epidural anesthesia, as compared to peripheral plasma concentrations of beta-endorphin of 223 +/- 71 and 193 +/- 47 pg/ml prior to and after injection of saline solution into epidural catheters, respectively, in 10 control subjects. Mean plasma levels of beta-endorphin in patients immediately prior to elective repeat cesarean section who were not in labor (151 +/- 23 pg/ml, n = 15) were significantly higher (p less than 0.005) than the levels in third-trimester control subjects. These data indicate that the pain associated with labor and the psychological stress of anticipating an operation are potent stimuli for the pituitary release of beta-endorphin.

Effect of intrathecal morphine during labor on maternal plasma beta-endorphin levels.

Plasma beta-endorphin was measured in 16 patients in labor prior to and after complete onset of analgesia with 1 mg of morphine administered intrathecally. Human beta-endorphin levels were determined by radioimmunoassay following silicic acid extraction of plasma samples and separation of the beta-endorphin fraction by gel chromatography. Plasma beta-endorphin levels decreased significantly (p less than 0.005) after intrathecal morphine from 76 +/- 9.7 to 46.3 +/- 9.1 fmol/ml (mean +/- SE), possibly because of decreased pituitary beta-endorphin secretion in response to alleviation of labor pain.

Chlamydia trachomatis is not an important cause of abnormal postcoital tests in ovulating patients.

To examine the role of Chlamydia trachomatis infections of the cervix and abnormal postcoital tests (PCT) in a general infertility clinic, 63 consecutive patients undergoing a midcycle PCT during a routine infertility workup underwent endocervical curettage, and a 10-ml blood sample was obtained. The endocervical tissue was cultured for C. trachomatis; the serum sample was analyzed for chlamydial IgG and IgM antibodies using an indirect microimmunofluorescence assay. A negative titer was considered to be less than or equal to 1:8 dilution for IgG antibodies and less than or equal to 1:32 dilution for IgM antibodies. A good PCT was defined as greater than or equal to 5 motile sperm per high power field (HPF). A poor PCT was defined as less than 2 motile sperm/HPF, and a fair PCT was defined as 2 to 4 motile sperm/HPF. Of the 63 PCTs done, 27 (42.9%) were good, 14 (22.2%) were fair, and 22 (34.9%) were poor. All endocervical tissue cultures for C. trachomatis obtained during PCTs were negative. All IgM chlamydial antibody titers were negative (less than or equal to 1:32 dilution), 55 (87.3%) of the patients having a zero titer. Eleven (17.5%) of the patients had negative IgG chlamydial antibody titers (less than or equal to 1:8 dilution), none of the patients had a 1:16 dilution, and 52 (82.5%) had positive IgG chlamydial antibody titers (greater than or equal to 1:32 dilution). Thus, chlamydial infections of the endocervix are rare and not commonly associated with poor PCTs in this patient population.

The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women.

One hundred nineteen euprolactinemic anovulatory infertility patients who were being evaluated for induction of ovulation with clomiphene citrate were studied to determine the prevalence of increased adrenal androgen (AA) secretion in this group. Fifty percent of these patients exhibited increased AA secretion, as evidenced by an elevated serum dehydroepiandrosterone sulfate (DHEA-S) level. Seventy-seven percent of these women with elevated levels of DHEA-S were nonhirsute . Twenty-six patients with elevated serum DHEA-S levels underwent adrenocorticotropic hormone (ACTH) stimulation tests in order to determine a possible mechanism(s) for the increase in DHEA-S. Plasma ACTH, as well as total, low-density lipoprotein, and high-density lipoprotein cholesterol were also measured. These levels were normal and did not correlate with the elevated levels of DHEA-S. Seven of 16 patients (34%) had exaggerated responses of serum DHEA-S and of 17-OH pregnenolone to ACTH stimulation. In six of these seven patients, our data suggested the occurrence of a mild deficiency of 3 beta-ol dehydrogenase-isomerase. All of these six patients were considered to have polycystic ovary syndrome. While these data do not explain the increased AA secretion in the majority of patients with elevated levels of DHEA-S, we suggest that serum DHEA-S is frequently elevated in anovulatory infertile patients.