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Background: Although semen analysis is routinely used to evaluate the male partner in infertile couples, sperm measurements that discriminate between fertile and infertile men are not well defined., Methods: We evaluated two semen specimens from each of the male partners in 765 infertile couples and 696 fertile couples at nine sites. The female partners in the infertile couples had normal results on fertility evaluation. The sperm concentration and motility were determined at the sites; semen smears were stained at the sites and shipped to a central laboratory for an assessment of morphologic features of sperm with the use of strict criteria. We used classification-and-regression-tree analysis to estimate threshold values for subfertility and fertility with respect to the sperm concentration, motility, and morphology. We also used an analysis of receiver-operating-characteristic curves to assess the relative value of these sperm measurements in discriminating between fertile and infertile men., Results: The subfertile ranges were a sperm concentration of less than 13.5 x 10(6) per milliliter, less than 32 percent of sperm with motility, and less than 9 percent with normal morphologic features. The fertile ranges were a concentration of more than 48.0 x 10(6) per milliliter, greater than 63 percent motility, and greater than 12 percent normal morphologic features. Values between these ranges indicated indeterminate fertility. There was extensive overlap between the fertile and the infertile men within both the subfertile and the fertile ranges for all three measurements. Although each of the sperm measurements helped to distinguish between fertile and infertile men, none was a powerful discriminator. The percentage of sperm with normal morphologic features had the greatest discriminatory power., Conclusions: Threshold values for sperm concentration, motility, and morphology can be used to classify men as subfertile, of indeterminate fertility, or fertile. None of the measures, however, are diagnostic of infertility.

Background: Induction of superovulation with gonadotropins and intrauterine insemination are frequently used to treat infertility. We conducted a large, randomized, controlled clinical trial of these treatments., Methods: We studied 932 couples in which the woman had no identifiable infertility factor and the man had motile sperm. The couples were randomly assigned to receive intracervical insemination, intrauterine insemination, superovulation and intracervical insemination, or superovulation and intrauterine insemination. Treatment continued for four cycles unless pregnancy was achieved., Results: The 231 couples in the group treated with superovulation and intrauterine insemination had a higher rate of pregnancy (33 percent) than the 234 couples in the intrauterine-insemination group (18 percent), the 234 couples in the group treated with superovulation and intracervical insemination (19 percent), or the 233 couples in the intracervical-insemination group (10 percent). Stratified, discrete-time Cox proportional-hazards analysis showed that the couples in the group treated with superovulation and intrauterine insemination were 3.2 times as likely to become pregnant as those in the intracervical-insemination group (95 percent confidence interval, 2.0 to 5.3) and 1.7 times as likely as those in the intrauterine-insemination group (95 percent confidence interval, 1.2 to 2.6). The couples in the intrauterine-insemination group and in the group treated with superovulation and intracervical insemination were nearly twice as likely to conceive as those in the intracervical-insemination group., Conclusions: Among infertile couples, treatment with induction of superovulation and intrauterine insemination is three times as likely to result in pregnancy as is intracervical insemination and twice as likely to result in pregnancy as is treatment with either superovulation and intracervical insemination or intrauterine insemination alone.

Background: Whether anesthetic agents administered during gamete intrafallopian transfer (GIFT) affect reproductive outcome is controversial. This multicenter pilot trial and survey had two purposes: to evaluate the effect of propofol, nitrous oxide, midazolam, and isoflurane on pregnancy outcome after GIFT, and to determine if a larger prospective, randomized study is warranted., Methods: A written invitation was mailed to all 50 fertility programs in the United States that are members of the Society for Assisted Reproductive Technology and perform more than 30 GIFT procedures per year. They were invited to contribute information from the medical records of women who underwent GIFT during the calendar years 1993 and 1994. They were asked to document whether propofol, nitrous oxide, midazolam, a potent inhaled anesthetic agent was used during the GIFT procedure; if the woman became pregnant; and if she delivered at least one live neonate., Results: Seven medical centers participated and contributed data from 455 women. The clinical pregnancy rate (number of pregnancies/total number of GIFT procedures) and the delivery rate (number of women who delivered at least one live baby/total number of GIFT procedures) were 35% and 32%, respectively. A statistically significant difference could not be found in the clinical pregnancy or delivery rates between those women who received propofol, nitrous oxide, midazolam, or isoflurane during GIFT and those who did not., Conclusions: No agent-related differences in pregnancy rates were found when propofol, nitrous oxide, isoflurane, or midazolam was used as part of the anesthetic technique for GIFT. Therefore, a more extensive prospective trial does not appear to be warranted.

Objective: To assess the feasibility of logistic regression analysis for determining the gestational ages at which detection of early pregnancy landmarks first can be observed., Design: Retrospective analysis., Setting: University-based tertiary care clinic., Patient(s): Eighty-two women with viable singleton pregnancies in whom ovulation had been achieved by an injection of hCG., Intervention(s): Two hundred fifteen transvaginal sonographic scans., Main Outcome Measure(s): Logistic regression was used to estimate the probability of detection of sonographic findings as a function of gestational age., Result(s): We found that the likelihood of visualization of a gestational sac or fetal heart motion could be represented accurately by logistic equations. Gestational age at which there was 95% probability of visualization was 35.5 days for the gestational sac and 44.5 days for fetal cardiac activity. The probability of detecting fetal cardiac activity was 95% when the mean gestational sac diameter was 1.6 cm and was 99% at 1.9 cm., Conclusion(s): The sonographic appearances of developmental landmarks in early pregnancy occurs within well-defined gestational time periods, and the probabilities for visualization can be closely approximated using a logistic model. Our results suggest that the number of sonographic examinations required to document infertility treatment success can be minimized by surveillance at standardized gestational ages.

Objective: To evaluate the effect of a routine breast examination on serum PRL levels., Design: Prospective clinical study., Setting: University-based reproductive endocrinology unit., Patients: Eleven nonlactating, euprolactinemic women of reproductive age with a history of regular menstrual cycles and currently taking no medications., Interventions: Breast examination using standard technique., Main Outcome Measure: Changes in serum PRL levels after breast examination., Results: Baseline PRL levels ranged from 3.64 to 19.23 ng/mL (mean 7.17 ng/mL; conversion factor to SI unit, 1.00). There were no significant increases in PRL levels after breast examination, with mean PRL levels after 15, 30, and 45 minutes of 6.59, 6.84, and 6.45 ng/mL, respectively., Conclusion: Routine breast examination does not alter acutely serum PRL levels in normal women.

Objective: To compare the obstetric outcomes of twin pregnancies obtained as a result of multifetal pregnancy reduction to those in which pregnancy reduction had not been used., Design: Retrospective analysis., Setting: University-based tertiary care infertility clinic., Patients: Seventy-four twin pregnancies continuing beyond 10 weeks. Of these, 32 gestations had undergone reduction to twins at 10 weeks., Main Outcome Measures: Gestational age at delivery, birth weights, pregnancy complications., Results: All pregnancies advanced beyond 20 weeks gestation. The mean gestational age at delivery of the reduction group was 33.8 versus 35.7 weeks in the nonreduced group; only 25% of reduced pregnancies reached 37 weeks compared with 57.9% of nonreduced twins. The mean fetal birth weights of the two groups differed significantly (reduced: 2,038 g, nonreduced: 2512 g). The gestational age at delivery in patients reduced from triplets was significantly greater than in pregnancies reduced from quadruplets or higher. Multiple regression analysis revealed that for a given gestational age at delivery, a history of pregnancy reduction was associated with decreased birth weight., Conclusion: These data suggest that multifetal pregnancy reduction does not reverse completely the decreased gestational age and impaired fetal growth associated with high-order multiple pregnancy. Furthermore, fetal growth of reduced pregnancies seems to be impaired independent of the gestational age at which delivery occurs.

A 31-year-old primigravida had a combined pregnancy consisting of intrauterine twins and an interstitial ectopic after in vitro fertilization/embryo transfer. The patient underwent repair of the ectopic pregnancy at 15 weeks of gestation, with subsequent delivery of mature twins close to term.

During the past decade, research on hypothalamic-pituitary-ovarian relationships in ovulation has explored the contributions of ovarian steroids and other possible ovarian-derived endocrine factors, such as inhibin, follistatin, and activin. Follistatin and activin probably have a significant intraovarian and intrapituitary function but are not likely to have critical endocrine roles during the follicular phase. Studies carried out with both recombinant and highly purified forms of follicle-stimulating hormone in humans and monkeys indicate that this hormone is the primary stimulant of follicular growth and development. Studies on animals may have led to incorrect emphasis on the local role of estradiol in primate follicular growth. It appears that estradiol is not a critical folliculotropin in humans, although it may have some important direct effects on the oocyte.

A simplified protocol for in vitro fertilization treatment was developed using low-dose clomiphene for ovarian stimulation, timing of human chorionic gonadotropin administration based solely on sonographic criteria, in-office egg retrieval and use of a simplified culture medium for embryo culture. Twenty-six infertile women underwent 39 treatment cycles, with 33 egg retrievals resulting in 29 embryo transfers. Clinical pregnancy was obtained in six patients (20.7% per embryo transfer), for a rate comparable to that achieved with conventional in vitro fertilization treatment in an age-matched control group. This simplification of in vitro fertilization treatment protocols can lead to decreased patient stress and costs without a substantially lower success rate.

Objective: Preimplantation mouse embryos were exposed to a commonly used inhalational anesthetic agent, isoflurane, to determine its effects on embryo development., Study Design: Two-cell embryos were exposed at various intervals (5 to 6 hours, 3 to 4 hours, and 0 to 1 hour) before the onset of their first cleavage in vitro. In addition, the effects of 5% isoflurane on four-cell embryos exposed about 2 hours after the first cleavage and morula stage embryos also were examined., Results: Development to the blastocyst stage was inhibited by 3% and 5% isoflurane (p less than 0.005) but not by 1.5% isoflurane when two-cell embryos were exposed 3 to 4 hours or 0 to 1 hour before the onset of cleavage. Most of the affected embryos completed cell division and came to a halt at the three- to four-cell stage. The development of embryos exposed to isoflurane at the four-cell or morula stage was unaffected., Conclusions: Isoflurane adversely affects subsequent preimplantation development when two-cell mouse embryos are exposed just before the onset of their first cleavage in vitro.

Visualization of free peritoneal fluid during sonographic examination is often of considerable clinical importance. To determine the sensitivity of transvaginal sonography in the detection of this finding, measured amounts of isotonic saline were instilled into the abdominal cavities of 15 women undergoing diagnostic laparoscopy while a 5-MHz transvaginal probe was employed to view the pelvic contents. Small amounts of free fluid could be visualized easily in all the patients (mean +/- SD, 25.8 +/- 6.4 mL). Fluid was first seen in the cul-de-sac in 10 patients and in the adnexal region in 5. When fluid instillation was continued to a total volume of 200 mL, the pelvic viscera were distinctly outlined in all the patients, markedly enhancing visualization of the uterus, tubes and ovaries. Transvaginal sonography seems to be a sensitive and reliable method of detecting free peritoneal fluid. Instillation of fluid into the peritoneal cavity may be a clinically useful technique for enhancing the sonographic visualization of pelvic structures.

The findings of our study indicate that women pretreated with E/progestin demonstrate increased gonadotropin requirements when undergoing ovulation induction. Whether this treatment has a significant effect on the outcome of ovulation induction in patients receiving gonadotropins remains to be established.

Estrogen (E)/progestin therapy for functional ovarian cysts is widely used in clinical practice, but the efficacy of this treatment has not been determined in controlled trials. In this study, we examined the effect of E/progestin administration in a group of infertility patients enrolled in a program of ovulation induction who had cysts identified by transvaginal sonography. Patients were randomized to receive either norethindrone 1 mg/mestranol 0.05 mg/d (group A, n = 24) or no treatment (group B, n = 24) for up to 6 weeks. Patients were re-evaluated by sonography at 3, 6, and 9 weeks after entry into the protocol. The ages, mean cyst diameters, and proportions of patients having received gonadotropins in the previous menstrual cycle were not significantly different among the two groups. All patients who had a sonographic abnormality persisting for 9 weeks were surgically explored and found to have pathological cysts. The rate of disappearance of functional ovarian cysts was not affected by E/progestin treatment.

Preimplantation mouse embryos were exposed to nitrous oxide for 30 min to determine its effects on subsequent development after short durations of exposure. Two-cell mouse embryos were exposed to 60% nitrous oxide/40% oxygen at 6-7 h, 3-4 h, or 0-1 h prior to the expected onset of their first cleavage in vitro, or at the 4-cell or morula stages. Effects of nitrous oxide were not observed except in 2-cell embryos treated within 4 h of the expected in vitro cleavage. At 3-4 h and 0-1 h prior to the onset of cleavage, exposure to 60% nitrous oxide/40% oxygen resulted in blastocyst development rates of 27.7% and 4.7%, respectively, while control rates ranged from 75% to 77%. The majority of affected embryos were halted at the 2-cell stage before completing cell division. Similar effects were obtained with 80% nitrous oxide/20% oxygen. Thus, we conclude that brief exposure of mouse preimplantation embryos to nitrous oxide may be deleterious to subsequent embryo cleavage, but this effect is highly dependent on the developmental stage at which exposure occurs.

Menstrual dysfunction can be associated with a number of systemic illnesses. Whereas the effects of some diseases on the reproductive system are simply a result of the pathophysiology of the disorders, in other cases, temporary cessation of reproductive function conserves energy for other tasks related to survival and well being.

The requirement to obtain a semen sample at a specific time for an infertility treatment procedure has potential to produce considerable performance anxiety. This study was designed to evaluate the semen quality of men participating in infertility treatments associated with heightened performance anxiety. The most recent pretreatment semen analysis and the infertility treatment semen analysis, as well as the first and last procedure semen analyses, were compared using paired t-tests for 77 patients undergoing assisted reproductive technology procedures and 121 patients undergoing intrauterine insemination. No significant differences were noted in either of these groups of patients. However, in men with total motile sperm counts of less than 40 million, semen parameters improved significantly in the procedure semen analyses. Thus, participation in infertility treatments associated with performance anxiety does not appear to be detrimental to semen quality, and in certain groups of patients semen quality may improve.

Aromatase, an enzyme complex localized in the endoplasmic reticulum of estrogen-producing cells, is composed of NADPH-cytochrome P-450 reductase, and aromatase cytochrome P-450 (cytochrome P-450AROM). To define the molecular mechanisms involved in the multifactorial regulation of cytochrome P-450AROM in estrogen-producing cells, we have isolated a cDNA specific for human cytochrome P-450AROM and have used this cDNA to isolate the human cytochrome P-450AROM gene. The cDNA sequence encodes a polypeptide of 503 amino acids and contains--near the carboxy-terminus, a region of high homology with the putative heme-binding regions of other P-450 cytochromes. COS1 cells transfected with an expression plasmid containing the cytochrome P-450AROM cDNA had the capacity to aromatize testosterone, androstenedione and 16 alpha-hydroxyandrostenedione, suggesting that a single polypeptide catalyzes all steps of the aromatization reaction using either of the three major C19-substrates. The human cytochrome P-450AROM gene is greater than 52 kb in size and consists of 10 exons and 9 introns. Hormonally induced changes in aromatase activity of human ovarian granulosa and adipose stromal cells are associated with comparable changes in cytochrome P-450AROM gene expression and synthesis, whereas the reductase component is only modestly affected. Studies are in progress to define the molecular mechanisms involved in the regulation of cytochrome P-450AROM gene expression in estrogen-producing cells.

Transvaginal sonography can overcome some of the inherent limitations of the transabdominal technique. Scanning with a transvaginal probe often provides increased resolution and greater patient comfort. This technique is likely to be employed more frequently in the future for the evaluation of numerous gynecologic problems.

A case of genital involvement with epidermolysis bullosa is described. Scarring led to vaginal obstruction and hematometra. The classification and treatment of this rare disorder are discussed.

Ninety patients undergoing a total of 92 endoscopic procedures were assessed regarding their subjective recovery times, their delays in returning to their places of employment, the duration of analgesic use, and their inhospital stays. A significant association (P less than 0.05) between recuperation parameters and the extent of the intra-abdominal surgery at laparoscopy was observed. A weak association also was noted between the number of incisions performed, the duration of surgery, and postoperative recuperation. Nonetheless, even the most radical endoscopic procedures required considerably less recuperation time when compared with laparotomies. With the out-of-work period reduced 5- to 6-fold, obese individuals appeared to tolerate these procedures as well as their thin counterparts.

The effects of FSH to increase the activity of aromatase, as well as the synthesis of the components of the aromatase enzyme complex, have been studied in human ovarian granulosa cells obtained from women undergoing oocyte retrieval. FSH increased aromatase activity, as well as the synthesis of aromatase cytochrome P-450 (P-450AROM) in a time-dependent fashion, whereas in the absence of FSH, both activity and synthesis declined with duration of culture. The effect of FSH was mimicked by forskolin, an activator of adenylate cyclase. FSH also increased the synthesis of NADPH-cytochrome P-450 reductase, but to a relatively modest extent. The levels of hybridizable mRNA species encoding cytochrome P-450AROM of lengths 3.0, 2.4, and 1.6 kilobases were also increased with FSH treatment. It is concluded that the regulation of aromatase activity by FSH in human granulosa cells is mediated primarily by changes in the synthesis of cytochrome P-450AROM, that this action of FSH is mediated by cAMP, and that the changes in cytochrome P-450AROM synthesis are the consequences of changes in the levels of mRNA encoding this enzyme.

The effects of growth factors to regulate the activity of aromatase, as well as the synthesis of aromatase cytochrome P-450 (P-450AROM) have been studied in human ovarian granulosa cells obtained from women undergoing oocyte retrieval. Insulin-like growth factor I (IGF-I) increased aromatase activity as well as the synthesis of P-450AROM, in a concentration-dependent fashion. The levels of hybridizable mRNA species encoding cytochrome P-450AROM were also increased with IGF-I treatment. By contrast, epidermal growth factor (EGF) had no effect on these parameters when added alone, but markedly inhibited the action of follicle-stimulating hormone (FSH) to stimulate aromatase activity, and the synthesis of cytochrome P-450AROM, as well as its ability to increase the levels of mRNA encoding the enzyme. It is concluded that these growth factors have opposite effects on aromatase activity, and that these actions reflect, in part, changes in the synthesis of cytochrome P-450AROM, which in turn are the consequence of changes in the levels of mRNA encoding this enzyme.