An application of multivariate ranks to assess effects from combining factors: metal exposures and semen analysis outcomes.

In studies of environmental effects on human health outcomes, it is often difficult to assess the effects of a group of exposure variables when the individual exposures do not appear to have statistically significant effects. To address this situation, we propose a method of U-scores applied to subsets of multivariate data. We illustrate the usefulness of this approach by applying it to data collected as part of a study on the effects of metal exposure on human semen parameters. In this analysis, profiles (pairs) of metals containing copper and/or manganese were negatively correlated with total motile sperm and profiles containing copper were negatively correlated with sperm morphology; profiles containing selenium and chromium were positively correlated with total motile sperm.

Forum of the End-Stage Renal Disease Networks' role in implementing the National Kidney Foundation-Dialysis Outcomes Quality Initiative Clinical Practice Guidelines.

The development and release of the National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Practice Guidelines marks an important step in the on-going process of improving the renal dialysis patient's outcomes. The Forum of End-Stage Renal Disease (ESRD) Networks' role in this process should be considered within the context of its mission and the ESRD Networks' Congressional mandate. In addition, facilitating the implementation of the NKF-DOQI Guidelines is one component of the Forum's current quality-related agenda. Environmental trends and current research indicate a variety of factors critical to the successful implementation of the NKF-DOQI Guidelines. The Forum's plan encompasses each of the following key elements: defining and evaluating the Guidelines and clinical performance measures (CPMs); prioritizing and locally disseminating NKF-DOQI Guidelines; converting NKF-DOQI Guidelines into CPMs; expanding the information infrastructure; and conducting quality activities and engaging local physicians. Keeping in mind the broader national agenda for quality improvement in the renal community, including continuing medical education programs focused on quality measurement and improvement tools and techniques, developing decision support tools and increasing on-line access to evidence-based reports and literature is important as well. Carrying out the Forum's plan for implementing the NKF-DOQI Guidelines, in collaboration with national nephrology professional and patient organizations, will facilitate Guideline adoption and use across the renal community.

Genetic offspring in patients with vaginal agenesis: specific medical and legal issues.

OBJECTIVE: There are new options for genetic offspring in patients with vaginal agenesis (Mayer-Rokitansky-Küster-Hauser syndrome). The reported world experience to date with genetic offspring of patients with vaginal agenesis consists of five pregnancies (including two reported here and two frozen embryos). The specifics of these cases are presented for discussion. STUDY DESIGN: We present a retrospective description of two women with vaginal agenesis and their matched gestational carriers with positive outcome of two live births. Care was delivered in a private in vitro fertilization and gamete intrafallopian transfer program. RESULTS: In vitro fertilization of oocytes gathered from the genetic mother with vaginal agenesis and sperm from the genetic father were transferred to a gestational carrier. Two live births and one blighted ovum pregnancy resulted. CONCLUSION: Until recently, treatment for patients with vaginal agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) has centered on the creation of a functional vagina. The technology of in vitro fertilization and embryo transfer, allowing for collection of oocytes from the genetic mother, fertilization by the genetic father, and placement into a gestational carrier, enables a woman without a uterus to have her own genetic children. The specific medical and legal issues involved in facilitating genetic offspring in these instances must be considered; these include the initial matching of the genetic parents with the gestational carrier, cycle synchronization for in vitro fertilization and embryo transfer, anatomic difficulties of oocyte retrieval, birth certificate documentation, and the current legal status of a gestational carrier.

Surgical treatment of endometriosis at the time of gamete intrafallopian transfer.

Gamete intrafallopian transfer (GIFT) was performed on 77 women with endometriosis in 92 cycles with or without concomitant laser therapy or electrofulguration of endometriosis. The pregnancy rates were 45% for laser cases, 25% for electrofulguration cases and 36.4% for GIFT only. The pregnancy rate for stage III endometriosis was 53% versus 14% and 47% for stages II and I, respectively. Although there was a trend toward an increased pregnancy yield with active therapy, no statistically significant difference was achieved. The postoperative fecundity in patients not conceiving with GIFT was poor for all the groups.

Septate versus bicornuate uteri: errors in imaging diagnosis.

Since two müllerian defects, the septate and bicornuate uteri, are no longer repaired by means of the same operative approach, an accurate preoperative diagnosis of these anomalies is now critical. A septum can be removed by means of hysteroscopic metroplasty. However, repair of a bicornuate uterus still requires abdominal surgery. Hysterosalpingography (HSG) has been the primary diagnostic modality for müllerian defects. On the basis of 63 patients, HSG findings alone, as interpreted by the radiologist, had a diagnostic accuracy of 55%. When this was supplemented with a gynecologic evaluation, the diagnostic accuracy improved to only 62.5%. However, when a diagnostic protocol that include ultrasound (US) examination with HSG was used for evaluating müllerian defects, the diagnostic accuracy improved to 90%, with all errors being noncritical. Therefore, it is concluded that HSG alone is not adequate to make the distinction between a septate and a bicornuate uterus unless the angle of divergence of two straight uterine cavities is 75 degrees or less, indicating a septate uterus. Luteal-phase US is frequently necessary to distinguish between these anomalies or to diagnose them in combination.

Follicle size by ultrasound versus cervical mucus quality: normal and abnormal patterns in spontaneous cycles.

Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. The findings were: (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.

Hysteroscopic metroplasty: six years' experience.

Seventy patients who underwent hysteroscopic metroplasty for uterine septa during a 6-year period were reviewed for subsequent gynecologic problems and obstetric outcome. Complete follow-up was obtained for 1 year in 60 patients and through the first pregnancy in 64. The 70 patients were divided into three groups based on obstetric history prior to surgery: 1) 40 with only first-trimester losses, 2) 15 whose histories included second-trimester losses or premature delivery, and 3) 15 with primary infertility. Long-term follow-up indicated no significant gynecologic abnormalities. Comparison of preoperative and postoperative obstetric outcomes indicated the following: 1) Hysteroscopic metroplasty was very effective in treating patients with septa and a history of first-trimester abortion; 2) patients with first-trimester loss and either second-trimester abortion or preterm birth benefited from metroplasty but were still at risk for preterm labor; and 3) hysteroscopic metroplasty does not "cure" unexplained infertility. When compared with abdominal metroplasty for efficacy, morbidity, and cost, hysteroscopic metroplasty appears to be the treatment of choice in patients with uterine septa associated with pregnancy loss. Those patients with a history of second-trimester loss and third-trimester preterm delivery continue to require close monitoring in subsequent pregnancies.

Treatment validation of ultrasound-defined abnormal follicular dynamics as a cause of infertility.

From March 1984 to February 1987, 109 patients with otherwise normal infertility evaluations (semen analysis, postcoital test, endometrial biopsy, hysterosalpingogram and/or hysteroscopy, and laparoscopy) underwent serial ultrasound (US) for follicular dynamics. Twenty-five patients were found to have repetitive abnormal follicular growth and/or rupture patterns. These patients were treated by ovulation induction protocols from clomiphene citrate (CC) to human menopausal gonadotropin (hMG). Of the 84 normal US patients, 47 elected no interventional therapy (control A). Twenty elected empiric treatment with hMG/hMG-intrauterine insemination (IUI) (control B). Seventeen were lost to follow-up or elected in vitro procedures within 1 year of diagnosis. Viable fecundibility (fv) was calculated for each group. Long-term viable conception was compared between groups by chi-square-Yates coefficient. Nineteen of 25 patients treated for abnormal US conceived on treatment (fv = 0.25) (chi-square to control A P less than 0.005, chi-square to control B P less than 0.05). Six of 20 control B patients conceived during treatment (fv = 0.11). Two control B patients conceived in nontreatment cycles (fv = 0.016). When nontreated and treated cycles are considered, the fv = 0.042, not significantly different from control A (fv = 0.035). There was no increase in control B pregnancies over the course of the study compared with control A (chi-square = 0). The authors concluded: (1) Abnormal follicular dynamics on US is a correctable cause of infertility. (2) Empiric treatment of unexplained infertility patients with hMG/hMG-IUI does not appear to improve long-term conception rates; rather, it tends to advance pregnancies into the treatment cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of human menopausal gonadotropins as therapy for abnormal cervical mucus.

Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.

Sector ultrasound in the diagnosis and treatment of hematometria secondary to Asherman's syndrome.

Sector ultrasound in patients with post-traumatic amenorrhea (Asherman's) performed at BBT-determined "menses" will diagnose patients with hematometria secondary to outlet obstruction. These patients can be treated in the outpatient setting using real-time ultrasound as a guide for intrauterine manipulation.

Ultrasonographic monitoring of follicular growth for luteal phase defects.

In the evaluation of 39 patients with untreated and treated luteal phase defect (LPD), serial ultrasonographic monitoring of follicular development identified three morphologically distinct growth patterns: normal-sized follicles, small follicles, and luteinized-unruptured follicles. All three patterns were observed in both untreated (46% had normal-sized follicles, 39% had small follicles, 15% had luteinized-unruptured follicles) and treated patients. A small follicle was observed uncommonly in histologically corrected LPD patients (6%). However, a luteinized-unruptured follicle (38%) may persist or be induced in situations where clomiphene citrate has been used to correct LPD or induce ovulation. Ultrasonographic evaluations of follicular growth in luteal phase defect support the theory that luteal phase defect represents a spectrum of normal and abnormal ovarian cycle events.

Evidence of short-loop inhibition of decidual prolactin synthesis by decidual proteins. Part I.

Induction of uterine endometrial prolactin synthesis is dependent on progesterone-induced decidualization of stromal cells. These decidual cells are not dependent on progesterone for continued prolactin synthesis. The factors modifying decidual prolactin synthesis remain largely unknown. To test the hypothesis that a decidual protein is the major modulator of new prolactin synthesis, decidua were cultured within dialysis membranes allowing the accumulation of proteins greater than 12,000 molecular weight in a metabolically neutral environment, and the rate of new synthesis was compared with prolactin synthesis from samples cultured in 10 times the available volume for protein distribution. The rate of new prolactin synthesis at 48-hour intervals up to 144 hours was compared. Initial and postculture decidual prolactin content was obtained and was found not to vary significantly between groups (0.05 less than p less than 0.10). At 48 hours significant suppression of decidual prolactin synthesis was apparent (p less than 0.05) within the dialysis membranes. As prolactin concentration increased during in vitro culture this suppression was enhanced (p less than 0.005). Gel chromatography and immunoprecipitation of iodine 125-labeled prolactin added at time 0 revealed no significant degradation of the 125I-labeled prolactin and maintenance of its immunoactivity even at 144 hours. This confirms that the plateauing of prolactin concentration within the dialysis membranes is due to suppression of new synthesis rather than metabolism of previously synthesized prolactin.

Evidence of short-loop inhibition of decidual prolactin synthesis by decidual proteins. Part II.

We have recently demonstrated the suppression of decidual prolactin synthesis by decidual proteins accumulating in a dialysis membrane. In this report the reversibility of this suppression and the molecular weight range of the suppressor(s) are examined. Samples of 300 mg of decidua (n = 10) were cultured in three environments: in 30 ml of medium (control), in 3 ml of medium in a dialysis membrane suspended in 27 ml of medium, and in 2.7 ml of medium with 0.3 ml of concentrated decidual proteins of 10,000 to 35,000 molecular weight (giving a time 0 prolactin concentration of 220 ng/ml) in a dialysis membrane suspended in 27 ml of medium (n = 5) or in 2.7 ml of medium with 0.3 ml of concentrated decidual proteins greater than 35,000 molecular weight (giving a time 0 prolactin concentration of 5 ng/ml) in a dialysis membrane suspended in 27 ml of medium (n = 5). Dialysis membranes were discontinued at 48, 96, and 144 hours and the decidua within was subsequently cultured in 30 ml of medium until 240 hours. The suppression of prolactin synthesis identified previously was confirmed in this study. Further it was found that the suppression of decidual prolactin synthesis was reversed by the removal of decidua from the high decidual protein-prolactin environments of the dialysis membranes. Third, only the addition of decidual proteins between 10,000 and 35,000 molecular weight with a high prolactin concentration enhanced the suppression of new prolactin synthesis. We conclude that a decidual protein(s) between 10,000 and 35,000 molecular weight, possibly prolactin itself, is the primary control factor(s) in the modulation of prolactin synthesis in term decidua. Further the normal physiologic state of decidua is a high prolactin concentration in equilibrium with low prolactin synthesis. Therefore studies intended to assess the effects of modulators of prolactin synthesis in decidua should not be performed in low prolactin concentration-high prolactin synthesis conditions during short time periods (as has been the case in a majority of studies to date) since such conditions do not reflect normal physiologic conditions and may result in invalid conclusions.

Hysteroscopic detection and treatment of adhesions at the tubal ostium/uterine junction in infertile patients.

In conclusion, we agree that most of the abnormalities previously reported on hysteroscopy are of little clinical importance and that previously undetected abnormalities of clinical significance are rare in the patient who has undergone HSG with fluoroscopy. However, as indicated by these three cases, small, strategically located lesions may be missed by HSG and may be a cause of infertility. We therefore think that, given the low complication rate of hysteroscopy, its high degree of safety, minimal time requirement, and negligible effect on postoperative course, hysteroscopy should be performed on most, if not all, infertile patients undergoing diagnostic laparoscopy.

Prolactin production by explants of normal, luteal phase defective, and corrected luteal phase defective late secretory endometrium.

The production of prolactin by explants of late secretory endometrium has been correlated with the extent of decidual differentiation. This correlation is strengthened by the observation that luteal phase defective endometrium produces less prolactin than normal control endometrium in a 24-hour in vitro culture system. In the present study the prolactin production by explants of normal, luteal phase defective, progesterone-corrected luteal phase defective, and clomiphene- or follicle-stimulating hormone/luteinizing hormone-corrected luteal phase defective late secretory endometrium was measured over 96 hours at 24-hour intervals. Progesterone in physiologic concentrations was added to the culture medium to maintain tissue integrity and prolactin synthesis. The prolactin production of normal late secretory endometrium rose over 96 hours under progesterone stimulation. The luteal phase defective endometrium produced significantly less prolactin under the same conditions. Histologically proven corrected luteal phase defective endometrium, regardless of treatment method, produced prolactin not different from the normal controls of the same dates. From these results it is concluded that histologic correction of luteal phase defective endometrium is associated with a corresponding biochemical correction with use of prolactin as a metabolic marker. The findings also strongly support timed endometrial biopsy as the method of diagnosis and evaluation of treatment of luteal phase defect.

Titrating the dose of bromocriptine when treating hyperprolactinemic infertile women.

We have shown that a smaller dose of bromocriptine is effective in lowering the PRL level to the normal range in some hyperprolactinemic women. Based on these findings, we recommend that when treating hyperprolactinemic women who desire conception, the dose of bromocriptine should be titrated according to the response of circulating PRL levels. This will minimize the dose, reduce cost, probably reduce side effects, and possibly avoid undesirable functional effects such as corpus luteum dysfunction.

Ultrasonographic assessment of luteinized unruptured follicle syndrome in unexplained infertility.

Ultrasound can be used to monitor the growth and rupture of the dominant follicle. Thirty-three patients with unexplained infertility underwent serial sonography (mean, 3.2 scans/cycle) for luteinized unruptured follicle syndrome (LUFS). The incidence of LUFS was 9% (three patients) in the initial scan cycle. Three patients (9%) demonstrated rupture of a follicle significantly smaller than the mean (22.1 mm) (z less than 0.01) in the initial scan cycle. At standard radiology fees ($7000 +/ diagnosed LUFS) the cost/benefit ratio of this method of diagnosis will be controversial. It is suggested that scanning at reduced fees in the gynecologist's office, particularly in conjunction with postcoital tests, would decrease cost and increase the potential benefit.