Effectiveness of a low-fat vegetarian diet in altering serum lipids in healthy premenopausal women.

Few controlled trials have studied cholesterol-lowering diets in premenopausal women. None has examined the cholesterol-lowering effect of a low-fat vegetarian diet, which, in other population groups, leads to marked reductions in serum cholesterol concentrations and, in combination with other life-style changes, a regression of atherosclerosis. We tested the hypothesis that a low-fat, vegetarian diet significantly reduces serum total and low-density lipoprotein (LDL) cholesterol concentrations in premenopausal women. In a crossover design, 35 women, aged 22 to 48, followed a low-fat vegetarian diet deriving approximately 10% of energy from fat for 2 menstrual cycles. For 2 additional cycles, they followed their customary diet while also taking a "supplement" (placebo) pill. Serum lipid concentrations were assessed at baseline and during each intervention phase. Mean serum LDL, high-density lipoprotein (HDL), and total cholesterol concentrations decreased 16. 9%, 16.5%, and 13.2%, respectively, from baseline to the intervention diet phase (p<0.001), whereas mean serum triacylglycerol concentration increased 18.7% (p<0.01). LDL/HDL ratio remained unchanged. Thus, in healthy premenopausal women, a low-fat vegetarian diet led to rapid and sizable reductions in serum total, LDL, and HDL cholesterol concentrations.

Apparent lability of neural tube closure in laboratory animals and humans.

Neural tube defects (NTDs), a set of structural abnormalities affecting the brain, spinal cord, and the skeletal and connective tissues that protect them, are common malformations among humans and laboratory animals. The embryogenesis of the neural tube is presented to convey the complexity of the phenomenon, the multiplicity of requisite cellular and subcellular processes, and the precise timing of events that must occur for successful neural tube development. Interruption, even transitory, of any of these intricate processes or disruption of an embryo's developmental schedule can lead to an NTD. The population distribution of human NTDs demonstrates that genetic predisposition functions in susceptibility to NTDs. Data from animal studies support these concepts. NTDs are common outcomes in developmental toxicity safety assessments, occurring among control and treated groups. Numerous agents have caused increased levels of NTDs in laboratory animals, and species with shorter gestational periods appear more prone to toxicant-induced NTDs than those with longer gestations. Data from post-implantation whole embryo culture, although not predictive of human risk, are useful in studying neurulation mechanisms and in demonstrating the importance of maintaining embryonic schedules of development. We conclude that the concept that NTDs are produced by only a few toxicants that selectively target the developing nervous system is untenable. Rather, the combination of the time in gestation that an agent is applied, its dose, and its ability to disrupt critical processes in neurulation leads to NTDs. We further conclude that, because of both the relatively high prevalence and the multifactorial nature of NTDs, the mere occurrence of an NTD is insufficient for inferring that the defect was caused by an exogenous agent.

Data availability in reproductive and developmental toxicology.

OBJECTIVE: To characterize the availability of reproductive and developmental toxicology information in the literature and the extent to which such information could produce alarm. METHODS: REPROTOX, a computerized data base, was evaluated as a surrogate for the available literature on reproductive and developmental toxicology. A review of 2528 summaries was performed and information in the summaries evaluated as nonreassuring or reassuring. RESULTS: Information on reproductive or developmental effects was available for about half of the summaries. Availability of information was greatest for pharmaceuticals (75% of summaries contained information) and was lowest for nonpesticide chemicals (36% of summaries contained information). Summaries contained nonreassuring information about two-thirds of the time. Information based on human data was variably available according to type of agent, ranging from a low of 5% of pesticide summaries to 88% of vitamin summaries. CONCLUSIONS: Counseling efforts depend on a literature base in which information is missing half the time and in which animal data may be the only available source of information. Information is available more often for pharmaceuticals than for other classes of agents.

A computerized consultation service in reproductive toxicology: summary of the first five years.

A computerized consultation service developed by the Reproductive Toxicology Center, Washington, DC, provides summaries of the literature on more than 1300 chemical and physical agents. During the first five years of operation, the service was used to evaluate exposures in 1089 individuals. Only 3% of the exposures involved men. Of the 1053 exposed women, 85% were pregnant and 8% were planning pregnancy. In this latter group, potentially hazardous exposures were reported in 17%. Pregnant women were primarily exposed to medications, although exposures to chemicals at work and in the home constituted other important sources of inquiries. Excluding ethanol and tobacco, 19% of pregnant women were exposed to agents that are known or probable reproductive toxins. Ethanol exposure occurred in 27% of the sample and tobacco use was reported in 13%. These findings suggest that even women concerned about exposure to agents during pregnancy commonly use known or probable reproductive toxins. Physician access to reproductive toxicology information and patient education will be necessary to reduce these exposures.

Salmonella sepsis and second-trimester pregnancy loss.

Salmonella can produce bacteremia and disseminated disease, including infection of the intrauterine contents and fetal death. Published experience with salmonella infection in pregnancy has involved typhoid; however, nontyphoid gastroenteritis may also produce sepsis and fetal loss. We present a case of second-trimester fetal death associated with group C1 salmonella sepsis. The literature suggests that early diagnosis and treatment of salmonella infection during gestation is associated with a good pregnancy outcome. We recommend that pregnant women with diarrheal illnesses be evaluated by stool culture for salmonella infection.

Diet and sex-hormone binding globulin, dysmenorrhea, and premenstrual symptoms.

OBJECTIVE: To test the hypothesis that a low-fat, vegetarian diet reduces dysmenorrhea and premenstrual symptoms by its effect on serum sex-hormone binding globulin concentration and estrogen activity. METHODS: In a crossover design, 33 women followed a low-fat, vegetarian diet for two menstrual cycles. For two additional cycles, they followed their customary diet while taking a supplement placebo pill. Dietary intake, serum sex-hormone binding globulin concentration, body weight, pain duration and intensity, and premenstrual symptoms were assessed during each study phase. RESULTS: Mean (+/- standard deviation [SD]) serum sex-hormone binding globulin concentration was higher during the diet phase (46.7 +/- 23.6 nmol/L) than during the supplement phase (39.3 +/- 19.8 nmol/L, P < .001). Mean (+/- SD) body weight was lower during the diet (66.1 +/- 11.3 kg) compared with the supplement phase (67.9 +/- 12.1 kg, P < .001). Mean dysmenorrhea duration fell significantly from baseline (3.9 +/- 1.7 days) to diet phase (2.7 +/- 1.9 days) compared with change from baseline to supplement phase (3.6 +/- 1.7 days, P < .01). Pain intensity fell significantly during the diet phase, compared with baseline, for the worst, second-worst, and third-worst days, and mean durations of premenstrual concentration, behavioral change, and water retention symptoms were reduced significantly, compared with the supplement phase. CONCLUSION: A low-fat vegetarian diet was associated with increased serum sex-hormone binding globulin concentration and reductions in body weight, dysmenorrhea duration and intensity, and premenstrual symptom duration. The symptom effects might be mediated by dietary influences on estrogen activity.

GnRH agonist and iron versus placebo and iron in the anemic patient before surgery for leiomyomas: a randomized controlled trial. Leuprolide Acetate Study Group.

OBJECTIVE: To determine the effectiveness of leuprolide acetate depot plus iron compared with iron alone in the preoperative treatment of anemia due to prolonged or excessive bleeding associated with uterine leiomyomas. METHODS: This was a phase III, stratified, randomized, double-blind, placebo-controlled, parallel-group, 12-week multicenter study. Enrolled patients had hemoglobin levels of 10.2 g/dL or less and/or hematocrit values of 30% or less. Patients were entered into one of two strata based on their pre-study hematocrit level: stratum A, hematocrit less than or equal to 28%, and stratum B, hematocrit greater than 28%. Patients within each stratum were randomized to one of three treatment arms: leuprolide acetate depot 7.5 mg, leuprolide acetate depot 3.75 mg, or placebo. All patients received iron orally. Response was defined as a hemoglobin level of 12 g/dL or more and a hematocrit value of 36% or greater. RESULTS: Three hundred nine patients were entered into the study, of whom 265 were evaluated. Using our response criteria, a significantly greater number of patients in both leuprolide acetate groups (combined strata) responded to therapy than did those in the placebo group: 74% in each leuprolide acetate group versus 46% in the placebo group (P < .001). Gonadotropin-releasing hormone agonist-treated patients had a significant reduction in uterine and myoma volume when compared with the placebo group (P < .01). Hot flashes and vaginitis were reported significantly more often (P < .001) in the leuprolide acetate-treated groups than in the placebo group. CONCLUSION: Both dosages of GnRH agonist plus iron were more effective than iron alone in treating the anemia of patients with uterine leiomyomas, in reducing uterine-myoma volume, and in alleviating bleeding and other leiomyoma-related symptoms.

Sustained benefits of leuprolide acetate with or without subsequent medroxyprogesterone acetate in the nonsurgical management of leiomyomata uteri.

OBJECTIVE: To determine the effectiveness of leuprolide acetate (LA) followed by medroxyprogesterone acetate (MPA) in the treatment of abnormal uterine bleeding attributed to leiomyomata uteri. DESIGN: Randomized, double-blinded, controlled clinical trial. SETTING: Human volunteers in an academic research environment. PATIENTS: Premenopausal women with abnormal uterine bleeding attributed to leiomyomata uteri. INTERVENTIONS: Subjects received 6 months of LA after which they were randomized to receive MPA or placebo. MAIN OUTCOME MEASURES: Control of bleeding as assessed by menstrual calendar and self-report; hematologic parameters (hemoglobin and ferritin); uterine size by ultrasonography. RESULTS: More than three quarters of subjects became amenorrheic on LA. The proportion of subjects with improvement in the bleeding abnormality after therapy was not different in the group receiving MPA compared with placebo; however, women who received MPA were less likely to be anemic after therapy than women receiving placebo. Among the women assigned to placebo, 55% experienced an improvement in bleeding compared with pre-GnRH agonist therapy that persisted after discontinuation of LA. There was a high dropout rate (51%), largely associated with failure of the regimens to control bleeding symptoms. CONCLUSIONS: Approximately one half of women with abnormal bleeding attributed to leiomyomata uteri have sustained symptomatic improvement after 6 months of therapy with LA even when only placebo therapy is given, although MPA decreases the incidence of anemia. Leuprolide acetate with or without subsequent progestin may be useful as a component of nonsurgical management of these tumors, with monitoring of hematologic status. The interpretability of these data is limited by the high rate of therapy discontinuation in women with abnormal bleeding of the severity studied here.

Intermittent leuprolide acetate for the nonsurgical management of women with leiomyomata uteri.

OBJECTIVE: To evaluate the feasibility of intermittent 6-month courses of leuprolide acetate for the long-term control of symptoms attributed to leiomyomata uteri. DESIGN: Prospective open-label feasibility study. SETTING: University department of obstetrics and gynecology. PATIENT(S): Thirty women with abnormal bleeding or discomfort (pain or pressure) due to leiomyomata uteri. INTERVENTION(S): Patients received an initial 6-month course of the GnRH agonist leuprolide acetate, after which they were observed for symptom recurrence. Symptom recurrence was managed by repeated 6-month courses of leuprolide acetate. MAIN OUTCOME MEASURE(S): Relief of symptoms, responses on a quality-of-life questionnaire, serum lipid levels, blood count, and ferritin level. The number of doses of leuprolide acetate required to maintain symptom control was recorded. Serial bone mineral density measurements were made in selected patients. RESULT(S): Twenty of the 30 women who began therapy with leuprolide acetate continued in the protocol. Each individual 6-month course of leuprolide acetate therapy was followed by a median of 9 additional months of symptom control (range, 2 to >25 months). Women remaining in the protocol experienced a mean decrease of 2.4% in bone mineral density of the lumbar spine; bone mineral density of the hip did not change. CONCLUSION(S): Intermittent courses of leuprolide acetate can be used in the nonsurgical management of women with symptomatic leiomyomata uteri. Use of antiresorptive add-back therapy and monitoring of bone mineral density can be considered when repeated courses of leuprolide acetate are given.

Leuprolide acetate and bone mineral density measured by quantitative digitized radiography.

Quantitative digitized radiography uses low-energy photons to measure bone density with precision not available in older techniques. Using this method, lumbar spine density was evaluated in 12 women before and after 6 months of therapy with LA. A 2.9% decrement in mean bone density was documented. The reproducibility of quantitative digitized radiography suggests that this small degree of bone mineral loss is a real phenomenon and not an artifact of measurement. The clinical significance of this degree of bone mineral loss has yet to be established.

Tampons, dioxins, and endometriosis.

Concern has been expressed that rayon tampons contain dioxins as a result of chlorine bleaching and, further, that the dioxins in tampons may increase the risk of endometriosis. Rayon tampons do not contain 2,3,7,8-tetrachlorodibenzo-p-dioxin, the chemical commonly meant when the generic term "dioxin" is used. In addition, rayon tampons contain only trivial amounts of dioxin-like environmental contaminants, similar to the amounts contained in unbleached cotton tampons. The amount of dioxin-like material that is theoretically available from tampons is at least six orders of magnitude lower than estimated daily food exposure levels to these contaminants. The evidence for a causal relationship between environmental exposure to dioxins and endometriosis is inconsistent. Prediction of the effective dioxin dose based on the most suggestive of the primate studies on endometriosis does not raise concerns about typical human food exposures to these compounds, let alone the considerably lower levels that could be present in tampons.

Rat embryo culture to detect nutritional deficiency in women with poor reproductive histories.

The cause of habitual early pregnancy loss is not known for most affected couples. It has been proposed that a deficiency of amino acids or other nutrients may contribute to early embryo loss, and an assay based on culture of rat embryos in human serum has been proposed to evaluate women with poor reproductive histories. We tested this assay in women with unexplained infertility (n = 27), habitual abortion (n = 15), and normal midtrimester pregnancies (n = 10) by examining the ability of subject's serum to support the normal development of rat embryos in culture with and without supplemental vitamins and amino acids. Nonpregnant women with nutrient deficiencies identified in this manner were given oral supplements or placebo and were retested. A similar proportion of women in each group had serum that was unable to support the normal development of rat embryos without supplemental vitamins and amino acids. When oral supplements were used, most sera were able to support normal embryo growth. There were no seroconversions on placebo. In spite of the apparent success in producing seroconversions on oral supplementation, only two women conceived, one on the placebo treatment and one on nutritional supplements. Because serum nutrient deficiencies identified by rat embryo culture could not distinguish normal pregnant women from women with unexplained infertility or habitual abortion, and because of the low pregnancy rates, we could not confirm the utility of this assay for the general population of women with habitual abortion.(ABSTRACT TRUNCATED AT 250 WORDS)

An assessment of the developmental toxicity of inorganic arsenic.

A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.

Assessment of reproductive disorders and birth defects in communities near hazardous chemical sites. II. Female reproductive disorders.

Members of the workgroup on female reproductive disorders discussed methods to evaluate five principal functions: menstrual dysfunction, infertility, pregnancy loss, lactation disorders, and pregnancy complications. To test each function, a nested strategy was considered, based on progressive levels of effort available to conduct field investigations. This strategy was analogous to the three-tier classification of biomarkers used by other workshops. The lowest level of effort, corresponding to Tier 1, consists only of questionnaires, diaries, and reviews of maternal and infant medical records. The medium level of effort (Tier 2) collects data from questionnaires and diaries, and some biologic specimens. Suggested laboratory analyses included measurement of progesterone in saliva and several glycoprotein hormones in urine that evaluate menstrual dysfunction, infertility, and pregnancy loss. The highest level of effort (Tier 3) involves prospective collection of diary information and simultaneous collection of biological specimens.

Evaluating chronic pelvic pain. A consensus recommendation. Pelvic Pain Expert Working Group.

OBJECTIVE: To identify a comprehensive approach to evaluating women with chronic pelvic pain based on findings in the literature. STUDY DESIGN: A working group of gynecologist pelvic pain specialists was convened to consider principles on which consensus could be reached and to identify areas in which consensus is not yet possible. RESULTS: Chronic pelvic pain affects 15% of American women. The diagnostic and therapeutic approach to the complaint may be influenced inordinately by the specialty of the practitioner to whom the woman presents. A comprehensive approach to the complaint requires recognition of the multiple organ systems that may be involved. Evaluation of the woman with chronic pelvic pain begins with a comprehensive history and physical examination, followed by selected laboratory and imaging studies. For those women in whom the evaluation does not yield a likely cause of the complaint, the empiric use of nonsteroidal antiinflammatory agents, oral contraceptives, and perhaps antibiotics or antispasmodics is indicated. Women who fail to respond to empiric therapy should be considered highly likely to have endometriosis or adenomyosis. Further diagnostic (laparoscopy) or therapeutic (gonadotropin-releasing hormone agonist) interventions should be directed toward the high likelihood of endometriosis or adenomyosis. CONCLUSION: A comprehensive approach to chronic pelvic pain includes consideration of multiple organ systems, with empiric therapy appropriate after a thorough history and physical examination, to further delineate the pain problem.

Amniotic fluid index in the uncomplicated term pregnancy. Prediction of outcome.

OBJECTIVE: To establish whether an association between oligohydramnios and pregnancy outcome is present in the uncomplicated term pregnancy. STUDY DESIGN: Pregnancies with a singleton fetus in cephalic presentation at term (> or = 37 weeks), a reactive non-stress test and an antepartum amniotic fluid index performed within four days of delivery between January 1994 and September 1998 were identified. Excluded were those with any maternal or fetal complication or unavailable outcome information. The primary outcome measure was rate of operative vaginal or abdominal delivery for a nonreassuring fetal heart rate tracing. Statistical analysis included Fisher's exact test and one-way analysis of variance, with a two-tailed P < .05 considered significant. RESULTS: Two hundred thirty-two women met the inclusion criteria; of them, 44 (19%) had an amniotic fluid index < or = 5 cm. There was no difference in the operative delivery rate for a nonreassuring fetal heart tracing between those with a normal amniotic fluid index > 5 cm vs. < or = 5 cm (39 [21%] vs. 5 [11%], P > .05). In addition, there were no differences between the two groups in rates of neonatal intensive care unit admissions or five-minute Apgar scores < 7. Patients with a normal amniotic fluid index had a significantly lower labor induction rate (96 [51%] vs. 42 [98%], P < .001) and higher rate of meconium-stained amniotic fluid (65 [35%] vs. 7 [16%], P = .01) than those with a low amniotic fluid index. CONCLUSION: In the uncomplicated pregnancy at term, an amniotic fluid index < or = 5 cm increases the incidence of labor induction but does not appear to affect the rate of operative delivery for abnormal fetal heart rate tracings.

Alternatives to hysterectomy for benign conditions.

Hysterectomy is the second most commonly performed major operation in the United States. Approximately one in three women will have this operation, resulting in 590,000 procedures per year. The most common indications for hysterectomy are leiomyomata uteri, abnormal uterine bleeding, endometriosis, pelvic pain, and pelvic organ prolapse. Although hysterectomy is an appropriate therapeutic option for some women with these conditions, in many instances less radical alternatives may be offered. Leiomyomata may be managed expectantly if symptoms are not bothersome; for women with troubling leiomyomata symptoms, alternatives to hysterectomy include: endoscopic removal or destruction of myomas, arterial embolization, or hormonal therapy to inhibit or modify bleeding. Endometriosis and abnormal uterine bleeding of leiomyomata are both amenable to hormonal therapy. Pelvic pain is most effectively approached with a thorough evaluation (particularly for nongynecologic illness), with specific therapy directed at the cause of the pain. Pelvic organ prolapse may respond symptomatically to pelvic floor exercises, or to the use of a pessary. After alternatives to removal of the uterus are discussed, the informed woman may decide that hysterectomy is the option best suited to her. It is unusual for hysterectomy to be her only option.