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Objective: To assess the relationship between SHBG and 18 other hormonal and metabolic parameters in well characterized, normally cycling premenopausal women., Design: Cross-sectional study., Setting: University general clinical research center., Subject(s): A total of 319 young healthy women with ovulatory menstrual cycles., Intervention(s): None., Main Outcome Measure(s): Midfollicular serum SHBG concentrations., Result(s): In our final linear regression model, SHBG was negatively associated with bioavailable T and positively associated with adiponectin, associations that were independent from other parameters. SHBG was also positively associated with estrone sulfate, but only when taking into account confounding variables. Unexpectedly, there was no straightforward relationship between SHBG and insulin resistance according to homeostasis-model assessment., Conclusion(s): Our results highlight the link between androgen action, as reflected by bioavailable T, and circulating SHBG concentrations in all premenopausal women and speak to the importance of the relationship between SHBG and adiponectin, which is at least in part independent from androgen action., Clinical Trial Registration Number: NCT00393172., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: It is well accepted that exercise can decrease breast cancer risk. Limited clinical evidence suggests that this risk could be mediated through changes in estrogen metabolism in premenopausal women. Our objective was to investigate the effects of exercise on premenopausal estrogen metabolism pertinent to breast cancer risk., Methods: Sedentary, healthy, young eumenorrheic women were randomized into an intervention of 30 minutes of moderate-to-vigorous aerobic exercise five times a week for approximately 16 weeks (n = 212), or into a usual-lifestyle sedentary control group (n = 179). Urinary levels of estrogens [estrone [E1], estradiol, and estriol] and nine estrogen metabolites were measured at baseline and at study end by liquid chromatography/tandem mass spectrometry. The ratios of 2-hydroxyestrone to 16α-hydroxyestrone (2-OHE1/16α-OHE1) and 2-OHE1 to 4-hydroxyestrone (2- OHE1/4-OHE1) were also calculated., Results: The exercise intervention resulted in significant increases in aerobic fitness and lean body mass and a significant decrease in percent body fat. For exercisers who completed the study (n = 165), 2-OHE1/16α-OHE1 increased significantly (P = 0.043), whereas E1 decreased significantly (P = 0.030) in control participants (n = 153). The change from baseline in 2-OHE1/16α-OHE1 was significantly different between groups (P = 0.045), even after adjustment for baseline values., Conclusions: The exercise intervention resulted in a significant increase in the 2-OHE1/16α-OHE1 ratio but no differences in other estrogen metabolites or ratios., Impact: Our results suggest that changes in premenopausal estrogen metabolism may be a mechanism by which increased physical activity lowers breast cancer risk.

The purpose of this trial was to determine whether exercise without weight loss would reduce F2-isoprostanes in previously sedentary young women. Participants (N=319) were randomized to four months of 150min/week aerobic exercise or a control group. Plasma free F2-isoprostanes were measured by gas chromatography-mass spectrometry. Other assessments included fitness and % body fat. Intervention groups were compared with stratification by quartiles of baseline plasma F2-isoprostane. This stratified comparison was linearly adjusted for baseline plasma F2-isoprostane and we also used baseline plasma F2-isoprostane as a propensity score to balance the intervention. Training resulted in significant improvements in aerobic fitness (0.88 METs) and body fat percent (1%) in exercisers compared to controls (p<0.001). The exercise group had significantly higher mean baseline plasma F2-isoprostanes (79.1 vs 67.9pg/mL) than the control group in the highest quartile of baseline plasma F2-isoprostanes. Within this highest quartile, exercise led to a greater decline in plasma F2-isoprostanes (-20.2±2.5pg/mL) than control (-7.4±2.5pg/mL); with adjustment for baseline plasma F2-isoprostanes and in the balanced groups, this difference was reduced but remained significant. Four months of exercise training resulted in significant reductions of systemic oxidative stress only among previously sedentary young women who were in the highest quartile of plasma F2-isoprostanes at baseline (≥57pg/mL). Our findings indicate that the benefits of aerobic exercise in reducing systemic oxidative stress may be limited to those who present higher baseline levels of plasma F2-isoprostanes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To describe outcomes of the first 100 consecutive infertility patients participating in a risk-sharing program with uncomplicated eligibility requirements. The program included the costs of FSH-containing gonadotropin preparations and provided a full payment refund if no birth occurred that resulted in a normal infant surviving to an age of 1 month., Design: Retrospective cohort study., Setting: Private IVF center., Patient(s): Infertility patients<35 years of age, considered to be good autologous oocyte IVF candidates at time of program enrollment., Intervention(s): Retrospective analysis of outcomes of fresh IVF-ET and frozen embryo transfer cycles involving conventional treatment protocols., Main Outcome Measure(s): Cumulative successful pregnancy rate., Result(s): Of the first 100 patients enrolled in the program, 82 have had a delivery of a normal infant surviving to an age of 1 month, and another 6 have undelivered ongoing pregnancies at 20+ weeks. Nine participants completed the program without completing a successful treatment cycle, and another three remain enrolled., Conclusion(s): Infertility patients<35 years of age participating in a risk-sharing program with uncomplicated eligibility requirements are very likely to have a successful pregnancy. Other centers may wish to incorporate some of the described program's features into their own risk-sharing IVF programs., (Copyright © 2011. Published by Elsevier Inc.)

Background: It is hypothesized that exercise can lead to a decrease in breast cancer risk through several hormonal and nonhormonal mechanisms. The WISER (Women In Steady Exercise Research) study investigated the effects of aerobic exercise on premenopausal sex hormone levels., Methods: Three hundred ninety-one sedentary, healthy, young eumenorrheic women were randomized either into an exercise intervention of 30 minutes of aerobic exercise 5 times a week for approximately 16 weeks (n = 212) or into a control group (n = 179). Serum levels of estradiol, estrone sulfate, testosterone, and sex hormone-binding globulin (SHBG), all in the midfollicular phase, and of progesterone, in the midluteal phase, were measured at baseline and at the end of the 16-week period., Results: Compared with the controls (n = 153), exercisers (n = 166) experienced significant increases in aerobic fitness, lean body mass, and decreases in percent body fat. There were no significant changes in body weight and menstrual cycle length between or within groups. Progesterone decreased significantly in exercisers; however, this reduction was similar to that of the control group. No significant changes between or within groups were found for any of the other sex hormones or SHBG., Conclusions: In premenopausal women, 16 weeks of 150 minutes per week of moderate aerobic exercise in young women did not significantly alter sex hormone or SHBG levels., Impact: Any favorable effects that moderate aerobic exercise without an associated weight change may have on breast cancer risk in premenopausal women are unlikely to be a consequence of changes in levels of sex hormones or SHBG., (©2011 AACR.)

Objective: To determine whether isoflavones exert estrogen-like effects in men by lowering bioavailable T through evaluation of the effects of soy protein or isoflavone intake on T, sex hormone-binding globulin (SHBG), free T, and free androgen index (FAI) in men., Design: PubMed and CAB Abstracts databases were searched through July 1, 2008, with use of controlled vocabulary specific to the databases, such as soy, isoflavones, genistein, phytoestrogens, red clover, androgen, testosterone, and SHBG. Peer-reviewed studies published in English were selected if [1] adult men consumed soy foods, isolated soy protein, or isoflavone extracts (from soy or red clover) and [2] circulating T, SHBG, free T, or calculated FAI was assessed. Data were extracted by two independent reviewers. Isoflavone exposure was abstracted directly from studies., Main Outcome Measure(s): Fifteen placebo-controlled treatment groups with baseline and ending measures were analyzed. In addition, 32 reports involving 36 treatment groups were assessed in simpler models to ascertain the results., Result(s): No significant effects of soy protein or isoflavone intake on T, SHBG, free T, or FAI were detected regardless of statistical model., Conclusion(s): The results of this meta-analysis suggest that neither soy foods nor isoflavone supplements alter measures of bioavailable T concentrations in men., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of probiotic capsules on plasma lipids., Design: A randomized, single-blinded, placebo-controlled, parallel-arm trial., Subjects: Fifty-five normocholesterolemic subjects ages 18-36 (33 premenopausal women and 22 men)., Intervention: Each subject consumed either three probiotic capsules each containing a total of 10(9) colony-forming units Lactobacillus acidophilus and Bifidobacterium longum and 10-15 mg fructo-oligosaccharide or three placebo capsules daily for 2 months (men) or two menstrual cycles (women). Plasma lipids were measured before and following the intervention (during the early follicular phase for women)., Results: Plasma concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride were not altered by consumption of probiotic or placebo capsules and were not different between treatment groups following the intervention., Conclusions: These results do not support a beneficial effect of Lactobacillus acidophilus strain DDS-1 and Bifidobacterium longum strain UABL-14 on plasma lipids in normocholesterolemic young women and men., Sponsorship: Supported by the Minnesota Agricultural Experiment Station and UAS Laboratories.

Background: Infectious complications are a major cause of morbidity and mortality in critically ill trauma patients. Therefore, fever and leukocytosis often trigger an extensive laboratory workup that includes a urine culture (UCx). The purposes of this study were to: 1) Define the current practice for obtaining UCxs in trauma patients admitted to the surgical and trauma intensive care unit (STICU); and 2) determine if there is an association between fever or leukocytosis and urinary tract infections (UTIs) during the initial 14 hospital days., Methods: An 18-month retrospective cohort analysis was performed on consecutive trauma patients admitted for at least two days to the STICU at a level I trauma center. Data collected included demographics, injuries, and daily maximal temperature (T(max)), leukocyte count, and UCx results for the first 14 days. Fever and leukocytosis were defined as T(max) > or =38.5 degrees C and leukocyte count > or =12,000/mm(3), respectively. Urinary tract infections were diagnosed with a positive UCx (> or =10(5) organisms/mL of urine)., Results: Five hundred ten patients were evaluated for a total of 3,839 patient-days. Their mean age and Injury Severity Score were 49 +/- 1 years and 19 +/- 1 points, respectively. Seventy-two percent were men, and 91% had sustained blunt injuries. Four hundred seven UCxs were obtained; 42 patients (8%) had 60 UTIs. The cohort had an indwelling urinary catheter for 97% of the patient-days, yielding an infection density of 16 UTIs/1,000 urinary catheter-days. There was a significant association between obtaining a UCx and fever and between fever and leukocytosis (both, p < 0.001), but no association of UTI with fever, leukocytosis, or the combination of fever and leukocytosis. Analysis using temperature and leukocyte count as continuous variables identified no temperature or leukocyte range associated with UTIs. Independent risk factors for UTI calculated by logistic regression were female sex, older age, low Injury Severity Score, and no antibiotics within 24 h before the UCx was obtained., Conclusions: The practice of obtaining a UCx from the STICU trauma patient was related to fever and fever with leukocytosis. However, neither fever nor leukocytosis nor both were associated with UTIs. These data suggest that there is an unnecessary emphasis on UTI as a source of fever and leukocytosis in injured patients during their first 14 STICU days. Our results suggest that the paradigm for evaluating UTI as a cause of fever needs to be reevaluated in critically ill trauma patients.

Objective: The aim of this study was to determine whether equol excretion status and plasma hormone and leptin concentrations can be influenced by consumption of a probiotic supplement. A secondary focus was to investigate whether male equol excretors have a hormone profile consistent with reduced prostate cancer risk., Design: The design was a randomized, single-blinded, placebo-controlled, parallel-arm trial., Subjects: Thirty-one (31) of the initially enrolled 39 subjects, 18 to 37 years old, completed all study requirements., Intervention: Subjects consumed either probiotic capsules (containing Lactobacillus acidophilus and Bifidobacterium longum) or placebo capsules for 2 months. Fasting plasma concentrations of testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide (AAG), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), and leptin were measured on days 1 and 57. Urinary excretion of genistein, glycitein, daidzein, O-desmethylangolensin (O-Dma), and equol was measured on days 4 and 61 following a 4-day soy challenge., Results: Probiotic consumption did not significantly alter equol excretor status, plasma hormone, or leptin concentrations in these subjects. At baseline, there were no differences in plasma hormone concentrations between equol excretors and nonexcretors; however, the low number of equol excretors included in this study limits the strength of this finding., Conclusions: The 2-month intervention with probiotic capsules did not significantly alter equol excretion, plasma hormone, or leptin concentrations in these subjects. A secondary finding was that male equol excretors in this study did not exhibit a hormone profile consistent with reduced prostate cancer risk, although this result should be interpreted with caution.

Objective: To confirm the results of an earlier study showing premenopausal equol excretors to have hormone profiles associated with reduced breast cancer risk, and to investigate whether equol excretion status and plasma hormone concentrations can be influenced by consumption of probiotics., Design: A randomized, single-blinded, placebo-controlled, parallel-arm trial., Subjects: In all, 34 of the initially enrolled 37 subjects completed all requirements., Intervention: All subjects were followed for two full menstrual cycles and the first seven days of a third cycle. During menstrual cycle 1, plasma concentrations of estradiol (E(2)), estrone (E(1)), estrone-sulfate (E(1)-S), testosterone (T), androstenedione (A), dehydroepiandrosterone-sulfate (DHEA-S), and sex-hormone-binding globulin (SHBG) were measured on cycle day 2, 3, or 4, and urinary equol measured on day 7 after a 4-day soy challenge. Subjects then received either probiotic capsules (containing Lactobacillus acidophilus and Bifidobacterium longum) or placebo capsules through day 7 of menstrual cycle 3, at which time both the plasma hormone concentrations and the post-soy challenge urinary equol measurements were repeated., Results: During menstrual cycle 1, equol excretors and non-excretors were not significantly different with respect to subject characteristics, diet, or hormone concentrations. Significant inverse correlations were found between E(2) and body mass index (BMI) (P=0.02), SHBG and BMI (P=0.01), DHEA-S and dietary fiber (P=0.04), and A and protein:carbohydrate ratio (P=0.02). Probiotic consumption failed to significantly alter equol excretor status or hormone concentrations during menstrual cycle 3, although there were trends towards decreased concentrations of T (P=0.14) and SHBG (P=0.10) in the probiotic group., Conclusions: We were unable to verify a previously reported finding of premenopausal equol excretors having plasma hormone concentrations different from those of nonexcretors. Furthermore, a 2-month intervention with probiotic capsules did not significantly alter equol excretion or plasma hormone concentrations.

The purpose of this report is to describe outcomes following laparoscopic transabdominal cervico-isthmic cerclage placement in cases of cervical incompetence not amenable to a conventional transvaginal procedure. We reviewed records of the first 11 patients at an academic teaching hospital who underwent laparoscopic transabdominal cerclage placement as an interval procedure, using a technique we previously first described. For all patients, the clinical course, including surgical complications and outcome of all subsequent pregnancies, is briefly described. One case was complicated by a small bowel injury secondary to concomitant extensive enterolysis. Otherwise there were no complications. Mean estimated blood loss was <40 ml. To date, 10 patients have conceived a total of 12 pregnancies following the procedure. Two pregnancies resulted in spontaneous losses at 8 weeks gestation, two in deliveries by Caesarean section at 34.5 weeks, and eight in deliveries by elective Caesarean section at 38 weeks or more. Each delivery resulted in the birth of a healthy infant. In conclusion, patients who require a transabdominal cerclage may undergo a laparoscopic interval procedure and achieve outcomes similar to those following placement via laparotomy during pregnancy.

Phyto-oestrogens are oestrogenic compounds found in plants and consist of isoflavones, lignans and coumestans. Epidemiological studies provide evidence for a protective role of isoflavones, and to a lesser extent lignans, against the development of numerous chronic diseases, including several cancers, cardiovascular disease and osteoporosis. The structural similarity of phyto-oestrogens to endogenous oestrogens has prompted the hypothesis that phyto-oestrogens exert hormonal or anti-hormonal effects relevant to the risk of hormone-dependent disease and/or their suitability as a dietary alternative to hormone replacement therapy. The many human studies that have evaluated the effects of isoflavones and lignans on various endpoints relating to risk of various diseases have greatly increased knowledge of how these compounds behave. At the same time, additional questions have been generated. For example, the increasing interest in extracting isoflavones from the soybean for incorporation into dietary supplements has raised important concerns regarding safety and efficacy. Overall, it is clear that phyto-oestrogens are an area of active and advancing research with great potential to continue to affect human health.

Isoflavonic phytoestrogens, or isoflavones, constitute a class of phytoestrogens that have properties similar to selective estrogen receptor modulators, and have attracted a substantial degree of attention in recent years, particularly as a possible alternative to the conventional hormone replacement therapy regimens used by postmenopausal women. Despite great promise, it is difficult to make many specific recommendations about their use at the current time, in light of the many outstanding questions that hopefully will be answered in the future by focused interventional studies involving humans. Studies to date indicate that the use of isoflavones to address vasomotor symptoms provides at most small benefits beyond a placebo effect, and no benefit for genital atrophy. As for postmenopausal women whose primary concern is cardiovascular disease, the recommendation of the American Heart Association to include soy protein foods as part of an otherwise healthy diet is well justified, and similarly the substitution of supplements containing soy protein for animal protein can also be recommended. The use of purified isoflavone supplements not containing soy protein may have some cardiovascular benefits, but these appear to be less substantial in degree than those provided by soy protein with isoflavones. In particular, more research is needed to assess the effects of isoflavones on osteoporosis, for which no recommendation regarding isoflavones can be made based on the current data. Also, isoflavones should not be taken by postmenopausal women for the specific purpose of decreasing their risk of breast or endometrial cancer, although, at least for those without pre-existing disease or at high risk, it seems quite unlikely that isoflavone use is harmful in this regard.

Objective: To assess the effect of soy isoflavone ingestion on plasma leptin concentrations in premenopausal and postmenopausal women., Design: Randomized, crossover studies, with blinding of participants and laboratory personnel., Setting: Procedures involving free-living individuals were carried out at the University of Minnesota General Clinical Research Center., Patient(s): Fourteen regularly cycling premenopausal women, and 18 postmenopausal women., Intervention(s): Each premenopausal participant consumed, on a daily basis, each of three soy protein powders containing different levels of isoflavones for three menstrual cycles plus 9 days, with plasma samples collected every other day the last 6 weeks of each diet period. Similarly, each postmenopausal participant consumed each of the three powders for 93 days, with plasma samples collected daily on days 64 to 66 and 92 to 94 of each diet period. The powders, dosed on a per-kilogram body weight basis, provided mean isoflavone intakes of 8, 65, and 130 mg/day, for the control, low-isoflavone, and high-isoflavone diet periods, respectively., Main Outcome Measure(s): Plasma leptin concentrations., Result(s): Isoflavone intake had essentially no effect on leptin concentrations in either premenopausal or postmenopausal participants. Concentrations in the premenopausal women were higher during the periovulatory and midluteal phases as compared to the early follicular and midfollicular phases., Conclusion(s): Despite the well-documented effect of estrogens to enhance leptin production, even high levels of isoflavone consumption do not alter leptin concentrations in women. Further studies are needed to more precisely delineate the nature of estrogenic and/or antiestrogenic effects of isoflavones in humans.

Before initiating treatment to induce ovulation in cases of PCOS, an appropriate evaluation of the patient and her partner, based on individual considerations, is important to optimize outcome. For obese patients with PCOS, weight-loss measures should be pursued before pharmacologic treatment is initiated. For most patients, the pharmacologic agent of choice to induce ovulation is clomiphene citrate, alone or in combination with a glucocorticoid. Treatment with metformin, alone or in combination with clomiphene citrate, may also be beneficial. For patients not responsive to clomiphene citrate, injectable gonadotropin treatment is usually warranted, although, depending on individual circumstances, laparoscopic ovarian drilling may be appropriate.

Objective: To report our initial IVF-ET experience combining assisted hatching performed 3 days after oocyte retrieval with day 5 embryo transfer (ET)., Design: Retrospective review of 110 consecutive IVF cycles not involving donor oocytes, including 16 cycles that involved assisted hatching performed 3 days after oocyte retrieval in combination with day 5 ET., Setting: Academic teaching hospital IVF center., Patient(s): Eighty-six consecutive IVF patients undergoing ET., Intervention(s): Assisted hatching using acid Tyrode's solution performed 3 days after oocyte retrieval in selected cases in combination with day 3 or 5 ETs., Main Outcome Measure(s): Clinical pregnancy rate per ET., Result(s): Of the 16 women undergoing day 5 ET following day 3 assisted hatching, 14 had a clinical pregnancy. These included 11 ongoing/delivered singletons and 2 ongoing/delivered twin pregnancies, neither of which was monochorionic. These clinical and ongoing/delivered pregnancy rates compared very favorably with those of 54% and 46%, respectively, for the 35 patients undergoing day 5 ETs without assisted hatching, even though the latter group appeared to be better IVF candidates based on the prognostic factors commonly used to predict success., Conclusion(s): Our experience suggests that day 3 assisted hatching followed by day 5 ET may be a useful combination in selected patients. Although not seen in our small series, an increased risk of monochorionic pregnancies remains a theoretical concern when such a combination is used, since both assisted hatching and blastocyst transfers have been independently linked to an increased risk in some reports.

Soy isoflavones are hypothesized to exert hormonal effects in women and thus may play a role in bone metabolism throughout life. In 2 randomized, cross-over studies, 14 pre- and 17 postmenopausal women were given 3 soy protein isolates containing different amounts of isoflavones [control, 0.13; low isoflavone (low-iso), 1.00; and high-iso, 2.01 mg/kg body wt/day, averaging 8, 65, and 130 mg/day, respectively], for over 3 months each. Food records, blood samples, and 24-h urine collections were obtained throughout the studies. The endpoints evaluated included plasma or serum concentrations of bone-specific alkaline phosphatase, osteocalcin, insulin-like growth factor-I (IGFI), IGF binding protein-3 (IGFBP3), and urine concentrations of deoxypyridinoline cross-links and carboxy-terminal telopeptide of type I collagen. In premenopausal women, IGFI and IGFBP3 concentrations were increased by the low-iso diet, and deoxypyridinoline cross-links was increased by both the low- and high-iso diets during certain phases of the menstrual cycle. In postmenopausal women, bone-specific alkaline phosphatase was decreased by both the low- and high-iso diets, and there were trends toward decreased osteocalcin, IGFI, and IGFBP3 concentrations with increasing isoflavone consumption. Although soy isoflavones do affect markers of bone turnover, the changes observed were of small magnitude and not likely to be clinically relevant. These data do not support the hypothesis that dietary isoflavones per se exert beneficial effects on bone turnover in women.

Increased urinary excretion of equol, a metabolite of the isoflavone daidzein, has been associated with a reduced risk of breast cancer. This risk reduction has generally been presumed to be a consequence of increased isoflavone consumption. However, only 30-40% of the population excretes more than trace amounts of equol, regardless of isoflavone intake. Accordingly, we hypothesized that the observed apparent protective effect of equol is at least in part attributable to hormonal differences between equol excretors and non-excretors, and that these differences are largely independent of isoflavone intake. We measured plasma hormone and sex hormone binding globulin (SHBG) concentrations in 14 normally cycling premenopausal women during each of three diet periods in which they consumed differing isoflavone doses (0.15, 1.0, and 2.0 mg/kg of body weight/day) as a component of soy protein isolate. The plasma hormone and SHBG concentrations of equol excretors (n = 5) were then compared with those of the non-excretors (n = 9). Results showed that even at the lowest dose, urinary equol excretion values for excretors far exceeded those for non-excretors consuming the highest dose. At all doses, equol excretors generally had lower concentrations of estrone, estrone-sulfate, testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA-sulfate, and cortisol and higher concentrations of SHBG and midluteal progesterone, a hormonal pattern overall consistent with lowered breast cancer risk. In conclusion, the association of equol excretion and lowered breast cancer risk may largely reflect the tendency of equol excretors to have more favorable hormonal profiles, as opposed to merely reflecting increased isoflavone intake. Equol may be a marker for the presence of colonic bacterial enzymatic activity that increases fecal steroid excretion. Alternatively, equol itself, even with very modest isoflavone intake, may exert beneficial effects on the regulation of endogenous hormones.

Background: Soy consumption is known to reduce plasma total cholesterol and LDL cholesterol in hypercholesterolemic subjects, but the responsible soy components and the effects in normocholesterolemic subjects remain unclear., Objective: The effects of soy isoflavone consumption on plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerol, apolipoprotein A-I, apolipoprotein B, and lipoprotein(a) concentrations and on LDL peak particle diameter were examined in normocholesterolemic, premenopausal women., Design: Thirteen healthy, normocholesterolemic, free-living, premenopausal female volunteers took part in this randomized, crossover-controlled trial. Each subject acted as her own control. Three soy isoflavone intakes (control: 10.0 +/- 1.1; low: 64.7 +/- 9.4; and high: 128.7 +/- 15.7 mg/d), provided as soy protein isolate, were consumed for 3 menstrual cycles each. Total cholesterol, HDL cholesterol, LDL cholesterol, and triacylglycerol were measured over the menstrual cycle. Apolipoprotein A-I, apolipoprotein B, lipoprotein(a), and LDL peak particle diameter were evaluated in the midluteal phase., Results: Total cholesterol, HDL-cholesterol, and LDL-cholesterol concentrations changed significantly across menstrual cycle phases (P < 0.005). During specific phases of the cycle, the high-isoflavone diet lowered LDL cholesterol by 7.6-10.0% (P < 0.05), the ratio of total cholesterol to HDL cholesterol by 10.2% (P < 0.005), and the ratio of LDL to HDL cholesterol by 13.8% (P < 0.002)., Conclusions: Isoflavones significantly improved the lipid profile across the menstrual cycle in normocholesterolemic, premenopausal women. Although of small magnitude, these effects could contribute to a lower risk of developing coronary heart disease in healthy people who consume soy over many years.

Endogenous estrogen metabolism may play an important role in the pathogenesis of hormone-related cancers, most notably breast cancer. Despite the importance of estrogen metabolism, little is known about estrogen metabolite profiles during different phases of the menstrual cycle. This study was performed to evaluate the effects of the menstrual cycle on endogenous estrogen metabolism. Twenty-four-hour urine samples were collected daily during 4 precisely defined phases of the menstrual cycle (early follicular, midfollicular, periovulatory, and midluteal phases) from 6 healthy premenopausal women. Urine samples were analyzed for 15 endogenous estrogens and their metabolites by an ion exchange chromatography and the capillary gas chromatography-mass spectrometry method. The patterns of urinary estrogen metabolites (including potentially genotoxic 16alpha-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone) followed those of plasma estradiol and estrone, showing significant increases in the periovulatory and midluteal phases. Compared to the early and midfollicular phases, the ratios of 2-hydroxyestrogens/16alpha-hydroxyestrogens and 2-hydroxyestrogens/4-hydroxyestrogens were significantly increased during the periovulatory and midluteal phases (by 28% and 72%, respectively; P < 0.05), suggesting that estrogen metabolism is significantly affected by menstrual cycle phase. These data indicate that menstrual cycle phase must be considered in studies of estrogen metabolism in premenopausal women.

Soy isoflavones have been hypothesized to exert hormonal effects in postmenopausal women. To test this hypothesis, we studied the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women. Isoflavones were consumed relative to bodyweight [control: 0.11 +/- 0.01; low isoflavone (low-iso): 1.00 +/- 0.01; high isoflavone (high-iso): 2.00 +/- 0.02 mg/kg/day] for 93 days each in a randomized crossover design. Blood was collected on day 1 of the study (baseline) and days 36-38, 64-66, and 92-94 of each diet period, for analysis of estrogens, androgens, gonadotropins, sex hormone binding globulin (SHBG), prolactin, insulin, cortisol, and thyroid hormones. Vaginal cytology specimens were obtained at baseline and at the end of each diet period, and endometrial biopsies were performed at baseline and at the end of the high-iso diet period, to provide additional measures of estrogen action. Overall, compared with the control diet, the effects of the low-iso and high-iso diets were modest in degree. The high-iso diet resulted in a small but significant decrease in estrone-sulfate (E1-S), a trend toward lower estradiol (E2) and estrone (E1), and a small but significant increase in SHBG. For the other hormones, the few significant changes noted were also small and probably not of physiological importance. There were no significant effects of the low-iso or high-iso diets on vaginal cytology or endometrial biopsy results. These data suggest that effects of isoflavones on plasma hormones per se are not significant mechanisms by which soy consumption may exert estrogen-like effects in postmenopausal women. These data also show that neither isoflavones nor soy exert clinically important estrogenic effects on vaginal epithelium or endometrium.

Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.

Objective: We assessed changes in creatinine clearance during the menstrual cycle of normally cycling women., Methods: We used a design that precisely identified the day of ovulation. Creatinine clearance was measured in 14 subjects on each of three days: cycle day 2 or 3, 1 or 2 days before the day of ovulation, and 6 or 7 days after ovulation., Results: Creatinine clearance was affected significantly by the menstrual cycle (P=.02), but the degree of this effect was modest. Mean (+/-standard error of mean) early follicular, preovulatory, and midluteal creatinine clearance values were 135+/-4, 131+/-5, and 142+/-5 mL/min, respectively, and only the difference between the preovulatory and midluteal values was significant. These changes in creatinine clearance were attributable largely to changes in creatinine excretion and not to changes in plasma creatinine concentrations., Conclusion: Despite the statistically significant luteal phase increase, creatinine clearance does not change in a clinically important manner during the normal menstrual cycle. Specifically, there is no substantial decrease in creatinine clearance around the time of ovulation.

Objective: To report a laparoscopic technique for placement of a transabdominal cervicoisthmic cerclage., Design: Detailed case report of one of three patients undergoing described procedure., Setting: University hospital., Patient: A 39-year-old infertile patient with a history of cervical adenocarcinoma in situ and two cone biopsies, resulting in an essentially absent exocervix., Intervention(s): Laparoscopic transabdominal cervicoisthmic cerclage placement, as an interval procedure, followed by ET of cryopreserved donor oocyte-derived embryos., Main Outcome Measure(s): Clinical outcome., Result(s): Establishment of a pregnancy delivered at 38 1/2 weeks of gestation by elective cesarean section., Conclusion(s): Patients believed to require a transabdominal cerclage may undergo a laparoscopic interval procedure, obviating the need for a laparotomy before or during pregnancy.

Objective: To report the successful use of recombinant human FSH in a patient with a history of a severe systemic immunoglobulin E (IgE)-mediated reaction to urofollitropin., Setting: University hospital., Patient: A 38-year-old infertility patient who had experienced a whole-body rash with hives, tachycardia, fever, and other symptoms after urofollitropin administration, with confirmation of IgE-mediated sensitivity to urofollitropin by intradermal skin testing., Intervention: In vitro fertilization-ET after the use of recombinant human FSH to stimulate ovarian follicular development., Results: Establishment of a clinical pregnancy., Conclusions: Our case provides evidence for the involvement of nongonadotropin proteins as the direct cause of some adverse reactions from conventional urine-derived human FSH preparations.

Objective: To report an unusual presentation of a patient with unicornuate uterus and a noncommunicating functional rudimentary horn and discuss related patient management issues., Setting: University hospital., Patient: A 27-year-old woman who presented with cyclic abdominal pain after a postpartum tubal ligation., Intervention: Diagnostic studies followed by a laparotomy and resection of the rudimentary horn., Results: Resolution of patient's symptoms., Conclusions: Patients with a unicornuate uterus and a rudimentary horn recognized for the first time during a tubal ligation require individualized management depending in part on the precise nature of the horn.

Objective: To compare the efficacy of a globulin-containing protein source, Synthetic Serum Substitute (Irvine Scientific, Santa Ana, CA) and human serum albumin (HSA) in the early culture of human oocytes and embryos., Design: Oocytes from 31 consecutive IVF cycles were assigned alternately to dishes containing human tubal fluid (HTF) and either Synthetic Serum Substitute or HSA as the protein source. Each semen sample was split for processing in Synthetic Serum Substitute or HSA. Sperm processed in Synthetic Serum Substitute was added to oocytes cultured in Synthetic Serum Substitute, and sperm processed in HSA was added to oocytes cultured in HSA. After determination of fertilization, zygotes were placed in HTF containing the same protein supplement. Before transfer, the embryos were graded morphologically., Main Outcome Measures: Occurrence of normal fertilization and embryo quality as assessed by morphological grading., Results: There was no significant difference in the occurrence of fertilization or in embryo morphological quality between oocytes cultured in Synthetic Serum Substitute as compared with HSA., Conclusions: The use of a globulin-containing protein source in culture for IVF-ET did not improve the fertilization rate or embryo quality. Our design did not allow for demonstration of an effect on pregnancy rate.

Lignans are a group of phytochemicals shown to have weakly estrogenic and antiestrogenic properties. Two specific lignans, enterodiol and enterolactone, are absorbed after formation in the intestinal tract from plant precursors particularly abundant in fiber-rich food and are excreted in the urine. We evaluated the effect of the ingestion of flax seed powder, known to produce high concentrations of urinary lignans, on the menstrual cycle in 18 normally cycling women, using a balanced randomized cross-over design. Each subject consumed her usual omnivorous, low fiber (control) diet for 3 cycles and her usual diet supplemented with flax seed for another 3 cycles. The second and third flax cycles were compared to the second and third control cycles. Three anovulatory cycles occurred during the 36 control cycles, compared to none during the 36 flax seed cycles. Compared to the ovulatory control cycles, the ovulatory flax cycles were consistently associated with longer luteal phase (LP) lengths (mean +/- SEM, 12.6 +/- 0.4 vs. 11.4 +/- 0.4 days; P = 0.002). There were no significant differences between flax and control cycles for concentrations of either estradiol or estrone during the early follicular phase, midfollicular phase, or LP. Although flax seed ingestion had no significant effect on LP progesterone concentrations, the LP progesterone/estradiol ratios were significantly higher during the flax cycles. Midfollicular phase testosterone concentrations were slightly higher during flax cycles. Flax seed ingestion had no effect on early follicular phase concentrations of DHEA-S, PRL, or sex hormone-binding globulin. Our data suggest a significant specific role for lignans in the relationship between diet and sex steroid action, and possibly between diet and the risk of breast and other hormonally dependent cancers.

Although the sequence of human GH-releasing hormone (GHRH) has been determined, all of the information concerning gene expression has been based on pathological sources of ectopic GHRH, since the only established physiological source of GHRH in humans is the hypothalamus. We recently reported the presence of extrahypothalamic GHRH-like mRNA and immunoreactive material in rat testis and placenta. To determine if human testis and placenta also contain immunoreactive GHRH-like peptides, tissue extracts were analyzed using enzyme-linked immunosorbent assay methodology. Both tissues had detectable quantities of immunoreactive peptide recognized by a monoclonal antibody to synthetic human GHRH-(1-44) (testis, 2.4 ng/g tissue, 0.68 ng/mg protein; placenta, 2.6 ng/g tissue, 0.36 ng/mg protein). The origin of these peptides was confirmed by extracting total RNA from human testis and placenta, with analysis on Northern blots probed with riboprobes for rat hypothalamic GHRH cDNA and human pancreatic tumor GHRH cDNA. Human testis and placenta total RNA both contain an approximately 790-nucleotide RNA species similar in size to that reported in ectopic GHRH-producing human tumors. In addition, two larger hybridization signals were seen at 3000 and 4900 nucleotides. These data suggest that testis and placenta are extrahypothalamic sites of expression of the human GHRH gene. Normal expression of the GHRH gene in extrahypothalamic sites may include transcription of larger mRNA species than those observed in ectopic pathological sources of GHRH expression.

Objective: To present the experience of a large referral center with patients with the rare but specific syndrome of uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis., Design, Patients: Between 1953 and 1991, 15 patients with the syndrome were evaluated by the authors; each patient's records were carefully reviewed., Main Outcome Measures: For each patient, the clinical course, specific anatomic findings, treatment(s) offered, and obstetrical outcome are presented., Results: The specificity of the association of uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis was confirmed by our series, the largest in the literature to date. The findings suggest a specific development anomaly of the müllerian ductal system, probably secondary to a wolffian duct anomaly. The most common clinical presentation was that of the onset of pelvic pain and/or dysmenorrhea shortly after menarche, in association with the finding of a vaginal/pelvic mass. When a communication between the two sides existed, symptoms of abnormal vaginal discharge and bleeding were common. Optimal outcome appears to have occurred for patients initially managed using a conservative surgical approach, i.e., simple vaginal septum resection combined with conservative treatment of associated endometriosis. Obstetrical outcome in our patients was similar to that in patients with the more common combination of uterus didelphys and sagittal vaginal septum., Conclusion: A greater awareness of the syndrome of uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis should lead to its prompt diagnosis, allowing for early and appropriate surgical intervention as well as decreased long-term morbidity.

Objective: To study the effect of human follicular fluid (FF) and the specific contribution of its epidermal growth factor (EGF) component on the in vitro maturation of cumulus-enclosed mouse oocytes., Design: A previously described mouse oocyte model system was used to study the effect of FF on oocyte maturation before and after extraction of EGF by immunoprecipitation. Follicular fluid specimens enclosing both mature and immature human oocytes were tested., Main Outcome Measures: The endpoints assessed were the percentage of oocytes undergoing germinal vesicle breakdown (GVBD) and polar body one formation at different intervals over a 24-hour period and the final degree of cumulus expansion achieved., Results: A concentration-related stimulatory effect of mature FF was noted when compared with the spontaneous increase of GVBD and polar body one formation observed for the EGF-free control medium. Overall, the effect of immature FF was inhibitory. After extraction of EGF from FF by immunoprecipitation from both immature and mature FF, the rates of GVBD and polar body one formation were decreased in both groups. The addition of 5 ng/mL of EGF to the extracted groups reversed this effect on polar body one formation. Cumulus expansion was maximal for oocytes incubated with mature FF and minimal for those incubated with EGF-free media., Conclusions: The positive effect of mature human FF on mouse oocyte maturation and cumulus expansion is to a large extent because of the presence of EGF.

We describe the first successful outcome of a case of combined tubal and intrauterine quadruplet pregnancy in the literature. The patient's risk factors for combined pregnancy included a history of PID as well as the use of hMG therapy. A laparoscopic salpingectomy was performed, followed by a multifetal pregnancy reduction procedure. Two healthy infants were delivered at 37 weeks of gestation.

Objective: Immature mammalian oocytes cultured in vitro undergo inadequate cytoplasmic maturation and hence have a limited potential for fertilization. Our primary objective was to determine if the addition of epidermal growth factor (EGF) to the in vitro culture system would have a positive effect on oocyte cytoplasmic maturation., Design: We studied the effect of different EGF concentrations on both denuded and cumulus-enclosed mouse oocytes cultured in vitro., Main Outcome Measures: The percentage of oocytes undergoing germinal vesicle breakdown (GVBD) and polar body one formation over time as a function of EGF concentration was determined., Results: A dose-related positive effect of EGF on both GVBD and polar body one formation over time was observed for mouse oocytes. As well, a similar effect of EGF was seen on immature human oocytes that had not been stimulated with exogenous gonadotropins., Conclusions: The use of EGF may allow for the performance of successful in vitro fertilization procedures using immature human oocytes retrieved during unstimulated cycles.

A case-control analysis of hospital-based data was conducted to evaluate whether low-dose combination oral contraceptives (OCs) protect against pelvic inflammatory disease (PID). Other categories of combination OCs based on estrogen dose were also assessed. The results indicate no OC confers protection if taken for less than 12 months. In contrast, the education-adjusted relative risk (RR) estimates for continuous exposure of greater than or equal to 12 months for various categories of combination OCs based on estrogen dose all ranged from 0.2 to 0.4 with overlapping 95% confidence intervals (CIs); however, the adjusted RR for low-dose pills was not statistically significant (RR = 0.4, 95% CI: 0.2, 1.1). These data are consistent with the hypothesis that low-dose estrogen pills as well as higher dose estrogen OCs potentially protect against PID requiring hospitalization. Low-dose estrogen combination OCs deserve further study in relation to PID generally, and more particularly, in regard to specific microorganisms causing PID.

Nicotine at concentrations found in the cervical mucus of female smokers appeared to enhance in vitro human sperm penetrability through ovulatory bovine cervical mucus. Sperm motility parameters were not affected by the addition of nicotine to semen samples incubated with BWW medium. Overall, these results suggest that a direct inhibitory effect of nicotine on sperm penetrability through cervical mucus is not responsible for the apparent increase in cervical factor infertility present in smoking women.

Hormone levels, physiologic parameters, electroencephalographic (EEG) activity, and changes in subjective feelings recorded using a nonverbal instrumental device were assessed following the double-blind intravenous administration of 500 micrograms of gonadotropin-releasing hormone (GnRH) or placebo to five normal males. Within 30 minutes of GnRH administration, prolactin (PRL) levels had risen by 4.3 +/- 1.2 ng/ml (mean +/- SEM) from a baseline of 8.5 +/- 0.9 ng/ml (overall increase P less than 0.005 vs. baseline, P less than 0.001 vs. placebo); maximally stimulated values had a mean of 16.7 +/- 2.3 ng/ml. The PRL elevations measured in absolute terms significantly correlated with increases in luteinizing hormone (LH) (r = 0.97) and follicle stimulating hormone (FSH) (r = 0.89). No changes in physiologic parameters or EEG activity occurred in response to GnRH, nor were any behavioral responses found. The increase in PRL following GnRH was specifically shown to be unrelated to experimental stress or the behavioral effects of GnRH.

A high incidence of luteal phase defect (LPD) has been reported using subcutaneous pulsatile gonadotropin-releasing hormone for induction of ovulation. We reviewed all patients treated with the combination of subcutaneous pulsatile gonadotropin-releasing hormone during the follicular phase and human chorionic gonadotropin during the luteal phase (GnRH-hCG) who underwent endometrial biopsy during a treatment cycle. All of these patients had biopsy-proven LPD which persisted despite traditional therapy with progesterone vaginal suppositories and/or clomiphene citrate. The mean number of biopsies out of phase per patient prior to GnRH-hCG treatment was 2.8 +/- 0.2 (+/- SEM). When treated with GnRH-hCG, 15/16 patients (94%) showed a normal endometrial biopsy. The probability of this result occurring by chance alone allowing for a 50% treatment independent correction rate is less than .001. These results show that the combination of subcutaneous pulsatile gonadotropin-releasing hormone and luteal-phase human chorionic gonadotropin can result in normal endometrial maturation in a high percentage of cycles when administered as described. It appears to be an effective alternative to traditional treatment modalities for luteal phase defect should one be needed.

Plasma levels of LH, FSH, prolactin (PRL), and testosterone (T) were assessed in six normal men following administration of a pharmacologic dose of gonadotropin releasing hormone (GnRH) (500 micrograms iv over a one-min period) with concomitant oral administration of either ethanol (0.695 g/kg of body weight over a 15-min period) or ethanol placebo. Acute ethanol administration had no effect on the response of either LH or FSH to GnRH. PRL levels increased following GnRH and administration of both ethanol and ethanol placebo. Ethanol administration enhanced the T response to GnRH (p less than 0.001 vs placebo). During the placebo condition, T levels did not rise significantly until 100 min after GnRH administration, at which time the mean increment over baseline was 101 +/- 20 ng/dl (+/- SEM). In contrast, following ethanol intake, T levels were significantly elevated within 30 min after GnRH administration, at which time the mean increment over baseline was 187 +/- 42 ng/dl. The mean T increments were 304 +/- 62 and 472 +/- 77 ng/dl, respectively, 60 and 105 min following GnRH and ethanol administration. The increase in T levels following acute ethanol intake and concomitant gonadotropin stimulation is in contrast to the well-documented effect of chronic ethanol intake on suppression of testosterone synthesis by testicular Leydig cells.

Smoking histories were compared in 901 women with infertility of different types and 1264 women admitted for delivery at seven collaborating hospitals. The relative risk for infertility associated with cigarette smoking prior to the infertility diagnosis for nulliparous cases or first live birth for controls was calculated using a multivariate logistic-regression model to control for potential confounding factors, including center, age, religion, education, number of sexual partners, and contraceptive use. The adjusted risk for infertility attributed primarily to cervical factor (n = 96) was 1.7 (P = 0.04), to tubal disease unrelated to endometriosis (n = 225) was 1.6 (P = 0.009), to ovulatory factor (n = 389) was 1.0 (not significant [NS]), and to endometriosis (n = 191) was 0.9 (NS). The authors conclude that cigarette smoking is significantly associated only with certain types of primary female infertility.

We studied the effect of the opiate antagonist naloxone on the peripheral GH response to the alpha 2-receptor agonist clonidine in eight normally cycling women during the mid-luteal phase. In a randomized, double-blind, cross-over design, each subject received clonidine and naloxone on one occasion and clonidine and placebo on the other. In seven of eight subjects, an attenuation of the GH response was associated with naloxone administration. The maximal GH increment above baseline (delta GHMAX) of 7.8 +/- 2.0 micrograms/L (mean +/- SEM) with placebo was higher than the delta GHMAX of 4.2 +/- 0.9 micrograms/L with naloxone (p = 0.05). Likewise, the area above baseline under the GH level-time curve following clonidine (delta GHAREA) was higher with placebo compared to naloxone (477 +/- 175 micrograms/L x min vs. 228 +/- 62 micrograms/L x min), although this difference was not quite statistically significant (p = 0.09). As expected, with placebo the increase in GH following clonidine was statistically significant by repeated measures analysis of variance (p = 0.001). The smaller increase in GH levels when naloxone was given was not significant. Both delta GHMAX and delta GHAREA values were significantly positively correlated with estradiol levels when placebo was given, but not when naloxone was given. GHRH was not detectable following clonidine administration under either the placebo or the naloxone conditions. Our data support the hypothesis that estrogen enhances the response of GH to provocative stimuli in women, at least in part by increasing endogenous opioid tone in the hypothalamus.