A randomized double-blind controlled proof-of-concept study of alanyl-glutamine for reduction of post-myomectomy adhesions.

STUDY OBJECTIVE: To test the hypothesis that intraperitoneal instillation of a single bolus dose of l-alanyl-l-glutamine (AG) will reduce the incidence, extent and/or severity of adhesions following myomectomy and establish preliminary safety and tolerability of AG in humans. DESIGN: Phase 1,2 Randomized, double-blind, placebo-controlled study (DBRCT). SETTING: Tertiary care gynecology surgical centre. PATIENTS: Thirty-eight women who underwent myomectomies by laparoscopy (N = 38; AG-19 vs Placebo-19) or laparotomy (N = 10; AG-5 vs Placebo-5) with a scheduled second-look laparoscopy (SLL) 6-8 weeks later. Thirty-two patients in the laparoscopy arm completed SLL. INTERVENTIONS: Bolus dose of AG or normal saline solution control (0.9% NaCl) administered intraperitoneally immediately prior to suture closure of the laparoscopic ports. The average dose was 170 mL of AG or control based on a dosing scheme of 1 g/kg bodyweight. MEASUREMENTS: Digital recordings obtained for all procedures. The primary endpoint was reduction in the incidence, severity and extent of post-operative adhesions analyzed by intention-to-treat (ITT) approach. Three independent, blinded reviewers evaluated all operative video recordings to assess presence of adhesions. Post-hoc analysis assessed presence or absence of adhesions in the peritoneal cavity. Secondary endpoints assessed safety and tolerability of AG. MAIN RESULTS: Administration of AG reduced the incidence, severity and/or extent of post-operative adhesions (p = 0.046). The presence of adhesions in the AG group was lower than in the Control group (p = 0.041). Adhesion improvement was achieved in 15 of 15 (100%) in the AG group versus 5 of 17 (29.6%) in the placebo group. No serious adverse events were reported. No differences in safety parameters were observed. CONCLUSIONS: Intraperitoneal l-alanyl-l-glutamine reduced adhesion formation in all patients following laparoscopic myomectomy. Complete absence of adhesions was achieved at all abdominal sites in 93% of patients. Results confirm AG's known effects on cellular mechanisms of adhesiogenesis and lay the foundation for new adhesion prophylaxis research and treatment.

Obesity, but not hyperandrogenism or insulin resistance, predicts skeletal muscle mass in reproductive-aged women with polycystic ovary syndrome: A systematic review and meta-analysis of 45 observational studies.

Women with polycystic ovary syndrome (PCOS) exhibit reduced muscle insulin-mediated glucose uptake, potentially attributed to altered muscle mass; however, this is inconclusive. Altered muscle mass may aggravate PCOS complications. Our systematic review and meta-analysis evaluated whether PCOS alters muscle mass and function. Databases (MEDLINE, Web of Science, Scopus) were searched through September 2, 2020, for studies documenting skeletal muscle mass (lean tissue mass) and function (strength) in PCOS and control groups. The primary outcome was total lean body mass (LBM) or fat-free mass (FFM). Data were pooled by random-effects models and expressed as mean differences and 95% confidence intervals. Forty-five studies (n = 3676 participants) were eligible. Women with PCOS had increased total (0.83 [0.08,1.58] kg; p = 0.03; I2  = 72.0%) yet comparable trunk (0.84 [-0.37,2.05] kg; p = 0.15; I2  = 73.0%) LBM or FFM versus controls. Results of meta-regression analyses showed no associations between mean differences between groups in total testosterone or homeostatic model assessment of insulin resistance and total or trunk LBM or FFM (All: p ≥ 0.75). Mean differences in body mass index (BMI) were associated with total (0.65 [0.23,1.06] kg; p < 0.01; I2  = 56.9%) and trunk (0.56 [0.11,1.01] kg; p = 0.02; I2  = 42.8%) LBM or FFM. The PCOS subgroup with BMI ≥ 25 kg/m2 had greater total LBM or FFM versus controls (1.58 [0.82,2.34] kg; p < 0.01; I2  = 64.0%) unlike the PCOS subgroup with BMI < 25 kg/m2 (-0.45 [-1.94,1.05] kg; p = 0.53; I2  = 69.5%). Appendicular lean mass and muscle strength data were contradictory and described narratively, as meta-analyses were impossible. Women with PCOS have higher total and trunk lean tissue mass attributed to overweight/obesity, unlike hyperandrogenism or insulin resistance.

Effects of Dietary Glycemic Index and Glycemic Load on Cardiometabolic and Reproductive Profiles in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Women with polycystic ovary syndrome (PCOS) exhibit cardiometabolic (e.g., insulin resistance) and associated reproductive disruptions. Lifestyle modification (e.g., diet) is recommended as the first-line therapy to manage PCOS; however, a favorable dietary regimen remains unclear beyond energy restriction. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to summarize evidence on impacts of dietary glycemic index (GI) or glycemic load (GL) on cardiometabolic and reproductive profiles to update the International Evidence-based Guideline for the Assessment and Management of PCOS. Databases of MEDLINE, Cochrane, Web of Science, and Scopus were searched through 30 October 2019, and confirmed on 25 March 2020, to identify RCTs (≥8 wk) comparing the effects of diets with lower (LGI/LGL) and higher (HGI/HGL) GI/GL on glucoregulatory outcomes, lipid profile, anthropometrics, and androgen status in PCOS. The primary outcome was HOMA-IR. Data were pooled by random-effects models and expressed as weighted mean differences and 95% CIs. The risk of bias was assessed by the Cochrane tool. Ten RCTs (n = 403) were eligible. Eight evaluated LGI and 2 LGL diets. LGI diets decreased HOMA-IR (-0.78; -1.20, -0.37; I2 = 86.6%), fasting insulin (-2.39; -4.78, 0.00 µIU/mL; I2 = 76.8%), total cholesterol (-11.13; -18.23, -4.04 mg/dL; I2 = 0.0%), LDL cholesterol (-6.27; -12.01, -0.53 mg/dL; I2 = 0.0%), triglycerides (-14.85; -28.75, -0.95 mg/dL; I2 = 31.0%), waist circumference (-2.81; -4.40, -1.23 cm; I2 = 53.9%), and total testosterone (-0.21; -0.32, -0.09 nmol/L; I2 = 8.6%) compared with HGI diets (all: P ≤ 0.05) without affecting fasting glucose, HDL cholesterol, weight, or free androgen index (all: P ≥ 0.07). Some results were contradictory and only described narratively for 2 RCTs that evaluated LGL diets, since inclusion in meta-analyses was not possible. LGI diets improved glucoregulatory outcomes (HOMA-IR, insulin), lipid profiles, abdominal adiposity, and androgen status, conceivably supporting their inclusion for dietary management of PCOS. Further RCTs should confirm these observations and address whether LGI diets improve more patient-pressing complications, including ovulatory cyclicity, infertility, and cardiovascular disease risk in this high-risk population. This review was registered at www.crd.york.ac.uk/PROSPERO as CRD42020175300.

A randomized controlled trial of a lifestyle intervention with longitudinal follow-up on ovarian dysmorphology in women with polycystic ovary syndrome.

OBJECTIVE: Effects of lifestyle modification on reproductive function in polycystic ovary syndrome (PCOS) remain poorly elucidated. We compared the effects of a pulse-based diet (lentils, beans, split peas and chickpeas) with Therapeutic Lifestyle Changes (TLC) diet on ultrasonographic markers of ovarian morphology, hyperandrogenism and menstrual irregularity in PCOS. DESIGN: Randomized controlled trial. PATIENTS: Women with PCOS (18-35 years). MEASUREMENTS: Thirty women randomized to the pulse-based and 31 to TLC groups completed a 16-week intervention without energy restriction. Groups performed aerobic exercise (minimum of 5 days/wk; 45 minutes/d) and received health counselling (monthly) and longitudinal follow-up. Follicle numbers per ovary (FNPO, 2-9 mm), ovarian volume (OV), free androgen index (FAI) and menstrual cycle length were measured pre- and postintervention. RESULTS: Follicle numbers per ovary (mean change ± SD, -10 ± 15), OV (-2.7 ± 4.8 mL), FAI (-3 ± 2) and menstrual cycle length (-13 ± 47 days) decreased over time in both groups (All: P < .01), without group-by-time interactions (All: P ≥ .13). Attrition rate was 33.7% and comparable between groups (P = .94). Adherence to diet intervention negatively correlated with changes in FNPO (r=-0.54), OV (r=-0.35) and FAI (r = -.29) in pooled groups (All: P ≤ .04). Groups maintained reduced OV, FNPO, FAI and menstrual cycles 6 months postintervention; however, decreased FNPO and FAI at 16 weeks tended to revert to baseline levels 12 months postintervention in both groups (All: P ≤ .05). CONCLUSIONS: Both interventions improved ovarian dysmorphology, hyperandrogenism and menstrual irregularity in PCOS, and no diet appeared to be superior at improving reproductive outcomes. Our observations highlight the importance of longitudinal surveillance for sustainable adherence to newly adopted healthy lifestyle behaviours and reproductive health in PCOS (ClinicalTrials.gov identifier, NCT01288638).

A pulse-based diet and the Therapeutic Lifestyle Changes diet in combination with health counseling and exercise improve health-related quality of life in women with polycystic ovary syndrome: secondary analysis of a randomized controlled trial.

Objective: A favorable dietary composition to increase health-related quality of life (HRQoL) in PCOS remains unclear. We compared changes in HRQoL of women with PCOS who participated in a low-glycemic-index pulse-based (lentils, beans, split peas, and chickpeas) or the Therapeutic Lifestyle Changes (TLC) diet intervention.Methods: Thirty women in the pulse-based and 31 in the TLC groups (18-35 years) completed a 16-week intervention without energy-restriction. Groups participated in health counseling (monthly) and aerobic exercise (5 days/week; 45 minutes/day).Results: Fifty-five (90.2%) women completed a PCOS-specific HRQoL survey. Greatest mean increases in time-effects occurred in the domains of healthy eating, PCOS knowledge, active living, healthcare satisfaction, feelings and experiences about intervention, and health concerns, respectively (p ≤ 0.02), without group-by-time interactions (p ≥ 0.13). Decreased weight (r = -0.35) and homeostatic model assessment of insulin resistance (r = -0.18) correlated with increased scores of PCOS knowledge; adherence to intervention correlated with increased scores of active living (r = 0.39) and healthy eating (r = 0.53; p ≤ 0.03).Conclusions: Both interventions improved HRQoL scores in women with PCOS without prescribed energy-restriction. Our observations add novel insights into current evidence and elucidate the need for future psychological research to target lifestyle modifications for improving HRQoL and unique psychological complications of PCOS in this high-risk population (CinicalTrials.gov identifier:NCT01288638).

Impact of right-left differences in ovarian morphology on the ultrasound diagnosis of polycystic ovary syndrome.

OBJECTIVE: To assess right-left differences in ultrasonographic markers of ovarian morphology and determine the impact on the diagnosis of polycystic ovarian morphology (PCOM). DESIGN: A cross-sectional study of data collected from 2006 to 2018. SETTING: Academic clinical research centers. PATIENT(S): Women with polycystic ovary syndrome (PCOS; n = 87) and controls (n = 67). INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): Follicle number per ovary (FNPO), follicle number per cross-section (FNPS), and ovarian volume (OV) were assessed in both ovaries using transvaginal ultrasonography. PCOM was identified based on recent international consensus guidelines or proposed diagnostic thresholds. RESULT(S): Overall, mean right-left differences were two follicles for FNPO, one follicle for FNPS, and 2 mL for OV. FNPO showed the strongest correlation between ovaries. Its assessment in a single ovary did not impact the diagnosis of PCOM in women with PCOS. However, there were differences in the probability of unilateral versus bilateral PCOM based on FNPS and OV in both groups. CONCLUSION(S): FNPO is the most reliable unilateral marker of PCOM in light of right-left differences in ovarian morphology. Use of FNPS or OV to define PCOM is discouraged when only one ovary is visualized.

Comprehensive Evaluation of Type 2 Diabetes and Cardiovascular Disease Risk Profiles in Reproductive-Age Women with Polycystic Ovary Syndrome: A Large Canadian Cohort.

OBJECTIVE: This study compared the prevalence of metabolic syndrome (MetS) and characterized type 2 diabetes (DM2) and cardiovascular disease (CVD) risk profiles between Canadian women with polycystic ovary syndrome (PCOS) and healthy women recruited from the general population. Furthermore, within the PCOS cohort, the study contrasted the CVD and DM2 risk profiles of women with or without MetS. METHODS: Measures of MetS (International Diabetes Federation; National Heart, Lung, and Blood Institute; and the American Heart Association definition), DM2 (Diabetes Canada Clinical Guidelines), and CVD risk factors (Androgen Excess and Polycystic Ovary Syndrome Society statement) were evaluated for 237 women with PCOS (Androgen Excess and PCOS Society definitions) and 42 controls (aged 18-36) in a prospective observational study (Canadian Task Force Classification II-2). RESULTS: The prevalence of MetS was 29.5% in the PCOS group, which was approximately six-fold higher than age-matched controls (P < 0.001). Women with PCOS exhibited higher glucose abnormality, acanthosis nigricans, total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C), and lower sex hormone-binding globulin concentrations when compared with controls after accounting for differences in the BMI (P < 0.01). Further, women with PCOS and MetS exhibited exacerbated insulin and glucose responses to a 75-g oral glucose tolerance test and greater acanthosis nigricans, hirsutism, TC/HDL-C, TC, and sex hormone-binding globulin concentrations compared with their BMI-adjusted counterparts without MetS (P < 0.05). CONCLUSION: Canadian reproductive-age women with PCOS have a high prevalence of MetS and exhibit adverse cardiometabolic risk factors that warrant early screening and regular monitoring across their reproductive lifespan.

A Comparison of a Pulse-Based Diet and the Therapeutic Lifestyle Changes Diet in Combination with Exercise and Health Counselling on the Cardio-Metabolic Risk Profile in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.

We compared the effects of a low-glycemic index pulse-based diet, containing lentils, beans, split peas, and chickpeas, to the Therapeutic Lifestyle Changes (TLC) diet on cardio-metabolic measures in women with polycystic ovary syndrome (PCOS). Ninety-five women (18⁻35 years) enrolled in a 16-week intervention; 30 women in the pulse-based and 31 in the TLC groups completed the study. Women participated in aerobic exercise training (minimum 5 days/week for 45 min/day) and were counselled (monthly) about PCOS and lifestyle modification. Women underwent longitudinal follow-up post-intervention. The pulse-based group had a greater reduction in total area under the curve for insulin response to a 75-g oral glucose tolerance test (mean change ± SD: -121.0 ± 229.9 vs. -27.4 ± 110.2 µIU/mL × min; p = 0.05); diastolic blood pressure (-3.6 ± 6.7 vs. -0.2 ± 6.7 mmHg, p = 0.05); triglyceride (-0.2 ± 0.6 vs. 0.0 ± 0.5 mmol/L, p = 0.04); low-density lipoprotein cholesterol (-0.2 ± 0.4 vs. -0.1 ± 0.4 mmol/L, p = 0.05); total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C; -0.4 ± 0.4 vs. 0.1 ± 0.4, p < 0.001); and a greater increase in HDL-C (0.1 ± 0.2 vs. -0.1 ± 0.2 mmol/L, p < 0.01) than the TLC group. Decreased TC/HDL-C (p = 0.02) at six-month and increased HDL-C and decreased TC/HDL-C (p ≤ 0.02) at 12-month post-intervention were maintained in the pulse-based group. A pulse-based diet may be more effective than the TLC diet at improving cardio-metabolic disease risk factors in women with PCOS. TRIAL REGISTRATION: CinicalTrials.gov identifier, NCT01288638.

Women With Polycystic Ovary Syndrome Have Comparable Hip Bone Geometry to Age-Matched Control Women.

Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting women of reproductive age manifesting with polycystic ovaries, menstrual irregularities, hyperandrogenism, hirsutism, and insulin resistance. The oligomenorrhea and amenorrhea characteristic to PCOS are associated with low bone mineral density (BMD); conversely, the hyperandrogenism and hyperinsulinemia may elicit a protective effect on BMD. As bone geometric properties provide additional information about bone strength, the objective of this study was to compare measures of hip geometry in women with PCOS to a healthy female population. Using dual-energy X-ray absorptiometry, BMD and measures of hip geometry were determined in women with PCOS (n = 60) and healthy controls (n = 60) aged 18-35 years. Clinical biochemical measures were also determined in women with PCOS. Measures of hip geometry, including cross-sectional area, cross-sectional moment of inertia, subperiosteal width (SPW), and section modulus, were similar between groups following correction for body mass index (BMI) (all p > 0.05) with intertrochanter SPW significantly lower in women with PCOS (p < 0.05). BMI-corrected whole body BMD as well as the lumbar spine and regions of proximal femur were also comparable between groups. In women with PCOS, BMI-corrected correlations were found between insulin and femoral shaft SPW (r = 0.322, p < 0.05), glucose and femoral neck (r = 0.301, p < 0.05), and trochanter BMD (0.348, p < 0.05), as well as between testosterone and femoral neck BMD (0.376, p < 0.05) and narrow neck cross-sectional area (0.306, p < 0.05). This study demonstrates that women with PCOS may have compromised intertrochanter SPW while oligomenorrhea appears to have no detrimental effect on bone density or geometry in women with PCOS.

Cycle-phase dependent associations between CRP, leptin, and reproductive hormones in an urban, Canadian sample.

OBJECTIVES: To assess the relationships among reproductive hormones, follicular development, inflammation, and adiposity in a sample of urban, Canadian women. MATERIALS AND METHODS: Participants (n = 41) had blood collected every 3 days through one interovulatory interval (IOI) to measure estradiol, progesterone, LH, FSH, leptin, and C-reactive protein (CRP). Participants underwent daily transvaginal ultrasound examinations during the IOI to quantify all follicles > 2 mm. CRP and leptin tertiles were used to compare conditions of high and low inflammatory processes and adiposity, respectively. RESULTS: Luteal phase estradiol, luteal phase LH, and follicular phase progesterone were lower among individuals in the highest CRP tertile (adjusted r(2) = 0.63, 0.70, 0.76, respectively). Luteal and follicular phase follicle diameter was greatest in the high CRP tertile (adjusted r(2) = 0.68, 0.71). Follicular phase progesterone was lowest among individuals in the highest leptin tertile, and follicular phase FSH was lowest among individuals in the lowest leptin tertile (adjusted r(2) = 0.54, 0.45). Luteal phase follicle diameter was highest among those in the moderate leptin tertile (adjusted r(2) = 0.49). DISCUSSION: This study is a first comprehensive assessment of the relationship between multiple ovarian function components and inflammatory biomarkers. The results are interpreted to mean that inflammatory and energetic stressors produce differential effects depending on population, adiposity, and cycle phase. Am J Phys Anthropol 160:389-396, 2016. © 2016 Wiley Periodicals, Inc.

Ultrasound features of polycystic ovaries relate to degree of reproductive and metabolic disturbance in polycystic ovary syndrome.

OBJECTIVE: To reexamine associations between polycystic ovarian morphology (PCOM) and degree of symptomatology in polycystic ovary syndrome (PCOS) using a well-defined PCOS population, newer ultrasound technology, and reliable offline assessments of sonographic parameters. DESIGN: Cross-sectional observational study. SETTING: Academic hospital and clinical research unit. PATIENT(S): Forty-nine women with PCOS as defined by hyperandrogenism and oligoamenorrhea. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number of follicles per follicle size category, antral follicle count (AFC), ovarian volume (OV), follicle distribution pattern, stromal area, ovarian area, stromal to ovarian area ratio (S/A) and stromal echogenicity index (SI), total (TT), androstenedione, LH, FSH, cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, C-reactive protein, glucose, insulin, and hemoglobin A1C, menstrual cycle length, hirsutism score, body mass index (BMI), waist:hip ratio, and blood pressure. RESULT(S): AFC, but not OV, was positively associated with TT (ρ = .610), androstenedione (ρ = .490), and LH:FSH (ρ = .402). SI was positively associated with androgen markers and LH:FSH, while S/A was negatively associated with these variables. Follicles ≤4 mm were negatively associated with various metabolic markers, whereas larger follicles (5-8 mm) showed positive associations. Stromal markers were not associated with cardiometabolic measures. LH:FSH best predicted follicles ≤4 mm, and BMI predicted 5- to 9-mm follicles. Dominant follicles ≥10 mm were best predicted by age. CONCLUSION(S): AFC, and not OV, reflected the severity of reproductive dysfunction in PCOS. Associations among different sized follicles were consistent with recruitable sized follicles, which reflects the severity of metabolic dysfunction in PCOS.

Follicle number, not assessments of the ovarian stroma, represents the best ultrasonographic marker of polycystic ovary syndrome.

OBJECTIVE: To compare the diagnostic potential of ultrasonographic markers of ovarian morphology, used alone or in combination, to predict polycystic ovary syndrome (PCOS). DESIGN: A diagnostic test study using cross-sectional data collected from 2006-2011. SETTING: Academic hospital and clinical research unit. PATIENT(S): Eighty-two women with PCOS and 60 healthy female volunteers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Follicle number per ovary (FNPO), ovarian volume (OV), follicle number per single cross-section (FNPS), follicle distribution pattern, stromal area, ovarian area, stromal-to-ovarian area ratio (S:A), and stromal index (SI). RESULT(S): Follicle number per ovary best predicted PCOS (R(2) = 67%) with 85% sensitivity and 98% specificity, followed by OV (R(2) = 44%), and FNPS (R(2) = 36%). Neither S:A nor SI had predictive power for PCOS. In combination, FNPO+S:A and FNPO+SI most significantly predicted PCOS (R(2) = 74% vs. 73%, respectively). The diagnostic potentials of OV and FNPS were substantially improved when used in combination (OV+FNPO, R(2) = 55%). CONCLUSION(S): As a single metric, FNPO best predicted PCOS. Although the addition of S:A or SI improved the predictive power of FNPO, gains were marginal, suggesting limited use in clinical practice. When image quality precludes a reliable estimation of FNPO, measurements of OV+FNPS provide the next closest level of diagnostic potential.

Aromatase inhibitor treatment with an intravaginal device and its effect on pre-ovulatory ovarian follicles in a bovine model.

BACKGROUND: Letrozole, a non-steroidal aromatase inhibitor, prevents the body from producing its own estrogen. The objectives of the present study were to test the hypotheses that letrozole treatment, initiated prior to selection of the preovulatory dominant follicle, will induce the growth of more than one follicle to a pre-ovulatory size, and will delay ovulation. METHODS: Post-pubertal beef heifers were given two luteolytic doses of PGF (12 h apart) and monitored by ultrasonography for ovulation. Five to eight days later, ovarian follicular wave emergence was synchronized by ultrasound-guided transvaginal follicular ablation (Day 0=wave emergence) and a luteolytic dose of PGF was given 60 and 72 h later. On Day 1, heifers were divided randomly into two groups (n=15/group) and an intravaginal device containing 1 g of letrozole or a blank device (control) was inserted. The intravaginal devices were removed on Day 7, or at the time of ovulation, whichever occurred first. Transrectal ultrasonography and blood sample collection were performed daily from the day of ablation to 12 days after subsequent ovulation. RESULTS: The mean (+/-SEM) interval from device placement to ovulation was longer in letrozole-treated animals compared to controls (6.1+/-0.25 vs 5.1+/-0.26 days, respectively; P<0.01). Single dominant follicles were present in both groups. The day-to-day diameter profiles of the dominant follicles of the ovulatory wave were larger (P<0.05) and the maximum diameters greater in letrozole-treated heifers (14.6+/-0.51 vs 12.4+/-0.53 mm, respectively; P<0.01). The diameter profile of the corpus luteum (CL) that formed after treatment did not differ between groups; however, plasma progesterone concentrations were higher (P<0.01) in heifers treated with letrozole. Estradiol concentrations were reduced following letrozole treatment (P<0.05), although a preovulatory rise of estradiol occurred in both groups. CONCLUSIONS: Administration of letrozole with an intravaginal device during growth of the ovulatory follicle delayed ovulation by 24 h and resulted in the formation of a CL that secreted higher levels of progesterone. A sustained-release intravaginal device may be useful for the development of an aromatase inhibitor-based protocol to control ovulation for herd synchronization and to enhance fertility by increasing circulating progesterone concentrations during the first 7 days post-ovulation in cattle.

Updated ultrasound criteria for polycystic ovary syndrome: reliable thresholds for elevated follicle population and ovarian volume.

STUDY QUESTION: Do the ultrasonographic criteria for polycystic ovaries supported by the 2003 Rotterdam consensus adequately discriminate between the normal and polycystic ovary syndrome (PCOS) condition in light of recent advancements in imaging technology and reliable methods for estimating follicle populations in PCOS? STUDY ANSWER: Using newer ultrasound technology and a reliable grid system approach to count follicles, we concluded that a substantially higher threshold of follicle counts throughout the entire ovary (FNPO)-26 versus 12 follicles-is required to distinguish among women with PCOS and healthy women from the general population. WHAT IS KNOWN ALREADY: The Rotterdam consensus defined the polycystic ovary as having 12 or more follicles, measuring between 2 and 9 mm (FNPO), and/or an ovarian volume (OV) >10 cm(3). Since their initial proposal in 2003, a heightened prevalence of polycystic ovaries has been described in healthy women with regular menstrual cycles, which has questioned the accuracy of these criteria and marginalized the specificity of polycystic ovaries as a diagnostic criterion for PCOS. STUDY DESIGN, SIZE, DURATION: A diagnostic test study was performed using cross-sectional data, collected from 2006 to 2011, from 168 women prospectively evaluated by transvaginal ultrasonography. Receiver operating characteristic (ROC) curve analyses were performed to determine the appropriate diagnostic thresholds for: (i) FNPO, (ii) follicle counts in a single cross section (FNPS) and (iii) OV. The levels of intra- and inter-observer reliability when five observers used the proposed criteria on 100 ultrasound cases were also determined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ninety-eight women diagnosed with PCOS by the National Institutes of Health criteria as having both oligo-amenorrhea and hyperandrogenism and 70 healthy female volunteers recruited from the general population. Participants were evaluated by transvaginal ultrasonography at the Royal University Hospital within the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Saskatchewan (Saskatoon, SK, Canada) and in the Division of Nutritional Sciences' Human Metabolic Research Unit, Cornell University (Ithaca, NY, USA). MAIN RESULTS: Diagnostic potential for PCOS was highest for FNPO (0.969), followed by FNPS (0.880) and OV (0.873) as judged by the area under the ROC curve. An FNPO threshold of 26 follicles had the best compromise between sensitivity (85%) and specificity (94%) when discriminating between controls and PCOS. Similarly, an FNPS threshold of nine follicles had a 69% sensitivity and 90% specificity, and an OV of 10 cm(3) had a 81% sensitivity and 84% specificity. Levels of intra-observer reliability were 0.81, 0.80 and 0.86 when assessing FNPO, FNPS and OV, respectively. Inter-observer reliability was 0.71, 0.72 and 0.82, respectively. LIMITATIONS, REASONS FOR CAUTION: Thresholds proposed by this study should be limited to use in women aged between 18 and 35 years. WIDER IMPLICATIONS OF THE FINDINGS: Polycystic ovarian morphology has excellent diagnostic potential for detecting PCOS. FNPO have better diagnostic potential and yield greater diagnostic confidence compared with assessments of FNPS or OV. Whenever possible, images throughout the entire ovary should be collected for the ultrasonographic evaluation of PCOS. STUDY FUNDING AND COMPETING INTEREST: This study was funded by Cornell University and fellowship awards from the Saskatchewan Health Research Foundation and Canadian Institutes of Health Research. The authors have no conflict of interests to disclose.

Effect of exercise training combined with isoflavone supplementation on bone and lipids in postmenopausal women: a randomized clinical trial.

We determined the effects of 2 years of exercise training and soy isoflavone supplementation on bone mass and lipids in postmenopausal women provided with calcium and vitamin D. Women were randomized to four groups: exercise training (Ex); isoflavone supplementation (Iso: 165 mg/d [105 mg/d aglycone equivalent]); combined Ex and Iso (ExIso); and placebo (control). Exercise included resistance training (2 days/week) and walking (4 days/week). Our primary outcomes were lumbar spine and hip bone mineral density (BMD). Secondary outcomes included hip geometry, tibia and radius speed of sound (SOS), dynamic balance (6 m backward tandem walking), blood lipids, mammography, and endometrial thickness. A total of 351 women (Ex = 86, Iso = 90, ExIso = 87, control = 88) were randomized, with 298 analyzed at 2 years (Ex = 77, Iso = 76, ExIso = 72, control = 73). There was a significant interaction for total hip BMD (p < 0.001) such that ExIso had a greater rate of decrease (absolute change [95% confidence interval] = -0.018 [-0.024, -0.012] g/cm(2) ) than either the Ex or Iso groups alone (-0.005 [-0.01, 0.001] and -0.005 [-0.011, 0.001] g/cm(2) , respectively). There were no differences between groups for changes in lumbar spine BMD and minimal significant changes in hip geometric properties and bone SOS. Exercise groups improved dynamic balance as measured by a decrease in backward tandem walking time over 6 m (p = 0.017). Isoflavone groups decreased low density lipoproteins (Iso: -0.20 [-0.37, -0.02] mmol/L; ExIso: -0.23 [-0.40, -0.06] mmol/L; p = 0.003) compared to non-isoflavone groups (Ex: 0.01 [-0.16, 0.18] mmol/L; control: -0.09 [-0.27, 0.08] mmol/L) and had lower adverse reports of menopausal symptoms (14% versus 33%; p = 0.01) compared to non-isoflavone groups. Isoflavone supplementation did not increase endometrial thickness or abnormal mammograms. We conclude exercise training and isoflavone supplementation maintain hip BMD compared to control, but these two interventions interfere with each other when combined. Isoflavone supplementation decreased LDL and adverse events related to menopausal symptoms.

The nerve of ovulation-inducing factor in semen.

A component in seminal fluid elicits an ovulatory response and has been discovered in every species examined thus far. The existence of an ovulation-inducing factor (OIF) in seminal plasma has broad implications and evokes questions about identity, tissue sources, mechanism of action, role among species, and clinical relevance in infertility. Most of these questions remain unanswered. The goal of this study was to determine the identity of OIF in support of the hypothesis that it is a single distinct and widely conserved entity. Seminal plasma from llamas and bulls was used as representative of induced and spontaneous ovulators, respectively. A fraction isolated from llama seminal plasma by column chromatography was identified as OIF by eliciting luteinizing hormone (LH) release and ovulation in llamas. MALDI-TOF revealed a molecular mass of 13,221 Da, and 12-23 aa sequences of OIF had homology with human, porcine, bovine, and murine sequences of ß nerve growth factor (ß-NGF). X-ray diffraction data were used to solve the full sequence and structure of OIF as ß-NGF. Neurite development and up-regulation of trkA in phaeochromocytoma (PC(12)) cells in vitro confirmed NGF-like properties of OIF. Western blot analysis of llama and bull seminal plasma confirmed immunorecognition of OIF using polyclonal mouse anti-NGF, and administration of ß-NGF from mouse submandibular glands induced ovulation in llamas. We conclude that OIF in seminal plasma is ß-NGF and that it is highly conserved. An endocrine route of action of NGF elucidates a previously unknown pathway for the direct influence of the male on the hypothalamo-pituitary-gonadal axis of the inseminated female.

Correlations between ultrasonographic characteristics of corpora lutea and systemic concentrations of progesterone during the discrete stages of corpora lutea lifespan and secretory activity in cyclic ewes.

Associations between physical characteristics and functionality of corpora lutea (CL) have previously been reported in monovulatory species, albeit several studies in cattle and humans have refuted the existence of temporal relationships between CL size, echotexture and serum progesterone (P(4)) concentrations. The main objective of the present study was to examine whether or not there were correlations between ultrasonographic image attributes of CL and systemic concentrations of P(4) during the discrete stages of the luteal phase in two breeds of sheep differing in ovulation rates (non-prolific Western White Face [WWF] ewes and prolific Finn [F] sheep). Transrectal ovarian ultrasonography utilized a 7.5-MHz linear-array transducer connected to a portable scanner (Aloka SSD-500) and the images were analyzed using commercially available image analytical software (Image ProPlus(®)) validated for the present application in sheep. The correlations were assessed using the Pearson's Product Moment (PPM) analysis and also, to increase the accuracy of statistical tests, the analysis of covariance (ANCOVA), with the number of CL as a co-factor. In WWF ewes, serum concentrations of P(4) correlated significantly with the total luteal area (TLA) during the CL growth phase (days 3-6; day 0 = ovulation) and functional luteolysis (days 12-15), and with numerical pixel values (NPVs--pixel intensity) during luteolysis; the results obtained by using two different statistical methods were generally similar. In prolific F ewes, serum P(4) concentrations were directly correlated with TLA during CL growth (days 3-6; ANCOVA), functional luteolysis (days 13-14; PPM), and structural CL regression (days 11-14; PPM and ANCOVA), and with NPVs during functional luteolysis (PPM and ANCOVA). We concluded that systemic P(4) concentrations could only be accurately predicted from the changes in luteal area during CL growth and regression, and from NPVs during luteolysis, in both prolific and non-prolific ewes, but the changes in size and echotexture of the luteal glands at mid-cycle were not indicative of serum P(4) concentrations in sheep.

Effects of a non-steroidal aromatase inhibitor on ovarian function in cattle.

Effects of the non-steroidal aromatase inhibitor letrozole on ovarian function in cattle were determined. The hypothesis that letrozole would arrest growth of the dominant follicle, resulting in emergence of a new follicular wave at a predictable post-treatment interval, was tested. Heifers were assigned randomly to four groups 4 days after follicular ablation (~2½ days after wave emergence) and given intravenous doses of 500 (n = 9), 250 (n = 10), or 125 µg kg⁻¹ (n = 10) letrozole or phosphate-buffered saline (controls; n = 10). Blood was collected and ovarian structures were monitored daily by transrectal ultrasonography. Plasma concentrations of LH and FSH were measured by radioimmunoassay; plasma concentrations of letrozole were determined by high-performance liquid chromatography tandem mass spectrometry. A single intravenous dose of letrozole did not induce regression of the dominant follicle present at the time of treatment, nor did it directly affect FSH release. Conversely, treatment with letrozole increased endogenous concentrations of LH and extended the lifespan of the dominant follicle, which delayed the next FSH surge and subsequent follicular wave emergence. Letrozole continues to have potential as a non-steroidal treatment for controlling ovarian function in cattle.

Ovarian antral folliculogenesis during the human menstrual cycle: a review.

BACKGROUND Ovarian follicles undergo dynamic morphologic and endocrinologic changes during the human menstrual cycle. The physiologic mechanisms underlying recruitment and selection of antral follicles in women are not fully elucidated. METHODS A comprehensive review of >200 studies was conducted using PubMed. The objective was to compare and contrast different perspectives on human antral folliculogenesis. RESULTS Antral folliculogenesis has been studied using histologic, endocrinologic and/or ultrasonographic techniques. Different theories of antral follicle recruitment include: (i) continuous recruitment throughout the menstrual cycle; (ii) recruitment of a 'cohort' of antral follicles once in the late-luteal phase or early-follicular phase of each cycle and (iii) recruitment of two or three 'cohorts' or 'waves'  during each cycle. Generally, a single dominant follicle is selected in the mid-follicular phase of each cycle and this follicle ovulates at mid-cycle. However, a dominant follicle may also be selected during anovulatory waves that precede the ovulatory wave in some women. CONCLUSIONS There is increasing evidence to indicate that multiple waves of antral follicles develop during the human menstrual cycle. Ovarian follicular waves in women are comparable with those documented in several animal species; however, species-specific differences exist. Enhancing our understanding of the endocrine and paracrine mechanisms underlying antral follicular wave dynamics has clinical implications for understanding age-related changes in reproductive function, optimizing hormonal contraceptive and ovarian stimulation regimens and identifying non-invasive markers of the physiologic status of follicles which are predictive of oocyte competence and assisted reproduction outcomes.