Does the environment affect menopause? A review of the effects of endocrine disrupting chemicals on menopause.

Endocrine disrupting chemicals are widely distributed in our environment. Humans are exposed to these compounds not only through their occupations, but also through dietary consumption and exposure to contaminated water, personal care products and textiles. Chemicals that are persistent in the body and in our environment include dioxins and polychlorinated biphenyls. Non-persistent chemicals including bisphenol A, phthalates and parabens are equally as important because they are ubiquitous in our environment. Heavy metals, including lead and cadmium, can also have endocrine disrupting properties. Although difficult to study due to their variety of sources of exposures and mechanisms of action, these chemicals have been associated with early menopause, increased frequency of vasomotor symptoms, altered steroid hormone levels and markers of diminished ovarian reserve. Understanding the impacts of these exposures is important given the potential for epigenetic modification, which can alter gene function and result in multi-generational effects. This review summarizes findings in humans and animals or cell-based models from the past decade of research. Continued research is needed to assess the effects of mixtures of chemicals, chronic exposures and new compounds that are continuously being developed as replacements for toxic chemicals that are being phased out.

Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two sepsis definitions.

Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quickSOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction.

Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. METHODS: Women with PPH 1000-1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. RESULTS: Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3-1.7), P =0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th-75th centile) of 1 (0-4.5) unit of allogeneic blood products and had an additional 300 (100-350) ml blood loss whereas those who received placebo also received 3 (0-6) units of allogeneic blood products and had 700 (200-1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. CONCLUSIONS: Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre -1 , but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis. TRIAL REGISTRATION: ISRCTN46295339 ( http://www.isrctn.com/ISRCTN46295339 , last accessed 5 July 2017), EudraCT 2012-005511-11 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11 , last accessed 5 July 2017).

Laboratory evaluation of a novel anaesthesia delivery device.

Here, we describe proof of concept of a novel method for delivering volatile anaesthetics, where the liquid anaesthetic (sevoflurane or isoflurane) is formulated into an emulsion that is contained in a compact, lightweight device through which carrier gas flows. Release of anaesthetic is achieved by stirring of the formulation, allowing controlled and responsive release of anaesthetic at a variety of fixed flow rates between 0.5 l.min-1 and 5 l.min-1 , with ventilated, non-ventilated and draw-over breathing systems. Anaesthetic release was evaluated using target anaesthetic concentrations ranging from 0.5% v/v to 8% v/v to mimic those typically required for induction and maintenance of anaesthesia, and lower concentrations suitable for sedation. Under all conditions, output could be maintained within 0.1% v/v of the intended setting, and the device could deliver a controlled level of anaesthetic for at least 60 min, with compensation for different ambient temperatures (10-30 °C) and carrier gas flow rates. This device offers a simple, inexpensive method of delivering safe concentrations of volatile anaesthetics for a wide range of applications.

Revised global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies.

A forward modelling approach for the estimation of oxygen extraction fraction by calibrated fMRI.

The measurement of the absolute rate of cerebral metabolic oxygen consumption (CMRO2) is likely to offer a valuable biomarker in many brain diseases and could prove to be important in our understanding of neural function. As such there is significant interest in developing robust MRI techniques that can quantify CMRO2 non-invasively. One potential MRI method for the measurement of CMRO2 is via the combination of fMRI and cerebral blood flow (CBF) data acquired during periods of hypercapnic and hyperoxic challenges. This method is based on the combination of two, previously independent, signal calibration techniques. As such analysis of the data has been approached in a stepwise manner, feeding the results of one calibration experiment into the next. Analysing the data in this manner can result in unstable estimates of the output parameter (CMRO2), due to the propagation of errors along the analysis pipeline. Here we present a forward modelling approach that estimates all the model parameters in a one-step solution. The method is implemented using a regularized non-linear least squares approach to provide a robust and computationally efficient solution. The proposed framework is compared with previous analytical approaches using modelling studies and in vivo acquisitions in healthy volunteers (n=10). The stability of parameter estimates is demonstrated to be superior to previous methods (both in vivo and in simulation). In vivo estimates made with the proposed framework also show better agreement with expected physiological variation, demonstrating a strong negative correlation between baseline CBF and oxygen extraction fraction. It is anticipated that the proposed analysis framework will increase the reliability of absolute CMRO2 measurements made with calibrated BOLD.

Developing a digital data collection platform to measure the prevalence of sepsis in Wales.

OBJECTIVE: To develop a secure, efficient, and easy-to-use data collection platform to measure the prevalence of sepsis in Wales over 24 hours. MATERIALS AND METHODS: Open Data Kit was used on Android devices with Google App Engine and a digital data collection form. RESULTS: A total of 184 students participated in the study using 59 devices across 16 hospitals, 1198 datasets were submitted, and 97% of participants found the Open Data Kit form easy to use. DISCUSSION: We successfully demonstrated that by combining a reliable Android device, a free open-source data collection framework, a scalable cloud-based server, and a team of 184 medical students, we can deliver a low-cost, highly reliable platform that requires little training or maintenance, providing results immediately on completion of data collection. CONCLUSION: Our platform allowed us to measure, for the first time, the prevalence of sepsis in Wales over 24 hours.

Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women.

CONTEXT: Serum estradiol (E2) levels are preserved in older reproductive-aged women with regular menstrual cycles despite declining ovarian function. OBJECTIVE: The objective of the study was to determine whether increased granulosa cell aromatase expression and activity account for preservation of E2 levels in older, regularly cycling women. DESIGN: The protocol included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. SUBJECTS: Healthy, regularly cycling older (36-45 y; n = 13) and younger (22-34 y; n = 14) women participated in the study. MAIN OUTCOME MEASURES: Hormone levels were measured in peripheral blood and follicular fluid aspirates and granulosa cell CYP19A1 (aromatase) and FSH-R mRNA expression were determined. RESULTS: Older women had higher FSH levels than younger women during the early follicular phase with similar E2 but lower inhibin B and antimullerian hormone levels. Late follicular phase serum E2 did not differ between the two groups. Follicular fluid E2 [older (O) = 960.0 [interquartile range (IQR) 765.0-1419.0]; younger (Y) = 994.5 [647.3-1426.5] ng/mL, P = 1.0], estrone (O = 39.6 [29.5-54.1]; Y = 28.8 [22.5-42.1] ng/mL, P = 0.3), and the E2 to testosterone (T) ratio (O = 109.0 ± 41.9; Y = 83.0 ± 18.6, P = .50) were preserved in older women. Granulosa cell CYP19A1 expression was increased 3-fold in older compared with younger women (P < .001), with no difference in FSH-R expression. CONCLUSIONS: Ovarian aromatase expression increases with age in regularly cycling women. Thus, up-regulation of aromatase activity appears to compensate for the known age-related decrease in granulosa cell number in the dominant follicle to maintain ovarian estrogen production in older premenopausal women.

Control of respiratory and cardiovascular functions by leptin.

Leptin, a peptide hormone produced by adipose tissue, acts in brain centers that control critical physiological functions such as metabolism, breathing and cardiovascular regulation. The importance of leptin for respiratory control is evident by the fact that leptin deficient mice exhibit impaired ventilatory responses to carbon dioxide (CO2), which can be corrected by intracerebroventricular leptin replacement therapy. Leptin is also recognized as an important link between obesity and hypertension. Humans and animal models lacking either leptin or functional leptin receptors exhibit many characteristics of the metabolic syndrome, including hyperinsulinemia, insulin resistance, hyperglycemia, dyslipidemia and visceral adiposity, but do not exhibit increased sympathetic nerve activity (SNA) and have normal to lower blood pressure (BP) compared to lean controls. Even though previous studies have extensively focused on the brain sites and intracellular signaling pathways involved in leptin effects on food intake and energy balance, the mechanisms that mediate the actions of leptin on breathing and cardiovascular function are only beginning to be elucidated. This mini-review summarizes recent advances on the effects of leptin on cardiovascular and respiratory control with emphasis on the neural control of respiratory function and autonomic activity.

Measurement of blood loss during postpartum haemorrhage.

BACKGROUND: We set out to validate the accuracy of gravimetric quantification of blood loss during simulated major postpartum haemorrhage and to evaluate the technique in a consecutive cohort of women experiencing major postpartum haemorrhage. The study took part in a large UK delivery suite over a one-year period. All women who experienced major postpartum haemorrhage were eligible for inclusion. METHODS: For the validation exercise, in a simulated postpartum haemorrhage scenario using known volumes of artificial blood, the accuracy of gravimetric measurement was compared with visual estimation made by delivery suite staff. In the clinical observation study, the blood volume lost during postpartum haemorrhage was measured gravimetrically according to our routine institutional protocol and was correlated with fall in haemoglobin. The main outcome measure was the accuracy of gravimetric measurement of blood loss. RESULTS: Validation exercise: the mean percentage error of gravimetrically measured blood volume was 4.0±2.7% compared to visually estimated blood volume with a mean percentage error of 34.7±32.1%. Clinical observation study: 356 out of 6187 deliveries were identified as having major postpartum haemorrhage. The correlation coefficient between measured blood loss and corrected fall in haemoglobin for all patients was 0.77; correlation was stronger (0.80) for postpartum haemorrhage >1500mL, and similar during routine and out-of-hours working. CONCLUSION: The accuracy of the gravimetric method was confirmed in simulated postpartum haemorrhage. The clinical study shows that gravimetric measurement of blood loss is correlated with the fall in haemoglobin in postpartum haemorrhage where blood loss exceeds 1500mL. The method is simple to perform, requires only basic equipment, and can be taught and used by all maternity services during major postpartum haemorrhage.

Activation of the brain melanocortin system is required for leptin-induced modulation of chemorespiratory function.

UNLABELLED: Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin. AIM: Here, we tested if MC4R also contributes to leptin's effects on respiratory function. METHODS: After control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT ), respiratory frequency (fR ) and pulmonary ventilation (VE ) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2 ). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE , VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice. RESULTS: Leptin (5 µg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1)  kg(-1) and SHU9119: 997 ± 67 mL min(-1)  kg(-1) , vs. PBS: 1379 ± 91 mL min(-1)  kg(-1) ). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercapnia (1391 ± 137 mL min(-1)  kg(-1) ). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R(-/-) mice. CONCLUSION: These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.

Accumulated deep sleep is a powerful predictor of LH pulse onset in pubertal children.

CONTEXT: During puberty, reactivation of the reproductive axis occurs during sleep, with LH pulses specifically tied to deep sleep. This association suggests that deep sleep may stimulate LH secretion, but there have been no interventional studies to determine the characteristics of deep sleep required for LH pulse initiation. OBJECTIVE: The objective of this study was to determine the effect of deep sleep fragmentation on LH secretion in pubertal children. DESIGN AND SETTING: Studies were performed in a clinical research center. SUBJECTS: Fourteen healthy pubertal children (11.3-14.1 y) participated in the study. INTERVENTIONS: Subjects were randomized to two overnight studies with polysomnography and frequent blood sampling, with or without deep sleep disruption via auditory stimuli. RESULTS: An average of 68.1 ±10.7 (± SE) auditory stimuli were delivered to interrupt deep sleep during the disruption night, limiting deep sleep to only brief episodes (average length disrupted 1.3 ± 0.2 min vs normal 7.1 ± 0.8 min, P < .001), and increasing the number of transitions between non-rapid eye movement (NREM), REM, and wake (disrupted 274.5 ± 33.4 vs normal 131.2 ± 8.1, P = .001). There were no differences in mean LH (normal: 3.2 ± 0.4 vs disrupted: 3.2 ± 0.5 IU/L), LH pulse frequency (0.6 ± 0.06 vs 0.6 ± 0.07 pulses/h), or LH pulse amplitude (2.8 ± 0.4 vs 2.8 ± 0.4 IU/L) between the two nights. Poisson process modeling demonstrated that the accumulation of deep sleep in the 20 minutes before an LH pulse, whether consolidated or fragmented, was a significant predictor of LH pulse onset (P < .001). CONCLUSION: In pubertal children, nocturnal LH augmentation and pulse patterning are resistant to deep sleep fragmentation. These data suggest that, even when fragmented, deep sleep is strongly related to activation of the GnRH pulse generator.

Effect of early tracheostomy on resource utilization and clinical outcomes in critically ill patients: meta-analysis of randomized controlled trials.

BACKGROUND: Early tracheostomy may decrease the duration of mechanical ventilation, sedation exposure, and intensive care stay, possibly resulting in improved clinical outcomes, but the evidence is conflicting. METHODS: Systematic review and meta-analysis of randomized trials in patients allocated to tracheostomy within 10 days of start of mechanical ventilation was compared with placement of tracheostomy after 10 days if still required. Medline, EMBASE, the Cochrane Controlled Clinical Trials Register, and Google Scholar were searched for eligible trials. The co-primary outcomes were mortality within 60 days, and duration of mechanical ventilation, sedation, and intensive care unit stay. Secondary outcomes were the number of tracheostomy procedures performed, and incidence of ventilator-associated pneumonia (VAP). Outcomes are described as relative risk or weighted mean difference with 95% confidence intervals. RESULTS: Of note, 4482 publications were identified and 14 trials enrolling 2406 patients were included. Tracheostomy within 10 days was not associated with any difference in mortality [risk ratio (RR): 0.93 (0.83-1.05)]. There were no differences in duration of mechanical ventilation [-0.19 days (-1.13-0.75)], intensive care stay [-0.83 days (-2.05-0.40)], or incidence of VAP. However, duration of sedation was reduced in the early tracheostomy groups [-2.78 days (-3.68 to -1.88)]. More tracheostomies were performed in patients randomly assigned to receive early tracheostomy [RR: 2.53 (1.18-5.40)]. CONCLUSION: We found no evidence that early (within 10 days) tracheostomy reduced mortality, duration of mechanical ventilation, intensive care stay, or VAP. Early tracheostomy leads to more procedures and a shorter duration of sedation.

Extracting drug mechanism and pharmacodynamic information from clinical electroencephalographic data using generalised semi-linear canonical correlation analysis.

Conventional analysis of clinical resting electroencephalography (EEG) recordings typically involves assessment of spectral power in pre-defined frequency bands at specific electrodes. EEG is a potentially useful technique in drug development for measuring the pharmacodynamic (PD) effects of a centrally acting compound and hence to assess the likelihood of success of a novel drug based on pharmacokinetic-pharmacodynamic (PK-PD) principles. However, the need to define the electrodes and spectral bands to be analysed a priori is limiting where the nature of the drug-induced EEG effects is initially not known. We describe the extension to human EEG data of a generalised semi-linear canonical correlation analysis (GSLCCA), developed for small animal data. GSLCCA uses data from the whole spectrum, the entire recording duration and multiple electrodes. It provides interpretable information on the mechanism of drug action and a PD measure suitable for use in PK-PD modelling. Data from a study with low (analgesic) doses of the µ-opioid agonist, remifentanil, in 12 healthy subjects were analysed using conventional spectral edge analysis and GSLCCA. At this low dose, the conventional analysis was unsuccessful but plausible results consistent with previous observations were obtained using GSLCCA, confirming that GSLCCA can be successfully applied to clinical EEG data.

Leptin into the ventrolateral medulla facilitates chemorespiratory response in leptin-deficient (ob/ob) mice.

AIM: Leptin, an adipocyte-derived hormone, is suggested to participate in the central control of breathing. We hypothesized that leptin may facilitate ventilatory responses to chemoreflex activation by acting on respiratory nuclei of the ventrolateral medulla. The baseline ventilation and the ventilatory responses to CO2 were evaluated before and after daily injections of leptin into the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) for 3 days in obese leptin-deficient (ob/ob) mice. METHODS: Male ob/ob mice (40-45 g, n = 7 per group) received daily microinjections of vehicle or leptin (1 µg per 100 nL) for 3 days into the RTN/pFRG. Respiratory responses to CO2 were measured by whole-body plethysmography. RESULTS: Unilateral microinjection of leptin into the RTN/pFRG in ob/ob mice increased baseline ventilation (VE ) from 1447 ± 96 to 2405 ± 174 mL min(-1) kg(-1) by increasing tidal volume (VT ) from 6.4 ± 0.4 to 9.1 ± 0.8 mL kg(-1) (P < 0.05). Leptin also enhanced ventilatory responses to 7% CO2 (Δ = 2172 ± 218 mL min(-1) kg(-1) , vs. control: Δ = 1255 ± 105 mL min(-1) kg(-1) ), which was also due to increased VT (Δ = 4.71 ± 0.51 mL kg(-1) , vs. control: Δ = 2.27 ± 0.20 mL kg(-1) ), without changes in respiratory frequency. Leptin treatment into the RTN/pFRG or into the surrounding areas decreased food intake (83 and 70%, respectively), without significantly changing body weight. CONCLUSION: The present results suggest that leptin acting in the respiratory nuclei of the ventrolateral medulla improves baseline VE and VT and facilitates respiratory responses to hypercapnia in ob/ob mice.

Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin.

OBJECTIVE: We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress. DESIGN: Forebrain Shp2(-/-) mice were generated by crossing Shp2(flox/flox) mice with CamKIIα-cre mice. At 22-24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry. RESULTS: Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2(flox/flox) control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2(flox/flox) mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice. CONCLUSION: These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.

Evidence that increased ovarian aromatase activity and expression account for higher estradiol levels in African American compared with Caucasian women.

CONTEXT: Serum estradiol levels are significantly higher across the menstrual cycle in African American (AAW) compared with Caucasian women (CW) in the presence of similar FSH levels, yet the mechanism underlying this disparity is unknown. OBJECTIVE: The objective of the study was to determine whether higher estradiol levels in AAW are due to increased granulosa cell aromatase mRNA expression and activity. DESIGN: The design of the study included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. SUBJECTS: Healthy, normal cycling AAW (n = 15) and CW (n = 14) aged 19-34 years participated in the study. MAIN OUTCOME MEASURES: Hormone levels in peripheral blood and follicular fluid (FF) aspirates and aromatase and FSH receptor mRNA expression in granulosa cells were measured. RESULTS: AAW had higher FF estradiol [1713.0 (1144.5-2032.5) vs 994.5 (647.3-1426.5) ng/mL; median (interquartile range); P < .001] and estrone [76.9 (36.6-173.4) vs 28.8 (22.5-42.1) ng/mL; P < .001] levels than CW, independent of follicle size. AAW also had lower FF androstenedione to estrone (7 ± 1.8 vs 15.8 ± 4.1; mean ± SE; P = .04) and T to estradiol (0.01 ± 0.002 vs 0.02 ± 0.005; P = .03) ratios, indicating enhanced ovarian aromatase activity. There was a 5-fold increase in granulosa cell aromatase mRNA expression in AAW compared with CW (P < .001) with no difference in expression of FSH receptor. FSH, inhibin A, inhibin B, and AMH levels were not different in AAW and CW. CONCLUSIONS: Increased ovarian aromatase mRNA expression, higher FF estradiol levels, and decreased FF androgen to estrogen ratios in AAW compared with CW provide compelling evidence that racial differences in ovarian aromatase activity contribute to higher levels of estradiol in AAW across the menstrual cycle. The absence of differences in FSH, FSH receptor expression, and AMH suggest that population-specific genetic variation in CYP19, the gene encoding aromatase, or in factors affecting its expression should be sought.