Wen Ye

Fetal Programming: Prenatal Androgen Disrupts Positive Feedback Actions of Estradiol but Does Not Affect Timing of Puberty in Female Sheep

Abstract We studied the impact of prenatal androgen exposure on the timing of onset of puberty, maintenance of cyclicity in the first breeding season, and the LH surge mechanism in female sheep. Pregnant sheep were injected with testosterone propionate (100 mg i.m.) twice each week from Day 30 to Day 90 (D30–90) or from Day 60 to Day 90 (D60–90) of gestation (term = 147 days). Concentrations of plasma progesterone and gonadotropins were measured in blood samples collected twice each week from control (n = 10), D60–90 (n = 13), and D30–90 (n = 3) animals. Rate of weight gain and initiation of estrous behavior were also monitored. After the first breeding season, when the animals entered anestrus, competency of the gonadotropin surge system to respond to estradiol positive feedback was tested in the absence or presence of progesterone priming for 12 days. Prenatally androgenized females had similar body weight gain and achieved puberty (start of first progestogenic cycle) at the same time as controls. Duration of the breeding season and the number of cycles that occurred during the first breeding season were similar between control and prenatally androgenized sheep. In contrast, prenatal exposure to androgens compromised the positive feedback effects of estradiol. Onset of LH/FSH surges following the estradiol stimulus was delayed in both groups of androgenized ewes compared with the controls in both the absence and presence of progesterone priming. In addition, the magnitude of LH and FSH surges in the two animals that surged in the D30–90 group were only one third and one half, respectively, of the magnitudes observed in the control and D60–90 groups. The present findings indicate that disruption of the surge system can account for the fertility problems that occur during adulthood in prenatally androgenized sheep.

Continence pessary compared with behavioral therapy or combined therapy for stress incontinence: A randomized controlled trial

OBJECTIVE: To compare the effectiveness of a continence pessary to evidence-based behavioral therapy for stress incontinence and to assess whether combined pessary and behavioral therapy is superior to single-modality therapy. METHODS: This was a multisite, randomized clinical trial (Ambulatory Treatments for Leakage Associated with Stress Incontinence [ATLAS]) that randomly assigned 446 women with stress incontinence to pessary, behavioral therapy, or combined treatment. Primary outcome measures, at 3 months, were Patient Global Impression of Improvement and the stress incontinence subscale of the Pelvic Floor Distress Inventory. A priori, to be considered clinically superior, combination therapy had to be better than both single-modality therapies. Outcome measures were repeated at 6 and 12 months. Primary analyses used an intention-to-treat approach. RESULTS: At 3 months, scores from 40% of the pessary group and 49% of the behavioral group were “much better” or “very much better” on the Patient Global Impression of Improvement (P=.10). Compared with the pessary group, more women in the behavioral group reported having no bothersome incontinence symptoms (49% compared with 33%, P=.006) and treatment satisfaction (75% compared with 63%, P=.02). Combination therapy was significantly better than pessary as shown on the Patient Global Impression of Improvement (53%, P=.02) and Pelvic Floor Distress Inventory (44%, P=.05) but not better than behavioral therapy; it was therefore not superior to single-modality therapy. Group differences were not sustained to 12 months on any measure, and patient satisfaction remained above 50% for all treatment groups. CONCLUSION: Behavioral therapy resulted in greater patient satisfaction and fewer bothersome incontinence symptoms than pessary at 3 months, but differences did not persist to 12 months. Combination therapy was not superior to single-modality therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00270998. LEVEL OF EVIDENCE: I

Growth failure and outcomes in infants with biliary atresia : A report from the biliary atresia research consortium

Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early transplantation or death in children with biliary atresia was determined. Serial weight‐ and length‐for‐age z‐scores were computed as part of a retrospective study of 100 infants who underwent hepatoportoenterostomy (HPE) for biliary atresia at 9 U.S. pediatric centers between 1997 and 2000. Poor outcome was defined as transplantation or death by 24 months of age (n = 46) and good outcome was defined as survival with native liver at 24 months of age with total serum bilirubin less than 6 mg/dL (n = 54). Growth velocity was significantly slower in the poor outcome group compared to the good outcome group (P < 0.001 for both weight and length). Mean weight z‐scores were significantly lower by 6 months after HPE in the poor outcome group (−2.1 ± 1.4) compared to the good outcome group (−1.2 ± 1.4) (P < 0.001). In a subgroup with total bilirubin between 2 and 6 mg/dL at 3 months after HPE (n = 28), the weight z‐scores at 3 months after HPE were significantly lower in the poor outcome group (−2.0 ±1.2) compared to the good outcome group (−1.0 ± 1.2) (P = 0.04) despite similar bilirubin concentrations. Conclusion: Growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z‐scores 3 months after HPE was also associated with poor clinical outcome. (HEPATOLOGY 2007.)

Racial Differences in Pelvic Anatomy by Magnetic Resonance Imaging

OBJECTIVES: To use static and dynamic magnetic resonance imaging (MRI) to compare dimensions of the bony pelvis and soft tissue structures in a sample of African-American and white women. METHODS: This study used data from 234 participants in the Childbirth and Pelvic Symptoms Imaging Study, a cohort study of 104 primiparous women with an obstetric anal sphincter tear, 94 who delivered vaginally without a recognized anal sphincter tear and 36 who underwent by cesarean delivery without labor. Race was self-reported. At 6–12 months postpartum, rapid acquisition T2-weighted pelvic MRIs were obtained. Bony and soft tissue dimensions were measured and compared between white and African-American participants using analysis of variance, while controlling for delivery type and age. RESULTS: The pelvic inlet was wider among 178 white women than 56 African-American women (10.7±0.7 cm compared with 10.0.+0.7 cm, P<.001). The outlet was also wider (mean intertuberous diameter 12.3±1.0 cm compared with 11.8±0.9 cm, P<.001). There were no significant differences between racial groups in interspinous diameter, angle of the subpubic arch, anteroposterior conjugate, levator thickness, or levator hiatus. In addition, among women who delivered vaginally without a sphincter tear, African-American women had more pelvic floor mobility than white women. This difference was not observed among women who had sustained an obstetric sphincter tear. CONCLUSION: White women have a wider pelvic inlet, wider outlet, and shallower anteroposterior outlet than African-American women. In addition, after vaginal delivery, white women demonstrate less pelvic floor mobility. These differences may contribute to observed racial differences in obstetric outcomes and to the development of pelvic floor disorders. LEVEL OF EVIDENCE: II

Evolving Self-Rated Health in Middle and Old Age: How Does it Differ Across Black, Hispanic, and White Americans?

Objective:This research focuses on ethnic variations in the intraindividual changes in self-rated health. Method: Data came from the Health and Retirement Study involving up to 6 repeated observations between 1995 and 2006 of a national sample of 18,486 Americans above 50 years of age. Hierarchical linear models were employed in depicting variations in self-rated health across White, Black, and Hispanic Americans. Results: Subjective health worsened over time albeit moderately. Relative to younger persons, older individuals rated their health poorer with a greater rate of deteriorating health. With reference to ethnic variations in the intercept and slope of perceived health, White Americans rated their health most positively, followed by Black Americans, with Hispanics rating their health least positively. This pattern held even when socioeconomic status, social networks, and prior health were adjusted. Discussion: Significant ethnic differences exist in the evolvement of self-rated health in middle and late life. Further inquiries may include analyzing ethnic heterogeneities from a person-centered perspective, health disparities across subgroups of Hispanics, effects of neighborhood attributes, and implications of left truncation.

Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, Part 1: Adrenocortical and pituitary glucocorticoid responsiveness

BACKGROUND Long-term ingestion of alcohol produces marked alterations in hypothalamic-pituitary-adrenal axis activity. The authors engaged in a series of studies to determine the distinct role of the hypothalamus and the pituitary and adrenal glands in the disturbances observed in abstinent alcohol-dependent subjects. In this first of a two-part study, the authors report on (1) the basal secretory profile of corticotropin and cortisol from 2000 to 0800 hrs, (2) adrenocortical sensitivity in both the presence and absence of endogenous pituitary activation, and (3) pituitary glucocorticoid sensitivity to dexamethasone. METHODS Eleven male, 4 to 6 weeks abstinent, alcohol-only-dependent subjects and 10 age-matched male healthy controls were studied. Basal circulating concentrations of corticotropin and cortisol were obtained from 2000 to 0800 hr. A submaximal dose of cosyntropin (0.01 microg/kg), a corticotropin analogue was then administered to assess adrenocortical sensitivity. In a separate session, cosyntropin was administered following high-dose dexamethasone (8 mg iv) to assess adrenocortical sensitivity in the relative absence of endogenous corticotropin. In addition, the corticotropin response to dexamethasone was measured to determine pituitary glucocorticoid responsiveness. RESULTS Cortisol, but not corticotropin, pulse amplitude (p < 0.05) and mean concentration (p= 0.05) was significantly lower in alcohol-dependent subjects compared with controls. The cortisol response to cosyntropin was lower in alcohol-dependent subjects following endogenous corticotropin suppression by high-dose dexamethasone (p <0.04) but not without dexamethasone pretreatment. Mean corticotropin (p <0.004) and cortisol (p <0.05) concentrations in response to dexamethasone were attenuated in the patients compared to controls. Basal concentrations of 11-deoxycortisol, the precursor to cortisol, were also decreased in alcohol-dependent subjects (p <0.05). CONCLUSION Attenuated basal and stimulated adrenocortical concentrations in abstinent alcohol-dependent men are coupled with a nonhomeostatic increase in pituitary glucocorticoid inhibition. A decrease in stress-axis responsivity in alcohol dependence may have implications for treatment outcome.

Ethnicity and Changing Functional Health in Middle and Late Life: A Person-Centered Approach

OBJECTIVES Following a person-centered approach, this research aims to depict distinct courses of disability and to ascertain how the probabilities of experiencing these trajectories vary across Black, Hispanic, and White middle-aged and older Americans. METHODS Data came from the 1995-2006 Health and Retirement Study, which involved a national sample of 18,486 Americans older than 50 years of age. Group-based semiparametric mixture models (Proc Traj) were used for data analysis. RESULTS Five trajectories were identified: (a) excellent functional health (61%), (b) good functional health with small increasing disability (25%), (c) accelerated increase in disability (7%), (d) high but stable disability (4%), and (e) persistent severe impairment (3%). However, when time-varying covariates (e.g., martial status and health conditions) were controlled, only 3 trajectories emerged: (a) healthy functioning (53%), moderate functional decrement (40%), and (c) large functional decrement (8%). Black and Hispanic Americans had significantly higher probabilities than White Americans in experiencing poor functional health trajectories, with Blacks at greater risks than Hispanics. CONCLUSIONS Parallel to the concepts of successful aging, usual aging, and pathological aging, there exist distinct courses of changing functional health over time. The mechanisms underlying changes in disability may vary between Black and Hispanic Americans.

Early Detection and Treatment of Type 2 Diabetes Reduce Cardiovascular Morbidity and Mortality: A Simulation of the Results of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Europe)

OBJECTIVE To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study. RESEARCH DESIGN AND METHODS We used the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors. RESULTS When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors. CONCLUSIONS Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted.

Developmental Programming: Deficits in Reproductive Hormone Dynamics and Ovulatory Outcomes in Prenatal, Testosterone-Treated Sheep

Abstract Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30–90 of gestation, term = 147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.

Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 2: response to ovine corticotropin-releasing factor and naloxone.

BACKGROUND Pituitary and adrenal responsiveness is suppressed in abstinent alcohol-dependent individuals. To clarify the specific organizational disruption in hypothalamic-pituitary-adrenal functioning during early abstinence, the authors separately assessed each level of the stress-response axis. In this second of a two-part study, ovine corticotropin-releasing factor (oCRH) was used to stimulate the pituitary corticotrophs, and naloxone was used to activate the axis at the hypothalamic level. In addition, pulsatile characteristics of corticotropin and cortisol were assessed over a 12-hr period (0800 to 2000 hr). METHODS Eleven abstinent alcohol-dependent men and 10 healthy comparison participants were assessed. All participants were between the ages of 30 and 50 years, and alcohol-dependent patients were abstinent from 4 to 6 weeks. Basal concentrations of corticotropin and cortisol were obtained every 10 min from 0800 to 2000 hr and subjected to pulsatile analysis. Plasma corticotropin and cortisol concentrations were then obtained every 5 to 10 min after low-dose, intravenously administered doses of oCRH (0.4 microg/kg) or naloxone (0.125 mg/kg). Medications were administered at 2000 hr and the two challenge studies were separated by 48 hr. RESULTS Pulsatile analysis revealed that the mean corticotropin amplitude was increased in alcohol-dependent patients relative to controls (p <0.05). Other pulsatile characteristics of corticotropin and all cortisol pulsatile measures were not significantly different between the two groups. The integrated cortisol response to oCRH was significantly lower in alcohol-dependent patients compared with controls (p <0.01), but the integrated corticotropin response was not significantly different. In contrast, neither the corticotropin nor the cortisol response to naloxone was significantly different between groups. CONCLUSIONS Adrenocorticoid hyposensitivity persists after oCRH infusion for at least 1 month after cessation of drinking, whereas hyporesponsiveness of the pituitary corticotrophs to CRH seems to resolve with continued abstinence. The authors suggest that adrenocortical hyporesponsiveness during prolonged abstinence may impact relapse risk.