Allen R. Kunselman

Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome

PURPOSE Women with polycystic ovary syndrome are hyperandrogenemic and insulin resistant, which are associated with alterations in circulating lipid and lipoprotein levels. We sought to determine the prevalence of, and risk factors for, lipid abnormalities in these women. SUBJECTS AND METHODS Non-Hispanic white women with polycystic ovary syndrome (n = 195) and ethnically matched control women (n = 62) had fasting blood obtained for hormone and lipid levels. Subjects were categorized by body mass index (nonobese <27 kg/m(2), obese > or =27 kg/m(2)), and analyses were adjusted for age. RESULTS Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels increased significantly in obese women with polycystic ovary syndrome (n = 153) compared with obese control women (n = 35; mean difference in total cholesterol level = 29 mg/dL; 95% confidence interval [CI]: 14 to 45 mg/dL; P <0.001; mean difference in LDL-C level = 16 mg/dL; 95% CI: 4 to 30 mg/dL; P = 0.006). Similarly, total cholesterol and LDL-C levels increased significantly in nonobese women with polycystic ovary syndrome (n = 42) compared with nonobese control women (n = 27; mean difference in total cholesterol = 32 mg/dL; 95% CI: 13 to 52 mg/dL; P <0.001; mean difference in LDL-C level = 32 mg/dL; 95% CI: 15 to 52 mg/dL; P <0.001). In obese women, high-density lipoprotein cholesterol (HDL-C) and triglyceride levels increased significantly in women with polycystic ovary syndrome compared with control women (mean difference in HDL-C level = 6 mg/dL; 95% CI: 2 to 12 mg/dL; P = 0.002; mean difference in triglyceride level = 34 mg/dL; 95% CI: 1 to 77 mg/dL; P = 0.04). Differences in LDL-C and HDL-C levels, but not triglyceride levels, remained significant after adjusting for alcohol intake, smoking, and exercise. Although age, body mass index, and polycystic ovary syndrome status were significant predictors of lipid levels, these factors accounted for no more than 25% of the variance. CONCLUSIONS In this large study of non-Hispanic white women, elevations in LDL-C levels were the predominant lipid abnormality in women with polycystic ovary syndrome, independent of obesity. The characteristic dyslipidemia of insulin resistance was absent. Indeed, obese women with polycystic ovary syndrome had relatively elevated HDL-C levels, which may confer some protection against cardiovascular disease.

Diminished paternity and gonadal function with increasing obesity in men

OBJECTIVE To examine the relationship of male obesity and reproductive function. DESIGN Observational study. SETTING Academic medical center. PATIENT(S) Eighty-seven adult men, body mass index (BMI) range from 16.1 to 47.0 kg/m(2) (mean = 29.3 kg/m(2); SD = 6.5 kg/m(2)). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Reproductive history, physical examination, inhibin B, FSH, LH, T, and unbound T levels, and semen analysis. RESULT(S) Body mass index was negatively correlated with testosterone (r = -0.38), FSH (r = -0.22), and inhibin B levels (r = -0.21) and was positively correlated with E(2) levels (r = 0.34). Testosterone also negatively correlated with skinfold thickness (r = -0.30). There was no correlation of BMI or skinfold thickness with semen analysis parameters (sperm density, volume, motility, or morphology). Inhibin B level correlated significantly with sperm motility (r = 0.23). Men with paternity had lower BMIs (28.0 kg/m(2) vs. 31.6 kg/m(2)) and lower skinfold thickness (24.7 mm vs. 34.1 mm) than men without. CONCLUSION(S) Obesity is an infertility factor in otherwise normal men. Obese men demonstrate a relative hypogonadotropic hypogonadism. Reduced inhibin B levels and diminished paternity suggest compromised reproductive capacity in this population.

Dendrite remodeling and other abnormalities in the retinal ganglion cells of Ins2 Akita diabetic mice.

PURPOSE To determine the extent of retinal ganglion cell loss and morphologic abnormalities in surviving ganglion cells in Ins2 Akita/+ diabetic mice. METHODS Mice that expressed cyan fluorescent protein (CFP) or yellow fluorescent protein (YFP) reporter genes under the transcriptional control of the Thy1 promoter were crossed with Ins2 Akita/+ mice. After 3 months of diabetes, the number and morphology of retinal ganglion cells was analyzed by confocal microscopy. The number of CFP-positive retinal ganglion cells was quantified in retinas of Ins2(Akita/+) Thy1-CFP mice. The morphology of surviving cells was examined, and dendritic density was quantified in Ins2 Akita/+ Thy1-YFP mice by using the Sholl analysis. RESULTS Thy1-CFP expression was limited to retinal ganglion cell bodies. There was a 16.4% reduction in the density of CFP-positive ganglion cells in the peripheral retina of Ins2 Akita/+ mice compared with wild-type control retinas (P < 0.017), but no significant change in the central retina. Thy1-YFP expression occurred throughout the entire structure of a smaller number of cells, including their soma, axons, and dendrites. Six different morphologic clusters of cells were identified in the mouse retinas. The structure of dendrites of ON-type retinal ganglion cells was affected by diabetes, having 32.4% more dendritic terminals (P < 0.05), 18.6% increase in total dendrite length (P < 0.05), and 15.3% greater dendritic density compared with control retinas, measured by Scholl analysis. Abnormal swelling on somas, axons, and dendrites were noted in all subtypes of ganglion cells including those expressing melanopsin. CONCLUSIONS The data show that retinal ganglion cells are lost from the peripheral retina of mice within the first 3 months of diabetes and that the dendrites of surviving large ON-type cells undergo morphologic changes. These abnormalities may explain some of the early anomalies in visual function induced by diabetes.

Prenatal Exposure to Bisphenol A and Child Wheeze from Birth to 3 Years of Age

Background: Bisphenol A (BPA), an endocrine-disrupting chemical that is routinely detected in > 90% of Americans, promotes experimental asthma in mice. The association of prenatal BPA exposure and wheeze has not been evaluated in humans. Objective: We examined the relationship between prenatal BPA exposure and wheeze in early childhood. Methods: We measured BPA concentrations in serial maternal urine samples from a prospective birth cohort of 398 mother–infant pairs and assessed parent-reported child wheeze every 6 months for 3 years. We used generalized estimating equations with a logit link to evaluate the association of prenatal urinary BPA concentration with the dichotomous outcome wheeze (wheeze over the previous 6 months). Results: Data were available for 365 children; BPA was detected in 99% of maternal urine samples during pregnancy. In multivariable analysis, a one-unit increase in log-transformed creatinine-standardized mean prenatal urinary BPA concentration was not significantly associated with child wheeze from birth to 3 years of age, but there was an interaction of BPA concentration with time (p = 0.003). Mean prenatal BPA above versus below the median was positively associated with wheeze at 6 months of age [adjusted odds ratio (AOR) = 2.3; 95% confidence interval (CI): 1.3, 4.1] but not at 3 years (AOR = 0.6; 95% CI: 0.3, 1.1). In secondary analyses evaluating associations of each prenatal BPA concentration separately, urinary BPA concentrations measured at 16 weeks gestation were associated with wheeze (AOR = 1.2; 95% CI: 1.0, 1.5), but BPA concentrations at 26 weeks of gestation or at birth were not. Conclusions: Mean prenatal BPA was associated with increased odds of wheeze in early life, and the effect diminished over time. Evaluating exposure at each prenatal time point demonstrated an association between wheeze from 6 months to 3 years and log-transformed BPA concentration at 16 weeks gestation only.

The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study

OBJECTIVE To determine if the combination of lifestyle (caloric restriction and exercise) and metformin (MET) would be superior to lifestyle and placebo (PBO) in improving the polycystic ovary syndrome (PCOS) phenotype. DESIGN Double-blind randomized 6-month trial of MET versus PBO. SETTING Two academic medical centers. PATIENT(S) One hundred fourteen subjects with PCOS were randomized to MET (N = 55) or PBO (N = 59). INTERVENTION(S) Subjects collected urine daily for ovulation monitoring, had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry, glucose tolerance, and were evaluated for quality of life at baseline and completion. MAIN OUTCOME MEASURE(S) Ovulation rates and testosterone levels. RESULT(S) Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 months compared with baseline (-3.4 kg, 95% confidence interval -5.3 to -1.5 kg). We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density increased significantly in MET. There were no differences in quality of life measures between the groups. The MET group had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints. CONCLUSION(S) The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS, although our study had limited power owing to a high dropout rate. It is not possible at baseline to identify women likely to drop out.

Effects of Gastric Bypass Surgery on Female Reproductive Function

CONTEXT Reproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear. OBJECTIVE The objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery. DESIGN This was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery. SETTING The study was conducted at an academic health center. PATIENTS Twenty-nine obese, reproductive-aged women not using confounding medications participated in the study. MAIN OUTCOME MEASURES The primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index. RESULTS Ninety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months. CONCLUSIONS Ovulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.

Urine Markers Do Not Predict Biopsy Findings or Presence of Bladder Ulcers in Interstitial Cystitis/Painful Bladder Syndrome

PURPOSE We tested for associations between urine markers, bladder biopsy features and bladder ulcers in interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS Subjects were 72 patients with interstitial cystitis/painful bladder syndrome undergoing bladder distention and biopsy. Urine was collected before the procedure. Urine marker levels were correlated with biopsy and cystoscopic findings. Patients with no previous interstitial cystitis/painful bladder syndrome treatments (47) were analyzed separately from previously treated patients (25). RESULTS For untreated patients urine interleukin-6 and cyclic guanosine monophosphate were associated with urothelial epidermal growth factor receptor staining (for interleukin-6 r = 0.29; 95% CI 0.07, 0.51; p = 0.01 and for cyclic guanosine monophosphate r = 0.34; 95% CI 0.13, 0.55; p = 0.002). Urine interleukin-8 was negatively associated with urothelial heparin-binding epidermal growth factor-like growth factor staining (r = -0.34; 95% CI -0.55, -0.12; p = 0.002) and positively associated with lamina propria mast cell count (r = 0.29; 95% CI 0.06, 0.52; p = 0.01). The latter association also was seen in treated patients (r = 0.46; 95% CI 0.20, 0.73; p <0.001). None of the urine markers was significantly different for ulcer vs nonulcer groups. All of the patients with ulcer had extensive inflammation on bladder biopsy including severe mononuclear cell infiltration, moderate or strong interleukin-6 staining in the urothelium and lamina propria, and leukocyte common antigen staining in more than 10% of the lamina propria. However, these features also were seen in 24% to 76% of the patients without ulcer. CONCLUSIONS Overall urine markers did not associate robustly with biopsy findings. The strongest association was a positive association between urine interleukin-8 levels and bladder mast cell count. Patients with ulcer consistently had bladder inflammation but the cystoscopic finding of ulcers was not a sensitive indicator of inflammation on bladder biopsy.

Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls.

OBJECTIVE. Using basal specimens from original gonadotropin radioimmunoassays, it was not possible to differentiate prepuberty from puberty hence gonadotropin-releasing hormone or gonadotropin-releasing hormone analog (GnRHa) testing was required to make this distinction. Third-generation gonadotropin assays have far greater specificity and sensitivity. Using a group of patients who had the diagnosis of central precocious puberty (CPP) verified or excluded by using GnRHa and traditional diagnostic criteria, the objective of this study was to determine if a single basal gonadotropin measurement was adequate to verify the diagnosis of CPP by using 2 third-generation gonadotropin assays. METHODS. Girls referred for assessment of early puberty had previously been evaluated for central precocious puberty including gonadotropin-releasing hormone analog stimulation testing with gonadotropin measurements by 2 different chemiluminescent third-generation immunoassays. Diagnosis of central precocious puberty was made on the basis of the response to the gonadotropin-releasing hormone analog, and clinical criteria. Girls with central precocious puberty had luteinizing hormone responses ranging from 9.1 to 67.6 U/L, the prepubertal luteinizing hormone response range was 0.2 to 5.0 U/L. Basal serum luteinizing hormone and follicle-stimulating hormone concentrations from these girls have been assessed to determine the utility of using such a single sample to diagnose central precocious puberty. RESULTS. Basal luteinizing hormone levels using the 2 third-generation gonadotropin assays were sufficient to diagnose central precocious puberty in >90% of the girls. Luteinizing hormone values were undetectable in both assays with different lower limits of detection (<0.15 and <0.20 U/L) in 29 of 34 prepubertal girls; the detectible values in 5 girls ranged from 0.20 to 0.66 U/L. All girls with central precocious puberty had values of >0.83 U/L, except a single value of 0.46 U/L. The basal follicle-stimulating hormone failed to differentiate prepubertal girls from those with central precocious puberty, whereas luteinizing hormone/follicle-stimulating hormone ratios would seem to have limited discernment. CONCLUSION. A single basal luteinizing hormone measurement is adequate to document a pubertal hypothalamic-pituitary-ovarian axis in most but not all girls with central precocious puberty.

Coronary blood flow responses to physiological stress in humans

Animal reports suggest that reflex activation of cardiac sympathetic nerves can evoke coronary vasoconstriction. Conversely, physiological stress may induce coronary vasodilation to meet an increased metabolic demand. Whether the sympathetic nervous system can modulate coronary vasomotor tone in response to stress in humans is unclear. Coronary blood velocity (CBV), an index of coronary blood flow, can be measured in humans by noninvasive duplex ultrasound. We studied 11 healthy volunteers and measured beat-by-beat changes in CBV, blood pressure, and heart rate during 1) static handgrip for 20 s at 10% and 70% of maximal voluntary contraction; 2) lower body negative pressure at -10 and -30 mmHg for 3 min each; 3) cold pressor test for 90 s; and 4) hypoxia (10% O(2)), hyperoxia (100% O(2)), and hypercapnia (5% CO(2)) for 5 min each. At the higher level of handgrip, mean blood pressure increased (P < 0.001), whereas CBV did not change [P = not significant (NS)]. In addition, during lower body negative pressure, CBV decreased (P < 0.02; and P < 0.01, for -10 and -30 mmHg, respectively), whereas blood pressure did not change (P = NS). The dissociation between the responses of CBV and blood pressure to handgrip and lower body negative pressure is consistent with coronary vasoconstriction. During hypoxia, CBV increased (P < 0.02) and decreased during hyperoxia (P < 0.01), although blood pressure did not change (P = NS), suggesting coronary vasodilation during hypoxia and vasoconstriction during hyperoxia. In contrast, concordant increases in CBV and blood pressure were noted during the cold pressor test, and hypercapnia had no effects on either parameter. Thus the physiological stress known to be associated with sympathetic activation can produce coronary vasoconstriction in humans. Contrasting responses were noted during systemic hypoxia and hyperoxia where mechanisms independent of autonomic influences appear to dominate the vascular end-organ effects.

Laryngoscopy and tracheal intubation in the head-elevated position in obese patients: a randomized, controlled, equivalence trial.

BACKGROUND:The proper positioning of patients before direct laryngoscopy is a key step that facilitates tracheal intubation. In obese patients, the 25 degree back-up or head-elevated laryngoscopic position, which is better than the supine position for tracheal intubation, is usually achieved by placing blankets or other devices under the patients head and shoulders. This position can also be achieved by reconfiguring the normally flat operating room (OR) table by flexing the table at the trunk-thigh hinge and raising the back (trunk) portion of the table (OR table ramp). This table-ramp method can be used without the added expense of positioning devices, and it reduces the possibility of injury to the patient or providers that can occur during removal of such devices once tracheal intubation is achieved. In this study, we sought to determine if the table-ramp method of patient positioning was equivalent to the blanket method with regard to the time required for tracheal intubation. METHODS:Eighty-five adults with a Body Mass Index >30 kg/m2, scheduled for elective surgery, consented to participate in this prospective randomized equivalence study conducted in a teaching hospital. The randomization scheme used permuted blocks with subjects equally allocated to be positioned using either the blanket method or the table-ramp method. The end-point in either case was to achieve a head-elevated position, where the patients external auditory meatus and sternal notch were in the same horizontal plane. Although all patients were positioned by the same anesthesiologist, laryngoscopy and tracheal intubation were performed by trainees with various levels of expertise. Standard IV induction and tracheal intubation techniques were used. The time from loss of consciousness to the time after tracheal intubation when end-tidal CO2 was detected was recorded. The effectiveness of mask ventilation and quality of laryngeal exposure were also noted. RESULTS:The mean time (sd) to tracheal intubation was 175 (66) s in the blanket group, as compared to 163 (71) s in the table-ramp group. Assuming the bounds for equivalence are −55,55 s, our study found a 95% confidence interval of −36.22, 13.52 s using two one-sided tests for equivalence corresponding to a significance level of 0.05. There was no difference in the number of attempts at laryngoscopy (P = 0.21) and tracheal intubation (P = 0.76) required to secure the airway between the two groups. CONCLUSIONS:Before induction of anesthesia, obese patients can be positioned with their head elevated above their shoulders on the operating table, on a ramp created by placing blankets under their upper body or by reconfiguring the OR table. For the purpose of direct laryngoscopy and tracheal intubation, these two methods are equivalent.