Clinical Performance of a Gene-Based Machine Learning Classifier in Assessing Risk of Developing OUD in Subjects Taking Oral Opioids: A Prospective Observational Study.

OBJECTIVE: To reduce the incidence of Opioid Use Disorder (OUD), multiple guidelines recommend assessing the risk of OUD prior to prescribing oral opioids. Although subjective risk assessments are available to help classify subjects at risk for OUD, we are aware of no clinically validated objective risk assessment tools. An objective risk assessment based on genetics may help inform shared decision-making prior to prescribing short-duration oral opioids. METHODS: A multicenter, observational cohort of adults exposed to prescription oral opioids for 4-30 days was conducted to determine the performance of an OUD classifier derived from machine learning (ML). From this cohort, the demographics of the U.S. adult opioid-prescribed population were used to create a blinded, random, representative group of subjects (n=385) for analysis to accurately estimate the performance characteristics in the intended use population. Genotyping was performed via a qualitative SNP microarray on DNA extracted from buccal samples. RESULTS: In the study subjects, the classifier demonstrated 82.5% sensitivity (95% confidence intervals: 76.1%-87.8%) and 79.9% specificity (73.7-85.2%), with no statistically significant differences in clinical performance observed based on gender, age, length of follow-up from opioid exposure, race, or ethnicity. CONCLUSION: This study demonstrates an ML classifier may provide additional objective information regarding a patient's risk of developing OUD. This information may enable subjects and healthcare providers to make more informed decisions when considering the use of oral opioids.

Multi-variant Genetic Panel for Genetic Risk of Opioid Addiction.

Over 116 million people worldwide have chronic pain and prescription dependence. In the US, opioids account for the majority of overdose deaths, and in 2014, almost 2 million Americans abused or were dependent on prescription opioids. Genetic factors may play a key role in opioid prescription addiction. Herein, we describe genetic variations between opioid addicted and non-addicted populations and derive a predictive model determining risk of opioid addiction. This case cohort study compares the frequency of 16 single nucleotide polymorphisms involved in the brain reward pathways in patients with and without opioid addiction. Data from 37 patients with prescription opioid or heroin addiction and 30 age and gender matched controls were used to design the predictive score. The predictive score was then tested on an additional 138 samples to determine generalizabilty. Results for Method Derivation of Observed data: ROC statistic=0.92, sensitivity=82% (95% CI: 66-90), specificity=75% (95% CI:56-87). TreeNet "learn" data: ROC statistic=0.92, sensitivity=92%, specificity=90%, precision=92%, and overall correct=91%. Results of Generalizability data: Sensitivity=97% (95% CI: 90 to 100), specificity=87% (95% CI: 86 to 93), positive likelihood ratio=7.3 (95% CI: 4.0 to 13.5), and negative likelihood ratio=0.03 (95% CI: 0.01 to 0.13). This negative likelihood ratio can be used as an evidence based measure to exclude patients with a high risk of opioid addicition or substance use disorder. By identifying patients with a lower risk for opioid addiction, our model may inform therapeutic decisions.

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory.

Cognitive changes that occur during mid-life and beyond are linked to both aging and the menopause transition. Studies in women suggest that the age at menopause onset can impact cognitive status later in life; yet, little is known about memory changes that occur during the transitional period to the postmenopausal state. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of perimenopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the trajectory of cognitive change across time with normal aging and aging with transitional menopause via VCD-induced follicular depletion, as well as to evaluate whether age at the onset of follicular depletion plays a role in cognitive outcomes. Animals experiencing the onset of menopause at a younger age exhibited impaired spatial memory early in the transition to a follicle-deplete state. Additionally, at the mid- and post- follicular depletion time points, VCD-induced follicular depletion amplified an age effect on memory. Overall, these findings suggest that age at the onset of menopause is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study illustrates how age at menopause onset might impact cognition in menopausal women, and provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition period. Hormone therapy during this critical juncture might be especially efficacious at attenuating age- and menopause- related cognitive decline, producing healthy brain aging profiles in women who retain their ovaries throughout their lifespan.

Influence of Obesity on Breast Density Reduction by Omega-3 Fatty Acids: Evidence from a Randomized Clinical Trial.

Preclinical data indicate that omega-3 fatty acids (n-3FA) potentiate the chemopreventive effect of the antiestrogen (AE) tamoxifen against mammary carcinogenesis. The role of n-3FA in breast cancer prevention in humans is controversial. Preclinical and epidemiologic data suggest that n-3FA may be preferentially protective in obese subjects. To directly test the protective effect of n-3FA against breast cancer, we conducted a 2-year, open-label randomized clinical trial in 266 healthy postmenopausal women (50% normal weight, 30% overweight, 20% obese) with high breast density (BD; ≥25%) detected on their routine screening mammograms. Eligible women were randomized to one of the following five groups (i) no treatment, control; (ii) raloxifene 60 mg; (iii) raloxifene 30 mg; (iv) n-3FA lovaza 4 g; and (v) lovaza 4 g plus raloxifene 30 mg. The 2-year change in BD, a validated biomarker of breast cancer risk, was the primary endpoint of the study. In subset analysis, we tested the prespecified hypothesis that body mass index (BMI) influences the relationship between plasma n-3FA on BD. While none of the interventions affected BD in the intention-to-treat analysis, increase in plasma DHA was associated with a decrease in absolute breast density but only in participants with BMI >29. Our results suggest that obese women may preferentially experience breast cancer risk reduction from n-3FA administration.

Pharmacological blockade of the aromatase enzyme, but not the androgen receptor, reverses androstenedione-induced cognitive impairments in young surgically menopausal rats.

Androstenedione, the main circulating ovarian hormone present after menopause, has been shown to positively correlate with poor spatial memory in an ovary-intact rodent model of follicular depletion, and to impair spatial memory when administered exogenously to surgically menopausal ovariectomized rats. Androstenedione can be converted directly to estrone via the aromatase enzyme, or to testosterone. The current study investigated the hormonal mechanism underlying androstenedione-induced cognitive impairments. Young adult ovariectomized rats were given either androstenedione, androstenedione plus the aromatase inhibitor anastrozole to block conversion to estrone, androstenedione plus the androgen receptor blocker flutamide to block androgen receptor activity, or vehicle treatment, and were then administered a battery of learning and memory maze tasks. Since we have previously shown that estrone administration to ovariectomized rats impaired cognition, we hypothesized that androstenedione's conversion to estrone underlies, in part, its negative cognitive impact. Here, androstenedione administration impaired spatial reference and working memory. Further, androstenedione did not induce memory deficits when co-administered with the aromatase inhibitor, anastrozole, whereas pharmacological blockade of the androgen receptor failed to block the cognitive impairing effects of androstenedione. Anastrozole alone did not impact performance on any cognitive measure. The current data support the tenet that androstenedione impairs memory through its conversion to estrone, rather than via actions on the androgen receptor. Studying the effects of aromatase and estrogen metabolism is critical to elucidating how hormones impact women's health across the lifespan, and results hold important implications for understanding and optimizing the hormone milieu from the many endogenous and exogenous hormone exposures across the lifetime.

Differential impact of body mass index on absolute and percent breast density: implications regarding their use as breast cancer risk biomarkers.

Percent breast density (PBD), a commonly used biomarker of breast cancer risk (BCR), is confounded by the influence of non-dense breast tissue on its measurement and factors, such as BMI, which have an impact on non-dense tissue. Consequently, BMI, a potent BCR factor, is, paradoxically, negatively correlated with PBD. We propose that absolute breast density (ABD) is a more accurate biomarker of BCR. We used a volumetric method to compare the correlation between PBD and ABD with baseline demographics and dietary and physical activity variables in a group of 169 postmenopausal women enrolled in a clinical trial prior to any intervention. As expected, a strong negative correlation between PBD and BMI was observed (Rho = -0.5, p < 5e(-12)). In contrast, we observed a strong, previously not well established, positive correlation of BMI with ABD (Rho = 0.41, p < 2.5e(-8)), which supports the use of ABD as a more accurate indicator of BCR. Correction of PBD by BMI did not frequently provide the same information as ABD. In addition, because of the strong influence of BMI on ABD, many correlations between dietary variables and ABD did not emerge, until adjustment was made for BMI. ABD corrected by BMI should be the gold standard BD measurement. These findings identify the optimal measurement of BD when testing the influence of an intervention on BD as a biomarker of BCR.

Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women.

BACKGROUND: Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes. OBJECTIVE: We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism. METHODS: We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/- 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels. RESULTS: All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH-cortisol relationship was maintained for TSH levels (uIU/L) ≤4.0, ≤3.5, ≤3.0, and ≤2.5 but not ≤2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels. CONCLUSIONS: Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study.

Determination of vitamin D in relation to body mass index and race in a defined population of black and white women.

OBJECTIVE: To examine the contributions of obesity and race to levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in a defined cohort of black and white women. METHODS: An interventional study was conducted from October 2004 to March 2008, among 219 healthy female volunteers. Serum 25(OH)D and PTH levels were determined in 117 African American women and 102 white women and the results were compared with body mass index (BMI), percentage body fat, serum lipids, and PTH levels. RESULTS: Black women had lower median levels of 25(OH)D compared with white women (27.3 nmol/L vs 52.4 nmol/L; P<0.001). Serum levels of 25(OH)D below 50 nmol/L were found in 98% of black women and 45% of white women (P<0.001). The differences between the racial groups in the levels of 25(OH)D persisted despite adjustments for body weight, percentage body fat, and BMI. Black women had higher median serum levels of PTH than white women (31.9 pg/mL vs 22.3 pg/mL; P<0.01). CONCLUSION: African American women are at significant risk for low vitamin D levels. Studies are needed to determine if low vitamin D status in young African American women is associated with a greater risk for vitamin D-related chronic diseases that can be reduced with vitamin D supplementation.

Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat.

CEE (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase-immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17ß-estradiol (17ß-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17ß-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, and does not increase ChAT-IR neuron number in basal forebrain, as does 17ß-E2. Thus, data from prior studies suggest that 17ß-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens.

Elevated bone turnover predicts for bone metastasis in postmenopausal breast cancer: results of NCIC CTG MA.14.

PURPOSE: We investigated the association of bone-only relapse with a pretreatment marker of bone resorption: serum beta C-terminal telopeptide (B-CTx) of type I collagen. METHODS: Pretreatment serum B-CTx concentrations were determined from 621 of 667 patients with primary breast cancer enrolled onto the NCIC CTG MA.14 phase III adjuvant trial of tamoxifen with or without octreotide. Recurrence-free survival (RFS) was a secondary end point; the focus here was bone-only relapse. We analyzed continuous or categorical (.71 ng/mL cut point) serum B-CTx in stepwise forward multivariate Cox regression, adjusted for trial stratification factors. We also examined B-CTx and bone relapse by pretrial chemotherapy status. RESULTS: At median 7.9 years follow-up, 123 of 621 patients experienced recurrence; 19 (3.1%) of 621 had bone-only recurrence, and 47 (7.5%) of 621 had bone plus other sites of recurrence. Larger pathologic tumor size (P = .001) and elevated continuous and categorical serum B-CTx were associated with shorter bone-only RFS (both P = .02) when added to a model with factors significant in the main trial analyses (hazard ratio [HR], 3.43 and 3.50, respectively; 95% CI, 1.20 to 9.77 and 1.26 to 9.75, respectively). The univariate HR for B-CTx was 2.80 (95% CI, 1.05 to 7.48; P = .03). Elevated serum B-CTx was also associated with shorter bone-only RFS (P = .02) when added to a model with factors significant in the main trial analyses. Serum B-CTx level was not associated with any other type of recurrence. Serum B-CTx was not significantly different for patients who underwent pretrial chemotherapy, compared with those who did not (P = .27), nor did pretrial chemotherapy affect bone relapse (P = .48 for bone only; P = .76 for bone with other relapse). CONCLUSION: Higher pretreatment serum B-CTx was a significant predictor of shorter RFS for bone-only metastasis. Increased bone resorption creates an environment that promotes growth of breast cancer cells.

The effects of Tamoxifen and fish oil on mammary carcinogenesis in polyoma middle T transgenic mice.

In these experiments, we tested the hypothesis that inhibition of the estrogen receptor (ER) with Tamoxifen and activation of PPARγ with fish oil (FO) rich in omega-3 (n-3; known PPAR agonists) inhibit the development of hormone-independent breast cancer in view of the known crosstalk between the ER and PPARγ pathways. We selected the polyoma middle T transgenic mouse model, since in this system the development of ER- tumors is preceded by ER positive preneoplastic lesions. Tamoxifen admixed with a 20% corn oil (CO) modified AIN-76A diet delayed mammary carcinogenesis and inhibited tumor multiplicity, volume, and weight in a dose-dependent (1, 10, and 100 ppm) fashion. Administration of increasing concentrations of FO in the diet (5%, 10%, and 17%) did not affect any of the tumor parameters. Combined administration of different doses of Tamoxifen and FO delayed carcinogenesis and suppressed tumor multiplicity and volume to the same extent as Tamoxifen alone. Mice fed 10% FO exhibited the expected increase in n-3/n-6 ratio in plasma and tumor based on diet analysis. Further increase in the n-3/n-6 ratio was not observed in mice fed the 17% FO diet. FO reduced tissue levels of arachidonic acid and its metabolite PGF-2α. Our results support the role of ER expression by preneoplastic lesions in the development of hormone-independent tumors and consequently the importance of including ER targeting in combination with mechanistically based novel chemopreventive agents.

Racial influence on the polycystic ovary syndrome phenotype: a black and white case-control study.

OBJECTIVE: To estimate racial disparities in the polycystic ovary syndrome (PCOS) phenotype between white and black women with PCOS. DESIGN: Case-control study. SETTING: Two academic medical centers. PATIENT(S): A total of 242 women not taking confounding medications in otherwise good health. INTERVENTION(S): Phenotyping during the follicular phase or anovulation after an overnight fast in women. MAIN OUTCOME MEASURE(S): Biometric, serum hormones, glycemic and metabolic parameters, and body composition by dual-energy x-ray absorptiometry. RESULT(S): We studied 77 white and 43 black women with PCOS and 35 white and 87 black controls. Black women with PCOS were similar reproductively to white women with PCOS. Black women with PCOS had lower levels of serum transaminases, higher high-density lipoprotein cholesterol levels (mean difference [MD], 18.2 mg/dL; 95% confidence intervals [CI], 14.3, 22.1 mg/dL), lower triglyceride levels (MD, -43.2 mg/dL; 95% CI, -64.5, -21.9), and enhanced insulinogenic index on the oral glucose tolerance test compared with white women with PCOS. Black women with PCOS had higher bone mineral density (MD, 0.1 g/cm(2); 95% CI, 0.1, 0.2 g/cm(2)), lower percent body fat on dual-energy x-ray absorptiometry (MD, -2.8%; 95% CI, -5.1%, -0.5%), and overall a higher quality of life. Although most of these findings disappeared when the differences with racially matched controls were compared, black women with PCOS compared with black controls had lower estradiol levels than white women with PCOS compared with white controls (MD, -12.9 pg/mL; 95% CI, -24.9, -0.8 pg/mL), higher systolic blood pressure (MD, 9.1 mm Hg; 95% CI, 0.8, 17.4 mm Hg), and lower fasting glucose levels (MD, -12.0 mg/dL; 95% CI, -22.3, -1.7 mg/dL). CONCLUSION(S): Racial disparities in PCOS phenotype are minor and mixed. Future studies should explore if race impacts treatment effects.

Effects of metformin in adolescents with polycystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study.

Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life.

Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: a phase I/II study.

PURPOSE: Controversy exists about whether vaginal estrogens interfere with the efficacy of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal atrophy in patients on AIs, a safe and effective nonestrogen therapy is necessary. We hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs. METHODS: Twenty-one postmenopausal breast cancer patients on AIs with symptoms of vaginal atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days. Ten women received a dose of 300 µg, 10 received 150 µg, and one was not evaluable. Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations with pH and vaginal cytology were compared before and after therapy. RESULTS: Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total symptom scores improved from 2.0 to 0.7 after treatment (p < .001) and remained improved 1 month thereafter (p = .003). Dyspareunia (p = .0014) and vaginal dryness (p <.001) improved. The median vaginal pH decreased from 5.5 to 5.0 (p = .028). The median maturation index rose from 20% to 40% (p < .001). Although improvement in total symptom score was similar for both doses (-1.3 for 300 µg, -0.8 for 150 µg; p = .37), only the 300-µg dose was associated with improved pH and maturation values. CONCLUSIONS: A 4-week course of vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels. Longer-term trials are warranted.

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.

Brachial artery conductance during reactive hyperemia is increased in women with polycystic ovary syndrome.

OBJECTIVE: To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls. STUDY DESIGN: This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia. RESULTS: Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P<0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P=0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P<0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels. CONCLUSIONS: Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.

Genetic Ancestry, Skin Reflectance and Pigmentation Genotypes in Association with Serum Vitamin D Metabolite Balance.

BACKGROUND: Lower serum vitamin D (25(OH)D) among individuals with African ancestry is attributed primarily to skin pigmentation. However, the influence of genetic polymorphisms controlling for skin melanin content has not been investigated. Therefore, we investigated differences in non-summer serum vitamin D metabolites according to self-reported race, genetic ancestry, skin reflectance and key pigmentation genes (SLC45A2 and SLC24A5). MATERIALS AND METHODS: Healthy individuals reporting at least half African American or half European American heritage were frequency matched to one another on age (+/- 2 years) and sex. 176 autosomal ancestry informative markers were used to estimate genetic ancestry. Melanin index was measured by reflectance spectrometry. Serum vitamin D metabolites (25(OH)D3, 25(OH)D 2 and 24,25(OH)2D3) were determined by high performance liquid chromatography (HPLC) tandem mass spectrometry. Percent 24,25(OH)2D3 was calculated as a percent of the parent metabolite (25(OH)D3). Stepwise and backward selection regression models were used to identify leading covariates. RESULTS: Fifty African Americans and 50 European Americans participated in the study. Compared with SLC24A5 111Thr homozygotes, individuals with the SLC24A5 111Thr/Ala and 111Ala/Ala genotypes had respectively lower levels of 25(OH)D3 (23.0 and 23.8 nmol/L lower, p-dominant=0.007), and percent 24,25(OH)2D3 (4.1 and 5.2 percent lower, p-dominant=0.003), controlling for tanning bed use, vitamin D/fish oil supplement intake, race/ethnicity, and genetic ancestry. Results were similar with melanin index adjustment, and were not confounded by glucocorticoid, oral contraceptive, or statin use. CONCLUSIONS: The SLC24A5 111Ala allele was associated with lower serum vitamin 25(OH)D3 and lower percent 24,25(OH)2D3, independently from melanin index and West African genetic ancestry.

Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial.

To determine the effects of statins on vascular function, inflammation, and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had low-density lipoprotein cholesterol levels >100 mg/dL to atorvastatin (40 mg/day) or placebo for 6 weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure; increased insulin levels and brachial artery conductance during reactive hyperemia; and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment.