Soy isoflavones interact with calcium and contribute to blood pressure homeostasis in women: a randomized, double-blind, placebo controlled trial.

BACKGROUND: Estrogens and calcium regulate vascular health but caused adverse cardiovascular events in randomized trials. OBJECTIVES: Whether phytoestrogenic soy isoflavones modulate the physiological effects of calcium on blood pressure was explored. DESIGN: A double-blind, randomized study assigned 99 premenopausal women to 136.6 mg isoflavones (as aglycone equivalents) and 98 to placebo for 5 days per week for up to 2 years. Blood pressure, serum calcium and urinary excretion of daidzein (DE) and genistein (GE) were measured repeatedly before and during treatment. RESULTS: Isoflavones did not affect blood pressure per intake dose assignment (i.e. intention-to-treat, n = 197), but significantly affected blood pressure per measured urinary excretion of isoflavones (i.e. per protocol analysis, n = 166). Isoflavones inversely moderated calcium effects on systolic blood pressure (SBP) (interaction term ß-estimates: - 3.1 for DE, - 12.86 for GE, all P < 0.05), and decreased diastolic blood pressure (DBP) (ß-estimates: - 0.84 for DE, - 2.82 for GE, all P < 0.05) after controlling for calcium. The net intervention effects between the maximum and no isoflavone excretion were - 17.7 and + 13.8 mmHg changes of SBP, respectively, at serum calcium of 10.61 and 8.0 mg/dL, and about 2.6 mmHg decrease of DBP. CONCLUSIONS: Moderation by isoflavones of the physiological effect of calcium tends to normalize SBP, and this effect is most significant when calcium concentrations are at the upper and lower limits of the physiological norm. Isoflavones decrease DBP independent of calcium levels. Further studies are needed to assess the impact of this novel micronutrient effect on blood pressure homeostasis and cardiovascular health. TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT00204490.

Soy isoflavones decrease fibroglandular breast tissue measured by magnetic resonance imaging in premenopausal women: A 2-year randomized double-blind placebo controlled clinical trial.

BACKGROUND & AIMS: Populations consuming soy have reduced risk for breast cancer, but the mechanisms are unclear. We tested the hypothesis that soy isoflavones, which have ovarian hormone-like effects, can reduce fibroglandular breast tissue (FGBT, 'breast density'), a strong risk marker for breast cancer. METHODS: Premenopausal women (age 30-42 years) were randomized to consume isoflavones (136.6 mg as aglycone equivalents, n = 99) or placebo (n = 98) for 5 days per week up to 2 years, and changes in breast composition measured by magnetic resonance imaging at baseline and yearly intervals were compared after square root transformation using linear mixed effects regression models. RESULTS: By intention-to-treat analyses (n = 194), regression coefficients (ß estimates) of the interaction of time and isoflavone treatment were -0.238 (P = 0.06) and -0.258 (P < 0.05) before and after BMI adjustment, respectively for FGBT, 0.620 (P < 0.05) and 0.248 (P = 0.160), respectively for fatty breast tissue (FBT), and -0.155 (P < 0.05) and -0.107 (P < 0.05), respectively for FGBT as percent of total breast (FGBT%). ß Estimates for interaction of treatment with serum calcium were -2.705 for FBT, and 0.588 for FGBT% (P < 0.05, before but not after BMI adjustment). BMI (not transformed) was related to the interaction of treatment with time (ß = 0.298) or with calcium (ß = -1.248) (P < 0.05). Urinary excretion of isoflavones in adherent subjects (n = 135) significantly predicted these changes in breast composition. Based on the modeling results, after an average of 1.2, 2.2 and 3.3 years of supplementation, a mean decrease of FGBT by 5.3, 12.1, and 19.3 cc, respectively, and a mean decrease of FGBT% by 1.37, 2.43, and 3.50%, respectively, were estimated for isoflavone exposure compared to placebo treatment. Subjects with maximum isoflavone excretion were estimated to have 38 cc less FGBT (or ∼3.13% less FGBT%) than subjects without isoflavone excretion. Decrease in FGBT and FGBT% was more precise with daidzein than genistein. CONCLUSIONS: Soy isoflavones can induce a time- and concentration-dependent decrease in FGBT, a biomarker for breast cancer risk, in premenopausal women, and moderate effects of calcium on BMI and breast fat, suggesting a beneficial effect of soy consumption. TRIAL REGISTRATION: www. CLINICALTRIALS: gov identifier: NCT00204490. TRIAL REGISTRATION: www. CLINICALTRIALS: gov identifier: NCT00204490.

Alkaline phosphatase and percentage body fat predict circulating C-reactive protein in premenopausal women.

C-reactive protein (CRP) is considered a marker of inflammation, which is a risk factor for many chronic diseases. However, determinants of CRP remain unclear and were studied in a strictly defined cohort of healthy premenopausal women (n=233) using multiple regression models. Independent predictors of serum CRP (model R(2)=0.59) were percentage body fat, serum alkaline phosphatase (ALP), sex hormone-binding globulin and white blood cell count. The close association between CRP and ALP suggests that enzymatic activity of ALP may be important for the anti-inflammatory effects of CRP, which should be confirmed with additional studies.

Lean body mass, not estrogen or progesterone, predicts peak bone mineral density in premenopausal women.

Estrogen and body fat content are important predictors of bone mineral density (BMD) in postmenopausal women, but their association with BMD in premenopausal women is less clear. Mounting evidence suggests that dietary fats can have detrimental effects on bone health. In a cross-sectional sample of healthy 30- to 40-y-old women (n = 242), we investigated the predictors of BMD at the hip and spine by multilevel multiple regression analyses. Predictor variables in the models included dietary intake of various fats, serum concentrations of sex steroids, blood chemistries and markers of metabolic syndrome, anthropometric variables, and ethnicity. Among these premenopausal women, lean body mass was the strongest independent predictor (P < 0.0001) and African-American ethnicity (P < 0.05) was another positive independent predictor of BMD at the hip and spine. Dietary fats were not independent predictors of BMD of hip and spine. Lean body mass and being African-American explained 33% of the variance in hip BMD. Lean body mass, African-American ethnicity, and serum concentrations of triglycerides (a negative predictor, P = 0.0001) explained 28% of the variance in spine BMD. In contrast, luteal phase serum concentrations of estradiol, progesterone, and testosterone were not predictors of BMD. It remains to be determined whether efforts to increase lean body mass in premenopausal women with normal levels of endogenous estrogen may be an effective preventive strategy to preserve bone health.

Dietary beta-tocopherol and linoleic acid, serum insulin, and waist circumference predict circulating sex hormone-binding globulin in premenopausal women.

Reduced levels of circulating sex hormone-binding globulin (SHBG) are implicated in the etiology of sex steroid-related pathologies and the metabolic syndrome. Dietary correlates of serum SHBG remain unclear and were studied in a convenient cross-sectional sample of healthy 30- to 40-y-old women (n = 255). By univariate analyses, serum SHBG correlated negatively with several indices of the metabolic syndrome, such as BMI, waist circumference, hip circumference (r = -0.36 to -0.44; P < 0.0001), fasting serum insulin (r = -0.41; P < 0.0001), serum triglycerides (r = -0.27; P < 0.0001), serum glucose (r = -0.23; P < 0.001), and plasma testosterone (r = -0.19; P = 0.002). Serum SHBG correlated positively with serum HDL-cholesterol (r = 0.33; P < 0.0001), plasma progesterone (r = 0.17; P = 0.007), and dietary intake of beta-tocopherol (r = 0.17; P = 0.006), and negatively with that of fructose (r = -0.13; P = 0.04). Principal component analysis (PCA) extracted 12 nutrient factors with eigenvalues > 1.0 from 54 nutrients and vitamins in food records. Multivariate regression analyses showed that the PCA-extracted nutrient factor most heavily loaded with beta-tocopherol and linoleic acid (P = 0.03) was an independent positive predictor of serum SHBG. When individual nutrients were the predictor variables, beta-tocopherol (P = 0.002), but not other tocopherols or fatty acids (including linoleic acid), was an independent positive predictor of serum SHBG. Circulating insulin (P = 0.02) and waist circumference (P = 0.002), but not serum lipids, were negative independent predictors of SHBG in all regression models. Additional studies are needed in women of other age groups and men to determine whether consumption of foods rich in beta-tocopherol and/or linoleic acid may increase serum SHBG concentrations and may thereby decrease the risk for metabolic syndrome and reproductive organ cancer.

Dietary intake of lactose as a strong predictor for secretor status of nipple aspirate fluid in healthy premenopausal nonlactating women.

PURPOSE: Nipple aspirate fluid (NAF) is considered a potential source for discovering breast cancer biomarkers. However, the success rate of obtaining NAF was reported to vary from 48% to 77%, and mechanisms for its secretion are not fully understood. The purpose of this study was to investigate dietary, demographic, reproductive, hormonal, and anthropometric factors that are associated with the ability to obtain NAF by aspiration (secretor status) from premenopausal women. STUDY DESIGN: NAF procedures were attempted for women who were 30 to 40 years old, not pregnant, not breast-feeding, and not taking contraceptive medications. RESULTS: Compared with nonsecretors, secretors of NAF consumed significantly more dietary lactose (mainly from milk), were more likely to be parous, were older at first and last childbirth, breast-fed their babies for a longer period of time, and had an earlier menarche and lower plasma concentrations of 17beta-estradiol (P < 0.05). Using multivariate logistic regression models, higher dietary intake of lactose [odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.5-4.8], earlier menarche (OR, 0.8; 95% CI, 0.7-1.0), being parous (OR, 2.3; 95% CI, 1.0-5.6), and being older at first childbirth (OR, 1.5; 95% CI, 1.0-2.1) were found to be independent and positive predictors for being a secretor of NAF. CONCLUSIONS: These findings suggest that dietary intake of lactose, a modifiable factor, may be used to change the NAF secretor status of women. This finding may facilitate the use of NAF as a diagnostic material for detecting breast diseases.

Daidzein and genistein have differential effects in decreasing whole body bone mineral density but had no effect on hip and spine density in premenopausal women: A 2-year randomized, double-blind, placebo-controlled study.

Soy isoflavones are potentially beneficial phytoestrogens, but their tissue-selective effects in women are poorly understood. We tested the hypothesis that soy isoflavones affect bone mineral density (BMD), which may be influenced by individual differences in isoflavone metabolism and serum calcium levels. Ninety-nine healthy premenopausal women were randomized to isoflavones (136.6 mg aglycone equivalence) and 98 to placebo for 5 days per week for up to 2 years. BMD, serum calcium, and urinary excretion of daidzein and genistein were measured before and during treatment. In 129 adherent subjects, we found that isoflavone exposure, determined by urinary excretion levels, but not by dose assignment, interacted with serum calcium in affecting whole body BMD, but not hip and spine BMD. The regression coefficient was -0.042 for genistein excretion (GE) and 0.091 for the interaction between GE and serum calcium (all P < .05). Daidzein excretion had similar but marginal effect. Genistein significantly decreased whole body BMD only at low normal serum calcium levels but increased whole body BMD at higher serum calcium levels. Comparing maximum to minimum GE, mean changes in whole body BMD were +0.033 and -0.113 g/cm2 at serum calcium levels of 10 and 8.15 mg/dL, respectively. These associations were not evident by intention-to-treat analysis, which could not model for inter-individual differences in isoflavone metabolism. In summary, soy isoflavones decrease whole body BMD only when serum calcium is low. Isoflavones are dietary substances that may influence calcium homeostasis by releasing calcium from bone while sparing the common fracture risk sites hip and spine.

Novel effects of phytoestrogenic soy isoflavones on serum calcium and chloride in premenopausal women: A 2-year double-blind, randomized, placebo-controlled study.

BACKGROUND: Soy phytoestrogens are potential alternatives to postmenopausal hormone replacement therapy (HRT). Adverse effects of HRT such as myocardial infarction, stroke, and pulmonary embolism are mediated by calcium-induced signaling. OBJECTIVE: To determine whether soy isoflavones affect serum calcium in healthy female subjects. DESIGN: In a double-blind trial, 197 premenopausal women were randomly assigned to either isoflavone (N = 99) or placebo pills (N = 98) 5 days per week for up to 2 years, plus prenatal vitamins. Isoflavone pills contained 60 mg genistein, 60 mg daidzein and 16.6 mg glycitein (expressed as aglycone equivalents). All pills contained 15 mg riboflavin as an adherence marker. Blood chemistries and urinary daidzein, genistein and riboflavin were measured multiple times during the luteal phase before and during treatment. RESULTS: Analysis of the adherent population (N = 83 per group), revealed significantly strong associations between urinary levels of isoflavones and serum concentrations of calcium (regression coefficients 0.082 for daidzein and 0.229 for genistein, all P < 0.01) and chloride (regression coefficient, -1.537 for genistein, P < 0.0001), mediated in part by albumin. The effects amounted to mean changes of +0.24 mg/dL for calcium and -1.45 mEq/L for chloride, with each visit for subjects excreting the most vs. the least amounts of isoflavones. These associations were not evident in the intention-to-treat analysis (N = 197) that did not assess expected variations in isoflavone levels within and between subjects from metabolism and adherence. CONCLUSIONS: These novel and strong effects of soy isoflavones on calcium homeostasis have important implications for long term effects of these natural substances on cardiovascular diseases.

Lower levels of urinary 2-hydroxyestrogens in polycystic ovary syndrome.

CONTEXT: Women with polycystic ovary syndrome (PCOS) have anovulation due to arrested follicular maturation. The substrate (2-hydroxyestrogen) and product (2-methoxyestrogen) of catechol-O-methyl transferase (COMT) have been shown to modulate proliferation and angiogenesis of granulosa cells. OBJECTIVE: The objective of the study was to evaluate COMT ovarian expression as well as the production of estrogen metabolites (2-hydroxyestrogen and 2-methoxyestrogen) in subjects with PCOS. DESIGN: Immunohistochemistry was used to assess COMT expression in ovarian tissues. Urinary levels of 10 different estrogens and estrogen metabolites were measured using enzyme-labeled immunoassays and/or liquid chromatography with tandem mass spectrometry. SETTING: The study was conducted at a tertiary university referral center. PATIENTS AND OTHER PARTICIPANTS: Ovarian tissues were obtained from six control subjects and six subjects with PCOS. Fasting first-void urinary samples were collected from 49 subjects with PCOS and 36 healthy control subjects. MAIN OUTCOME MEASURE(S): COMT protein expression in ovarian tissues was measured. Urinary levels of 2-hydroxyestrogen and 2-methoxyestrogen levels in PCOS patients were also measured. RESULTS: Whereas immunohistochemistry showed that COMT was expressed in ovaries from control and PCOS subjects, its expression was significantly higher in ovaries from subjects with PCOS, in both the follicular structures and ovarian stroma. The urinary 2-hydroxyestrogen level was significantly lower in subjects with PCOS, compared with normal controls (P = 0.009). Additionally, urinary 2-hydroxyestrogen levels negatively correlated with serum insulin levels in subjects with PCOS (r = -0.333, P =0 .031). CONCLUSIONS: Urinary 2-hydroxyestrogen is decreased in subjects with PCOS, which could be due in part to increased ovarian expression of COMT. Further studies are needed to ascertain the role of estrogen metabolism in PCOS before this information can be used in clinical settings.

Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance.

Our objective was to evaluate the effectiveness of the insulin-sensitizing agent rosiglitazone in obese women with polycystic ovary syndrome (PCOS) and severe insulin resistance. Twelve obese women with PCOS were recruited. All were hirsute and anovulatory with acanthosis nigricans indicating severe insulin resistance. All women were treated with 4 mg of rosiglitazone daily for 6 months. A standard 75-g oral glucose tolerance test with insulin levels was performed before and after the women were treated with rosiglitazone. Glucose and insulin areas under the curve (AUC) were calculated. Serum levels of total and free testosterone, dehydroepiandrosterone sulfate, LH, and 17-hydroxyprogesterone were also measured before and after treatment. The body mass index was determined before and after treatment. There was a highly significant (r = 0.881, P < 0.0001) positive correlation between insulin response during oral glucose tolerance test and basal total testosterone levels. After treatment with rosiglitazone, there were significant decreases in fasting insulin levels (46.0 +/- 6.5 vs. 16.9 +/- 2.0 microU/ml; P < 0.001), insulin AUC (749.3 +/- 136.3 vs. 225.0 +/- 15.7 microU/ml; P = 0.003), fasting glucose levels (90.8 +/- 3.0 vs. 81.8 +/- 1.9 mg/dl; P = 0.003), and glucose AUC (437.9 +/- 25.0 vs. 322.5 +/- 14.7 mg/dl; P < 0.001). Both total testosterone (96.3 +/- 17.3 vs. 56.1 +/- 5.8 ng/dl; P = 0.01) and free testosterone (5.8 +/- 0.6 vs. 3.4 +/- 0.5 pg/ml; P < 0.001) decreased significantly after treatment, although there was no significant change in LH levels. Levels of SHBG increased significantly (18.3 +/- 3.4 vs. 25.8 +/- 6.6 nmol/liter; P = 0.009) after treatment, and dehydroepiandrosterone sulfate levels decreased significantly (P = 0.04). There was no significant change in body mass index (40.4 +/- 2.4 vs. 41.1 +/- 2.7 kg/m(2)). Eleven of the women reverted to regular ovulatory cycles during the treatment period. We conclude that 1) rosiglitazone therapy improves insulin resistance and glucose tolerance in obese women with PCOS; 2) rosiglitazone decreases ovarian androgen production, which appears to be independent of any changes in LH levels; 3) hyperinsulinemia appears to play a key role in the overproduction of ovarian androgens in these women because attenuation of insulin levels is associated with decreased testosterone levels; and 4) short-term rosiglitazone therapy helps restore spontaneous ovulation.

Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women during consumption of soy-containing isoflavones.

CONTEXT: TNF-alpha is a key mediator of inflammatory responses and may play a pivotal role in the development of cancer and in bone resorption. OBJECTIVE: This study determined the effect of soy rich in isoflavones on levels of TNF-alpha. DESIGN: Twelve postmenopausal women ingested a 36-oz portion of soymilk containing isoflavones daily for 16 wk and provided fasting blood samples multiple times before, during, and after soy consumption for the analyses of cytokines and monocyte content. RESULTS: Compared with prediet levels (36.3 +/- 14.0 pg/ml), serum levels of TNF-alpha decreased by 25.1% (27.2 +/- 10.3 pg/ml; P < 0.01) as early as 2 wk after soy consumption and by 66.7% (11.6 +/- 5.3 pg/ml; P < 0.01) 10 wk after soy consumption and recovered to the prediet levels 4 wk after the termination of soy consumption (38.6 +/- 19.6 pg/ml; P = 0.66). A similar decrease of up to 56.6 and 14.4% was found for serum IL-1alpha and the mean percentage of blood monocytes during soy consumption, respectively, but not for IL-6. In cultures of monocytes or whole blood from postmenopausal women, soy isoflavones (genistein and daidzein, 10-1000 nm), tamoxifen (10-1000 nm), or 17beta-estradiol (0.1-10 nm) inhibited lipopolysaccharide (1 microg/ml)-induced TNF-alpha production by up to 55.8%. CONCLUSIONS: Isoflavones may be the active components in soy responsible for the decrease of TNF-alpha found in postmenopausal women during a soy diet. This antiinflammatory effect of the isoflavones may be important in immune modulation and the prevention of bone loss and cancer.

Adiponectin levels in women with polycystic ovary syndrome and severe insulin resistance.

OBJECTIVE: Adiponectin is an adipokine that is decreased in obesity and type 2 diabetes. Women with polycystic ovarian syndrome (PCOS) are obese and are at risk for type 2 diabetes. The objective of the current study was to investigate the relationship of adiponectin to obesity and insulin resistance in women with PCOS and severe insulin resistance. METHODS: Thirty women with PCOS and acanthosis nigricans indicating severe insulin resistance were included in the study. Eleven body mass index (BMI)-matched women with normal ovulatory cycles served as controls. Fasting glucose, insulin, and adiponectin levels were measured, and a standard oral glucose tolerance test (OGTT) with insulin levels was performed. To further investigate the role of insulin sensitivity on adiponectin levels, 10 women with PCOS were treated with 4 mg rosiglitazone daily for 6 months and adiponectin levels were measured before and after treatment. RESULTS: Fasting insulin levels (33.5 +/- 3.8 microU/mL; P <.001) and insulin area under the curve (AUC) during OGTT (536.2 +/- 70.5 microU/mL; P <.01) were higher in women with PCOS, while glucose levels were similar to controls. Adiponectin levels were lower (P <.01) in women with PCOS (5.6 +/- 2.6 microg/mL) compared with controls (8.5 +/- 3.9 microg/mL). There was a significant negative correlation between adiponectin levels and fasting insulin levels (r = -0.40, P = .02), insulin AUC during OGTT (r = -0.47, P = .008), fasting glucose levels (r = -0.45, P = .01), and glucose AUC during OGTT (r = -0.51, P = .003). There was no correlation between BMI and serum adiponectin (r = -0.12, P = .508) in women with PCOS, while there was a negative correlation (r = -0.746, P = .013) in controls. There was a significant (P <.01) increase in adiponectin levels when treated with rosiglitazone, despite unchanged BMI. CONCLUSION: These results indicate that in women with PCOS and severe insulin resistance, insulin sensitivity appears to be the major determinant of adiponectin levels rather than adiposity. Low adiponectin levels may predict women with PCOS who are at high risk for developing type 2 diabetes.

Expression of messenger ribonucleic acid encoding steroidogenic enzymes in postmenopausal ovaries.

To investigate expression of steroidogenic enzymes involved in androgen and estrogen synthesis in the stroma of postmenopausal ovaries.Ovarian stromal tissue samples were obtained at hysterectomy from postmenopausal women who had hysterectomy and oophorectomy. Tissues were frozen immediately in liquid nitrogen and kept frozen until RNA was extracted. Total RNA was examined by Northern blot analysis using (32)P-labeled cDNA probes encoding human P450 side chain cleavage (P450(SSC)), P450(17alpha), and cytochrome P450 aromatase (P450(arom)). Concentrations of mRNA encoding cytochrome P450(SSC), cytochrome P450 17alpha-hydroxylase (CYP17), and P450(arom) were determined in the ovarian stroma. We detected P450(SSC) mRNA in all postmenopausal ovaries studied. P450(SSC) mRNA was increased threefold in the ovarian stroma of postmenopausal women with endometrial cancer and endometrial hyperplasia. CYP17 mRNA was detected in the ovarian stroma of all women with endometrial cancer. P450(arom) mRNA was not detected in the ovaries studied. Postmenopausal ovaries possess enzymes for initiation of steroidogenesis. Enzymes essential for androgen synthesis were expressed in the ovarian stroma of postmenopausal women with endometrial cancer or hyperplasia.

Efficacy of second versus third generation oral contraceptives in the treatment of hirsutism.

OBJECTIVE: To compare second versus third generation combination oral contraceptives (OCs) in the treatment of hirsutism. METHODS: Women with hirsutism, as defined by a minimum Ferriman-Gallwey score of 10, were randomized in a double-blind fashion to receive an OC containing either ethinyl estradiol/desogestrel or ethinyl estradiol/levonorgestrel for 9 months of treatment. Ferriman-Gallwey scores, androgen levels and sex hormone-binding globulin were measured at baseline and every 3 months for the duration of the study. Hormones were measured in duplicate by radioimmunoassay. RESULTS: Of the 47 women enrolled, 24 were randomized to ethinyl estradiol/desogestrel and 23 were randomized to ethinyl estradiol/levonorgestrel. Mean sex hormone-binding globulin increased significantly in subjects using the desogestrel-containing contraceptive compared with the levonorgestrel-containing contraceptive. Ten subjects completed the 9 months of treatment in the levonorgestrel group and 11 completed the study in the desogestrel group. Mean free testosterone and 3alpha-androstanediol glucuronide decreased significantly in the group receiving ethinyl estradiol/desogestrel but not in the ethinyl estradiol/levonorgestrel group. Mean Ferriman-Gallwey scores decreased significantly in both treatment groups. Improvement in mean Ferriman-Gallwey score was 35.7 +/- 38.1% (p < 0.001) for the ethinyl estradiol/desogestrel arm and 33.4 +/- 27.3% (p < 0.001) for the ethinyl estradiol/levonorgestrel arm. There were no statistically significant differences found in the improvement of Ferriman-Gallwey scores between the two treatment arms, although the power to detect a difference was limited by the small sample size. CONCLUSIONS: Treatment of hirsute women with third generation OCs containing desogestrel results in a significant increase in sex hormone-binding globulin and decrease in free testosterone and 3alpha-androstanediol glucuronide. Both second and third generation OCs were clinically effective in treating hirsutism.

Similarity of fibroglandular breast tissue content measured from magnetic resonance and mammographic images and by a mathematical algorithm.

Women with high breast density (BD) have a 4- to 6-fold greater risk for breast cancer than women with low BD. We found that BD can be easily computed from a mathematical algorithm using routine mammographic imaging data or by a curve-fitting algorithm using fat and nonfat suppression magnetic resonance imaging (MRI) data. These BD measures in a strictly defined group of premenopausal women providing both mammographic and breast MRI images were predicted as well by the same set of strong predictor variables as were measures from a published laborious histogram segmentation method and a full field digital mammographic unit in multivariate regression models. We also found that the number of completed pregnancies, C-reactive protein, aspartate aminotransferase, and progesterone were more strongly associated with amounts of glandular tissue than adipose tissue, while fat body mass, alanine aminotransferase, and insulin like growth factor-II appear to be more associated with the amount of breast adipose tissue. Our results show that methods of breast imaging and modalities for estimating the amount of glandular tissue have no effects on the strength of these predictors of BD. Thus, the more convenient mathematical algorithm and the safer MRI protocols may facilitate prospective measurements of BD.

Increased secretion of amylin in women with polycystic ovary syndrome.

OBJECTIVE: To investigate amylin secretion in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, case-control study. SETTING: Academic institution. PATIENT(S): Twenty women with PCOS and 10 with ovulatory cycles who matched for body mass index. INTERVENTION(S): An oral glucose tolerance test was performed, and glucose, insulin, and amylin levels were measured at fasting and after glucose ingestion. The area under the curve for insulin, amylin, and glucose was calculated. Ten women with PCOS were treated with metformin and 10 women with rosiglitazone for 6 months. Amylin levels were measured before and after treatment. RESULT(S): Fasting amylin levels and amylin response to oral glucose were significantly increased in women with PCOS. At fasting, there was significant positive correlation between insulin and amylin levels both in women with PCOS and control subjects. After glucose ingestion, amylin response correlated with the glucose response in women with PCOS. Amylin levels decreased with metformin but not with rosiglitazone treatment. CONCLUSION(S): In women with PCOS, [1] there is increased secretion of amylin, [2] insulin and amylin secretion is coregulated in the fasting state, [3] after glucose ingestion, glucose levels regulate amylin release, and [4] the insulin-sensitizing agent metformin, but not rosiglitazone, reduces amylin secretion.

Peripubertal hyperinsulinemia upregulates phosphatidylinositol 3-kinase/akt pathway in rat ovaries.

OBJECTIVE: Polycystic ovary syndrome (PCOS) usually develops during peripuberty and is often associated with hyperinsulinemia. Paradoxically, hyperinsulinemic patients with PCOS develop peripheral insulin resistance but retain ovarian insulin sensitivity. We investigated the effect of peripubertal hyperinsulinemia on insulin signaling pathways in rat ovaries. METHODS: Hyperinsulinemia was induced in peripubertal female rats by infusing insulin (0.14 IU/day) for 4 weeks. Control animals received normal saline. At autopsy, trunk blood was collected for insulin assay; ovaries were collected for examining the effect of hyperinsulinemia on phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) and mitogen-activated protein kinase (MAPK/ERK1/2) pathways. RESULTS: Compared with control, ovarian protein levels of total Akt, phospho-Akt, and phospho-glycogen synthase kinase-3beta were upregulated and phospho-phosphatase and tensin homolog was downregulated in hyperinsulinemic animals. The MAPK/ERK1/2 pathway was unaffected. CONCLUSIONS: Peripubertal hyperinsulinemia upregulates the PI3-K/Akt pathway in rat ovaries. Ovarian insulin sensitivity in hyperinsulinemic patients with PCOS is potentially retained by this mechanism.

Extended culture of human spermatozoa in the laboratory may have practical value in the assisted reproductive procedures.

Spermatozoa were cultured in vitro to monitor time-dependent changes in motility, viability, morphology, and membrane integrity. The degree of preservation of these clinically relevant sperm parameters over time was satisfactory. Extended culture probably can be used as a transient storage for sperm to compensate for a male's inability to produce sperm to synchronize oocyte retrieval in assisted reproduction.

Effects of raloxifene on insulin sensitivity, beta-cell function, and hepatic insulin extraction in normal postmenopausal women.

OBJECTIVE: To investigate the effect of raloxifene on insulin sensitivity, beta-cell function, hepatic insulin clearance, and glucose tolerance in postmenopausal women. DESIGN: Prospective study. SETTING: University of Texas Medical Branch at Galveston, Texas. PATIENT(S): Twenty normal postmenopausal women. INTERVENTION(S): An oral glucose tolerance test (OGTT) was performed on all study participants before and after treatment with 60 mg of raloxifene daily for 3 months. Blood samples were obtained at baseline and 1, 2, and 3 hours after 75-g oral glucose administration for measurement of glucose, insulin, proinsulin, and c-peptide levels. Insulin tolerance test (ITT) and euglycemic clamp studies were also performed before and after treatment. MAIN OUTCOME MEASURE(S): Glucose and insulin area under curve (AUC) were calculated. The c-peptide to insulin ratio was determined to assess hepatic clearance of insulin. The homeostasis model assessment (HOMA) was used to calculate the index of insulin resistance (HOMA-IR) and beta-cell function (HOMA-%beta). Insulin sensitivity was assessed by insulin tolerance test and glucose infusion rate (GIR) during euglycemic clamp studies. RESULT(S): There was no change in fasting or AUC glucose levels. Fasting insulin levels were not statistically significantly different, but the insulin levels at 2 hours and insulin AUC were higher after treatment compared with before treatment. Proinsulin, c-peptide levels, and HOMA-%beta did not change. The c-peptide to insulin molar ratio was statistically significantly decreased after treatment. There was no change in insulin sensitivity. CONCLUSION(S): These results indicate that raloxifene has no adverse effect on insulin sensitivity or glucose tolerance, and it does not affect beta-cell function. After glucose load, raloxifene decreases hepatic insulin extraction and thus conserves insulin, which may be beneficial to patients with decreased beta-cell reserve or those predisposed to type 2 diabetes.