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author:("lansley, Bill")
1.  Continuously delivered ovarian steroids do not alter dendritic spine density or morphology in macaque dorsolateral prefrontal cortical neurons 
Neuroscience  2013;255:219-225.
Aged ovariectomized female monkeys, a model for menopause in humans, show declines in spine density in the dlPFC and diminished performance in cognitive tasks requiring this brain region. Previous studies in our laboratory have shown that long-term cyclic treatment with 17β-estradiol (E) produces an increase in spine density and in the proportion of thinner spines in layer III pyramidal neurons in the dorsolateral prefrontal cortex (dlPFC) of both young and aged ovariectomized rhesus monkeys. Here we used 3D reconstruction of Lucifer yellow-loaded neurons to investigate whether clinically relevant schedules of hormone therapy would produce similar changes in prefrontal cortical neuronal morphology as long-term cyclic E treatment in young female monkeys. We found that continuously delivered E, with or without a cyclic progesterone treatment, did not alter spine density or morphology in the dlPFC of young adult OVX rhesus monkeys. We also found that the increased density of thinner spines evident in the dlPFC 24 hours after E administration in the context of long-term cyclic E therapy is no longer detectable 20 days after E treatment. When compared with the results of our previously published investigations, our results suggest that cyclic fluctuations in serum E levels may cause corresponding fluctuations in the density of thin spines in the dlPFC. By contrast, continuous administration of E does not support sustained increases in thin spine density. Physiological fluctuations in E concentration may be necessary to maintain the morphological sensitivity of the dlPFC to E.
doi:10.1016/j.neuroscience.2013.09.062
PMCID: PMC3957098  PMID: 24120552
Hormone replacement therapy; aging; primate; menopause; dendritic spine; dorsolateral prefrontal cortex; Prefrontal cortex; estrogen; progesterone
2.  Multiple clinically-relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys 
Neurobiology of aging  2013;34(7):1882-1890.
Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of four HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex.
doi:10.1016/j.neurobiolaging.2012.12.017
PMCID: PMC3622837  PMID: 23369546
ovarian hormones; aging; macaque; learning; memory; prefrontal; temporal
3.  Dehydroepiandrosterone sulfate (DHEAS) levels reflect endogenous LH production and response to human chorionic gonadotropin (hCG) challenge in the older female macaque (Macaca fascicularis) 
Menopause (New York, N.Y.)  2013;20(3):329-335.
Hypothesis
We propose that the adrenal gland of an older higher primate female animal model will respond to a human chorionic gonadotropic (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically-castrated animals will provide proof-of-concept and a validated animal model for future studies to explore the rise of DHEAS during the menopausal transition of women.
Methods
Twenty four 18–26 y/o female cynomolgus monkeys were screened for ovarian function then either ovariectomized (n=4) or treated with a gonadotropic releasing hormone agonist (GnRHa) (n=20) to block ovarian steroid production. Following a recovery period from surgery or down-regulation, a single dose challenge (1,000 IU; IM) of human chorionic gonadotropin (hCG) was then administered in order to determine if LH/CG could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH and urinary metabolites of ovarian sex steroids were monitored before, during and following these treatments.
Results
Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days post administration of GnRHa. Urinary metabolites of estradiol and progesterone remained low following surgery or the flare reaction to GnRHa. Circulating DHEAS levels were increased following hCG administration and the increase in individual animals was proportional to the pre-treatment DHEAS baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to, and were increased by hCG challenge while no concomitant change was observed in ovarian steroid hormone excretion.
Conclusion
These data demonstrate a positive adrenal androgen response to LH/CG in older female higher primates and suggests a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon.
doi:10.1097/GME.0b013e3182698f80
PMCID: PMC3546135  PMID: 23435031
DHEAS; menopause; adrenal androgens; LH/hCG
4.  Modulation of Higher Primate Adrenal Androgen Secretion with Estradiol or Estradiol and Progesterone Intervention 
Menopause (New York, N.Y.)  2013;20(3):10.1097/GME.0b013e318273a070.
Background
Circulating adrenal steroids rise during the menopausal transition (MT) in most mid-aged women and may contribute to differences in between-woman symptoms as well as ultimate health outcomes. However, the mechanism(s) for this shift in adrenal steroid production in mid-aged women is not known.
Objective
To determine if hormone replacement therapy (HT) for one year can modulate adrenal androgen production.
Method
Younger (9.8 +/− 0.4 y/o, n=20) and older (22.7+/−0.4 y/o, n=37) female laboratory macaques were ovariectomized (OVX), and then each group was treated with different regimens of HT for up to one year. Changes in adrenal histology and circulating adrenal androgens were monitored following estradiol treatment alone (E) or estrogen plus progesterone (E+P), and these changes were compare to the same measures in similar aged animals given vehicle (V).
Results
Zona reticularis (ZR) area and serum dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were higher in younger compared to older V-treated animals (P< 0.02). Both E and E+P treatments decreased circulating DHEAS in the younger group (P<0.05). While E also decreased DHEAS in the older group, this was not statistically significant. In contrast, E+P treatment in the older group resulted in a rise in DHEAS over V, which was significantly higher than the results of E alone (p< 0.01). Circulating concentrations of DHEA exhibited similar trends but these changes did not reach statistical significance.
Conclusion
These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determines the adrenal response.
doi:10.1097/GME.0b013e318273a070
PMCID: PMC3610787  PMID: 23435030
Adrenal; Steroids; Hormone Therapy; Replacement
5.  Menopausal Transition Stage-Specific Changes in Circulating Adrenal Androgens 
Menopause (New York, N.y.)  2012;19(6):658-663.
Objective
It is now recognized that mean circulating DHEAS concentrations in most midlife women exhibit a positive inflection starting in the early perimenopause, continuing through the early post menopause and returning to early perimenopausal levels by late post menopause. This rise in mean DHEAS is accompanied by concomitant rises in testosterone (T), dehydroepiandrosteone (DHEA), androstenedione (Adione), and an equal rise androstenediol (Adiol). These observations suggest that there is a specific relationship between the circulating levels of steroids emanating from the adrenal, declining ovarian function and stages of the menopausal transition (MT). This study was designed to test the hypothesis that the menopausal stage-specific change in circulating DHEAS is associated with concomitant changes in the circulating pattern of adrenal steroids and that some of these adrenal androgens could influence the circulating estrogen/androgen balance.
Methods
Stored annual serum samples (n=120) were first selected to represent four longitudinal DS profiles of individual women in order to assess and compare changes in the adrenal contribution to circulating steroids.
Results
Changes in mean circulating DHEAS levels in midlife women during the MT is associated with changes in mean circulating Testosterone (T), androstendione (Adione), and androstenediol (Adiol). Mean Adione and T concentrations changed the least while mean DHEAS and Adiol changed the most.
Conclusion
Changes in circulating steroid hormone emanating from the adrenal during the menopausal transition may be more important than the decline of ovarian function in terms of altering the estrogen/androgen balance.
doi:10.1097/gme.0b013e31823fe274
PMCID: PMC3366025  PMID: 22415570
DHEAS; androstenediol; estrogen; estrogenicity; menopause; adrenal
6.  Androstenediol Complements Estrogenic Bioactivity during the Menopausal Transition 
Menopause (New York, N.y.)  2012;19(6):650-657.
Objective
The perimenopausal increase in circulating dehydroepiandrosterone sulfate (DHEAS) levels during the menopausal transition (MT) is accompanied by other adrenal steroids that have the potential to alter the estrogen/androgen balance and explain the wide inter-woman range of estrogen-related symptoms experienced during the MT.
Methods
Annual serum samples from the Study of Women’s Health Across the Nation (SWAN), which had previously been analyzed for immunoreactive estradiol (E2), testosterone (T), DHEAS and sex hormone binding globulin (SHBG), were selected based on DHEAS concentration and analyzed for immunoreactive and bioactive estrogens and androgens, including immunoreactive androstenedione (Adione), dehydroepiandrosterone (DHEA) and 5-androstene-3β,17β-diol (androstenediol, Adiol).
Results
A two-fold increase in circulating Adione and T was found to rise in parallel with the rise in circulating DHEAS, while DHEA and Adiol concentrations rose seven to eightfold. Circulating Adiol, which has both androgenic and estrogenic biological activity, was significantly associated (p<0.02) with circulating estrogen bioactivity only when E2 concentrations were low and Adiol levels were high.
Conclusions
The wide range of circulating levels of Adiol and its contribution to total circulating estrogenicity during the MT is consistent with the observed inter-woman difference in symptoms at this time. Therefore, we conclude that Adiol contributes to circulating estrogenicity when E2 production falls at menopause and may contribute significantly to the endocrine changes experienced by midlife women.
doi:10.1097/gme.0b013e31823df577
PMCID: PMC3366061  PMID: 22415563
Androstenediol; estrogenicity; menopause; adrenal
7.  Clinically relevant hormone treatments fail to induce spinogenesis in prefrontal cortex of aged female rhesus monkeys 
Preclinical animal models have provided strong evidence that estrogen therapy (ET) enhances cognition and induces spinogenesis in neuronal circuits. However, clinical studies have been inconsistent, with some studies revealing adverse effects of ET, including an increased risk of dementia. In an effort to bridge this disconnect between the preclinical and clinical data, we have developed a non-human primate (NHP) model of ET combined with high-resolution dendritic spine analysis of dorsolateral prefrontal cortical (dlPFC) neurons. Previously, we reported cyclic ET in aged, ovariectomized NHPs increased spine density on dlPFC neurons. Here, we report that monkeys treated with cyclic E treatment paired with cyclic progesterone (P), continuous E combined with P (either cyclic or continuous), or unopposed continuous E failed to increase spines on dlPFC neurons. Given that the most prevalent form of ET prescribed to women is a combined and continuous E and P, these data bring into convergence the human neuropsychological findings and preclinical neurobiological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models.
doi:10.1523/JNEUROSCI.1881-12.2012
PMCID: PMC3657730  PMID: 22915112
8.  Clinically Relevant Hormone Treatments Fail to Induce Spinogenesis in Prefrontal Cortex of Aged Female Rhesus Monkeys 
The Journal of Neuroscience  2012;32(34):11700-11705.
Preclinical animal models have provided strong evidence that estrogen (E) therapy (ET) enhances cognition and induces spinogenesis in neuronal circuits. However, clinical studies have been inconsistent, with some studies revealing adverse effects of ET, including an increased risk of dementia. In an effort to bridge this disconnect between the preclinical and clinical data, we have developed a nonhuman primate (NHP) model of ET combined with high-resolution dendritic spine analysis of dorsolateral prefrontal cortical (dlPFC) neurons. Previously, we reported cyclic ET in aged, ovariectomized NHPs increased spine density on dlPFC neurons. Here, we report that monkeys treated with cyclic E treatment paired with cyclic progesterone (P), continuous E combined with P (either cyclic or continuous), or unopposed continuous E failed to increase spines on dlPFC neurons. Given that the most prevalent form of ET prescribed to women is a combined and continuous E and P, these data bring into convergence the human neuropsychological findings and preclinical neurobiological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models.
doi:10.1523/JNEUROSCI.1881-12.2012
PMCID: PMC3657730  PMID: 22915112
9.  Circulating Dehydroepiandrosterone Sulfate Levels in Women with Bilateral Salpingo-Oophorectomy during the Menopausal Transition 
Menopause (New York, N.Y.)  2011;18(5):494-498.
Background
A rise in circulating dehydroepiandrosterone sulfate (DHEAS) concentration occurs during the menopausal transition (MT) that is ovarian-stage but not age-related. The objective of this study was to determine the source of the rise in circulating DHEAS.
Methods
Circulating DS concentrations in women that had undergone bilateral salpingo-oophorectomy (BSO) were compared to the pattern of circulating DHEAS in women that progressed through the MT naturally. Annual serum samples from the Study of Women's Health Across the Nation (SWAN) over a ten year study period were used. From1272 women in the SWAN cohort that were eligible for longitudinal evaluation of DHEAS annual samples, eighty one underwent BSO during the pre- or early-perimenopause stage of the menopausal transition and were potentially available for study. Of these eighty one BSO participants, twenty had sufficient annual samples for evaluation of the post-BSO trajectory of circulating DHEAS. SWAN women not having previous hormone replacement therapy those with intact ovaries were compared to women that underwent a BSO immediately after a pre- or early perimenopausal annual visit. There were no intervention and circulating concentrations of DHEAS was the main outcome.
Results
A detectable rise in DHEAS was observed in fourteen (70%) of the twenty BSO women which is similar to the proportion (85%) of women with intact ovaries that had a detectable DHEAS rise. The mean rise in DHEAS (5-8%) was similar in both BSO and non-BSO women.
Conclusion
The MT rise in DHEAS (5-8%) occurring in the absence of ovaries is largely of adrenal origin.
doi:10.1097/gme.0b013e3181fb53fc
PMCID: PMC3123411  PMID: 21178790
Dehydroepiandrosterone sulfate; menopause; adrenal; ovary
10.  Effects of Triclocarban on Intact Immature Male Rat 
Reproductive Sciences  2011;18(2):119-127.
Triclocarban (TCC; 3,4,4′-trichlorocarbanilide) is an antimicrobial agent used widely in various personal hygiene products including soaps. Recently, TCC has been shown to enhance testosterone-induced effects in vitro and to enlarge accessory sex organs in castrated male rats. This study was designed to evaluate the effects of TCC on intact age-matched male rats and on human prostate LNCaP and C4–2B cells. Seven-week-old male Sprague-Dawley rats received either a normal diet or a diet supplemented with TCC (0.25% in diet) for 10 days. Triclocarban induced hyperplasia of accessory sex organs in the absence of significant qualitative histological changes. Serum luteinizing hormone (LH) and testosterone were not significantly altered by TCC treatment. In prostate cancer-derived LNCaP and C4–2B cells, TCC potentiated androgen actions via androgen receptor-dependent actions. In conclusion, TCC significantly affects intact male reproductive organs and potentiates androgen effects in prostate cancer cells.
doi:10.1177/1933719110382581
PMCID: PMC3031453  PMID: 20889956
triclocarban; androgen receptor; luteinizing hormone; testosterone; endocrine-disrupting substance
11.  Reproductive Hormones and Obesity: 9 Years of Observation From the Study of Women's Health Across the Nation 
American Journal of Epidemiology  2010;171(11):1203-1213.
The effect of change in reproductive hormones and menopause on incident obesity (body mass index ≥30 kg/m2) and severe obesity (body mass index ≥35 kg/m2) was evaluated over 9 years in 3,260 US women recruited in the multiethnic Study of Women's Health Across the Nation in 1996–1997. After 9 years, cumulative incidences of obesity and severe obesity reached 21.8% and 12.3%, respectively. In multivariate analysis, hormone changes, chronic health conditions, lower physical activity, race/ethnicity, and age were significantly associated with incident obesity and/or severe obesity. The odds of incident severe obesity increased with surgical menopause (odds ratio (OR) = 5.07, 95% confidence interval (CI): 2.29, 11.20; P < 0.001) and initiation of hormone therapy prior to 12 months of amenorrhea (OR = 2.94, 95% CI: 1.14, 7.58; P = 0.03). Predictors of obesity included an increase in free androgen index (OR = 1.37, 95% CI: 1.12, 1.68; P = 0.002) and a decrease in sex hormone-binding globulin (OR = 0.60, 95% CI: 0.45, 0.80; P = 0.0005). Similar results were found for severe obesity. Obesity rates varied by race, but no hormone-by-race interactions were observed. These longitudinal data demonstrate that higher androgens, lower sex hormone-binding globulin, surgical menopause, and early hormone therapy use predict incident obesity and/or severe obesity in a multiracial cohort of women transitioning into menopause.
doi:10.1093/aje/kwq049
PMCID: PMC2915490  PMID: 20427327
hormones; menopause; obesity; reproduction
12.  Effects of triclocarban on intact immature male rat: augmentation of androgen action 
Triclocarban (TCC; 3,4,4′-trichlorocarbanilide) is an antimicrobial agent used widely in various personal hygiene products including soaps. Recently, TCC has been shown to enhance testosterone-induced effects in vitro and to enlarge accessory sex organs in castrated male rats. This study was designed to evaluate the effects of TCC on intact age matched male rats and on human prostate LNCaP and C4–2B cells. Seven-week old male Sprague-Dawley rats received either a normal diet or a diet supplemented with TCC (0.25% in diet) for ten days. TCC induced hyperplasia of accessory sex organs in the absence of significant qualitative histological changes. Serum LH and testosterone were not significantly altered by TCC treatment. In prostate cancer derived LNCaP and C4–2B cells, TCC potentiated androgen actions via androgen receptor-dependent actions. In conclusion, TCC significantly affects intact male reproductive organs and potentiates androgen effects in prostate cancer cells.
doi:10.1177/1933719110382581
PMCID: PMC3031453  PMID: 20889956
Triclocarban (TCC); androgen receptor (AR); Luteinizing hormone (LH); testosterone (T); endocrine-disrupting substance (EDS)
13.  Menopause and the Metabolic Syndrome 
Archives of internal medicine  2008;168(14):1568-1575.
Background
Cross-sectional studies suggest that prevalence of the metabolic syndrome (MetS) increases from premenopause to postmenopause in women, independent of age. Little is known about why. We hypothesized that the incidence of the MetS increases with progression through menopause and that this increase is explained by the progressive androgenicity of the hormonal milieu.
Methods
This longitudinal, 9-year study of 949 participants in the Study of Women’s Health Across the Nation investigates the natural history of the menopausal transition. Participants of 5 ethnicities at 7 geographic sites were recruited when they were premenopausal or early perimenopausal and were eligible for this study if they (1) reached menopause during the study; (2) had never taken hormone therapy, and (3) did not have diabetes mellitus or the MetS at baseline. The primary outcome was the presence of MetS using National Cholesterol Education Program Adult Treatment Panel III criteria. Secondary outcomes were the components of the MetS.
Results
By the final menstrual period, 13.7% of the women had new-onset MetS. Longitudinal analyses, centered at the final menstrual period, were adjusted for age at menopause, ethnicity, study site, marital status, education, body mass index, smoking, and aging. Odds of developing the MetS per year in perimenopause were 1.45 (95% confidence interval, 1.35-1.56); after menopause, 1.24 (95% confidence interval, 1.18-1.30). These odds were significantly different (P<.001). An increase in bioavailable testosterone or a decrease in sex hormone–binding globulin levels increased the odds.
Conclusions
As testosterone progressively dominates the hormonal milieu during the menopausal transition, the prevalence of MetS increases, independent of aging and other important covariates. This may be a pathway by which cardiovascular disease increases during menopause.
doi:10.1001/archinte.168.14.1568
PMCID: PMC2894539  PMID: 18663170
14.  Dietary fat subgroups, zinc and vegetable components are related to urine F2a-isoprostane concentration, a measure of oxidative stress, in midlife women1 
The Journal of nutrition  2007;137(11):2412-2419.
Smoking, diet and physical activity may impact chronic diseases, in part, by promoting or attenuating oxidative stress. We evaluated associations between lifestyle factors and urine F2a-isoprostanes, a marker of oxidative stress among 1610 participants of Study of Women’s Health Across the Nation (SWAN). Dietary intake and physical activity were assessed at baseline and year 05 (Y05). These data were related to Y05 urinary F2a-isoprostane concentration with regression analyses. Median urine F2a-isoprostane concentration was 433 ng/L overall, 917 ng/L in smokers (inter-quartile range: 467, 1832 ng/L) and 403 ng/L in non-smokers (inter-quartile range: 228, 709 ng/L; P<0.0001 for difference). Higher trans fat intake was associated with higher urine F2a-isoprostane concentration; partial Spearman correlations (ρx|y) between Y05 urine F2a-isoprostane concentration and trans fatty acids were 0.19 (P=0.03) and 0.13 (P <0.0001) in smokers and non-smokers, respectively. Increased log trans fat intake from baseline to Y05 was associated with higher concentration of logurine F2a-isoprostanes in non-smokers (β=0.131, SE=0.04, P =0.0003). In non-smokers, the partial correlation (ρx|y) between lutein and urine F2a-isoprostane concentration was −0.13 (P <0.0001). Increased intake of log lutein from baseline to Y05 was also associated with lower log urine F2a-isoprostane concentration (β= −0.096, SE=0.03, P =0.0005) in non-smokers. Increased zinc intake from baseline to Y05 was associated with lower log urine F2a-isoprostane concentration in smokers and non-smokers (β= −0.346, SE=0.14, P =0.01), and −0.117, 0.04 (P =0.001), respectively]. In conclusion, diet (fat subtypes, zinc, vegetable components) and smoking were associated with urine F2a-isoprostanes, a marker of oxidative stress.
PMCID: PMC2730459  PMID: 17951478
diet; physical activity; cigarette smoking; isoprostanes; oxidative stress
15.  Estrogen metabolites and their relation to isoprostanes as a measure of oxidative stress 
Clinical endocrinology  2007;68(5):806-813.
Objective:
Estradiol (E2) and its metabolites [2-hydroxyestrone (2-OHE1) and 16α-hydroxyestrone (16α-OHE1)] are believed to curtail greater oxidative stress found in the development and progression of disease conditions including atherosclerosis. We related estrogen levels to F2a-isoprostane levels, a biomarker of oxidative stress.
Design and Participants:
Data were from 1647 women, aged 47-57 years, participating in the 5th annual follow-up of the Study of Women's Health Across the Nation (SWAN), a study of the menopausal transition.
Measurements:
Serum E2 and urinary 2-OHE1 and 16α-OHE1 concentrations were assayed by ELISA while urinary F2a-isoprostanes were assayed by EIA.
Results:
F2a-isoprostane concentrations were elevated in women who smoked, a behavior associated with increased oxidative stress, but not in stages of the natural menopause. Mean F2a-isoprostane concentrations among premenopausal and postmenopausal women who smoked were 1082 and 1064 pg/mL, respectively, values double those in premenopausal (343 pg/mL) and postmenopausal (379 pg/mL) non-smoking women. 2-OHE1 and F2a-isoprostane concentrations were positively and highly related [partial correlations ρY|X = 0.44 and ρY|X = 0.43 in premenopausal and postmenopausal women, respectively]. Likewise, 16α-OHE1 concentrations were positively and highly correlated with F2a-isoprostane concentrations [ρY|X = 0.52 and ρY|X = 0.59 in premenopausal and postmenopausal women, respectively]. E2 was significantly correlated with F2a-isoprostanes only in postmenopausal women [ρY|X = 0.20]. Associations were adjusted for age, body mass index, race/ethnicity, lipids, physical activity level, and alcohol consumption.
Conclusions:
This study does not support the commonly-held hypothesis that levels of endogenous estradiol or its estrone metabolites favorably modify oxidative stress by decreasing F2a-isoprostane levels.
doi:10.1111/j.1365-2265.2007.03108.x
PMCID: PMC2727613  PMID: 17980014
isoprostanes; estrogen; oxidative stress; antioxidant; smoking
16.  Levels of sex steroid and CVD measures in premenopausal and hormone-treated women at mid-life: implications for the “timing hypothesis” 
Archives of internal medicine  2008;168(19):2146-2153.
Background
The “timing hypothesis”, in addressing findings from the Women’s Health Initiative trial, suggests that hormone therapy (HT) use should be initiated within six years of the menopause transition to extend a favorable estrogenic environment after menopause.
Methods
We compared sex steroid and cardiovascular profiles at visit 05 in a community-based, longitudinal study of the menopause transition (Study of Women’s Health Across the Nation). Women, aged 47–57 years, were in one of four groups: premenopausal, using conjugated equine estrogen (CEE) with or without progestin, or postmenopausal (<5 years). Cardiovascular assays included low density lipoprotein cholesterol (LDL-c), oxidized LDL-c, high density lipoprotein cholesterol (HDL-c), triglycerides, apolipoproteins A-1 and B, F2a-isoprostanes, C-reactive protein (CRP), and lipoprotein(a)-1. Sex steroid assays were for estradiol (E2), estrogen receptor ligand load (ERLL), 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), total testosterone, and sex hormone-binding globulin (SHBG).
Results
HT users had 50% higher SHBG levels (p<0.0001 for both groups), which limits sex steroids binding to their receptors, and higher excreted estrone metabolites (more than 60%, p<0.0001 for both groups) than pre- or postmenopausal women. These were, in turn, associated with higher F2a-isoprostanes, an oxidative stress measure, compared to premenopausal women. HT users had a more favorable HDL-c/LDL-c ratio than pre- or postmenopausal women (p<0.01), but higher triglyceride levels (p<0.01).
Conclusions
Though HT users had some more favorable lipid profiles than pre- and postmenopausal women, there was evidence of adverse HT effects even in women free of atherosclerosis evaluated within the approximate 6-year time period proposed with the “timing hypothesis”.
doi:10.1001/archinte.168.19.2146
PMCID: PMC2727614  PMID: 18955645
hormone therapy; conjugated equine estrogens (CEE); estrogen; cardiovascular disease; lipids; sex hormone binding globulin
17.  In Vitro Biologic Activities of the Antimicrobials Triclocarban, Its Analogs, and Triclosan in Bioassay Screens: Receptor-Based Bioassay Screens 
Environmental Health Perspectives  2008;116(9):1203-1210.
Background
Concerns have been raised about the biological and toxicologic effects of the antimicrobials triclocarban (TCC) and triclosan (TCS) in personal care products. Few studies have evaluated their biological activities in mammalian cells to assess their potential for adverse effects.
Objectives
In this study, we assessed the activity of TCC, its analogs, and TCS in in vitro nuclear-receptor–responsive and calcium signaling bioassays.
Materials and methods
We determined the biological activities of the compounds in in vitro, cell-based, and nuclear-receptor–responsive bioassays for receptors for aryl hydrocarbon (AhR), estrogen (ER), androgen (AR), and ryanodine (RyR1).
Results
Some carbanilide compounds, including TCC (1–10 μM), enhanced estradiol (E2)-dependent or testosterone-dependent activation of ER- and AR-responsive gene expression up to 2.5-fold but exhibited little or no agonistic activity alone. Some carbanilides and TCS exhibited weak agonistic and/or antagonistic activity in the AhR-responsive bioassay. TCS exhibited antagonistic activity in both ER- and AR-responsive bioassays. TCS (0.1–10 μM) significantly enhanced the binding of [3H]ryanodine to RyR1 and caused elevation of resting cytosolic [Ca2+] in primary skeletal myotubes, but carbanilides had no effect.
Conclusions
Carbanilides, including TCC, enhanced hormone-dependent induction of ER- and AR-dependent gene expression but had little agonist activity, suggesting a new mechanism of action of endocrine-disrupting compounds. TCS, structurally similar to noncoplanar ortho-substituted poly-chlorinated biphenyls, exhibited weak AhR activity but interacted with RyR1 and stimulated Ca2+ mobilization. These observations have potential implications for human and animal health. Further investigations are needed into the biological and toxicologic effects of TCC, its analogs, and TCS.
doi:10.1289/ehp.11200
PMCID: PMC2535623  PMID: 18795164
androgen receptor; antimicrobial; aryl hydrocarbon receptor; bioactivity; carbanilide analog; estrogen receptor; ryanodine receptor; sensitization; signal amplification; triclocarban; triclosan
19.  Cigarette Smoking and Effects on Hormone Function in Premenopausal Women 
Environmental Health Perspectives  2005;113(10):1285-1290.
Cigarette smoke contains compounds that are suspected to cause reproductive damage and possibly affect hormone activity; therefore, we examined hormone metabolite patterns in relation to validated smoking status. We previously conducted a prospective study of women of reproductive age (n = 403) recruited from a large health maintenance organization, who collected urine daily during an average of three to four menstrual cycles. Data on covariates and daily smoking habits were obtained from a baseline interview and daily diary, and smoking status was validated by cotinine assay. Urinary metabolite levels of estrogen and progesterone were measured daily throughout the cycles. For the present study, we measured urinary levels of the pituitary hormone follicle-stimulating hormone (FSH) in a subset of about 300 menstrual cycles, selected by smoking status, with the time of transition between two cycles being of primary interest. Compared with nonsmokers, moderate to heavy smokers (≥ 10 cigarettes/day) had baseline levels (e.g., early follicular phase) of both steroid metabolites that were 25–35% higher, and heavy smokers (≥ 20 cigarettes/day) had lower luteal-phase progesterone metabolite levels. The mean daily urinary FSH levels around the cycle transition were increased at least 30–35% with moderate smoking, even after adjustment. These patterns suggest that chemicals in tobacco smoke alter endocrine function, perhaps at the level of the ovary, which in turn effects release of the pituitary hormones. This endocrine disruption likely contributes to the reported associations of smoking with adverse reproductive outcomes, including menstrual dysfunction, infertility, and earlier menopause.
doi:10.1289/ehp.7899
PMCID: PMC1281267  PMID: 16203235
cigarette smoking; endocrine disruption; estrogen; follicle-stimulating hormone; hormones; menstrual dysfunction; progesterone; steroids; women’s health
20.  Effect of Environmental Tobacco Smoke on Levels of Urinary Hormone Markers 
Environmental Health Perspectives  2005;113(4):412-417.
Our recent study showed a dose–response relationship between environmental tobacco smoke (ETS) and the risk of early pregnancy loss. Smoking is known to affect female reproductive hormones. We explored whether ETS affects reproductive hormone profiles as characterized by urinary pregnanediol-3-glucuronide (PdG) and estrone conjugate (E1C) levels. We prospectively studied 371 healthy newly married nonsmoking women in China who intended to conceive and had stopped contraception. Daily records of vaginal bleeding, active and passive cigarette smoking, and daily first-morning urine specimens were collected for up to 1 year or until a clinical pregnancy was achieved. We determined the day of ovulation for each menstrual cycle. The effects of ETS exposure on daily urinary PdG and E1C levels in a ±10 day window around the day of ovulation were analyzed for conception and nonconception cycles, respectively. Our analysis included 344 nonconception cycles and 329 conception cycles. In nonconception cycles, cycles with ETS exposure had significantly lower urinary E1C levels (β= –0.43, SE = 0.08, p < 0.001 in log scale) compared with the cycles without ETS exposure. There was no significant difference in urinary PdG levels in cycles having ETS exposure (β= –0.07, SE = 0.15, p = 0.637 in log scale) compared with no ETS exposure. Among conception cycles, there were no significant differences in E1C and PdG levels between ETS exposure and nonexposure. In conclusion, ETS exposure was associated with significantly lower urinary E1C levels among nonconception cycles, suggesting that the adverse reproductive effect of ETS may act partly through its antiestrogen effects.
doi:10.1289/ehp.7436
PMCID: PMC1278480  PMID: 15811831
environmental tobacco smoke; estrone conjugates (E1C); pregnanediol-3-glucuronide (PdG); prospective study; urinary hormone levels
21.  Bone resorption is affected by follicular phase length in female rotating shift workers. 
Environmental Health Perspectives  2003;111(4):618-622.
Stressors as subtle as night work or shift work can lead to irregular menstrual cycles, and changes in reproductive hormone profiles can adversely affect bone health. This study was conducted to determine if stresses associated with the disruption of regular work schedule can induce alterations in ovarian function which, in turn, are associated with transient bone resorption. Urine samples from 12 rotating shift workers from a textile mill in Anqing, China, were collected in 1996-1998 during pairs of sequential menstrual cycles, of which one was longer than the other (28.4 vs. 37.4 days). Longer cycles were characterized by a prolonged follicular phase. Work schedules during the luteal-follicular phase transition (LFPT) preceding each of the two cycles were evaluated. All but one of the shorter cycles were associated with regular, forward phase work shift progression during the preceding LFPT. In contrast, five longer cycles were preceded by a work shift interrupted either by an irregular shift or a number of "off days." Urinary follicle-stimulating hormone levels were reduced in the LFPT preceding longer cycles compared with those in the LFPT preceding shorter cycles. There was greater bone resorption in the follicular phase of longer cycles than in that of shorter cycles, as measured by urinary deoxypyridinoline. These data confirm reports that changes in work shift can lead to irregularity in menstrual cycle length. In addition, these data indicate that there may be an association between accelerated bone resorption in menstrual cycles and changes of regularity in work schedule during the preceding LFPT.
PMCID: PMC1241454  PMID: 12676625
22.  Detection of xenoestrogens in serum after immunoprecipitation of endogenous steroidal estrogens. 
Environmental Health Perspectives  2002;110(8):791-795.
In this article we report a simple and efficient method for detecting nonsteroidal estrogens in a biologic sample. This method uses polyclonal antibodies to estradiol (E2) to immunoprecipitate these major biologically active steroidal estrogens, leaving behind the nonsteroidal estrogens, which are then detected in a cell-based transcriptional activation bioassay for estrogen receptor agonist. The immunoprecipitation method efficiently removed 99% of radiolabeled E2 and estrone (E1) from human serum. In experiments in which supraphysiologic concentrations of E2 and E1 to human serum, all of the immunoreactive estrogens were still removed by the immunoprecipitation protocol. We carried out an in vivo validation study of this method in which we treated female macaques with the xenoestrogen nonylphenol (NP), during the late follicular phase of the menstrual cycle. We used blood samples collected before and after treatment to evaluate and characterize endogenous and exogenous serum estrogens. An immunoassay for E2 did not detect the NP in treated monkeys. The cell-based bioassay also did not detect the estrogenic activity of NP because of its saturation by the endogenous serum steroidal estrogens. However, when steroidal estrogens were removed by immunoprecipitation, we detected the estrogenic activity of NP in the bioassay. Thus, this approach is appropriate for detecting exogenous, nonsteroidal estrogens in serum samples.
PMCID: PMC1240950  PMID: 12153760

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