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1.  Reduced-Calorie Dietary Weight Loss, Exercise, and Sex Hormones in Postmenopausal Women: Randomized Controlled Trial 
Journal of Clinical Oncology  2012;30(19):2314-2326.
Estrogens and androgens are elevated in obesity and associated with increased postmenopausal breast cancer risk, but the effect of weight loss on these biomarkers is unknown. We evaluated the individual and combined effects of a reduced-calorie weight loss diet and exercise on serum sex hormones in overweight and obese postmenopausal women.
Patients and Methods
We conducted a single-blind, 12-month, randomized controlled trial from 2005 to 2009. Participants (age 50 to 75 years; body mass index > 25.0 kg/m2, exercising < 100 minutes/wk) were randomly assigned using a computer-generated sequence to (1) reduced-calorie weight loss diet (“diet”; n = 118), (2) moderate- to vigorous-intensity aerobic exercise (“exercise”; n = 117), (3) combined reduced-calorie weight loss diet and moderate- to vigorous-intensity aerobic exercise (“diet + exercise”; n = 117), or (4) control (n = 87). Outcomes were estrone concentration (primary) and estradiol, free estradiol, total testosterone, free testosterone, androstenedione, and sex hormone–binding globulin (SHBG) concentrations (secondary).
Mean age and body mass index were 58 years and 30.9 kg/m2, respectively. Compared with controls, estrone decreased 9.6% (P = .001) with diet, 5.5% (P = .01) with exercise, and 11.1% (P < .001) with diet + exercise. Estradiol decreased 16.2% (P < .001) with diet, 4.9% (P = .10) with exercise, and 20.3% (P < .001) with diet + exercise. SHBG increased 22.4% (P < .001) with diet and 25.8% (P < .001) with diet + exercise. Free estradiol decreased 21.4% (P < .001) with diet and 26.0% (P < .001) with diet + exercise. Free testosterone decreased 10.0% (P < .001) with diet and 15.6% (P < .001) with diet + exercise. Greater weight loss produced stronger effects on estrogens and SHBG.
Weight loss significantly lowered serum estrogens and free testosterone, supporting weight loss for risk reduction through lowering exposure to breast cancer biomarkers.
PMCID: PMC3675691  PMID: 22614972
A considerable number of postmenopausal women who receive estrogen therapy (ET) are also treated for hypercholesterolemia with cholesterol-lowering statins. Statins and steroid hormones can compete for the same steroid-metabolizing enzymes. We investigated whether long-term administration of statins had an effect on serum estrogen and androgen levels in postmenopausal women receiving and not receiving oral ET.
A subgroup analysis from the Estrogen in the Prevention of Atherosclerosis Trial, a randomized, double-blind, placebo-controlled trial, was performed. A total of 222 women were randomized to receive either placebo or 1 mg of oral micronized E2 daily for 2 years. In both the placebo and treatment groups, participants with LDL-cholesterol levels >160 mg/dL were treated with statins. Blood samples were obtained at baseline and every 6 months during the trial. Serum levels of DHEA, androstenedione, testosterone, estrone and E2 were measured by RIA.
Among 86 placebo- and 90 estradiol-treated subjects with baseline and on-trial hormone measurements, no significant differences were observed between the statin-free and statin-treated groups in mean changes from baseline to on-trial levels in any of the androgens or estrogens, whether or not the postmenopausal women were treated with estrogen.
The results suggest that ET and statins can be used simultaneously with no deleterious effects on circulating hormone levels.
PMCID: PMC3105754  PMID: 20450412
statins; estrogen therapy; estrogens; androgens; postmenopausal women
3.  Serum 25 HydroxyVitamin D Concentrations and the Risk of Hip Fractures: The Women's Health Initiative 
Annals of internal medicine  2008;149(4):242-250.
The association between and vitamin D levels and fractures is uncertain.
To test the hypothesis that serum 25-hydroxyVitamin D (25(OH) vitamin D) levels are associated with the risk of hip fracture in community dwelling women.
Nested case-control study.
40 US clinical centers.
We studied 400 cases of incident hip fractures and 400 controls matched on age, race/ethnicity and date of blood draw (average follow-up time, 7.1 years). Subjects were selected from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies.
Serum 25(OH) vitamin D was measured on baseline serum using radioimmunoassay with DiaSorin reagents and divided into quartiles. Conditional logistic regression was used to estimate the odds ratio with 95% confidence intervals (CI). Multivariable models included age, body mass index, parental and personal history of fractures, smoking, alcohol and calcium intake, geographic location and corticosteroid use.
The mean (standard deviation, SD) 25(OH) vitamin D (nM) was lower in cases, 56.2(20.3) compared to controls, 59.7(18), p=0.007. A 25 nM (10ng/ml) decrease in 25(OH) vitamin D was associated with a 33% increased risk of hip fracture (odds ratio=1.33; 95%CI,1.06, 1.68) in multivariable models. Compared to women with 25(OH) vitamin D ≥70.7 nM (Quartile 4), the odds ratio of hip fracture was 1.71 (1.05, 2.79), 1.09 (0.70, 1.71) and 0.82 (0.51, 1.31) in women with 25(OH) vitamin D <47.5 nM, 47.5 to 60 nM, 60 to <70 nM, respectively, p trend =0.015. This association was in part mediated by a marker of bone resorption but remained statistically significant. Adjustment for falls, physical function, frailty, renal function, or sex steroid hormones had no effect on this association.
No measure of bone density.
Low serum 25(OH) vitamin D concentrations are associated with a higher risk of hip fracture. Measurement of 25(OH) vitamin D may be useful in identifying women at high risk of hip fracture.
PMCID: PMC2743412  PMID: 18711154
4.  Effect of protease inhibitors on steady state pharmacokinetics of oral norethindrone contraception in HIV infected women 
Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV infected women.
Methods and design
We conducted an open-label, prospective, non-randomized trial to characterize the steady-state pharmacokinetics of serum NET in HIVinfected women receiving PI compared to a control group of HIVinfected women receiving other non interacting drugs. Following 21 days of NET 0.35 mg ingestion once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation.
Thirty-five women were enrolled, two withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half life, and maximum concentration were not significantly different between the two groups. Minimum concentration of NET was significantly higher in the PI group (p=0.01). The ratio of the geometric mean NET area under the curve in the PI group compared to controls was 1.5 (90% confidence interval 1.21-1.86). NET serum concentrations are significantly higher in HIVinfected women taking a PI compared to controls (p=0.004).
Co-administration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports increased utilization of progestin only pills in HIV infected women receiving certain PI regimens.
PMCID: PMC3946363  PMID: 24025339
HIV; hormonal contraception; protease inhibitor; progestin only pills; norethindrone; pharmacokinetics; contraception; drug interaction; efficacy
5.  Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women 
Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR −/−) participating in a breast cancer case-control study. We also measured the same steroid hormones, as well as estrone sulfate, and SHBG in serum from these patients and 100 controls matched on ages at blood collection and on menopause.
Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER−/PR− breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER−/PR− breast cancer, although differences were only significant for testosterone.
These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER−/PR− breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.
PMCID: PMC4159754  PMID: 21870130
sex steroid hormone; breast adipose; breast cancer; intratissue; hormone receptor
7.  Circulating adipokine levels and endometrial cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively.
We conducted a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n=78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of adiponectin, leptin and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels.
Adiponectin levels were inversely associated with risk of endometrial cancer [OR T3vsT1=0.48 (95%CI: 0.29-0.80); p-trend<0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60-4.79); p-trend<0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.27 (0.09-0.80); p-trend=0.01 and 4.29 (1.07-17.15); p-trend=0.02, respectively]. Non-significant positive associations were observed for visfatin.
Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT.
Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association.
PMCID: PMC3819202  PMID: 23696194
endometrial cancer risk; adiponectin; leptin; visfatin; obesity
8.  Psychological reactivity to laboratory stress is associated with hormonal responses in postmenopausal women 
The present study examined associations between psychological reactivity and hormonal responses to a standardized laboratory stressor (the Trier Social Stress Test [TSST]) in postmenopausal women.
Forty postmenopausal women ages 50–74 completed anxiety and mood assessments prior to and following the TSST. Blood samples were drawn across multiple time points for assessment of cortisol, adrenocorticotropic hormone (ACTH), and DHEA.
As expected, significant increases in anxiety and negative affect and decreases in positive affect were observed from pre- to post-TSST; however, the magnitude of change in anxiety and mood varied considerably across individuals. Analyses indicated that greater increases in anxiety and negative affect from pre- to post-TSST were associated with higher levels of cortisol, ACTH, and DHEA, controlling for race, age, body mass index, and smoking status. Changes in positive affect were not associated with cortisol, ACTH, or DHEA.
These findings suggest that enhanced reactivity to stress is associated with higher hormone levels among postmenopausal women, which could have potential implications for health.
PMCID: PMC4046251  PMID: 24595153
Trier Social Stress Test; anxiety; negative affect; cortisol; DHEA; ACTH
9.  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.
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.
To determine if hormone replacement therapy (HT) for one year can modulate adrenal androgen production.
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).
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.
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.
PMCID: PMC3610787  PMID: 23435030
Adrenal; Steroids; Hormone Therapy; Replacement
10.  Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study 
Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.
PMCID: PMC3939005  PMID: 24596595
Circulating levels; Hispanics; genetic polymorphisms; SNPs; genotype-phenotype correlation; vitamin D
11.  Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users 
Contraception  2012;87(2):220-226.
Pharmacokinetic (PK) parameters based on short sampling times (48 h or less) may contain inaccuracies due to their dependency on extrapolated values. This study was designed to measure PK parameters with greater accuracy in obese users of a low-dose oral contraceptive (OC), and to correlate drug levels with assessments of end-organ activity.
Study design
Obese (BMI ≥30 kg/m2), ovulatory, otherwise healthy, women (n = 32) received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) for two cycles. EE and LNG PK parameters were characterized for 168 h at the end of Cycle 1. During Cycle 2, biweekly outpatient visits were performed to assess cervical mucus, monitor ovarian activity with transvaginal ultrasound, and obtain serum samples to measure EE, LNG, estradiol (E2), and progesterone (P) levels. PK parameters were calculated and correlated with end-organ activity and compared against control samples obtained from normal and obese women sampled up to 48 h in a previous study. Standard determination of PK accuracy was performed; defined by the dependency on extrapolated values (‘excess’ area under the curve of 25% or less).
The mean BMI was 39.4 kg/m2 (SD 6.6) with a range of 30–64 kg/m2. Key LNG PK parameters were as follows: clearance 0.52 L/h (SD 0.24), half-life 65 h (SD 40), AUC 232 h*ng/mL (SD 102) and time to reach steady-state 13.6 days (SD 8.4). The majority of subjects had increased ovarian activity with diameter of follicles ≥8 mm (n = 25) but only seven women had follicles ≥10 mm plus cervical mucus scores ≥5. Evidence of poor end-organ suppression did not correlate with the severity of the alterations in PK. As compared to historical normal and obese controls (48 h PK sampling), clearance, half-life, area under the curve (AUC) and time to reach steady-state were found to be significantly different (p ≤ 0.05) in obese women undergoing a longer duration of PK sampling (168 h). Longer sampling also improved PK accuracy for obese women (excess AUC 20%) as compared to both normal and obese controls undergoing shorter sampling times (48 h) with excess AUCs of 25% and 50%, respectively.
Obesity results in significant alterations in OC steroid PK parameters but the severity of these alterations did not correlate with end-organ suppression. A longer PK sampling interval (168 h vs. 48 h) improved the accuracy of PK testing.
PMCID: PMC3925642  PMID: 23153898
12.  Sleep duration, spot urinary 6-sulfatoxymelatonin levels and risk of breast cancer among Chinese women in Singapore 
We previously reported an inverse association between sleep duration and breast cancer risk in the prospective, population-based Singapore Chinese Health Study (SCHS) cohort (Wu et al., Carcinogenesis 2008;29:1244–8). Sleep duration was significantly positively associated with 6-sulfatoxymelatonin (aMT6s) levels determined in a spot urine, but aMT6s levels in breast cancer cases were lacking (Wu et al., Carcinogenesis 2008;29:1244–8). We updated the sleep duration–breast cancer association with 14 years of follow-up of 34,028 women in the SCHS. In a nested case–control study conducted within the SCHS, randomly timed, prediagnostic urinary aMT6s concentrations were compared between 248 incident breast cancer and 743 individually matched cohort controls. Three female controls were individually matched to each case on age at baseline interview (within 3 years), dialect group, menopausal status, date of baseline interview (within 2 years), date of urine sample collection (within 6 months) and timing of urine collection during the day (within 1 hr). Cox proportional hazards and conditional regression models with appropriate adjustment for confounders were used to examine the sleep– and aMT6s–breast cancer relationships. Breast cancer risk was not significantly associated with sleep duration; adjusted odds ratio (OR) for 9+ vs. ≤6 hr is 0.89 [95% confidence interval (95% CI) 5 0.64–1.22]. Prediagnostic aMT6s levels did not differ between breast cancer cases and matched controls; adjusted OR for highest versus lowest quartiles is 1.00 (95% CI 5 0.64-1.54). We conclude that sleep duration is not significantly associated with breast cancer risk reduction. Melatonin levels derived from randomly timed spot urine are unrelated to breast cancer. Randomly timed, spot urine-derived melatonin levels are noninformative as surrogates of nocturnal melatonin production.
PMCID: PMC3477268  PMID: 22644618
sleep duration; spot urinary melatonin; breast cancer; prospective; Singaporean Chinese
Fertility and sterility  2012;99(2):599-604.
To determine the impact of ovary-secreted products on adrenocortical function in women with PCOS by studying the adrenocortical response to acute adrenocorticotropic-stimulating hormone (ACTH) stimulation before and after bilateral oophorectomy.
Prospective study.
Tertiary care medical center
Fourteen women with PCOS scheduled for bilateral oophorectomy for benign indications, on transdermal estradiol (E2) postoperatively.
Physical exam, blood sampling before and after oophorectomy, measurement of hormone levels. Basal (Steroid0), maximum stimulated (Steroid60), and net increment (ΔSteroid) levels of androstenedione (A4), dehydroepiandrosterone (DHEA), and cortisol (F) before and after ACTH-1–24 stimulation were assessed.
Main Outcome Measures
Pre- and post-operative basal and ACTH(1–24)-stimulated hormonal levels.
Total testosterone, free testosterone, and estrone levels decreased, and FSH levels increased significantly following oophorectomy. No significant differences in E2, DHEA sulfate (DHEAS) or sex hormone binding globulin levels were detected. Basal and ACTH-stimulated A4 levels decreased significantly following oophorectomy, and ΔA4 was significantly increased. No significant differences in DHEA0, DHEA60, or F0 levels were detected; F60 and ΔF levels tended to increase following oophorectomy, but the differencesdid not reach significance.
Ovarian factors do not appear to contribute significantly to the adrenocortical dysfunction of PCOS.
PMCID: PMC3563739  PMID: 23122827
Polycystic ovary syndrome; adrenal androgen; oophorectomy
14.  Individual Variations in Serum Melatonin Levels through Time: Implications for Epidemiologic Studies 
PLoS ONE  2013;8(12):e83208.
Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36±0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83±0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02±1.25 pg/ml, p = 0.007) compared to never (6.66±0.66 pg/ml) and former (5.59±0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding.
PMCID: PMC3871612  PMID: 24376664
Endocrine  2012;42(3):726-735.
We determined the effect of chronic androgen suppression on inflammation in women with Polycystic Ovary Syndrome (PCOS) compared to weight-matched controls.
We performed a pilot project using samples from previous prospective, controlled studies. Nine women with PCOS (5 obese, 4 lean) and 9 ovulatory controls (5 obese, 4 lean) participated in the study. Androgens, C-reactive protein (CRP), interleukin-6 (IL-6), free fatty acids (FFA) and body weight were measured before and after 3 and 6 months of gonadotropin releasing hormone (GnRH) agonist administration.
GnRH agonist treatment decreased estradiol, testosterone and androstenedione to similar levels in all subjects. CRP and IL-6 increased in obese women with PCOS, was unaltered in lean women with PCOS and obese controls, and decreased in lean controls after 6 months of treatment. FFA decreased and body weight increased in obese women with PCOS, but did not change significantly in lean women with PCOS and in either control group after 6 months of treatment. The testosterone reduction was related to increases in weight and IL-6. The fall in FFA was related to the rise in CRP. The increases in weight and IL-6 were related to the rise in CRP.
We propose that hyperandrogenism in PCOS may exert an anti-inflammatory effect when obesity is present, but may not promote inflammation in the disorder; and that circulating androgens have a pleiotropic effect on inflammation depending on the combination of PCOS and weight status in a given individual.
PMCID: PMC3488360  PMID: 22752961
androgens; inflammation; adiposity; lypolysis
16.  Daidzein-metabolizing phenotypes in relation to bone density and body composition among premenopausal women in the United States 
Metabolism: clinical and experimental  2012;61(12):1678-1682.
Bone density has been suggested as a marker of cumulative hormone exposure. Small studies also suggest that patterns of daidzein metabolism may be related to hormone concentrations. To our knowledge, no studies in premenopausal women have compared bone density by daidzein-metabolizing phenotypes in the absence of a soy intervention.
To evaluate the relationship between daidzein-metabolizing phenotypes [equol and O-desmethylangolensin (ODMA) production] and bone density and body composition in premenopausal women in the United States.
Two hundred and three women attended a clinic visit during which their bone density and body composition was measured by DXA, and 200 (99 %) provided a urine sample following a 3-day soy challenge. Samples were analyzed for isoflavones to determine daidzein-metabolizing phenotypes.
In adjusted analyses, there were no differences in hip, spine, femoral neck, or head bone mineral density (BMD) or body composition between producers and non-producers of either equol or ODMA (p > 0.05).
In this population of low-soy consuming premenopausal women, there were no associations between daidzein-metabolizing phenotypes and hip, spine, femoral neck, or head BMD or body composition, suggesting that these phenotypes per se do not influence premenopausal bone density or body composition.
PMCID: PMC3504616  PMID: 22819530
equol; isoflavones; O-desmethylangolensin; soy challenge
17.  Antimüllerian Hormone as a Predictor of Natural Fecundability in Women Aged 30–42 Years 
Obstetrics and gynecology  2011;117(4):10.1097/AOG.0b013e3182116bc8.
To generate estimates of the association between markers of ovarian aging and natural fertility in a community sample at risk for ovarian aging.
Women aged 30–44 years with no history of infertility who had been trying to conceive for less than 3 months provided early-follicular phase serum and urine (N=100). Subsequently, these women kept a diary to record menstrual bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. Serum was analyzed for estradiol, follicle-stimulating hormone (FSH), antimüllerian hormone, and inhibin B. Urine was analyzed for FSH and estrone 3-glucuronide (E13G). Diary data on menstrual cycle day and patterns of intercourse were used to calculate day-specific fecundability ratios.
Sixty-three percent of subjects conceived within 6 months. After adjusting for age, 18 women (18%) with serum antimüllerian hormone levels of 0.7 ng/ml or less had significantly reduced fecundability given intercourse on a fertile day compared to women with higher antimüllerian hormone levels (fecundability ratio 0.38, 95% CI:0.08–0.91). The day-specific fecundability for women with early-follicular phase serum FSH values greater than 10 mIU/ml compared to women with lower FSH levels was also reduced, though nonsignificantly (11% of women affected; fecundability ratio 0.44, 95% CI: 0.08, 1.10). The association with urinary FSH was weaker (27% women affected; fecundability ratio 0.61, 95% CI: 0.26, 1.26), and the associations for the other markers were weaker still.
Early-follicular phase antimüllerian hormone appears to be associated with natural fertility in the general population.
PMCID: PMC3825553  PMID: 21422850
18.  Associations of serum sex steroid hormones and 5α-androstane-3α,17β-diol glucuronide concentrations with prostate cancer risk among men treated with finasteride 
Finasteride, an inhibitor of 5 α-reductase (Type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG). It also modestly increases serum testosterone (T), estrone (E1) and estradiol (E2). In this altered hormonal milieu, it is unknown whether serum concentrations of these hormones are associated with prostate cancer risk.
In this nested case-control study of men in the finasteride arm of the Prostate Cancer Prevention Trial, sex steroid hormones and sex hormone binding globulin (SHBG) were measured at baseline and approximately 3-years post-treatment in 553 prostate cancer cases and 694 controls.
Median post-treatment changes in concentrations of 3α-dG, T, E1, and E2 were −73.8%, +10.1%, +11.2%, and +7.5% (all p<0.001), respectively. Neither the pre- nor post-treatment concentrations of 3α-dG, nor its change, were associated with risk. Pre-treatment, high concentrations of E1 and low concentrations of T were associated with increased cancer risk (Odds Ratio[95% CI] quartile 4 vs 1: 1.38[0.99–1.93] ptrend=0.03; 0.64 [0.43–0.93] ptrend=0.07, respectively). Post-treatment, high concentrations of both E1 and E2 and were associated with increased cancer risk (OR[95% CI] quartile 4 vs 1: 1.54[1.09–2.17] ptrend=0.03; 1.49[1.07–2.07] ptrend=0.02, respectively).
Among finasteride-treated men, concentrations of 3α-dG were not associated with total or Gleason grades 2–6, 7–10 or 8–10 cancer. High serum estrogens may increase cancer risk when intraprostatic DHT is pharmacologically lowered.
Low post-treatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer.
PMCID: PMC3467348  PMID: 22879203
19.  Effect of 2 month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women 
There have been no controlled intervention studies to investigate the effects of green tea on circulating hormone levels, an established breast cancer risk factor. We conducted a randomized, double-blind, placebo-controlled intervention study to investigate the effect of the main green tea catechin, epigallocatechin gallate (EGCG), taken in a green tea extract, Polyphenon E (PPE). Postmenopausal women (n=103) were randomized into three arms: placebo, 400 mg EGCG as PPE, or 800 mg EGCG as PPE as capsules per day for 2 months. Urinary tea catechin and serum estrogen, androgen, lipid, glucose-related markers, adiponectin, and growth factor levels were measured at baseline and at the end of months 1 and 2 of intervention. Based on urinary tea catechin concentrations, compliance was excellent. Supplementation with PPE did not produce consistent patterns of changes in estradiol (E2), estrone (E1), or testosterone (T) levels. Low density lipoprotein (LDL)-cholesterol decreased significantly in both PPE groups but was unchanged in the placebo group; the change in LDL-cholesterol differed between the placebo and PPE groups (P=0.02). Glucose and insulin levels decreased nonsignificantly in the PPE groups but increased in the placebo group; statistically significant differences in changes in glucose (P=0.008) and insulin (P=0.01) were found. In summary, green tea (400 and 800 mg EGCG as PPE; ~5–10 cups) supplementation for 2 months had suggestive beneficial effects on LDL cholesterol concentrations and glucose-related markers.
PMCID: PMC3777853  PMID: 22246619
green tea; hormones; lipids; glucose; intervention
20.  Menopausal Transition Stage-Specific Changes in Circulating Adrenal Androgens 
Menopause (New York, N.y.)  2012;19(6):658-663.
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.
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.
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.
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.
PMCID: PMC3366025  PMID: 22415570
DHEAS; androstenediol; estrogen; estrogenicity; menopause; adrenal
21.  Androstenediol Complements Estrogenic Bioactivity during the Menopausal Transition 
Menopause (New York, N.y.)  2012;19(6):650-657.
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.
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).
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.
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.
PMCID: PMC3366061  PMID: 22415563
Androstenediol; estrogenicity; menopause; adrenal
22.  Maternal hormone levels and perinatal characteristics: implications for testicular cancer 
Annals of epidemiology  2006;17(2):85-92.
It has been hypothesized that the risk of testicular germ cell tumors (TGCT) is associated with maternal hormone levels. To examine the hypothesis, some studies have used perinatal factors as surrogates for hormone levels. To determine the validity of this assumption, hormone-perinatal factor relationships were examined in the Collaborative Perinatal Project.
Maternal estradiol, estriol and testosterone levels in first and third trimester serum samples were correlated with perinatal factors among 300 mothers representative of populations at high (white Americans) or low (black Americans) risk of TGCT.
Among white participants, testosterone levels, were negatively associated with maternal height (p<0.01) and age (p=0.02), and positively associated with maternal weight (p=0.02) and BMI (p<0.01), while estradiol levels were negatively associated with height (p=0.03) and positively associated with son’s birthweight (p=0.04). Among black participants, estriol levels were negatively associated with maternal weight (p=0.01), BMI (p=0.02) and gestational age p<0.01), and positively associated with son’s birthweight (p<0.01), length (p=0.04) and head circumference (p=0.03).
These findings indicate that the use of perinatal characteristics as surrogates for hormone levels should be limited to a specific ethnic group. Among white men, previously reported associations of TGCT with maternal weight and age may be due to lower maternal testosterone levels.
PMCID: PMC3659778  PMID: 16882463
testicular cancer; maternal hormones; perinatal factors
23.  Deficiencies in immunoassay methods used to monitor serum Estradiol levels during aromatase inhibitor treatment in postmenopausal breast cancer patients 
SpringerPlus  2013;2:5.
Optimal care for breast cancer patients undergoing aromatase inhibitor (AI) treatment is ensured when estradiol (E2) levels are adequately suppressed. To assess treatment efficacy accurately, it is important to measure the serum E2 levels using a well validated assay method with high sensitivity and specificity. This translates into the urgent need to evaluate various E2 immunoassay kits, which are frequently used in hospital settings to measure E2 serum levels in patients undergoing AI treatment, so clinicians obtain accurate and reliable measurements allowing appropriate clinical decision making. Our objective was to evaluate the performance of different commercially available and commonly used E2 immunoassay kits regarding measurement of E2 levels in the serum of postmenopausal breast cancer patients treated with AIs, in comparison to a highly accurate and reliable mass spectrometry assay. Clinical and demographic data were obtained from 77 postmenopausal breast cancer patients who were treated with an AI. Serum E2 levels were measured by 6 immunoassay methods and by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which served as the standard for comparison. Analysis of E2 by LC-MS/MS showed that 70% of the samples had levels that were <5 pg/ml. Three of the assays carried out with commercial E2 immunoassay kits had poor sensitivities and were not able to detect E2 levels <10 or <20 pg/ml. Although two of the E2 assays using commercial kits demonstrated a better sensitivity (5 pg/ml), the measured E2 values were substantially higher than those obtained by LC-MS/MS. The assay with the sixth commercial E2 kit grossly underestimated the true E2 values. E2 assays carried out with commercial E2 immunoassay kits lack the accuracy to measure the very low serum E2 levels found in patients being treated with AIs. Serum samples from such patients should be sent to laboratories that use a mass spectrometry assay.
PMCID: PMC3599208  PMID: 23520572
24.  The vitamin D pathway and mammographic breast density among postmenopausal women 
Laboratory studies have demonstrated that vitamin D has a number of chemopreventive properties, and that these properties may be mediated or modified by other molecules in the vitamin D pathway, such as parathyroid hormone (PTH) or calcium. However, there is little epidemiologic data exploring the effects of vitamin D on breast cancer risk in the context of these other molecules. We examined a panel of molecules in the vitamin D pathway in relation to mammographic breast density, a marker of breast cancer risk, in the Wisconsin Breast Density Study. A total of 238 postmenopausal women (ages 55-70, with no history of postmenopausal hormone use) were enrolled from mammography clinics in Madison, Wisconsin. Subjects provided blood samples that were analyzed for levels of 25-hydroxy vitamin D [25(OH)D], PTH, insulin-like growth factor-1 (IGF1), IGF-binding protein 3 (IGFBP3), retinol, and calcium. Percent breast density was measured using Cumulus software. In age-adjusted analyses there was a positive association between 25(OH)D and percent breast density (P=0.05; mean percent density=11.3% vs. 15.6% for 1st vs. 4th quartile of 25(OH)D). Breast density was inversely associated with PTH (P=0.05; 16.0% vs. 11.4% for Q1 vs. Q4) and positively associated with the IGF-1:IGFBP-3 molar ratio (P=0.02; 11.9% vs. 15.6% for Q1 vs. Q4). However, these associations were all null after further adjustment for body mass index (BMI; P>0.25). The independent relation between 25(OH)D and breast density remained null among subgroups defined by BMI and serum levels of retinol, calcium, and estradiol. These results suggest no strong independent associations between the circulating molecules of the vitamin D pathway and mammographic breast density in postmenopausal women. While it remains possible that vitamin D could influence breast cancer risk, our results suggest that such an effect would be mediated through pathways other than breast density.
PMCID: PMC3250989  PMID: 21847642
mammographic breast density; vitamin D; calcium; parathyroid hormone; breast cancer
25.  Pharmacokinetics of a combined oral contraceptive in obese and normal weight women 
Contraception  2010;81(6):474-480.
This study was conducted to compare oral contraceptive (OC) pharmacokinetics (PK) in normal weight (BMI 19.0-24.9) and obese (BMI 30.0-39.9) women.
Study Design
During the third week of the third cycle of OC use, we admitted 15 normal weight and 15 obese women for collection of 12 venous specimens over 24 h. Using RIA techniques, we measured levels of ethinyl estradiol (EE) and levonorgestrel (LNG). During the same cycle, women underwent twice-weekly sonography to assess ovarian follicular development and blood draws to measure endogenous estradiol (E2) and progesterone levels.
Obese women had a lower area under the curve (AUC; 1077.2 pg*h/mL vs 1413.7 pg*h/mL) and lower maximum values (85.7 pg/mL vs 129.5 pg/mL) for EE than normal weight women (p = 0.04 and 0.01, respectively); EE trough levels were similar between BMI groups. The similar, but smaller, differences in their LNG levels for AUC and maximum values (Cmax) were not statistically significant. While peak values differed somewhat, the LNG trough levels were similar for obese and normal weight women (2.6 ng/mL and 2.5 ng/mL, respectively). Women with greater EE AUC had smaller follicular diameters (p = 0.05) and lower E2 levels (p = 0.04). While follicular diameters tended to be larger among obese women, these differences were not statistically significant.
OC hormone peak levels are lower among obese women compared to normal weight women, but their trough levels are similar. In this small study, the observed PK differences did not translate into more ovarian follicular activity among obese OC users.
PMCID: PMC3522459  PMID: 20472113

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