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Dose-response effects of aerobic exercise on estrogen among women at high risk for breast cancer: a randomized controlled trial.
Schmitz, KH, Williams, NI, Kontos, D, Domchek, S, Morales, KH, Hwang, WT, Grant, LL, DiGiovanni, L, Salvatore, D, Fenderson, D, et al
Breast cancer research and treatment. 2015;(2):309-18
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Abstract
UNLABELLED Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18-50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m(2). 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise <75 min/week. PRIMARY OUTCOME Area under curve (AUC) for urinary estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose-response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies.
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Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).
Langley, RE, Cafferty, FH, Alhasso, AA, Rosen, SD, Sundaram, SK, Freeman, SC, Pollock, P, Jinks, RC, Godsland, IF, Kockelbergh, R, et al
The Lancet. Oncology. 2013;(4):306-16
Abstract
BACKGROUND Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. METHODS In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. FINDINGS 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). INTERPRETATION Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. FUNDING Cancer Research UK, MRC Clinical Trials Unit.
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Effect of oral estrogen on substrate utilization in postmenopausal women.
Lwin, R, Darnell, B, Oster, R, Lawrence, J, Foster, J, Azziz, R, Gower, BA
Fertility and sterility. 2008;(4):1275-8
Abstract
We tested the hypothesis that a 2-month intervention with unopposed oral conjugated equine estrogens (0.625 mg/d) would decrease lipid oxidation, as assessed by 24-hour, whole-room, indirect calorimetry in 14 postmenopausal women. Estrogen (E) treatment was associated with declines in both 24-hour and postprandial lipid oxidation and an increase in fat mass (mean [+/-SD] 2-month difference 1.1 +/- 1.0 kg; mean 6-month difference 1.8 +/- 2.2 kg), suggesting that, on an acute basis, oral E may increase adiposity by limiting lipid oxidation.
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Frovatriptan vs. transdermal oestrogens or naproxen sodium for the prophylaxis of menstrual migraine.
Guidotti, M, Mauri, M, Barrilà, C, Guidotti, F, Belloni, C
The journal of headache and pain. 2007;(5):283-8
Abstract
Acute treatment of menstrual migraine (MM) attacks is often incomplete and unsatisfactory, and perimenstrual prophylaxis with triptans, oestrogen supplementation or naproxen sodium may be needed for decreasing frequency and severity of the attack. In this pilot, open-label, non-randomised, parallel group study we evaluated, in 38 women with a history of MM, the efficacy of frovatriptan (n=14) 2.5 mg per os or transdermal oestrogens (n=10) 25 microg or naproxen sodium (n=14) 500 mg per os once-daily for the short-term prevention of MM. All treatments were administered in the morning for 6 days, beginning 2 days before the expected onset of menstrual headache. All women were asked to fill in a diary card, in the absence of (baseline) and under treatment, in order to score headache severity. All women reported at least one episode of MM at baseline. During treatment all patients taking transdermal oestrogens or naproxen sodium and 13 out of the 14 patients (93%) taking frovatriptan had at least one migraine attack (p=0.424). Daily incidence of migraine was significantly (p=0.045) lower under frovatriptan than under transdermal oestrogens or NS. At baseline, the overall median score of headache severity was 4.6, 4.2 and 4.3 in the group subsequently treated with frovatriptan, transdermal oestrogens and naproxen sodium, respectively (p=0.819). During treatment the median score was significantly lower under frovatriptan (2.5) than under transdermal oestrogens (3.0) and naproxen sodium (3.9, p=0.049). This was evident also for each single day of observation (p=0.016). Among treatments differences were particularly evident for the subgroup of patients with true MM (n=22) and for frovatriptan vs. naproxen sodium. This study suggests that short-term prophylaxis of MM with frovatriptan may be more effective than that based on transdermal oestrogens or naproxen sodium.
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A controlled 2-mo dietary fat reduction and soy food supplementation study in postmenopausal women.
Wu, AH, Stanczyk, FZ, Martinez, C, Tseng, CC, Hendrich, S, Murphy, P, Chaikittisilpa, S, Stram, DO, Pike, MC
The American journal of clinical nutrition. 2005;(5):1133-41
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Abstract
BACKGROUND Low intake of dietary fat and high intake of soy foods have been suggested to partly explain the lower breast cancer rates in Asia, perhaps because of lower endogenous estrogens. OBJECTIVE The objective was to assess the hormonal and nonhormonal effects of diets resembling an Asian diet in terms of total fat and soy food contents. DESIGN Fifty-seven postmenopausal women participated in a randomized, controlled, dietary intervention study. The subjects consumed a very-low-fat diet (VLFD; 11% of energy as fat), a Step I diet (25% of energy as fat) supplemented with soy food (SFD; 50 mg isoflavones/d), or a control Step I diet (CD; 27% of energy as fat) with no soy food. All diets were prepared at the General Clinical Research Center of the University of Southern California. Serum hormones and other markers were measured at baseline and every 2 wk during the 8 wk of intervention. RESULTS There were no significant differences in total estradiol and sex hormone binding globulin at the completion of the intervention between women in the SFD and VLFD groups and those in the CD group. Serum insulin decreased significantly in the SFD group, and leptin decreased significantly in the SFD and VLFD groups; however, these changes did not differ significantly from the changes in the CD group. CONCLUSIONS This study does not provide evidence that ingestion of soy food or a VLFD significantly reduces estrogen concentrations in postmenopausal women. However, short-term changes in diet may have significant and beneficial effects on blood insulin and leptin concentrations.
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Positive effects of conjugated equine estrogen on triglyceride metabolism in oophorectomized women based on a stratification analysis of pretreatment values.
Hashimoto, K, Nozaki, M, Nakano, H
Fertility and sterility. 2004;(4):1041-6
Abstract
OBJECTIVE To evaluate the effects of conjugated equine estrogen (CEE) on the triglyceride (TG) metabolism in oophorectomized women based on a stratified analysis. DESIGN Randomized, clinical study. SETTING Menopause Clinic of Kyushu University Hospital. PATIENT(S): Three hundred oophorectomized women. INTERVENTION(S): Three hundred oophorectomized women were randomly divided into two groups and treated by the following regimens for a year: group 1 received calcium alone, group 2 received 0.625 mg/day of CEE and calcium. MAIN OUTCOME MEASURE(S): The changes in serum lipid profile were analyzed according to the individual initial levels in each group. Apolipoprotein E was also measured. RESULT(S): A greater reduction in low-density lipoprotein cholesterol (LDL-C) levels was observed in group 2 women with higher initial levels. For high-density lipoprotein cholesterol (HDL-C) a greater increase was observed in group 2 women with lower initial levels. Although TG levels increased as a whole in group 2, a reduction was observed in the high-TG groups. The initial values of apolipoprotein E were higher in the high-TG groups and decreased to greater amounts in group 2 patients. CONCLUSION(S): Administration of CEE induced positive changes in the serum lipid profile according to the individual initial levels, including levels of TG. Therefore, changes in the TG levels shown by the stratification may be related to the apolipoprotein E changes that are observed following CEE replacement.
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A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers.
Decensi, A, Robertson, C, Viale, G, Pigatto, F, Johansson, H, Kisanga, ER, Veronesi, P, Torrisi, R, Cazzaniga, M, Mora, S, et al
Journal of the National Cancer Institute. 2003;(11):779-90
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Abstract
BACKGROUND Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk. METHODS We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided. RESULTS Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P =.81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose-response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels. CONCLUSIONS The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.
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Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial.
Pfrunder, A, Schiesser, M, Gerber, S, Haschke, M, Bitzer, J, Drewe, J
British journal of clinical pharmacology. 2003;(6):683-90
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Abstract
AIMS: Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. METHODS Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. RESULTS During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3-ketodesogestrel decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h (43.9%; 95% confidence interval (CI) -49.3, -38.5, P = 0.001) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8%; CI -29.9, -5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI -47.9, -35.6; P = 0.001) and by 22.8% (CI -31.2, -13.3; P < 0.001) during cycle B respectively, compared with the control cycle. CONCLUSIONS There was no evidence of ovulation during low-dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies.
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Evidence of estrogenic effect by the three-month-intervention of isoflavone on vaginal maturation and bone metabolism in early postmenopausal women.
Uesugi, T, Toda, T, Okuhira, T, Chen, JT
Endocrine journal. 2003;(5):613-9
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Abstract
Objective of the present study is to determine the estrogenic effect of isoflavone on vaginal epithelia and bone metabolism in early postmenopausal women. Twenty-two postmenopausal women were randomly assigned to either a group that was given isoflavone extract (61.8 mg) for three months or a control group that was given placebo. We measured the L2-4 bone mineral density (BMD) before and 3 months after treatment by dual X-ray absorptiometry (DXA). Blood and urine samples were obtained from the women before and 3 months after treatment. We measured FSH using radioimmunoassay and, urinary pyridinoline and deoxypyridinoline levels by HPLC. For endocrine cytology, vaginal smears were collected before and 3 months after the treatment. Three months after the treatment, the serum FSH levels and the BMD values did not significantly differ between the two groups. Urinary excretion of isoflavone was significantly higher in the group given isoflavone compared with that given placebo (p<0.03). Numbers of parabasal and intermediate types of cells were significantly decreased (58.2 +/- 12.4% to 25.0 +/- 10.7%; p<0.05) and increased (24.1 +/- 8.7% to 63.7 +/- 10.7%; p<0.05), respectively in the isoflavone group, but remained unchanged in the control group. Urinary pyridinoline excretion was significantly decreased (49.6% vs. before, p<0.01 by paired t-test) in the isoflavone group. The intake of 60 mg of isoflavone daily for 3 months produced maturational changes of vaginal epithelia without affecting serum FSH levels, and could possibly slow down bone turnover rates as judged by decreased urinary pyridinoline excretion.
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Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids.
Genazzani, AD, Stomati, M, Bernardi, F, Pieri, M, Rovati, L, Genazzani, AR
Fertility and sterility. 2003;(6):1495-501
Abstract
OBJECTIVE To evaluate the effects of a low-dose DHEA supplementation on hormonal parameters in early and late postmenopausal women. DESIGN Prospective case study. SETTING Postmenopausal women in a clinical research environment. PATIENT(S): Twenty postmenopausal women were divided in two groups according to age (50-55 and 60-65 years). INTERVENTION(S): All patients underwent hormonal evaluation before and at 3, 6, 9, and 12 months of therapy (25 mg/d of DHEA orally). Pelvic ultrasound examination and Kupperman score were performed before and after 3, 6, and 12 months of therapy. MAIN OUTCOME MEASURE(S): Plasma DHEA, DHEAS, estrone (E1), E2, P, androstenedione (A), T, dihydrotestosterone, 17alpha-hydroxyprogesterone (17-OHP), cortisol (F), allopregnanolone, beta-endorphin, sexual hormone-binding globulin (SHBG), LH, FSH, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) concentrations. RESULT(S): The levels of all the steroids that derive from DHEA metabolism increased in plasma with DHEA administration. Also neurosteroids (namely allopregnanolone) and endorphin showed increased plasma levels, whereas both gonadotropins were significantly reduced. Endometrial thickness did not change throughout the study period. CONCLUSION(S): Administration of low doses (25 mg) of DHEA positively modulates several endocrine parameters in early and late postmenopausal women, inducing the increase of the androgenic, estrogenic, and progestogenic milieu and reducing the climateric symptoms, similarly to estroprogestin replacement therapy. These data suggest that DHEA supplementation is a more effective replacement therapy than a simple "dietary supplement."