Plasma Levels Of Estrone Research Articles

Estrone and Estradiol Levels in Breast Cancer Patients Using Anastrozole Are Not Related to Body Mass Index.

Objective Obesity is associated with an increased risk for breast cancer. Recent studies have shown that aromatase inhibitors may be less effective in women with a high body mass index (BMI). The aim of this study was to establish the relationship between the BMI and plasma estrone and estradiol levels in postmenopausal women with hormone receptor-positive breast cancer using anastrozole. Methods In this cohort study, the patients were divided into three groups according to BMI (normal weight, overweight and obese) to compare and correlate plasma hormone levels before starting anastrozole hormone therapy and three months after treatment. Plasma hormone levels were compared for age and use of chemotherapy. Results A statistically significant reduction in estrone and estradiol levels was observed between baseline and three months after starting the anastrozole treatment (p < 0.05). There was no statistically significant difference in plasma estrone and estradiol levels among the BMI groups (p > 0.05), but a significant reduction in plasma estrone levels was observed after three-months' treatment relative to baseline in all groups, as well as a reduction in estradiol in the obese group (p < 0.05). The use of chemotherapy and age > 65 years had no influence on plasma steroid levels. Conclusion Changes in estrone and estradiol levels in the studied groups were not associated with BMI, chemotherapy or age.

Endogenous sex hormones and cognitive function in older women

IntroductionWe examined the association between endogenous sex hormones and both objective and subjective measures of cognitive function. MethodsWe followed 3044 women up to 23 years in a prospective cohort study. We measured plasma levels of estrone, estrone sulfate, estradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) in 1989–1990, conducted neuropsychologic testing in 1999–2008, and inquired about subjective cognition in 2012. ResultsOverall, we observed little relation between plasma levels of hormones and either neuropsychologic test performance or subjective cognition. However, after adjustment for age and education, we observed a borderline significant association of higher levels of plasma estrone with higher scores for both overall cognition (P trend = .10) and verbal memory (P trend = .08). DiscussionThere were no clear associations of endogenous hormone levels at midlife and cognition in later life, although a suggested finding of higher levels of plasma estrone associated with better cognitive function merits further research.

276P - Biological and Clinical Implications of Aromatase Inhibitors for Neoadjuvant Therapy in Breast Cancer

ABSTRACT Aim: Neoadjuvant aromatase inhibitors (AIs) therapy has become acceptable. Estrogens play a major role in promoting the growth of breast cancers (BCs). Androst-5-ene-3b,17b-diol (ADIOL) possesses estrogenic properties. Here we report the efficacy of AIs and the influence of letrozole (LET) on BC tissue and plasma levels of estrone (E1), estradiol (E2), estrone sulfate (E1S), ADIOL, and androstendione (AONE) in postmenopausal women undergoing neoadjuvant therapy for estrogen receptor (ER)–positive BCs. Methods: Twenty-nine postmenopausal patients with stage I (n = 3), IIA (n = 11), IIB (n = 5), IIIA (n = 2) and IIIB (n = 9) BCs were treated with anastrozole, LET or exemestane as neoadjuvant treatment. One patient had bilateral BC. Plasma and BC tissue samples were obtained from 9 patients before and after 4 months of neoadjuvant therapy with LET. Steroids concentrations were measured by liquid chromatography/ electrospray tandem mass spectrometry. Results: One of 30 tumors showed complete response (CR), 15 showed partial response (PR) and 14 showed stable disease (SD). All treatments were well tolerated. After treatment, a decrease of progesterone receptor expression was more frequent in responding tumors (93.8%) than in non-responding tumors (35.7%). Suppression of Ki67 after treatment was significantly greater in responding tumors than in non-responding tumors (P = 0.002). The mean BC tissue levels of E1, E2, E1S, ADIOL, and AONE at base line were 0.534, 0.409, 0.13, 1.65, and 6.09 pmol/g, respectively. After neoadjuvant therapy, the levels of E1, E2, E1S, ADIOL, and AONE were 0.002, 0008, 0.002, 2.22, and 5.63 pmol/g, respectively. The mean plasma levels of E1, E2, E1S, ADIOL, and AONE at base line were 621.5, 27.0, 1799.5, 1033, and 2258 pmol/l, respectively. After therapy, the levels of E1, E2, E1S, ADIOL, and AONE were 1.7, 1.6, 3.4, 1111, and 2826 pmol/l, respectively. LET significantly suppressed estrogens. Although plasma and tissue ADIOL levels were high after treatment, there was no progress disease in the 9 cases. With a median follow up of 69 months, there was no significant difference in overall survival between patients with CR or PR and those with SD. Conclusions: Neoadjuvant AIs therapy provided satisfactory efficacy and safety profiles. The activity of AIs was correlated with significantly reduced estrogens levels, but not with ADIOL levels. Disclosure: All authors have declared no conflicts of interest.

Hormone and Metabolite Profiles in Nesting Green and Flatback Turtles: Turtle Species with Different Life Histories

Herbivorous turtle, Chelonia mydas, inhabiting the south China Sea and breeding in Peninsular Malaysia, and Natator depressus, a carnivorous turtle inhabiting the Great Barrier Reef and breeding at Curtis Island in Queensland, Australia, differ both in diet and life history. Analysis of plasma metabolites levels and six sex steroid hormones during the peak of their nesting season in both species showed hormonal and metabolite variations. When compared with results from other studies progesterone levels were the highest whereas dihydrotestosterone was the plasma steroid hormone present at the lowest concentration in both C. mydas and N. depressus plasma. Interestingly, oestrone was observed at relatively high concentrations in comparison to oestradiol levels recorded in previous studies suggesting that it plays a significant role in nesting turtles. Also, hormonal correlations between the studied species indicate unique physiological interactions during nesting. Pearson correlation analysis showed that in N. depressus the time of oviposition was associated with elevations in both plasma corticosterone and oestrone levels. Therefore, we conclude that corticosterone and oestrone may influence nesting behaviour and physiology in N. depressus. To summarise, these two nesting turtle species can be distinguished based on the hormonal profile of oestrone, progesterone, and testosterone using discriminant analysis.

Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors

Women with breast cancer who are treated with aromatase inhibitors often experience vaginal atrophy symptoms and sexual dysfunction. This work aims to study proliferation and the presence and distribution of steroid hormone receptors in vaginal biopsies in relation to vaginal atrophy and vaginal pH in women with breast cancer who are on adjuvant endocrine treatment and in healthy postmenopausal women. This is a cross-sectional study that compares postmenopausal aromatase inhibitor-treated women with breast cancer (n = 15) with tamoxifen-treated women with breast cancer (n = 16) and age-matched postmenopausal women without treatment (n = 19) or with vaginal estrogen therapy (n = 16). Immunohistochemistry was used to study proliferation and steroid hormone receptor staining intensity. Data was correlated with estrogen and androgen levels, vaginal atrophy scores, and vaginal pH. Aromatase inhibitor-treated women had a lower grade of proliferation, weaker progesterone receptor staining, and stronger androgen receptor staining, which correlated with plasma estrone levels, vaginal atrophy scores, and vaginal pH. Women with aromatase inhibitor-treated breast cancer exhibit reduced proliferation and altered steroid hormone receptor staining intensity in the vagina, which are related to clinical signs of vaginal atrophy. Although these effects are most probably attributable to estrogen suppression, a possible local inhibition of aromatase cannot be ruled out.

Association Between Sex Hormones and Colorectal Cancer Risk in Men and Women

There is observational and clinical evidence that indicates that sex hormones affect development of colorectal cancer in men and women. However, the relationship between endogenous sex hormone levels and colorectal cancer is unclear. We collected data on lifestyle, medical history, and diet (through 2008), along with blood samples, from the Nurses' Health Study, the Women's Health Study, the Health Professional Follow-up Study, and the Physicians' Health Study II. We measured plasma levels of estrone, estradiol, testosterone, sex hormone binding globulin (SHBG), and C-peptide among 730 women (293 cases of colorectal cancer and 437 healthy individuals as controls) and 1158 men (439 colorectal cancer cases and 719 controls) and used unconditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals. All statistical tests were 2-sided. Total testosterone, SHBG, and the ratio of estradiol to testosterone were associated with colorectal cancer in men after adjustments for matching and risk factors for colorectal cancer, including body mass index and plasma levels of C-peptide. The RRs in the highest relative to the lowest quartile were 0.62 for testosterone (95% confidence interval, 0.40-0.96), 0.65 for SHBG (95% confidence interval, 0.42-0.99), and 2.63 for the ratio (95% confidence interval, 1.58-4.36) (P values for trend ≤ .02). However, in women, only the ratio of estradiol to testosterone was (inversely) associated with colorectal cancer after adjustments for all factors (RR, 0.43; 95% confidence interval, 0.22-0.84; P value for trend = .03). On the basis of combined data from 4 population studies, there appears to be an association between levels of sex hormones and colorectal cancer risk in men. There also appears to be an inverse association between the ratio of estradiol to testosterone and colorectal cancer in postmenopausal women.

Abstract LB-338: A prospective evaluation of circulating sex hormones in relation to colorectal cancer risk in men and women

Abstract Background: Observational studies and randomized trials have supported a potential role of sex hormones in colorectal cancer development in both men and women. However, data on the relationship between endogenous sex hormone levels and colorectal cancer are very limited. Methods: We prospectively evaluated plasma levels of estrone, estradiol, and testosterone in relation to colorectal cancer risk in men and postmenopausal women not using hormone therapy from four large female and male study cohorts including the Nurses’ Health Study, Women's Health Study, Health Professional Follow-Up Study, and Physicians’ Health Study II. A total of 293 female and 438 male cases along with 437 female and 719 male controls were included in the present analysis. Unconditional logistic regression controlling for matching, risk factors, and plasma c-peptide was used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two sided. Results: Total testosterone, sex hormone binding globulin (SHBG), and the ratio of estradiol over testosterone were associated with colorectal cancer in men after adjustment for all confounding factors including body mass index (BMI) and c-peptide levels; the RRs (95% CI) in the highest relative to the lowest quartile were 0.62 (0.40-0.96) for testosterone, 0.65 (0.42-0.99) for SHBG, and 2.63 (1.58-4.36) for the ratio (p-values for trend ≤0.02). In addition, no effect modification by BMI in men was found on the association between sex steroids and colorectal cancer (p-values for interaction ≥0.46). In women, a higher ratio of estradiol to testosterone, reflecting higher aromatase activity and likely increased estradiol production, was associated with lower colorectal cancer risk after adjustment for all factors (RR=0.43, 95% CI=0.22-0.84, p-value for trend=0.03). Specifically, the inverse association between the ratio and colorectal cancer risk was seen only among normal weight women (p-value for interaction=0.07); the multivariate RRs in the higher quartile groups were 0.26-0.72 (p-value for tend=0.03). Conversely, there was no association between the ratio and colorectal cancer in overweight and obese women (RRs=1.15-1.2, p-value for trend=0.89). Stratifying analysis by BMI for other sex steroids did not significantly change the overall association (p-values for interaction ≥0.25). Conclusion: Our data offers the first observational evidence supporting an inverse association of circulating testosterone and SHBG with colorectal cancer in men. Conversely, normal weight women with a higher ratio of estradiol over testosterone may be at a lower risk for colorectal cancer. Validation of our results in other studies will help elucidate the effects attributable to sex steroids on colorectal cancer and refine risk profiles of colorectal cancer development in both men and women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-338. doi:1538-7445.AM2012-LB-338

Tissue bioaccumulation patterns, xenobiotic biotransformation and steroid hormone levels in Atlantic salmon ( Salmo salar) fed a diet containing perfluoroactane sulfonic or perfluorooctane carboxylic acids

In the present study, groups of juvenile Atlantic salmon ( Salmo salar) were fed gelatine capsules containing fish-food spiked with PFOA or PFOS (0.2 mg kg −1 fish) and solvent (methanol). The capsules were given at days 0, 3 and 6. Blood, liver and whole kidney samples were collected prior to exposure (no solvent control), and at days 2, 5, 8 and 14 after exposure (Note: that day 14 after exposure is equal to 7 d recovery period). We report on the differences in the tissue bioaccumulation patterns of PFOS and PFOA, in addition to tissue and compound differences in modulation pattern of biotransformation enzyme genes. We observed that the level of PFOS and PFOA increased in the blood, liver and kidney during the exposure period. Different PFOS and PFOA bioaccumulation patterns were observed in the kidney and liver during exposure- and after the recovery periods. Particularly, after the recovery period, PFOA levels in the kidney and liver tissues were almost at the control level. On the contrary, PFOS maintained an increase with tissue-specific differences, showing a higher bioaccumulation potential (also in the blood), compared with PFOA. While PFOS and PFOA produced an apparent time-dependent increase in kidney CYP3A, CYP1A1 and GST expression, similar effects were only temporary in the liver, significantly increasing at sampling day 2. PFOA and PFOS exposure resulted in significant decreases in plasma estrone, testosterone and cortisol levels at sampling day 2, and their effects differed with 17α-methyltestostrerone showing significant decrease by PFOA (also for cholesterol) and increase by PFOS. PFOA significantly increased estrone and testosterone, and no effects were observed for cortisol, 17α-methyltestosterone and cholesterol at sampling day 5. Overall, the changes in plasma steroid hormone levels parallel changes in CYP3A mRNA levels. Given that there are no known studies that have demonstrated such tissue differences in bioaccumulation patterns with associated differences in toxicological responses in any fish species or lower vertebrate, the present findings provide some potential insights and basis for a better understanding of the possible mechanisms of PFCs toxicity that need to be studied in more detail.

Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis

In this open-label, randomized, multiple-dose, two-treatment crossover study, 24 postmenopausal women with moderate to severe atrophic vaginitis received 0.3 mg conjugated estrogens daily for 14 days: 7 days orally (0.3 mg tablet) and 7 days vaginally (0.5 g cream). Steady-state plasma concentrations of E2 and estrone were one-third lower after vaginal versus oral administration of conjugated estrogens.

Association of genetic polymorphisms in CYP19A1 and blood levels of sex hormones among postmenopausal Chinese women

Circulating estrogen levels have been related to the risk of several female cancers. Blood levels of estrogen are controlled by estrogen synthesis enzymes. Genetic variation of estrogen genes thus may influence circulating estrogen levels. We investigated the associations of genetic polymorphisms in CYP19A1, a critical gene involved in estrogen synthesis, with plasma levels of sex hormones among postmenopausal Chinese women. Included in this study were 345 postmenopausal community controls from a population-based case-control study conducted in Shanghai. Fasting blood samples from those women were measured for blood estradiol, estrone, estrone sulfate, and testosterone. A total of 19 genetic polymorphisms in CYP19A1 were genotyped using ABI7900 or PCR-restriction fragment length polymorphism methods. Differences in plasma levels of hormones by genotype were examined using variance analysis. The geometric means of plasma levels of estradiol, estrone, estrone sulfate, and testosterone were 10.1, 16.8, 969.0, and 202.9 pg/ml, respectively, for this study population. We found that plasma levels of estrone were associated with rs28566535 (P=0.0180), rs730154 (P=0.0141), and rs936306 (P=0.0274) in block 2. In the same block, the haplotype CGCTA was related to level of estrone (P=0.0064). Single nucleotide polymorphism rs1902584 in block 1 was associated with estradiol only in overweight postmenopausal women. No clear association with sex hormones was noted for the other genetic polymorphisms evaluated in the study. Single nucleotide polymorphisms in blocks 1 and 2 of the CYP19A1 gene are related to plasma levels of estrogen among postmenopausal Chinese women and may therefore play an important role in the etiology of hormone-related cancers.

An optimised, highly sensitive radioimmunoassay for the simultaneous measurement of estrone, estradiol and estrone sulfate in the ultra-low range in human plasma samples

Following the introduction of potent aromatase inhibitors for the treatment of breast cancer patients, highly sensitive methods have become mandatory to evaluate the influence of these drugs on plasma estrogen levels. Commercially available kits for estrogen measurements are not suitable for these kinds of evaluations due to their detection limits that are close to baseline estrogen levels in postmenopausal women. We describe here an optimised radioimmunoassay suitable for the simultaneous measurement of plasma estrone (E 1), estradiol (E 2) and estrone sulfate (E 1S) levels in the ultra-low range. Following incubation with [ 3H]-labelled estrogens as internal standards, crude estrogen fractions were separated by ether extraction. The E 1S fraction was hydrolysed with sulfatase followed by eluation on a Sephadex column. Free estrogens (E 1, E 2) were separated by chromatography (LH-20). Estrone and E 1S (following hydrolysis) were converted into E 2, and each estrogen fraction was measured by the same highly sensitive and specific radioimmunoassay using estradiol-6-(O-carboxymethyl)-oximino-2-(2-[ 125I]-iodo-histamine) as ligand. Although several purification steps were involved, the internal recovery values for tritiated estrogens were found to be 88%, 90%, and 49% for E 1, E 2 and E 1S, respectively. The intra-assay coefficient of variation was <5% for all recovery measurements. The detection limits were calculated following repeated blank measurements and found to be 1.14 pmol/L for E 1, 0.67 pmol/L for E 2, and 0.55 pmol/L for E 1S, respectively. The intra-assay coefficient of variation (CV) was found to be 3.4% for E 1, 5.1% for E 2 and 6.1% for E 1S, while the inter-assay CV was 13.6%, 7.6% and 7.5% for E 1, E 2, and E 1S, respectively. Considering normal plasma levels for E 2 (15 pmol/L), E 1 (80 pmol/L) and E 1S (400 pmol/L) in postmenopausal women, the method allows theoretically to detect suppression of plasma E 2, E 1 and E 1S levels by 95.5%, 98.6% and 99.9% when starting from average, normal postmenopausal levels. Thus, the method presented here is to our knowledge the currently most sensitive assay available for plasma estrogen measurements in the ultra-low range and, as such, a reliable tool for a proper evaluation of potent aromatase inhibitors and other potential drugs influencing on plasma estrogen levels.

Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels

The adipocytokine leptin has recently been shown to enhance the expression of aromatase via promoter II and I.3 using an AP-1 motif. Thus, we evaluated the correlation between plasma leptin concentrations and total body aromatization (TBA) as well as plasma levels of estrone (E 1), estradiol (E 2) and estrone sulfate (E 1S) in postmenopausal breast cancer patients. Twenty-two postmenopausal women with metastatic breast cancer, participating in tracer studies for the measurement of total body aromatization (TBA) in vivo, were available. In addition, blood samples for plasma estrogens and leptin measurements were available from another 22 breast cancer patients and 114 healthy postmenopausal women participating in the mammography-screening program. Values for TBA varied from 1.46 to 4.72% while plasma leptin levels ranged from 1.83 to 95.51 ng/ml in the same group of patients. All plasma estrogen levels were in the normal range expected for postmenopausal women. We found a significant correlation between pretreatment leptin levels and TBA ( r s 0.452, P = 0.01). In contrast, basal levels of TBA did not correlate to body mass index (BMI) in the same group of patients. Plasma leptin levels correlated to plasma levels of estradiol ( r s 0.659, P = 0.007), and estrone sulfate ( r s 0.562, P = 0.01) in the group of breast cancer patients ( n = 44) as well as in the group of healthy postmenopausal women (estradiol, r s 0.363, P ≤ 0.001, estrone sulfate r s 0.353, P ≤ 0.001). In conclusion, we found plasma leptin levels to correlate to TBA in breast cancer patients and to plasma levels of estradiol and estrone sulfate in breast cancer patients as well as in healthy postmenopausal females. These findings suggest that leptin may influence on aromatase activity in vivo, providing a possible link between body weight and plasma estrogen levels as well as breast cancer risk.

Treatment with high-dose estrogen (diethylstilbestrol) significantly decreases plasma estrogen and androgen levels but does not influence in vivo aromatization in postmenopausal breast cancer patients

While growth factors and hormones are known to influence aromatase expression in experimental systems, little is know about potential factors influencing peripheral aromatization in postmenopausal women. The fact that peripheral aromatase activity is higher in old compared to young women and the finding of relatively high tissue estradiol (E 2) concentrations after the menopause suggests peripheral aromatization could be influenced by estrogen concentration. To test this hypothesis, we determined plasma hormone levels ( n = 9) and in vivo aromatization ( n = 3) in postmenopausal women suffering from advanced breast cancer before and during treatment (4 weeks) with diethylstilbestrol (DES) 5 mg three times daily. Plasma levels of cortisol (C), corticosteroid-binding globulin (CBG), and sex hormone binding globulin (SHBG) were significantly increased in all patients ( P < 0.05 for all). While we found no change in total body aromatization and plasma estrone (E 1) levels, estradiol (E 2) and estrone sulfate (E 1S) were suppressed by a mean of 48.8 and 68.2%, respectively ( P = 0.043 and 0.008). Surprisingly, plasma levels of androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) were also suppressed by a mean in the range of 32.1 to 52.6% ( P < 0.05 for all androgens). In contrast, no change in plasma progesterone or 17α-hydroxyprogesterone was found. Thus, one possible explanation to our findings could be that DES administered in high doses reduces 17,20-lyase activity in the adrenal gland.

Effects of oral estrone on rat energy balance

Oral doses of estrone from 10 nmol/(kg day) to 10 μmol/(kg day) were given to adult Wistar male rats for 10 days. Body composition, energy balance, total body estrone balance and plasma metabolites and hormones were measured at the end of the treatment. Body weight (as well as food intake, body energy, fat and water accrual) increased at doses in the 10–100 nmol/(kg day) range, but decreased at higher doses. Energy expenditure decreased with increasing doses of estrone. Plasma metabolite changes suggested the maintenance of energy homeostasis, and lipid parameters indicated that lipid mobilization increased with the increasing doses of estrone. Plasma estrone, acyl-estrone and estradiol levels decreased at low doses and increased at high doses of estrone. We conclude that: (a) repeated estrone gavages, even at very high doses, do not result in the accrual of estrone in the body; (b) low doses of estrone promote growth and high doses decrease body mass and fat accretion; (c) administration of estrone at low doses decreases its circulating levels and the levels of estradiol and acyl-estrone, a situation reverted at higher doses and (d) estrone administration induces a dose-dependent shift towards lower energy expenditure.

Effects of menstrual cycle and physical training on heat loss responses during dynamic exercise at moderate intensity in a temperate environment

We evaluated the effects of the menstrual cycle and physical training on heat loss (sweating and cutaneous vasodilation) responses during moderate exercise in a temperate environment. Ten untrained (group U) and seven endurance-trained (group T) women (maximal O2 uptake of 36.7+/-1.1 vs. 49.4+/-1.7 ml.kg-1.min-1, respectively; P<0.05) performed a cycling exercise at 50% maximal O2 uptake for 30 min during both the midfollicular and midluteal menstrual phase in a temperate environment (ambient temperature of 25 degrees C, relative humidity of 45%). In group U, plasma levels of estrone, estradiol, and progesterone at rest and esophageal temperature (Tes) during exercise were significantly higher during the midluteal than during the midfollicular phase (P<0.05). Sweating rate and cutaneous blood flow (measured via laser-Doppler flowmetry) on the chest, back, forearm, and thigh were lower during the midluteal than during the midfollicular phase during exercise. Tes threshold for heat loss responses was significantly higher and sensitivity of the heat loss responses was significantly lower in the midluteal than in the midfollicular phase, regardless of body site. These effects of the menstrual cycle in group U were not observed in group T. The sweating rate and cutaneous blood flow were significantly higher in group T than in group U, regardless of menstrual phase or body site. Tes threshold for heat loss responses was significantly lower and sensitivity of heat loss responses was significantly greater in group T than in group U in the midluteal phase; however, sensitivity of the sweating response was significantly greater in the midfollicular phase. These results suggest that heat loss responses in group U were inhibited in the midluteal phase compared with in the midfollicular phase. Menstrual cycle had no remarkable effects in group T. Physical training improved heat loss responses, which was more marked in the midluteal than in the midfollicular phase.

Tea and circulating estrogen levels in postmenopausal Chinese women in Singapore

The role of tea in the etiology of breast cancer is controversial. We recently provided the first set of human evidence that breast cancer risk is significantly inversely associated with tea intake, largely confined to intake of green tea. Since black tea and green tea possess comparable levels of the total tea polyphenols that possess antioxidative activities, reasons for the paradoxical effects of green tea and black tea on breast cancer protection are not apparent. Some limited evidence suggests that green tea may have downregulatory effects on circulating sex-steroid hormones, whereas black tea may have upregulatory effects. We therefore, investigated the relationship between tea intake, and plasma estrogen and androstenedione levels in a cross-sectional study of healthy postmenopausal Chinese women in Singapore. In this group of 130 women, 84 were non or irregular (less than once a week) tea drinkers, 27 were regular (weekly/daily) green tea drinkers and 19 were regular (weekly/daily) black tea drinkers. Relative to plasma estrone levels in non- or irregular tea drinkers (29.5 pg/ml) the levels were 13% lower in regular green tea drinkers (25.8 pg/ml) and 19% higher in regular black tea drinkers (35.0 pg/ml). These differences in estrone levels were statistically significant (P = 0.03) inspite of adjusting for age, body mass index, intake of soy, and other covariates. A similar pattern of differences between tea intake, and plasma levels of estradiol (P = 0.08) and androstenedione (P = 0.14) were found. In addition, the tea-estrogen associations were observed irrespective of the genotype of catechol-O-methyltransferase (COMT), a major enzyme that aids in the excretion of tea polyphenols in humans. Larger studies are needed to confirm results from this cross-sectional study and to better understand the potentially differing effect of black and green tea on circulating estrogen levels and ultimately on the risk of breast cancer.

Hormonal effects of aromatase inhibitors: focus on premenopausal effects and interaction with tamoxifen

Third generation aromatase inhibitors have excellent specificity. Some reports indicate that letrozole may have a minor effect on cortisol synthesis but these were not confirmed: valid comparisons with other aromatase inhibitors requires randomised study. The putative use of a third generation inhibitor as a single agent in premenopausal women has been investigated using YM511. It was hypothesised that in this situation site-specific suppression of estrogens in breast carcinomas, without systemic effects, may lead to a down-regulation of tumour proliferation. Plasma levels of androstenedione and testosterone were significantly increased by 2 weeks treatment with YM511. Mean plasma estrone levels were suppressed, but some plasma estradiol levels were abnormally high and others abnormally low. These differential effects of YM511 on circulating estrogens supported the concept that peripheral synthesis of estrogens might be suppressed while ovarian production remained high. However, YM511 did not demonstrate anti-proliferative effects in hormone sensitive breast carcinomas. Consideration of the pharmacology of the estrogen receptor during tamoxifen therapy indicates that tamoxifen effectively saturates the receptor (>99.94% occupancy) in postmenopausal women. The addition of an aromatase inhibitor in this situation would be very unlikely to affect the biological activity of the estrogen receptor. This provides a possible explanation why the clinical efficacy of tamoxifen combined with an aromatase inhibitor appears to be equivalent to that of tamoxifen alone.

Conjugated estrogen administration improves common carotid artery elastic properties in normotensive postmenopausal women.

Various vascular effects of estrogens have been proposed to explain further the beneficial effect of replacement therapy in cardiovascular events. The study was undertaken to assess the effect of conjugated estrogen on the elastic properties of the large arteries in normotensive, healthy, postmenopausal women. Toward this end, we investigated the acute effect of conjugated estrogen on the elastic properties of the common carotid artery (CCA) in 20 normotensive, healthy, postmenopausal women (age 54+/-3 years) at baseline and 20 min after the intravenous administration of 1.25 mg conjugated estrogens. The CCA distensibility was derived by a combination of surface ultrasonographic data and simultaneous blood pressure measurements at the brachial artery. The carotid pulsatility index, a measure of brain impedance, was determined electronically by tracing the CCA Doppler waveform. At baseline, CCA distensibility had a negative correlation with both patients' age and time since menopause (r = -0.57 and r = -0.48, p < 0.05 for both cases). After estrogen administration, estradiol and estrone plasma levels were restored to the range of usual premenopausal values. Estrogen induced a significant increase in CCA distensibility by 0.92+/-0.005 dyne(-1) x cm2 x 10(-6) (from 2.03 to 2.95 dyne(-1) x cm2 x 10(-6)) and a significant reduction in CCA pulsatility index by 0.24+/-0.06, (from 2.17 to 1.93) (p < 0.001 for both cases). The improvement in CCA distensibility had a negative correlation with both patients' age and time since menopause (r= -0.46 and r = -0.44, respectively, p < 0.05 for both cases). Acute conjugated estrogen administration induced an improvement in CCA elasticity and a reduction in brain impedance in normotensive, postmenopausal women. As the age of women and the time since menopause increased, the improvement in carotid distensibility decreased in such selected subjects.

Influence of Letrozole and Anastrozole on Total Body Aromatization and Plasma Estrogen Levels in Postmenopausal Breast Cancer Patients Evaluated in a Randomized, Cross-Over Study

To compare the effects of the two novel, potent, nonsteroidal aromatase inhibitors anastrozole and letrozole on total-body aromatization and plasma estrogen levels. Twelve postmenopausal women with estrogen receptor-positive, metastatic breast cancer were treated with anastrozole 1 mg orally (PO) and letrozole 2.5 mg PO once daily, each given for a time interval of 6 weeks in a randomized sequence. Total-body aromatization was determined before treatment and at the end of each treatment period using a dual-label isotopic technique involving isolation of the metabolites with high-performance liquid chromatography. Plasma levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) were determined in samples obtained before each injection using highly sensitive radioimmunoassays. Pretreatment aromatase levels ranged from 1.68% to 4.27%. On-treatment levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole (mean percentage inhibition in the whole group, 97.3%) but in none of the 12 patients during treatment with letrozole (> 99.1% suppression in all patients; Wilcoxon, P =.0022, comparing the two drug regimens). Treatment with anastrozole suppressed plasma levels of E(1), E(2), and E(1)S by a mean of 81.0%, 84.9%, and 93.5%, respectively, whereas treatment with letrozole caused a corresponding decrease of 84.3%, 87.8% and 98.0%, respectively. The suppression of E(1) and E(1)S was found to be significantly better during treatment with letrozole compared with anastrozole (P =.019 and.0037, respectively). This study revealed letrozole (2.5 mg once daily) to be a more potent suppressor of total-body aromatization and plasma estrogen levels compared with anastrozole (1 mg once daily) in postmenopausal women with metastatic breast cancer.

Review of estrone sulfatase and its inhibitors--an important new target against hormone dependent breast cancer.

A high proportion (approximately 40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens. However, the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer, not only must the AR enzyme be inhibited, but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate, a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3 beta,17 beta-diol, which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid/estrone sulfatase inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken to date, as well as possible future development with respect to dual inhibitors of both estrone sulfatase and AR.