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Risk of coronary heart disease is higher in African-American than in Caucasian women.The aim of this study was to evaluate the contribution of sex hormone levels, race, and measures of body fat to the variation in plasma lipid levels, a well-established risk factor for coronary heart disease.This was a cross-sectional study.The study was conducted in the general community.Sixty Caucasian and 117 African-American premenopausal women participated.Body weight, body mass index (BMI), and waist to hip circumference ratio (WHR), as well as plasma lipid and serum sex hormone levels, were assessed.Relative to Caucasian women, African-American women had significantly higher mean BMI (23.92 +/- 3.87 vs. 26.99 +/- 5.87 kg/m2, respectively; P0.001), and WHR (0.733 +/- 0.052 vs. 0.757 +/- 0.068; P0.03). Also, plasma triglyceride (TG) levels were significantly lower in African-American women (81 +/- 61 vs. 55 +/- 24 mg/dl; P0.0001). Serum estrone sulfate (556 +/- 323 vs. 442 +/- 332 pg/ml, Caucasian vs. African-American; P0.001), estradiol (E2) (55.1 +/- 43.6 vs. 35.8 +/- 17.7 pg/ml; P0.0001), androstenedione (2.6 +/- 0.9 vs. 1.6 +/- 0.7 ng/ml; P0.0001), and testosterone (0.36 +/- 0.12 vs. 0.31 +/- 0.19 ng/ml; P0.002) levels were significantly lower in African-American women than in Caucasian women. After correction for the effects of age, BMI, and WHR, serum E2 levels were significantly and positively associated with plasma high-density lipoprotein cholesterol levels in all women, and serum estrone sulfate levels with plasma total cholesterol and TG levels in African-American women.Our results indicate that race is an important determinant of plasma TG and serum sex hormone levels, even after adjustment for differences in body size. A significant association between endogenous E2 and high-density lipoprotein cholesterol levels exists in premenopausal women, independent of their race.

Background. This study examines interrelationships among age, hormones, and cognition for middle-aged and elderly men, and tests whether hormones predict lower cognitive functioning and mediate the age–cognition relationship. Methods. We analyzed Time 2 data from the Massachusetts Male Aging Study, a population-based cohort study. Selection criteria included complete information on cognition and hormones (n ¼ 981). Cognitive measures included working memory (Backward Digit Span test), speed/attention (Digit Symbol Substitution test), and spatial ability (Figural Relations test). Hormones included free testosterone, total testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstanediol glucuronide (3 a-A-diol-gluc), luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (alternatively known as a ‘‘binding protein’’) (SHBG), prolactin (PRL), estrone (E1), and cortisol (CRT). Age was measured in years. Adjusted analyses added educational attainment, health conditions and behaviors, body mass index, and depression. Results. Older age was associated with lower cognitive functioning. In unadjusted models, logged free and total testosterone, DHEA, and DHEAS related to higher functioning in at least one cognitive domain; logged FSH, SHBG, and LH related to lower functioning in at least one cognitive domain; and logged E1, CRT, and PRL were not significant. In adjusted models, logged hormones did not relate to cognitive function except for logged E1 and CRT, which had negative effects. Logged hormones did not mediate the age–cognition relationship. Conclusions. The direct effects of hormones on cognition are not significant when salient factors are considered. Further, hormones do not mediate the age–cognition relationship; it is necessary to look to other explanatory pathways.

Objectives: Physical activity has demonstrable effects on estrogen levels in pre- and postmenopausal women. Increased oxidation of estrone to 2-hydroxyestrone (2HE) relative to 16α-hydroxyestrone (16HE) has been hypothesized to reduce breast cancer risk, but little is known about the effect of physical activity and body size in relation to the ratio of 2HE and 16HE in women. We examined these relationships in cross-sectional analyses of 157 North American and Chinese women. Methods: Physical activity was assessed using validated questionnaires. Adiposity was assessed as body mass index (BMI, kg/m2) and by anthropometric methods (% body fat). Estrone metabolites, 2HE and 16HE, were determined from urine via ELISA. Results: Regression analyses on the 2HE/16HE ratio revealed an interaction between leisure-time physical activities and adiposity in both North American and Chinese women (p≤ 0.05). Women reporting low levels of leisure-time physical activity who had higher BMI levels had 2HE/16HE ratios that were lower than their lean counterparts. In contrast, women with higher BMI levels that were physically active maintained higher 2HE/16HE ratios. Conclusion: These findings suggest that physical activity participation has the potential to modify the adverse effect of increased adiposity on estrogen metabolism in North American and Chinese women.

Obese women and women with upper body fat distribution have been shown to have a hormonal profile associated with increased risk of breast cancer. This study examines the relationships between obesity and body fat distribution, and sex hormones. Data from 47 healthy nulliparous premenopausal Caucasian women were collected cross-sectionally. Eight were obese and 39 non-obese. Thirteen had normal body fat (NBF), while 34 lower body fat (LBF) phenotypes. The concentrations of serum estrone, estrone sulfate, estradiol, free estradiol (Free E2), %Free E2, androstenedione, testosterone, free testosterone (Free T), %Free T, prolactin and sex hormone-binding globulin (SHBG) levels were determined in the mid-follicular phase. Results showed that in multivariate regression analyses controlling for age, age at menarche and body mass index (BMI), a 0.1 unit increase in waist-to-hip circumference ratio (WHR) towards the normal range decreased %FreeT by 18% (p=0.03), %FreeE2 by 15% (p=0.07) and increased SHBG by 36% (p=0.07). In similar analyses controlling for WHR, a unit increase in BMI increased %FreeE2 by 0.25%(p=0.04), %FreeT by 0.23% (p=0.07), and decreased that SHBG by 0.52% (p=0.07). Multivariate comparison showed SHBG levels to be higher by 39% (p=0.02) and %FreeE2 lower by 13% (p=0.07) in NBF compared to LBF phenotype women. Multivariate comparison between obese and nonobese women, however, showed SHBG levels to be lower by 24% (p=0.04), and %FreeE2 higher by 18% (p=0.04) in obese women. Results suggested that obesity and increasing BMI are associated with a serum sex hormone profile that increases breast cancer risk; however, increasing WHR towards the normal range is not associated with a high risk sex hormone profile. WHR in the normal range appears to be associated with a sex hormone profile that is more protective compared to the lower range.

Androstenedione is a steroid hormone and the major precursor to testosterone. It is available without prescription and taken with the expectation that it will be converted to testosterone endogenously and increase strength and athletic performance. The metabolism of orally administered testosterone has not been well studied.We randomly assigned 37 healthy men to receive 0, 100, or 300 mg oral androstenedione in a single daily dose for 7 d. Single 8-h urine collections were performed on the day before the start of the androstenedione administration and on d 1 and 7 to assess excretion rates of free and glucuronide- conjugated testosterone, androsterone, etiocholanolone, and dihydrotestosterone. Serum testosterone glucuronide concentrations were measured by frequent blood sampling over 8 h on d 1 in 16 subjects (5 each in the 0 and 100 mg group and 6 in the 300 mg group).In the control group, mean (±se) d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 3 ± 1, 215 ± 26, 175 ± 26, and 0.4 ± 0.1 μg/h, respectively. In the 100 mg group, mean d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 47 ± 11, 3,836 ± 458, 4,306 ± 458, and 1.6 ± 0.2 μg/h, respectively. In the 300 mg group, mean d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 115 ± 39, 8,142 ± 1,362, 10,070 ± 1,999, and 7.7 ± 1.5μ g/h, respectively. Urinary excretion rates of all metabolites were greater in both the 100 and 300 mg groups than in controls (P < 0.0001). Urinary excretion rates of testosterone (P = 0.007), androsterone (P = 0.009), etiocholanolone (P= 0.0005), and dihydrotestosterone (P < 0.0001) were greater in the subjects who received 300 mg androstenedione than in those who received 100 mg. In the treated groups, excretion of free testosterone accounted for less than 0.1% of the total excreted testosterone measured. Serum testosterone glucuronide levels increased significantly during frequent blood sampling in both the 100 and 300 mg groups compared with controls (P = 0.0005 for the 100 mg group; P < 0.0001 for the 300 mg group). The net mean changes in area under the curve for serum testosterone glucuronide were −18 ± 25%, 579 ± 572%, and 1267 ± 1675% in the groups receiving 0, 100, and 300 mg/d androstenedione, respectively.We conclude that the administration of both 100 and 300 mg androstenedione increases the excretion rates of conjugated testosterone, androsterone, etiocholanolone, and dihydrotestosterone and the serum levels of testosterone glucuronide in men. The magnitude of these increases is much greater than the changes observed in serum total testosterone concentrations. These findings demonstrate that orally administered androstenedione is largely metabolized to testosterone glucuronide and other androgen metabolites before release into the general circulation.

Low circulating levels of the adrenal steroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are thought to be associated with increased risk of cardiovascular disease (CVD) in men. In women, either a positive or null association with CVD has been found. The nature of the relation between DHEAS and CVD risk factors in women is unclear and is based on cross-sectional data. We present results from a longitudinal investigation of serum DHEA and DHEAS and cardiovascular disease risk factors in 236 women, initially 50-60 years old, from a population-based prospective (1986-1995) study of the menopausal transition. We used generalized estimating equations to model the relation of serum DHEA and DHEAS to systolic and diastolic blood pressure and serum levels of total cholesterol, high density lipoprotein cholesterol, and apolipoproteins A and B, adjusting for other factors related to CVD. Both DHEA and DHEAS were positively related to diastolic and systolic blood pressure, and DHEAS was negatively related to apolipoprotein A. DHEA and DHEAS were also positively related to smoking, alcohol use, estrone, and estradiol levels, and inversely related to age. Our results suggest that higher levels of DHEA and DHEAS in middle-aged women may indicate increased CVD risk.

PURPOSE: Serum concentrations of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS), both of which decline with age more markedly than other sex hormone levels, have been alternately credited and discredited as “protective” correlates of heart disease. Baseline data from the Massachusetts Male Aging Study (MMAS), collected in 1987–89, provided a large population-based random sample (n = 1709) in which to examine cross-sectionally the relation of DHEA and DHEAS levels to heart disease, while controlling for a comprehensive set of potential confounders including serum lipid and hormone levels as well as smoking, alcohol intake, obesity, hypertension, diabetes, diet, medication, physical activity, and psychological measures. METHODS: The subjects were men aged 40–70 years, randomly sampled from the Massachusetts state census listing, measured and interviewed at home. Nonfasting blood samples were assayed for hormones and lipids. RESULTS: In all strata of age, smoking, and alcohol intake, the age-adjusted odds ratio for self-reported heart disease was between 0.55 and 0.85 per standard deviation (SD) of log DHEA and DHEAS concentration. Multiple logistic regression analysis indicated a strong independent role for DHEAS as a predictor of self-reported heart disease, controlling for age and the potential confounders listed above. The multiply-adjusted odds ratio for heart disease was 0.64 per SD log DHEAS concentration, with 95% confidence interval (CI) 0.50–0.83 (P = 0.0002). The DHEAS effect was not diminished by controlling for use of cardiac, vasodilator, antihypertensive, or lipid-lowering medication. CONCLUSIONS: These findings suggest that serum DHEAS levels bear an inverse relationship to heart disease, independently of a large set of established cardiovascular risk factors. The cross-sectional nature of this study requires that the findings be interpreted with caution.

We conducted a controlled feeding study to evaluate the effects of fat and fiber consumption on plasma and urine sex hormones in men. The study had a crossover design and included 43 healthy men aged 19-56 y. Men were initially randomly assigned to either a low-fat, high-fiber or high-fat, low-fiber diet for 10 wk and after a 2-wk washout period crossed over to the other diet. The energy content of diets was varied to maintain constant body weight but averaged approximately 13.3 MJ (3170 kcal)/d on both diets. The low-fat diet provided 18.8% of energy from fat with a ratio of polyunsaturated to saturated fat (P:S) of 1.3, whereas the high-fat diet provided 41.0% of energy from fat with a P:S of 0.6. Total dietary fiber consumption from the low- and high-fat diets averaged 4.6 and 2.0 g.MJ-1.d-1, respectively. Mean plasma concentrations of total and sex-hormone-binding-globulin (SHBG)-bound testosterone were 13% and 15% higher, respectively, on the high-fat, low-fiber diet and the difference from the low-fat, high-fiber diet was significant for the SHBG-bound fraction (P = 0.04). Men's daily urinary excretion of testosterone also was 13% higher with the high-fat, low-fiber diet than with the low-fat, high-fiber diet (P = 0.01). Conversely, their urinary excretion of estradiol and estrone and their 2-hydroxy metabolites were 12-28% lower with the high-fat, low-fiber diet (P < or = 0.01). Results of this study suggest that diet may alter endogenous sex hormone metabolism in men.

To evaluate whether diet may influence the incidence of hormone-dependent cancers through an effect on blood estrogen and androgen concentrations, we analyzed diet-blood hormone relations in a cross-sectional study. Dietary energy, fat, and fiber intakes were estimated from 7-d food records completed by 90 premenopausal women on days 14-20 of their menstrual cycles. Fasting blood specimens were collected on days 5-7, 12-15, and 21-23 of each participant's cycle and pooled to create follicular-, midcycle-, and luteal-phase samples, respectively, for analysis. Energy intake was associated inversely with plasma androstenedione and dehydroepiandrosterone sulfate (DHEAS), averaged across the three menstrual cycle phases, and directly with the probability of a luteal-phase rise in progesterone. For each additional 1 MJ (239 kcal) consumed, androstenedione decreased by 6.0% (95% CI: -8.4%, -3.6%), DHEAS decreased by 5.1% (95% CI: -9.6%, -0.4%), and the probability of a progesterone rise increased by 60% (95% CI: 5%, 145%). After energy intake was adjusted for, the ratio of polyunsaturated to saturated fat (P:S) in the diet was significantly inversely associated with plasma estradiol and estrone during the luteal phase of the menstrual cycle. For each 0.1 increment in the P:S, there was a 7.6% (95% CI: -14.3%, -0.5%) decrease in estradiol and a 6.8% (95% CI: -12.7%, -0.6%) decrease in estrone. Results of this cross-sectional study support a relation between both energy and fat ingestion and plasma sex hormone concentrations in premenopausal women.

To test the hypothesis that the concentrations of estrone, estradiol, and free estradiol give separate information on the presence of hot flashes, lipid levels, and changes in lipid levels over a 3-year time span, we used longitudinal data from the Massachusetts Women's Health Study. We also examined whether sex hormone-binding globulin (SHBG) is associated with these end points. Two hundred and forty-one women who were initially pre- or peri-menopausal were followed for a 3-year period (1986-1990). Over this time estrogen levels declined by 32-45% and SHBG concentrations increased 81%. The three estrogen measures were highly correlated, and all three were negatively associated with the presence of hot flashes, but free estradiol did not add to the information provided by estrone and estradiol. None of the three estrogens was associated concurrently with any lipid levels. The SHBG concentration was not associated with hot flashes but was related to the concentrations of triglycerides and apoprotein-B (negatively) and to the log high-density li-poprotein-cholesterol (HDL-C) and log apoprotein A-I (Apo-A-I) concentrations (positively). Changes in estrogen levels were unrelated to changes in triglycerides and HDL-C. Change in estrone levels was positively associated with change in Apo-A-I but estradiol and free estradiol were negatively associated with change in Apo-A-I. In conclusion, our data indicate that, although highly intercorrelated, the three estrogen measures cannot be used interchangeably in predicting the selected end points, hot flashes, and lipids.

We assessed the relation of plasma hormone levels and nonhormonal factors with subsequent occurrence of surgical treatment for benign prostatic hyperplasia (BPH) among participants in the Physicians' Health Study. Frozen plasma samples, collected at the study onset, were available for 320 men who developed surgically treated BPH up to 9 years later and for 320 age-matched controls. Plasma testosterone (T), dihydrotestosterone (DHT), androstenedione, estradiol (E2), and estrone (E1) were measured for each case-control pair. In unadjusted analyses, none of the hormones or hormone ratios were associated with BPH; for example, for T and E2 the odds ratios (OR) comparing the highest quintile (Q5) with the lowest (Q1) were 0.74 (95% CI = 0.42, 1.30) and 1.07 (95% CI = 0.51, 2.22), respectively. However, in multivariate analyses controlling diastolic blood pressure, exercise, alcohol, E1, and DHT:T ratio, we observed a strong trend for increasing risk across quintiles for E2 (Q5 vs. Q1 OR = 3.56, P trend = 0.009), and a weak inverse trend for E1 (Q5 vs Q1 OR = 0.51, P trend = 0.07). The excess risk associated with E2 was confined to men with relatively low androgen levels. Three nonhormonal factors previously suspected as risk factors were independently associated with surgical BPH in these data. The OR for a 1-mm Hg difference in diastolic blood pressure was 1.04 (95% CI = 1.01, 1.07). Alcohol use and infrequent exercise were inversely associated with risk of BPH surgery; however, risk estimates were not consistent across categories of exercise and alcohol frequency. Our results indicate that normal variation in circulating androgen levels does not influence development of BPH, but that variation in estrogen levels might be important.

The relationships of cigarette smoking, age, relative weight, and dietary intake to serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, cortisol, 3-alpha-androstanediol, 3-alpha-androstanediol-glucuronide, testosterone, albumin-bound testosterone, free testosterone, dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) were examined cross-sectionally in 1241 randomly sampled middle-aged U.S. men. Compared with nonsmokers and independent of relative weight (body mass index) and age, cigarette smokers had increased serum levels of DHEA (18% higher, P = 0.0002), DHEAS (13% higher, P = 0.0007), cortisol (5% higher, P = 0.01), androstenedione (33% higher, P = 0.0001), testosterone (9% higher, P = 0.009), DHT (14% higher, P = 0.004), and SHBG (8% higher, P = 0.004). Androstenedione, total plasma testosterone, albumin-bound testosterone, DHT, and SHBG decreased with increasing relative weight. Age was positively associated with serum SHBG and negatively associated with albumin-bound testosterone, DHEA, and DHEAS. An association was found between alcohol intake and DHEA (r = 0.15; P = 0.0001), cortisol (r = 0.10; P = 0.0007), and 3-alpha-androstanediol-glucuronide (r = 0.08; P = 0.0004). Cortisol was the only hormone that was associated with carbohydrate intake (r = -0.09; P = 0.002). The only hormones associated with dietary lipids were DHT (for vegetable fat, r = 0.07; P = 0.02), cortisol (for total fat, r = 0.08; P = 0.007), and SHBG (for animal fat, r = -0.06; P = 0.05). In addition, SHBG was positively associated with dietary (r = 0.07; P = 0.008) and crude (r = 0.08; P = 0.007) fiber. These data suggest that serum adrenal steroid and sex hormone concentrations in middle-aged men are more influenced by cigarette smoking, age, and obesity than by dietary intake; however, serum adrenal steroids were influenced by alcohol intake.

Obesity offers protection against osteoporosis in older women. The mechanisms are not well understood, but relate in part to increased aromatization of adrenal androgens to estrone in peripheral fat and muscle tissue. Two hundred and one white and 77 black women previously reported to be free of skeletal disease and to have normal bone mass had measurements of total body bone mineral (TBBM), fat mass (TBFM), and lean mass (TBLM) performed by dual energy x-ray absorptiometry. Serum estrone, androstenedione, and dihydroepiandrostenedione sulfate were measured on the same day. Body weight, body mass index, TBFM, and TBLM were all significantly higher in the black women. However, proportionately, there were no differences in body composition between the two groups. This suggests that the black women were not more obese despite their greater body mass index, and that future studies on the health impact of obesity in older black women should take this into consideration. Despite the greater TBFM and TBLM in the black women and no difference in serum androstenedione levels, the serum estrone level was not higher in the black women, and the higher bone mass in blacks was not related to serum estrone. In both ethnic groups, TBBM was significantly related to body weight (white, r = 0.80; black, r = 0.85; P0.001 for both). Both TBFM and TBLM were significantly related to TBBM in both ethnic groups. Serum estrone was significantly related to all measures of body mass in the white women, but to no measures of body mass in the black women, indicating apparent differences in the metabolism of estrone between older white and black women.

The effect of dietary fiber and fat on serum sex hormones was studied in premenopausal women. After an initial control period during which the diet was high in fat (40% of calories as fat) and low in fiber (12 g/day), the amounts of fat and fiber were varied in the setting of a metabolic kitchen and carefully monitored meals. Forty-eight women completed 58 protocols. When the diet was changed to low-fat (20-25% calories as fat) and high fiber (40 g/day), there were significant decreases in serum concentrations of estrone, estrone sulfate, testosterone, androstenedione, and sex hormone binding globulin (SHBG) and near significant decreases in estradiol and free estradiol. When independent effects were examined, high fiber alone caused a decrease in estradiol and SHBG, whereas fat and fiber caused the observed decrease in estrone sulfate. Dietary fat independently influenced the serum concentration of androstenedione. Increased dietary fiber caused a lengthening of the menstrual cycle by 0.72 day and a lengthening of the follicular phase by 0.85 day.

We investigated the acute effects of surgery, i.e. ovariectomy, the long-term effects of ovariectomy, and the effects of progesterone on the peripheral aromatization of androstenedione in rhesus monkeys (Macaca mulatta). For the acute effects of surgery, 7 rhesus monkeys were given a pulse of [3H]androstenedione/[14C]estrone 2 weeks before and immediately after ovariectomy. In each case all urine was collected for 4 days and analyzed for radioactivity as estrone glucuronide and the peripheral aromatization calculated from the isotope ratios. Similarly, 5 monkeys were studied before and 18 months after ovariectomy. The acute effects of surgery resulted in a significant decrease in the peripheral aromatization of androstenedione to estrone from a mean +/- SE of 0.94 +/- 0.26 to 0.61 +/- 0.19%, P = 0.0452. Conversely, the long-term effects of ovariectomy resulted in a significant increase in peripheral aromatization from 0.38 +/- 0.06 to 0.67 +/- 0.12%, P = 0.0207. In 7 monkeys the peripheral aromatization was measured before and 10 days after the administration of progesterone, 100 mg in oil. There was no difference in peripheral aromatization before, 0.62 +/- 0.04% and after progesterone, 0.58 +/- 0.05%, P = 0.10. We conclude that the acute stress of ovariectomy, or possibly the loss of ovarian aromatizing tissue, results in a decline in peripheral aromatization, but ovariectomy will have the long-term effect of an increase in aromatization, and that the presence or absence of progesterone does not play a role.

To study the interrelationships of steroids within the follicle, combined 6-h infusions of [3H]dehydroepiandrosterone sulfate and [14C] testosterone ([14C]T) were performed in four normal women treated with menotropins who were undergoing medically indicated surgery. The concentrations of tracer and/or nonisotopic dehydroepiandrosterone sulfate, androst-5-ene-3 beta,17 beta-diol sulfate, androst-5-ene-3 beta,17 beta-diol, dehydroepiandrosterone, androstenedione, T, dihydrotestosterone, estrone (E1), and estradiol (E2) were determined in arterial and venous blood and follicular fluid. The log-transformed product/precursor ratio of [3H]dihydrotestosterone/[3H]T in follicular fluid was negatively correlated with the log-transformed follicular concentrations of E1 (P = 0.01) and E2 (P = 0.02), suggesting a reciprocal relationship between 5 alpha-reductase and follicular E1 and E2. E2 and T were positively correlated in follicular fluid (r = 0.84; P = 0.0003), suggesting a stimulatory action of follicular T on aromatase. These findings along with extensive published data suggest that follicular T functions as a follicular regulator, enhancing follicular aromatase activity when adequate amounts of FSH are available. These conclusions have important implications with regard to mechanisms for selecting the dominant follicle and producing atresia in the remaining cohort of follicles, and they describe a final common path in the pathophysiology of anovulation.

Background Most epidemiologic studies of the relationship between alcohol consumption and breast cancer risk over the past decade have shown that persons who consume a moderate amount of alcohol are at 40%-100% greater risk of breast cancer than those who do not consume alcohol. Dose-response effects have been observed, but no causal relationship has been established. Purpose This study examines the hypothesis that alcohol consumption affects levels of reproductive hormones. Methods A controlled-diet study lasting for six consecutive menstrual cycles was conducted. Participants were randomly assigned to two groups, and a crossover design was used. During the last three menstrual cycles, alcohol consumption of the two groups was reversed. Thirty-four premenopausal women, aged 21-40 years, with a history of regular menstrual cycles, consumed 30 g of ethanol (equivalent to approximately two average drinks) per day for three menstrual cycles and no alcohol for the other three. All food and alcohol consumed were provided by the study. Caloric intake was monitored to ensure that each woman would maintain body weight at approximately the baseline level. Hormone assays were performed on pooled plasma or 24-hour urine specimens collected during the follicular (days 5-7), peri-ovulatory (days 12-15), and mid-luteal (days 21-23) phases of the third menstrual cycle for subjects on each diet. Results Alcohol consumption was associated with statistically significant increases in levels of several hormones. Plasma dehydroepiandrosterone sulfate levels were 7.0% higher in the follicular phase (P = .05). In the peri-ovulatory phase, there were increases of 21.2% (P = .01) in plasma estrone levels, 27.5% (P = .01) in plasma estradiol levels, and 31.9% (P = .009) in urinary estradiol levels. In the luteal phase, urinary estrone levels rose 15.2% (P = .05), estradiol levels increased 21.6% (P = .02), and estriol levels rose 29.1% (P = .03). No changes were found in the percent of bioavailable estradiol, defined by the sum of percent free estradiol and percent albumin-bound estradiol. However, increased total estradiol levels in the peri-ovulatory phase suggest elevated absolute amounts of bioavailable estradiol. Conclusion This study has shown increases in total estrogen levels and amount of bioavailable estrogens in association with alcohol consumption in premenopausal women. Implication This possible explanatory mechanism for a positive association between alcohol consumption and breast cancer risk merits further investigation.

Previous studies have shown a relationship between age and weight and the MCR and conversions ([rho]) of androgens and estrogens. To assess the relative importance of these relationships in the metabolism and conversion of the androgens and estrogens, we used a series of statistical analyses, including t test, Pearson's correlation, and a step-wise regression analysis of the data obtained from the constant infusion of radiolabeled androgens and estrogens to normal women, 18-90 yr old. The MCRs of testosterone (T), androstenedione (A), and estrone (E1) were strongly correlated with weight, but not age or menopausal status. The MCR of estradiol (E2) was strongly correlated with weight and less strongly correlated with age, but was not correlated with menopausal status. The interconversions of the androgens ([rho]T,ABB and [rho]A,TBB, i.e. percentage of precursor infused measured as product in blood) and estrogens ([rho]E1,E2BB and [rho]E2,E1BB) were not correlated with age or weight, but there was a weak correlation between [rho]T,ABB and menopausal status. The aromatization of androgens to estrogens ([rho] A,E1BM and [rho]T,E2BM, i.e. percentage of androgens infused measured as estrogen glucuronide in the urine) was highly correlated with age, less strongly correlated with weight, and not correlated with menopausal status. The correlation with weight and MCR is a reflection of the extrasplanchnic metabolism of steroids. The lack of correlation with weight for the interconversions of androgens and estrogens indicates that the enzyme(s) responsible is affected differently in extrasplanchnic tissue than is the aromatase complex. The relationship between age and aromatization, while strong, remains unexplained.

We evaluated the influence of dietary, anthropomorphic, and hormonal factors on bone density in a cross-sectional sample of 281 pre- and perimenopausal women age 50-60 years living in Massachusetts. The sample included only women who had intact ovaries and were not currently using estrogen. Information on diet was obtained through a semiquantitative food frequency questionnaire. We measured bone density using single-photon absorptiometry in the non-dominant arm in two sites: the midshaft and the ultradistal radius. We observed no important associations between midshaft bone density and dietary variables but found linear relations between ultradistal radius bone density and body mass index [b = 1.10 gm/cm2 per kg/m2, standard error (SE) = 0.56], follicle-stimulating hormone (FSH) (b = -0.36 gm/cm2 per IU/liter, SE = 0.15), and several nutrients: calcium (b = 0.012 gm/cm2 per mg/day, SE = 0.007), retinol (b = 0.002 gm/cm2 per IU/day, SE = 0.0008), vitamin C (b = 0.025 gm/cm2 per mg/day, SE = 0.013), and vitamin D (b = 0.040 gm/cm2 per IU/day, SE = 0.018). We could not clearly distinguish the independent contribution of these micronutrients, however, because many were commonly ingested together in the form of supplements. Caffeine was inversely associated with bone density (b = -0.035, SE = 0.017) independent of dietary, anthropometric, and hormonal factors. Analyses of individual caffeinated beverages revealed consistent inverse associations for coffee (b = -3.42 gm/cm2 per cups/day, SE = 1.49), tea (b = -2.85 gm/cm2 per cups/day, SE = 1.56), and caffeinated cola (b = -14.0 gm/cm2 per cans/day, SE = 5.1), but not for decaffeinated coffee or decaffeinated cola [corrected]. [ABSTRACT TRUNCATED AT 250 WORDS)

At the time of surgery, women were infused with [3H]dehydroepiandrosterone sulfate ([3H]DS)/[14C]testosterone ([14C]T) for 6 h; blood samples were obtained from an artery the ovarian veins, and a peripheral vein; and fluid was obtained from ovarian follicles. Both blood and follicular fluid samples were analyzed for radioactivity as DS, dehydroepiandrosterone (D), androstenedione (delta 4A). T, and dihydrotestosterone (DHT), and the blood was also analyzed for the concentration of nonisotopic DS by RIA. In other subjects the concentrations of D and DS were measured in paired samples of blood and follicular fluid. From these data, values of 13.6 +/- 0.69 L/day four (mean +/- SE; n = 4) for MCRDS, 607 +/- 90 L/day (n = 3) for MCRT, and 0.0190 +/- 0.0089 (n = 3) for [p]DS-T (fraction of plasma DS metabolized to plasma T) were obtained. The ratio of the concentration of the tracer-labeled steroid in the follicular fluid to the concentration in the arterial plasma sample was elevated significantly above 1 for three 3H-labeled and three [14C-labeled metabolites: [3H]D (21-fold; P less than 0.001), [3H]T (81-fold; P less than 0.001), [3H]DHT (19-fold; P less than 0.001), [14C]T (4-fold; P less than 0.025), [14C]DHT (21-fold; P less than 0.01), and [14C]delta 4A (50-fold; P less than 0.001). The estimated concentrations of steroids in follicular fluid derived from DS based on specific activity calculations were as follows: [geometric mean (95% confidence limits; n)]: DS, 5600 (4800-6500 nmol/L; 12); D, 370 (88-1500 nmol/L; 10); delta 4 A, 120 (67-220 nmol/L; 12); T, 130 (39-450 nmol/L; 10); and DHT, 64 (35-120 nmol/L; 8). Comparison of these data to known follicular fluid steroid concentrations shows that DS from the intravascular pool can be used as an ovarian prehormone.

The relationships between concentrations of endogenous hormones in serum and dietary intakes of alcohol, fats, fiber, and caffeine were examined in 325 healthy Massachusetts women aged 50-60 y who reported having a normal menstrual period within the previous 12 mo. Diet was assessed by a semiquantitative food frequency questionnaire. Hormones assayed were estrone, estradiol, percent free estradiol, sex-hormone-binding globulin (SHBG), cortisol, and gonadotropins. Alcohol intake was not associated with concentrations of estrogens or gonadotropins. Neither total fat intake nor the fat composition of the diet influenced hormone concentrations. Fiber intake was positively correlated with SHBG; no associations with estrogens were seen. Caffeine intake was inversely correlated with free estradiol and positively correlated with SHBG. These data suggest that fat, fiber, and alcohol intakes of US women at climacteric are not determinants of variations in estrone and either total or percent free estradiol.

Although the administration of estrogens and androgens can affect the concentrations of sex hormone-binding globulin (SHBG) in men, the relationships between endogenous estrogens and androgens and SHBG are uncertain. Therefore, in a randomly selected cohort of 1640 middle-aged men we measured androgen, estrogen, and SHBG concentrations and obtained the subjects' weight, ethanol intake, and smoking histories. The data were analyzed by stepwise multiple regression, with SHBG as the dependent variable, to compare the role of hormones with that of other factors in the control of SHBG levels. Neither estrone or estradiol nor the testosterone/estradiol ratio was predictive of SHBG levels. However, SHBG concentrations were positively correlated with total testosterone and negatively correlated with percent free and percent albumin-bound testosterone. SHBG concentrations were negatively correlated with estrone sulfate, but were positively correlated with the testosterone/estrone sulfate ratio and the concentrations of free and albumin-bound testosterone. In addition, in all models tested age and body mass index (wt/ht2), but not smoking or ethanol, were strong predictors of SHBG concentrations. Thus, when present in physiological amounts in the blood as a result of glandular secretion, there is a positive relationship between SHBG concentrations and testosterone and, to a lesser extent, free- and albumin-bound testosterone, but age and body mass index appear to be more important in predicting the SHBG concentration.

Although there have been numerous studies on the production of prostaglandins (PGs) by human endometrium in vitro during the menstrual cycle, considerable variation exists in the levels reported during the proliferative vs. the secretory phase. Such variation may be due in part to the difficulty in obtaining endometrium from a precisely known hormonal environment and in part to the use of the different culture systems employed. The aim of the present study was to develop a non-human primate model in which precisely dated endometrial tissue could be obtained reliably. Moreover, PG levels in the endometrium of the rhesus monkey or other primates have not previously been reported during the artificial menstrual cycle. An important objective in establishing such a model was to permit future manipulations of the cycle in vivo [e.g. by omitting the midcycle estradiol (E) peak] to further dissect specific roles of E and progesterone (P) in regulating PG synthesis during the menstrual cycle. Ovariectomized rhesus monkeys were maintained on a standard artificial menstrual cycle via the insertion and removal of Silastic capsules containing E or P. Samples of endometrium (approximately 50 mg) were obtained by hysterotomy under sterile conditions at predetermined stages of separate menstrual cycles: day 9 (midproliferative; n = 5), day 13 (E peak; n = 3), day 14 (1 day post-E peak; n = 5), and day 23 (midsecretory; n = 8). Measurement of the primary PGs in unextracted medium by RIA over 4 days of organ culture indicated PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 greater than thromboxane-B2, PGD2 greater than leukotrienes. PGF2 alpha, the most abundant PG produced on the first day of culture, was low on day 9 and increased dramatically on day 13 (P less than 0.01). On day 14, PGF2 alpha levels fell significantly only 1 day post-E peak (P less than 0.01), while on day 23, after exposure to P in vivo, PGF2 alpha was 10-fold higher (P less than 0.01) than on cycle days 9 and 14. The other PGs measured showed a lower but similar profile at the cycle stages examined. Physiological concentrations of P (5.0 ng/mL) added to cycle day 23 cultures in both the absence and presence of low or high E markedly inhibited the high levels of PGs found in day 23 cultures (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

To determine whether there was a significant relationship between circulating lipids or lipoproteins and circulating estrogens or sex hormone-binding globulin (SHBG) in pre- and premenopausal women, 352 women were chosen randomly from communities in Eastern Massachusetts. These women had nonfasting blood samples drawn and analyzed for total cholesterol, high density lipoprotein cholesterol (HDL-C), HDL-2, HDL-3, apolipoprotein-A-I (apo-A-I), apo-B, triglycerides (TG), estrone, estradiol (E2), free E2, SHBG, and FSH. In addition, their body mass index (BMI; wt/ht2) was calculated, and a history of smoking, ethanol intake, current medication use, and the date of their last menstrual period was obtained. When the women were grouped according to the months from their last menses (less than 1, 1-3, and 4-11 months), those 4 months or longer since last menses had significantly lower E2 concentrations and significantly greater total cholesterol and FSH concentrations than the other two groups. However, when regressed on hormones, BMI, ethanol intake, and last menstrual period, total cholesterol was significantly related only to the time from last menses; TG, HDL-C, HDL-2, and apo-A-I were related to SHBG. Relationships between the lipids, with the exception of cholesterol and apo-B, were also noted with BMI and/or ethanol. Apo-B was related to the time from last menses. Differences in circulating estrogens appeared to be related only minimally, if at all, to the differences in total cholesterol that are seen in perimenopausal women. The relationships between lipids and lipoproteins and SHBG are probably epiphenomena as a result of similar sites of synthesis. Changes in lipids and lipoproteins that are seen at the time of the menopause are probably multifactorial in origin.

To examine the effects of hypothyroidism on androstenedione (A) and estrone (E1) metabolism, we infused eight women with [3H]androstenedione and [14C]estrone when they were hypothyroid and again when they were euthyroid after levo-T4 administration. MCRs and conversion ratios were measured using concentrations of radioactivity in the blood pools of A and E1. Peripheral aromatization was measured from the concentrations of radioactivity in the E1 glucuronide pool in the urine. After the women were euthyroid, the MCR of A had increased in seven of eight, the MCR of E1 increased in all eight, and peripheral aromatization had decreased in seven of eight. These findings indicate that hypothyroidism results in a decrease in the MCRs of A and E1 and, in most subjects, an increase in peripheral aromatization of A to E1.

As part of a study on hormones and bone density in peri-menopausal women, metabolic clearance rates (MCR), and interconversions of androgens and estrogens and the peripheral aromatization of androgens were measured twice 2 yr apart. Measurements of clearance rates and interconversions were made from blood samples obtained during constant infusions of [3H]androgens and [14C]estrogens. Measurements of peripheral aromatization were made from the estrogen glucuronides in a pooled 4-day urine collection timed from the start of the infusions. The women were divided into 3 groups: Group A (n = 15) were having menstrual cycles throughout the 2 yr interval; Group B (n = 11) were having menstrual cycles at the time of Study 1 but had been amenorrheic for at least 1 yr at the time of Study 2; Group C (n = 28) were amenorrheic for at least 1 yr at the time of Study 1 and had remained amenorrheic through Study 2. The MCRs for testosterone, androstenedione, estrone and estradiol were not different for Study 1 and Study 2 in any of the groups. The interconversions of the androgens were similar in both studies for all groups. The conversion of estrone to estradiol decreased in Group A, otherwise the interconversions of the estrogens did not vary between the studies for the other groups. The peripheral aromatization of androstenedione, but not of testosterone, was significantly greater at study 2 compared to Study 1 for all groups. We conclude that the MCRs and interconversions of androgens and of estrogens are stable over time, but that the peripheral aromatization of androstenedione increases over a 2 yr interval. This increase may be menopausal and/or age related.

Androstenedione is a steroid hormone and an intermediate in the synthetic pathway of both testosterone and estradiol in men and women. It is available without prescription and taken with the expectation that it may have beneficial effects on strength, general well-being, libido, and quality of life. Although studies have shown that oral androstenedione increases serum testosterone and estradiol levels in men, the hormonal effects of androstenedione in postmenopausal women are unknown. We randomly assigned 30 healthy postmenopausal women to receive 0, 50, or 100 mg androstenedione as a single oral dose. After androstenedione administration, we made hourly measurements of serum androstenedione, estrone, estradiol, and testosterone concentrations during 12 h of frequent blood sampling. The mean change (+/-SD) in serum androstenedione area under the curve (AUC) was greater in both the 50-mg (79 +/- 39%) and 100-mg dose groups (242 +/- 184%) than in the control group (-29 +/- 28%) (P < 0.0001 for controls vs. 50-mg group and controls vs. 100-mg group). The mean change in serum androstenedione AUC was also greater in the 100-mg than 50-mg dose group (P = 0.0026). The mean change in serum estrone AUC was greater in both the 50-mg (108 +/- 72%) and 100-mg dose groups (116 +/- 119%) than in the control group (-5 +/- 19%), although the control vs. 100-mg group comparison did not quite meet statistical significance (P < 0.0001 for controls vs. 50-mg group, P = 0.0631 controls vs. 100-mg group). The mean change in serum estradiol AUC remained stable after supplementation in all groups without any between-group differences observed (-11 +/- 17%, 2.8 +/- 34%, -11 +/- 27%, for the control, 50-mg, and 100-mg groups, respectively). The mean change in serum testosterone AUC was greater in both the 50-mg (185 +/- 146%) and 100-mg dose groups (457 +/- 601%) than in the control group (-27 +/- 13%) (P < 0.0001 for controls vs. 50-mg group and for controls vs. 100-mg group). The mean change in testosterone AUC was also greater in the 100-mg dose group than 50-mg dose group (P = 0.0257). There was considerable individual variability in the changes of serum androstenedione, estrone, and testosterone levels in the treated groups with peak serum testosterone levels exceeding the upper limit of normal in 4 of 10 women in the 50-mg dose group and 6 of 10 in the 100-mg dose group. We concluded that the acute administration of both 50-mg and 100-mg of androstenedione increases serum testosterone and estrone levels, but not estradiol levels, in postmenopausal women. If these hormonal effects are sustained during long-term administration, regular use of this supplement by postmenopausal women could thus cause both beneficial and adverse effects.

We used longitudinal data from the Massachusetts Male Aging Study, a large population-based random-sample cohort of men aged 40-70 yr at baseline, to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends. Of 1,709 men enrolled in 1987-1989, 1,156 were followed up 7-10 yr afterward. By repeated-measures statistical analysis, we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data, the cross-sectional trend between subjects within the follow-up data, and the longitudinal trend within subjects between baseline and follow-up. Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data, whereas both free and albumin-bound T declined at about 2%/yr, all significantly more steeply than within the baseline data. Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data, similarly to baseline. The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T (1.6%/yr) and bioavailable T (2-3%/yr). Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and PRL rose longitudinally. Apparent good health, defined as absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10-15% to the level of several androgens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends. The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.

Our purpose was to examine the roles of natural (estradiol (E2) and estrone (E1)) and synthetic estrogens (ethinyl estradiol (EE), moxestrol (MOX), and tamoxifene (TAM)) in regulating production of sex hormone-binding globulin (SHBG) by human hepatoma G2 (Hep G2) cells, the rationale being that synthetic estrogens are less rapidly metabolized than natural estrogens and, thus, may alter SHBG levels more readily. In Hep G2 cells, E2, E1, and EE at 10(-7) M did not result in significantly greater SHBG secretion compared to control cells. The synthetic estrogens, MOX and TAM, caused significant, P < 0.001, increases of 30% and 51% in SHBG secretion at 10(-7) M compared to controls. However, when TAM and E2 were added together, each at 10(-7) M, no increase in SHBG secretion was noted. We conclude that natural estrogens at physiologic concentrations do not increase SHBG secretion by Hep G2 cells, but the increase of SHBG secretion caused by MOX and TAM suggests that the lack of effect of E2 and E1 may, in part, be due to their rapid metabolism. In addition, TAM stimulates SHBG secretion by interaction with the genome that is different, in certain respects, from that of E2.

ContextAndrostenedione, a steroid hormone and the major precursor to testosterone, is available without prescription and is purported to increase strength and athletic performance. The hormonal effects of androstenedione, however, are unknown.ObjectiveTo determine if oral administration of androstenedione increases serum testosterone levels in healthy men.DesignOpen-label randomized controlled trial conducted between October 1998 and April 1999.SettingGeneral clinical research center of a tertiary-care, university-affiliated hospital.ParticipantsForty-two healthy men aged 20 to 40 years.InterventionSubjects were randomized to receive oral androstenedione (either 100 mg/d [n = 15] or 300 mg/d [n = 14]) or no androstenedione (n = 13) for 7 days.Main Outcome MeasuresChanges in serum testosterone, androstenedione, estrone, and estradiol levels, measured by frequent blood sampling, compared among the 3 treatment groups.ResultsMean (SE) changes in the area under the curve (AUC) for serum testosterone concentrations were −2% (7%), −4% (4%), and 34% (14%) in the groups receiving 0, 100, and 300 mg/d of androstenedione, respectively. When compared with the control group, the change in testosterone AUC was significant for the 300-mg/d group (P

The concentration of androgens in the blood peaks in early adulthood. While the concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) decline steadily, the concentrations of androstenedione (A) and testosterone (T) decline just before or at the menopause. DHEAS is bound strongly to albumin, resulting in a very low metabolic clearance rate (MCR) of about 12 L/day. DHEA and A are bound weakly to albumin and their MCRs are 1800 to 2000 L/day. T is bound strongly to sex hormone-binding globulin (SHBG), and the MCR of T is about 500 L/day. There are no significant changes in the MCRs at the menopause or with age. The pathways of metabolism are not altered at the menopause but aromatization of DHEA, A, and T to estrone and estradiol all increase with age. Thus, androgen metabolism in general is affected more by age than by the menopause itself.

Chronic feeding of dehydroepiandrosterone (DHEA) and its sulfated metabolite, dehydroepiandrosterone sulfate (DHEAS), has previously been reported to decrease hyperglycemia, obesity, cancer, and autoantibody generation in a number of animal models and to increase muscle mass and physiological and psychological well-being in elderly humans, although these latter studies remain controversial. The present study was carried out to determine whether large amounts of DHEAS given orally would prevent the occurrence of spontaneous and iodine-induced autoimmune lymphocytic thyroiditis (LT) and/or spontaneous insulin-dependent diabetes mellitus (DM) in male and female BB/Wor rats. DHEAS was administered by gavage (44 mg/rat/day) or in the chow (133 mg/rat/day) to LT- and DM-prone rats from 30 to 120 days of life; some of these rats also received iodine in the drinking water to enhance the incidence and intensity of LT. Onset of DM requiring protamine zinc insulin and its maintenance dose were assessed. Rats were killed at 90 or 120 days of age and blood, thyroid, adrenals, pancreases, testes, and ovaries were removed. Serum glucose, DHEA, DHEAS, thyroxine (T4), tri-iodothyronine (T3) and thyrotropin (TSH) concentrations were measured in all rats in both experiments. Serum DHEAS concentrations were 10-fold higher in the rats given the steroid by gavage or in the diet compared with levels in control rats. DHEAS administered over a prolonged period of time had no significant effect on body weight, incidence and severity of DM, incidence and intensity of spontaneous and iodine-induced LT, and thyroid, pancreas and testes weights but did significantly decrease adrenal and ovarian weights. Serum T4, T3, and TSH concentrations were similar in control and DHEAS-treated rats. In conclusion, DHEAS did not prevent the occurrence of iodine-induced or spontaneous autoimmune LT or spontaneous DM in the BB/Wor rat, at variance with its reported immunosuppressive effects in other animal models.

The ability to create artificial menstrual cycles in the rhesus monkey provides a model for studies on the regulation of genes and gene networks by estradiol or progesterone (P) in the primate endometrium. This model allowed us to create both a normal level of secretory phase P or an inadequate level of secretory phase P, i.e. endometria that cannot support implantation. The objective of our present study focused on PCR analyses of genes for several factors that are believed to be important in the proper maturation of the endometrium. Complementary DNA (cDNA) populations were prepared from endometria harvested on day 13 (peak E level), days 21-23 of an adequate secretory phase (PcDNA) and days 21-23 of an inadequate secretory phase (IcDNA). Although placental protein 14, leukemia inhibitory factor and 17-beta hydroxysteroid dehydrogenase displayed highly upregulated levels in PcDNA (P-activated genes), there was little or no up-regulation in IcDNA. Transforming growth factor-beta 2 and its receptor and insulin growth factor-I and its receptor were up-regulated in PcDNA, whereas little or no expression was observed in IcDNA. Regulators of the cell cycle and transcription, such as retinoblastoma, c-fos, and c-jun genes, were also greatly underexpressed in IcDNA compared with PcDNA. Interestingly, one gene that we studied, keratinocyte growth factor, that was up-regulated by P (peak E levels vs. PcDNA) was more highly expressed in IcDNA. This latter result suggests that low levels of circulating P are sufficient for expression of this gene, whereas high sustained P levels result in an autologous down-regulation. These data show that the regulation of genes that may play pivotal roles in endometrial maturation are differentially expressed in IcDNA vs. PcDNA and may, in part, characterize improper endometrial maturation.

Background: In the United States, 5-year survival rates of 69% and 84%, respectively, have recently been reported for African-American and Caucasian women diagnosed with breast cancer. Differences in the levels of endogenous sex hormones in these populations could explain some of the variation in survival rates, since estrogen is recognized as a risk factor for this type of cancer. Purpose: Dietary factors are known to affect endogenous hormone levels; therefore, our study was designed to determine the serum hormone levels of African-Ameri can women consuming a typical North American diet, to determine the effect of a low-fat and high-Fiber diet on their serum hormone levels, and to compare the base-line serum hormone levels in the AfricanAmerican women with hormone data from our study of Caucasian women (n = 68) consuming the same control diet. Methods: Twenty-one healthy, premenopausal, AfricanAmerican women who agreed to eat only food prepared in a clinical study unit were recruited into the study. The control diet was similar to their usual diet, being high in fat (40% of calories from fat) and low in fiber (12 g/day), and was consumed on average for 3 weeks. The concentrations of estrone (E!), estrone sulfate (EjSO^, estradiol (E2), free E2, androstenedione, and sex hormone-binding globulin (SHBG) in serum samples obtained from the participants during the last week of the control diet and during the follicular phase of their menstrual cycle were determined. The women were then switched to a diet low in fat (20% of calories as fat) and high in Tiber (40 g/day); they consumed this diet for two menstrual cycles before blood samples were collected for determination of serum hormone levels. Repeated-measures regression modeling was used to investigate the relationship between diet and hormone levels in African-Ameri can and Caucasian women. All P values resulted from two-sided statistical tests. Results: Analysis of serum hormone levels in the African-American women indicated that the change in diet caused a significant decrease in E2 (-8.5%; 95% confidence interval [CI] = -16.1% to -0.3%; P

Because of the biologic effects on a variety of end points reported for dehydroepiandrosterone (DHA) and its sulfate (DHAS) after oral administration, we studied the metabolism of DHA in six female rhesus monkeys after oral and after intravenous administration. We administered [4- 14 C]DHA p.o. and [7- 3 H]DHA i.v. simultaneously, drawing blood samples at increasingly longer intervals for 24 h. The mean ± SE metabolic clearance rate of the intravenous DHA was 404 ± 49 L/day. The mean metabolic clearance rate was 2,601 ± 261 L/day after oral administration, and the calculated absorption was 16.3 ± 2.5%. There was rapid conversion of p.o. DHA to DHAS, as the conversion ratio of the orally administered DHA measured in the blood as [4- 14 C]DHAS was 63.3 ± 13.6, whereas the conversion ratio of intravenously administered DHA to DHAS was 9.3 ± 2.0. Small amounts of DHA were measured in the blood as testosterone and androstenedione after both forms of administration. We conclude that there is marked metabolism in splanchnic tissue of orally administered DHA to DHAS prior to its entry into the bloodstream, and the absorption of DHA itself is minimal when administered by mouth to the rhesus monkey.

Background : Alcohol use, height, and postmenopausal adiposity have each been positively associated with postmenopausal breast cancer risk in most epidemiologic studies. The mechanism underlying these associations is unclear, although an effect of these factors on hormone levels has been hypothesized. Few previous studies have evaluated the relationship of either alcohol consumption or height with plasma hormone levels. A positive association between adiposity and plasma estrogen levels in postmenopausal women has been reported consistently. Purpose : Using archived frozen plasma samples and corresponding data from participants in the Nurses' Health Study, we determined plasma hormone levels and assessed these levels in relation to alcohol consumption, height, and adiposity among postmenopausal women. Methods : Blood samples were collected from a subset of participants in the Nurses' Health Study in 1989 and 1990, then stored in liquid nitrogen. Hormone concentrations in 217 archived plasma samples (from healthy postmenopausal women) were analyzed in 1993. Spearman correlation coefficients were calculated to assess the linear association between alcohol consumption during the previous year (mean daily intake in grams per day ascertained from semiquantitative food-frequency questionnaires completed in 1990 or 1991), height, and adiposity (as measured by body mass index [BMI] in kg/m 2 , with weight reported at time of blood collection), and plasma hormone levels. Two-sided P values were also calculated. Results : After controlling for age, height, smoking status, and BMI, alcohol consumption was positively associated with estrone sulfate concentrations (r =.17 ; P =.02) ; no statistically significant association was noted for the other plasma hormones measured. Mean plasma estrone sulfate levels were 159 pg/mL in women who reported no alcohol use versus 211 pg/mL in women consuming 30 g or more of alcohol per day. After adjusting for the other covariates, we observed a strong positive correlation between BMI and plasma estrogens (r ranging from.37 for estrone and estrone sulfate to.63 for bioavailable estradiol, with all P values ≤.01 ; prolactin was the only hormone unassociated with BMI, r = -.01). Height was unrelated to either plasma estrogens or prolactin. Conclusions : BMI and alcohol use were positively associated with postmenopausal plasma estrogen and estrone sulfate levels, respectively. Implications : The association of alcohol consumption and postmenopausal obesity with subsequent breast cancer risk might be mediated, at least in part, through an influence on postmenopausal plasma estrogen levels. Additional studies are needed to further quantify the relationship between alcohol consumption and plasma hormone levels and to elucidate the physiologic basis for this association.

We have investigated the effects of a low-fat, high-fiber diet on plasma lipid and lipoprotein levels and serum sex hormone concentrations in 22 normal premenopausal women (mean age, 25.8 +/- 3.8 years). Participants consumed a baseline diet for 4 weeks (40% of calories as fat, 16% as saturated fatty acids, 8% as polyunsaturated fatty acids, 400 mg/d cholesterol, and 12 g/d dietary fiber) and then a low-fat, high-fiber diet for 8 to 10 weeks (16% to 18% of calories as fat, 4% as saturated fatty acids, 4% as polyunsaturated fatty acids, 150 mg/d cholesterol, and 40 g/d fiber). Blood samples for determination of plasma lipids and serum hormones were obtained during the follicular and luteal phases of the menstrual cycle during both diets. Compared with the baseline diet, the low-fat, high-fiber diet resulted in significant decreases in total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations during both the follicular and luteal phases (TC, -14% and -16%; LDL cholesterol, -14% and -17%; and HDL cholesterol, -15% and -18%, respectively). During the follicular phase but not the luteal phase on the low-fat, high-fiber diet, women exhibited significant increases in plasma triglyceride ([TG] 22%) and very-low-density lipoprotein (VLDL)-TG (36%) concentrations. During the follicular phase, serum estrone sulfate concentrations decreased by 25% (P < .0001) when subjects were fed the low-fat, high-fiber diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Parity, age at first birth, age at menarche, and a family history of breast cancer have each been associated consistently with breast cancer risk. Whether this increase in risk is mediated, at least in part, through changes in endogenous hormone levels is unclear. We conducted a cross-sectional study of the relationships between these factors and plasma hormone levels in 216 healthy postmenopausal women in the Nurses' Health Study (United States). The hormones evaluated were estradiol, percent and total free estradiol, percent and total bioavailable estradiol, estrone, estrone sulfate, and prolactin. After controlling for age, body mass index (weight/height2), and alcohol use, we observed inverse associations between estrone sulfate and parity (r = -0.15, P = 0.03) and between percent bioavailable estradiol and age at first birth (r = -0.17, P = 0.02). Although women with a family history of breast cancer tended to have higher estrogen levels compared with women without such history, the differences were not statistically significant. Age at menarche was not related significantly to any of the hormones. These data provide some additional evidence that the inverse relationship observed between parity and breast cancer risk may be mediated, at least in part, through decreased estrogen levels. Our data do not support a substantial influence of either family history of breast cancer or age at menarche on postmenopausal estrogen or prolactin levels.

In order to study the metabolism of estrone sulfate in the adult female rhesus monkey, we gave four monkeys a pulse injection of [3H]estrone sulfate and obtained blood samples at 15, 30, 60, 120, 300, and 1,440 minutes after the pulse. All blood samples were analyzed for [3H]estrone sulfate. The mean +/- SE for the initial volume of distribution was 4.6 +/- 0.9 L. The mean metabolic clearance rate (MCR) was 42.0 +/- 2.9 L/day. In addition, 2 monkeys were infused for 240 minutes with [3H]estrone sulfate and 5 monkeys were infused for 240 minutes with [3H]estrone sulfate/[14C]estrone. Three blood samples were obtained during the last hour of the infusions and analyzed for radioactivity as estrone sulfate, estrone, and estradiol, and MCRs, conversion ratios, and [rho]BB values were calculated. The mean +/- SE for the MCR was 67.5 +/- 8.3 L/day, and for the conversion ratio, estradiol to estrone sulfate was 0.054 +/- 0.016. The mean [rho]BB value for estrone sulfate conversion to estrone was 43.6 +/- 3.4% and for estrone conversion to estrone sulfate was 33.5 +/- 6.6%. Thus estrone sulfate is cleared slowly and is converted to both estrone and estradiol. The hydrolysis of estrone sulfate to estrone is not significantly different than the conversion of estrone to estrone sulfate.

We undertook a cross-sectional study in 107 premenopausal women in Maryland (United States) of alcohol intake and hormonal status in order to evaluate whether plasma hormone levels might mediate the reported positive relation between alcohol ingestion and breast cancer risk. Alcohol ingestion was estimated using a drinking pattern questionnaire, a food frequency questionnaire, and seven-day food records. Fasting blood specimens were collected on days 5-7, 12-15, and 21-23 of each participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Estrone, estrone sulfate, estradiol, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) in plasma were measured by radioimmunoassay, and sex-hormone binding globulin (SHBG) was measured by an immunoradiometric assay. After adjusting for age, weight, and total energy intake, alcohol ingestion was not associated with plasma estrogens in the follicular, midcycle, or luteal phases of the menstrual cycle, nor with the level of SHBG or DHEAS in plasma averaged from the three phases of the cycle. Alcohol, however, was significantly positively associated with the average level of plasma androstenedione. Based on these cross-sectional findings among premenopausal women, the increased risk of breast cancer related to alcohol ingestion does not appear to be mediated by elevated plasma estrogen levels. Androstenedione, however, may mediate the alcohol/breast cancer-association.

The hypothesis that dietary constituents affect estrogen metabolism arose, in part, from epidemiological data suggesting that dietary fat was related to breast cancer1-3. These data showed that in populations that ate large quantities of animal fat the incidence of breast cancer was greater than in populations eating minimal amounts of animal fat1,2,4. Since there was evidence that estrogens might be associated with breast cancer, it was felt that low fat diets might reduce the risk of breast cancer by lowering estrogen levels.

In order to determine the contribution of serum dehydroepiandrosterone sulfate (DS) to estrone (E1) production in normal women and the effect of chronic elevation of the serum DS concentration on DS metabolism, four normal women and four women with high endogenous serum DS were infused with [3H]DS and [14C]E1 or [14C]testosterone for 6 h. Blood samples were analyzed for radioactivity as DS, dehydroepiandrosterone (D), androstenedione, testosterone, and dihydrotestosterone. Urine was collected for analysis of creatinine, 17-ketosteroids (17-KS), and radioactivity as estrone (E1). The serum DS of 12.4 +/- 1.44 mumol/L (mean +/- SE) in the group with high DS was higher than that of 3.96 +/- 1.0 mumol/L (1.46 +/- 0.37 micrograms/mL) in the normals (P less than 0.005). Those with high DS also had increased 17-KS (13.2 +/- 2.0 vs. 5.68 +/- 0.68 mg/day, P less than 0.025) and a higher blood production rate of DS (PBDS) (126 +/- 21 (n = 3) vs. 54.3 +/- 13.8 mmol/day, P less than 0.05) but a lower MCRDS (10.94 +/- 0.61 (n = 3) vs. 13.8 +/- 0.27 L/day, P less than 0.01) than that in normals. In the four normal women the fraction of infused DS converted to estrone ( [rho]BMDS E1) was 0.00078 +/- 0.00018, the amount of E1 produced from serum DS was 41.3 +/- 15 nmol/day, the basal plasma E1 was 102 +/- 18 pmol/L, the MCRE1 was 1340 +/- 181 L/day, the value for blood production of E1 (PBE1) was 129 +/- 12 nmol/day, and the portion of E1 derived from DS was 30.4 +/- 9.4%. Correlation analysis of the data from these eight subjects showed that 17-KS, PBDS, and the serum DS were all correlated with body surface area, body weight, and ponderal index and that 17-KS excretion, PBDS, and serum DS were all correlated with one another. The most important predictors of 17-KS excretion were serum DS (P less than 0.001) and the ponderal index (P less than 0.05).

In order to measure the interconversions of estrone (E1) and estradiol (E2) and their conversion to the 16 alpha-hydroxylated estrogens, 16 alpha-hydroxy estrone (16 alpha-OHE1) and estriol (E3), we infused 11 female rhesus monkeys with [3H]E2 and [14C]E1 and measured radioactivity in the blood as E1, E2 and 16 alpha-OHE1 (n = 9) and in the urine as the glucuronides of E1, E2, 16 alpha-OHE1, and E3 (n = 11). The mean conversion of E1 to E2 as measured in blood (percent of infused E1 measured in blood as E2, [rho]1.2BB) was 29.2 +/- 1.6% and as measured in the urine of the same animals, [rho]1.2BM, was 77.4 +/- 5.9%. The mean conversion of E2 to E1, [rho]2.1BB was 21.5 +/- 1.0% and as measured in urine, [rho]2.1BM was 67.7 +/- 4.6%. Thus for both estrone and estradiol only 30-35% of the interconversions occurred in pools which were in equilibrium with the blood pool of these estrogens. The remaining 65-70% occurred in a pool, probably liver, in which glucuronidation occurred immediately after conversion. The conversion ratios (the ratio of the concentration in the blood of radioactivity as 16 alpha-OHE1 to its precursor, CRPrec,16 alpha-OHE1) was 0.036 +/- 0.008 for CRE1,16 alpha-OHE1 and 0.0039 +/- 0.0010 for CRE2,16 alpha-OHE1. The percentages of administered E1 excreted in the urine as the glucuronides of E1, E2, 16 alpha-OHE1 and E3 were 20.1 +/- 1.5, 1.6 +/- 0.2, 0.96 +/- 0.20 and 0.76 +/- 0.07 respectively. The percentages of administered E2 excreted in the urine as E1, E2, 16 alpha-OHE1 and E3 were 14.4 +/- 1.0, 2.2 +/- 0.3, 0.57 +/- 0.05 and 0.68 +/- 0.11 respectively. Thus there are minor differences in the patterns of excreted metabolites of E1 and E2. Furthermore, 16 alpha-OHE1 and E3 are not major metabolites of E1 or E2 in the female rhesus monkey.

To determine the effects of serum proteins on the biologic activity of estrogens, we perfused isolated livers from ovariectomized female rats with oxygenated Krebs-Henseleit-bicarbonate buffer (KHBB), with and without 4% human serum albumin (4% HSA), with and without added estrogens, or with charcoal-stripped human serum (CSHS) with and without added estradiol. At the end of the perfusions, the cytosolic and nuclear estrogen receptors were measured by an exchange assay. When added to KHBB, estradiol 10(-9) or 10(-8) M or estrone 10(-8) M did not cause any significant increase in the percent of receptors measured in the nucleus. When the livers were perfused with KHBB containing 4% HSA and estradiol 10(-9) to 10(-7) M or estrone 10(-8) M, there was an increase in nuclear receptors. Perfusion with estradiol 10(-8) M in CSHS resulted in significantly less receptor in the nucleus than after estradiol in KHBB plus 4% HSA. We conclude that the presence of 4% HSA in the perfusion medium increases the biologic activity of estradiol and estrone on the isolated rat liver, and this increase is inhibited in the presence of sex hormone-binding globulin. The exact mechanism by which HSA increases the biologic activity is uncertain, but may be due in part to better diffusion of estrogen through the liver.

We conducted a nested case-control study to prospectively evaluate the relationship of serum estrogens and androgens to risk of breast cancer in postmenopausal women. From 1977 to 1987, 3375 postmenopausal women free of cancer and not taking replacement estrogens donated blood to the Breast Cancer Serum Bank in Columbia, Missouri. Of these, 72 were subsequently diagnosed with breast cancer. For each case, two controls matched on age and date and time of day of blood collection were selected using incidence density matching. The median age of subjects at blood collection was 62 years; the time from blood collection to diagnosis ranged from less than 1 to 9.5 years with a median of 2.9 years. Risk of breast cancer was positively and significantly associated with serum levels of estrogens and androgens. Compared to women in the lowest quartile, those in the highest quartile for non-sex hormone-binding globulin (non-SHBG) bound (bioavailable) estradiol had a relative risk of 5.2 (95% confidence interval [CI] = 1.5-18.5) and those in the highest quartile for testosterone had a relative risk of 6.2 (95% CI = 2.0-19.0). Our results lend considerable support to the hypothesis that serum concentrations of estrogens and androgens are related to the subsequent diagnosis of breast cancer in postmenopausal women.

We have evaluated radial bone mass and sex steroid concentrations in a group of postmenopausal white type 2 diabetics, that group at greatest risk of developing osteoporosis. The linear regression of midshaft bone mass on age for 79 patients showed a rate of loss about half the rate for normals. These data suggest that bone is lost at a slower rate by this group, and the difference cannot be explained by obesity or glucose control alone. A subset of 40 of these subjects was chosen for further study. As expected, these women had significantly higher bone mass than normals; in addition, they were significantly heavier (82.4 +/- 2.7 kg v 65.3 +/- 1.8 kg, P less than .001), and had higher body mass index (32.1 +/- 1.0 kg/m2 v 25.2 +/- 0.6 kg/m2, P less than .001), than controls. Serum estrone concentrations were higher (49.8 +/- 3.7 pg/mL v 28.5 +/- 1.8 pg/mL, P less than .001); serum androstenedione (0.28 +/- 0.03 ng/mL v 0.51 +/- 0.04 ng/mL, P less than .001), and serum testosterone (0.18 +/- 0.02 ng/mL v 0.26 +/- 0.02 ng/mL, P less than .02) concentrations were lower among diabetics than controls. Serum estradiol (15.1 +/- 1.7 pg/mL v 15.3 +/- 1.0 pg/mL, P greater than .5) was not significantly different. Multiple regression analysis indicates that the excess level of estrone concentration among diabetics increased with the degree of obesity. The explanation for the lower concentration of the other sex steroids among diabetics is not known.

Androstenedione and testosterone labeled with 3H and 14C were fused simultaneously at constant rates into the brachial arm vein of 10 normal men. During the infusions blood samples were obtained from the brachial artery, a deep vein draining primarily muscle and a superficial vein draining primarily adipose tissue of the arm contra-lateral to the infusion. In the 10 men the mean +/- SE value for the fractional metabolism of adrostenedione by muscle is 0.20 +/- 0.30 which is not different from the mean value for the fractional metabolism by androstenedione by adipose tissue, 0.29 +/- 0.04. The mean value for the metabolism of testosterone by muscle, 0.04 +/- *.01, is significantly less than the metabolism by adipose tissue, *.11 +/- 0.01. Interconversion between adrostenedione and testosterone occurs in both tissues. The mean value for pA,T A,M is 0.024 + 0.005 and for pA,T A,AT is 0.024 +/- 0.005. The mean value for pT,A A,M is 0.005 +/- 0.003 and for pT,A A,AT is 0.008 +/- 0.003. The fractional metabolism of these androgens by these tissues is similar to the fractional metabolism of estrone and estradiol by these same tissues. Muscle appears to contribute about 5-12% of the overall metabolism of androstenedione and testosterone and 10-15% to theoverall conversion of androstenedione to testosterone. Adipose tissue contributes about 2-7% of the overall metabolism of these androgens and 5-10% of the overall conversion of androstenedione to testosterone, but less than 2% to the overall conversion of testosterone to androstenedione. In normal men, muscle appears to be more important to the metabolism of androstenedione and testosterone than is adipose tissue.

[7-3H]Androstenedione and [4-14C]es-trone or [7-3H]testosterone and [14C]estradiol were infused at constant rates into brachial arm veins of 15 normal men. During the infusions blood samples were obtained from the brachial artery, a deep vein draining primarily muscle, and a superficial vein draining primarily adipose tissue of the arm contralateral to the infusion. In seven men the mean ± SE value for the fractional conversion of androstenedione to estrone was 0.013 ± 0.004 for muscle and 0.014 ± 0.002 for adipose tissue. In eight men the mean SEvalue for the frac-tional conversion of testosterone to estradiol was 0.0007± 0.0001 for muscle and 0.0012 ± 0.0002 for adipose tissue. Both of these values were significantly (P < 0.01) less than the respective values of androstenedione aromatization to estrone. If constancy of tissue aromatization throughout the body is assumed, the muscle accounts for 25-30% and adipose tissue for 10-15% of the total extragonadal aromatization of androgens to estrogens. (J Cli...