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Men undergoing heart transplantation during the early 1990s had declines in testosterone associated with rapid bone loss. It is unclear whether low testosterone still occurs in an era of lower prednisone doses, whether cyclosporine A (CsA) contributes, whether hypothalamic-pituitary-gonadal (HPG) suppression or direct testicular effects are responsible, and whether low testosterone influences bone loss in men receiving therapy to prevent osteoporosis.Serum testosterone, estradiol, sex hormone binding globulin, gonadotropins, and bone density were measured and prednisone and CsA doses and levels for the first 2 years after transplantation were recorded in a more recently transplanted cohort of 108 participants in a trial comparing alendronate and calcitriol for prevention of posttransplant osteoporosis.Total and free testosterone levels were lowest during the first month (257+/-131 and 6.2+/-3 ng/dL, respectively) and normalized by 2 months. Gonadotropins were low in the majority, suggesting HPG suppression. Low total testosterone persisted in 14% at 1 year and 18% at 2 years. Prednisone was the major predictor of serum testosterone. No adverse effect of CsA and no relationship between serum testosterone and bone density change were detected.Low serum testosterone levels still occur in the early posttransplant period, probably related to HPG suppression by prednisone rather than direct testicular effects of CsA. They are not associated with bone loss in men receiving therapies to prevent osteoporosis. At later time points, low testosterone levels are common and apparently related to primary gonadal dysfunction, suggesting that long-term male heart transplant recipients should be evaluated for hypogonadism.

Although serum testosterone levels decrease acutely in critically ill patients, estrogen levels rise. We hypothesized that increased rates of aromatization of androgens to estrogens underlie the increase in serum estrogen levels. Eleven men and three women (age 42–69 yr) were prospectively studied before and again after elective coronary artery bypass graft surgery (CABG). Each patient received priming doses of [14C]androgen and [3H]estrogen that were immediately followed by peripheral infusions for 210 min. Eight men and three women received androstenedione (A4)/estrone (E1) and three men received testosterone (T)/estradiol (E2). Adipose tissue biopsies were obtained in another six men before and after CABG to evaluate levels of P450 aromatase mRNA. Serum T levels decreased postoperatively in all 17 men ( P < 0.001), whereas E1 levels rose ( P = 0.004), with a trend toward a rise in E2 ( P = 0.23). Peripheral aromatization rates of androgens to estrogens rose markedly in all 14 patients ( P < 0.0001). Estrogen clearance rates rose ( P < 0.002). Mean serum A4 levels increased slightly postoperatively ( P = 0.04), although no increase in A4 production rates (PRs) was observed. T PRs decreased in two of three men, whereas clearance rates increased in all three. Adipose tissue P450 aromatase mRNA content increased postoperatively ( P < 0.001). We conclude that the primary cause of increased estrogen levels in acute illness is increased aromatase P450 gene expression, resulting in enhanced aromatization of androgens to estrogens, a previously undescribed endocrine response to acute illness. Both increased T clearance and decreased T production contribute to decreased serum T levels. Animal studies suggest that these opposing changes in circulating estrogen and androgen levels may be important to reduce morbidity and mortality in critical illness.

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.

Little is known about the descriptive epidemiology of androgen deficiency. In this study, we sought to address this issue by providing estimates of the crude and age-specific prevalence and incidence rates of androgen deficiency in a randomly sampled population-based cohort of middle-aged and older men. Data on androgen deficiency (defined using both signs/symptoms plus total and calculated free testosterone) were available for n = 1691 (baseline) and n = 1087 (follow-up) men from the Massachusetts Male Aging Study. Crude and age-specific prevalence and incidence rates were calculated. Based on these estimates, projections for the number of cases of androgen deficiency in the 40- to 69-yr-old U.S. male population were computed. Estimates of the crude prevalence of androgen deficiency at baseline and follow-up were 6.0 and 12.3%, respectively. Prevalence increased significantly with age. From baseline age-specific prevalence data, it is estimated that there are approximately 2.4 million 40- to 69-yr-old U.S. males with androgen deficiency. The crude incidence rate of androgen deficiency was 12.3 per 1,000 person-years, and the rate increased significantly (P < 0.0001) with age. Based on these incidence data, we can expect approximately 481,000 new cases of androgen deficiency per year in U.S. men 40–69 yr old.

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.

As men age, serum testosterone levels decrease, a factor that may contribute to some aspects of age-related physiological deterioration. Although androgen replacement has been shown to have beneficial effects in frankly hypogonadal men, its use in elderly men with borderline hypogonadism is controversial. Furthermore, current testosterone replacement methods have important limitations.We investigated the ability of the orally administered aromatase inhibitor, anastrozole, to increase endogenous testosterone production in 37 elderly men (aged 62–74 yr) with screening serum testosterone levels less than 350 ng/dl. Subjects were randomized in a double-blind fashion to the following 12-wk oral regimens: group 1: anastrozole 1 mg daily (n = 12); group 2: anastrozole 1 mg twice weekly (n = 11); and group 3: placebo daily (n = 14). Hormone levels, quality of life (MOS Short-Form Health Survey), sexual function (International Index of Erectile Function), benign prostate hyperplasia severity (American Urological Association Symptom Index Score), prostate-specific antigen, and measures of safety were compared among groups.Mean ± sd bioavailable testosterone increased from 99 ± 31 to 207 ± 65 ng/dl in group 1 and from 115 ± 37 to 178 ± 55 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.054 group 1 vs. group 2). Total testosterone levels increased from 343 ± 61 to 572 ± 139 ng/dl in group 1 and from 397 ± 106 to 520 ± 91 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.012 group 1 vs. group 2). Serum estradiol levels decreased from 26 ± 8 to 17 ± 6 pg/ml in group 1 and from 27 ± 8 to 17 ± 5 pg/ml in group 2 (P < 0.001 vs. placebo for both groups and P = NS group 1 vs. group 2). Serum LH levels increased from 5.1 ± 4.8 to 7.9 ± 6.5 U/liter and from 4.1 ± 1.6 to 7.2 ± 2.8 U/liter in groups 1 and 2, respectively (P = 0.007 group 1 vs. placebo, P = 0.003 group 2 vs. placebo, and P = NS group 1 vs. group 2). Scores for hematocrit, MOS Short-Form Health Survey, International Index of Erectile Function, and American Urological Association Symptom Index Score did not change. Serum prostate-specific antigen levels increased in group 2 only (1.7 ± 1.0 to 2.2 ± 1.5 ng/ml, P = 0.031, compared with placebo).These data demonstrate that aromatase inhibition increases serum bioavailable and total testosterone levels to the youthful normal range in older men with mild hypogonadism. Serum estradiol levels decrease modestly but remain within the normal male range. The physiological consequences of these changes remain to be determined.

Estrogen levels are higher during the luteal compared with the follicular phase of the menstrual cycle. It was hypothesized that the luteal compared with the follicular phase has a lipid and lipoprotein profile associated with decreased coronary heart disease (CHD) risk. This was tested using well-defined data from healthy, well-characterized premenopausal Caucasian women under very controlled metabolic conditions. The percent differences in lipid, lipoprotein, and sex hormone levels between the follicular and luteal phases were estimated using generalized estimating equations after adjusting for age, body mass index, calendar time, and season. The low-density lipoprotein cholesterol (LDL-C) level was 6.2% lower (P = 0.015), and the total cholesterol/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were 5.1% (P = 0.0006) and 8.4% (P = 0.002) lower, respectively, during the luteal phase. Levels of estradiol and other estrogens were significantly higher (by100% each; P0.0001 in all cases) in the luteal phase. These findings support the study hypothesis. Fluctuations in levels of LDL-C and the total cholesterol/HDL-C and LDL-C/HDL-C ratios between menstrual cycle phases need to be considered in the screening and medical monitoring of premenopausal women, especially those with borderline levels. Although small, such fluctuations may prove to be clinically significant in the long run. Studies involving premenopausal women need to more clearly define and validate menstrual cycle phase in the design and interpretation of study results.

To measure hot flashes by sternal skin conductance in an urban Mexican population and to determine variables associated with hot flash reporting and measurement.From June 1999 to August 2000, 67 perimenopausal women aged 40 to 65 years participated in interviews, anthropometric measures, and a 2-h recording of sternal skin conductance. Changes in sweating were used to demonstrate the presence/absence of a hot flash. During the test, women were asked to report if they experienced a hot flash.During the study period, 10 women reported and demonstrated every hot flash, 24 women never reported or demonstrated a hot flash, 7 demonstrated hot flashes but did not report any of them, 7 reported hot flashes but did not demonstrate any of them, and 19 showed a mixture of responses. Women who demonstrated hot flashes by sternal skin conductance were measured in a warmer room, had more years of education, consumed more eggs as a child, recalled a heavier weight at age 18, and had a lower body mass index at interview compared with women who did not demonstrate hot flashes by sternal skin conductance. Women who subjectively reported hot flashes were measured in a warmer room, were more likely to be postmenopausal, reported more frequent consumption of coffee, and spent fewer months breast-feeding their last child compared with women who did not report the experience of hot flashes during the testing period.Room temperature explained part of the variation between women who did and did not demonstrate hot flashes via sternal skin conductance, between women who did and did not report the experience of hot flashes, and between women who did and did not demonstrate concordance in objective and subjective measures. In addition to room temperature, coffee intake, months spent breast-feeding the last child, and recalled weight at age 18 were important variables predicting hot flash experience.

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.

This study measured bone mineral content (BMC), bone mineral density (BMD), and bone area at the spine and hip to learn whether bone loss takes place premenopausally. Participants were 130 non-Hispanic white women 31 to 50 years of age who were in good general health and had taken no drugs that affect bone metabolism. Measurements were made by dual-energy x-ray absorptiometry at the L2-4 segment of the lumbar spine, in the femoral neck, and in the total hip. The studies were repeated at least twice over 1 to 9 years. Both BMC and bone area increased significantly over time in the spine, as did BMD. If, however, BMC was normalized by bone volume, there was no age-related change in volumetric density. Measurements of the total hip showed no significant change with age. BMD in the femoral neck declined at a rate of about 0.0036 g/cm2 per year. BMC was lost as well, so the drop in BMD was not an artifact of bone expansion. Changes in BMD correlated positively with weight change and estradiol levels and negatively with gonadotropin levels. Somewhat less bone loss was noted in subjects who gained more weight during the study. Higher levels of LH and FSH were documented in women who lost more than 1% of BMD per year. Estrogen levels were highest in women who manifested no bone loss. Declining BMD was more a result of a loss of BMC in women with high FSH levels, but due more to an expansion in bone area in those with relatively low FSH levels. The positive association between body weight change and BMD was not entirely mediated by higher estrogen. Premenopausal women more than 30 years of age in this study lost BMD at the femoral neck at an average annual rate of 0.4%. Bone loss was less in women who gained more weight but greater in those with reduced estrogen levels even in the absence of symptoms. Early bone loss might be preventable if premenopausal women with suboptimal sex hormone levels are detected at an early stage.

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.

Objectives. To determine whether prediagnostic serum hormones are predictive of prostate cancer risk in a sample of men 40 to 70 years old at baseline. Methods. Seventeen serum hormones, including androgens, estrogens, and adrenal and pituitary hormones, were measured at baseline (1987 to 1989) and used to predict incident prostate cancer by follow-up (1995 to 1997) using data from the Massachusetts Male Aging Study, a prospective, population-based random sample. Results. Seventy men (4%) of 1576 were diagnosed with prostate cancer between the baseline and follow-up periods (approximately 8 years). None of the hormones were associated with prostate cancer risk except for androstanediol glucuronide (AAG), which exhibited a nonlinear, inverse relationship with prostate cancer (P

Objective To address the association between depression and absolute levels of estradiol, and change in estradiol, among women during the menopausal transition. Methods This was a prospective, obse...

The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) have been characterized as "protective" against ischemic heart disease (IHD), especially in men, on the basis of sparse epidemiologic evidence. The authors used data from the Massachusetts Male Aging Study, a random sample prospective study of 1,709 men aged 40-70 years at baseline, to test whether serum levels of DHEA or DHEAS could predict incident IHD over a 9-year interval. At baseline (1987-1989) and follow-up (1995-1997), an interviewer-phlebotomist visited each subject in his home to obtain comprehensive health information, body measurements, and blood samples for hormone and lipid analysis. Incident IHD between baseline and follow-up was ascertained from hospital records and death registries, supplemented by self-report and evidence of medication. In the analysis sample of 1,167 men, those with serum DHEAS in the lowest quartile at baseline (

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.

Objective: To assess the ability of the level of follicle-stimulating hormone (FSH) to distinguish among premenopausal, perimenopausal, and postmenopausal women. Methods: We examined cross-sectional and longitudinal data from the second phase of the Massachusetts Women’s Health Study (1986 to 1995), a population-based cohort of 427 premenopausal and perimenopausal women identified from the first phase of the Massachusetts Women’s Health Study (1981 to 1986). Results: Boxplots of FSH levels throughout the menopausal transition displayed considerable overlap. Logistic regressions and their resulting receiver operating characteristic curves further demonstrated that, although FSH is a statistically significant predictor of menopausal status, no single value of FSH is expedient for distinguishing premenopausal from perimenopausal or perimenopausal from postmenopausal women. Conclusion: FSH alone is not an effective predictor of transition into the perimenopausal or postmenopausal period. Specifically, the frequently recommended FSH cutoff of 40 IU/L is inappropriate by itself for clinical determination of postmenopausal status. (Endocr Pract. 1998;4:137-141)

The purpose of this study was to determine whether bone density in older men was associated with serum sex steroids or sex hormone binding globulin (SHBG). Bone density and sex steroids were measured in men over age 65 at 6-mo intervals for an average of 2.1 yr. Bone density was significantly positively associated with greater serum E2 concentrations (+0.21 < r < +0.35; 0.01 < P < 0.05) at all skeletal sites. There were weak negative correlations between serum testosterone and bone density (-0.20 < r < -0.28; 0.03 < P < 0.10) at the spine and hip. SHBG was negatively associated only with bone density in the greater trochanter (r = -0.26, P < 0.05). Greater body weight was associated with lower serum testosterone and SHBG, and greater E2. Because of these associations, regression models which adjusted for age, body weight, and serum sex steroids were constructed; these accounted for 10-30% of the variability in bone density, and showed consistent, significant positive associations between bone density and serum E2 concentrations in men, even after adjustments for weight and SHBG. These data suggest that estrogens may play an important role in the development or maintenance of the male skeleton, much as is the case for the female skeleton. These data also indicate that, within the normal range, lower serum testosterone concentrations are not associated with low bone density in men.

Measuring levels of steroid hormones in epidemiologic studies is difficult because pulsatile release can cause the levels of many hormones to vary markedly over short intervals, leading to a loss of precision in between-subject comparisons. Clinicians often control this variation by collecting several samples from each subject at defined intervals and pooling these samples for assay. The number of samples per subject that would adequately control such variation in an epidemiologic study has not been fully investigated. This study examines the effects of collecting 1, 2, or 3 samples per subject on the variances of 11 hormones and sex hormone binding globulin in men and 6 hormones in women. Three samples were collected at 30-minute intervals from each of 20 men and 59 women and were assayed separately. Variances that would be obtained in studies collecting one, two, or three samples per subject were then estimated. Collecting more than one sample substantially reduced the variances of several hormones in men but not in 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 analyzed data from a cross-sectional study of 107 premenopausal women to evaluate the relations of height, weight, and body mass index (BMI) with plasma hormone levels. Participants were 20- to 40-year old women residing in Maryland (United States), whose reported menstrual cycle lengths were not more than 35 days and whose measured weights for height were 85 to 130 percent of 'desirable' based on 1983 Metropolitan Life Insurance tables. Fasting blood specimens were collected on each of days 5-7, 12-15, and 21-23 of every participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Adjusted for age, taller women had significantly higher follicular-phase plasma-estradiol levels (percent difference/cm = 1.5, 95 percent confidence interval [CI] = 0.3-2.7, and heavier women had significantly lower plasma sex-hormone binding globulin (SHBG) levels averaged across the menstrual cycle phases (percent difference/kg = -1.2; CI = -1.9-(-0.6). Body weight within the range studied, however, was not related significantly to the concentration of SHBG-bound estradiol during any phase of the menstrual cycle. The results of this cross-sectional study suggest a possible mechanism by which height may influence breast cancer risk.

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.

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.

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.

Presentation of Case A 56-year-old woman was referred to the hospital because of male-pattern baldness and hirsutism. The patient's menarche had occurred at the age of 13 years, and her menses were regular in the absence of premenstrual molimina or dysmenorrhea. Her gynecologist, since deceased, told her that she would never have children, although she did not recall his explanation. She was sexually active during much of her married life. She used no contraceptive measures but never conceived. Seven years before entry her menses became less frequent and ceased; she did not have hot flashes. A year and a half . . .

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.

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)

To evaluate the hypothesis that endocrine profiles change with aging independently of specific disease states, we examined the age trends of 17 major sex hormones, metabolites, and related serum proteins in 2 large groups of adult males drawn from the Massachusetts Male Aging Study, a population-based cross-sectional survey of men aged 39-70 yr conducted in 1986-89. Group 1 consisted of 415 men who were free of obesity, alcoholism, all prescription medication, prostate problems, and chronic illness (cancer, coronary heart disease, hypertension, diabetes, and ulcer). Group 2 consisted of 1294 men who reported 1 or more of the above conditions. Each age trend was satisfactorily described by a constant percent change per yr between ages 39-70 yr. Free testosterone declined by 1.2%/yr, and albumin-bound testosterone by 1.0%/yr. Sex hormone-binding globulin (SHBG), the major serum carrier of testosterone, increased by 1.2%/yr, with the net effect that total serum testosterone declined more slowly (0.4%/yr) than the free or albumin-bound pools alone. Among the major androgens and metabolites, androstane-3 alpha,17 beta-diol (androstanediol; 0.8%/yr) and androstanediol glucuronide (0.6%/yr) declined less rapidly than free testosterone, while 5 alpha-dihydrotestosterone remained essentially constant between ages 39-70 yr. Androstenedione declined at 1.3%/yr, a rate comparable to that of free testosterone, while the adrenal androgen dehydroepiandrosterone (3.1%/yr) and its sulfate (2.2%/yr) declined 2-3 times more rapidly. The levels of testosterone, SHBG, and several androgen metabolites followed a parallel course in groups 1 and 2, remaining consistently 10-15% lower in group 2 across the age range of the study. Subgroup analyses suggested that obese subjects might be responsible for much of the group difference in androgen level. Serum concentrations of estrogens and cortisol did not change significantly with age or differ between groups. Of the pituitary gonadotropins, FSH increased at 1.9%/yr, LH increased at 1.3%/yr, and PRL declined at 0.4%/yr, with no significant difference between groups 1 and 2.(ABSTRACT TRUNCATED AT 400 WORDS)

With critical illness, serum testosterone levels fall markedly, whereas estrogen levels rise. Although animal studies suggest adaptive advantages, no prospective model has been available for studies in humans. We hypothesized that coronary artery bypass graft (CABG) surgery would provide such a model by eliciting the same reproductive hormone and other endocrine responses as reported with major nonsurgical illnesses. We further hypothesized that those responses would occur consistently in all CABG patients with predictable time courses, providing reliable windows for prospective studies. In 17 men undergoing CABG, serum levels of reproductive hormones, cortisol, thyroid hormones, and IGF-I were measured before and for up to 5 wk after surgery. Changes in serum levels of reproductive and other hormones were similar to those reported in nonsurgical critically ill patients. Time course for onset, duration, and recovery of reproductive hormone changes were consistent among all patients. A window for studying the testosterone and estrogen responses was established as the first 5 days following CABG. Practical use of this model was demonstrated by evaluating, in another seven men, changes in gonadotroph responsiveness to GnRH following CABG. Finally, to determine whether our findings in CABG could be extended to other surgeries, we demonstrated similar endocrine responses in 12 men following abdominal aortic aneurysm resection. We conclude that patients undergoing CABG surgery provide a useful human model for the prospective evaluation of the reproductive axis responses to acute illness. Other major surgeries are likely to also be suitable for these studies.

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.

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.

The ovaries of postmenopausal women are smaller than those of premenopausal women and consist primarily of stromal cells. These cells have receptors for, and respond to, gonadotropins and secrete testosterone and lesser amounts of other androgens and estrogens. The ovaries of some postmenopausal women contain P-450 aromatase and secrete estradiol. There is little evidence that inhibins A or B are secreted by postmenopausal ovaries.

Objective The purpose of this study was to address whether: (1) there is an association between menopause status and various aspects of sexual functioning, and (2) the relative contributions of menopause status and other variables to various aspects of sexual functioning. Design Analyses are based on 200 women from the Massachusetts Women's Health Study II, a population-based sample of women transitioning through the menopause who were not HRT users, who had not had a surgical menopause, and who had partners. The women were classified as pre-, peri-, or postmenopausal according to menstrual cycle characteristics. Estradiol, estrone, and follicle-stimulating hormone were also measured. Sexual functioning was measured in terms of satisfaction, desire, frequency of sexual intercourse, belief that interest declines with age, arousal compared with a younger age, difficulty reaching orgasm, and pain. Predictor variables included sociodemographics, health, vasomotor symptoms, psychological variables, partner variables, and lifestyle behaviors. Results Menopause status was significantly related to lower sexual desire, a belief that interest in sexual activity declines with age, and women's reports of decreased arousal compared with when in their 40s. Menopause status was unrelated to other aspects of sexual functioning in either unadjusted or multiple regression analyses. In analyses in which log estradiol (E2) was included in addition to menopause status, log E2 was only related to pain. In multiple regression analyses, other factors such as health, marital status (or new partner), mental health, and smoking had a greater impact on women's sexual functioning than menopause status. Conclusions Menopause status, but not E2, is related to some, but not all, aspects of sexual functioning. This may be due to menopause per se or other factors associated with menopause and aging (e.g., increased sexual dysfunction among aging men). Menopause status has a smaller impact on sexual functioning than health or other factors.

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

Because benign prostatic hyperplasia (BPH) may be influenced by plasma steroid hormones, we examined their relation in the Health Professionals Follow-up Study. In 1993-1995, 18,000 cohort members provided blood. We selected as cases men who had had surgery for BPH (n=174) or who scored 20-35 points (n=126) on the American Urological Association index of severity of lower urinary tract symptoms. Cases were matched by age to men who scored/=3 points and without an enlarged prostate or elevated prostate-specific antigen. We estimated the odds ratio (OR) of BPH surgery and severe lower urinary tract symptoms for plasma testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide (AAG), estradiol (E2), and sex hormone binding globulin (SHBG) in multivariable conditional logistic regression models. Compared to the lowest tertiles, men in the middle (OR=1.42) and top (OR=1.78) tertiles of AAG were at increased risk for having either BPH surgery or severe lower urinary tract symptoms (P-trend=0.02). Men in the middle (OR=0.58) and top (OR=0.60) tertiles of E2 were at lower risk. T level was unrelated to surgery and symptoms. Our findings support opposing roles for DHT, reflected by its metabolite AAG, and E2 in the etiology of BPH.

Low bone mass is a major determinant of the osteoporotic fractures that are becoming increasingly common as the population ages. Low bone mass at the time of a fracture may result from either low p...

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.

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

Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted.We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer.Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided.No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P.001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 4 years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (2.5 ng/mL) were excluded from the analyses.High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.

Although bone loss around the time of menopause is driven by estrogen deficiency, the roles of estrogens and androgens in the preservation of skeletal mass at other stages of life are less well understood. To address this issue we studied 231 women between the ages of 32 and 77 with multiple measurements of sex steroids and bone mass over a period of 2-8 yr. In all women bone mass was negatively associated with concentrations of sex-hormone binding globulin, and positively associated with weight. Bone loss occurred from all skeletal sites in peri- and postmenopausal women, but premenopausal women lost bone only from the hip (-0.3%/yr) and had positive rates of change in the radius and spine. Bone loss was significantly associated with lower androgen concentrations in premenopausal women, and with lower estrogens and androgens in peri- and postmenopausal women. Sex steroids are important for the maintenance of skeletal integrity before menopause, and for as long as 20-25 yr afterwards.

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.

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.

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.

Sex hormone-binding globulin (SHBG) is a protein that binds certain androgens and estrogens with high affinity (1)(2) and restricts the access of such steroids to tissues as long as the steroids remain bound to SHBG (3). Measurements of SHBG are often done on a clinical basis and can be used to determine the amounts of free and bioavailable estradiol and testosterone (3)(4)(5). Initially, the measurements were indirect (6)(7)(8)(9), but radioimmunoassays were developed (10)(11). Now several commercial methods are available to measure SHBG directly using the interaction of SHBG with an antibody. We have found marked differences in the values obtained by these methods. Blood samples were obtained from 20 men (ages 21–30 years) and 20 women (ages 21–42 years) between 0800 and 1000. The men and women were healthy by history and a brief physical exam, and were taking no medications. The women all had regular menstrual cycles. The samples were allowed to clot, and the serum was collected, divided into aliquots, and stored at −80 °C until analyzed. Analyses were carried out within 3 months of blood collection. The protocol was approved by the Institutional Review Board …

The study of testosterone is likely to be prominent in future epidemiological work on endocrine function and the clinical treatment of age-related diseases. Thus, understanding the hormonal changes involved in the normal male aging process will be critical. Using techniques of meta-analysis, the authors examined 88 published studies of the age-testosterone relation in men. These studies reported conflicting results: age-testosterone correlations ranged from −0.68 to +0.68. In cross-study comparisons, certain research design characteristics (e.g. time of day of blood sampling) and various sample characteristics (e.g. volunteers vs patients as subjects) were related to both mean testosterone level and the slope of the age-testosterone relation. For example, for subgroups of subjects that did not exclude ill men, the mean testosterone levels were low, and did not decline with age. Subgroups that included only healthy subjects, in contrast, had higher overall testosterone levels and showed a decline of testosterone with age. Implications of these results for design, analysis and reporting of future epidemiologic studies will be discussed. These results also illustrate the utility of meta-analysis for research with the aged.