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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.

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.

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 (

The serum concentration of sex hormone-binding globulin (SHBG) is inversely related to weight and in animal studies is inversely related to protein intake. As SHBG can affect the biological activity of testosterone and estradiol, we wished to determine the role of protein intake on SHBG levels in men. Using data from the Massachusetts Male Aging Study we examined cross-sectional relationships between dietary components and SHBG levels in 1552 men (aged 40-70 yr) for whom these factors were known. Analyzed by multiple regression, controlling for testosterone and estradiol levels, age (P

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.

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.

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.

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.

We measured the concentrations of estradiol, progesterone, and the sex hormone-binding globulin capacity (rhSHBG) in serum of female rhesus monkeys (Macaca mulatta). Although the serum rhSHBG capacity was altered by the removal of ovarian hormones, presumably estradiol, acute changes in serum estradiol and progesterone did not influence SHBG capacity. There appears to be a relatively low threshold for the effect of estradiol on rhSHBG capacity. The threshold must be present for a finite length of time to have that effect.

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.

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)

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)

The precise sites of action of the negative feed-back effects of gonadal steroids in men remain unclear. To determine whether testosterone (T) administration can suppress gonadotropin secretion directly at the level of the pituitary, the pituitary responses to physiological doses of GnRH were assessed in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous T infusion (15 mg/day). Their responses were compared with the effects of identical T infusions on spontaneous gonadotropin secretion and the response to a 100-micrograms GnRH bolus in six normal men. Both groups were monitored with 15 h of frequent blood sampling before and during the last day of the T infusion. In the GnRH-deficient men, the first three GnRH doses were identical and were chosen to produce LH pulses with amplitudes in the midphysiological range of our normal men (i.e. a physiological dose), while the last four doses spanned 1.5 log orders (7.5, 25, 75, and 250 ng/kg). The 250 ng/kg dose was always administered last because it is known to be pharmacological. In the GnRH-deficient men, mean LH (P less than 0.02) and FSH (P less than 0.01) levels as well as LH pulse amplitude (P less than 0.05) decreased significantly during T infusion, demonstrating a direct pituitary-suppressive effect of T and/or its metabolites. Mean LH levels were suppressed to a greater extent in the normal than in the GnRH-deficient men (58 +/- 15% vs. 28 +/- 7%; P less than 0.05). In addition, LH frequency decreased significantly (P less than 0.01) during T administration in the normal men. These latter two findings suggest that T administration also suppresses hypothalamic GnRH release. T was unable to suppress gonadotropin secretion in one GnRH-deficient and one normal man. In both groups, the suppressive effect of T administration was present only in response to physiological doses of GnRH. Because the pituitary- and hypothalamus-suppressive effects of T could be mediated by its aromatization to estrogens, five GnRH-deficient and five normal men underwent identical T infusions with concomitant administration of the aromatase inhibitor testolactone (TL; 500 mg, orally, every 6 h). As an additional control, four GnRH-deficient and four normal men received TL alone. TL administration completely prevented the effect of T administration to suppress gonadotropin secretion in both the normal and GnRH-deficient men, and mean LH levels increased significantly in both the GnRH-deficient (P less than 0.01) and the normal (P less than 0.001) men who received TL alone. The increase in mean LH levels was greater (P less than 0.01) in the normal men who received TL alone than in the normal men who received T plus TL, thus revealing a direct effect of androgens in normal men. Measurements of T and estradiol production rates in three men demonstrated that TL effectively blocked aromatization.(ABSTRACT TRUNCATED AT 400 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.

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.

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.

On day 9 of an artificial menstrual cycle (28 day) in the rhesus monkey, endometrial epithelia and stroma and myometrial smooth muscle cells showed positive immunoreactivity for estradiol (E2) and progesterone (P) receptor. On day 23 a reduction of staining for E2 and P receptor was observed for epithelial cells in endometrial zones I, II, and III with a pronounced loss of E2 receptor staining in stromal cells. Glandular epithelial cells in zone IV retained strong positive staining for both E2 and P receptor. Cytosolic and occupied nuclear E2 receptor analyzed biochemically were significantly reduced on day 23. These data suggest that P induces a zonal-dependent distribution of immunoreactive E2 and P receptor and that epithelial cells of zone IV are distinguished by the combined presence of strong immunoreactive staining for both receptors.

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.

Postmenopausal women with elevated serum estrogens and androgens are at an increased risk of breast cancer. We evaluated associations of serum estrogen and androgen levels with age, anthropometry, and reproductive history to assess whether these characteristics could potentially modify breast cancer risk through hormonal mechanisms. A cross-sectional study was conducted among 133 postmenopausal women who donated blood to the serum bank (Columbia, MO) and served as controls in a previous prospective nested case control study of serum hormones and breast cancer risk. Standard regression methods were used to calculate adjusted means and test for trends in relationships of serum hormone concentrations with breast cancer risk factors. All analyses were performed on the log(e) scale, and all models included assay batch, date, and time of blood collection. Serum levels of estradiol, non-sex hormone binding globulin bound estradiol, estrone, estrone sulfate, and testosterone increased significantly with increasing body mass index (BMI), whereas sex hormone binding globulin levels decreased. After adjusting for BMI, nulliparous women tended to have higher testosterone levels compared with parous women (P = 0.05), but there was no evidence of a trend of decreasing testosterone with increasing parity. Dehydroepiandrosterone, its sulfate, and androstenediol decreased significantly with increasing age. Although BMI and parity could potentially modify breast cancer risk through hormonal mechanisms, age-related increases in breast cancer incidence do not appear to be mediated through changes in serum levels of the hormones evaluated.