Characterization of a prospective human model for study of the reproductive hormone responses to major illness.

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.

Serum testosterone levels after cardiac transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization.

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 [(14)C]androgen and [(3)H]estrogen that were immediately followed by peripheral infusions for 210 min. Eight men and three women received androstenedione (A(4))/estrone (E(1)) and three men received testosterone (T)/estradiol (E(2)). 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 E(1) levels rose (P = 0.004), with a trend toward a rise in E(2) (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 A(4) levels increased slightly postoperatively (P = 0.04), although no increase in A(4) 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.

Differences in serum sex hormone and plasma lipid levels in Caucasian and African-American premenopausal women.

CONTEXT: Risk of coronary heart disease is higher in African-American than in Caucasian women. OBJECTIVE: 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. DESIGN: This was a cross-sectional study. SETTING: The study was conducted in the general community. STUDY PARTICIPANTS: Sixty Caucasian and 117 African-American premenopausal women participated. MAIN OUTCOME MEASURES: 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. RESULTS: Relative to Caucasian women, African-American women had significantly higher mean BMI (23.92 +/- 3.87 vs. 26.99 +/- 5.87 kg/m2, respectively; P < 0.001), and WHR (0.733 +/- 0.052 vs. 0.757 +/- 0.068; P < 0.03). Also, plasma triglyceride (TG) levels were significantly lower in African-American women (81 +/- 61 vs. 55 +/- 24 mg/dl; P < 0.0001). Serum estrone sulfate (556 +/- 323 vs. 442 +/- 332 pg/ml, Caucasian vs. African-American; P < 0.001), estradiol (E2) (55.1 +/- 43.6 vs. 35.8 +/- 17.7 pg/ml; P < 0.0001), androstenedione (2.6 +/- 0.9 vs. 1.6 +/- 0.7 ng/ml; P < 0.0001), and testosterone (0.36 +/- 0.12 vs. 0.31 +/- 0.19 ng/ml; P < 0.002) 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. CONCLUSIONS: 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.

Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study.

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 = 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 alpha-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.

Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study.

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.

Physical activity, body size, and estrogen metabolism in women.

OBJECTIVES: Physical activity has demonstrable effects on estrogen levels in pre- and postmenopausal women. Increased oxidation of estrone to 2-hydroxyestrone (2HE) relative to 16alpha-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 < or = 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.

Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels.

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.

Plasma lipid and lipoprotein levels during the follicular and luteal phases of the menstrual cycle.

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 (by>100% each; P < 0.0001 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.

Serum sex hormones and breast cancer risk factors in postmenopausal women.

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.

Difference in bone mass between black and white American children: attributable to body build, sex hormone levels, or bone turnover?

A cross-sectional study of 232 healthy children, with about equal numbers of boys and girls and blacks and whites, aged 4 to 16 yr, was conducted to investigate the racial differences in bone mineral. Bone mineral content (BMC) by dual x-ray absorptiometry was found to be similar between blacks and whites at the spine after controlling for age and Tanner stage. However, total body BMC was higher in blacks, compared with whites of the same age and Tanner stage. Height and weight alone reduced the racial difference in BMC from 152 g to 66 g in girls and from 163 g to 105 g in boys, in whom the difference was further reduced to 66 g after accounting for lean and fat body mass and subscapular skinfold. The only significant sex hormone was androstenedione, which explained another 4-5 g of the racial difference in total body BMC for both boys and girls. Among the biochemical variables, only 25OH vitamin D reduced the residual racial difference in total body BMC to 39 g in girls, whereas serum PTH, urine free deoxypyridinoline ratio, and 1,25(OH)(2) vitamin D reduced the residual difference to 25 g in boys. The residual racial differences in bone mass were not statistically significant.

Effects of oral androstenedione administration on serum testosterone and estradiol levels in postmenopausal women.

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.

Serum androgen concentrations in young men: a longitudinal analysis of associations with age, obesity, and race. The CARDIA male hormone study.

Serum testosterone concentration appears to be higher in black men than white men, particularly at younger ages. The higher incidence of prostate cancer in blacks has been attributed, at least in part, to this difference. Other factors associated with androgen levels in men include age and obesity. However, most of the studies of adult androgen levels are limited by their cross-sectional design. We conducted longitudinal analyses (Generalized Estimating Equation) of the associations of age, body mass index (BMI), and waist circumference with total and free testosterone and sex hormone-binding globulin (SHBG) concentrations during an 8-year period and compared these hormonal factors between black (n = 483) and white (n = 695) male participants of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. For men ages 24 years and older at the time of the first hormone measurement, increasing age was associated with a statistically significant decrease in serum total and free testosterone and an increase in SHBG (P < 0.05). BMI and waist circumference were inversely associated with total testosterone and SHBG, but only BMI was inversely associated with free testosterone. After adjustment for age and BMI, total testosterone was higher in blacks (0.21 ng/ml; P = 0.028) than whites, an approximately 3% difference. However, after further adjustment for waist circumference, there was no black-white difference (0.05 ng/ml; P = 0.62). These results indicate that the age-associated decrease in circulating testosterone and increase in SHBG begin during the 3rd decade of life, and that increasing obesity, particularly central obesity, is associated with decreasing total testosterone and SHBG. Results also suggest that the previously observed difference in total testosterone between black and white men could be attributed, for the most part, to racial differences in abdominal obesity.

Measurement of hot flashes by sternal skin conductance and subjective hot flash report in Puebla, Mexico.

OBJECTIVE: To measure hot flashes by sternal skin conductance in an urban Mexican population and to determine variables associated with hot flash reporting and measurement. DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Bone loss at the femoral neck in premenopausal white women: effects of weight change and sex-hormone levels.

To investigate whether bone loss occurs in the premenopause, we measured the bone mineral content (BMC), bone mineral density (BMD), and bone area in the spine (L2-L4), femoral neck, and total hip, as well as the sex hormone levels of 130 healthy premenopausal white women (age, 31-50 yr) at least three times over 1-9 yr. We found an increase in all three bone measurements at the spine but no change in volumetric density. Neither could we detect any age-related changes in any of the three measurements in the total hip. In contrast, we detected a significant decrease in femoral neck BMD over time, due to a decrease in BMC and increase in bone area. Greater loss in femoral neck BMD was associated independently with weight loss and lower levels of estrone sulfate or E2. Separating the women into those with FSH spikes (>20 IU/liter) and women with consistently low FSH, we found the latter group had smaller decrease in BMD and that the decrease was due less to a decline in BMC and more to an increase in bone area. In summary, femoral neck BMD decreases in premenopausal women, particularly those with lower levels of estrogens resulting from slowing ovarian function despite regular menses. This decrease can be offset by more rapid weight gain.

Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.

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.