We have isolated a novel liver-specific organic anion transporter, LST-1, that is expressed exclusively in the human, rat, and mouse liver. LST-1 is a new gene family located between the organic anion transporter family and prostaglandin transporter. LST-1 transports taurocholate (Km = 13.6 microM) in a sodium-independent manner. LST-1 also shows broad substrate specificity. It transports conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17beta-glucuronide, and estrone-3-sulfate), eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, leukotriene E4), and thyroid hormones (thyroxine, Km = 3.0 microM and triiodothyronine, Km = 2.7 microM), reflecting hepatic multispecificity. LST-1 is probably the most important transporter in human liver for clearance of bile acids and organic anions because hepatic levels of another organic anion transporter, OATP, is very low. This is also the first report of the human molecule that transports thyroid hormones.

The human cytochrome P4503A forms show expression patterns subject to developmental influence. CYP3A7 and CYP3A4 are generally classified as the major fetal and adult liver forms, respectively. However, characterization of CYP3A4, -3A5, and -3A7 developmental expression has historically been confounded by the lack of CYP3A isoform-specific antibodies or marker enzyme activities. Therefore, the objective of this study was to characterize the developmental expression of hepatic CYP3A forms from early gestation to 18 years of age using up to 212 fetal and pediatric liver samples. Based on immunoquantitation, CYP3A5 protein expression was found to be highly variable, generally independent of age, and more frequently observed for African-American individuals. For differentiation of CYP3A4 and -3A7 levels, dehydroepiandrosterone metabolite patterns for expressed CYP3A forms were characterized and used for simultaneous quantitation of protein levels within liver microsome samples. The major metabolite formed by CYP3A4, 7beta-hydroxy-dehydroepiandrosterone, was identified based on cochromatography and mass spectra matching with the authentic standard. Kinetic analysis showed a 34-fold greater intrinsic clearance of 7beta-hydroxy-dehydroepiandrosterone by CYP3A4 versus -3A7, whereas CYP3A7 showed the highest 16alpha-hydroxy-dehydroepiandrosterone intrinsic clearance. Metabolite profiles for the expressed enzymes were fit to a multiple response model and CYP3A4 and -3A7 levels in fetal and pediatric liver microsome samples were calculated. Fetal liver microsomes showed extremely high CYP3A7 levels (311-158 pmol/mg protein) and significant expression through 6 months postnatal age. Low CYP3A4 expression was noted for fetal liver (< or =10 pmol/mg), with mean levels increasing with postnatal age.

BACKGROUND

Alcohol ingestion is associated with an increased risk of breast cancer in most epidemiologic studies. Results, however, are heterogeneous at lower levels of alcohol intake, and a biologic mechanism for the association has not been clearly identified. To determine whether alcohol consumption by postmenopausal women elevates serum levels of hormones associated with an increased risk of breast cancer, we performed a controlled feeding study.

METHODS

Participants were 51 healthy postmenopausal women not using hormone replacement therapy. Each participant rotated through three 8-week dietary periods in which she consumed 15 or 30 g of alcohol per day or an alcohol-free placebo beverage. The order of assignment to the three alcohol levels was random. During the dietary periods, all food and beverages were supplied by the study, and energy intake was adjusted to keep body weight constant. Levels of estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenediol were measured by radioimmunoassays in serum collected at the end of each dietary period. All statistical tests are two-sided.

RESULTS

When women consumed 15 or 30 g of alcohol per day, respectively, estrone sulfate concentrations increased by 7.5% (95% confidence interval [CI] = -0.3% to 15.9%; P =.06) and 10.7% (95% CI = 2.7% to 19.3%; P =.009) and DHEAS concentrations increased by 5.1% (95% CI = 1.4% to 9.0%; P =.008) and 7.5% (95% CI = 3.7% to 11.5%; P<.001) relative to levels when women consumed placebo. None of the other hormones measured changed statistically significantly when women consumed alcohol.

CONCLUSIONS

Results suggest a possible mechanism by which consumption of one or two alcoholic drinks per day by postmenopausal women could increase their risk of breast cancer.

DHEA, together with DHEAS, is the most abundant steroid in the blood of young adult humans. Levels in humans decline with age and during certain types of illness or stress. We have found that DHEA(S) can prevent or reduce the neurotoxic actions in the hippocampus of the glutamate agonists N-methyl-D-aspartic acid (NMDA) both in vitro and in vivo or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Pre-treatment with DHEA (10-100 nM for 6-8 h) protected primary hippocampal cultures from embryonic day 18 (E18) embryos against NMDA-induced toxicity (0.1, 1, 10, and 50 mM). DHEA added either with NMDA (1 mM) or 1 h later had lesser, but still significant, protective actions. DHEAS also reduced NMDA-induced toxicity (1 mM), although the lowest effective dose of DHEAS (100 nM) was higher than that of DHEA (10 nM). DHEA (100 nM) protected cultured neurons against the neurotoxic actions of either AMPA (25 microM) or kainic acid (1 mM) as well. In vivo, s.c. pellets of DHEA, which resulted in plasma levels that resembled those in young adult humans, protected hippocampal CA1/2 neurons against unilateral infusions of 5 or 10 nmol of NMDA. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults, these results suggest that decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage.

Incidentally discovered adrenal masses are mostly benign, asymptomatic lesions, often arbitrarily considered as nonfunctioning tumors. Recent studies, however, have reported increasing evidence that subtle cortisol production and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent than previously thought. The purpose of this study was to investigate the clinical and hormonal features of patients with incidentally discovered adrenal adenomas, in relation to their clinical outcome. Fifty consecutive patients with incidentally detected adrenal adenomas, selected from a total of 65 cases of adrenal incidentalomas, were prospectively evaluated. All of them underwent abdominal computed tomography scan and hormonal assays of the HPA axis function: circadian rhythm of plasma cortisol and ACTH, urinary cortisol excretion, 17-hydroxyprogesterone, androgens, corticotropin stimulation test and low-dose (2 mg) dexamethasone test. The patients were reevaluated at regular intervals (6, 12, and 24 months) for a median period of 38 months. Subtle hypercortisolism, defined as abnormal response to at least 2 standard tests of the HPA axis function in the absence of clinical signs of Cushing's syndrome (CS), was defined as subclinical CS. Mild-to-severe hypertension was found in 24 of 50 (48%) patients, type-2 diabetes in 12 of 50 (24%), and glucose intolerance in 6 of 50 (12%) patients. Moreover, 18 of 50 patients (36%) were diffusely obese (body mass index, determined as weight/height2,>> 25), and 14 patients (28%) had serum lipid concentration abnormalities (cholesterol>> or = 6.21 mmol/L, low-density lipoprotein cholesterol>> or = 4.14 mmol/L and/or triglycerides>> or = 1.8 mmol/L). Compared with a healthy population, bone mineral density Z-score, determined by the DEXA technique, tended to be slightly (but not significantly) lower in patients with adrenal adenoma (-0.41 SD). Endocrine data were compared with 107 sex- and age-matched controls, and patients with adenomas were found to have heterogeneous hormonal abnormalities. In particular, significantly higher serum cortisol values (P < 0.001), lower ACTH concentration (P < 0.05), and impaired cortisol suppression by dexamethasone (P < 0.001) were observed. Moreover, in patients with adenomas, cortisol, 17-OH progesterone, and androstenedione responses to corticotropin were significantly increased (P < 0.001, all), whereas dehydroepiandrosterone sulfate levels were significantly lower at baseline, with blunted response to corticotropin (P < 0.001, both). However, the criteria for subclinical CS were met by 12 of 50 (24%) patients. Of these, 6 (50%) were diffusely obese, 11 (91.6%) had mild-to-severe hypertension, 5 (41.6%) had type-2 diabetes mellitus, and 6 (50%) had abnormal serum lipids. The clinical and hormonal features improved in all patients treated by adrenalectomy, but seemed unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months), except for one, who was previously found as having nonfunctioning adenoma and then revealed to have subclinical CS. In conclusion, an unexpectedly high prevalence of subtle autonomous cortisol secretion, associated with high occurrence of hypertension, diabetes mellitus, elevated lipids, and diffuse obesity, was found in incidentally discovered adrenal adenomas. Although the pathological entity of a subclinical hypercortisolism state remained mostly stable in time during follow-up, hypertension, metabolic disorders, and hormonal abnormalities improved in all patients treated by adrenalectomy. These findings support the hypothesis that clinically silent hypercortisolism is probably not completely asymptomatic.

BACKGROUND

Sex hormone levels in men change during aging. These changes may be associated with insulin sensitivity and the metabolic syndrome.

METHODS

We studied the association between endogenous sex hormones and characteristics of the metabolic syndrome in 400 independently living men between 40 and 80 yr of age in a cross-sectional study. Serum concentrations of lipids, glucose, insulin, total testosterone (TT), SHBG, estradiol (E2), and dehydroepiandrosterone sulfate (DHEA-S) were measured. Bioavailable testosterone (BT) was calculated using TT and SHBG. Body height, weight, waist-hip circumference, blood pressure, and physical activity were assessed. Smoking and alcohol consumption was estimated from self-report. The metabolic syndrome was defined according to the National Cholesterol Education Program definition, and insulin sensitivity was calculated by use of the quantitative insulin sensitivity check index.

RESULTS

Multiple logistic regression analyses showed an inverse relationship according to 1 sd increase for circulating TT [odds ratio (OR) = 0.43; 95% confidence interval (CI), 0.32-0.59], BT (OR = 0.62; 95% CI, 0.46-0.83), SHBG (OR = 0.46; 95% CI, 0.33-0.64), and DHEA-S (OR = 0.76; 95% CI, 0.56-1.02) with the metabolic syndrome. Each sd increase in E2 levels was not significantly associated with the metabolic syndrome (OR = 1.16; 95% CI, 0.92-1.45). Linear regression analyses showed that higher TT, BT, and SHBG levels were related to higher insulin sensitivity; beta-coefficients (95% CI) were 0.011 (0.008-0.015), 0.005 (0.001-0.009), and 0.013 (0.010-0.017), respectively, whereas no effects were found for DHEA-S and E2. Estimates were adjusted for age, smoking, alcohol consumption, and physical activity score. Further adjustment for insulin levels and body composition measurements attenuated the estimates, and the associations were similar in the group free of cardiovascular disease and diabetes.

CONCLUSIONS

Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome.

Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome (PCOS). Dietary-induced weight loss and the administration of insulin-lowering drugs, such as metformin, are usually followed by improved hyperandrogenism and related clinical abnormalities. This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones in a group of 20 obese PCOS women [body mass index (BMI)>> 28 kg/m2] with the abdominal phenotype (waist to hip ratio >0.80), and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS. At baseline, we measured sex hormone, sex hormone-binding globulin (SHBG), and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography (CT) at the L4-L5 level, to measure sc adipose tissue area (SAT) and visceral adipose tissue area. All women were then given a low-calorie diet (1,200-1,400 kcal/day) alone for one month, after which anthropometric parameters and CT scan were newly measured. While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a random order, on metformin (850 mg/os, twice daily) (12 and 8, respectively) or placebo (8 and 12, respectively), according to a double-blind design, for the following 6 months. Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment. During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo). The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment. On the contrary, visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment significantly higher than that of placebo. Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Neither metformin or placebo significantly modified the levels of LH, FSH, dehydroepiandrosterone sulphate, and progesterone in any group, whereas testosterone concentrations decreased only in PCOS women treated with metformin. SHBG concentrations remained unchanged in all PCOS women; whereas in the control group, they significantly increased after both metformin and placebo. Leptin levels decreased only during metformin treatment in both PCOS and control groups. (ABSTRACT TRUNCATED)

Depression has been likened to a state of "accelerated aging," and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress-related depression may contribute to "accelerated aging," cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic-pituitary-adrenal axis (e.g., hyper- or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain-derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re-conceptualization of depression as a whole body disease rather than just a "mental illness," and to the rational development of new classes of medications to treat depression and its related medical comorbidities.

A cDNA encoding a multispecific organic anion transporter 3 (hOAT3) was isolated from a human kidney cDNA library. The hOAT3 cDNA consisted of 2179 base pairs that encoded a 543-amino-acid residue protein with 12 putative transmembrane domains. The deduced amino acid sequence of hOAT3 showed 36 to 51% identity to those of other members of the OAT family. Northern blot analysis revealed that hOAT3 mRNA is expressed in the kidney, brain, and skeletal muscle. When expressed in Xenopus laevis oocytes, hOAT3 mediated the transport of estrone sulfate (K(m) = 3.1 microM), p-aminohippurate (K(m) = 87.2 microM), methotrexate (K(m) = 10.9 microM), and cimetidine (K(m) = 57.4 microM) in a sodium-independent manner. hOAT3 also mediated the transport of dehydroepiandrosterone sulfate, ochratoxin A, PGE(2), estradiol glucuronide, taurocholate, glutarate, cAMP and uric acid. Estrone sulfate did not show any trans-stimulatory effects on either influx or efflux of [(3)H]estrone sulfate via hOAT3. hOAT3 interacted with chemically heterogeneous anionic compounds, such as nonsteroidal anti-inflammatory drugs, diuretics, sulfobromophthalein, penicillin G, bile salts and tetraethyl ammonium bromide. The hOAT3 protein was shown to be localized in the basolateral membrane of renal proximal tubules and the hOAT3 gene was determined to be located on the human chromosome 11q12-q13.3 by fluorescent in situ hybridization analysis. These results suggest an important role of hOAT3 in the excretion/detoxification of endogenous and exogenous organic anions in the kidney.

OBJECTIVE

The geriatric syndrome of frailty has been conceptualized as a loss of physiologic reserve associated with endocrine dysregulation and immune dysfunction. Our prior studies suggest that the frailty syndrome is associated with elevated serum IL-6 levels. In the present study, our aim is to evaluate the possible role of endocrine dysregulation and its relationship with serum IL-6 in the pathogenesis of this syndrome.

METHODS

Using a recently validated screening algorithm for frailty, we identified 18 frail and 33 non-frail community-dwelling older adults for inclusion in this study. Serum levels of insulin-like growth factor-I (IGF-I), DHEA-S, and IL-6 were measured by immunoassays. The inter-relationships among serum levels of IL-6, DHEA-S, and IGF-I were determined by linear regression analysis.

RESULTS

Age-adjusted serum levels of IGF-I (88+/-49 vs 122+/-47 [ng/mL], p<0.023) and DHEA-S (0.30+/-0.21 vs 0.53+/-0.25 [microg/mL], p=0.016) were significantly lower in frail vs non-frail individuals, respectively. There was a trend for IL-6 to be inversely correlated with IGF-I in the frail (r=-0.42; p=0.082) but not the non-frail group (r=0.12, p=0.521).

CONCLUSIONS

Frail subjects have lower levels of serum IGF-I and DHEA-S and higher levels of IL-6 than do non-frail, age-matched individuals. The trend toward an inverse correlation between IGF-I and IL-6 in the frail, but not the non-frail group, suggests potential interaction between endocrine and immune/cytokine dysregulation that requires further study in larger cohorts.

OBJECTIVE

Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3.

METHODS

A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk.

RESULTS

In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed.

CONCLUSIONS

These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

A cDNA encoding a novel multispecific organic anion transporter, OAT4, was isolated from a human kidney cDNA library. The OAT4 cDNA consisted of 2210 base pairs that encoded a 550-amino acid residue protein with 12 putative membrane-spanning domains. The amino acid sequence of OAT4 showed 38 to 44% identity to those of other members of the OAT family. Northern blot analysis revealed that OAT4 mRNA is abundantly expressed in the placenta as well as in the kidney. When expressed in Xenopus oocytes, OAT4 mediated the high affinity transport of estrone sulfate (K(m) = 1.01 microM) and dehydroepiandrosterone sulfate (K(m) = 0.63 microM) in a sodium-independent manner. OAT4 also mediated the transport of ochratoxin A. OAT4-mediated transport of estrone sulfate was inhibited by several sulfate conjugates, such as p-nitrophenyl sulfate, alpha-naphthyl sulfate, beta-estradiol sulfate, and 4-methylumbelliferyl sulfate. By contrast, glucuronide conjugates showed little or no inhibitory effect on the OAT4-mediated transport of estrone sulfate. OAT4 interacted with chemically heterogeneous anionic compounds, such as nonsteroidal anti-inflammatory drugs, diuretics, sulfobromophthalein, penicillin G, and bile salts, whereas tetraethylammonium, an organic cation, did not. OAT4 is the first member of the multispecific organic anion transporter family, which is expressed abundantly in the placenta. OAT4 might be responsible for the elimination and detoxification of harmful anionic substances from the fetus.

Diazepam binding inhibitor (DBI) is a 9-kD polypeptide that was first isolated in 1983 from rat brain by monitoring its ability to displace diazepam from the benzodiazepine (BZD) recognition site located on the extracellular domain of the type A receptor for gamma-aminobutyric acid (GABAA receptor) and from the mitochondrial BZD receptor (MBR) located on the outer mitochondrial membrane. In brain, DBI and its two major processing products [DBI 33-50, or octadecaneuropeptide (ODN) and DBI 17-50, or triakontatetraneuropeptide (TTN)] are unevenly distributed in neurons, with the highest concentrations of DBI (10 to 50 microMs) being present in the hypothalamus, amygdala, cerebellum, and discrete areas of the thalamus, hippocampus, and cortex. DBI is also present in specialized glial cells (astroglia and Bergmann glia) and in peripheral tissues. In the periphery, the highest concentration of DBI occurs in cells of the zona glomerulosa and fasciculata of the adrenal cortex and in Leydig cells of the testis; interestingly, these are the same cell types in which MBRs are highly concentrated. Stimulation of MBRs by appropriate ligands (including DBI and TTN) facilitates cholesterol influx into mitochondria and the subsequent formation of pregnenolone, the parent molecule for endogenous steroid production; this facilitation occurs not only in peripheral steroidogenic tissues, but also in glial cells, the steroidogenic cells of the brain. Some of the steroids (pregnenolone sulfate, dehydroepiandrosterone sulfate, 3 alpha-hydroxy-5 alpha-pregnan-20-one, and 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one) produced in brain (neurosteroids) function as potent (with effects in the nanomolar concentration range) positive or negative allosteric modulators of GABAA receptor function. Thus, accumulating evidence suggests that the various neurobiological actions of DBI and its processing products may be attributable to the ability of these peptides either to bind to BZD recognition sites associated with GABAA receptors or to bind to glial cell MBRs and modulate the rate and quality of neurosteroidogenesis. The neurobiological effects of DBI and its processing products in physiological and pathological conditions (hepatic encephlopaty, depression, panic) concentrations may therefore be explained by interactions with different types of BZD recognition site. In addition, recent reports that DBI and some of its fragments inhibit (in nanomolar concentrations) glucose-induced insulin release from pancreatic islets and bind acyl-coenzyme A with high affinity support the hypothesis that DBI isa precursor of biologically active peptides with multiple actions in the brain and in peripheral tissues.

OBJECTIVE

To determine the relationship between aging, life-style factors and health-related factors and endogenous sex hormone levels.

METHODS

Cross-sectional study of 400 independently living men between 40 and 80 Years of age.

METHODS

After exclusion of subjects who were not physically or mentally able to visit the study center, 400 men were randomly selected from a population-based sample. Total testosterone (TT), bioavailable testosterone (BT) (i.e. not bound to sex hormone-binding globulin (SHBG)), SHBG, estradiol (E(2)) and dehydroepiandrosterone-sulfate (DHEA-S) were investigated for their relationship with age, body mass index (BMI), waist circumference, smoking, physical activity and general health status. Multivariate models using ANCOVA analyses were used to examine the contribution of life-style factors to sex hormone variability.

RESULTS

TT, BT and DHEA-S decreased with age; 0.2, 0.7 and 1.2%/Year respectively. SHBG showed an increase with age of 1.1%/Year. No changes with age were found for E(2). General health status modified the association of TT and SHBG with age (P interaction 0.10 and 0.002 respectively). Increased BMI and waist circumference were associated with decreased TT, BT, SHBG and DHEA-S and increased E(2) (all P<0.01). Current smoking, lower alcohol intake and a higher physical activity score were associated with higher TT and SHBG levels.

CONCLUSIONS

This study showed the important determinants of sex hormones were age, BMI, waist circumference, smoking, general health status and physical activity. Furthermore, it can be concluded that general health status modified the effect between sex hormones and age. For future observational studies it should be taken into account that the above-mentioned determinants may alter the association between sex hormones and diseases and related conditions.

OBJECTIVE AND CONTEXT: Our objective was to examine predictability of reproductive hormone concentrations for bone mineral density (BMD) loss during the menopausal transition.

METHODS

We conducted a longitudinal (five annual examinations), multiple-site (n = 5) cohort study, the Study of Women's Health Across the Nation (SWAN).

METHODS

Participants included, at baseline, 2311 premenopausal or early perimenopausal African-American, Caucasian, Chinese, and Japanese women.

METHODS

We assessed annual dual-energy x-ray absorptiometry lumbar spine and total hip BMD measures, with endogenous estradiol (E2), FSH, androgens, and self-reported menstrual bleeding patterns.

RESULTS

Over the 4-yr period, lumbar spine BMD loss was 5.6% in natural postmenopause, 3.9% in surgical postmenopause, or 3.2% in late perimenopause. Baseline FSH concentrations, subsequent FSH levels, and their interaction predicted 4-yr BMD loss. If baseline FSH was less than 25 mIU/ml, higher follow-up FSH (>70 mIU/ml) predicted a 4-yr spine BMD loss of -0.05 g/cm(2). If baseline FSH values were more than 35-45 mIU/ml, lower follow-up FSH (i.e. 40-50 mIU/ml) predicted a -0.05 g/cm(2) 4-yr spine BMD loss. Charts show amounts of predicted BMD losses with combinations of baseline FSH values and FSH levels over time. E2 concentrations less than 35 pg/ml were associated with lower BMD, but annual E2 measures and changes did not predict BMD loss. Testosterone, free androgen index, and dehydroepiandrosterone sulfate concentrations were not significantly associated with BMD loss.

CONCLUSIONS

Spine and hip BMD losses during the menopause transition were most strongly related to the interaction between initial FSH levels and longitudinal FSH changes and not to E2 or androgen levels or changes.

BACKGROUND

It is not clear whether cortisol or dehydroepiandrosterone (DHEA) hypersecretion increases the risk for major depression in the presence of undesirable life events.

OBJECTIVE

To determine whether there is a specific pattern of psychoendocrine factors that predicts the onset of major depressive disorder.

METHODS

180 adolescents (73 boys, 107 girls) at high risk for psychopathology were assessed for cortisol, DHEA, depressive symptoms, life events and psychiatric disorder at entry and 12 months later.

RESULTS

Major depression was predicted for both genders by the additive effects of: higher depressive symptoms; personal disappointments and losses only in the month before onset; one or more daily levels of cortisol at 08.00 h or DHEA at 20.00 h greater than the 80th percentile of the daily mean.

CONCLUSIONS

A subgroup of adolescents may carry a physiological risk for major depression which may be either of genetic and/or earlier psychosocial origin.

A wide range of biomarkers, reflecting activity in a number of biological systems (e.g., neuroendocrine, immune, cardiovascular, and metabolic), have been found to prospectively predict disability, morbidity, and mortality outcomes in older adult populations. Levels of these biomarkers, singly or in combination, may serve as an early warning system of risk for future adverse health outcomes. In the current investigation, 13 biomarkers were examined as predictors of mortality occurrence over a 12-year period in a sample of men and women (n = 1,189) 70-79 years of age at enrollment into the study. Biomarkers examined in analyses included markers of neuroendocrine functioning (epinephrine, norepinephrine, cortisol, and dehydroepiandrosterone), immune activity (C-reactive protein, fibrinogen, IL-6, and albumin), cardiovascular functioning (systolic and diastolic blood pressure), and metabolic activity [high-density lipoprotein (HDL) cholesterol, total to HDL cholesterol ratio, and glycosylated hemoglobin]. Recursive partitioning techniques were used to identify a set of pathways, composed of combinations of different biomarkers, that were associated with a high-risk of mortality over the 12-year period. Of the 13 biomarkers examined, almost all entered into one or more high-risk pathways although combinations of neuroendocrine and immune markers appeared frequently in high-risk male pathways, and systolic blood pressure was present in combination with other biomarkers in all high-risk female pathways. These findings illustrate the utility of recursive partitioning techniques in identifying biomarker combinations predictive of mortal outcomes in older adults, as well as the multiplicity of biological pathways to mortality in elderly populations.

The aim of this study was to examine the hypothesis that hypersecretion of ovarian androgens in polycystic ovary syndrome results from an intrinsic abnormality of androgen biosynthesis by thecal cells. Steroid accumulation by human thecal cells from normal and polycystic ovaries (PCO-theca) was examined under basal and LH-stimulated conditions. A method for dispersing and culturing human thecal cells as primary monolayers in serum-free medium was developed. LH increased androstenedione (A), progesterone (P), 17 alpha-hydroxyprogesterone, dehydroepiandrosterone, and estradiol accumulation in the overlying medium in a dose-dependent manner at a maximum effective dose of 2.5 ng/mL. The principal variables affecting the magnitude of steroid accumulation were plating density, duration of incubation, and follicle size. Using only theca from follicles less than 10 mm and keeping plating density constant, 48-h steroid production by theca from five normal ovaries was compared to that from nine polycystic ovaries isolated from both anovulatory and ovulatory women. There was a significant increase in both basal (median, 32.1 pmol/1000 cells.48 h; range, 18.7-250) and LH-stimulated (56 pmol/1000 cells; range, 40.7-406) A accumulation by PCO-theca compared to basal (1.7 pmol/1000 cells; range, 1.1-4.3) and LH-stimulated (2.8 pmol/1000 cells; range, 2.0-8.1) A accumulation by normal theca, with no overlap in values between the two. Although P production was also increased in the PCO-theca, the A to P ratios under both basal and LH-stimulated conditions were significantly higher in the PCO-theca [A/P ratio normal; PCO basal, 0.1 and 0.53 (P < 0.01); LH-stimulated, 0.04 and 0.65 (P < 0.001)], suggesting increased conversion of P to A. The steroid response to LH was similar in both groups. This is the first report of a difference in thecal androgen production between normal and polycystic ovaries and supports the hypothesis that there is a primary abnormality in the regulation of androgen production in PCOS.

This study examined the prevalence of both basal and glucose-stimulated hyperinsulinemia and acanthosis nigricans (AN) as well as the relationship between insulin and androgen levels in hyperandrogenic women. Sixty-two women who had an elevation of 1 or more plasma androgen levels were studied. The results in these women, grouped for analysis on the basis of obesity and ovulatory status, were compared to those in 36 control women of similar ages and weights. The anovulatory hyperandrogenic women had the clinical and biochemical features of the polycystic ovary syndrome (PCO). Oral glucose tolerance tests were performed with measurement of glucose, insulin, sex hormone-binding globulin (SHBG), and total and non-SHBG-bound sex steroid levels. AN was present in 29% of the hyperandrogenic women, the majority of them obese. Fifty percent of obese PCO women had AN, but they did not otherwise differ from PCO women lacking this dermatological change. Only women with PCO had significant hyperinsulinemia independent of obesity, and obese PCO women with AN had the highest serum insulin levels. Plasma glucose values during the oral glucose tolerance test were significantly increased in obese PCO women independent of the presence of AN, and 20% of these women had frank impairment of glucose tolerance. Ovulatory hyperandrogenic women had normal insulin levels and glucose tolerance. Obese and nonobese women had different relationships between sex steroid and insulin levels; obese women had significant correlations between insulin and non-SHBG testosterone levels (r = 0.30; P less than 0.05), whereas nonobese women had significant correlations between insulin and FSH (r = 0.40; P less than 0.01), dehydroepiandrosterone sulfate (r = 0.33; P less than 0.05), and SHBG (r = 0.37; P less than 0.05) levels, suggesting that the mechanisms underlying the association between sex steroid and insulin levels are complex. These findings suggest that 1) only women with PCO have hyperinsulinemia independent of obesity; hyperinsulinemia is not a feature of hyperandrogenic states in general; 2) AN is a common finding in obese hyperandrogenic women, particularly those with PCO; 3) only obese PCO women are at risk for impairment of glucose tolerance, independent of the presence of AN, suggesting that the negative impact of PCO and obesity on insulin action is additive; and 4) PCO women with AN can be considered as a subgroup of PCO and do not appear to have a distinct endocrine disorder.

The nuclear receptor PXR (pregnane X receptor) protects the body from hepatotoxicity of secondary bile acids such as lithocholic acid (LCA) by inducing expression of the hydroxylating cytochrome P450 enzyme CYP3A and promoting detoxification. We found that activation of PXR also increases the activity and gene expression of the phase II conjugating enzyme dehydroepiandrosterone sulfotransferase (STD) known to sulfate LCA to facilitate its elimination. This activation is direct and appears to extend to other xenobiotic sulfotransferases as well as to 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), an enzyme that generates the donor cofactor for the reaction. Because sulfation plays an important role in the metabolism of many xenobiotics, prescription drugs, and toxins, we propose that PXR serves as a master regulator of the phase I and II responses to facilitate rapid and efficient detoxification and elimination of foreign chemicals.

BACKGROUND

The physiologic role of dehydroepiandrosterone in humans is still unclear. Adrenal insufficiency leads to a deficiency of dehydroepiandrosterone; we therefore, investigated the effects of dehydroepiandrosterone replacement, in patients with adrenal insufficiency.

METHODS

In a double-blind study, 24 women with adrenal insufficiency received in random order 50 mg of dehydroepiandrosterone orally each morning for four months and placebo daily for four months, with a one-month washout period. We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively. The women were assessed before treatment, after one and four months of treatment with dehydroepiandrosterone, after one and four months of placebo, and one month after the end of the second treatment period.

RESULTS

Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly. Dehydroepiandrosterone significantly improved overall well-being as well as scores for depression and anxiety. For the global severity index, the mean (+/-SD) change from base line was -0.18+/-0.29 after four months of dehydroepiandrosterone therapy, as compared with 0.03+/-0.29 after four months of placebo (P=0.02). As compared with placebo, dehydroepiandrosterone significantly increased the frequency of sexual thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively).

CONCLUSIONS

Dehydroepiandrosterone improves well-being and sexuality in women with adrenal insufficiency.

17 beta-Hydroxysteroid dehydrogenase (17 beta-HSD) controls the last step in the formation of all androgens and all estrogens. This crucial role of 17 beta-HSD is performed by at least five 17 beta-HSD isoenzymes having individual cell-specific expression, substrate specificity, regulation mechanisms, and reductive or oxidative catalytic activity. Both estrogenic and androgenic 17 beta-HSD activities were found in all 25 rhesus monkey and 15 human peripheral intracrine tissues examined. Type 1 17 beta-HSD is a protein of 327 amino acids catalyzing the formation of 17 beta-estradiol from estrone. Its x-ray structure was the first to be determined among mammalian steroidogenic enzymes. Initially crystallized with NAD, the crystal structure of type 1 17 beta-HSD has just been determined as a complex with 17 beta-estradiol, thereby illustrating the conformation of the substrate-binding site. Type 2 17 beta-HSD degrades 17 beta-estradiol into estrone and testosterone into androstenedione, and type 4 17 beta-HSD mainly degrades 17 beta-estradiol into estrone and androst-5-ene-3 beta, 17 beta-diol into dehydroepiandrosterone. Types 3 and 5 17 beta-HSD, on the other hand, catalyze the formation of testosterone from androstenedione in the testis and peripheral tissues, respectively. The various types of human 17 beta-HSD, because of their tissue-specific expression and substrate specificity, provide each peripheral cell with the necessary mechanisms to control the level of intracellular androgens and/or estrogens, a new area of hormonal control that we call intracrinology.

Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. To determine if this nutritional intervention has similar actions in a long-lived primate species, the National Institute on Aging (NIA) initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta) of a broad age range. We have observed physiological effects of CR that parallel rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study have demonstrated that CR decreases body weight and fat mass, improves glucoregulatory function, decreases blood pressure and blood lipids, and decreases body temperature. Juvenile males exhibited delayed skeletal and sexual maturation. Adult bone mass was not affected by CR in females nor were several reproductive hormones or menstrual cycling. CR attenuated the age-associated decline in both dehydroepiandrosterone (DHEA) and melatonin in males. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that CR will have beneficial effects on morbidity and mortality. We are now preparing a battery of measures to provide a thorough and relevant analysis of the effectiveness of CR at delaying the onset of age-related disease and maintaining function later into life.

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.

OBJECTIVE

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.

CONCLUSIONS

This study has shown increases in total estrogen levels and amount of bioavailable estrogens in association with alcohol consumption in premenopausal women.

CONCLUSIONS

This possible explanatory mechanism for a positive association between alcohol consumption and breast cancer risk merits further investigation.