Citations
All
Search in:AllTitleAbstractAuthor name
Publications
(11K+)
Patents
Grants
Pathways
Clinical trials
Publication
Journal: Journal of Urology
January/6/1994
Abstract
We provide current, normative data on the prevalence of impotence, and its physiological and psychosocial correlates in a general population using results from the Massachusetts Male Aging Study. The Massachusetts Male Aging Study was a community based, random sample observational survey of noninstitutionalized men 40 to 70 years old conducted from 1987 to 1989 in cities and towns near Boston, Massachusetts. Blood samples, physiological measures, socio-demographic variables, psychological indexes, and information on health status, medications, smoking and lifestyle were collected by trained interviewers in the subject's home. A self-administered sexual activity questionnaire was used to characterize erectile potency. The combined prevalence of minimal, moderate and complete impotence was 52%. The prevalence of complete impotence tripled from 5 to 15% between subject ages 40 and 70 years. Subject age was the variable most strongly associated with impotence. After adjustment for age, a higher probability of impotence was directly correlated with heart disease, hypertension, diabetes, associated medications, and indexes of anger and depression, and inversely correlated with serum dehydroepiandrosterone, high density lipoprotein cholesterol and an index of dominant personality. Cigarette smoking was associated with a greater probability of complete impotence in men with heart disease and hypertension. We conclude that impotence is a major health concern in light of the high prevalence, is strongly associated with age, has multiple determinants, including some risk factors for vascular disease, and may be due partly to modifiable para-aging phenomena.
Publication
Journal: Journal of the National Cancer Institute
May/5/2002
Abstract
BACKGROUND
Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women.
METHODS
We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate.
RESULTS
The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis.
CONCLUSIONS
Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
February/28/2002
Abstract
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.
Publication
Journal: Journal of the National Cancer Institute
September/1/2003
Abstract
BACKGROUND
Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations.
METHODS
We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided.
RESULTS
Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk.
CONCLUSIONS
The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.
Publication
Journal: FASEB Journal
April/15/1992
Abstract
Neuroactive steroids are natural or synthetic steroids that rapidly alter the excitability of neurons by binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters. The best-studied neuroactive steroids are a series of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnane steroids that include the major metabolites of progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC), respectively. These 3 alpha-hydroxysteroids do not interact with classical intracellular steroid receptors but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in brain, gamma-amino-butyric acid (GABA). Biochemical and electrophysiological studies have shown that these steroids markedly augment GABA-activated chloride ion currents in a manner similar (but not identical) to that of anesthetic barbiturates. Several steroids have also been observed to have convulsant or proconvulsant properties, including the synthetic amidine 3 alpha-hydroxy-16-imino-5 beta-17-azaandrostan-11-one (RU5135) and the natural sulfate esters of pregnenolone and dehydroepiandrosterone. Several of these have been shown to be bicuculline or picrotoxin-like GABAA receptor antagonists. Examples of steroids that alter neuronal excitability rapidly by augmenting or inhibiting excitatory amino acid receptor-mediated responses have also been reported. Recently, allopregnanolone and allotetrahydroDOC have also been measured in brain and plasma where their levels have been shown to fluctuate in response to stress and during the estrous and menstrual cycles of rats and humans, respectively. Although the major fraction of allopregnanolone in tissue, including brain, is of adrenal and/or ovarian origin, appreciable levels of allopregnanolone can still be measured in the brains of adrenalectomized and/or oophorectomized animals. Receptor-active neurosteroids may represent an important class of neuromodulators that can rapidly alter central nervous system excitability via novel nongenomic mechanisms.
Publication
Journal: JAMA - Journal of the American Medical Association
April/11/2006
Abstract
BACKGROUND
Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans.
OBJECTIVE
To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women.
METHODS
Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La.
METHODS
Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet).
METHODS
Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature.
RESULTS
Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005).
CONCLUSIONS
Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans.
BACKGROUND
ClinicalTrials.gov Identifier: NCT00099151.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
October/7/1998
Abstract
Estimates of the prevalence of the polycystic ovary syndrome (PCOS) in the general population have ranged from 2-20%. The vast majority of these reports have studied White populations in Europe, used limited definitions of the disorder, and/or used bias populations, such as those seeking medical care. To estimate the prevalence of this disorder in the United States and address these limitations, we prospectively determined the prevalence of PCOS in a reproductive-aged population of 369 consecutive women (174 White and 195 Black; aged 18-45 yr), examined at the time of their preemployment physical. Body measures were obtained, and body hair was quantified by a modified Ferriman-Gallwey (F-G) method. All exams were initially performed by 2 trained nurses, and any subject with an F-G score above 3 was reexamined by a physician, the same for all patients. Of the 369 women, 277 (75.1%) also agreed to complete a questionnaire and have additional blood drawn. Subjects were studied regardless of current estrogen/progestin hormonal use (28.5%). PCOS was defined as 1) oligoovulation, 2) clinical hyperandrogenism (i.e. hirsutism) and/or hyperandrogenemia, and 3) exclusion of other related disorders, such as hyperprolactinemia, thyroid abnormalities, and non-classic adrenal hyperplasia. Hirsutism was defined by a F-G score of 6 or more, and hyperandrogenemia was defined as a total or free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate level above the 95th percentile of control values [i.e. all eumenorrheic women in the study, who had no hirsutism (F-G < or = 5) or acne and were receiving no hormonal therapy; n = 98]. Considering all 369 women studied, White and Black women had similar mean ages (29.4 +/- 7.1 and 31.1 +/- 7.8 yr, respectively), although White women had a lesser body mass than Black women (24.9 +/- 6.1 vs. 29.2 +/- 8.1 kg/m2, respectively; P < 0.001). Of these 7.6%, 4.6%, and 1.9% demonstrated a F-G score of 6 or more, 8 or 10, respectively, and there was no significant racial difference, with hirsutism prevalences of 8.0%, 2.8%, and 1.6% in Whites, and 7.1%, 6.1%, and 2.1% in Blacks, respectively. Of the 277 women consenting to a history and hormonal evaluation, 4.0% had PCOS as defined, 4.7% (6 of 129) of Whites and 3.4% (5 of 148) of Blacks. In conclusion, in our consecutive population of unselected women the prevalence of hirsutism varied from 2-8% depending on the chosen cut-off F-G score, with no significant difference between White and Black women. Using an F-G score of 6 or more as indicative of hirsutism, 3.4% of Blacks and 4.7% of Whites had PCOS as defined. These data suggest that PCOS may be one of most common reproductive endocrinological disorders of women.
Publication
Journal: Clinical Cancer Research
October/3/2004
Abstract
OBJECTIVE
Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.
METHODS
Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.
RESULTS
Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 +/- SD 0.115 and percentage positive nuclei, 83.7 +/- 11.6) was similar to benign prostate (mean optical density, 0.315 +/- 0.044 and percentage positive nuclei, 77.3 +/- 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 +/- 2.34 pmol/g tissue) and benign prostate (3.26 +/- 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P = 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgen-regulated gene product, prostate-specific antigen, at 8.80 +/- 10.80 nmol/g tissue.
CONCLUSIONS
Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
August/7/2000
Abstract
We prospectively estimated the prevalence of the polycystic ovary syndrome (PCOS), as defined by the NIH/NICHHD 1990 endocrine criteria, in a population of 154 Caucasian women of reproductive age reporting spontaneously for blood donation. Anthropometric data; the presence of hirsutism, acne, and androgenic alopecia; and the menstrual history were recorded by a single investigator. In 145 women, blood samples were also obtained for measurement of serum androgen levels. PCOS was defined by the presence of 1) oligomenorrhea, 2) clinical and/or biochemical hyperandrogenism, and 3) exclusion of hyperprolactinemia, thyroid disorders, and nonclassic 21-hydroxylase deficiency. Hirsutism was defined by a modified Ferriman-Gallwey score of 8 or more, acne was considered as a sign of hyperandrogenism when persistent after the second decade of life, and hyperandrogenemia was defined by an increase in circulating testosterone or dehydroepiandrosterone sulfate or an increase in the free androgen index above the 95th percentile of the control values derived from the nonhirsute, nonacneic women having regular menses who were not receiving hormonal therapy. PCOS was present in 10(6.5%), hirsutism was present in 11 (7.1%), and acne was present in 19 (12.3%) of the 154 women. Our results demonstrate a 6.5% prevalence of PCOS, as defined, in a minimally biased population of Caucasian women from Spain. The polycystic ovary syndrome, hirsutism, and acne are common endocrine disorders in women.
Publication
Journal: Annual Review of Clinical Psychology
September/20/2007
Abstract
This review discusses neurobiological and psychosocial factors associated with stress-induced depression and compares these factors with those believed to characterize stress resilience. Neurobiological factors that are discussed and contrasted include serotonin, the 5-HT1A receptor, polymorphisms of the 5-HT transporter gene, norepinephrine, alpha-2 adrenergic receptors, neuropeptide Y, polymorphisms of the alpha-2 adrenergic gene, dopamine, corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), cortisol, and CRH receptors. These factors are described in the context of brain regions believed to be involved in stress, depression, and resilience to stress. Psychosocial factors associated with depression and/or stress resilience include positive emotions and optimism, humor, cognitive flexibility, cognitive explanatory style and reappraisal, acceptance, religion/spirituality, altruism, social support, role models, coping style, exercise, capacity to recover from negative events, and stress inoculation. The review concludes with potential psychological, social, spiritual, and neurobiological approaches to enhancing stress resilience, decreasing the likelihood of developing stress-induced depression/anxiety, and treating stress-induced psychopathology.
Publication
Journal: Journal of the National Cancer Institute
February/18/2008
Abstract
BACKGROUND
Sex hormones in serum have been hypothesized to influence the risk of prostate cancer. We performed a collaborative analysis of the existing worldwide epidemiologic data to examine these associations in a uniform manner and to provide more precise estimates of risks.
METHODS
Data on serum concentrations of sex hormones from 18 prospective studies that included 3886 men with incident prostate cancer and 6438 control subjects were pooled by the Endogenous Hormones and Prostate Cancer Collaborative Group. Relative risks (RRs) of prostate cancer by fifths of serum hormone concentration were estimated by use of conditional logistic regression with stratification by study, age at recruitment, and year of recruitment. All statistical tests were two-sided.
RESULTS
No associations were found between the risk of prostate cancer and serum concentrations of testosterone, calculated free testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated free estradiol. The serum concentration of sex hormone-binding globulin was modestly inversely associated with prostate cancer risk (RR in the highest vs lowest fifth = 0.86, 95% confidence interval = 0.75 to 0.98; P(trend) = .01). There was no statistical evidence of heterogeneity among studies, and adjustment for potential confounders made little difference to the risk estimates.
CONCLUSIONS
In this collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, serum concentrations of sex hormones were not associated with the risk of prostate cancer.
Publication
Journal: The Journal of laboratory and clinical medicine
April/25/2001
Abstract
Sarcopenia is a term utilized to define the loss of muscle mass and strength that occurs with aging. Sarcopenia is believed to play a major role in the pathogenesis of frailty and functional impairment that occurs with old age. Progressive muscle wasting occurs with aging. The prevalence of clinically significant sarcopenia is estimated to range from 8.8% in young old women to 17.5% in old old men. Persons who are obese and sarcopenic (the "fat frail") have worse outcomes than those who are sarcopenic and non-obese. There is a disproportionate atrophy of type IIa muscle fibers with aging. There is also evidence of an age-related decrease in the synthesis rate of myosin heavy chain proteins, the major anabolic protein. Motor units innervating muscle decline with aging, and there is increased irregularity of muscle unit firing. There are indications that cytokines-especially interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6-play a role in the pathogenesis of sarcopenia. Similarly, the decline in anabolic hormones-namely, testosterone, dehydroepiandrosterone growth hormone, and insulin-like growth factor-I-is also implicated in the sarcopenic process. The role of the physiologic anorexia of aging remains to be determined. Decreased physical activity with aging appears to be the key factor involved in producing sarcopenia. An increased research emphasis on the factors involved in the pathogenesis of sarcopenia is needed.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
September/17/1984
Abstract
In a cross-sectional study, serum dehydroepiandrosterone sulfate (DS) concentrations were measured in 981 men and 481 women, aged 11-89, yr. The resulting data were asymetrically distributed and were normalized by logarithmic transformation and analyzed by 5-yr age grouping (e.g. 15-19 yr, 20-24 yr, etc.). The DS concentration peaked at age 20-24 yr in men (logarithmic mean, 3470 ng/ml) and at age 15-19 yr in women (log mean, 2470 ng/ml). Mean values then declined steadily in both sexes (log mean at greater than 70 yr of age, 670 ng/ml in men and 450 ng/ml in women) and were significantly higher in men than women at ages from 20-69 yr. Analysis of 517 randomly selected sera (from women) which had been stored frozen for 10-15 yr gave results indistinguishable from values obtained from fresh specimens. In a supplementary study, a longitudinal analysis of weekly specimens from 4 normal men, aged 36-59 yr, revealed individual variability (mean coefficient of variation, 19%) and failed to demonstrate any monthly, seasonal, or annual rhythmicity. Based on the above analyses, a table of normal serum DS ranges for adult men and women is presented for use as a clinical reference.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
February/29/2004
Abstract
In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017alpha. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017alpha and P450 aromatase, in pyramidal neurons in the CA1-CA3 regions, as well as in the granule cells in the dentate gyrus, by means of immunohistochemical staining of slices. Only a weak immunoreaction of these P450s was observed in astrocytes and oligodendrocytes. ImmunoGold electron microscopy revealed that P45017alpha and P450 aromatase were localized in pre- and postsynaptic compartments as well as in the endoplasmic reticulum in principal neurons. The expression of these cytochromes was further verified by using Western blot analysis and RT-PCR. Stimulation of hippocampal neurons with N-methyl-d-aspartate induced a significant net production of estradiol. Analysis of radioactive metabolites demonstrated the conversion from [(3)H]pregnenolone to [(3)H]estradiol through dehydroepiandrosterone and testosterone. This activity was abolished by the application of specific inhibitors of cytochrome P450s. Interestingly, estradiol was not significantly converted to other steroid metabolites. Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17beta-estradiol is synthesized by P45017alpha and P450 aromatase localized in hippocampal neurons from endogenous cholesterol. This synthesis may be regulated by a glutamate-mediated synaptic communication that evokes Ca(2+) signals.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
June/15/1992
Abstract
Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Nature (London) 347, 645-650], which encodes a 97% similar protein with a particularly well-conserved putative ligand-binding domain. To search for physiologically occurring activators, we established a transcriptional transactivation assay by stably expressing in CHO cells a chimera of rat PPAR and the human glucocorticoid receptor that activates expression of the placental alkaline phosphatase reporter gene under the control of the mouse mammary tumor virus promoter. Testing of compounds related to lipid metabolism or peroxisomal proliferation revealed that 150 microM concentrations of arachidonic or linoleic acid but not of dehydroepiandrosterone, cholesterol, or 25-hydroxy-cholesterol, activate the receptor chimera. In addition, saturated fatty acids induce the reporter gene. Shortening the chain length to n = 6 or introduction of an omega-terminal carboxylic group abolished the activation potential of the fatty acid. In conclusion, the present results indicate that fatty acids can regulate gene expression mediated by a member of the steroid nuclear receptor superfamily.
Publication
Journal: The Lancet
July/2/2003
Abstract
Adrenal insufficiency is caused by either primary adrenal failure (mostly due to autoimmune adrenalitis) or by hypothalamic-pituitary impairment of the corticotropic axis (predominantly due to pituitary disease). It is a rare disease, but is life threatening when overlooked. Main presenting symptoms such as fatigue, anorexia, and weight loss are non-specific, thus diagnosis is often delayed. The diagnostic work-up is well established but some pitfalls remain, particularly in the identification of secondary adrenal insufficiency. Despite optimised life-saving glucocorticoid-replacement and mineralocorticoid-replacement therapy, health-related quality of life in adrenal insufficiency is more severely impaired than previously thought. Dehydroepiandrosterone-replacement therapy has been introduced that could help to restore quality of life. Monitoring of glucocorticoid-replacement quality is hampered by lack of objective methods of assessment, and is therefore largely based on clinical grounds. Thus, long-term management of patients with adrenal insufficiency remains a challenge, requiring an experienced specialist. However, all doctors should know how to diagnose and manage suspected acute adrenal failure.
Publication
Journal: Journal of the National Cancer Institute
September/17/1998
Abstract
BACKGROUND
A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study.
METHODS
Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection.
RESULTS
From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy.
CONCLUSIONS
Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.
Publication
Journal: Journal of the National Cancer Institute
December/27/2004
Abstract
BACKGROUND
Levels of endogenous hormones have been associated with the risk of breast cancer among postmenopausal women. Little research, however, has investigated the association between hormone levels and tumor receptor status or invasive versus in situ tumor status. Nor has the relation between breast cancer risk and postmenopausal progesterone levels been investigated. We prospectively investigated these relations in a case-control study nested within the Nurses' Health Study.
METHODS
Blood samples were prospectively collected during 1989 and 1990. Among eligible postmenopausal women, 322 cases of breast cancer (264 invasive, 41 in situ, 153 estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [ER+/PR+], and 39 ER-negative and PR-negative [ER-/PR-] disease) were reported through June 30, 1998. For each case subject, two control subjects (n = 643) were matched on age and blood collection (by month and time of day). Endogenous hormone levels were measured in blood plasma. We used conditional and unconditional logistic regression analyses to assess associations and to control for established breast cancer risk factors.
RESULTS
We observed a statistically significant direct association between breast cancer risk and the level of both estrogens and androgens, but we did not find any (by year) statistically significant associations between this risk and the level of progesterone or sex hormone binding globulin. When we restricted the analysis to case subjects with ER+/PR+ tumors and compared the highest with the lowest fourths of plasma hormone concentration, we observed an increased risk of breast cancer associated with estradiol (relative risk [RR] = 3.3, 95% confidence interval [CI] = 2.0 to 5.4), testosterone (RR = 2.0, 95% CI = 1.2 to 3.4), androstenedione (RR = 2.5, 95% CI = 1.4 to 4.3), and dehydroepiandrosterone sulfate (RR = 2.3, 95% CI = 1.3 to 4.1). In addition, all hormones tended to be associated most strongly with in situ disease.
CONCLUSIONS
Circulating levels of sex steroid hormones may be most strongly associated with risk of ER+/PR+ breast tumors.
Publication
Journal: Endocrine-Related Cancer
March/9/2006
Abstract
Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has been advocated for the prevention of osteoporosis and improved sexual well-being. We have con