CiteULike: FW_Gibb's library [320 articles]

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism.

S Loves — 2008-07-02T09:28:07-00:00

European journal of endocrinology / European Federation of Endocrine Societies, Vol. 158, No. 5. (May 2008), pp. 741-747.

OBJECTIVE: Isolated hypogonadotropic hypogonadism (IHH) is frequently observed in severely obese men, probably as a result of increased estradiol (E(2)) production and E(2)-mediated negative feedback on pituitary LH secretion. Aromatase inhibitors can reverse this process. This study evaluates whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect. DESIGN: Open, uncontrolled 6-month pilot study in 12 severely obese men (body mass index>35.0 kg/m(2)) with obesity-related IHH and free testosterone levels <225 pmol/l, treated with 2.5 mg letrozole once a week for 6 months. RESULTS: Six weeks of treatment reduced total E(2) from 123+/-11 to 58+/-7 pmol/l (P<0.001, mean+/-s.e.m.), and increased serum LH from 4.4+/-0.6 to 11.1+/-1.5 U/l (P<0.001). Total testosterone rose from 5.9+/-0.5 to 19.6+/-1.4 nmol/l (P<0.001), and free testosterone from 163+/-13 to 604+/-50 pmol/l (P<0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E(2) levels were stable throughout the week and during the 6-month treatment period. CONCLUSION: Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose <2.5 mg once a week is recommended.

Changes in muscle, fat and bone mass after 36weeks of maximal androgen blockade for prostate cancer

Galvao — 2008-06-07T17:46:10-00:00

BJU International, Vol. 102, No. 1. (July 2008), pp. 44-47.

Androgens and metabolic syndrome: Lessons from androgen receptor knock out (ARKO) mice.

T Yanase — 2008-06-04T09:44:45-00:00

The Journal of steroid biochemistry and molecular biology, Vol. 109, No. 3-5. (April 2008), pp. 254-257.

Testosterone (T) is an important factor for determining body composition in males. Abdominal obesity is inversely correlated with serum T levels in men, leading to greater mortality. Pathologically hypogonadal men also have a significantly higher fat mass, which is reversed by T administration. However, the mechanism for such anti-obesity effect of androgen has not been well clarified. Androgen receptor (AR) null male mice revealed late-onset obesity. Male ARKO mice were euphagic compared to the wild-type male controls, but also less dynamic and less oxygen consuming. Transcript profiling indicated that male ARKO mice had lower transcripts for the thermogenetic uncoupling protein 1 (UCP1). We also found enhanced secretion of adiponectin, which is insulin-sensitizing, from adipose tissue in comparison to wild type, which might partly explain why the overall insulin sensitivity of male ARKO mice remained almost intact despite their apparent obesity. In addition, decreased lipolysis rather than increased lipid synthesis was observed, which might also account for the increased adiposity in male ARKO mice. The results revealed that AR plays important roles in male metabolism by affecting the energy balance, and is negative to both adiposity and insulin sensitivity.

Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition.

Laura Baglietto — 2008-06-04T09:42:04-00:00

Breast cancer research and treatment (29 May 2008)

Steroid hormones are associated with the risk of postmenopausal breast cancer and evidence suggests that increased concentrations of oestrogens from peripheral aromatisation in adipose tissue partly explains the association between body mass index (BMI) and risk of postmenopausal breast cancer. This study examined the associations between circulating concentrations of steroid hormones and anthropometric measurements in a sample of naturally postmenopausal women from the Melbourne Collaborative Cohort Study, not using hormone replacement therapy. We measured plasma concentration of total oestradiol, oestrone sulphate, dehydroepiandrosterone sulphate, androstenedione, testosterone and sex hormone binding globulin (SHBG) and calculated concentration of free oestradiol. Body measurements included height, weight, BMI, waist circumference, fat mass and fat-free mass, the last two estimated by bioelectrical impedance analysis. BMI was positively associated with both oestrogens and androgens and negatively with SHBG. Fat mass was the principal measure responsible for the association observed between body size and total oestradiol. The associations between oestrone sulphate and androgens and body size were mainly with waist circumference. The associations between oestrogens and body size were close to null for the first 6 years since menopause and became positive thereafter. Our results are compatible with the hypothesis that after the menopause excess fat mass increases oestrogen concentrations through the peripheral aromatisation of androgens in adipose tissue. This effect requires around 6 years to be detectable by way of circulating steroid hormone levels.

Depot-specific steroidogenic gene transcription in human adipose tissue.

Scott M Mackenzie — 2008-05-30T09:54:25-00:00

Clinical endocrinology (10 April 2008)

Context: Sex steroids (androgens and estrogens) and corticosteroids (glucocorticoids and mineralocorticoids) have a major impact on fat distribution. Several genes involved in steroid synthesis and metabolism, such as 11beta-hydroxysteroid dehydrogenase type 1 and aromatase, are known to be expressed within adipose tissue, thus modulating local steroid levels; however our knowledge of which genes are expressed and at what level is incomplete. Objective: To detect by realtime qRT-PCR which of 13 key steroidogenic genes are transcribed within human adipose tissue and to assess whether mRNA levels differ significantly between the subcutaneous abdominal and omental adipose depots. Patients: 8 women undergoing caesarean section (age 29.1+/-6.5 years, BMI 28.9+/-8.4kg/m(2)). Results: Genes transcribed in both depots were StAR (Steroidogenic acute regulatory protein), CYP11A1 (side-chain cleavage enzyme), HSD3B2 (3beta-hydroxysteroid dehydrogenase type 2), CYP21B (21-hydroxylase), CYP19 (aromatase), HSD11B1 (11beta-hydroxysteroid dehydrogenase type 1), HSD17B3, HSD17B5, HSD17B7 (17beta-hydroxysteroid dehydrogenase types 3, 5 and 7) and SRD5A2 (5alpha-reductase type 2). All but SRD5A2 varied significantly in abundance between depots. CYP17 (17alpha-hydroxylase), CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) transcription were not detected. Conclusions: This study confirms and significantly extends our knowledge of steroidogenic gene expression within adipose tissue, showing that transcript levels are depot-specific. We demonstrate that de novo synthesis from cholesterol of sex steroids, cortisol and aldosterone is not possible due to the absence of key steroidogenic mRNAs. Instead, the pattern of transcription suggests that 11-deoxycorticosterone, a mineralocorticoid, would be the ultimate product of any de novo adipose synthesis.

Effect of smoking on the paradox of high waist-to-hip ratio and low body mass index.

SH Jee — 2008-05-28T10:42:54-00:00

Obesity research, Vol. 10, No. 9. (September 2002), pp. 891-895.

OBJECTIVE: Research on diabetes mellitus (DM) indicates that people with a low body mass index (BMI) but a high waist-to-hip ratio (WHR) are in a particularly high-risk group. The purpose of this study was to investigate the prevalence of and the effect of smoking on this paradoxical relationship. RESEARCH METHODS AND PROCEDURES: Our study sample consisted of 3450 men and 4250 women who had participated in the Korean Nationwide Health Examination Survey. We divided the study sample into tertiles (low, medium, and high), according to the level of WHR and of BMI, which yielded nine different combinations. Individuals exhibiting so-called paradox A had the highest WHR and the lowest BMI. RESULTS: The prevalence of paradox A was 4.7% for men and 3.8% for women. The overall agreement of WHR and BMI groups was poor [for men: kappa = 0.31 and 95% confidence interval (CI) = 0.29 to 0.34; for women: kappa = 0.39 and 95% CI = 0.37 to 0.42 for women]. The odds ratios for subjects having paradox A were estimated using a logistic regression model after adjusting for age, age(2), height, education, smoking, use of alcohol, and exercise. The risk for paradox A among current smokers was 2.1-fold (95% CI, 1.5 to 3.0) higher for men and 2.5-fold (95% CI, 1.6 to 3.9) higher for women than for nonsmokers, after adjusting for age and covariates. DISCUSSION: Cigarette smoking may increase the risk of paradox A. The findings of this study should be crossvalidated to different populations.

Cigarette smoking and fat distribution in 21,828 British men and women: a population-based study.

D Canoy — 2008-05-28T10:40:09-00:00

Obesity research, Vol. 13, No. 8. (August 2005), pp. 1466-1475.

OBJECTIVE: To examine the relationship between cigarette smoking habits and fat distribution in a population-based cohort of men and women. RESEARCH METHODS AND PROCEDURES: We analyzed cross-sectional data from 21,828 men and women who were 45 to 79 years of age, residents in Norfolk, United Kingdom, and were recruited between 1993 and 1997. Cigarette smoking habits and other lifestyle factors were assessed using self-reported questionnaires. Anthropometric measures were obtained during a health examination. RESULTS: Waist-hip ratio was highest among current smokers and least among never smokers after adjusting for age, BMI, alcohol intake, total energy intake, physical activity, and education. Higher waist-hip ratio was directly associated with higher smoking pack-years in current and former smokers and inversely with duration since quitting smoking in former smokers. Adjusting for age, BMI, and other covariates, current smokers had higher waist circumference but lower hip circumference compared with former or never smokers. DISCUSSION: Cigarette smoking habits seem to influence fat distribution patterns. Although smokers have lower mean BMI compared with nonsmokers, they have a more metabolically adverse fat distribution profile, with higher central adiposity. The explanation for this association may help elucidate the mechanisms underlying the adverse health consequences of cigarette smoking and abdominal obesity.

Microarray analysis of the global alterations in the gene expression in the placentas from cigarette-smoking mothers.

P Huuskonen — 2008-05-28T10:06:52-00:00

Clinical pharmacology and therapeutics, Vol. 83, No. 4. (April 2008), pp. 542-550.

The effects of maternal cigarette smoking on the transcriptome of human full-term placentas were investigated by a microarray analysis. QPCR was performed for a selected set of metabolizing genes. Differentially expressed genes were selected by fold change (+/-1.5-fold) and analysis of variance (P<0.05) between the control and smoker groups. The expression of 174 probe sets was affected significantly. Chronic cigarette smoking induced the expression of CYP1A1. A trend toward a decrease in the expression of several steroid hormone-metabolizing enzymes, including CYP19A1, was detected. The expression of phase II enzymes was not altered, and no enriched categories were observed among the regulated genes, except for aryl hydrocarbon receptor (AhR)-CYP1A1. The unaltered expression of phase II enzymes may result in an increase in the levels of active metabolites and elevated oxidative chemical stress in the placenta and the fetus. On the basis of our results, it seems that cigarette smoke acts as a hormone disrupter in the placenta.

Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking.

JJ Michnovicz — 2008-05-27T10:07:38-00:00

The New England journal of medicine, Vol. 315, No. 21. (20 November 1986), pp. 1305-1309.

Epidemiologic data indicate that cigarette smoking is associated with an important anti-estrogenic effect, and increased hepatic metabolism has been suggested as a possible mechanism. We examined the hypothesis that cigarette smoking in women induces an increase in estradiol 2-hydroxylation. This irreversible metabolic pathway yields 2-hydroxyestrogens, which possess minimal peripheral estrogenic activity and are cleared rapidly from the circulation. We found a significant increase in estradiol 2-hydroxylation in premenopausal women who smoked at least 15 cigarettes per day. The extent of the reaction (mean +/- SEM) was 53.6 +/- 2.2 percent among 14 smokers and 35.1 +/- 1.8 percent among 13 nonsmoking controls--an increase of approximately 50 percent (P less than 0.001). The extent of 2-hydroxylation among five smokers did not vary during the follicular and luteal phases of their menstrual cycles. In addition, urinary excretion of estriol relative to estrone was significantly decreased among smokers (P less than 0.01), providing evidence that the smoking-induced increase in 2-hydroxylation diminishes the competing metabolic pathway involving 16 alpha-hydroxylation. This study demonstrates that smoking exerts a powerful inducing effect on the 2-hydroxylation pathway of estradiol metabolism, which is likely to lead to decreased bioavailability at estrogen target tissues. Elucidation of the mechanism responsible for smoking-induced changes in 2-hydroxylation may be useful in the development of strategies to reduce the risk of hormone-dependent tumors.

Increased urinary catechol estrogen excretion in female smokers

Jon Michnovicz — 2008-05-27T10:05:54-00:00

Steroids, Vol. 52, No. 1-2. ( 1988), pp. 69-83.

Premenopausal female smokers show significantly increased estrogen 2-hydroxylation, which may account in part for the anti-estrogenic effects of cigarette smoking. We have measured five major urinary estrogens, including estradiol (E2), estrone (E1), 16[alpha]-hydroxyestrone (16[alpha]OHE1), estriol (E3), and 2-hydroxyestrone (2OHE1), in premenopausal female smokers and non-smokers, to determine whether increased C-2 hydroxylation affected the urinary excretory patterns in these subjects. While total measured estrogen excretion in the follicular phase did not differ significantly between the two groups, urinary 2OHE1 among the smokers constituted a significantly greater proportion of the total (31.1 vs 18.2%, P < 0.02). This difference was largely caused by significantly increased urinary 2OHE1 and decreased E3 observed in smokers. A urinary catechol estrogen index, defined by [2OHE1]/[E3], was significantly elevated in smokers compared with non-smokers (1.67 ± 0.21 vs 0.56 ± 0.08, P<0.001), and this urinary index correlated strongly with radiometrically determined estrogen 2-hydroxylation (r=0.84, P <0.01). Ratios of the various estrogen metabolites did not vary substantially throughout the menstrual cycle. Urinary estrogen indices as described here may therefore be useful in demonstrating differences in estrogen metabolism, specifically 2-hydroxylation vs 16[alpha]-hydroxylation, in selected populations.

Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause

J Jensen — 2008-05-27T09:45:05-00:00

N Engl J Med, Vol. 313, No. 16. (17 October 1985), pp. 973-975.

To elucidate the effect of smoking on estrogen metabolism, we examined 136 postmenopausal women treated for one year with one of three different doses of combined estrogen-progestogen or placebo. The women were grouped according to smoking status, and serum levels of estrone and estradiol were measured before and after treatment. The results showed reduced levels of both estrogens in smokers as compared with nonsmokers in all three dosage groups. This reduction was most pronounced in the high-dose group (4 mg of estradiol), in which the serum levels of estrone and estradiol in smokers were only 50 per cent of those in nonsmokers (P less than 0.001 and less than 0.05, respectively). In contrast, no significant changes could be demonstrated in the corresponding placebo groups. Moreover, it was possible to demonstrate significant inverse correlations between the number of cigarettes smoked daily and the changes in the levels of serum estrone and estradiol, respectively, (P less than 0.001). This study suggests that an increased hepatic metabolism of estrogens results in lower estrogen levels among postmenopausal smokers. This may contribute to the reported risk of osteoporosis among smokers.

Aromatase inhibitors in cigarette smoke, tobacco leaves and other plants.

Y Osawa — 2008-05-26T17:01:46-00:00

Journal of enzyme inhibition, Vol. 4, No. 2. (1990), pp. 187-200.

A chance observation that cigarette smoke interferes with the aromatase assay led us to investigate tobacco leaf and smoke extracts for the presence of aromatase inhibitors. The highest inhibitory activity was found in the basic fraction of cigarette smoke. Further purification of this fraction led to the identification of N-n-octanoylnornicotine. Synthesis and testing of a series of acylated nornicotines and anabasines for their ability to inhibit aromatase showed an interesting correlation of activity with the length of the acyl carbon chain, with maximum activity at C-11. The acylated derivatives showed activity which was significantly greater than that of nicotine and anabasine. In vivo studies in rats indicated that administration of this inhibitor delayed the onset of NMU-induced breast carcinoma and altered the estrus cycle. These in vivo studies suggest that tobacco alkaloid derivatives exert their effects by suppression of the aromatase enzyme system. Toxicity studies indicated relatively low toxicity with LD50 for N-n-octanoylnornicotine = 367 mg/kg body weight. When extracts from thirty five varieties of vegetables, plant leaves, and fruits were analyzed, seventeen showed quantitatively significant aromatase inhibition which was comparable to that of green tobacco leaf, suggesting that naturally occurring substances may affect endocrine function through aromatase inhibition.

In Men, Peripheral Estradiol Levels Directly Reflect the Action of Estrogens at the Hypothalamo-Pituitary Level to Inhibit Gonadotropin Secretion

Garrett Raven — 2008-05-26T10:16:07-00:00

J Clin Endocrinol Metab, Vol. 91, No. 9. (1 September 2006), pp. 3324-3328.

Context: Estradiol inhibits gonadotropin release in men by an action at the hypothalamus and pituitary. Because of the tissue-specific regulation of aromatase, peripheral estradiol levels may not reflect brain estradiol concentrations. Objective: We evaluated whether local aromatization of testosterone in the hypothalamus or pituitary is important for gonadotropin release and to what extent circulating estrogens affect gonadotropin levels and peripheral testosterone levels. Design, Subjects, and Interventions: We suppressed aromatase activity in 10 young healthy men with letrozole 2.5 mg once daily, restored plasma estradiol levels with estradiol patches (100 microg/d for the first week, 50 microg/d the second week, 25 microg/d the third week, and no estradiol patch the fourth week) and measured plasma testosterone, estradiol, LH, FSH, and SHBG levels. Results: The mean estradiol and testosterone levels during the study ranged between 68.6 +/- 38.3 and 12.6 +/- 7.21 pg/ml for estradiol and 179 +/- 91 and 955 +/- 292 ng/dl (mean +/- SD) for testosterone. Levels of testosterone, LH, and FSH were inversely related to peripheral estradiol levels. During letrozole use, the mean plasma estradiol level needed to restore testosterone, LH, and FSH levels to baseline levels was not significantly different from the baseline mean estradiol level. Conclusions: Local aromatization of testosterone in the hypothalamo-pituitary compartment is not a prerequisite for expression of the inhibitory action of estrogens on gonadotropin secretion in men. Peripheral estradiol levels directly reflect the inhibitory tone exerted by estrogens on gonadotropin release and are a major determinant of peripheral testosterone, LH, and FSH levels. 10.1210/jc.2006-0462

The antiestrogenic effect of cigarette smoking in women.

JA Baron — 2008-05-23T10:11:30-00:00

American journal of obstetrics and gynecology, Vol. 162, No. 2. (February 1990), pp. 502-514.

Epidemiologic results indicate that women who smoke cigarettes are relatively estrogen-deficient. Smokers have an early natural menopause, a lowered risk of cancer of the endometrium, and an increased risk of some osteoporotic fractures. Moreover, women who smoke may have a reduced risk of uterine fibroids, endometriosis, hyperemesis gravidarum, and benign breast disease. Several possible mechanisms for these effects have been identified. Smoking does not appear to be clearly related to estradiol levels, at least in postmenopausal women, although levels of adrenal androgens are increased. Moreover, smoking appears to alter the metabolism of estradiol, leading to enhanced formation of the inactive catechol estrogens.

Smoking and estrogen-related disease.

JA Baron — 2008-05-23T10:08:58-00:00

American journal of epidemiology, Vol. 119, No. 1. (January 1984), pp. 9-22.

Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro.

RL Barbieri — 2008-05-23T10:03:09-00:00

The Journal of clinical investigation, Vol. 77, No. 6. (June 1986), pp. 1727-1733.

Epidemiologic studies suggest that women who smoke have lower endogenous estrogen than nonsmokers. To explore the possible link between cigarette smoking and decreased endogenous estrogens, we have examined the effects of constituents of tobacco on estrogen production in human choriocarcinoma cells and term placental microsomes. In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. Removal of nicotine, cotinine, and anabasine from the culture medium resulted in the complete reversal of the inhibition of aromatase. In the choriocarcinoma cell cultures, a supraphysiologic concentration of androstenedione (73 microM) in the culture medium blocked the inhibition of aromatase caused by nicotine, cotinine, and anabasine. In preparations of term placental microsomes, nicotine, cotinine, and anabasine inhibited the conversion of testosterone to estrogen. Kinetic analysis demonstrated the inhibition to be competitive with respect to the substrate. These findings suggest that some nicotinic alkaloids directly inhibit aromatase. This mechanism may explain, in part, the decreased estrogen observed in women who smoke.

Constituents of cigarette smoke inhibit human granulosa cell aromatase.

RL Barbieri — 2008-05-23T10:00:41-00:00

Fertility and sterility, Vol. 46, No. 2. (August 1986), pp. 232-236.

Recent epidemiologic studies suggest that women smokers have lower endogenous estrogen levels than nonsmokers. The effects of aqueous extracts of cigarette smoke on aromatase were evaluated in cultures of human granulosa cells. Aqueous extracts of cigarette smoke inhibited the conversion of androstenedione (delta 4A) to estradiol in a dose-dependent manner. Dialysis experiments demonstrated that 90% of the inhibitory activity of aqueous extracts of cigarette smoke was in the less than 1000 mol wt fraction. Removal of the aqueous extract of cigarette smoke from the culture medium resulted in a complete reversal of the inhibition of delta 4A aromatization. Addition of supraphysiologic concentrations of delta 4A (73 microM) to the culture medium blocked the smoke-induced inhibition of aromatization. Two low-molecular-weight components of cigarette smoke, nicotine and anabasine, inhibited granulosa cell aromatase in a dose-dependent manner. These studies suggest that constituents of cigarette smoke inhibit a major steroidogenic pathway.

Cigarette smoking during pregnancy lowers aromatase cytochrome P-450 in the human placenta.

J Kitawaki — 2008-05-23T09:54:00-00:00

The Journal of steroid biochemistry and molecular biology, Vol. 45, No. 6. (June 1993), pp. 485-491.

To clarify whether cigarette smoking during pregnancy causes an organic alteration in placental estrogen producing ability, we determined the catalytic activity of aromatase by the tritiated water assay, and tissue level of aromatase cytochrome P-450 (P-450arom) by the specific enzyme-linked immunosorbent assay, in placental samples from nonsmokers and smokers. As pregnancy progressed, both aromatase activity and P-450arom concentration increased in placentas from nonsmokers and smokers. However, the gradient of the increase was significantly less in heavy smokers (> or = 20 cigarettes a day) than in normal and moderate smokers (< 20 cigarettes a day). At term, the mean aromatase activity and P-450arom concentration in placentas from heavy smokers were significantly lower than in nonsmokers and moderate smokers, while aromatase activity per P-450arom (turnover rate) and the mean placental weight were comparable among the three groups. In contrast, the ratio of aryl hydrocarbon hydroxylase activity to aromatase activity was higher in placentas from heavy smokers. Immunohistochemical studies showed that P-450arom was localized in the cytoplasm of syncytiotrophoblasts of chorionic villi in placentas from both nonsmokers and smokers. These results suggest that the induction of placental P-450arom during gestation is suppressed by maternal smoking, resulting in a reduction in estrogen producing ability, while placental xenobiotic P-450 is induced.

Consequences of smoking for body weight, body fat distribution, and insulin resistance

Arnaud Chiolero — 2008-05-23T09:52:33-00:00

Am J Clin Nutr, Vol. 87, No. 4. (1 April 2008), pp. 801-809.

Our aim was to critically evaluate the relations among smoking, body weight, body fat distribution, and insulin resistance as reported in the literature. In the short term, nicotine increases energy expenditure and could reduce appetite, which may explain why smokers tend to have lower body weight than do nonsmokers and why smoking cessation is frequently followed by weight gain. In contrast, heavy smokers tend to have greater body weight than do light smokers or nonsmokers, which likely reflects a clustering of risky behaviors (eg, low degree of physical activity, poor diet, and smoking) that is conducive to weight gain. Other factors, such as weight cycling, could also be involved. In addition, smoking increases insulin resistance and is associated with central fat accumulation. As a result, smoking increases the risk of metabolic syndrome and diabetes, and these factors increase risk of cardiovascular disease. In the context of the worldwide obesity epidemic and a high prevalence of smoking, the greater risk of (central) obesity and insulin resistance among smokers is a matter of major concern.

Hyperleptinemia without obesity in male mice lacking androgen receptor in adipose tissue

I-Chen Yu — 2008-03-17T12:05:21-00:00

Endocrinology (14 February 2008), en.2007-0516.

Insulin resistance occurs through an inadequate response to insulin by insulin target organs such as liver, muscle, and adipose tissue with consequent insufficient glucose uptake. In previous studies we demonstrated that whole body androgen receptor (AR) knockout (AR-/y) mice develop obesity and exhibit insulin and leptin resistance at advanced age. By examining adipose tissue specific AR knockout (A-AR-/y) mice, we found A-AR-/y mice were hyperleptinemic, while showing no leptin resistance, although body weight and adiposity index of A-AR-/y mice were identical with those of male wild-type control mice. Hypotriglyceridemia and hypocholesterolemia found in non-obese A-AR-/y mice suggested a beneficial effect of high leptin levels independent of fat deposition. Further examination showed that androgen-AR signaling in adipose tissue plays a direct regulatory role in leptin expression via enhanced estrogen receptor (ER) transactivation activity due to elevated intra-adipose estrogens. The present study in A-AR-/y mice suggests a differential tissue-specific role of AR in energy balance control in males. 10.1210/en.2007-0516

Insulin Secretion and Clearance after Subacute Estradiol Administration in Postmenopausal Women

Rachael Van Pelt — 2008-02-08T11:42:29-00:00

J Clin Endocrinol Metab, Vol. 93, No. 2. (1 February 2008), pp. 484-490.

Context: Data from large clinical trials of postmenopausal women suggest that the incidence of diabetes is reduced in women randomized to estrogen-based hormone therapy when compared with placebo. Whether this is due to an effect of estrogen on insulin or glucose metabolism remains unclear. Objective: Our objective was to test the hypothesis that estradiol (E2) increases insulin secretion and clearance. Design: Serum insulin and C-peptide (CPEP) responses to hyperglycemia (250 mg/dl) plus iv L-arginine were measured on 2 separate days, with (EST) and without [control (CON)] subacute (24 h) transdermal E2 administration. Study Participants: There were 11 postmenopausal women (mean +/- SD; 55 +/- 4 yr) included in this study. Main Outcomes: Insulin secretion and clearance were estimated from the CPEP area under the curve and the molar ratio of CPEP to insulin area under the curve, respectively. Mean glucose disposal rate (GDR) was estimated from the rate of glucose infusion during the final 30 min of the hyperglycemic clamp. Results: There were no differences in insulin secretion or clearance between the EST and CON days. Fasting glucose was lower on the EST compared with the CON (93 +/- 6 vs. 98 +/- 8 mg/dl), but mean GDR was not different. However, when one outlier was excluded from analysis, GDR was increased after EST compared with CON. Furthermore, a strong inverse association was observed between years since menopause and E2-mediated changes in GDR (r = 0.794; P = 0.004). Conclusions: Contrary to our hypothesis, 24-h transdermal E2 administration did not alter insulin secretion or clearance in postmenopausal women. However, a longer time since menopause was associated with a reduced effect of E2 to increase glucose uptake. 10.1210/jc.2007-1657

Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial.

MH Emmelot-Vonk — 2008-01-07T22:38:03-00:00

JAMA, Vol. 299, No. 1. (2 January 2008), pp. 39-52.

CONTEXT: Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes. OBJECTIVE: To investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands. INTERVENTION: Participants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months. MAIN OUTCOME MEASURES: Functional mobility (Stanford Health Assessment Questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, hemoglobin, and hematocrit). RESULTS: A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected. CONCLUSION: Testosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN23688581.

Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha.

RP Barros — 2008-01-16T22:35:59-00:00

Proc Natl Acad Sci U S A, Vol. 103, No. 5. (31 January 2006), pp. 1605-1608.

Estrogen is known to influence glucose homeostasis with dominant effects in the liver, but the role of estrogen receptors in muscle glucose metabolism is unknown. In the present study, we investigated the expression of the two estrogen receptors, ERalpha and ERbeta, and their influence on regulation of the glucose transporter, GLUT4, and its associated structural protein, caveolin-1, in mouse gastrocnemius muscle. Immunohistochemical analysis revealed that ERalpha and ERbeta are coexpressed in the nuclei of most muscle cells, and that their levels were not affected by absence of estradiol [in aromatase-knockout (ArKO) mice]. GLUT4 expression on the muscle cell membrane was not affected by loss of ERbeta but was extremely reduced in ERalpha(-/-) mice and elevated in ArKO mice. RT-PCR confirmed a parallel reduction in GLUT4 mRNA levels in ERalpha(-/-) mice. Upon treatment of ArKO mice with the ERbeta agonist 2,3-bis(4-hydroxyphenyl)propionitrile, GLUT4 expression was reduced. By immunofluorescence and Western blotting, caveolin-1 expression was higher in ArKO mice and lower in ERbeta(-/-) and ERalpha(-/-) mice than in WT littermates. GLUT4 and caveolin-1 were colocalized in WT and ArKO mice but not in ERbeta(-/-) and ERalpha(-/-) mice. These results reveal that ERalpha is a positive regulator of GLUT4 expression, whereas ERbeta has a suppressive role. Both ERbeta and ERalpha are necessary for optimal caveolin-1 expression. Taken together, these results indicate that colocalization of caveolin-1 and GLUT4 is not an absolute requirement for muscle glucose metabolism but that reduction in GLUT4 could be contributing to the insulin resistance observed in ERalpha(-/-) mice.

Fetal and infant growth and impaired glucose tolerance at age 64.

CN Hales — 2008-01-16T12:28:35-00:00

BMJ, Vol. 303, No. 6809. (26 October 1991), pp. 1019-1022.

OBJECTIVE--To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life. DESIGN--Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known. SETTING--Hertfordshire, England. SUBJECTS--468 men born in east Hertfordshire and still living there. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink. RESULTS--93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations. CONCLUSIONS--Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.

The influence of temperature on the multiple separation of estrogenic steroids using mobile phases modified with beta-cyclodextrin in high-performance liquid chromatography.

PK Zarzycki — 2008-01-14T17:18:50-00:00

J Pharm Biomed Anal, Vol. 15, No. 9-10. (June 1997), pp. 1281-1287.

The effect of temperature on the retention and multiple separation of six estrogenic steroids in reversed-phase liquid chromatography has been studied. Capacity factors (k') of estriol, 17 beta-estradiol, 17 alpha-estradiol, d-equilenin, equilin and estrone were measured using mobile phase modified with different concentrations of beta-cyclodextrin (from 0-16 mM), a fixed solvent composition (acetonitrile-water) and a wide range of column temperatures (from 5 to 80 degrees C). The plots of capacity factors vs. reciprocal of absolute temperature are nonlinear in each case when mobile phase modified with beta-cyclodextrin was used. Particularly strong nonlinearity was observed at lower temperature and at higher beta-cyclodextrin concentration. The complex chromatograms were evaluated using optimization parameters such as capacity factor of the last-eluted peak (k'max), the smallest resolution between adjacent peaks (Rs,min) and relative resolution product (r). The results presented describe precisely the role of temperature in high-performance liquid chromatography systems in which mobile phases modified with cyclodextrin were used. Moreover, the elution order of estrogenic steroids on modified and unmodified mobile phases has been discussed.

Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta).

A Naaz — 2008-01-14T16:55:49-00:00

Horm Metab Res, Vol. 34, No. 11-12. (c 2002), pp. 758-763.

Adipose tissue deposition is highly responsive to estrogen; ovariectomy increases adipose deposition, and estrogen replacement reverses this. Estrogen receptor alpha (ERalpha) plays a major role in adipose tissue. ERalpha knockout (alphaERKO) mice show an increase in adipose tissue of over a 100 % compared to wild-type mice. However, alphaERKO mice undergo a 10-fold increase in 17beta-estradiol (E2), and persistent or even increased signaling through ERbeta could be a factor in obesity of alphaERKO mice. To test the hypothesis that ERbeta plays a role in adipose tissue, adult female alphaERKO mice were ovariectomized or sham-ovariectomized and fed a phytoestrogen-free diet. Ovariectomized mice were treated with vehicle or E2, and bodyweights and food consumption were measured. Mice were killed after 28 days and inguinal and parametrial fat pads collected. Sham-ovariectomized alphaERKO mice had increased body weight, ovariectomized alphaERKO mice showed a 6 % decrease, and E2 replacement restored body weight to sham levels. Fat pads of ovariectomized alphaERKO mice showed 45 % and 16 % decreases in weight and adipocyte circumference, respectively, compared to sham-ovariectomized or E2-replaced ovariectomized alphaERKO mice. Ovariectomized alphaERKO mice showed a trend towards decreased feed consumption that did not reach significance. Blood glucose levels were lower both before and after glucose injection in ovariectomized compared to sham alphaERKO mice, and E2 treatment reversed this. Insulin levels following glucose challenge were lower in ovariectomized compared to sham-ovariectomized alphaERKO mice, indicating that ovariectomy ameliorated the glucose intolerance and insulin resistance in alphaERKO mice. Immunohistochemical analysis revealed strong staining for ERbeta in adipose tissue. These observations indicate that removing E2/ERbeta signaling in alphaERKO mice by ovariectomy decreases body and fat-pad weights and adipocyte size, while improving insulin and glucose metabolism. ERbeta mediated effects on adipose tissue are opposite those of ERalpha, although E2 effects on adipose tissue are predominately through ERalpha.

Characterisation of aromatase expression in the human adipocyte cell line SGBS.

Kerry McInnes — 2008-01-14T11:34:40-00:00

Breast Cancer Res Treat (5 January 2008)

Aromatase is a member of the cytochrome P450 superfamily of enzymes which catalyses the rate-limiting step in the biosynthesis of estrogens. A number of clinical studies have highlighted the importance of local estrogen production in adipose tissue. In particular, in the postmenopausal woman, the degree of her estrogenization is mainly determined by the extent of her adiposity and it is this extragonadal source of estrogen that likely contributes to breast cancer development and progression. The mechanisms regulating aromatase expression in adipose tissue however, have not been fully elucidated. In this study, we have characterised the expression of aromatase and its activity in a human preadipocyte cell strain, SGBS. Aromatase is expressed in SGBS cells and its expression and activity are strongly stimulated by forskolin (FSK) and phorbol 12-myristate-13-acetate (PMA) treatment. Consistent with this, FSK and PMA treatment also increased activation of the proximal aromatase promoter, promoter II. These findings mimic those that have previously been shown in isolated primary human preadipocytes. These data suggest that SGBS cells are a valuable model with which to further elucidate the mechanisms regulating aromatase expression, and therefore local estrogen synthesis in human adipose tissue.

Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins.

Michael L Power — 2008-01-14T10:50:03-00:00

Br J Nutr (1 November 2007), pp. 1-10.

Human beings are susceptible to sustained weight gain in the modern environment. Although both men and women can get fat, they get fat in different ways, and suffer different consequences. We review differences between men and women in the incidence of obesity, fat deposition patterns, fat metabolism, and the health consequences of obesity, and examine potential evolutionary explanations for these differences. Women generally have a larger proportion of body mass as fat, and are more likely to deposit fat subcutaneously and on their lower extremities; men are more likely to deposit fat in the abdominal region. Excess adipose tissue in the abdominal region, especially visceral fat, is associated with more health risks. Women have higher rates of reuptake of NEFA into adipose tissue; however, they also have higher rates of fat oxidation during prolonged exercise. Oestrogen appears to underlie many of these differences. Women bear higher nutrient costs during reproduction. Fat and fertility are linked in women, through leptin. Low leptin levels reduce fertility. Ovarian function of adult women is associated with their fatness at birth. In our evolutionary past food insecurity was a frequent occurrence. Women would have benefited from an increased ability to store fat in easily metabolisable depots. We suggest that the pattern of central obesity, more commonly seen in men, is not adaptive, but rather reflects the genetic drift hypothesis of human susceptibility to obesity. Female obesity, with excess adiposity in the lower extremities, reflects an exaggeration of an adaptation for female reproductive success.

Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue.

MK Shadoan — 2008-01-14T10:46:20-00:00

Metabolism, Vol. 56, No. 6. (June 2007), pp. 830-837.

The purpose of this study was to determine if the insulin resistance we have previously reported in surgically postmenopausal primates treated with combined hormone therapy (HT) is due in part to effects on adipose tissue. Eighty-seven ovariectomized monkeys were fed a moderately atherogenic diet (0.28 mg cholesterol per kilocalorie [0.07 mg/kJ]) and randomized to receive no hormones (control, n = 29), estrogen therapy (ET, conjugated equine estrogens, 0.625 mg/d human equivalent; n = 29), or HT (ET + medroxyprogesterone acetate, 2.5 mg/d human equivalent; n = 29) in the diet for 2 years. Fasting glycemic measures were made at baseline and at the end of treatment. Circulating adiponectin measures, insulin tolerance tests, glucose tolerance tests, and isolated adipocyte glucose uptake assays were performed at the end of the trial. Hormone therapy-treated animals were insulin resistant, as determined by greater fasting insulin concentrations (P = .008), greater homeostasis model assessment of insulin resistance (HOMA-R) value (P = .005) and slower glucose disposal after insulin administration (K(ITT); P = .02) when compared with controls. Subcutaneous adipocytes from HT-treated monkeys had a greater ED(50) for insulin (P = .04) and lower maximal glucose uptake per cell (P < .001) compared with controls, suggesting impaired adipocyte insulin sensitivity. Adipocytes were smaller (P = .001) and adiponectin concentrations were greatest in the ET group (P = .02), with no difference between controls and HT-treated monkeys. In conclusion, estrogen therapy resulted in smaller adipocyte size and greater adiponectin concentrations than control or HT. Hormone therapy resulted in impaired insulin sensitivity and adipocyte glucose uptake compared with controls, whereas there was no difference between ET and controls. Because no adverse effects were found with ET alone, it is likely that the progestin, medroxyprogesterone acetate, resulted in the negative effects of the combined HT regimen on whole-body insulin sensitivity, which were mediated, in part, by reductions in adipose tissue responses to insulin.

Estrogens and glucocorticoid hormones in adipose tissue metabolism.

C Mattsson — 2008-01-14T10:43:47-00:00

Curr Med Chem, Vol. 14, No. 27. (2007), pp. 2918-2924.

Women have a higher percentage of body fat than men, and there is a gender-specific difference in fat distribution: Females tend to accumulate fat around the hips, buttocks, and thighs while men have a larger intra-abdominal (visceral) fat mass. After menopause, there is a redistribution of fat depots, and post-menopausal women develop increased amounts of visceral fat. The risk of developing obesity-related diseases is significantly lower in pre-menopausal women compared to men, a difference that is abolished after menopause, suggesting that the female sex steroid estrogen influences adipogenesis and adipose metabolism. Experimentally, estrogen increases the size and number of subcutaneous adipocytes and attenuates lipolysis. Post-menopausal women also develop a more atherogenic lipid pattern and decreased levels of the prothrombotic protein plasminogen activator inhibitor-1, which attenuates fibrinolysis. Pathologically increased circulating cortisol concentration is associated with dysmetabolic features e.g., central obesity, elevated blood pressure, insulin resistance, and dyslipidemia. In "simple obesity," glucocorticoid production is elevated. Peak levels of circulating cortisol are however low or normal, possibly because of increased clearance and/or tissue-specific changes in cortisol production. In addition to the adrenal production of cortisol, cortisol is also generated in adipose tissue by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inactive cortisone to active cortisol. The enzyme activity in subcutaneous fat increases with increasing body weight. Estrogen seems to have a tissue-specific influence on 11betaHSD1 enzyme activity, attenuating it in liver, kidney, and testis but upregulating 11betaHSD1 mRNA expression in preadipocytes from women. In the present review, we summarize and discuss the interaction between glucocorticoids and sex steroids and their influence on adipocyte metabolism.

The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.

D Kapoor — 2008-01-14T10:37:04-00:00

Eur J Endocrinol, Vol. 156, No. 5. (May 2007), pp. 595-602.

OBJECTIVE: Serum testosterone levels are known to inversely correlate with insulin sensitivity and obesity in men. Furthermore, there is evidence to suggest that testosterone replacement therapy reduces insulin resistance and visceral adiposity in type 2 diabetic men. Adipocytokines are hormones secreted by adipose tissue and contribute to insulin resistance. We examined the effects of testosterone replacement treatment on various adipocytokines and C-reactive protein (CRP) in type 2 diabetic men. DESIGN: Double-blinded placebo-controlled crossover study in 20 hypogonadal type 2 diabetic men. Patients were treated with testosterone (sustanon 200 mg) or placebo intramuscularly every 2 weeks for 3 months in random order followed by a washout period of 1 month before the alternate treatment phase. METHODS: Leptin, adiponectin, resistin, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and CRP levels were measured before and after each treatment phase. Body mass index (BMI) and waist circumference were also recorded. RESULTS: At baseline, leptin levels significantly correlated with BMI and waist circumference. There was a significant inverse correlation between baseline IL-6 and total testosterone (r=-0.68; P=0.002) and bioavailable testosterone levels (r=-0.73; P=0.007). CRP levels also correlated significantly with total testosterone levels (r=-0.59; P=0.01). Testosterone treatment reduced leptin (-7141.9 +/- 1461.8 pg/ml; P=0.0001) and adiponectin levels (-2075.8 +/- 852.3 ng/ml; P=0.02). There was a significant reduction in waist circumference. No significant effects of testosterone therapy on resistin, TNF-alpha, IL-6 or CRP levels were observed. CONCLUSION: Testosterone replacement treatment decreases leptin and adiponectin levels in type 2 diabetic men. Moreover, low levels of testosterone in men are associated with pro-inflammatory profile, though testosterone treatment over 3 months had no effect on inflammatory markers.

Testosterone deficiency impairs glucose oxidation through defective insulin and its receptor gene expression in target tissues of adult male rats.

T Muthusamy — 2008-01-14T10:34:51-00:00

Life Sci, Vol. 81, No. 7. (26 July 2007), pp. 534-542.

Testosterone and insulin interact in their actions on target tissues. Most of the studies that address this issue have focused on the physiological concentration of testosterone, which maintains normal insulin sensitivity but has deleterious effects on the same when the concentration of testosterone is out of this range. However, molecular basis of the action of testosterone in the early step of insulin action is not known. The present study has been designed to assess the impact of testosterone on insulin receptor gene expression and glucose oxidation in target tissues of adult male rat. Adult male albino rats were orchidectomized and supplemented with testosterone (100 microg/100 g b. wt., twice daily) for 15 days from the 11th day of post orchidectomy. On the day after the last treatment, animals were euthanized and blood was collected for the assay of plasma glucose, serum testosterone and insulin. Skeletal muscles, such as gracilis and quadriceps, liver and adipose tissue were dissected out and used for the assay of various parameters such as insulin receptor concentration, insulin receptor mRNA level and glucose oxidation. Testosterone deprivation due to orchidectomy decreased serum insulin concentration. In addition to this, insulin receptor number and its mRNA level and glucose oxidation in target tissues were significantly decreased (p<0.05) when compared to control. However, testosterone replacement in orchidectomized rats restored all these parameters to control level. It is concluded from this study that testosterone deficiency-induced defective glucose oxidation in skeletal muscles, liver and adipose tissue is mediated through impaired expression of insulin and its receptor gene.

Effects of spironolactone on glucose transport and interleukin-6 secretion in adipose cells of women.

A Corbould — 2008-01-14T10:32:04-00:00

Horm Metab Res, Vol. 39, No. 12. (December 2007), pp. 915-918.

Adipose tissue inflammation and insulin resistance are central to the pathogenesis of the metabolic syndrome. Spironolactone, an antagonist of mineralocorticoid receptor, glucocorticoid receptor and androgen receptor, and agonist of progesterone receptor, has anti-inflammatory activity. Blockade of the renin-angiotensin-aldosterone system has been shown to improve glucose metabolism. We have investigated whether spironolactone has direct effects on glucose uptake and interleukin-6 secretion in human adipocytes. Spironolactone, but not its active metabolite canrenoic acid, significantly increased basal and insulin-stimulated glucose uptake in cultured IN VITRO-differentiated adipocytes of women, without affecting insulin sensitivity. The effect was not due to changes in abundance of glucose transporters 1 or 4 or in degree of cell differentiation. Spironolactone, but not canrenoic acid, significantly reduced basal interleukin-6 secretion by cultured stromal-vascular cells. These effects of spironolactone were not mediated by ligand-dependent antagonism of the mineralocorticoid, glucocorticoid, or androgen receptors. Spironolactone may have a novel role in increasing glucose uptake into adipose cells and attenuating adipose tissue inflammation, with implications for management of metabolic syndrome.

Gene Expression Analyses in Cynomolgus Monkeys Provides Mechanistic Insight into High Density Lipoprotein-Cholesterol Reduction by Androgens in Primates.

Pascale Nantermet — 2008-01-14T10:30:03-00:00

Endocrinology (10 January 2008)

Androgens increase muscle mass, decrease fat mass, and reduce high density lipoprotein cholesterol (HDL-C), but the relationship between body composition, lipoprotein metabolism and androgens has not been explained. Here we treated ovariectomized cynomolgus monkeys with 5alpha-dihydrotestosterone (DHT) or vehicle for 14 days and measured lipoprotein and triglycerides. Nuclear magnetic resonance analysis revealed that DHT dose-dependently reduced the cholesterol content of large HDL particles and decreased mean HDL particle size (p<0.01) and also tended to lower LDL cholesterol without altering other lipoprotein particles. Liver and visceral fat biopsies taken before and after DHT treatment for 1 or 14 days were analyzed by genome-wide microarrays. In liver, DHT did not alter the expression of most genes involved in cholesterol synthesis or uptake, but rapidly increased SHP RNA, along with concomitant repression of CYP7A1, a target of SHP transcriptional repression and the rate-limiting enzyme in bile acid synthesis. DHT regulation of SHP and CYP7A1 also occurs in rats, indicating a conserved mechanism. In adipose tissue, pathway analyses suggested coordinate regulation of adipogenesis, tissue remodeling and lipid homeostasis. Genes encoding insulin-like growth factor I and beta-catenin were induced, as were extracellular matrix, cell adhesion, and cytoskeletal components, while there was consistent down-regulation of genes involved in triacylglycerol metabolism. Interestingly, cholesterol ester transfer protein (CETP) RNA was induced rapidly in monkey adipose tissue, while its inhibitor apolipoprotein CI (APOCI) was repressed. These data provide insight into the androgenic regulation of lipoprotein homeostasis and suggest that changes in adipose lipoprotein metabolism could contribute to HDL-C reduction.

Rosiglitazone decreases postprandial production of acylation stimulating protein in type 2 diabetics

Youssef Tahiri — 2007-05-10T04:12:04-00:00

Nutrition & Metabolism, Vol. 4 (09 May 2007), 11.

Superiority of gas chromatography/tandem mass spectrometry assay (GC/MS/MS) for estradiol for monitoring of aromatase inhibitor therapy.

RJ Santen — 2008-01-10T16:21:42-00:00

Steroids, Vol. 72, No. 8. (July 2007), pp. 666-671.

Currently available radioimmunoassay methods for estradiol in serum lack sufficient sensitivity and precision to monitor estradiol levels in patients placed on third generation aromatase inhibitors. We recently validated a gas chromatography/tandem mass spectrometry assay (GC/MS/MS) for estradiol and determined estrogen levels in normal post-menopausal women and in women with breast cancer before and during administration of aromatase inhibitors. Validation of the GC/MS/MS assay in human plasma and human serum included determination of assay sensitivity (<0.63 pg/ml), precision (all CVs less than 17.8%), recovery (98-103%), and linearity of recovery (R=0.998). Levels of estradiol were lower when assayed by GC/MS/MS compared to RIA under all conditions (7.26+/-4.82 pg/ml versus 11.9+12.0 pg/ml in normal post-menopausal women; 5.88+/-3.43 pg/ml versus 13.8+/-7.5 pg/ml in breast cancer patients prior to treatment; and<0.63 pg/ml versus 5.8+/-4.1 pg/ml during aromatase inhibitor therapy). Fifty-five women treated either with atamestane/toremiphene or letrozole/placebo were monitored for estradiol levels at 4, 8 and 12 weeks of therapy. The mean levels of estradiol during aromatase inhibitor therapy was 5.8+/-4.1 pg/ml as measured by RIA and <0.63 pg/ml by GC/MS/MS. The degree of suppression with the aromatase inhibitors as detected by RIA was 58% versus >89% by GC/MS. These results suggest that most RIA methods detect cross-reacting estrogen metabolites and yield higher measured levels than GC/MS/MS. Several pharmacological and clinical considerations suggest that GC/MS/MS should become the preferred method for monitoring aromatase inhibitor therapy.

Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women--a clinical research center study.

JC Lovejoy — 2008-01-10T11:23:19-00:00

J Clin Endocrinol Metab, Vol. 81, No. 6. (June 1996), pp. 2198-2203.

Abdominal fat distribution is influenced by androgen levels in both men and women. The purpose of this study was to assess the effects on fat distribution of administering nandrolone decanoate (ND; an anabolic steroid with weak androgenic activity) or spironolactone (SP; an antiandrogen) in obese postmenopausal women. The design was a randomized, placebo-controlled, 9-month trial with simultaneous calorie restriction for weight loss. Women in all three groups lost comparable amounts of weight, but the ND-treated women gained lean mass relative to the other two groups (P < 0.0005) and lost more body fat than women in the SP group (P < 0.01). The resting metabolic rate also increased slightly in the ND group. ND treatment produced a gain in visceral fat, as determined by computed tomography scan, and a relatively greater loss of sc abdominal fat. SP-treated women lost significantly less sc fat than the other two groups. Serum cholesterol decreased in the placebo group, but increased slightly in the other two groups (significant for SP vs. placebo, P < 0.05). High density lipoprotein cholesterol decreased significantly in the ND-treated women. There were no significant changes in fasting glucose or insulin sensitivity. We conclude that administration of exogenous androgens modulates body composition in obese postmenopausal women and independently affects visceral and sc abdominal fat.

The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity.

JM Zmuda — 2008-01-10T11:04:45-00:00

Metabolism, Vol. 42, No. 4. (April 1993), pp. 446-450.

Stanozolol, an oral 17 alpha-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, -20%; HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL3-C levels by 13% (P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment (P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of testosterone on abdominal adipose tissue in men.

M Rebuffé-Scrive — 2008-01-10T10:49:46-00:00

Int J Obes, Vol. 15, No. 11. (November 1991), pp. 791-795.

Recent studies in men have shown that abdominal fat increases with age and decreasing testosterone concentrations. Furthermore, in cell culture, testosterone expresses an increased lipolytic potential and depresses lipoprotein lipase activity (LPL) in adipose cells. These metabolic characteristics are found in abdominal adipose tissue in young men. In order to see whether abdominal fat masses in moderately obese middle-aged men might be diminished by testosterone, this hormone was given either as a single injection (500 mg) or in moderate doses (40 mg X 4) for 6 weeks in an oral preparation, bypassing the liver. When measured 1 week after the single dose, abdominal LPL tended to decrease. After 6 weeks a dramatic decrease of abdominal LPL was found, as well as an increase in the lipolytic responsiveness to norepinephrine, both changes confined solely to the abdominal, and not femoral adipose tissue regions. The waist/hip circumference decreased in 9 out of the 11 examined men. No untoward effects were seen in behavioural variables, blood pressure, triglyceride or cholesterol values, and liver function tests. These preliminary results suggest that administration of testosterone in moderate doses to middle-aged men lead to adaptations of the metabolism of adipose tissue expected to be followed by a diminution of this mass.

Plasma adrenal, gonadal, and conjugated steroids before and after long-term overfeeding in identical twins.

J Pritchard — 2008-01-10T09:52:01-00:00

J Clin Endocrinol Metab, Vol. 83, No. 9. (September 1998), pp. 3277-3284.

An analysis of the data collected in the Quebec Overfeeding Study of identical twins was undertaken to determine any evidence of a genotype effect on plasma levels of adrenal and gonadal steroids arising from long term positive energy balance. Plasma levels of sex hormone-binding globulin (SHBG), testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), androsterone glucuronide, androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-DIOL-G), and cortisol were measured in 12 pairs of young, sedentary, male monozygotic twins before and after 100 days of overfeeding. The dietary energy excess of 4.2 MJ/day (1000 Cal), 6 days a week, resulted in a total positive energy balance of 353 MJ (84,000 Cal). Overfeeding induced significant changes (P < 0.0001) in body weight and other measures of body composition. Within-twin pair resemblance was observed at baseline in all steroids, except cortisol [intraclass correlation range: DHEA-S, 0.50 (P < 0.05); DHT, 0.77 (P < 0.001)] and was lost with overfeeding, except for DHT and SHBG (P < 0.05). SHBG levels fell and 3 alpha-DIOL-G rose with the gain in body fatness. The change in testosterone was a significant correlate of the change in upper body fat (r = -0.48; P < 0.05). The change in 3 alpha-DIOL-G correlated positively with increases in all measures of central adiposity (r = 0.52; P < 0.01). A decrease in DHEA-S occurred with a higher, but not with a lower, gain in abdominal visceral fat (P < 0.05). Thus, analysis of adrenal and gonadal steroids and of conjugated metabolites before and after overfeeding in monozygous twins supports the idea that there is a genotype effect on steroid circulating steroid levels and that these blood levels are correlated with the pattern of body fat distribution. Moreover, the baseline within-twin pairs similarity in steroid levels was attenuated by prolonged positive energy balance and body fat gain.

Splanchnic lipolysis in human obesity.

S Nielsen — 2008-01-10T09:20:01-00:00

J Clin Invest, Vol. 113, No. 11. (June 2004), pp. 1582-1588.

Elevated FFA concentrations have been shown to reproduce some of the metabolic abnormalities of obesity. It has been hypothesized that visceral adipose tissue lipolysis releases excess FFAs into the portal vein, exposing the liver to higher FFA concentrations. We used isotope dilution/hepatic vein catheterization techniques to examine whether intra-abdominal fat contributes a greater portion of hepatic FFA delivery in visceral obesity. Obese women (n = 24) and men (n = 20) with a range of obesity phenotypes, taken together with healthy, lean women (n = 12) and men (n = 12), were studied. Systemic, splanchnic, and leg FFA kinetics were measured. The results showed that plasma FFA concentrations were approximately 20% greater in obese men and obese women. The contribution of splanchnic lipolysis to hepatic FFA delivery ranged from less than 10% to almost 50% and increased as a function of visceral fat in women (r = 0.49, P = 0.002) and in men (r = 0.52, P = 0.002); the slope of the relationship was greater in women than in men (P < 0.05). Leg and splanchnic tissues contributed a greater portion of systemic FFA release in obese men and women than in lean men and women. We conclude that the contribution of visceral adipose tissue lipolysis to hepatic FFA delivery increases with increasing visceral fat in humans and that this effect is greater in women than in men.

Are gender differences in cardiovascular disease risk factors explained by the level of visceral adipose tissue?

S Lemieux — 2008-01-09T17:48:04-00:00

Diabetologia, Vol. 37, No. 8. (August 1994), pp. 757-764.

It has been suggested that the lower prevalence of cardiovascular disease in women before menopause in comparison with men may be explained by differences in body fat distribution, plasma lipoprotein levels and indices of plasma glucose-insulin homeostasis. Thus, gender differences in visceral adipose tissue accumulation measured by computed tomography and metabolic variables were studied in 80 men and 69 pre-menopausal women, aged 23-50 years. Despite the fact that women had higher levels of total body fat (p < 0.0001), they displayed lower areas of abdominal visceral adipose tissue (p < 0.06) and a lower ratio of abdominal visceral to mid-thigh adipose tissue areas than men (p < 0.0001). After adjustment for body fat mass, women generally displayed a more favourable risk profile than men which included higher plasma HDL2-cholesterol and lower plasma insulin, apolipoprotein B and triglyceride levels (p < 0.01). Metabolic variables adjusted for body fat mass were then compared between genders after control for differences in abdominal visceral adipose tissue area. After such controls, variables related to plasma glucose-insulin homeostasis were no longer significantly different between men and women. Gender differences for plasma concentrations of triglyceride, apolipoprotein B and the ratio of HDL2-cholesterol/HDL3-cholesterol also disappeared, whereas plasma concentrations of HDL-cholesterol, HDL2-cholesterol as well as the ratio of HDL-cholesterol/total cholesterol remained significantly higher in women than in men (p < 0.01). These results suggest that abdominal visceral adipose tissue is an important correlate of gender differences in cardiovascular disease risk. However, additional factors are likely to be involved in gender differences in plasma HDL-cholesterol levels.

Waist circumference and abdominal adipose tissue distribution: influence of age and sex

Jennifer Kuk — 2008-01-09T17:45:36-00:00

Am J Clin Nutr, Vol. 81, No. 6. (1 June 2005), pp. 1330-1334.

Background: The influence of age and sex on the distribution of abdominal adipose tissue for a given waist circumference (WC) is unclear. Objective: The objective was to investigate the influence of age and sex on total (TAAT), visceral (VAT), and abdominal subcutaneous (ASAT) adipose tissue for a given WC. Design: Body composition was assessed by whole-body magnetic resonance imaging in 147 younger men (< 50 y), 83 older men, 171 younger (premenopausal) women, and 80 older (postmenopausal) women with a wide range (16-40; in kg/m2) of body mass indexes. Results: Within each sex, the regression lines between WC and TAAT were not significantly different (P > 0.1) between younger and older groups. Collapsed across age groups, women had more TAAT for a given WC than did men; however, this difference was significantly reduced with increasing WC (P < 0.05). Within each sex, regression lines derived for WC and ASAT were not significantly different between younger and older groups (P > 0.1). Collapsed across age groups, women had 1.8 kg more ASAT for a given WC (P < 0.05) than did men across the range of WCs. Within each sex, older men and women had a significantly greater increase in VAT for a given WC (P < 0.05) than did younger men and women. Furthermore, independent of age group, the slopes for WC and VAT were significantly higher (P < 0.05) in men than in women. Conclusions: There are significant sex differences in TAAT, VAT, and ASAT for a given WC. Furthermore, the relation between WC and VAT is substantially influenced by age.