Background and Aims
Whether glycemic control, as opposed to diabetes status, is associated with the severity of NAFLD is open for study. We aimed to evaluate whether degree of glycemic control in the ...years preceding liver biopsy predicts the histological severity of NASH.
Approach and Results
Using the Duke NAFLD Clinical Database, we examined patients with biopsy‐proven NAFLD/NASH (n = 713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%) and White (84%) with median (interquartile range) age of 50 (42, 58) years; 49% had diabetes (n = 348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histological features of NAFLD/NASH. Histological features were graded and staged according to the NASH Clinical Research Network system. Group‐based trajectory analysis was used to examine patients with at least three HbA1c (n = 298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR, 1.15; 95% CI, 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR, 1.74; 95% CI, 1.01, 3.01; P = 0.048) and hepatic fibrosis (HF; OR, 4.59; 95% CI, 2.33, 9.06; P < 0.01).
Conclusions
Glycemic control predicts severity of ballooned hepatocytes and HF in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH‐related fibrosis progression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Context: Erythrocytosis is a dose-limiting adverse effect of testosterone therapy, especially in older men.
Objective: Our objective was to compare the dose-related changes in hemoglobin and ...hematocrit in young and older men and determine whether age-related differences in erythropoietic response to testosterone can be explained by changes in erythropoietin and soluble transferrin receptor (sTfR) levels.
Design: We conducted a secondary analysis of data from a testosterone dose-response study in young and older men who received long-acting GnRH agonist monthly plus one of five weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg im) for 20 wk.
Setting: The study took place at a General Clinical Research Center.
Participants: Participants included 60 older men aged 60–75 yr and 61 young men aged 19–35 yr.
Outcome Measures: Outcome measures included hematocrit and hemoglobin and serum erythropoietin and sTfR levels.
Results: Hemoglobin and hematocrit increased significantly in a linear, dose-dependent fashion in both young and older men in response to graded doses of testosterone (P < 0.0001). The increases in hemoglobin and hematocrit were significantly greater in older than young men. There was no significant difference in percent change from baseline in erythropoietin or sTfR levels across groups in either young or older men. Changes in erythropoietin or sTfR levels were not significantly correlated with changes in total or free testosterone levels.
Conclusions: Testosterone has a dose-dependent stimulatory effect on erythropoiesis in men that is more pronounced in older men. The testosterone-induced rise in hemoglobin and hematocrit and age-related differences in response to testosterone therapy may be mediated by factors other than erythropoietin and sTfR.
Objectives The aim of this study was to assess the relationship between sex hormones and natriuretic peptide levels in community-based adults. Background Women have higher circulating natriuretic ...peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion. Methods We measured N-terminal pro–B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone–binding globulin plasma levels in 4,056 men and women (mean age 40 ± 9 years) from the Framingham Heart Study Third-Generation cohort. Sex/hormone status was grouped as: 1) men; 2) post-menopausal women not receiving hormone replacement therapy; 3) pre-menopausal women not receiving hormonal contraceptives; 4) post-menopausal women receiving hormone replacement therapy; and 5) pre-menopausal women receiving hormonal contraceptives. Results Circulating NT-proBNP levels were associated with sex/hormone status (overall p < 0.0001). Men had lower NT-proBNP levels than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP levels than women who were not receiving hormone therapy (all p < 0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, free testosterone (FT) levels decreased and sex hormone–binding globulin levels increased in tandem with increasing NT-proBNP levels. In sex-specific analyses, NT-proBNP levels decreased across increasing quartiles of FT in men (p for trend <0.01) and women (p for trend <0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations. Conclusions These findings suggest that lower levels of circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Context: Adult women with polycystic ovary syndrome (PCOS) have an increased prevalence of the metabolic syndrome (MBS). The prevalence of MBS is also increasing in adolescents.
Objective: Our ...objective was to test the hypothesis that the prevalence of MBS is increased in adolescent girls with PCOS compared with the general population and to determine the factors associated with an increased risk of the MBS in PCOS.
Design and Setting: We conducted a cross-sectional case-control study at academic medical centers with general clinical research centers.
Participants: Participants included 49 adolescent girls with PCOS and 165 girls from the Third National Health and Nutrition Examination Survey (NHANES III) adolescent population of similar age and ethnic background.
Main Outcome Measure: We assessed the prevalence of MBS according to currently proposed adolescent MBS criteria.
Results: Thirty-seven percent of adolescent girls with PCOS had MBS compared with 5% of NHANES III girls (P < 0.0001). None of the girls of normal body mass index (BMI) had MBS, whereas 11% of overweight and 63% of obese girls with PCOS had MBS compared with 0 and 32% of NHANES III girls, respectively. Girls with PCOS were 4.5 times more likely to have MBS than age-matched NHANES III girls after adjusting for BMI (odds ratio, 4.5; 95% confidence interval, 1.1–17.7; P = 0.03). The odds of having the MBS were 3.8 times higher for every quartile increase in bioavailable testosterone in girls with PCOS after adjusting for BMI and insulin resistance (odds ratio, 3.8; 95% confidence interval, 1.4–10.2; P = 0.008).
Conclusions: Adolescent girls with PCOS have a higher prevalence of MBS than the general adolescent population. Hyperandrogenemia is a risk factor for MBS independent of obesity and insulin resistance.
Adverse Events Associated with Testosterone Administration Basaria, Shehzad; Coviello, Andrea D; Travison, Thomas G ...
New England journal of medicine/The New England journal of medicine,
07/2010, Volume:
363, Issue:
2
Journal Article
Peer reviewed
Open access
In a randomized trial, men 65 years of age or older who had low serum testosterone levels and limitations in mobility were assigned to either placebo or testosterone gel to be applied daily for 6 ...months. The primary end point was improvement in leg-press strength, which was greater with testosterone therapy than with placebo. However, the trial was stopped early because of a greater number of cardiac adverse events in the testosterone group.
In men 65 years of age or older with low serum testosterone levels and limitations in mobility, improvement in leg-press strength was greater with testosterone therapy than with placebo. However, there were more cardiac adverse events in the testosterone group.
Limited mobility is a common geriatric condition that is a predictor of disability, poor quality of life, and death.
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In men, an age-related decline in the serum testosterone concentration is associated with reduced muscle mass and lower-extremity strength, limitations in physical function, and poor mobility.
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Testosterone supplementation increases muscle mass and strength and leg power, all of which are important determinants of mobility.
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Previous trials of testosterone supplementation have been conducted primarily among healthy older men. The safety and efficacy of testosterone treatment in improving muscle performance and physical function in older men with limitations in mobility . . .
IMPORTANCE: Testosterone use in older men is increasing, but its long-term effects on progression of atherosclerosis are unknown. OBJECTIVE: To determine the effect of testosterone administration on ...subclinical atherosclerosis progression in older men with low or low-normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Testosterone’s Effects on Atherosclerosis Progression in Aging Men (TEAAM) was a placebo-controlled, double-blind, parallel-group randomized trial involving 308 men 60 years or older with low or low-normal testosterone levels (100-400 ng/dL; free testosterone <50 pg/mL), recruited at 3 US centers. Recruitment took place between September 2004 and February 2009; the last participant completed the study in May 2012. INTERVENTIONS: One hundred fifty-six participants were randomized to receive 7.5 g of 1% testosterone and 152 were randomized to receive placebo gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. MAIN OUTCOMES AND MEASURES: Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium; secondary outcomes included sexual function and health–related quality of life. RESULTS: Baseline characteristics were similar between groups: patients were a mean age of 67.6 years; 42% had hypertension; 15%, diabetes; 15%, cardiovascular disease; and 27%, obesity. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference adjusted for age and trial site, 0.0002 mm/year; 95% CI, −0.003 to 0.003, P = .89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (adjusted mean difference, −10.8 Agatston units/year; 95% CI, −45.7 to 24.2; P = .54). Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone. Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit and prostate-specific antigen levels increased more in testosterone group. CONCLUSIONS AND RELEVANCE: Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00287586
Background:
The natriuretic peptides play an important role in salt homeostasis and blood pressure regulation. It has been suggested that obesity promotes a relative natriuretic peptide deficiency, ...but this has been a variable finding in prior studies and the cause is unknown.
Aim:
The aim of this study was to examine the association between obesity and natriuretic peptide levels and evaluate the role of hyperinsulinemia and testosterone as mediators of this interaction.
Methods:
We studied 7770 individuals from the Framingham Heart Study (n = 3833, 54% women) and the Malmö Diet and Cancer study (n = 3918, 60% women). We examined the relation of plasma N-terminal pro-B-type natriuretic peptide levels (N-BNP) with obesity, insulin resistance, and various metabolic subtypes.
Results:
Obesity was associated with 6–20% lower levels of N-BNP (P < 0.001 in Framingham, P = 0.001 in Malmö), whereas insulin resistance was associated with 10–30% lower levels of N-BNP (P < 0.001 in both cohorts). Individuals with obesity who were insulin sensitive had only modest reductions in N-BNP compared with nonobese, insulin-sensitive individuals. On the other hand, individuals who were nonobese but insulin resistant had 26% lower N-BNP in Framingham (P < 0.001) and 10% lower N-BNP in Malmö (P < 0.001), compared with nonobese and insulin-sensitive individuals. Adjustment for serum-free testosterone did not alter these associations.
Conclusions:
In both nonobese and obese individuals, insulin resistance is associated with lower natriuretic peptide levels. The relative natriuretic peptide deficiency seen in obesity could be partly attributable to insulin resistance, and could be one mechanism by which insulin resistance promotes hypertension.
OBJECTIVE: The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We ...determined whether testosterone or sex hormone–binding globulin (SHBG) is independently associated with the risk of metabolic syndrome. RESEARCH DESIGN AND METHODS: Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography–tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance HOMA-IR). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components. CONCLUSIONS: SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men.
Introduction: In mice, C-C motif chemokine receptor (CCR)5 deletion protects against insulin resistance, hepatic steatosis, and glucose intolerance. We aimed to characterize the metabolic effects of ...cenicriviroc (CVC), a potent CCR2/5 inhibitor, in type 2 diabetes mellitus (T2DM) patients with nonalcoholic steatohepatitis (NASH) fibrosis from the Phase 2b CENTAUR study.
Methods: Subjects from CENTAUR with T2DM, biopsy-proven NASH, and fibrosis Stages F1-3 were included. CVC-exposed subjects for 1 year (Arm A) and placebo (PBO) Arms B and C were analyzed. Liver, metabolic, and inflammatory biomarkers were analyzed. Homeostatic model assessments (HOMA-IR and -b) were calculated. Change (from baseline to Year 1) was compared between groups using a general parametric linear model analysis of covariance (2-sided ANCOVA) based on the mITT population.
Results: Of the 289 subjects in CENTAUR, 134 (46%) had T2DM and were included in this analysis. Baseline characteristics were similar for CVC (n=76) and PBO (n=58) groups (mean ±SD): age 57.5 ±7.75 years vs. 55.41 ±8.65 years, HbA1c 7.30 ±1.29 vs. 7.20 ±1.21 %, BMI 33.02 ±5.25 vs. 35.16 ±7.67 kg/m2, NAS 5.25 ±1.06 vs. 5.52 ±1.13, and fibrosis scores of F1 (31.6%), F2 (21%), and F3 (47.4%) vs. F1 (24.2%), F2 (22.4%), and F3 (53.4%), respectively. At 1 year, there was a significant decrease in HOMA-IR and interleukin (IL)-6 in the CVC group. The least squares mean changes (SE) in HOMA-IR (p=0.0159) and IL-6 (p=0.0094), respectively, were −2.75 (1.27) and −1.9 (0.35) for CVC and 1.94 (1.45) and −0.5 (0.39) for PBO. After 1-year exposure to CVC or PBO, no significant differences vs. baseline in HOMA-b, HDL cholesterol, LDL cholesterol, ALT, and AST were noted.
Conclusion: CVC may improve HOMA-IR and pro-inflammatory cytokine IL-6, suggesting that CVC could potentially improve insulin resistance in NASH patients. These findings warrant further investigation.
Disclosure
A.D. Coviello: Consultant; Self; GI Dynamics Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., GENFIT, Orthus Health. Speaker’s Bureau; Self; Novo Nordisk Inc. G. Rodriguez: Employee; Self; Allergan plc. E.B. Martins: Employee; Self; Allergan plc. Stock/Shareholder; Self; Allergan plc. N. Alkhouri: Research Support; Self; Allergan plc. M.F. Abdelmalek: None.
Funding
Allergan plc
Context: Women with polycystic ovary syndrome (PCOS) have twice the risk for metabolic syndrome (MetS) compared to women from the general population. Mothers and sisters of affected women also have ...an increased prevalence of MetS.
Objective: The aim of the study was to determine the prevalence of MetS in fathers and brothers of women with PCOS compared to men from the general population.
Design and Setting: We conducted a cross-sectional observational study at academic medical centers.
Participants: A total of 211 fathers and 58 brothers of women with PCOS were studied and compared to 1153 and 582 Third National Health and Nutrition Survey (NHANES III) men of similar age and race/ethnicity, respectively.
Main Outcome Measure: We measured MetS prevalence.
Results: The prevalence of MetS was increased in fathers (42 vs. 32%; P = 0.006) and brothers (22 vs. 9%; P = 0.001) compared to NHANES III men. Fathers and brothers had higher body mass index (BMI) than NHANES III men (P < 0.0001). MetS rates were similar in fathers and brothers compared to NHANES III groups after adjusting for BMI. Total testosterone was inversely related to MetS in both fathers and brothers, but this relationship was also accounted for by the higher BMI in male relatives.
Conclusion: Male relatives of women with PCOS had increased prevalence rates of MetS and obesity compared to the general U.S. male population from NHANES III. In contrast to women with PCOS and their female relatives, the higher prevalence of MetS in male relatives was accounted for by elevated BMI. These findings suggest that the high rates of MetS in male relatives of women with PCOS are related to higher rates of obesity than the general population.
The high prevalence of metabolic syndrome in first degree male relatives of women affected by PCOS compared to similar men in the NHANES III population is attributable to higher rates of obesity than the general population.
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