Showing papers by "Howard N. Hodis published in 2018"

Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline

Abstract: Objective To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. Participants The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus process One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.

Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans.

Abstract: Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease Here we demonstrate that humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating humanin levels In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that humanin is an important factor in cognitive aging

Plasma Tryptophan-Kynurenine Metabolites Are Altered in Human Immunodeficiency Virus Infection and Associated With Progression of Carotid Artery Atherosclerosis.

Abstract: Background It is unknown whether disrupted tryptophan catabolism is associated with cardiovascular disease (CVD) in human immunodeficiency virus (HIV)-infected individuals. Methods Plasma tryptophan and kynurenic acid were measured in 737 women and men (520 HIV+, 217 HIV-) from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Repeated B-mode carotid artery ultrasound imaging was obtained from 2004 through 2013. We examined associations of baseline tryptophan, kynurenic acid, and kynurenic acid-to-tryptophan (KYNA/TRP) ratio, with risk of carotid plaque. Results After a 7-year follow-up, 112 participants developed carotid plaque. Compared to those without HIV infection, HIV-infected participants had lower tryptophan (P < .001), higher KYNA/TRP (P = .01), and similar kynurenic acid levels (P = .51). Tryptophan, kynurenic acid, and KYNA/TRP were correlated with T-cell activation (CD38+HLA-DR+) and immune activation markers (serum sCD14, galectin-3) but had few correlations with interleukin-6, C-reactive protein, or CVD risk factors (blood pressure, lipids). Adjusted for demographic and behavioral factors, each standard deviation (SD) increment in tryptophan was associated with a 29% (95% confidence interval [CI], 17%-38%) decreased risk of carotid plaque (P < .001), while each SD increment in kynurenic acid (P = .02) and KYNA/TRP (P < .001) was associated with a 34% (6%-69%) and a 47% (26%-73%) increased risk of carotid plaque, respectively. After further adjustment for CVD risk factors and immune activation markers, these associations were attenuated but remained significant. Conclusions Plasma tryptophan-kynurenine metabolites are altered in HIV infection and associated with progression of carotid artery atherosclerosis.

Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?

Abstract: The relationship between menopausal hormone therapy (HT) and breast cancer is complex and further complicated by misinformation, perception, and overgeneralization of data. These issues are address...

Gut microbial-related choline metabolite trimethylamine-N-oxide is associated with progression of carotid artery atherosclerosis in HIV infection

Abstract: We examined associations of 5 plasma choline metabolites with carotid plaque among 520 HIV-infected and 217 HIV-uninfected participants (112 incident plaque cases) over 7 years. After multivariable adjustment, higher gut microbiota-related metabolite trimethylamine-N-oxide (TMAO) was associated with an increased risk of carotid plaque in HIV-infected participants (risk ratio = 1.25 per standard deviation increment; 95% confidence interval, 1.05-1.50; P = .01). TMAO was positively correlated with biomarkers of monocyte activation and inflammation (sCD14, sCD163). Further adjustment for these biomarkers attenuated the association between TMAO and carotid plaque (P = .08). Among HIV-infected individuals, plasma TMAO was associated with carotid atherosclerosis progression, partially through immune activation and inflammation.

Carotid artery atherosclerosis is associated with mortality in HIV-positive women and men.

Abstract: Objective Among people with HIV, there are few long-term studies of noninvasive ultrasound-based measurements of the carotid artery predicting major health events. We hypothesized that such measurements are associated with 10-year mortality in the Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS), and that associations differ by HIV serostatus. Design Nested cohort study. Methods Participants without coronary heart disease underwent B-mode carotid artery ultrasound, with measurement of common carotid artery intima-media thickness (IMT); carotid artery plaque (focal IMT > 1.5 mm) at six locations; and Young's modulus of elasticity, a measure of arterial stiffness. We examined all-cause mortality using Cox models, controlling for demographic, behavioral, cardiometabolic, and HIV-related factors. Results Among 1722 women (median age 40 years, 90% nonwhite, 71% HIV-positive) and 1304 men (median age 50, 39% nonwhite, 62% HIV-positive), 11% died during follow-up. Mortality was higher among HIV-positive women [19.9 deaths/1000 person-years, 95% confidence interval (CI) 14.7-28.8] than HIV-positive men (15.1/1000, 95% CI 8.3-26.8). In adjusted analyses, plaque was associated with mortality (hazard ratio 1.44, 95% CI 1.10-1.88) regardless of HIV serostatus, and varied by sex (among women, hazard ratio 1.06, 95% CI 0.74-1.52; among men; hazard ratio 2.19, 95% CI 1.41-3.43). The association of plaque with mortality was more pronounced among HIV-negative (hazard ratio 3.87, 95% 1.95-7.66) than HIV-positive participants (hazard ratio 1.35, 95% CI 1.00-1.84). Arterial stiffness was also associated with mortality (hazard ratio 1.43 for highest versus lowest quartile, 95% CI 1.02-2.01). Greater common carotid artery-IMT was not associated with mortality. Conclusion Carotid artery plaque was predictive of mortality, with differences observed by sex and HIV serostatus.

Carotid Artery Stiffness and Cognitive Decline Among Women With or at Risk for HIV Infection.

Abstract: BACKGROUND Vascular stiffness is associated with aging and cognitive impairment in older populations without HIV. HIV has been linked to increased vascular stiffness. We examined whether vascular stiffness relates to cognitive decline at younger ages in women with or at risk for HIV. METHODS We evaluated the association of carotid artery stiffness with decline in neuropsychological test performance among participants in the Women's Interagency HIV Study and assessed whether HIV modified the association. Baseline carotid stiffness, defined by the distensibility index, was determined at a single visit using carotid artery ultrasound. Longitudinal neuropsychological testing from 2004-2016 included Trail Making Tests A and B and the Symbol Digit Modalities Test. Relationships were assessed with linear mixed-effect models adjusted for demographic, behavioral, cardiometabolic, and neuropsychological factors. RESULTS Among 1662 women (1192 [72%] HIV+), median baseline age was 41 years (interquartile range 34-47), with 60% non-Hispanic black and 28% Hispanic. Lower baseline distensibility (greater carotid stiffness) was associated with greater decline in neuropsychological test scores over 10-year follow-up as measured by Symbol Digit Modalities Test (adjusted β = -0.06 per SD, P < 0.001), Trail Making Test A (β = -0.08 per SD; P < 0.001), and Trail Making Test B (β = -0.08 per SD; P < 0.001). Changes in cognitive function did not differ by HIV serostatus, or HIV-related factors. CONCLUSIONS Higher carotid stiffness was independently associated with faster decline in executive functioning, information processing, and psychomotor speed even in mostly middle-aged minority women and regardless of HIV serostatus. Our study highlights the need for cardiovascular risk factor modification to prevent premature cognitive deterioration in this at-risk population.

Cardiovascular risk after withdrawal of hormone therapy.

Abstract: nitric oxide resulting in vasoconstriction, exposure to activated U sing data derived from a National Death Registry mandated for all deaths in Finland, Mikkola et al reported from the largest study conducted nationwide over 15 years with 2 million woman follow-up years of 332,202 women that discontinuing hormone therapy (HT) is harmful. Within the first year of discontinuing HT, women <60 years old had a two to threefold increased risk of cardiac mortality and stroke mortality compared with the agestandardized background population death rate of the entire country. This study was criticized because women who suffered a nonfatal myocardial infarction or stroke before HT termination were not excluded from the analysis. To address this criticism, the authors conducted the current study in the same population with exclusion of women who suffered a nonfatal myocardial infarction or stroke before HT termination while increasing the follow-up time by another 4 years and the woman-years of follow-up to 3.2 million. The results of this new study with exclusion of women who suffered a nonfatal myocardial infarction or stroke before HT termination are not substantially different from the original report where these women were included in the analysis. Using the age-standardized background population death rates to estimate the expected number of deaths, the risk of cardiac death was significantly elevated in the first year of HT discontinuation in women <60 years of age, whether HT was used for <5 years (standardized mortality ratio [SMR] 1.52, 95% confidence interval [CI] 1.13-2.00) or for >5 years (SMR 2.08, 95% CI 1.44-2.90). The risk of stroke death was also elevated during the first year of post-treatment in women <60 years of age, whether HT was used for <5 years (SMR 2.62, 95% CI 2.07-3.28) or for >5 years (SMR 3.22, 95% CI 2.29-4.40). The increased risk of cardiovascular death was not observed in women <60 years of age and >1 year post-treatment, or in women 60 years of age when discontinuing HT. The death risks were even greater when HT discontinuers were compared with age-matched HT users. In this case, elevated risk of cardiac and stroke mortality was also seen in women 60 years of age who discontinued HT. In addition, elevated risk was also apparent in the women >1 year post-treatment regardless of age at discontinuing HT. As the authors of the current report point out, there is biological plausibility that supports their findings. Although the mechanistic link between HT withdrawal and cardiovascular events is unclear, the rapidity of cardiovascular death (<1 year) after HT withdrawal suggests several nongenomic mechanisms. These mechanisms include decreased production of