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1.  Lipodystrophy and Inflammation Predict Later Grip Strength in HIV-Infected Men: The MACS Body Composition Substudy 
AIDS Research and Human Retroviruses  2013;29(8):1138-1145.
Body fat changes in HIV-infected persons are associated with increased systemic inflammation and increased mortality. It is unknown whether lipodystrophy is also associated with declines in physical function. Between 2001 and 2003, 33 HIV-infected men with evidence of lipodystrophy (LIPO+), 23 HIV-infected men without lipodystrophy (LIPO−), and 33 seronegative men were recruited from the Multicenter AIDS Cohort Study (MACS) for the Body Composition substudy. Visceral adipose tissue (VAT) was assessed by quantitative computed tomography. Lean body mass (LBM) and extremity fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was estimated by Homeostatic Model Assessment (HOMA). Serum interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptors I and II (sTNFRI and sTNFRII), and highly sensitive C-reactive protein (hs-CRP) concentrations were quantified from archived serum samples. These measurements were correlated with grip strength measured in 2007 using linear regression. At the substudy visit, the LIPO+ group had higher HOMA, sTNFRI, sTNFRII, and IL-6 levels than the LIPO− group. In 2007, the LIPO+ group had lower median grip strength than the LIPO− group (34.4 vs. 42.7 kg, p=0.002). Multivariable analysis of HIV+ men showed older age, lower LBM, higher sTNFRII concentrations, and LIPO+ status [adjusted mean difference −4.9 kg (p=0.045)] at the substudy visit were independently associated with lower subsequent grip strength. Inflammation, lower LBM, and lipodystrophy in HIV-infected men were associated with lower subsequent grip strength. These findings suggest that inflammation may contribute to declines in functional performance, independent of age.
PMCID: PMC3715766  PMID: 23550976
2.  The Association of Endogenous Sex hormones with Lipoprotein Subfraction Profile in the Multi-Ethnic Study of Atherosclerosis (MESA) 
There traditional lipid profile differs by sex hormone levels. However, associations of sex hormones with lipoprotein subfractions, which may more accurately represent metabolic pathways to atherosclerosis, are not well studied. We quantified the cross-sectional associations of endogenous sex hormones with lipoprotein subfractions in 3143 men and 2038 postmenopausal women who were not on hormone replacement therapy, aged 45–84 years, in the Multi-Ethnic Study of Atherosclerosis baseline examination. Particle sizes and numbers of Very Low Density (VLDL), Low Density (LDL) and High Density (HDL) Lipoproteins were measured by Nuclear Magnetic Resonance. In both men and women, after multivariable adjustment, higher Sex Hormone Binding Globulin (SHBG) levels are associated with smaller, fewer VLDL, larger, fewer LDL, and larger, more numerous HDL particles; while higher endogenous estradiol levels are associated with smaller VLDL, and smaller, more numerous HDL and LDL particles (all p < 0.05). Testosterone (adjusted for SHBG) is associated with a smaller VLDL particles in men but not women (sex difference p = 0.040). Higher dehydroepiandrosterone (DHEA) levels are associated with more numerous, smaller VLDL particles only in women (sex difference p = 0.030, 0.004, respectively). In conclusion, we found sex differences in the association of endogenous androgens with lipoprotein particle sizes and numbers. Higher endogenous estradiol, but lower SHBG is associated with a more atherogenic lipoprotein particle profile. These findings highlight the potential to improve the lipoprotein profile with sex hormones, but emphasize the intricacies of the interactions.
PMCID: PMC4017356  PMID: 18502260
3.  Lower Adiponectin is Associated with Subclinical Cardiovascular Disease among HIV-infected Men 
AIDS (London, England)  2014;28(6):901-909.
To examine if altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons.
Nested cohort study.
We studied HIV-infected(HIV+) and HIV-uninfected(HIV−) men in the Multicenter AIDS Cohort Study with noncontrast CT to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus and CVD risk factors (RFs).
Significant findings were limited to adiponectin. HIV+ men (n=493) had lower adiponectin levels than HIV− men (n=250) after adjusting for CVD RFs (p<0.0001), which became non-significant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV+ men, lower adiponectin levels were associated with higher CD4+ T cell counts (p= 0.004), longer duration of antiretroviral therapy (p= 0.006) and undetectable HIV RNA levels (p = 0.04) after adjusting for age, race and CVD RFs; only CD4+ cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis > 50% (p <0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV+ and of mixed plaque in HIV− men.
Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.
PMCID: PMC3967406  PMID: 24401646
Adipokines; adiponectin; leptin; heart; subclinical coronary atherosclerosis; metabolic side effects of HIV infection; coronary CT angiography; cardiac CT
4.  Relationship between sex hormones and cognitive performance in men with substance use* 
Drug and alcohol dependence  2012;128(3):250-254.
Hypogonadism is common with opiate-like drug use and may contribute to cognitive abnormalities. With the increasing epidemic of HIV and substance use (SU) worldwide, it is important to understand the impact of these conditions on cognition, which may affect quality of life and possibly decrease adherence to treatment. We hypothesized that men with SU, by virtue of hypogonadism secondary to HIV and/or SU, may demonstrate impaired cognition.
We recruited men aged 18-50 from a population of low income, innercity individuals. Details of HIV and SU status, serum blood levels of total testosterone (TT), free testosterone (FT) and estradiol (E2) were assessed. All subjects were administered ten neuropsychological tests.
Our sample consisted of 68 men (mean age: 43.2 years (SD 5.8), African Americans: 86.6%). The recruited population was primarily from low socioeconomic status and unemployed. The mean level of TT was 553.9 ng/dL (SD 262.0), the mean level of FT was 69.5 pg/mL (SD 34.8), mean E2 was 3.2 pg/mL (SD 4.4). We found that 30.9% were hypogonadal and it was associated with higher SU.
We observed some relationships between sex hormones and cognitive domains, however, after adjustment for age, drug use category, education, depression, HIV, there was no statistically significant correlation between cognitive performance and sex hormone levels.
In this cross-sectional study of men with a high prevalence of SU and hypogonadism, endogenous levels of TT, FT or E2 were not related to cognitive performance. Other factors need to be identified which may contribute to poor cognitive function in the setting of SU.
PMCID: PMC3637021  PMID: 23021515
Testosterone; estradiol; sex hormones; cognitive function; illicit drug users; substance use
5.  Morning free and total testosterone in HIV-infected men: implications for the assessment of hypogonadism 
Hypogonadism is common among HIV-infected men, even among men receiving antiretroviral therapy (ART). Our objective in this study was to determine the prevalence of biochemical hypogonadism among HIV-infected men compared with HIV-uninfected controls. We also examined the use of free testosterone (FT) and total testosterone (TT) measurements in the assessment of biochemical hypogonadism in HIV-infected and –uninfected men.
This was a cross-sectional analysis from the Multicenter AIDS Cohort Study (MACS). TT levels were measured from archived serum using liquid chromatography-tandem mass spectrometry. FT was calculated from TT and sex hormone-binding globulin (SHBG) (measured by radioimmunoassay) using the Vermeulen equation. Biochemical hypogonadism was defined as having low TT, low FT, or both.
Of 945 men in the MACS Cardiovascular Substudy, T assays were not performed in 89 because of insufficient/no stored serum (n = 18) or use of T replacement therapy (TRT) (n = 71). 530 men had morning (AM) T measurements; 364 (68.7%) were HIV-infected. The prevalence of biochemical hypogonadism was similar in HIV-infected (34/364 = 9.3%) and HIV-uninfected (12/166 = 7.2%) men. Prevalence of hypogonadism, when men on TRT (n = 71) were included in the group of hypogonadal men, was higher in HIV-infected (104/434 = 24.0%) compared with HIV-uninfected (13/167 = 7.8%) men (p < 0.0001). Of 34 HIV-infected men with biochemical hypogonadism not on TRT, 11 (32.4%) had normal TT, but low FT. Of 12 HIV-uninfected men with biochemical hypogonadism not on TRT, none were in this category (p = 0.04) – all had low TT.
The prevalence of biochemical hypogonadism in our sample of HIV-infected men was approximately 10%, with a substantial proportion of these men having a normal TT, but low FT. The measurement of AM FT, rather than TT, in the assessment of hypogonadism in HIV-infected men will likely increase diagnostic sensitivity and should be recommended.
PMCID: PMC3900935  PMID: 24450960
Testosterone; Sex hormone binding globulin; HIV; Hypogonadism
6.  Racial/ethnic differences in serum sex steroid hormone concentrations in US adolescent males 
Cancer causes & control : CCC  2013;24(4):10.1007/s10552-013-0154-8.
Contrary to the hypothesis that the racial/ethnic disparity in prostate cancer has a hormonal basis, we did not observe a difference in serum testosterone concentration between non-Hispanic black and white men in the Third National Health and Nutrition Examination Survey (NHANES III), although non-Hispanic black men had a higher estradiol level. Unexpectedly, Mexican-American men had the highest testosterone level. Next, we evaluated whether the same patterns are observed during adolescence, the time of prostate maturation.
We measured serum testosterone, estradiol, and sex hormone binding globulin (SHBG) by immunoassay in 134 males aged 12–19 in NHANES III. Mean concentrations were compared by race/ethnicity adjusting for age, Tanner stage, percent body fat, waist, physical activity, tobacco smoke, and the other hormones.
After multivariable adjustment, in the 12–15 year-old males, testosterone concentration was lower in non-Hispanic blacks than whites (P=0.043), SHBG concentration did not significantly differ between the two groups. Mexican-Americans had the highest testosterone (versus non-Hispanic black: P=0.002) and lowest SHBG (versus non-Hispanic white: P=0.010; versus non-Hispanic black: P=0.047) concentrations. Estradiol concentration was lower in non-Hispanic blacks (P=0.11) and Mexican-Americans (P=0.033) compared with non-Hispanic whites. After multivariable adjustment, in the 16–19 year-old males, testosterone, estradiol, and SHBG concentrations did not differ between non-Hispanic blacks and whites. Mexican-Americans had the highest testosterone concentration (versus non-Hispanic white: P=0.08), but did not differ from the other groups on estradiol and SHBG concentrations. In both age groups, these patterns were generally present, but less pronounced after adjusting for age and Tanner stage only.
In adolescent males, non-Hispanic blacks did not have a higher testosterone concentration than non-Hispanic whites, and Mexican-Americans had the highest testosterone concentration, patterns similar to adult males.
PMCID: PMC3850289  PMID: 23354421
testosterone; adolescence; race and ethnicity
7.  Testosterone and Abnormal Glucose Metabolism in an Inner-City Cohort 
Journal of men's health  2012;9(3):10.1016/j.jomh.2012.03.010.
Low testosterone (T) has been associated with insulin resistance and diabetes mellitus (DM) among men in population-based studies. These studies included racially diverse men, but did not target for inclusion individuals with opiate use, Hepatitis C Virus (HCV) infection, or Human Immunodeficiency Virus (HIV) infection, which disproportionately affect inner-city populations and may alter the relationship between T and DM.
We studied the association between free T (FT) and abnormal glucose metabolism among male participants in the Study of HIV, Injection Drug Use, Nutrition, and Endocrinology (SHINE). We used logistic regression to examine the relationship between log FT and both insulin resistance and prediabetes/DM.
Of 175 men, 43 (24.6%) had low FT (FT < 52 pg/mL). There were more men in the low FT group on methadone maintenance (39.5% v. 15.2%, p=.001), but there was no difference in FT by HIV or HCV status. Overall, 23 men (13.1%) had prediabetes/DM, which was unrelated to FT (OR of prediabetes/DM for each log increase in FT = 0.56, 95% CI 0.13–2.41). FT was also not related to insulin resistance.
The prevalence of hypogonadism was high in this inner-city cohort and was associated with methadone use. However, low FT was not related to insulin resistance or prediabetes/DM. Continued work to identify diabetes risk factors among inner-city populations will help determine targets for intervention to reduce diabetes incidence. Treatment trials of testosterone to reduce diabetes among hypogonadal men may be of particular relevance to opiate users, many of whom are hypogonadal.
PMCID: PMC3809764  PMID: 24174995
Testosterone; Diabetes; Insulin Resistance; Methadone
8.  Association Between Sex Steroid Hormones and Hematocrit in a Nationally Representative Sample of Men 
Journal of andrology  2012;33(6):1332-1341.
Low or high hematocrit levels are associated with increased morbidity and mortality, mediated via anemia or thromboembolic events, respectively. It is therefore important to identify factors that influence hematocrit. Although androgens are known to stimulate hematopoietic cells, it is unknown whether circulating sex steroid hormones affect hematocrit. The association between serum sex steroid hormone concentrations and hematocrit in men aged ≥20 years was evaluated in a cross-sectional study of 1273 men in the Third National Health and Nutrition Examination Survey (1988–1991). Outcomes were low (<10th percentile), high (>90th percentile), and mean hematocrit. Men with low free testosterone levels had a lower hematocrit than men with normal free testosterone levels (P = .03), although no relationship was found between total testosterone level and hematocrit. The relationship between sex hormone–binding globulin (SHBG) and hematocrit was complex, with both low (P < .001) and high (P = .01) SHBG levels associated with lower hematocrit in men aged ≥20 years and only high (P = .01) SHBG levels in men aged ≥50 years. The odds ratio (OR) of high vs normal hematocrit increased as total estradiol (OR, 2.84; P trend = .04) and free estradiol (OR, 2.23; P trend = .09) levels increased. In this nationally representative study of men, sex steroid hormone levels, particularly low free testosterone and high SHBG levels, were associated with lower hematocrit, and high total and free estradiol levels were associated with high hematocrit. Thus, changes in sex hormone levels with aging may contribute to the increased prevalence of anemia and thromboembolic stroke in men as they age.
PMCID: PMC3774012  PMID: 22604627
Testosterone; estradiol; sex hormone–binding globulin; NHANES III
9.  Association of Baseline Sex Hormone Levels with Baseline and Longitudinal Changes in Waist-to-Hip Ratio : Multi-Ethnic Study of Atherosclerosis 
Waist-to-hip ratio (WHR) is strongly associated with prevalent atherosclerosis. We analyzed the associations of baseline serum levels of testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA) with WHR in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
Baseline data was available for 3144 men and 2038 postmenopausal women, who were non-users of hormone therapy, who were 45–84 years of age, and of White, Chinese, Black or Hispanic racial/ethnic groups. Of these, 2708 men and 1678 women also had longitudinal measurements of WHR measured at the second and/or the third study visits (median follow-up 578 days, and 1135 days, respectively).
In cross-sectional analyses adjusted for age, race, and cardiovascular disease risk factors, T was negatively associated with baseline WHR in men, while in both sexes, E2 was positively associated and SHBG was negatively associated with WHR (all p<0.001). In longitudinal analyses, further adjusted for follow-up time and baseline WHR, baseline T was negatively associated with WHR at follow-up (p=0.001) in men, while in both sexes, E2 was positively associated (p=0.004), and SHBG was negatively associated with WHR (p<0.001). The longitudinal association of E2, but not T, was independent of SHBG. In both cross-sectional or longitudinal analyses, there were no associations between DHEA and WHR in either men or women.
Sex hormones are associated with WHR at baseline and also during follow-up above and beyond their baseline association. Future research is needed to determine if manipulation of hormones is associated with changes in central obesity.
PMCID: PMC3342434  PMID: 22270378
Sex Hormones; epidemiology; waist to hip ratio
10.  Relationship of sex steroid hormones with bone mineral density (BMD) in a nationally representative sample of men 
Clinical endocrinology  2008;70(1):26-34.
Sex steroid hormones influence bone mineral density (BMD) in women, but are less well-studied in men. We evaluated the association of serum total and free sex steroid hormones and SHBG with osteopaenia in a nationally representative sample of men aged 20 – 90 years.
BMD and sex steroid hormones were measured among participants in NHANES III, a cross-sectional study of the US population.
A total of 1185 adult men in morning examination session of Phase I of NHANES III (1988 – 91).
Relation of oestradiol (E2), testosterone, and SHBG concentrations with BMD. Osteopaenia was defined as 1–2·5 SD below the mean for white men aged 20 – 29 years.
Men in the lowest quartile of free E2 had 70% increasedodds (OR = 1·69, 95% CI 0·95 – 2·98) of osteopaenia compared with men in the highest quartile. Men in the lowest quartile of free testosterone had nearly four times the odds of osteopaenia than those in the highest quartile (OR = 3·82, 95% CI 1·87 – 7·78). Lower concentrations of SHBG appeared protective against osteopaenia (P-trend = 0·01). Neither total testosterone nor total E2 was associated with BMD, although men with clinically low E2 (< 20 ng/l) had lower BMD (0·930 g/cm2, 95% CI 0·88 – 0·98) than men with normal-range E2 (1·024 g/cm2, 95% CI 1·01–1·04; P = 0·004). Findings for free E2 were most pronounced among elderly men, while the findings for free testosterone were most pronounced among younger men.
In this nationally representative study, men with lower free E2, lower free testosterone, and higher SHBG concentrations in circulation were more likely to have low BMD.
PMCID: PMC3494466  PMID: 18485120
11.  Sex Hormones, Insulin Resistance, and Diabetes Mellitus among Men with or at Risk for HIV Infection 
To examine the relationship of free testosterone (FT) and sex hormone-binding globulin (SHBG) with insulin resistance and diabetes mellitus (DM) in HIV disease.
Cross-sectional analysis from 322 HIV-uninfected and 534 HIV-infected men in the Multicenter AIDS Cohort Study.
The main outcomes were DM and Homeostasis model assessment–insulin resistance (HOMA-IR). DM was defined as fasting serum glucose (FG) ≥ 126 or self-reported DM and use of DM medications. Homeostasis model assessment–insulin resistance (HOMA-IR) was calculated from FG and fasting insulin.
Compared with HIV-uninfected men in our sample, HIV-infected men were younger, with lower BMI, and more often black. HIV-infected men had lower FT (p < 0.001) and higher SHBG (p < 0.0001). The adjusted odds ratio for DM was 1.98 (95% CI 1.04–3.78); mean adjusted log HOMA-IR was 0.21 units higher in HIV-infected men (p < 0.0001). Log SHBG, but not log FT, was associated with DM (OR = 0.44, 95% CI 0.25, 0.80) in both groups. Log FT and log SHBG were inversely related to insulin resistance (p < 0.05 for both) independent of HIV.
Compared to HIV-uninfected men, HIV-infected men had lower FT, higher SHBG, and more insulin resistance and DM. Lower FT and lower SHBG were associated with insulin resistance regardless of HIV serostatus. This suggests that sex hormones play a role in the pathogenesis of glucose abnormalities among HIV-infected men.
PMCID: PMC3175332  PMID: 21705912
Testosterone; Sex Hormone-Binding Globulin; Insulin Resistance; Diabetes Mellitus; HIV
12.  The prevalence of low sex steroid hormone concentrations in men in the Third National Health and Nutrition Examination Survey (NHANES III) 
Clinical endocrinology  2011;75(2):232-239.
Physiologic processes during aging leading to multi-morbidity and diseases that increase risk of premature death may be influenced by aging-associated changes in endogenous hormone production.
To evaluate the decline in sex steroid hormone levels across age and estimate the number of US men 40+ years old who may have low hormone levels.
We measured serum testosterone, estradiol, and sex hormone binding globulin by immunoassay in 1,351 men 20+ years old in NHANES III. We estimated free hormones by mass action.
Free testosterone declined most rapidly with age (a 2% decline in geometric mean concentration occurred after aging 1.3 years), followed by total testosterone (2.4 years), free estradiol (4.1 years), and total estradiol (8.1 years). These hormone changes with age translated into 25.0% and 30.2% of men 70+ years old having low total (which we defined as <10.4 nmol/L) and free (<0.17 nmol/L) testosterone, respectively, and 8.3% and 23.9% having low total (<73.4 pmol/L) and free (<2.2 pmol/L) estradiol. Using population size projections between the 2000 and 2010 Censuses, we estimated that 8.4 (95% CI 4.7-12.2), 6.2 (3.1-9.2), and 6.0 (3.1-9.0) million 40+ year old men may have low total testosterone, free testosterone, and free estradiol, respectively. The prevalences were only modestly lower in men without prevalent chronic diseases.
Although no consensus exists for defining low hormone levels in aging men, a substantial number of US men may have low sex steroid hormone levels, possibly putting them at risk for adverse health consequences and pre-mature death.
PMCID: PMC3130833  PMID: 21521312
NHANES III; testosterone; men; aging
13.  Age-Related Skeletal Muscle Decline Is Similar in HIV-Infected and Uninfected Individuals 
Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.
Whole-body 1H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.
At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.
Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss.
PMCID: PMC3041474  PMID: 21310810
Sarcopenia; Lipoatrophy; Fat redistribution; Body composition
14.  Prevalence of Low Bone Mineral Density in a Low-Income Inner-City Population 
Bone mineral density (BMD) is an important factor linked to bone health. Little is known of the prevalence of low BMD and its associated risk factors in an urban underserved population. Between 2001 and 2004, we recruited 338 subjects who completed drug use and medical history questionnaires, underwent hormonal measurements, and underwent whole-body dual-energy X-ray absorptiometry (DXA) for evaluation of BMD and body composition. Of these, 132 subjects had site-specific DXA (lumbar spine and hip) performed. Osteoporosis was defined as a T-score of –2.5 or less for men 50 years of age and older and postmenopausal women and a Z-score of –2.0 or less in men younger than 50 years of age and premenopausal women at either the lumbar spine, total hip, or femoral neck, according to National Osteoporosis Foundation (NOF) guidelines. The cohort consisted of mostly African-American, middle-aged people with a high prevalence of illicit drug use, 50% HIV+, and 39% hepatitis C+. Osteoporosis was identified in 22% of subjects (24 men, 5 women), with the majority of cases (90%) attributable to osteoporosis at the lumbar spine. Osteoporosis was more common in men than in women. Lower whole-body BMD among women was associated with multiple risk factors, but only with lower lean mass among men. Osteoporosis was highly prevalent in men, mainly at the spine. The risk factors for bone loss in this population need to be further clarified. Screening men for osteoporosis starting at age 50 might be warranted in this population given the multiple risk factors and the unexpectedly high prevalence of low BMD. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179342  PMID: 20721937
15.  Illicit drug use and HIV treatment outcomes in a US cohort 
AIDS (London, England)  2008;22(3):357-365.
To determine the prevalence of illicit drug use and the impact on HIV treatment.
Multivariable regression of cross-sectional data from 1163 HIV-infected and 294 controls from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
An analysis of (1) prevalence of specific illicit drug use (ever, current), (2) being on HAART among those with an indication and (3) current HIV RNA and CD4 cell count among HAART users.
Median age was 42 years, approximately 50% were non-Caucasian and 33% were women. Eighty-six percent of HIV-infected and 67% of controls reported ever using illicit drugs (P <0.0001); 28% of HIV-infected and 16% of controls reported current use (P = 0.0001). In adjusted models, current cocaine use and past heroin use were associated with not currently being on HAART. Among HAART users, those reporting past heroin use were as likely to have an undetectable HIV viral load as those who had never used heroin. Current and past cocaine use and current heroin use was associated with lower odds of undetectable HIV RNA. Past amphetamine use was associated with having an undetectable HIV. Similar results were seen for CD4 lymphocyte counts.
Illicit drug use in the US is common, although far fewer report current use than past use. Among HIV-infected patients, understanding of the type of illicit drugs used and whether drug use was in the past or ongoing is important, because of their differential effects on HIV treatment outcomes.
PMCID: PMC3189479  PMID: 18195562
amphetamines; cocaine; heroin; HIV; street drugs; viral load
16.  Lack of an Effect of High Dose Isoflavones in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy 
The Journal of urology  2009;182(5):2265-2272.
The profound hypogonadism due to androgen deprivation therapy for prostate cancer results in complications such as sexual dysfunction, poor quality of life, vasomotor symptoms and altered cognition. Since estrogen is associated with cardiovascular risks, phytoestrogens are being increasingly evaluated as a potential treatment for these adverse effects. We evaluated the effects of high dose isoflavones, equivalent to that consumed by Asian populations, on the aforementioned consequences of androgen deprivation therapy.
Materials and Methods
A total of 33 men undergoing androgen deprivation therapy for prostate cancer were enrolled in this randomized, double-blind, placebo controlled, 12-week pilot trial. Participants were randomly assigned to receive 20 gm soy protein containing 160 mg total isoflavones (17) vs taste matched placebo, that is 20 gm whole milk protein (16). The study was performed at a tertiary care center in the United States.
At baseline the groups were well matched in demographic parameters, sleep quality, cognition and overall quality of life. However, men in the isoflavone group had a higher baseline prevalence of hot flashes and poor intercourse satisfaction compared to those on placebo. At 12 weeks there were no significant differences between the 2 groups in any outcome measure.
This pilot study of high dose isoflavones in androgen deprived men showed no significant improvement in cognition, vasomotor symptoms or any other aspect of quality of life measures compared to placebo. Future studies should use variable doses of isoflavones for a longer period before ruling out beneficial isoflavone effects in this population.
PMCID: PMC3089061  PMID: 19758646
prostate; prostatic neoplasms; antiandrogens; isoflavones; quality of life
17.  Association of Serum Cholesterol and Cholesterol-Lowering Drug Use with Serum Sex Steroid Hormones in Men in NHANES III 
Cancer causes & control : CCC  2010;21(10):1575-1583.
Low cholesterol levels and statin drugs may protect against prostate cancer with a worse prognosis. Their protective mechanism is unknown, but has been hypothesized to be related to cholesterol’s role as a sex steroid hormone precursor. We evaluated whether serum testosterone and estradiol differ by cholesterol or cholesterol-lowering drug use.
Materials and Methods
Testosterone and estradiol were measured for 1,457 male participants in the Third National Health and Nutrition Examination Survey (NHANES III). We estimated multivariable-adjusted geometric mean hormone concentration by quintiles of cholesterol concentration and by cholesterol-lowering drugs use.
Across quintiles of cholesterol, testosterone level did not differ (mean, 95% confidence interval (CI); Q1: 5.18, 4.90–5.47, Q5: 5.09, 4.80–5.40 ng/mL; p-trend=0.64), whereas estradiol levels were lower (Q1: 38.6, 36.9–40.3; Q5: 33.1, 31.8–34.5 pg/mL; p-trend<0.0001). Neither testosterone (no: 5.11, 4.96–5.27, yes: 5.19, 4.71–5.72 ng/mL, p=0.79) nor estradiol (no: 35.9, 34.8–37.1; yes: 34.1, 29.5–39.4 pg/mL; p=0.43) differed by cholesterol-lowering drugs use.
Testosterone did not differ by cholesterol or cholesterol-lowering drug use. Estradiol was lower in men with higher cholesterol, but did not differ by cholesterol-lowering drug use. Our results suggest that the lower risk of advanced prostate cancer among statin users is not readily explained by a cholesterol-mediated effect of statins on sex hormone levels.
PMCID: PMC3004148  PMID: 20512526
18.  Association of cigarette smoking, alcohol consumption and physical activity with sex steroid hormone levels in U.S. men 
Cancer causes & control : CCC  2009;20(6):877-886.
We evaluated the associations of smoking, alcohol consumption, and physical activity with sex steroid hormone concentrations among 1,275 men 20–90 years old who participated in the Third National Health and Nutrition Examination Survey (NHANES III).
Serum concentrations of testosterone, estradiol and sex hormone-binding globulin (SHBG) were measured. We compared geometric mean concentrations across levels of smoking, alcohol, and physical activity using multiple linear regression.
Current smokers had higher total testosterone (5.42, 5.10 and 5.26 ng/mL in current, former and never smokers), free testosterone (0.110, 0.102 and 0.104 ng/mL), total estradiol (40.0, 34.5 and 33.5 pg/mL) and free estradiol (1.05, 0.88 pg/mL and 0.84 pg/mL) compared with former and never smokers (all P≤0.05). Men who consumed ≥1 drink/day had lower SHBG than men who drank less frequently (31.5 vs. 34.8 nmol/L, P=0.01); total (P-trend=0.08) and free testosterone (P-trend=0.06) increased with number of drinks per day. Physical activity was positively associated with total (P-trend=0.01) and free testosterone (P-trend=0.05).
In this nationally-representative sample of men, smoking, alcohol and physical activity were associated with hormones and SHBG, thus these factors should be considered as possible confounders or upstream variables in studies of hormones and men’s health, including prostate cancer.
PMCID: PMC3004151  PMID: 19277882
hormones; men; physical activity; alcohol; smoking
19.  Association of Endogenous Sex Hormones With Diabetes andImpaired Fasting Glucose in Men 
Diabetes Care  2009;32(6):1049-1051.
To assess associations of sex hormones with impaired fasting glucose (IFG) and type 2 diabetes in men.
A total of 3,156 African American, Non-Hispanic white, Hispanic, and Chinese-American men aged 45–84 years who participated in the baseline visit of the Multi-Ethnic Study of Atherosclerosis (MESA) were included. Oddsratios and95% CIs for type 2 diabetes and IFG compared with normal fasting glucose for quartiles of hormones were estimated.
After adjusting for age, ethnicity, BMI, and waist circumference, IFG and diabetes were associated inversely with total testosterone and sex hormone–binding globulin (SHBG) and positively with estradiol (E2). Dehydroepiandrosterone was positively associated with IFG but not with diabetes. Associations did not differ across ethnic groups.
Regardless of obesity, total testosterone and SHBG were associated inversely and E2 was associated positively with IFG and diabetes in men. Further research is warranted to better understand the underlying biological mechanisms.
PMCID: PMC2681025  PMID: 19289858
20.  Sex Hormones Levels and Subclinical Atherosclerosis in Postmenopausal Women: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;204(1):255-261.
We examined cross-sectional associations between sex hormones and carotid artery intimal-medial thickness (cIMT) and coronary artery calcium in women in the Multi-Ethnic Study of Atherosclerosis.
Serum testosterone, estradiol, sex hormone binding globulin (SHBG), and dehydroepiandrosterone levels were measured in 1,947 postmenopausal women aged 45-84 years (30% White, 14% Chinese-American, 31% Black, and 25% Hispanic) and not on hormone therapy. Using multiple linear regression we evaluated associations between log(sex hormone) levels and log(cIMT) adjusted for age, ethnicity, body mass index (BMI) and cardiac risk factors. Associations between sex hormone levels and the presence and extent of coronary calcium were evaluated.
Total and bioavailable testosterone were positively associated with common cIMT independent of age, BMI, hypertension, smoking, HDL-cholesterol, LDL-cholesterol and insulin sensitivity (p=0.009 and p=0.002 respectively). SHBG was negatively associated with common cIMT (p=0.001) but further adjustment for BMI, cardiovascular risk factors, and LDL- and HDL-cholesterol removed significance. Estradiol and dehydroepiandrosterone were not associated with common cIMT. Sex hormones were not associated with presence of coronary calcium. Among women with measurable coronary calcium, higher SHBG (p=0.012) and lower bioavailable testosterone (p=0.007) were associated with greater coronary calcium score. No heterogeneity by ethnicity was found. In postmenopausal women, testosterone is independently associated with greater common cIMT. SHBG is negatively associated and this may be mediated by LDL- and HDL-cholesterol. In contrast, SHBG and testosterone were associated with extent of coronary calcium but in the opposite direction compared to carotid intimal-medial thickness. These differences warrant further evaluation.
PMCID: PMC2729280  PMID: 18849030
Gonadal steroid hormones; atherosclerosis; postmenopausal women; carotid intimal-medial thickness; coronary calcium
21.  Heavy injection drug use is associated with lower percent body fat in a multi-ethnic cohort of HIV-positive and HIV-negative drug users from three U.S. cities 
The clinical implications of lower body weight in drug using populations are uncertain given that lower mean weights may still fall within the healthy range.
To determine the effect of type, mode and frequency of drug use on underlying body composition after accounting for differences in body shape and size.
We conducted a cross-sectional analysis of 511 participants from the Tufts Nutrition Collaborative (TNC) Study. Data included measures of body composition, a 24-hour dietary recall, and a detailed health history and lifestyle questionnaire. Multivariate regression analysis was used to determine the independent effect of drug use on percent body fat (BF) after adjusting for BMI and waist circumference.
Heavy injection drug users (IDUs) had a 2.6% lower percent BF than non-users after adjusting for BMI, waist circumference, and other confounders. (p=0.0006). Differences in percent BF were predominantly due to higher lean mass, rather than lower fat mass. Cocaine and heroin had similar effects on body composition.
In the U.S., where the general population is prone to over-nutrition, the average percent BF for heavy injectors does not fall into a range low enough to suggest harmful effects. However, in populations with substantial levels of under-nutrition, small differences in percent BF among drug users will have a greater impact on health status.
Scientific Significance
Differences in BMI, weight and body composition are not always straightforward. Accounting for underlying nutritional status and relative differences in fat and FFM is critical when interpreting results.
PMCID: PMC2837874  PMID: 20141402
22.  Sex-Based Differences in Pain Perception and Treatment 
Pain medicine (Malden, Mass.)  2009;10(2):289-299.
This review highlights research on sex-based differences in pain perception and treatment. We sought to illuminate the complex factors contributing to differences in pain and analgesic responses between males and females, ranging from psychosocial to biological processes.
We reviewed published studies of pain induction by chemical, electric, heat, surgical, or psychological means, and opioid and nonopioid analgesia comparing responses in men and women.
A substantial body of research indicates that women experience greater clinical pain, suffer greater pain-related distress, and show heightened sensitivity to experimentally induced pain compared with men. Research on sex-based differences in the pain experience and treatment is beginning to uncover patterns that may enable tailoring of pain treatment to individual characteristics. The factors underpinning sex differences in the experience of pain are multifactorial and complex; for example, psychosocial factors such as pain-related catastrophizing may explain sex-based differences in reporting certain types of pain, as women tend to use catastrophizing to a greater degree. Gonadal hormone levels in cycling women also have a substantial impact on pain perception and analgesic response. Women perceive more pain during the luteal phase, and estrogen antagonists provide long-term pain relief in certain situations.
Collectively, greater understanding of the factors that commonly and differentially affect the disparity in pain perception, as well as analgesic response, are beginning to illuminate research targets and promising areas of therapeutic intervention for improved pain management.
PMCID: PMC2745644  PMID: 19207233
Sex; Sex Differences; Pain; Experimental Pain; Analgesia; Psychosocial
23.  Fat distribution and longitudinal anthropometric changes in HIV-infected men with and without clinical evidence of lipodystrophy and HIV-uninfected controls: A substudy of the Multicenter AIDS Cohort Study 
Fat abnormalities are common among HIV-infected persons, but few studies have compared regional body fat distribution, including visceral fat, in HIV-infected and HIV-uninfected persons and their subsequent trajectories in body composition over time.
Between 1999 and 2002, 33 men with clinical evidence of lipodystrophy (LIPO+), 23 HIV-infected men without clinical evidence of lipodytrophy (LIPO-), and 33 HIV-uninfected men were recruited from the four sites of the Multicenter AIDS Cohort Study (MACS). Participants underwent dual-energy x-ray absorptiometry, quantitative computerized tomography of the abdomen and thigh, and circumference measurements of the waist, hip and thigh. Circumference measurements at each semi-annual MACS visit between recruitment and 2008 were used to compare average annual anthropometric changes in the 3 groups.
Body mass index (BMI) was lower in LIPO+ men than in the LIPO- men and the HIV- uninfected controls (BMI: 23.6 ± 0.4 vs 26.8 ± 1.5 vs 28.7 ± 0.9 kg/m2, respectively, p < 0.001). The average amount of visceral adipose tissue (VAT) was similar in all three groups (p = 0.26), but after adjustment for BMI, VAT was higher in the LIPO+ group (169 ± 10 cm2) compared to the LIPO- men (129 ± 12 cm2, p = 0.03) and the HIV-uninfected group (133 ± 11 cm2, p = 0.07). Subcutaneous adipose tissue (thigh, abdomen) and total extremity fat were less in the HIV-infected men (LIPO+ and LIPO-) than in the HIV-uninfected men. Over an average of 6 years of follow-up, waist circumference increased at a faster rate in LIPO+ group, compared to the LIPO- men (0.51 cm/year vs 0.08 cm/year, p = 0.02) and HIV-uninfected control men (0.21 cm/year, p = 0.06). The annual changes in hip and thigh circumferences were similar in all three groups
Subcutaneous lipoatrophy was observed in HIV-infected patients, even those without clinical evidence of lipodystrophy, compared to age-matched HIV-uninfected men. Despite markedly lower BMI, HIV-infected men with lipodystrophy had a similar amount of VAT as HIV-uninfected men and tended to have more rapid increases in waist circumference over 6 years of follow-up. These longitudinal increases in waist circumference may contribute to the development of cardiovascular risk in HIV-infected patients with lipodystrophy.
PMCID: PMC2686733  PMID: 19439092
24.  Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir 
Complementary and alternative medicine (CAM) use is prevalent among HIV-infected patients to reduce the toxicity of antiretroviral therapy. Ginseng has been used for treatment of hyperglycemia and insulin resistance, a common side effect of some HIV-1 protease inhibitors (PI). However, it is unknown whether American ginseng (AG) can reverse insulin resistance induced by the PI indinavir (IDV), and whether these two agents interact pharmacologically. We evaluated potential pharmacokinetic interactions between IDV and AG, and assessed whether AG improves IDV-induced insulin resistance.
After baseline assessment of insulin sensitivity using the insulin clamp technique, healthy volunteers received IDV 800 mg q8 h for 3 days and then IDV and AG 1g q8h for 14 days. IDV pharmacokinetics and insulin sensitivity were assessed before and after AG co-administration.
There was no difference in the area-under the plasma-concentration-time curve after the co-administration of AG, compared to IDV alone (n = 13). Although insulin-stimulated glucose disposal per unit of insulin (M/I) decreased by an average of 14.8 ± 5.9% after 3 days of IDV (from 0.113 ± 0.012 to 0.096 ± 0.014 mg/kgFFM/min per μU/ml of insulin, p = 0.03, n = 11), M/I remained unchanged after co-administration of IDV and AG.
IDV decreases insulin sensitivity, which is unaltered by AG co-administration. AG does not significantly affect IDV pharmacokinetics.
PMCID: PMC2542349  PMID: 18713456
25.  Androgen Levels in Older Men Who Have or Who Are at Risk of Acquiring HIV Infection 
To determine the prevalence of, risk factors for, and clinical manifestations of low androgen levels in older men who have or who are at risk of acquiring human immunodeficiency virus (HIV) infection, we performed a cross-sectional analysis of an observational cohort of men aged ≥49 years old.
A standardized interview (regarding demographic characteristics, behaviors, and medical history) was performed, and body mass index, HIV serologic data, CD4+ cell count, the presence of hepatitis C virus (HCV) markers, and serum testosterone and human sex-binding hormone levels were determined. Factors associated with androgen levels were assessed using logistic regression models.
Among 502 men (age, 49−81 years) who were not taking androgens, 54% had total testosterone levels of <300 ng/dL. Low androgen levels were associated with injection drug use, HCV infection, high body mass index, and use of psychotropic medications (P < .05); black race was associated with higher androgen levels. Only among men who reported having sex with men was low testosterone level associated with HIV infection (adjusted odds ratio [ORadj] for total testosterone level of <300 ng/dL, 5.1; 95% confidence interval [CI], 1.2−22.4), but among all HIV-seropositive men, HIV load of >10,000 copies/mL was associated with a testosterone level of <200 ng/dL (ORadj, 2.1; 95% CI, 1.1−4.3; P = .03). On univariate analysis, low androgen levels were associated with decreased interest in sex, depressive symptoms, loss of concentration/memory, difficulty sleeping, osteopenia, and poorer subjective health (P < .05).
Most older men at risk for HIV infection have low androgen levels. Injection drug use, high body mass index, HCV infection, and use of psychotropic medications are associated with low androgen levels, and low androgen levels are associated with symptoms of hypogonadism.
PMCID: PMC2426822  PMID: 16288406

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