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1.  Effect of Testosterone Administration on Liver Fat in Older Men With Mobility Limitation: Results From a Randomized Controlled Trial 
Background.
Androgen receptor (AR) knockout male mice display hepatic steatosis, suggesting that AR signaling may regulate hepatic fat. However, the effects of testosterone replacement on hepatic fat in men are unknown. The aim of this study was to determine the effects of testosterone administration on hepatic fat in older men with mobility limitation and low testosterone levels who were participating in a randomized trial (the Testosterone in Older Men trial).
Methods.
Two hundred and nine men with mobility limitation and low total or free testosterone were randomized in the parent trial to either placebo or 10-g testosterone gel daily for 6 months. Hepatic fat was determined by magnetic resonance imaging in 73 men (36 in placebo and 37 in testosterone group) using the volumetric method. Insulin sensitivity (homeostatic model assessment–insulin resistance) was derived from fasting glucose and insulin.
Results.
Baseline characteristics were similar between the two groups, including liver volumes (1583±363 in the testosterone group vs 1522±271mL in the placebo group, p = .42). Testosterone concentrations increased from 250±72 to 632±363ng/dL in testosterone group but did not change in placebo group. Changes in liver volume during intervention did not differ significantly between groups (p = .5) and were not related to on-treatment testosterone concentrations. The change in homeostatic model assessment–insulin resistance also did not differ significantly between groups and was not related to either baseline or change in liver fat.
Conclusion.
Testosterone administration in older men with mobility limitation and low testosterone levels was not associated with a reduction in hepatic fat. Larger trials are needed to determine whether testosterone replacement improves liver fat in men with nonalcoholic hepatic steatosis.
doi:10.1093/gerona/gls259
PMCID: PMC3826861  PMID: 23292288
Testosterone; Older men; Liver fat; Insulin resistance.
2.  Age Trends in Estradiol and Estrone Levels Measured Using Liquid Chromatography Tandem Mass Spectrometry in Community-Dwelling Men of the Framingham Heart Study 
Background.
Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone–binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study.
Methods.
Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation.
Results.
There were 1,461 eligible men (mean age [±SD] 61.1±9.5 years and body mass index [BMI] 28.8±4.5kg/m2). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others.
Conclusions.
Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings.
doi:10.1093/gerona/gls216
PMCID: PMC3660115  PMID: 23105044
Age trends; Estrogen levels in men; LC-MS/MS; Age-related changes in estrone and estradiol; Determinants of estrogen levels in men.
3.  The Effect of Testosterone on Mood and Well-being in Men with Erectile Dysfunction in a Randomized, Placebo-Controlled Trial 
Andrology  2013;1(3):475-482.
The relationship between testosterone, well-being and mood is poorly understood. We investigated the effect of testosterone supplementation on mood, well-being, and self-reported health in men with erectile dysfunction (ED) and low serum testosterone levels. This was a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov registration number NCT00512707) in which 140 men, 40 to 70-years, with ED and low serum testosterone levels were first optimized on sildenafil alone for 3 to 7-weeks and then randomized to receive either sildenafil plus testosterone gel (n = 70) or sildenafil plus placebo (n = 70) gel for 14-weeks. Using multiple imputations and generalized linear regression, we compared psychological changes in well-being, evaluated by the Psychological General Well-Being Index, and mood, evaluated by Derogatis Affects Balance Scale. Mood and well-being scores were similar between the two groups at baseline and did not substantially change during the administration of sildenafil or after randomization to testosterone. Our findings show that the addition of testosterone to sildenafil in men with ED and low serum testosterone levels was not associated with improvement in either well-being or mood.
doi:10.1111/j.2047-2927.2013.00075.x
PMCID: PMC3630276  PMID: 23494931
Erectile dysfunction; testosterone replacement; mood; affectivity balance; well-being; androgen deficiency
4.  Risk Factors Associated With Cardiovascular Events During Testosterone Administration in Older Men With Mobility Limitation 
Background.
Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of cardiovascular events in men randomized to testosterone, resulting in enrollment cessation by trial's Data and Safety Monitoring Board. We evaluated changes in gonadal hormones and markers of inflammation and coagulation to elucidate risk factors associated with cardiovascular events.
Methods.
Men aged 65 years or more, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Changes in total and free testosterone, estradiol and estrone, C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor-1, and pro-brain naturetic peptide were compared between groups and within the testosterone group between subjects who experienced cardiovascular events and those who did not.
Results.
Of 209 men randomized (mean age 74 years), gonadal hormones and biomarkers were available in 179 men. Baseline body mass index, gonadal hormones, lipids, Framingham risk scores, and other biomarkers were similar in the two treatment groups. Within the testosterone group, the 6-month increase in free testosterone was significantly greater in men who experienced cardiovascular events than in those who did not [mean (95% confidence interval), 10.6 (4.6–16.7) vs 5.2 (3.0–7.5) ng/dL, p = .05]. In multivariable logistic regression analysis, the change in the serum levels of free testosterone was associated with cardiovascular events.
Conclusion.
Mobility-limited older men who experienced cardiovascular events had greater increases in serum free testosterone levels than those who did not.
doi:10.1093/gerona/gls138
PMCID: PMC3598355  PMID: 22562960
Testosterone; Older men; Mobility limitation; Cardiovascular disease
5.  The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men 
Background.
Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity.
Objectives.
To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.
Methods.
In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.
Results.
LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation.
Conclusions.
LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.
doi:10.1093/gerona/gls078
PMCID: PMC4111291  PMID: 22459616
Selective androgen receptor modulators; SARMs; Sarcopenia; Function promoting anabolic therapies; Cachexia
6.  Relationship of sex steroid hormones with bone mineral density (BMD) in a nationally representative sample of men 
Clinical endocrinology  2008;70(1):26-34.
Summary
Objective
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.
Design
BMD and sex steroid hormones were measured among participants in NHANES III, a cross-sectional study of the US population.
Population
A total of 1185 adult men in morning examination session of Phase I of NHANES III (1988 – 91).
Measurements
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1365-2265.2008.03300.x
PMCID: PMC3494466  PMID: 18485120
7.  Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation 
Context.
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial’s Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant’s perception of change.
Methods.
Men aged 65 years and older, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared.
Results.
Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change.
Conclusions.
Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
doi:10.1093/gerona/glr100
PMCID: PMC3202898  PMID: 21697501
Testosterone; Minimally important difference; Mobility limitation; Older men; Function promoting therapies
8.  Adverse Events Associated with Testosterone Administration 
The New England journal of medicine  2010;363(2):109-122.
Background
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.
Methods
Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.
Results
A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.
Conclusions
In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.
doi:10.1056/NEJMoa1000485
PMCID: PMC3440621  PMID: 20592293
9.  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.
Background
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.
Objective
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.
Design
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1365-2265.2011.04043.x
PMCID: PMC3130833  PMID: 21521312
NHANES III; testosterone; men; aging
10.  A Lifelong Smoker with Hypopituitarism: Rethinking the Hypothesis of a Tumor in the Hypophysis 
Case Reports in Medicine  2012;2012:853568.
Pituitary adenomas are the most common cause of a sellar mass. Metastases to the pituitary gland, a rare occurrence, may mimic benign pituitary adenomas. We report here a case of a 61-year-old woman with an 80-pack-year smoking history who presented with headache and diplopia. Visual field testing demonstrated bitemporal hemianopsia. Pituitary MRI revealed a 2.0 cm sellar mass impinging upon the optic chiasm. Hypopituitarism was present, with no evidence of diabetes insipidus. The patient was referred to our service for transsphenoidal resection of a presumed pituitary macroadenoma. As part of her preoperative evaluation, a chest radiograph was obtained, which showed a large hilar mass. In light of the patient's extensive smoking history, the differential diagnosis was expanded to include metastatic lesion to the sella. Transsphenoidal resection of the tumor was performed and histopathology revealed small cell carcinoma. The patient received chemotherapy, but died 18 months later due to widespread brain metastases. Although the presence of diabetes insipidus may help to discriminate between pituitary adenomas and metastatic lesions, this is not a sensitive finding. This case illustrates the need for maintaining a high index of suspicion for pituitary metastasis in patients with known risk factors for malignancy.
doi:10.1155/2012/853568
PMCID: PMC3347466  PMID: 22577392
11.  Gonadal Status and physical performance in older men 
Background
Male aging is characterized by a progressive decline in serum testosterone levels and physical performance. Low testosterone levels may be implicated in the decline of physical performance and consequent mobility disability that occurs with aging. During the recent years many consensus reports have advocated that one of the potential effects of testosterone supplementation is the improvement in mobility. However, to the best of our knowledge no study has fully investigated the relationship between gonadal status and objective measures of physical performance in older men and their determinants.
Methods
We evaluated 455 ≥ 65 year old male participants of InCHIANTI study a population based study in two municipalities of Tuscany, Italy with complete data on testosterone levels, hand grip strength, cross-sectional muscle area (CSMA), short physical performance battery (SPPB). Linear models were used to test the relationship between gonadal status and determinants of physical performance.
Results
According to baseline serum levels of total testosterone, three different groups of older men were created: 1) severely hypogonadal (N= 23),total testosterone levels ≤230 ng /dl; 2) moderately hypogonadal (N=88), total testosterone >230 and <350 ng/dL), and 3) eugonadal (N=344), testosterone levels ≥350 ng/dL. With increased severity of hypogonadal status, participants were significantly older while their BMI was substantially similar. In the age and BMI adjusted analysis, there was a significant difference in hemoglobin levels, hand grip strength and SPPB score (p for trend<0.001) among −3 groups, with severely hypogonadal men having lower values of hemoglobin, muscle strength and physical performance. We found no association between testosterone group assignment and calf muscle mass and 4 meter walking speed. In the multivariate analysis grip strength (p for trend=0.004) and haemoglobin (p for trend <0.0001) but not SPPB and other determinants of physical performance were significantly different between the 3 groups.
Conclusions
In older men, gonadal status is independently associated with some determinants (hemoglobin and muscle strength) of physical performance.
doi:10.3109/13685538.2010.518179
PMCID: PMC3142745  PMID: 20937007
testosterone; physical performance; older men
12.  Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications 
Asian Journal of Andrology  2012;14(2):222-225.
Prostate cancer (PCa) is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.
doi:10.1038/aja.2011.109
PMCID: PMC3735099  PMID: 22343494
androgen deprivation therapy; cardiovascular disease; diabetes; hypogonadism; prostate cancer
13.  Time to raise awareness regarding complications of androgen deprivation therapy 
Asian Journal of Andrology  2012;14(2):175-176.
doi:10.1038/aja.2011.105
PMCID: PMC3735103  PMID: 22367185
14.  High Dose Isoflavones do not improve Metabolic and Inflammatory Parameters in Androgen Deprived Men with Prostate Cancer 
Journal of andrology  2010;32(1):40-48.
Background
The profound hypogonadism that occurs with androgen-deprivation therapy (ADT) for prostate cancer (PCa) results in complications such as diabetes and metabolic syndrome that predispose to cardiovascular disease. Since phytoestrogens have been associated with an improvement in metabolic parameters, we evaluated their role in men undergoing ADT.
Objective
To evaluate the effects of high-dose isoflavones on metabolic and inflammatory parameters in men undergoing ADT.
Methods
This was a randomized, double-blind, placebo-controlled, 12-week pilot study. Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). The study was conducted at a tertiary care center in the United States.
Results
Thirty-three men (isoflavones=17, placebo=16) undergoing ADT for PCa completed this pilot study. Mean age in the two groups was 69 years and majority of men were Caucasians. Mean duration of ADT in both groups was approximately 2 years (P=0.70). The two groups were well-matched at baseline. After 12-weeks of intervention, there was no significant difference in either metabolic or inflammatory parameters between the two groups.
Conclusion
High-dose isoflavones over a course of 12-weeks do not improve metabolic or inflammatory parameters in androgen deprived men.
doi:10.2164/jandrol.110.010983
PMCID: PMC3005077  PMID: 20798386
15.  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.
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.juro.2009.07.030
PMCID: PMC3089061  PMID: 19758646
prostate; prostatic neoplasms; antiandrogens; isoflavones; quality of life
16.  Estradiol and Metabolic Syndrome in Older Italian Men: the InCHIANTI Study 
Journal of andrology  2008;31(2):155-162.
The increasing prevalence of metabolic syndrome (MS) with age in older men has been linked with decreasing testosterone levels. Interestingly, while testosterone levels decline with age, estradiol (E2) levels remain relatively stable resulting in a decreased testosterone/estradiol ratio. Because E2 levels tend to be elevated in morbid obesity, insulin resistance and diabetes, it is reasonable to hypothesize that high E2 levels are associated with MS in older men.
We studied the relationship of total and free E2 with MS after adjustment for multiple confounders including age, BMI, smoking, alcohol consumption, physical activity, interleukin-6 (IL-6), fasting insulin and testosterone.
452 men 65 yr or older (age range 65–96) had complete data on estradiol, testosterone, fasting insulin, sex hormone binding globulin, interleukin-6 (IL-6), and albumin. Concentrations of free estradiol and free testosterone were calculated using the mass action equations. MS was defined according to ATPIII criteria.
Participants with MS had significantly higher serum free and total E2 (p<.001) (p=0.003). After adjusting for confounders, including age, smoking, alcohol consumption, physical activity, log (IL-6), log (insulin), participants with higher log (total E2) (OR: 2.31, 95 % CI 1.39–4.70, p=0.02) and higher log (free E2) (OR: 2.69, 1.38–5.24, p<0.001) had an increased risk of having MS. Log (free E2) (p=0.04) maintained significant correlation with MS even after further adjustment for BMI.
In older men high E2 is independently associated with MS. Whether confirmed in other studies, assessment of E2 should be also considered in older men. Whether changes in this hormonal pattern play a role in the development of MS should be further tested in longitudinal studies.
doi:10.2164/jandrol.108.006098
PMCID: PMC2842460  PMID: 19059904
estradiol; metabolic syndrome; older men
17.  Endogenous sex steroid hormones and measures of chronic kidney disease in a nationally representative sample of men 
Clinical endocrinology  2008;71(2):246-252.
Context
Sex steroid hormones may play a role in the pathogenesis of chronic kidney disease (CKD).
Objective
To determine whether sex steroid hormone concentrations are associated with kidney function or kidney damage in men in the general US population. We hypothesized that lower serum testosterone and estradiol concentrations are associated with CKD.
Design, Patients and Measurements
Serum sex steroid hormones were measured by electrochemiluminescence immunoassays for 1470 men who attended the morning session of Phase I of the Third National Health and Nutrition Examination Survey (NHANES III). We used two measures of CKD, estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 calculated using serum creatinine or cystatin C levels and the abbreviated Modification of Diet in Renal Disease Study formulae and urinary albumin to creatinine ratio (UACR) ≥ 17 mg/g.
Results
Mean free testosterone concentration was higher in men with an eGFR < 60mL/min/1.73m2 than in men with a higher eGFR. In multivariable adjusted models, the odds of an eGFR < 60mL/min/1.73m2 or UACR ≥ 17 mg/g did not differ across tertiles of hormones with the exception of free estradiol; those in the highest vs. lowest tertile had an elevated odds of decreased eGFR (OR: 3.04, 95% CI (1.22, 7.57); p-trend=0.02).
Conclusions
In a nationally representative sample of US adult men, higher free estradiol concentration was significantly associated with an eGFR < 60mL/min/1.73m2 as assessed by serum creatinine or cystatin C even after multivariable adjustment. These findings are in contrast to the hypothesis that estrogens may protect against CKD, though reverse causation cannot be ruled out. Longitudinal investigation of the role of estrogens in kidney hemodynamics, function, and pathophysiology is warranted.
doi:10.1111/j.1365-2265.2008.03455.x
PMCID: PMC2740644  PMID: 19178534
18.  Safety and efficacy of testosterone gel in the treatment of male hypogonadism 
Transdermal testosterone gels were first introduced in the US in 2000. Since then, they have emerged as a favorable mode of testosterone substitution. Serum testosterone levels reach a steady-state in the first 24 hours of application and remain in the normal range for the duration of the application. This pharmacokinetic profile is comparable to that of testosterone patch but superior to injectable testosterone esters that are associated with peaks and troughs with each dose. Testosterone gels are as efficacious as patches and injectable forms in their effects on sexual function and mood. Anticipated increases in prostate-specific antigen with testosterone therapy are not significantly different with testosterone gels, and the risk of polycythemia is lower than injectable modalities. Application site reactions, a major drawback of testosterone patches, occur less frequently with testosterone gels. However, inter-personal transfer is a concern if appropriate precautions are not taken. Superior tolerability and dose flexibility make testosterone gel highly desirable over other modalities of testosterone replacement. Androgel and Testim, the two currently available testosterone gel products in the US, have certain brand-specific properties that clinicians may consider prior to prescribing.
PMCID: PMC2785864  PMID: 19966909
testosterone gel; Androgel; Testim; hypogonadism
19.  Effects of High-Dose Isoflavones on Metabolic and Inflammatory Markers in Healthy Postmenopausal Women 
Menopause (New York, N.Y.)  2009;16(2):395-400.
Context
After menopause, women experience changes in body composition, especially increase in fat mass. Additionally, advancing age, decreased physical activity and increased inflammation may predispose them to develop type-2 diabetes. Isoflavones have been shown to improve metabolic parameters in postmenopausal women. However, the effect of isoflavones on adipo-cytokines remains unclear.
Objective
To evaluate the effect of high dose isoflavones on inflammatory and metabolic markers in postmenopausal women.
Study Design
We measured glucose, insulin and adipokines/cytokines in 75 healthy postmenopausal women who were randomized to receive 20 gm of soy protein with 160 mg of total isoflavones (64mg genistein, 63 mg diadzein, 34 mg glycitein) or 20 gm of soy protein placebo for 12 weeks. Women on estrogen discontinued therapy at least three months prior to the study. The supplements were given in a powder form and consumed once daily with milk or other beverages.
Results
Mean age in the placebo and active groups was similar (p=0.4). Average time since menopause was 9 yrs and two-thirds of the women underwent natural menopause. There was no significant difference in the BMI at baseline between the groups [placebo (25.1 kg/m2), active (26 kg/m2)] and it did not change significantly during the study. At baseline, placebo group had significantly higher levels of TNF-α (p<0.0001), otherwise there was no difference in any other parameter. After 12 weeks of treatment, there were significant positive changes in TNF-α levels within the placebo group (p<0.0001) and adiponectin levels within the isoflavones group (p=0.03). Comparison of pre-post change between the groups showed a small but significant increase in serum adiponectin levels in the isoflavone group (p=0.03) compared to placebo. No significant changes were seen in any other parameter between the two groups.
Conclusion
Healthy, normal-weight postmenopausal women may not experience improvement in metabolic parameters when given high dose isoflavones despite an increase in serum adiponectin levels. Role of isoflavones in obese and insulin resistant postmenopausal women needs exploration.
doi:10.1097/gme.0b013e3181857979
PMCID: PMC2695501  PMID: 18981951
20.  Association Between Hormones and Metabolic Syndrome in Older Italian Men 
OBJECTIVES
To determine whether low levels of testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEAS) and high levels of cortisol and leptin would be associated with metabolic syndrome (MS).
DESIGN
Cross-sectional.
SETTING
Population-based sample of older Italian men.
PARTICIPANTS
Four hundred fifty-two men aged 65 and older enrolled in the Invecchiare in Chianti (InCHIANTI) study.
MEASUREMENTS
Complete data on testosterone, cortisol, DHEAS, SHBG, fasting insulin, IGF-1 and leptin. MS was defined according to Adult Treatment Panel III criteria.
RESULTS
MS was present in 73 men (15.8% of the sample). After adjusting for confounders, total testosterone (P<.05) and log (SHBG) (P<.001) were inversely associated, whereas log (leptin) was positively associated with MS (P<.001). Independent of age, log (SHBG) was positively associated with high-density lipoprotein cholesterol (P<.05) and negatively associated with abdominal obesity (P<.001) and triglycerides (P<.001). Log (leptin) was significantly associated with each component of MS. Cortisol, DHEAS, free and bioavailable testosterone, and IGF-1 were not associated with MS. Having three or more hormones in the lower (for hormones lower in MS) or the upper (for hormones higher in MS) quartile was associated with three times the risk of being affected by MS (odds ratio =2.8, 95% confidence interval =1.3–6.9) (P=.005), compared with not having this condition.
CONCLUSION
Total testosterone and SHBG are negatively and leptin is positively associated with MS in older men. Whether specific patterns of hormonal dysregulation predict the development of MS should be tested in longitudinal studies.
doi:10.1111/j.1532-5415.2006.00963.x
PMCID: PMC2653255  PMID: 17198487
SHBG; testosterone; hormonal dysregulation; older men; metabolic syndrome
21.  Relationship Between Low Levels of Anabolic Hormones and 6-Year Mortality in Older Men 
Archives of internal medicine  2007;167(20):2249-2254.
Background
Aging in men is characterized by a progressive decline in levels of anabolic hormones, such as testosterone, insulinlike growth factor 1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S). We hypothesized that in older men a parallel age-associated decline in bioavailable testosterone, IGF-1, and DHEA-S secretion is associated with higher mortality independent of potential confounders.
Methods
Testosterone, IGF-1, DHEA-S, and demographic features were evaluated in a representative sample of 410 men 65 years and older enrolled in the Aging in the Chianti Area (InCHIANTI) study. A total of 126 men died during the 6-year follow-up. Thresholds for lowest-quartile definitions were 70 ng/dL (to convert to nanomoles per liter, multiply by 0.0347) for bioavailable testosterone, 63.9 ng/mL (to convert to nanomoles per liter, multiply by 0.131) for total IGF-1, and 50 μg/dL (to convert to micromoles per liter, multiply by 0.027) for DHEA-S. Men were divided into 4 groups: no hormone in the lowest quartile (reference) and 1, 2, and 3 hormones in the lowest quartiles. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis.
Results
Compared with men with levels of all 3 hormones above the lowest quartiles, having 1, 2, and 3 dysregulated hormones was associated with hazard ratios for mortality of 1.47 (95% confidence interval [CI], 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68), respectively (test for trend, P <.001). In the fully adjusted analysis, only men with 3 anabolic hormone deficiencies had a significant increase in mortality (hazard ratio, 2.44; 95% CI, 1.09-5.46 (test for trend, P <.001).
Conclusions
Age-associated decline in anabolic hormone levels is a strong independent predictor of mortality in older men. Having multiple hormonal deficiencies rather than a deficiency in a single anabolic hormone is a robust biomarker of health status in older persons.
doi:10.1001/archinte.167.20.2249
PMCID: PMC2646096  PMID: 17998499
22.  Relation of Angiotensin-Converting Enzyme Inhibitor Treatment to Insulin-Like Growth Factor-1 Serum Levels in Subjects >65 Years of Age (the InCHIANTI Study) 
The American journal of cardiology  2006;97(10):1525-1529.
Observational studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin II, which is a potent inhibitor of insulin-like growth factor-1 (IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects (417 women, 328 men) enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models. After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors (mean ± SD 129.0 ± 56.1 ng/ml) compared with the rest of the study population (mean ± SD 116.5 ± 54.8 ng/ml) (p <0.001). Participants with short (<3 years) and long (3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group (p <0.05). In conclusion, in older subjects, treatment with ACE inhibitors for <3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects.
doi:10.1016/j.amjcard.2005.11.089
PMCID: PMC2646084  PMID: 16679098
23.  Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study 
Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.
doi:10.1152/ajpendo.00339.2006
PMCID: PMC2645662  PMID: 16968811
sex hormone-binding globulin; hormonal dysregulation; insulin-like growth factor I; androgens
24.  Low Testosterone Levels and the Risk of Anemia in Older Men and Women 
Archives of internal medicine  2006;166(13):1380-1388.
Background
Anemia is a frequent feature of male hypogonadism and anti-androgenic treatment. We hypothesized that the presence of low testosterone levels in older persons is a risk factor for anemia.
Methods
Testosterone and hemoglobin levels were measured in a representative sample of 905 persons 65 years or older without cancer, renal insufficiency, or anti-androgenic treatments. Hemoglobin levels were reassessed after 3 years.
Results
At baseline, 31 men and 57 women had anemia. Adjusting for confounders, we found that total and bioavailable testosterone levels were associated with hemoglobin levels in women (P=.001 and P=.02, respectively) and in men (P<.001 and P=.03, respectively). Men and women in the lowest quartile of total and bioavailable testosterone were more likely than those in the highest to have anemia (men, 14/99 vs 3/100; odds ratio [OR], 5.4; 95% confidence interval [CI], 1.4–21.8 for total and 16/99 vs 1/99; OR, 13.1; 95% CI, 1.5–116.9 for bioavailable testosterone; women, 21/129 vs 12/127; OR, 2.1; 95% CI, 0.9–5.0 for total and 24/127 vs 6/127; OR, 3.4; 95% CI, 1.2–9.4 for bioavailable testosterone). Among nonanemic participants and independent of confounders, men and women with low vs normal total and bioavailable testosterone levels had a significantly higher risk of developing anemia at 3-year follow-up (21/167 vs 28/444; relative risk, 2.1; 95% CI, 1.1–4.1 for total and 26/143 vs 23/468; relative risk, 3.9; 95% CI, 1.9–7.8 for bioavailable testosterone).
Conclusion
Older men and women with low testosterone levels have a higher risk of anemia.
doi:10.1001/archinte.166.13.1380
PMCID: PMC2645631  PMID: 16832003
25.  The association of urinary cadmium with sex steroid hormone concentrations in a general population sample of US adult men 
BMC Public Health  2008;8:72.
Background
Studies investigating the association of cadmium and sex steroid hormones in men have been inconsistent, but previous studies were relatively small.
Methods
In a nationally representative sample of 1,262 men participating in the morning examination session of phase I (1998–1991) of the third National Health and Nutrition Examination Survey, creatinine corrected urinary cadmium and serum concentrations of sex steroid hormones were measured following a standardized protocol.
Results
After adjustment for age and race-ethnicity, higher cadmium levels were associated with higher levels of total testosterone, total estradiol, sex hormone-binding globulin, estimated free testosterone, and estimated free estradiol (each p-trend < 0.05). After additionally adjusting for smoking status and serum cotinine, none of the hormones maintained an association with urinary cadmium (each p-trend > 0.05).
Conclusion
Urinary cadmium levels were not associated with sex steroid hormone concentrations in a large nationally representative sample of US men.
doi:10.1186/1471-2458-8-72
PMCID: PMC2267786  PMID: 18294394

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