Is a 502 Testosterone Reading High or Low for a 69 Year Old Man

J Clin Endocrinol Metab. 2008 Jan; 93(i): 68–75.

Low Serum Testosterone and Mortality in Older Men

Received 2007 Aug 10; Accustomed 2007 Sep 24.

Abstruse

Context: Declining testosterone levels in elderly men are idea to underlie many of the symptoms and diseases of aging; however, studies demonstrating associations of low testosterone with clinical outcomes are few.

Objective: The objective of the report was to examine the association of endogenous testosterone levels with mortality in older customs-dwelling men.

Design, Setting, and Participants: This was a prospective, population-based study of 794 men, aged 50–91 (median 73.6) yr who had serum testosterone measurements at baseline (1984–1987) and were followed for mortality through July 2004.

Master Issue Measure: All-cause mortality by serum testosterone level was measured.

Results: During an average xi.viii-yr follow-upwards, 538 deaths occurred. Men whose total testosterone levels were in the everyman quartile (<241 ng/dl) were xl% [hazards ratio (HR) one.40; 95% conviction interval (CI) 1.14–one.71] more likely to die than those with higher levels, independent of historic period, adiposity, and lifestyle. Additional adjustment for wellness status markers, lipids, lipoproteins, blood pressure level, glycemia, adipocytokines, and estradiol levels had minimal effect on results. The low testosterone-mortality association was likewise independent of the metabolic syndrome, diabetes, and prevalent cardiovascular disease just was adulterate by aligning for IL-6 and C-reactive poly peptide. In cause-specific analyses, low testosterone predicted increased risk of cardiovascular (Hr i.38; 95% CI i.02–1.85) and respiratory disease (HR ii.29; 95% CI 1.25–4.xx) mortality merely was not significantly related to cancer expiry (Hr 1.34; 95% CI 0.89–2.00). Results were similar for bioavailable testosterone.

Conclusions: Testosterone insufficiency in older men is associated with increased adventure of expiry over the following 20 yr, contained of multiple risk factors and several preexisting health weather condition.

In dissimilarity to the dramatic fall in estrogen levels at the time of menopause in women, testosterone concentrations in men turn down gradually with crumbling. Many agin aspects of male person aging have been attributed to the decrease in endogenous testosterone, stimulating a surge of interest in testosterone therapy for eye-aged and older men. Testosterone sales in the United States increased 20-fold during the 1990s (1). However, solid evidence linking testosterone insufficiency to health-related outcomes in older men is just beginning to emerge, and fifty-fifty less information is available on testosterone and bloodshed.

Approximately 30% of men sixty yr old and older are estimated to have depression testosterone (2), which is ofttimes accompanied by undesirable signs and symptoms such equally low bone and muscle mass; increased fat mass (especially fundamental adiposity); low energy; and impaired physical, sexual, and cerebral function. That these complaints have clinical consequences is supported by prospective cohort studies showing that men with depression testosterone are at increased gamble of falls (3); hip fracture (if estradiol is besides low) (4); anemia (5); blazon 2 diabetes (half-dozen); depressive illness (seven); and, in some studies, Alzheimer'due south disease (8,nine). Whether these associations interpret into reduced survival is less clear.

A minor study of men living in a geriatric rehabilitation unit found that those with low testosterone had increased 6-month mortality, compared with men of the same age, and medical morbidity whose testosterone levels were normal (10). Low testosterone levels were besides associated with increased bloodshed over the post-obit 8 year in a larger retrospective study of male veterans who attended a infirmary dispensary (11). However, the men in these studies were in poor wellness, and acute affliction is known to reduce testosterone production (12). Ii recent population-based studies of comparatively healthy men with longer follow-up (15–16 year) did non find an association of testosterone with survival (xiii,14). Nonetheless, the men in these studies were relatively young at baseline (mean historic period early 50s) and the survival effects of testosterone insufficiency may only be apparent late in the lifespan.

Nosotros report here the association of serum testosterone with all cause and cause-specific mortality among 794 customs-dwelling older men from the Rancho Bernardo Report whose average age was 72 year at baseline and who were followed for twenty twelvemonth.

Subjects and Methods

Study population

The Rancho Bernardo Study is a population-based study of salubrious aging in Caucasian residents of a Southern California customs. Between 1984 and 1987, 82% (due north = 1060) of surviving community-abode older male person participants attended a research clinic visit. During this visit, information regarding medical history, medication utilise, concrete action (practise 3+ times per week, yes/no), alcohol consumption (ane+drinks/day vs. less or none), and current smoking (yes/no) was obtained using standard questionnaires. Electric current medication use was validated by exam of pills and prescriptions brought to the dispensary for that purpose. The study protocol was canonical by the Institutional Review Board of the University of California, San Diego. All participants gave written informed consent.

Of the 1060 men who attended the 1984–1987 clinic visit, 885 (84%) had sufficient stored sera for measurement of testosterone and other sexual activity hormones. Xx men were excluded for testosterone levels suggestive of surgical or biochemical castration (<ninety ng/dl), 53 decedents considering death certificates accept not been obtained, and 18 for loss to follow-up. The remaining 794 men (75% of the original cohort) are the subject of this written report. Compared with those without hormone assays, men with testosterone measurements were slightly younger and less likely to have diabetes just did not differ in terms of weight, trunk mass alphabetize (BMI), waist girth, lifestyle characteristics, or known heart disease.

Clinical measurements

Height, weight, and waist and hip girth were measured in the clinic with participants wearing calorie-free vesture and no shoes. BMI (kilograms per square meter) and waist to hip ratio were used as estimates of overall and fundamental adiposity. Systolic claret pressure was measured twice in seated resting subjects using the Hypertension Detection and Follow–upwardly Program protocol (15); the mean of ii readings was used in analyses. Weight change, an indicator of wellness status, was determined by subtracting the participant'south weight at the 1984–1987 visit from that obtained at a 1972–1974 visit (99% of participants).

Claret samples were obtained past venipuncture between 0730 and 1100 h later on a requested 12-h fast; serum and plasma were separated and frozen at −70 C until get-go thawed for sexual practice hormone assays in 1992–1994. Hormone levels were measured in the Academy of California, San Diego, endocrinology research laboratory of South. S. C. Yen. Full testosterone and estradiol levels were measured by RIA after solvent extraction and celite column chromatography; procedural losses were monitored by improver of tritiated standard to each sample before the extraction stride. Bioavailable testosterone and estradiol (the non-SHBG jump fractions) were measured by an accommodation of the Tremblay and Dube ammonium-sulfate precipitation method (16). In 2000, plasma C-reactive protein (CRP) and IL-6 were measured on a subset of 614 participants in a university laboratory past an automated, high-sensitivity method (N Latex CRP mono; Dade Behring, Deerfield, IL; sensitivity: 0.2 mg/liter) and a high sensitivity (0.094 pg/ml) ELISA with an alkaline phosphatase signal amplification arrangement (Quantikine HS, human IL-half dozen immunoassay; R&D Systems, Minneapolis, MN), respectively. In 2004 adiponectin and leptin levels were measured by RIA on twice-thawed serum samples at Linco Diagnostics Laboratory (St. Louis, MO). The sensitivity and intra- and interassay coefficients of variation, respectively, were 3 pg/ml and 6 and 7% for estradiol; 3 pg/ml × percentage gratuitous and 6 and 8% for bioavailable estradiol; 20 pg/ml and 4 and five% for testosterone; 20 pg/ml × percentage free and 7%, and 11% for bioavailable testosterone; 0·viii mg/liter and half-dozen% and 7% for adiponectin; and 0·v ng/ml and four% and 5% for leptin. Adiponectin, leptin and sex hormone levels did not vary past years of frozen sample storage.

Fasting plasma full, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, and triglyceride levels were measured in a Centers for Disease Control and Prevention Certified Lipid Research Clinic Laboratory. Full cholesterol and triglyceride levels were measured by enzymatic techniques using an ABA-200 biochromatic analyzer (Abbott Laboratories, Irving, TX). HDL was measured afterwards precipitation of the other lipoproteins with heparin and manganese chloride. LDL was estimated using the Friedewald formula (17). Plasma glucose levels were measured by the glucose oxidase method, plasma insulin by double-antibiotic RIA, and serum creatinine by the Jaffe reaction method. Homeostasis model cess for insulin resistance (HOMA-IR) was used to estimate insulin resistance according to the formula: insulin (milliunits per liter) × glucose (millimoles per liter)]/22.v.

Prevalent conditions and mortality assessment

Information on diabetes and cardiovascular disease (CVD) history was obtained using standard interview questionnaires. Prevalent CVD included angina [by physician diagnosis, Rose questionnaire (18), or angina medication employ], doctor-diagnosed myocardial infarction, cardiac revascularization, congestive heart failure, stroke or transient ischemic attack, carotid surgery, peripheral arterial surgery, or physician-diagnosed intermittent claudication. Diabetes was defined past md diagnosis, fasting plasma glucose 7.0 mmol/liter or greater (126 mg/dl), 2-h postchallenge glucose 11.i mmol/liter or greater (200 mg/dl), or use of diabetes medication (19). The metabolic syndrome was divers using 2002 National Cholesterol Teaching Program Developed Treatment Panel Three criteria (20). Hypertension was defined every bit blood pressure 130/85 mm Hg or greater or use of antihypertensive medication.

Participants were followed through July 2004 by annual mailers and periodic dispensary visits. Vital condition was known for 98% of participants. Death certificates, obtained for 92% of decedents, were classified for underlying crusade of death by a certified nosologist using the International Classification of Diseases, Ninth Revision. CVD deaths included codes 401–448, cancer deaths codes 140–208, and respiratory disease deaths codes 460–519.

Statistical analysis

Sex hormone, HDL cholesterol, triglycerides, HOMA-IR, IL-half-dozen, CRP, leptin, and adiponectin levels were non normally distributed and were natural log transformed for analyses; reported values are geometric means and interquartile ranges. The age-adjusted association of testosterone with baseline characteristics was assessed by partial Pearson correlations for continuous variables and comparison testosterone levels for those with and without each dichotomous characteristic using ANOVA.

The association betwixt baseline testosterone levels and all-crusade bloodshed was determined using Cox proportional hazards regressions; goodness of fit was confirmed by the method by May and Hosmer (21). Total and bioavailable testosterone levels were examined as quartiles based on the entire population and as dichotomous variables comparison the lowest quartile to all higher. Total testosterone was further examined as deciles to determine the optimal level. Three separate regression models were evaluated in mortality analyses: the first adjusted for age, the second added adjustment for BMI and waist to hip ratio, the tertiary added adjustment for lifestyle factors including physical activity (3+ times per week, yeah/no), alcohol utilize (1+ drinks/d vs. less or none), and current smoking addiction (yes/no). Secondary models added adjustment for testosterone covariates and potential biological mediators. There was no multicollinearity between independent variables in these models, and no significant interactions were found. The proportional odds assumption, assessed visually using log minus log plots, was met by all models.

All P presented are ii tailed; P ≤ 0.05 was considered statistically significant. Data were analyzed using SAS (version 9.i; SAS Constitute, Cary, NC) and SPSS (version xv.0; SPSS Inc., Chicago, IL).

Results

Baseline characteristics are shown in Tables i and 2 . The median age of these 794 men was 73.8 yr (range 50–91), ten% had a BMI greater than thirty kg/m², and 15% met Adult Handling Panel III criteria for central obesity (waist girth > 102 cm). Simply xi% reported current smoking, half consumed at least one alcohol potable daily, and 84% reported exercising 3 or more times per week. The median full testosterone level was 300 ng/dl, and 27% of values were beneath the lower limit (246 ng/dl) of the reference range for young men for the assay used in this study. The median bioavailable testosterone level was 96 ng/dl (no reference range is bachelor).

Table 1

Baseline characteristics and age-adjusted correlations with full testosterone (total T) and bioavailable testosterone (BioT) levels

	Hateful	Interquartile range	Total T R^a	BioT R^a
Age, yr	71.ii	63.half dozen–78.9	0.06	−0.46^b
Anthropomorphic parameters
Weight, kg	78.0	70.3–84.eight	−0.28^b	−0.xi^c
BMI, kg/mⁱⁱ	25.vii	23.5–27.4	−0.28^b	−0.07^d
Waist to hip ratio	0.91	0.88–0.94	−0.20^b	−0.05
Cardiovascular risk factors
Heart rate	60.9	54–67	−0.04	−0.03
SBP, mm Hg	139.7	126–151	−0.11^c	−0.02
DBP, mm Hg	78.two	72–84	−0.13^b	0.01
Fasting glucose, mg/dl^eastward	102.1	93–109	−0.14^c	0.02
Fasting insulin, mIU/ml^e,^f	12.0	8.2–16.0	−0.25^b	−0.10^d
HOMA-IR^{due east},^f,^thou	ii.97	2.ane–4.2	−0.27^b	−0.09^d
Cholesterol, mg/dl
Total	210.v	186–235	−0.01	0.05
LDL	133.1	111–155	0.07	0.09^d
HDL^e	51.2	43–60	0.23^b	0.03
Triglycerides, mg/dl^{due east}	105.6	71–148	−0.35^b	−0.04
Biomarkers
CRP, mg/liter^e,^h	ane.78	0.9–3.4	−0.21^b	−0.12^c
IL-six, mg/liter^{due east},^h	2.63	1.7–three.nine	−0.14^c	−0.13^c
Adiponectin, mg/liter^e	9.72	6.eight–fourteen.6	0.29^b	−0.01
Leptin, μg/liter^east	half dozen.22	iv.1–nine.0	−0.32^b	−0.10^c
Serum creatinine, mg/dl^eastward	1.22	1.1–ane.4	−0.04	0.03
Sex hormones
Testosterone, ng/dl^e	300	242–371		0.53^b
Biotestosterone, pg/ml^e	94	78–116	0.53^b
Estradiol, pg/ml^e	xix	16–24	0.l^b	0.35^b
Bioestradiol, pg/ml^east	12	10–16	0.25^b	0.52^b

Table 2

Age-adapted total and bioavailable testosterone levels in men with and without selected lifestyle variables, health status markers, and prevalent weather condition

	Prevalence, %	Total T with/without (ng/dl)	British indian ocean territory with/without (ng/dl)
Lifestyle
Electric current smoking	11	316 / 296	96 / 94
Alcohol use, ≥ane drinks/d	51	291 / 306^a	94 / 93
Exercise, ≥3 times/wk	85	299 / 294	95 / 91
Health status markers
x-yr weight loss ≥ 10 lb	23	311 / 294^a	90 / 95^a
10-yr weight gain ≥ 10 lb	17	262 / 306^b	91 / 95
Ii or more than medico visits in past year	69	292 / 311^a	93 / 96
Two or more than current medications	31	287 / 303^a	93 / 94
Prevalent atmospheric condition
Hypertension	75	292 / 317^b	94 / 93
Metabolic syndrome	18	244 / 311^c	90 / 95
Diabetes	15	284 / 300	95 / 94
CVD	35	298 / 302	93 / 95

Testosterone and baseline characteristics

The associations of testosterone levels with baseline characteristics, lifestyle variables, health status markers, and prevalent conditions are presented in Tables 1 and 2 . In these elderly men, bioavailable, but not full, testosterone levels were inversely related to age. Nevertheless, after adjusting for age, total testosterone levels were associated with more risk factors than bioavailable testosterone and the association was more often than not stronger. Total testosterone was inversely associated with weight, BMI, waist to hip ratio, systolic and diastolic blood pressure, fasting plasma glucose and serum insulin, HOMA-IR, triglycerides, CRP and leptin levels and positively related to HDL cholesterol and adiponectin levels (all P < 0.01).

Full testosterone did not differ by smoking addiction or exercise just was slightly lower among men who consumed at least one booze drink daily, compared with those who drank less or not at all (P < 0.05). Levels of full testosterone were higher in men who had lost 10 or more pounds in the past ten yr (P < 0.05) and lower in men who had gained at least x pounds (P < 0.001), those who reported 2 or more visits to the doctor in the by year (P < 0.05), and men who were taking 2 or more medications (P < 0.05). Total testosterone did not differ significantly for men with or without CVD or diabetes just was 8% lower for men who had hypertension and 22% lower for men who had the metabolic syndrome, compared with those who did non (both P < 0.001). Bioavailable testosterone levels were modestly lower in men who had lost weight (P < 0.05) but did not differ by other categorical variables.

Testosterone and mortality

During an boilerplate xi.eight-yr follow-up, 538 deaths occurred, a mortality rate of 57.5 per 1000 person-years. In historic period-adjusted analyses, the run a risk of decease was significantly elevated for men in the lowest quartile of the total and bioavailable testosterone distributions, compared with those in the highest quartiles, but did not differ significantly for men in the 2nd and third quartiles (Table 3 ). In a model adjusting for historic period, adiposity, and lifestyle choices, the risk of death was 44% higher [hazards ratio (Hr) 1.44, 95% confidence interval (CI) 1.12, ane.84)] for men in the lowest quartile of total testosterone relative to the highest, with similar results for bioavailable testosterone (60 minutes 1.50, 95% CI 1.15, 1.96) (Table 3 ).

Table 3

HRs of total testosterone and bioavailable testosterone for all-cause mortality

Hormone quartile	Median hormone level (ng/dl)	Model 1 Hr (95% CI)^a	Model 2 HR (95% CI)^b	Model 3 60 minutes (95% CI)^c
Testosterone (ng/dl)
Q4 (>370)	436	one.0 (ref)	1.0 (ref)	1.0 (ref)
Q3 (300–370)	331	0.90 (0.71, 1.15)	0.95 (0.74, 1.21)	0.93 (0.73, 1.xix)
Q2 (241–299)	273	one.04 (0.82, 1.32)	i.14 (0.89, ane.45)	ane.xv (0.90, 1.47)
Q1 (<241)	204	ane.29 (one.02, 1.64)	1.42 (ane.11, 1.82)	1.44 (1.12, 1.84)
P_Tendency		0.026	0.003	0.002
Bioavailable T (ng/dl)
Q4 (>117)	135	1.0 (ref)	1.0 (ref)	1.0 (ref)
Q3 (96–117)	105	0.93 (0.71, 1.22)	0.96 (0.73, 1.27)	0.94 (0.72, i.24)
Q2 (78–95)	87	i.11 (0.85, one.44)	1.17 (0.89, 1.53)	1.sixteen (0.89, 1.52)
Q1 (<78)	65	one.46 (ane.12, 1.89)	ane.52 (1.17, 1.99)	one.50 (ane.15, i.96)
P_Tendency		0.001	<0.001	<0.001

Examination of the association of total testosterone with all-cause mortality by testosterone decile indicated that for men with levels below the median (300 ng/dl), progressively lower levels were associated with a footstep-wise increase in the risk of death and that there was no boosted survival benefit for men in the 4 highest testosterone deciles, compared with those with midrange levels (Fig. i ).

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All-cause mortality according to deciles of total testosterone adjusting for historic period, BMI, waist to hip ratio, current smoking, alcohol utilise, and exercise. The squares correspond point estimates for HRs, the lines indicate 95% CIs. The median full testosterone values for deciles ane–10 were 171, 209, 241, 266, 288, 314, 338, 370, 422, and 507 ng/dl, respectively.

The influence of testosterone covariates and potential biological mediators was examined past adding variables one by one and in combination to the basic model (historic period, adiposity, and lifestyle adjusted) and comparing men in the lowest testosterone quartile with those with higher values (Table 4 ). The forcefulness of the associations of depression total and depression bioavailable testosterone with increased bloodshed risk was essentially unchanged later boosted adjustment for prevalent diabetes, CVD, or the metabolic syndrome or past exclusion of those with these weather condition. Improver of a combination of health status markers, HOMA-IR or adiponectin and leptin, also failed to influence results, equally did adjustment for estradiol or bioavailable estradiol levels. Adjustment for the inflammatory markers IL-half dozen and CRP attenuated the mortality clan with low testosterone levels using either total or bioavailable measures. In analyses stratified past CRP level, the HR (95% CI) for low full testosterone was 0.78 (0.52, ane.15) for the 174 men (n = 125 deaths) with CRP 3 mg/dl or greater and 1.66 (one.23, ii.24) for the 440 men (n = 256 deaths) with lower CRP (P for interaction =.021).

Table 4

HRs of low full testosterone and low bioavailable testosterone for all-cause mortality adjusting for (or excluding) potential covariates and mediators

	Depression T 60 minutes (95% CI)	Low BioT 60 minutes (95% CI)
Everyman quartile vs. higher^a	1.40 (i.14, 1.71)	1.44 (ane.19, 1.74)
Plus hypertension^b	1.39 (1.14, ane.70)	one.45 (1.19, 1.75)
Plus diabetes	1.37 (ane.12, 1.69)	1.47 (one.21, 1.79)
Plus CVD	one.35 (1.eleven, 1.64)	1.44 (1.19, ane.75)
Plus metabolic syndrome	one.30 (i.06, one.61)	ane.45 (i.19, 1.76)
Plus wellness status markers^c	i.36 (1.10, 1.67)	1.57 (1.29, 1.92)
Plus HOMA-IR^d	1.41 (1.08, i.85)	1.61 (one.24, 2.10)
Plus adiponectin, leptin	1.43 (1.xvi, 1.77)	1.45 (i.twenty, 1.77)
Plus CRP, IL-six^e	1.27 (0.96, i.57)	1.23 (0.96, 1.58)
Plus estradiol	1.35 (1.08, one.68)	1.40 (1.15, 1.lxx)
Plus bioavailable estradiol	one.34 (1.09, one.66)	1.39 (1.12, 1.71)
Excluding prevalent:
Diabetes (n = 116)	1.45 (1.xv, 1.82)	1.34 (one.09, 1.66)
CVD (north = 274)	1.39 (one.09, one.77)	1.40 (1.12, 1.76)
Metabolic syndrome (n = 140)	i.43 (1.12, 1.83)	ane.32 (1.06, 1.64)

In age-, adiposity-, and lifestyle-adjusted analyses of cause-specific bloodshed, low total and bioavailable testosterone were each significantly associated with elevated 20-yr take a chance of CVD bloodshed and decease due to respiratory affliction simply not with cancer death or death due to other causes (Table 5 ). The clan of low testosterone with all-crusade, CVD, and respiratory affliction mortality remained meaning after excluding deaths that occurred during the first 5 year of follow-upwardly.

Table 5

HRs of low full testosterone and low bioavailable testosterone for cause-specific mortality by years of follow-up

Cause of death	0–20 yr follow-up		v–20 yr follow-up
Cause of death	due north	Hr (95% CI)	n	60 minutes (95% CI)
Low total testosterone^a
All-cause	529	i.38 (one.12, 1.69)	409	1.60 (one.27, ii.02)
CVD	264	1.38 (1.02, 1.85)	199	1.73 (one.23, ii.45)
Cancer	127	1.34 (0.89, two.00)	90	one.22 (0.75, 1.99)
Respiratory disease	54	ii.29 (1.25, iv.20)	46	2.67 (1.37, v.xx)
Other	96	ane.xiii (0.68, 1.88)	83	1.51 (0.89, two.56)
Low biotestosterone^b
All-crusade	529	ane.44 (1.19, i.74)	409	ane.44 (1.16, 1.fourscore)
CVD	264	i.36 (one.04, i.79)	199	1.39 (1.01, 1.92)
Cancer	127	1.50 (0.99, ii.26)	xc	1.38 (0.82, 2.31)
Respiratory disease	54	1.84 (1.03, 3.28)	46	1.65 (0.86, three.14)
Other	96	1.43 (0.91, 2.24)	83	1.56 (0.96, ii.53)

Word

To our knowledge, this is the first prospective population-based written report to testify that depression serum testosterone is associated with increased risk of decease in older community-dwelling men. Men with total testosterone levels below the 25th percentile for this population (241 ng/dl) had twoscore% higher risk of death over the post-obit 20 yr, compared with men with higher endogenous testosterone, independent of age, obesity, and lifestyle choices. These results were like for the bioavailable fraction of testosterone and were not explained by overall health condition.

Testicular office is suppressed in many acute and chronic illnesses, resulting in reduced serum testosterone (12). Low testosterone has been reported in type 2 diabetes, chronic obstructive pulmonary disease, alcoholic liver illness, and chronic renal disease (12). In improver, several cohort studies (22), including this one, accept observed lower testosterone in men with the metabolic syndrome, and as many as one in four men with coronary middle disease has testosterone levels in the hypogonadal range (23). Low testosterone could be a marking of preexisting affliction and not an independent risk factor for decease. However, exclusion of men with diabetes, the metabolic syndrome, or cardiovascular disease had negligible consequence on the association of low testosterone with all-cause mortality in this study. Furthermore, the take a chance estimates for full testosterone were stronger for cardiovascular and respiratory deaths when deaths that occurred during the commencement 5 year of follow-up were excluded, suggesting that the testosterone-mortality association is not explained by concurrent disease, whether known or hidden.

Inquiry suggests a function for metabolic effects of androgen deficiency in the link betwixt low testosterone and mortality. Nosotros, and others, have shown that low testosterone precedes the development of central obesity (24,25), the metabolic syndrome (26,27), and diabetes (6,27,28) over the following 10–15 yr in nonobese men without these conditions at baseline. In this study, lower full testosterone levels were associated with central obesity and established CVD chance factors including insulin and insulin resistance, glycemia, lipid profile, and blood pressure level besides every bit emerging risk factors such as leptin, adiponectin, IL-6, and CRP. In intervention studies, testosterone therapy improves, and testosterone ablation worsens, central obesity and many of these biomarkers (29), evidence for a causal association. Adjustment for most of these factors had minimal effect on the association of low testosterone with increased mortality. Although a subset analysis suggested some arbitration by inflammatory processes, low testosterone was non associated with bloodshed in men with elevated levels of CRP. Withal, the strong association of androgen deficiency with central obesity and obesity-related factors remains a plausible pathway through which testosterone influences the development of disease and subsequent mortality.

These results differ from those in other prospective studies of testosterone and mortality in relatively healthy community-dwelling house men. Testosterone levels were non associated with all-cause bloodshed in either the Caerphilly Study (13) of 2512 men or the Massachusetts Male Crumbling Study (MMAS) (14) of 1686 men. The mean elapsing of follow-up in those studies (sixteen.five and xv.3 year, respectively) was somewhat longer than ours (12.4 yr), but the proportion dying was much lower (19 and 31%, respectively, vs. 68% for Rancho Bernardo men), reflecting the well-nigh 20 year older average historic period of men in the Rancho Bernardo Report. The absent-minded clan in the earlier studies may reflect other population differences or hormone assay differences, or the importance of low testosterone for survival may go increasingly important as men age.

The observed depression testosterone-mortality association was not specific to a single etiology. Afterwards excluding the first v yr of follow-upward (to minimize reverse causality by comorbidity), testosterone was strongly associated with deaths due to cardiovascular and respiratory disease. An clan of low testosterone with respiratory illness mortality was as well reported past the MMAS (xiv). Unlike the nowadays study, the association in MMAS was observed only with calculated complimentary testosterone and not with total testosterone. In Rancho Bernardo, measured bioavailable testosterone, which includes both the albumin-bound and free testosterone fractions, was significantly associated with respiratory disease death as well every bit with all-cause mortality; costless testosterone was not assayed.

The prevalence of hypogonadism in male populations is non known with certainty, in part due to a lack of consensus on the threshold that should be used to define testosterone insufficiency. Some investigators recommend a total testosterone less than 300 ng/dl; others advocate cutting points of 250 or even 200 ng/dl (29). The median testosterone level for the nowadays study (300 ng/dl) was lower than that reported for ii population-based cohorts of men of like age: the Osteoporotic Fractures in Men study of men 65 twelvemonth quondam and older reported a mean total testosterone level of 423 ng/dl (xxx), and the Health in Men study of men aged 70 yr and older reported a hateful of 444 ng/dl (31). Lower testosterone levels in our written report are likely due to differences in assay methods: both the Osteoporotic Fractures in Men and Wellness in Men studies measured testosterone using straight assays, whereas the RIA used in this report was preceded by ii purification steps (organic solvent extraction and celite column chromatography), minimizing cross-reactivity with interfering substances (32).

Based on the lower overall mean testosterone, it could be argued that our cut point of 241 ng/dl was too high and overestimates the prevalence of depression testosterone. Nonetheless, the 25% of men with values beneath this threshold were at a 40% increased take chances of death over the following xx yr, suggesting that a sizable proportion of older community-dwelling men may take clinically significant testosterone insufficiency. In a sensitivity analysis, lowering the threshold to 200 ng/dl reduced the proportion of men with depression testosterone to 12% and increased the excess mortality risk to 45% (P = 0.007). Information technology should exist noted that use of these thresholds is arbitrary. There is no current consensus on what constitutes a testosterone insufficient state in older men, or indeed, if one even exists.

There is ongoing debate over the risk-benefit potential of testosterone therapy for men who are not conspicuously hypogonadal (33,34). Results of the present written report propose that raising circulating testosterone levels in a higher place 300 ng/dl (the median for this population) offers no boosted benefit, at least in terms of survival. This, plus the express availability of information on safety of testosterone replacement, argues against a recommendation for testosterone supplementation to starting time effects of male aging in men without documented androgen deficiency.

The nowadays written report has some limitations. Results were based on an almost entirely Caucasian eye- to upper-center-course community and may non apply to other indigenous and socioeconomic groups. Repeat sampling of men with an initially low testosterone level is recommended to confirm androgen deficiency (35), merely this and other epidemiological studies were based on a single measurement of testosterone. All the same, misclassification of men with low testosterone would exist expected to underestimate, non cause, associations. In addition, blood for testosterone samples was obtained in the morning time from fasting men, minimizing any diurnal variation still present in this age grouping, and sampling at a single time bespeak adequately reliably reflects mean annual testosterone levels for older men (36). Although it is possible that testosterone exerts its benefit by conversion to estradiol, the addition of estradiol to these analyses did not materially alter the results, and estradiol was less strongly associated with CVD risk factors than testosterone (data non shown).

In summary, in this accomplice, older men with depression levels of circulating full testosterone had a 40% increased risk of decease over the following twenty yr, compared with men with normal testosterone, independent of age, adiposity, and lifestyle. This association was not explained by preexisting disease and was non specific to a unmarried crusade of death. Testosterone levels above the median for this population did non confer whatsoever boosted survival benefit, offering no support for widespread testosterone therapy for crumbling men. Randomized, placebo-controlled trials are necessary to determine whether physiological testosterone replacement tin can safely extend the quality and duration of life for older men with well-documented testosterone insufficiency.

Footnotes

Kickoff Published Online October 2, 2007

Abbreviations: BMI, Torso mass alphabetize; CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; Hour, hazards ratio; LDL, low-density lipoprotein; MMAS, Massachusetts Male person Crumbling Study.

This work was supported past G. A. Laughlin American Heart Association Honor 0315024Y. The Rancho Bernardo Study was funded by Research Grant AG07181 from the National Institute on Crumbling and Grant DK31801 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Disclosure Argument: M.A.50., E.B.-C., and J.B. have null to declare.

References

Bhasin Southward, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR 2003 Managing the risks of prostate illness during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. J Androl 24:299–311 [PubMed] [Google Scholar]
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR 2001 Longitudinal effects of aging on serum total and complimentary testosterone levels in salubrious men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86:724–731 [PubMed] [Google Scholar]
Orwoll E, Lambert LC, Marshall LM, Bare J, Barrett-Connor E, Cauley J, Ensrud Grand, Cummings SR 2006 Endogenous testosterone levels, concrete operation, and fall run a risk in older men. Arch Intern Med 166:2124–2131 [PubMed] [Google Scholar]
Amin S, Zhang Y, Felson DT, Sawin CT, Hannan MT, Wilson Pw, Kiel DP 2006 Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med 119:426–433 [PubMed] [Google Scholar]
Ferrucci L, Maggio M, Bandinelli Due south, Basaria S, Lauretani F, Ble A, Valenti G, Ershler WB, Guralnik JM, Longo DL 2006 Depression testosterone levels and the adventure of anemia in older men and women. Arch Intern Med 166:1380–1388 [PMC free commodity] [PubMed] [Google Scholar]
Ding EL, Song Y, Malik VS, Liu S 2006 Sex differences of endogenous sexual activity hormones and chance of blazon 2 diabetes: a systematic review and meta-assay. JAMA 295:1288–1299 [PubMed] [Google Scholar]
Shores MM, Sloan KL, Matsumoto AM, Moceri VM, Felker B, Kivlahan DR 2004 Increased incidence of diagnosed depressive disease in hypogonadal older men. Curvation Gen Psychiatry 61:162–167 [PubMed] [Google Scholar]
Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM 2002 Longitudinal assessment of serum free testosterone concentration predicts retentiveness performance and cognitive condition in elderly men. J Clin Endocrinol Metab 87:5001–5007 [PubMed] [Google Scholar]
Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA 2002 Low levels of endogenous androgens increase the hazard of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 87:3632–3639 [PubMed] [Google Scholar]
Shores MM, Moceri VM, Gruenewald DA, Brodkin KI, Matsumoto AM, Kivlahan DR 2004 Depression testosterone is associated with decreased function and increased bloodshed gamble: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc 52:2077–2081 [PubMed] [Google Scholar]
Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR 2006 Depression serum testosterone and mortality in male veterans. Arch Intern Med 166:1660–1665 [PubMed] [Google Scholar]
Karagiannis A, Harsoulis F 2005 Gonadal dysfunction in systemic diseases. Eur J Endocrinol 152:501–513 [PubMed] [Google Scholar]
Smith GD, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman South, Elwood P 2005 Cortisol, testosterone, and coronary center disease: prospective evidence from the Caerphilly study. Apportionment 112:332–340 [PubMed] [Google Scholar]
Araujo AB, Kupelian V, Page ST, Bremner WJ, McKinlay JB 2007 Sexual practice steroids and all-crusade and cause-specific bloodshed in men. Curvation Intern Med 167:1252–1260 [PubMed] [Google Scholar]
1976 The Hypertension Detection and Follow-Up Programme: Hypertension Detection and Follow-up Program Cooperative Group. Prev Med 5:207–215 [PubMed] [Google Scholar]
Tremblay RR, Dube JY 1974 Plasma concentrations of free and not-TeBG jump testosterone in women on oral contraceptives. Contraception 10:599–605 [PubMed] [Google Scholar]
Friedwald W, Levy R, Frederickson D 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma without apply of preparative ultracentrifuge. Clin Chem 459–502 [PubMed] [Google Scholar]
Rose G, McCartney P, Reid DD 1977 Self-administration of a questionnaire on chest hurting and intermittent claudication. Br J Prev Soc Med 31:42–48 [PMC free article] [PubMed] [Google Scholar]
1999 Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Office one: Diagnosis and classification of diabetes mellitus. Geneva: World Wellness Organization [Google Scholar]
National Cholesterol Didactics Program (NCEP) Good Console on Detection E, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel 3) 2002 Third Report of the National Cholesterol Didactics Programme (NCEP) Good Console on Detection, Evaluation, and Treatment of Loftier Blood Cholesterol in Adults (Developed Handling Panel Three) terminal report. Circulation 106:3143–3421 [PubMed] [Google Scholar]
May Due south, Hosmer DW 1998 A simplified method of calculating an overall goodness-of-fit test for the Cox proportional hazards model. Lifetime Data Anal 4:109–120 [PubMed] [Google Scholar]
Makhsida N, Shah J, Yan G, Fisch H, Shabsigh R 2005 Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol 174:827–834 [PubMed] [Google Scholar]
Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS 2005 Testosterone and atherosclerosis in aging men: purported association and clinical implications. Am J Cardiovasc Drugs v:141–154 [PubMed] [Google Scholar]
Khaw KT, Barrett-Connor E 1992 Lower endogenous androgens predict central adiposity in men. Ann Epidemiol 2:675–682 [PubMed] [Google Scholar]
Derby CA, Zilber S, Brambilla D, Morales KH, McKinlay JB 2006 Body mass alphabetize, waist circumference and waist to hip ratio and alter in sex steroid hormones: the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 65:125–131 [PubMed] [Google Scholar]
Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB 2006 Low sexual practice hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab 91:843–850 [PubMed] [Google Scholar]
Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen G, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT 2004 Testosterone and sexual practice hormone-binding globulin predict the metabolic syndrome and diabetes in center-aged men. Diabetes Care 27:1036–1041 [PubMed] [Google Scholar]
Oh JY, Barrett-Connor Due east, Wedick NM, Wingard DL 2002 Endogenous sex hormones and the development of type ii diabetes in older men and women: the Rancho Bernardo report. Diabetes Care 25:55–threescore [PubMed] [Google Scholar]
Miner MM, Seftel AD 2007 Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead? Int J Clin Pract 61:622–632 [PubMed] [Google Scholar]
Orwoll E, Lambert LC, Marshall LM, Phipps M, Blank J, Barrett-Connor E, Cauley J, Ensrud One thousand, Cummings Southward 2006 Testosterone and estradiol amidst older men. J Clin Endocrinol Metab 91:1336–1344 [PubMed] [Google Scholar]
Yeap BB, Almeida OP, Hyde Z, Norman PE, Chubb SA, Jamrozik K, Flicker L 2007 In men older than seventy years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study. Eur J Endocrinol 156:585–594 [PubMed] [Google Scholar]
Anderson DC, Hopper BR, Lasley BL, Yen SS 1976 A uncomplicated method for the analysis of 8 steroids in small volumes of plasma. Steroids 28:179–196 [PubMed] [Google Scholar]
Snyder PJ 2004 Hypogonadism in elderly men—what to exercise until the evidence comes. N Engl J Med 350:440–442 [PubMed] [Google Scholar]
Handelsman DJ 2006 Testosterone: utilise, misuse and abuse. Med J Aust 185:436–439 [PubMed] [Google Scholar]
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM 2006 Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 91:1995–2010 [PubMed] [Google Scholar]
Vermeulen A, Verdonck 1000 1992 Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. J Clin Endocrinol Metab 74:939–942 [PubMed] [Google Scholar]

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190742/