ORIGINAL ARTICLE: Accuracy of calculated free testosterone formulae in men

Background As reference laboratory methods for measuring free testosterone (FT) by equilibrium dialysis (ED) are laborious, costly and nonautomatable, FT levels are often calculated (cFT) rather than measured. However, the predictive accuracy of such estimates in routine use relative to laboratory measurements is not well defined. We provide a large‐scale evaluation of the predictive accuracy for different FT formulae compared with laboratory ED measurement and an analysis of clinical factors that may influence accuracy. Methods The accuracy of five different cFT formulae (two equilibrium binding, three empirical) based on immunoassays of total testosterone (TT) and SHBG was evaluated by comparing those estimates with FT measurement by ED in 2159 serum samples from men at a single research laboratory over several years. Results cFT formulae show systematic discrepancies from the two equilibrium‐binding formulae. One empirical formula overestimated FT relative to ED measurements, whereas two newer empirical cFT formulae were more concordant. These discrepancies persisted after correction for serum albumin and were not influenced by obesity, ethnicity or gonadal status. Conclusions Commonly used cFT formulae significantly overestimate FT relative to laboratory measurement by ED in male serum samples. The accuracy of the formulae is not influenced by correction for serum albumin, obesity, ethnicity or gonadal status. Such inaccuracy relative to the reference method renders some cFT estimates unreliable for evaluating androgen deficiency as recommended by clinical best practice guidelines.     

A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men

OBJECTIVE: In the absence of widely available measures of determining free and/or bioavailable testosterone (BioT) physicians may use formulae such as the free androgen index (FAI) to estimate free testosterone. We compared the efficacy of calculated markers of androgen status in predicting serum BioT and hypogonadism. DESIGN: Total testosterone (TT), sex hormone binding globulin (SHBG) and BioT were determined in a large cohort of men. Comparison of calculated androgen levels was performed following endocrine assessment. METHODS: TT and SHBG were determined by ELISA, and BioT was determined by ammonium sulphate precipitation. From these data we calculated FAI and free testosterone using two other published formulae - FTnw (free testosterone as calculated by the method of Nanjeee and Wheeler) and FTv (free testosterone as calculated by the method of Vermeulen). A novel formula was derived to calculate BioT from given levels of TT and SHBG (BTcalculated). The ability of the methods (FAI, FTnw, FTv, BTcalc) to predict BioT were compared using regression analysis. The ability of these markers of androgen status to predict biochemical hypogonadism was compared using area under receiver operator curve (auROC). RESULTS: The equation derived from our data was the best predictor of BioT (R(2)=0.73, P<0.0001) although TT was also a good marker (R(2)=0.68, P=0.0001). In the determination of hypogonadism, of all currently available formulae none were better that the TT (auROC: TT=0.93, FAI=0.72, FTnw=0.91, FTv=0.88) although when TT is borderline (7.5相似文献   

Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men

Objective Low circulating levels of testosterone and sex‐hormone‐binding globulin (SHBG) are associated with increased cardiovascular risk in men. This association may be partially mediated through changes in glucose metabolism, but relatively few data are available on the relationship between sex hormones and markers of long‐term glycaemia. We assessed the associations of endogenous testosterone and SHBG with glycated haemoglobin (HbA_1c) in men. Design and subjects Cross‐sectional study of 1292 men from the Norfolk population of European Prospective Investigation into Cancer (EPIC‐Norfolk). Measurements Glycated haemoglobin, total testosterone (TT) and SHBG levels were measured, and free testosterone (FT) levels were calculated. Multiple linear regression models were used to assess the associations of TT, SHBG and FT with HbA_1c. Results Men with diabetes had lower testosterone and SHBG levels. In non‐diabetic men, HbA_1c levels were inversely associated with TT and calculated FT independently of age, body mass index, smoking, alcohol consumption and physical activity. The adjusted change in HbA_1c was 0·055 (95% CI 0·025; 0·085) per standard deviation (SD) decrease in TT and 0·041 (95% CI 0·010; 0·073) per SD decrease in calculated FT, respectively. SHBG levels were inversely associated with HbA_1c after multivariable adjustment (β = 0·038 per SD decrease (95% CI 0·004; 0·071)). Conclusions In middle‐aged and older men, low endogenous testosterone and SHBG levels are associated with glycaemia, even below the threshold for diabetes. Further studies are needed to determine the effects of interventions that raise testosterone levels in men having increased HbA_1c and subnormal testosterone levels.     

Is it necessary to measure free testosterone to assess hyperandrogenemia in women? The role of calculated free and bioavailable testosterone.

Hirsutism in women is defined as excessive facial and/or body terminal hairs showing a masculine distribution; the condition affects approximately 7% of women of reproductive age, and chronic anovulation is a common problem for infertile couples, with a rate of 20-25%. There is a general consensus that these women should be evaluated endocrinologically, as many are found to have an androgen excess (AE) disorder. Free testosterone (FT) is the most prevalent marker in women with androgen excess, but the reference measurement procedures for FT are time-consuming and complex manual procedures that are not routinely practicable in large laboratories. Recently, models have been developed for calculating FT from total testosterone (TT), sex hormone binding globulin (SHBG), and albumin. These calculated values have been found to correlate closely with values estimated using the reference measurement procedures. This study compared measured endocrinological parameters--TT, free testosterone (aFT) by analogue ligand immunoassay method, dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEAS), (SHBG), And calculated parameters--calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), and the free androgen index (FAI) in hirsute women and women with polycystic ovary syndrome (PCOS)--with the values in control individuals. A modified Ferriman-Gallwey score was use to describe the hirsutism pattern. No differences were observed when the measured hormone parameters were compared, while the calculated parameters were significantly increased in women in the hirsutism and PCOS groups in comparison with the values in the control group. Calculate parameters mat be more appropriate markers for assessing hyperandrogenemia in women in comparison with measured values of simple enzyme immuno-assays. These calculated values may be capable of replacing the values estimated using reference measurement procedures, so that time-consuming and complex manual procedures for measuring free testosterone with the reference methods may be dispensable in clinical practice.     

The effect of changes in adiposity on testosterone levels in older men: longitudinal results from the Massachusetts Male Aging Study

OBJECTIVE: Changes in adiposity affecting total testosterone (TT) and free testosterone (FT) levels have not been examined in a population-based survey. We aimed to determine whether changes in adiposity predict follow-up levels and rates of change in TT, FT and sex hormone-binding globulin (SHBG) in men. DESIGN: The Massachusetts Male Aging Study is a randomly sampled, population-based cohort interviewed at baseline (T(1), 1987-1989; n = 1,709; aged 40-70 years) and followed-up approximately 9 years later (T(2), 1995-1997; n = 1,156). Men were categorized as overweight (body mass index (BMI) >or= 25 kg/m(2)) or having obesity (BMI >or= 30 kg/m(2)), waist obesity (waist circumference >or= 102 cm), or waist-to-hip ratio (WHR) obesity (WHR>0.95). For each adiposity group, we constructed four categories to represent changes between T(1) and T(2): overweight (or obese, etc.) at neither wave, T(1) only, T(2) only, or both waves. RESULTS: After adjustment for confounding variables, men who were overweight at T(2) only, or at both waves, had significantly lower mean T(2) TT and SHBG levels than men in the neither group (P<0.05). Mean FT did not differ between any overweight group and the neither group. Men who were obese at both times, had the highest mean BMI, the highest fraction of severely obese men, and significantly greater rate of decline in FT than the neither group. CONCLUSIONS: In men who become overweight, the greater rate of decline in TT, but not FT, is related mostly to a lesser age-related increase in SHBG. Since weight gain is highly prevalent in older men, over-reliance on TT levels in the diagnosis of androgen deficiency could result in substantial misclassification.     

雄激素及其受体与老年男性冠状动脉粥样硬化性心脏病的相关性研究

目的 观察老年男性冠状动脉粥样硬化性心脏病(冠心病)患者性激素及雄激素受体水平的变化及相关性. 方法 横断面调查老年男性539例,其中健康人(对照组)400例,年龄62～92岁,平均(71.4±5.2)岁;冠心病患者139例,年龄60～88岁,平均(73.6±6.4)岁.测定总睾酮、游离睾酮、脱氢表雄酮硫酸酯(DHEAS)、性激素结合球蛋白(SHBG)、雌二醇、黄体生成素(LH)、卵泡刺激素(FSH)水平,同时采用流式细胞术检测外周血雄激素受体(AR)水平. 结果 老年男性冠心病患者DHAES、总睾酮、SHBG、游离睾酮、AR荧光强度均低于对照组(均为P<0.01),而FSH、E2高于对照组(均为P<0.01).年龄与总睾酮、游离睾酮呈负相关(r分别为-0.28、-0.17,P<0.01和P<0.05);与E2、SHBG呈正相关(r分别为0.33、0.14,P<0.01和P<0.05).AR荧光强度与收缩压呈负相关(r=-0.12,P<0.01).Logistic回归分析显示,总睾酮(OR=1.065,95%CI:1.012～1.121,P<0.05)、SHBG(OR=0.994,95%CI:0.990～0.998,P<0.01)和AR(OR=0.971,95%CI:0.956～0.986,P<0.01)与老年男性冠心病相关. 结论 老年男性冠心病患者存在低水平的DHEAS、总睾酮、SHBG、游离睾酮、AR,同时存在高水平的FSH、E2;低水平总睾酮、SHBG和AR可能是老年男性冠心病独立的危险因素.     

血清性激素水平与老年男性认知功能相关性研究

目的探讨老年男性血清性激素水平与认知功能的关系。方法选取2008年12月至2009年12月间在第六人民医院老科就诊的老年患者62例采用简易智能量表（MMSE）评估认知功能,男性患者按照MMSE测定分数分为认知功能正常组（30例）与认知功能障碍组（32例）。采用化学发光法测定所有患者血清总睾酮（TT）和性激素结合球蛋白（SHBG）及雌二醇（E2）水平,并根据Vermeulen公式计算游离睾酮（FT）,比较两组患者TT、E2和FT水平的差异,并分析TT、E2、FT与老年认知功能的相关性。结果老年男性中认知功能障碍组的雌二醇[（20．88±5．10）pmol／L vs（27．00±9．61）pmol／LP〈0．05]、总睾酮[（4．52±1．88）mmol／L vs（6．42±1．84）mmol／L P〈0．05]、游离睾酮[（0．043±0．022）nmol／L vs（0．092±0．034）nmol／L P〈0．05]水平较认知功能正常组低（P〈0．05）。结论老年男性认知功能障碍可能与性激素水平下降相关。     

Evaluation of assays available to measure free testosterone

This study compared the results of various testosterone assays in a cross-sectional study of 50 male subjects age 28 to 90 years. The purpose of the study was to determine the relationship of the various testosterone assays to one another. In addition, we determined week-to-week variability in testosterone and bioavailable testosterone in 16 subjects. The following assays were undertaken: total testosterone (T), free testosterone by equilibrium dialysis (FT(D)), bioavailable testosterone (BT), free testosterone by ultracentrifugation (FT(U)), and direct estimation of serum free T by an analog ligand radioimmunoassay (FT(A)). In addition, using total T and sex hormone-binding globulin (SHBG), we calculated the free androgen index (FAI = T/SHBG) and the free testosterone index (FTI) using the method of Vermeulen. In a second study, we measured the week-to-week variation in T and BT in a group of older males. Lastly, we demonstrated excellent stability of serum stored at -70 degrees C for up to 7 years for T and BT. Correlations of the various assays to increasing age were significant for all assays except total T (r = -.126). The best correlation was found with BT (r = -.744, P <.001). All measures were statistically significantly correlated with FT. The best correlations were FTI (r =.807, P <.007) and BT (r =.670, P <.001). If T was used to classify hypogonadism in comparison to BT, it resulted in misclassification in 42% of cases. In addition, we demonstrated a marked week-to-week variability in T and BT in older men with the T and BT being in the eugonadal range some weeks and hypogonadal on other occasions. This occurred in 8 of 16 men for T and 10 of 16 men for BT. Based on these data, we suggest that the FTI or BT are the most practical methods to determine hypogonadism. There is a need for increased awareness that marked week-to-week variability within a single individual can occur for measurements of both T and BT.     

The relationship of testosterone and AR CAG repeat genotype with knee extensor muscle function of young and older men

The inter-relationship between muscle strength and serum testosterone is not fully understood, and may be confounded or influenced by age. The polymorphism of androgen receptor gene CAG number (AR CAGn) could also influence these variables. The study examined the relationship between total testosterone (TT), free testosterone (FT) and AR CAGn with the muscle strength of young (YM, 18-30 yrs, n=82) and older (OM, 60-70 yrs, n=101) Caucasian men. Knee extensor strength was measured isometrically and isokinetically, and thigh and whole-body lean mass of the OM was determined by DXA. TT and serum hormone binding globulin (SHBG) were assayed by ELISA and used to calculate FT. AR CAGn was determined using polymerase chain reaction and microchip electrophoresis. OM were weaker than YM (-20 to -29%, all P<0.001), and serum androgens were lower (TT, -13%; FT, -13%; both P<0.001). TT was unrelated to any strength measurement in YM or OM. In the OM only, FT had a weak positive association with all three strength measures (r(2)=4.1-9.3%, P<0.036) and both whole body and thigh lean mass (r(2)=6.1-8.6%; P<0.013). Muscle strength was unrelated to AR CAGn for either the YM or OM, or when data were collapsed across both age groups (age normalised strength). Lean mass in the older cohort was also independent of AR CAGn. In conclusion, FT, but not TT or AR CAGn, was positively associated with muscle strength, but only as values declined with age.     

Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Ageing Study

OBJECTIVE: Cross-sectional data suggest that obesity, particularly central obesity, may be associated with decreased production of sex steroid hormones in men. However, longitudinal hormone data on men in relation to obesity status are limited. Previous studies have not consistently demonstrated whether sex steroids are associated specifically to body mass index or to measures of central obesity. Our objective was to examine the relation of obesity (body mass index > 30 kg/m2), and of central obesity (waist circumference > 100 cm or waist to hip ratio > 0.95) to longitudinal change in sex steroid hormones in men. DESIGN: Prospective follow-up of a population-based sample of men in Boston. PATIENTS: Nine hundred forty-two (942) men in the Massachusetts Male Ageing Study with complete anthropometry and hormone data at baseline (1987-1989, ages 40-70) and follow-up (1995-1997). MEASUREMENTS: Free and total testosterone (FT and TT), dehydroepiandrosterone sulphate (DHEAS), and sex hormone-binding globulin (SHBG) were assessed using standardized methods. Health behaviours and medical history were obtained by structured interview. Repeated measures regression was used to describe trends in steroid hormones and SHBG in relation to obesity status, adjusting for age, smoking, alcohol, comorbidities, and physical activity. RESULTS: Obesity was associated with decreased levels of total and free testosterone, and of SHBG at follow-up relative to baseline. For any given baseline concentration of TT, FT or SHBG, follow-up levels were lowest among men who remained obese or who became obese during follow-up. This was true for all three indices of obesity. Central adiposity was associated with lower DHEAS levels at follow-up, while elevated body mass index was not. CONCLUSIONS: Obesity may predict greater decline in testosterone and SHBG levels with age. Central adiposity may be a more important predictor of decline in DHEAS than is body mass index.     

Sex steroids and mortality in men referred for coronary angiography

Objective Accumulating evidence suggests that sex steroids are associated with various chronic diseases. We aimed at evaluating whether total testosterone (TT), free testosterone (FT) and sex hormone–binding globulin (SHBG) are associated with all‐cause mortality and specific fatal events. Design, Setting and Participants We measured TT and SHBG levels in 2078 men who were routinely referred for coronary angiography (1997–2000). FT was calculated according to Vermeulen. Measurements The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non‐cardiovascular causes and from cancer according to SHBG, FT and TT. Results Multivariable‐adjusted HRs (with 95% confidence intervals) in the fourth compared to the first SHBG quartile for all‐cause, non‐cardiovascular and cancer mortality were 1·61 (1·16–2·23), 2·44 (1·39–4·28), and 2·86 (1·03–7·32), respectively. There was no significant association of SHBG levels with cardiovascular mortality. All‐cause mortality was significantly reduced per 1 SD increase in FT in the multivariate‐adjusted analyses [0·49 (0·30–0·81)]. We observed no significant associations of FT with cardiovascular and cancer mortality, and TT levels were not independently related to any fatal events. Conclusion High levels of SHBG are associated with adverse health outcomes in a large cohort of older men referred for coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms for our findings.     

年龄依赖性胰岛素抵抗与睾酮水平的相关性

目的探讨健康男性年龄对胰岛素抵抗的影响和胰岛素抵抗与睾酮的关系。方法在北京、上海、西安和重庆四城市调查20～78岁健康男性1080例,同时测定空腹血糖、胰岛素、总睾酮、雌二醇、黄体生成激素(LH)、卵泡刺激激素(FSH)和性激素结合球蛋白(SHBG),计算稳态模型胰岛素抵抗指数(HOMA-IR)、游离睾酮(cFT)、睾酮分泌指数(TSI)和游离睾酮指数(FTI),将空腹血糖、胰岛素和HOMA-IR与其他检验结果进行相关分析。结果空腹血糖、胰岛素和HOMA-IR与年龄(r=0.1644、0.1536和0.1587;均为P<0.01)、LH(r=0.1909、0.1310和0.1920;均为P<0.01)和FSH(r=0.1 704、0.1543和0.1907;均为P<0.01)呈显著正相关,与总睾酮(r=-0.0825、-0.2187和-0.1619;P>0.05、P<0.01和P<0.01)、cFT(r=0.1238、-0.1 567和-0.1346;P<0.01、P<0.01和P<0.05)和TSI(r=-0.2143、-0.2098和-0.2488;均为P<0.01)呈显著负相关。结论健康男性随年龄增长伴有空腹血糖、胰岛素和HOMA-IR的逐渐升高,年龄依赖性雄激素水平降低对这种胰岛素抵抗的变化可能起着重要作用。     

Interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men

CONTEXT: Reduced testosterone levels have been implicated as a potential causative factor in cognitive decline with older age. Men who possess the apolipoprotein E (APOE) epsilon4 allele have an increased risk of developing Alzheimer's disease; however, no studies have examined whether the influence of testosterone on cognition in healthy older men may be modulated by this genetic predisposition. OBJECTIVE: The objective of the study was to investigate the association between serum testosterone concentrations and cognitive performance in healthy older men, taking into account APOE epsilon4 status. DESIGN: This was a cross-sectional study conducted from 2003 to 2004. SETTING: The study population consisted of community-dwelling males residing in Perth, Western Australia. PARTICIPANTS: Healthy men over 55 yr, free of cognitive impairment and dementia (n = 45), were included in the study. MAIN OUTCOME MEASURES: Participants had fasting early morning blood samples for testosterone and SHBG and were assessed for mood as well as indices of general cognition, verbal and visual memory, executive functioning, working memory, and attention. RESULTS: There was a significant interaction between calculated free testosterone (FT) and APOE epsilon4 on general cognition (P = 0.01) and executive functioning, working memory, and attention (P < 0.01). Higher levels of FT were associated with better general cognition in non-epsilon4 carriers (P = 0.01). By contrast, in epsilon4 carriers higher FT levels were associated with lower scores on tests of executive functioning, working memory, and attention (P = 0.02). In men at increased risk for Alzheimer's disease, higher testosterone levels were not associated with better cognitive function. CONCLUSIONS: Cross-sectional and prospective studies of testosterone and cognition in older men should take into account APOE epsilon4 status.     

Relationship of level of sex hormone and sex hormone receptor with development of metabolic syndrome in elderly men

Objective The sex hormone and the corresponding receptor may play some roles in the development of the metabolic syndrome （MS） in the elderly men. This study was designed to examine the relationship of level of the sex hormone and androgen receptor with MS in elderly men, thus to investigate the possible pathogenesis of MS. Methods This cross sectional study enrolled 587 elderly men, including 400 healthy controlls aged 62-92 years and 187 MS patients aged 60-87 years in Wan Shou Lu area of Beijing city. Dehydroepiandrosterone sulfate （DHAE-S）, total testosterone （TT）, sex hormone binding globulin （SHBG）, free testosterone （FT）, follicle-stimulating hormone （FSH）,Estradiol （E2）,luteinizing hormone（LH） and androgen receptor （AR） in blood were tested. Statistical analyses included the comparison analysis of variables and independent variables, correlation analysis using multi-factor linear regression, and multiple logistic regression analysis. Results DHAE-S, TT, SHBG, FT and AR fluorescence intensity in healthy control group were higher than those in MS group, however, FSH and E2 levels were lower in healthy group. Age was negatively correlated with diastolic blood pressure （DBP） and FT, but positively correlated with systolic blood pressure （SBP） and E2. AR fluorescence intensity was negatively correlated with SBP and LH. The logistic regression equation showed the negative correlation between DHEA-S, SHBG and the development of MS. Conclusions There are low levels of DHEA-S, TT, SHBG, FT and AR in the elderly patients with MS. On the contrary, FSH and E2 concentration are higher. It can be suggested that low levels of DHEA-S and SHBG may be the potential risk factors of MS in elderly men.     

Low free testosterone is an independent risk factor for Alzheimer's disease

The purpose of this study was to assess pituitary gonadotropins and free testosterone levels in a larger cohort of men with Alzheimer's disease (AD, n=112) and age-matched controls (n=98) from the Oxford Project to Investigate Memory and Ageing (OPTIMA). We measured gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and total testosterone (TT) using enzyme immunoassays. AD cases had significantly higher LH and FSH and lower free testosterone levels. LH, FSH and SHBG all increased with age, while free testosterone decreased. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high SHBG, low TT, high LH, an older age and low body mass index (BMI). In controls, low thyroid stimulating hormone levels were also associated with low free testosterone. Elderly AD cases had raised levels of gonadotropins. This response may be an attempt to normalize low free testosterone levels. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. Lowering SHBG and/or screening for subclinical thyroid disease may prevent cognitive decline and/or wasting in men at risk for AD.     

性激素和雄激素受体与老年男性糖尿病的相关性研究

目的 研究老年男性糖尿病患者的性激素和雄激素受体水平的变化,探讨老年男性糖尿病患者性激素和雄激素受体与糖尿病的相关性. 方法横断面调查老年男性492例,其中健康对照组104例,平均年龄(71.4±5.2)岁;非糖尿病对照组259例,平均年龄(71.5±5.0)岁;糖尿病组129例,平均年龄(73.0±6.3)岁.测定总睾酮(TT)、游离睾酮(FT)、脱氢表雄酮硫酸酯(DHEAS)、性激素结合球蛋白(SHBG)、雌二醇(E_2)、黄体生成素(LH)、卵泡刺激素(FSH)水平,采用流式细胞术检测外周血白细胞雄激素受体(AR)水平. 结果糖尿病组TT水平显著低于两对照组,分别为(17.1±6.1)、(15.8±6.0)nmol/L和(13.8±4.7)nmol/L(P<0.01),FT、SHBG、AR阳性率、AR荧光强度健康对照组、非糖尿病对照组和糖尿病组3组间呈下降趋势.但差异无统计学意义.多元回归分析町见TT、E_2,E_2/T,SHBG与血糖水平呈负相关;SHBG与糖尿病病程呈正相关.TT和AR阳性率与糖尿病病程呈负相关.Logistic多元同归分析示年龄、腰臀围比、FSH、SHBG、AR阳性率是糖尿病的危险因素. 结论低水平的TT、SHBG和AR可能是糖尿病的危险因素,在老年男性糖尿病的发生和发展中起到一定作用.     

Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers

OBJECTIVEThere are few detailed studies of annual or seasonal variations in hormone concentrations in man. This study examines the components of biological variation, including seasonality, in plasma TSH, total T3 (TT3), free T4 (FT4), PRL, cortisol and testosterone in healthy volunteers. DESIGNMonthly blood samplings for the assay of the above hormones were collected during one calendar year. SUBJECTSThirteen normal men and 13 normal women participated in the present study (mean age 38.7 ± 13.4 years). MEASUREMENTSAssays of TSH, TT3 and FT4 were carried out by means of Immunoradiometric assays (IRMA), PRL by ELISA, cortisol by a fluorescence immunoassay, and testosterone with RIA. The time series were analysed by means of (bivariate or multivariate) spectral and cosinor analyses. RESULTSSignificant annual, four-monthly and biannual rhythms were detected in serum TSH; the lowest TSH values were observed in spring. A significant annual rhythm was detected in TT3, with lower values in spring and summer than in the other seasons. The peak–trough differences in the yearly variation expressed as a percentage of the mean were 29.1% and 8.2% for TSH and TT3, respectively. The yearly variation in plasma cortisol was significantly different between men and women: in men, 5.9% of the variation was explained by an annual rhythm, while in women 14.7% was explained by the fourth and seventh harmonical wave. The peak–trough differences in the yearly variation in plasma cortisol were 17.6% and 31.8% in men and women, respectively. There were no significant seasonal rhythms in PRL, FT4 or testosterone. The intraindividual/interindividual CV values were: TSH 29.3/48.4%, TT3 9.4/18.5%, FT4 7.1/9.1%, PRL 39.2/65.0%, cortisol 21.7/46.2%, and testosterone 12.6/40.8%. CONCLUSIONSThe degree of individuality measured in the plasma hormones is such that conventional population-based reference ranges may not correctly identify major alterations in these hormones in individual subjects.     

Obesity and testicular function

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.     

Free testosterone index: comparison with plasma free testosterone

Blood-free testosterone indices were measured among 28 normal men (age; 24-48 yrs.), 20 normal women (20-36 yrs.), 18 pregnant women (22-31 yrs.), 17 males with hypogonadism (23-56 yrs.), 17 males with chronic hepatitis (20-42 yrs.), 24 males with liver cirrhosis (29-68 yrs.), 34 males with hyperthyroidism (20-42 yrs.) and 7 hirsute women (18-31 yrs.), and these were compared with the plasma concentrations of free testosterone. The testosterone index was obtained by multiplying the plasma concentration of testosterone by the percent of sex hormone-binding globulin (SHBG), non-bound testosterone precipitated by dextran-coated charcoal. A significant increase of plasma testosterone was observed in patients with chronic hepatitis (p less than 0.001) and hyperthyroidism (p less than 0.001) as compared with normal men and was also observed in pregnant (p less than 0.01) and hirsute women (p less than 0.01) as compared with normal women. The close negative correlation between plasma levels of testosterone and the percent of SHBG non-bound testosterone (r = -0.87, n = 79, p less than 0.001) was observed among normal men, male patients with chronic hepatitis and hyperthyroidism. The sex hormone binding capacity was increased from two to three fold in patients with chronic hepatitis and hyperthyroidism. The patients with compensated liver cirrhosis had increased plasma testosterone and a decreased percent of SHBG non-bound testosterone, and those with decompensated liver cirrhosis had decreased plasma testosterone and a normal percent of SHBG non-bound testosterone. The plasma concentration of free testosterone was normal in patients with chronic hepatitis and hyperthyroidism. It decreased in pregnancy (p less than 0.01) and increased in hirsute women (p less than 0.01). The blood free testosterone index was slightly high in one third of the patients with chronic hepatitis and hyperthyroidism as compared with that in normal men. However, a close correlation of the percent of SHBG non-bound testosterone and fractional free testosterone (%) measured by equilibrium dialysis (gamma = 0.82, p less than 0.001) was obtained in all subjects (n = 170). These data suggest that the blood free testosterone index parallels the plasma concentration of free testosterone and is useful to evaluate the status of androgenicity.     

Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys

CONTEXT: Adverse secular trends in male reproductive health have been reported to be reflected in increased testicular cancer risk and decreased semen quality in more recently born men. These secular trends may also be reflected by changes in Leydig cell function. OBJECTIVE: The objective of the study was to examine whether an age-independent time trend in male serum testosterone levels exists. DESIGN AND SETTING: Testosterone and SHBG were analyzed in 5350 male serum samples from four large Danish population surveys conducted in 1982-1983, 1986-1987, 1991-1992, and 1999-2001. Free testosterone levels were calculated. The effects of age, year of birth, and time period on hormone levels were estimated in a general linear statistical model. MAIN OUTCOME MEASURES: Testosterone, SHBG, and calculated free testosterone levels in Danish men in relation to age, study period, and year of birth were measured. RESULTS: Serum testosterone levels decreased and SHBG levels increased with increasing age. In addition to this expected age effect, significant secular trends in testosterone and SHBG serum levels were observed in age-matched men with lower levels in the more recently born/studied men. No significant age-independent effect was observed for free testosterone. Adjustment for a concurrent secular increase in body mass index reduced the observed cohort/period-related changes in testosterone, which no longer were significant. The observed cohort/period-related changes in SHBG levels remained significant after adjustment for body mass index. CONCLUSIONS: The observed age-independent changes in SHBG and testosterone may be explained by an initial change in SHBG levels, which subsequently lead to adjustment of testosterone at a lower level to sustain free testosterone levels.