Interactive ToolsLeen Antonio, Frederick C. Currently, free testosterone low symptoms suggest using TT to diagnose androgen deficiency and free testosterone low symptoms reserve cFT only for men with borderline TT. Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. A total of sympgoms men, aged 40—79 years, were included free testosterone low symptoms this study. A total stmptoms men had normal TT They 100 mg proviron for gyno higher SHBG and LH and reported more sexual and physical symptoms, whereas hemoglobin and bone ultrasound parameters were lower compared to the referent group.
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Leen Antonio, Frederick C. Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints.
A total of community-dwelling men, aged 40—79 years, were included in this study. A total of men had normal TT They had higher SHBG and LH and reported more sexual and physical symptoms, whereas hemoglobin and bone ultrasound parameters were lower compared to the referent group. Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms; therefore, cFT levels should be assessed in men with suspected hypogonadal symptoms.
We studied if low free testosterone T or low total T is more strongly associated with androgen-related clinical endpoints. We showed that low free T is associated with hypogonadal signs and symptoms even if total T is normal. Currently, the physiological significance as well as the applicability of FT in clinical practice remain unclear 2. The Endocrine Society guideline suggests using a repeated measurement of morning TT to confirm the diagnosis of hypogonadism in symptomatic men.
In men with borderline TT levels and expected alterations in SHBG levels such as in older men, obesity, or thyroid disorders , measuring FT concentrations by equilibrium dialysis in a reliable reference laboratory is recommended 4. However, both guidelines acknowledge that there is no consensus regarding the role of FT in the diagnosis of hypogonadism and that a well-established reference limit is lacking.
To date, it remains unclear to what extent FT and TT levels are differentially associated with hypogonadal symptoms in men. Currently, directly measuring FT remains technically challenging and expensive 2 , 4. Equilibrium dialysis, the gold standard, is an expensive and technically challenging method, being only available in research and a few commercial laboratories, and its place in routine clinical practice is therefore very limited.
Instead of equilibrium dialysis, calculated FT cFT is commonly used, with the most commonly used calculation the Vermeulen formula being based on the law of mass action 4 — 7. Therefore, cFT can be a valid and practical alternative for measured FT 5. However, the utility of cFT or measured FT concentrations in assessing androgen status in aging men has not been investigated systematically.
The primary aim of our study was to examine if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints in a population sample of middle-aged and elderly men. Briefly, men, aged 40—79 years, were recruited for participation in EMAS in eight European centers: After a median follow-up time of 4.
From the original cohort, men had died and were lost to follow-up. Ethical approval was acquired in accordance with local institutional requirements.
All men gave written informed consent. At both phases, a single fasting morning venous blood sample was obtained from each subject. Hematological and biochemical parameters were assessed at the local health care facility. The lower limit of quantification was 0. Calculated free T and calculated free estradiol were derived from TT and estradiol, respectively, and SHBG and albumin levels by the Vermeulen formula 6 , Insulin resistance was calculated using the homeostasis model assessment At both phases, a postal questionnaire was used to obtain information on demographic factors, smoking habits and alcohol consumption, general health, comorbidities, and the use of prescription and nonprescription medication.
Anthropometric measurements and Reuben's physical performance test time to walk 50 feet 14 were performed according to standardized methods 9. Mid-upper arm circumference was used as an indicator of lean body mass.
An estimation of body fat percentage was calculated by the Siri equation, based on a subject's average density which was calculated from skinfold thickness at triceps, biceps, subscapular, and iliac crest sites 15 , Quantitative ultrasound of the left calcaneus was used to measure bone density because bone ultrasound measurements are a good indicator of future fracture risk 9 , The four categories were: We used receiver operating characteristic curves to assess the optimal cutoff for TT.
A TT cutoff of Smoking status was stratified as current vs never and ex-smokers referent. Alcohol intake was categorized as less than 4 days per week referent vs 5 or more days per week.
Questionnaire responses were assessed as multicategory ordinal variables. For frequency of sexual thoughts and morning erection frequency, the response sets were categorized as 1: For physical symptoms, the response sets were 1: Adjustments were made for age, center, and the presence of comorbidities. Except when assessing body composition parameters, models were also adjusted for body mass index BMI.
All data were analyzed using Stata version Of the EMAS subjects recruited at baseline, 35 men were excluded because of missing TT or cFT; this analysis therefore included data from men. At baseline, Characteristics of the four groups are presented in Table 1. Continuous variables are expressed as mean standard deviation , categorical variables as percentages.
Linear regression with adjustments for age, center, BMI, and comorbidities. Ordinal logistic regression, with adjustments for age, center, BMI, and comorbidities. In the fully adjusted models, psychological symptoms were not different between the different groups Table 3. Glucose levels were increased and men were more insulin resistant in all three groups Tables 1 and 4.
Linear regression analysis with adjustments for age, center, BMI, and comorbidities. Only the latter group had a higher mortality risk at follow-up Table 5. Logistic regression analysis with adjustments for age, center, BMI, presence of comorbidities. Cox regression for mortality with adjustments for age, center, BMI, and presence of comorbidities.
An association between either low TT or low FT and symptoms of androgen deficiency has been described in several large epidemiologic studies in aging men 23 , 27 — However, to date, the association between TT or FT with a specific clinical variable has been reported for each T parameter separately.
In contrast to previous studies, we have used a combined approach, which enables the investigation of both TT and FT levels concurrently in the same subject to evaluate their relative importance in the assessment of androgen status. They have lower hemoglobin and bone ultrasound parameters.
We confirm the association between low TT and obesity and MetS 30 — As expected, these men also have higher hs-CRP levels and are more insulin resistant than the referent group. Both a proinflammatory state as indicated by hs-CRP , as well as insulin resistance, have a negative effect on SHBG concentrations 34 , 35 , which in turn result in a concomitant decrease in TT in obese men.
However, as long as FT remains within the reference range, evidence of androgen deficiency appears to be lacking. We also confirm the association between low FT and aging. Previous studies have shown a clear association between low FT and older age, with a concurrent elevation in LH 3 , 30 , There are remarkable differences in SHBG concentrations between the four groups. Apart from age and obesity, multiple other factors can have an impact on serum SHBG concentrations. Smoking status and alcohol intake are not different between the different groups; neither are there any clear differences in thyroid function.
Differences in SHBG concentrations across the groups could therefore, at least in part, be related to the well-established inverse relationship between IGF-1 concentrations and hepatic SHBG production 34 , Our findings therefore suggest that free and not total sex steroid levels regulate LH secretion via negative feedback to the hypothalamus and the pituitary gland.
They also have the lowest mean TT level 7. This is also the only group of men that has an increased mortality risk, independent of age, BMI, and comorbidities. Both low TT and low cFT have been associated with all-cause mortality 39 — Our findings have important clinical implications.
First, in older men with low-normal TT and high SHBG levels, resulting in low cFT levels, the presence of increased sexual and physical symptoms could be regarded as evidence of androgen deficiency.
Thus, cFT levels are important in the confirmation of hypogonadism in elderly symptomatic men. Second, if a man is obese and has low TT, low SHBG, but normal cFT levels, it is plausible that symptoms may be nonspecific and unrelated to androgen deficiency despite the apparently low TT suggesting otherwise.
Based on the cutoffs of In other words, if we would only use TT to diagnose low T, the chance of a false negative finding is 9. The main strengths of our study include the large sample of community-dwelling men, the standardized methods used to collect a broad range of personal and clinical data and the mass spectrometry-based methods to measure sex steroids.
However, there are also some limitations to our study. Different methods for calculating FT have been published—our results are based on the Vermeulen method because this is the most commonly used formula to calculate FT in clinical practice. Because of the observational, cross-sectional design of the study, we do not address the question if men with low cFT can benefit from T substitution and we cannot discriminate between cause and effect.
Although only a single measurement of TT was available, this is a stable analyte and single measurements of TT on a morning blood sample can provide representative and reliable data in large epidemiological studies such as EMAS Extrapolating our findings to other populations should be done with some caution. In the presence of normal TT levels, low cFT levels are associated with androgen-related signs and symptoms in middle-aged and elderly men.
We thank Joseph Finn for his invaluable contribution to the European Male Ageing Study and the men who participated and the research and nursing staff in the eight centers. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
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