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From the * Institute for Community Medicine, the
Department of Gastroenterology, Endocrinology,
and Nutrition, the Institute of Pharmacology,
and the Institute of Clinical Chemistry and
Laboratory Medicine, Ernst Moritz Arndt University, Greifswald, Germany.
| Correspondence to: Dr Nele Friedrich, Institute for Community Medicine, Ernst Moritz Arndt University, Walther Rathenau Str 48, D-17487 Greifswald, Germany (e-mail: nele.friedrich{at}uni-greifswald.de). |
| Received for publication April 3, 2008; accepted for publication July 3, 2008. |
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Abstract |
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Key words: Total testosterone, dehydroepiandrosterone sulfate, reference ranges, quantile regression, Study of Health in Pomerania (SHIP)
In adulthood, a decline in serum total testosterone with increasing age is well documented (Leifke et al, 2000; Harman et al, 2001; Liu et al, 2007) and has been implicated in a wide variety of physiological changes of the aging male. Several studies showed that low testosterone levels are associated with depression, loss of muscle tone, increased abdominal fat, low bone density, reduced sexual function, Alzheimer disease, and heart disease (Chute et al, 1987; Phillips et al, 1994; Morley, 2001; Tan and Pu, 2003; Carnahan and Perry, 2004; Rucker et al, 2004).
For the use of serum DHEAS and serum testosterone as diagnostic markers or for monitoring testosterone therapy, age-dependent reference values are necessary. Currently available reference values of serum DHEAS were calculated only for children or young adults (Elmlinger et al, 2002), for very old subjects (Birkenhager-Gillesse et al, 1994), or by using nonrepresentative samples of adult men (Elmlinger et al, 2003; IMMULITE 2500 DHEA-SO4, 2004). Hence, the representativity of such studies remains low. Regarding serum testosterone, a wider range of references values are available, especially for adult men (Elmlinger et al, 2003, 2005; Schatzl et al, 2003; Boyce et al, 2004; IMMULITE 2500 Total Testosterone, 2004; Mohr et al, 2005; Okamura et al, 2005). However, almost all available reference values are not adequately adjusted for age (Boyce et al, 2004; IMMULITE 2500 Total Testosterone, 2004; Okamura et al, 2005) and refer to nonrepresentative samples of men (Schatzl et al, 2003; Elmlinger et al, 2005).
Furthermore, we demonstrated recently that the use of sufficient statistical method has an important influence on the accuracy of reference values (Friedrich et al, 2008). Although the general concept of mean ± 2 SD assumes a normal Gaussian distribution of the analyte and the calculation of SD is highly sensitive to outliers, a nonparametric approach of quantile regression analysis reaches a better concordance to the data and covers exactly the central 95% range.
The objective of the present study was to calculate age-specific reference values for serum DHEAS and serum testosterone using 1) linear regression and the mean ± 2 SD concept and 2) the quantile regression method in a population-based sample of German men.
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Material and Methods |
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TopAbstractMaterial and MethodsResultsDiscussionReferences |
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Of the 2117 men, 524 men were excluded because of the presence of at least
1 of the following diseases (overlap exists): diabetes mellitus (n = 186),
renal diseases (n = 134), liver diseases (n = 124), chronic obstructive
pulmonary disease (n = 135), diseases of the pituitary gland (n = 1), and all
subjects older than 45 years with a fractional shortening less than 20% (n =
18). In addition, all medications taken in the last 7 days were recorded and
categorized in a standardized fashion using the Anatomical Therapeutic
Chemical (ATC) classification index, which classifies drugs on the basis of
the target organ or system and on the therapeutic and chemical characteristics
of the drug (Fricke and Güntler,
2002). Thirty-one men who received sexual hormones (ATC G03),
testosterone 5
reductase inhibitors (G04CB), sexual hormone antagonists
(L02B), ketoconazole (D01AC08, G01AF11, J02AB02), spironolactone (C03DA01,
C03EC01, C03EC21, C03EC41, C03ED01), anabolic steroids (A14A), glucocorticoids
(H02AB), or opiates (N02A) were identified and therefore excluded. In more
detail (overlap exists): testosterone (G03BA03; n = 1), finasteride (G04CB01;
n = 2), flutamide (L02BB01, n = 1), spironolactone (C03DA01, C03EC41; n = 1),
methylprednisolone (H02AB04; n = 1), prednisolone (H02AB06; n = 6), prednisone
(H02AB07; n = 2), triamcinolone (H02AB08, H02AB58; n = 2), morphine (N02AA01,
n = 1), codeine (N02AA66, N02AA69, n = 4), tramadole (N02AX02; n = 1), and
tilidine (N02AX51; n = 1). None of the subjects reported use of anabolic
steroids (A14A) or received chemotherapy (D06B, D06C). Men with a daily
alcohol intake higher than 60 g were also excluded (n = 88). Furthermore, we
excluded all subjects with a body mass index (BMI) greater than 30 or less
than 18 kg/m2 (n = 328) and with missing data for serum
testosterone or DHEAS levels (n = 68). Altogether the final study population
comprised 1078 men who were included in the present analyses.
Measurements
A computer-aided personal interview was used to collect information on
medical history, behavioral, and sociodemographic characteristics. BMI was
calculated in kg/m2. Alcohol consumption was assessed using a
drink-specific quantity-frequency measure. Average alcohol consumption (in
grams per day) was calculated by multiplying frequency and amount of alcohol
from beer, wine, and spirits, respectively, using a standard ethanol content
of 4.8% (by volume) in beer, 11% (by volume) in wine and 33% (by volume) in
spirits to conversion (Bühringer et
al, 2002). The definition of diabetes based on self-reported
physician's diagnosis or self-reported use of antidiabetic medication (ATC
A10) in the last 7 days. Diseases of the pituitary gland were diagnosed as
self-reported intake of pituitary gland or hypothalamus hormones (ATC H01). A
blood sample was drawn from the cubital vein in the supine position. Serum
aliquots were prepared for immediate analysis and for storage at
–80°C for further analysis. From fresh serum, creatinine levels were
determined with the Jaffé method (Hitachi 717, Roche Diagnostics GmbH,
Mannheim, Germany). Creatinine clearance (CrCl) was estimated using the
Cockroft-Gault formula. Renal diseases were defined on self-reported renal
diseases or a CrCl of less than 50. Gamma-glutamyl transferase (GGT),
aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) levels
were measured photometrically (Hitachi 717). The definition of liver diseases
was based on self-reported liver cirrhosis or atrophy of the liver.
Additionally, all subjects with ASAT, ALAT, or GGT levels greater than the
population mean + 2 SD were classified as subjects with liver diseases.
Chronic obstructive pulmonary disease was defined as productive cough for at
least 3 consecutive months during the past 12 months.
DHEAS and total testosterone levels were measured from frozen serum aliquots using competitive chemiluminescent enzyme immunoassays on an IMMULITE 2500 analyzer (Siemens IMMULITE 2500 DHEA-SO4, ref L5KDS, lot 106, and Siemens IMMULITE 2500 Total Testosterone, ref L5KTW, lot 110; Siemens Healthcare Medical Diagnostics, Bad Nauheim, Germany). Measurement was carried out from December 2005 to January 2006. An aliquot of 2 alternating levels of a third-party commercial control material (Bio-Rad Lyphochek Immunoassay Plus Control, lots 40151 and 40152; Bio-Rad, Munich, Germany) was included in each series in single determination. During the course of the study the interassay coefficient of variation was 14.0% with a systematic deviation of +0.21% at the 48 µg/dL level and 8.4% with a systematic deviation of –5.0% at the 128 µg/dL level in the DHEAS assay. In the total testosterone assay the interassay coefficient of variation was 13.2% with a systematic deviation of +2.3% at the 3.2 nmol/L level, and 8.9% with a systematic deviation of +0.24% at the 22.5 nmol/L level. All assays were performed according to the manufacturers' recommendations by skilled technical personnel. In men who had blood drawn before noon, serum testosterone levels were on average 1.4 nmol/L higher than in men with blood drawn after noon (Table 1).
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Statistical Analyses
Continuous data are expressed as median (25th; 75th percentiles). For the
evaluation of reference values of serum DHEAS and testosterone levels we
performed 2 statistical approaches: 1) linear regression and the mean ±
1.96 SD concept and 2) quantile regression, a statistical method for
estimating models for the conditional median function and other conditional
quantile functions (Koenker,
2005). Unlike the nonparametric quantile regression, linear
regression is a parametric approach and assumes that the reference
distribution follows a Gaussian distribution. For this reason an initial
transformation of the serum DHEAS levels has been carried out. Transformations
(log, powers between 0.2 and 0.8) were compared to determine the best
conformance to the normal distribution of our DHEAS data. The best conformance
was found for the log transformation and was constant over different age
groups in both sexes. For serum testosterone levels no transformation was
necessary. In both statistical approaches restricted cubic splines
(Stone and Koo, 1985) were
used to detect a possible nonlinear dependency of serum DHEAS and testosterone
levels on age. Three knots were prespecified, located at the 10th, 50th, and
90th percentiles as recommended by Stone and Koo
(1985), resulting in 1
component of the spline function: age'. In linear regression, reference
curves for back-transformed DHEAS and testosterone data were calculated as
exp[fDHEAS(age) ± 1.96SD] and
fT (age) ± 1.96SD based on the SD
of the transformed DHEAS and original testosterone data, respectively. In
quantile regression, the 2.5th, 50th, and 97.5th percentiles of the serum
DHEAS and testosterone levels were fitted.
All data were weighted to adjust for nonresponse and to reflect age-sex distribution of the European adult population (Gesundheitsberichterstattung des Bundes, 2006). PROC REG and PROC QUANTREG in SAS were used for statistical analyses (SAS version 9.1.3; SAS Institute, Inc, Cary, North Carolina).
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Results |
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TopAbstractMaterial and MethodsResultsDiscussionReferences |
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Given these results, we calculated age-dependent references values for DHEAS and testosterone. Linear regression models for mean serum testosterone levels and after initial transformation for mean serum DHEAS levels were fitted (Table 3). The reference curves (Figure) corresponded to mean ± 1.96 SD. Quantile regression yielded for each of the 2.5th, 50th, and 97.5th percentiles 1 fitted model (Table 4). The calculated reference curves are also displayed in the Figure. Serum DHEAS and testosterone reference values for selected ages resulting from both statistical methods are given in Table 5. Both methods reflect the age-related decline in DHEAS and testosterone levels.
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Comparison Between Linear and Quantile Regression
With respect to serum DHEAS levels
(Figure) the upper reference
limit based on linear regression was above and the lower reference limit below
those that resulted from quantile regression. Thus, the reference range based
on linear regression was wider over the full age range compared to the
reference range calculated by quantile regression. Using the reference range
derived from linear regression, 17 subjects had serum DHEAS levels outside the
reference range (7 above and 10 below the reference range), whereas 54
subjects were diagnosed to have serum DHEAS levels outside the reference range
(27 above and 27 below the reference range) using quantile regression.
The widths of the reference ranges based on linear and quantile regression for serum testosterone levels were comparable. However, both upper and lower reference limits calculated by linear regression were below those of quantile regression. Based on linear regression, 45 individuals had serum testosterone levels outside the reference range (37 above and 8 below the reference range), whereas the reference data calculated by quantile regression detected 50 subjects who had levels outside the reference range (25 above and 25 below the reference range; Figure).
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Discussion |
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TopAbstractMaterial and MethodsResultsDiscussionReferences |
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Serum DHEAS
Both methods reflect the documented age-related decline in serum DHEAS
levels (Morley, 2001;
Feldman et al, 2002;
Elmlinger et al, 2003).
However, the reference range based on linear regression is wider for young men
and converges to the width provided by quantile regression in older men.
Reference values for adult men are currently provided by the manufacturers
(IMMULITE 2500 DHEA-SO4,
2004), who quote only the 5th and 95th percentiles, and a German
study (Elmlinger et al, 2003),
which also measured serum DHEAS levels with the IMMULITE system and determined
the central 95% range. The reference limits based on quantile regression are
well comparable to the reference limits of the German study
(Elmlinger et al, 2003).
However, in younger subjects the upper reference limit calculated by linear
regression exceeds the values of the German study by 5–13 µg/dL
(Elmlinger et al, 2003).
Serum Testosterone
Also for testosterone the results of both statistical methods show the
known age trend (Leifke et al,
2000; Harman et al,
2001; Liu et al,
2007). The lower limits of the age-dependent reference ranges for
serum testosterone levels based on quantile regression presented here are in
good agreement with other studies (Elmlinger et al,
2003,
2005;
Schatzl et al, 2003;
Mohr et al, 2005)
(Table 6). The upper reference
limits in men older than 39 years based on quantile regression, however, were
up to 10 nmol/L higher compared to these provided by the majority of these
studies (Elmlinger et al, 2003,
2005;
Schatzl et al, 2003).
Nevertheless, 1 study (Mohr et al,
2005) provided similar upper reference limits to our results. Some
of the studies (Elmlinger et al,
2003,
2005) calculated the central
95% range only for 10-year groups and not as a continuous function of age or
using the mean ± 2 SD concept
(Schatzl et al, 2003). The
differences in reference ranges might be because of the use of
nonrepresentative studies, different exclusion criteria, and relatively small
sample sizes (Elmlinger et al,
2003,
2005;
Schatzl et al, 2003).
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Gaussian vs Quantile Reference Limits
As previously noted (Friedrich et al,
2008), quantile regression has some statistical advantages
(Buchinsky, 1998;
Gannoun et al, 2002;
Koenker, 2005) over linear
regression, including 1) the nonparametric approach, by which no initial
transformation is necessary; 2) the estimation of conditional quantile
functions and the independence of a global distribution parameter like the SD;
and 3) the robustness to outlier observations in the response variable. Our
study reflects the latter point particularly for the upper reference limit of
DHEAS (Figure). In young men,
outliers led to an up to 400 µg/dL higher upper reference limit in linear
regression compared to the limit calculated by quantile regression.
Reference ranges should cover the central 95% range of distribution, which denotes that 5% of subjects lie outside the reference range, with 2.5% above and 2.5% below. The reference ranges based on quantile regression fulfill this condition and detected 54 (5.0%) subjects (above: 27 [2.5%]; below: 27 [2.5%]) and 50 (4.6%) subjects (above: 25 [2.3%]; below: 25 [2.3%]) with serum DHEAS and serum testosterone levels outside the reference range, respectively. In contrast, linear regression revealed 17 (1.6%) subjects (above: 7 [0.6%]; below: 10 [0.9%]) and 45 (4.2%) subjects (above: 37 [3.4%]; below: 8 [0.7%]) who had serum DHEAS and serum testosterone levels outside the reference range, respectively.
The major strength of our study is the use of data from a large population-based sample of adult men, compared with former studies which used non–population-based or clinical human samples (Elmlinger et al, 2003, 2005; Schatzl et al, 2003; IMMULITE 2500 DHEA-SO4, 2004; IMMULITE 2500 Total Testosterone, 2004). Furthermore, we were able to exclude subjects with disorders known to affect DHEAS and testosterone levels not only on the basis of self-report questionnaires as in other studies (Elmlinger et al, 2003, 2005; Schatzl et al, 2003; Okamura et al, 2005) but also based on clinical and laboratory examinations as well as medication use. A further strength is the measurement of the hormones used. All assays were conducted by a single technician, thus minimizing technician variability. Our study is limited by the lack of free testosterone, SHGB, or albumin for calculation of bioavailable testosterone. Furthermore, it is well known that current assay technology for testosterone lacks a certain degree of precision and accuracy. Mass spectrometry is the gold standard method for measuring testosterone, as previously demonstrated (Wang et al, 2004). Nevertheless, the comparison of the immunoassays used with mass spectrometry demonstrated that automated immunoassays are capable of distinguishing eugonadal from hypogonadal males. However, the same authors stated that reference ranges have been established in each individual laboratory for adult men (Wang et al, 2004). Our reference data for testosterone was appraised on the IMMULITE 2500 platform, which is declared to be technically identical to IMMULITE 1000 and IMMULITE 2000 by the manufacturer. The data should not be assigned to other measurement platforms in an uncritical way, which means without a method comparison in a sufficient population.
In conclusion, the present study established age-specific reference ranges for serum DHEAS and testosterone values standardized for the European age distribution using data from apparently healthy men. The advantages of the quantile regression led to a better adaptation of reference limits to the original data. This statistical approach might be preferable for the calculation of reference ranges in particular by nonnormal distributed variables. Our data might help clinicians reach a consensus on the definition of androgen deficiency.
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Acknowledgments |
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Footnotes |
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