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Endocrine Care |
Endocrine Research Unit, Division of Endocrinology, Metabolism, and Nutrition, Department of Internal Medicine (S.K.), and Department of Health Sciences Research, Mayo Clinic and Foundation (L.J.M., E.J.A., W.M.O.), Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu
Abstract
Estrogen appears to play an important role in determining bone mineral density in men, but it remains unclear whether estrogen primarily determines peak bone mass or also affects bone loss in elderly men. Thus, we assessed longitudinal rates of change in bone mineral density in young (22–39 yr; n = 88) vs. elderly (60–90 yr; n = 130) men and related these to circulating total and bioavailable estrogen and testosterone levels. In young men bone mineral density increased significantly over 4 yr at the mid-radius and ulna and at the total hip (by 0.32–0.43%/yr), whereas it decreased in the elderly men at the forearm sites (by 0.49–0.66%/yr), but did not change at the total hip. The rate of increase in bone mineral density at the forearm sites in the young men was significantly correlated to serum total and bioavailable estradiol and estrone levels (r = 0.22–0.35), but not with total or bioavailable testosterone levels. In the elderly men the rates of bone loss at the forearm sites were most closely associated with serum bioavailable estradiol levels (r = 0.29–0.33) rather than bioavailable testosterone levels. Moreover, elderly men with bioavailable estradiol levels below the median [40 pmol/liter (11 pg/ml)] had significantly higher rates of bone loss and levels of bone resorption markers than men with bioavailable estradiol levels above 40 pmol/liter. These data thus indicate that estrogen plays a key role both in the acquisition of peak bone mass in young men and in bone loss in elderly men. Moreover, our findings suggest that age-related decreases in bioavailable estradiol levels to below 40 pmol/liter may well be the major cause of bone loss in elderly men. This subset of men is perhaps most likely to benefit from preventive therapy.
ALTHOUGH MEN DO not have the equivalent of the menopause and hence lack the rapid early phase of bone loss present in postmenopausal women, rates of age-related bone loss in elderly men are comparable to those in older women (1, 2, 3, 4). This translates into a significant increase in the risk of osteoporotic fractures in elderly men (5, 6), with their attendant costs to the healthcare system (7). However, although estrogen (E) deficiency has clearly been established as the major factor leading to both the early and late phases of bone loss in women (8), the mechanism(s) responsible for age-related bone loss in men remains unclear at present.
Recent evidence from an ER
-negative male (9) and two
aromatase-deficient males (10, 11, 12) has established that E
plays an important role in skeletal metabolism in men. These
individuals had unfused epiphyses, osteopenia, and elevated markers of
bone turnover. Moreover, in the case of the aromatase-deficient
males, these abnormalities were reversed by E replacement therapy
(11, 12, 13). These findings clearly demonstrated that E was
important for the normal growth and maturation of the male skeleton.
Left unresolved, however, was the issue of whether E continued to play
an important role in mediating the bone loss seen in elderly men.
In an attempt to address this issue, a number of cross-sectional observational studies have examined the relationship between testosterone (T) and E vs. bone mineral density (BMD) in men (14, 15, 16, 17, 18, 19, 20). In general, they have found that E, and particularly the non-SHBG-bound (or bioavailable) E, correlated better with BMD at multiple sites than T. Moreover, although total T or E levels change little through life in men, the bioavailable fractions decline significantly, principally in response to a marked age-related increase in serum SHBG levels (16, 20). This has led to the hypothesis that the decline in bioavailable sex steroid levels, particularly bioavailable E levels, contributes to age-related bone loss in men (8). Although the available cross-sectional data are consistent with this hypothesis, longitudinal studies are necessary to directly address this issue.
In the present study we assessed rates of change in BMD in young (aged 22–39 yr), middle-aged (aged 40–59 yr), and elderly (aged 60–90 yr) men and related these to sex steroid levels. Thus, in contrast to the previous cross-sectional studies, our longitudinal study was able to dissociate possible effects of E on bone mass acquisition in young men vs. bone loss in elderly men.
Subjects and Methods
Study subjects
Subjects were recruited from an age-stratified random sample of Rochester, MN, men that were selected using the medical records linkage system of the Rochester Epidemiology Project (21). Over half of the Rochester population is identified annually in this system, and the majority are seen in any 3-yr period. Thus, the enumerated population approximates the underlying population of the community, including both free-living and institutionalized individuals. Altogether 1138 men, aged 20 yr and over, were approached, but 239 men were ineligible (109 were demented and could not give informed consent, 13 were radiation workers, 91 died before contact, 25 were debilitated due to terminal cancer, and 1 was unable to participate due to pending legal action). Of the 899 eligible men, 348 participated and provided full study data, although 2 were excluded from this analysis because 1 was receiving T therapy and 1 had inexplicably high (into the range of premenopausal women) estradiol (E2) and estrone (E1) levels. For the present longitudinal study we analyzed data from the 315 men who returned for more than 1 visit. All but 11 of the 315 men were Caucasian, reflecting the ethnic composition of the population (96% white in 1990). The men ranged in age from 22–90 yr. For the analyses, we divided the men into young (aged 22–39 yr; mean ± SD, 31.2 ± 4.9 yr; n = 88), middle-aged (40–59 yr; 50.1 ± 5.8 yr; n = 97), and elderly (60–90 yr; 73.7 ± 8.6 yr; n = 130) groups.
Study protocol
BMD (grams per cm2) was determined for the lumbar spine (L2–L4), total hip, and mid-distal radius and ulna using dual energy x-ray absorptiometry with the QDR2000 instrument (Hologic, Inc., Waltham, MA) using software version 5.40. As we did not specifically exclude subjects with spinal osteoarthritis or aortic calcification, which can confound the BMD measurement (22), we assessed the midlateral instead of the antero-posterior spine, which largely excludes these confounders from the scanning field. The coefficients of variation (CVs) for the lateral spine, total hip, and radius were 2.1%, 1.8%, and 1.7%, respectively. BMD was measured at baseline, 2 yr, and 4 yr, and annualized rates of change were calculated.
Fasting state serum samples were obtained between 0800–0900 h, and a 24-h urine collection was turned in. All samples were stored at -70 C until analyzed.
Laboratory methods
All of the assays were performed at the Mayo General Clinical Research Center Immunochemical Core Laboratory. Fasting serum samples were assayed by RIA for total T (Diagnostic Products, Los Angeles, CA; interassay CV, 11%), E2 (Diagnostic Products; interassay CV, <16%), E1 (Diagnostics Systems Laboratories, Inc., Webster, TX; interassay CV, 9%), and SHBG (Wien Laboratories, Succasunna, NJ; interassay CV, 7%). In addition, the non-SHBG-bound (bioavailable) fraction of total T and E2 was measured using a modification of the technique of O’Connor et al. (23) and Tremblay et al. (24), as previously described (16).
Bone formation was assessed by serum osteocalcin, measured by RIA using antibody G12 (interassay CV, <6%) (25) as well as by serum bone-specific alkaline phosphatase measured by ELISA (25) (interassay CV, <11%). Bone resorption was evaluated by measurement of serum levels of the N-telopeptide of type I collagen (NTx) by an ELISA kit (Osteomark NTx Serum, Ostex International, Inc., Seattle, WA; interassay CV, <17%) as well as 24-h urine levels of NTx, assessed as nanomoles per liter glomerular filtrate, also measured by an ELISA kit (Osteomark, Ostex International, Inc.; interassay CV, 10%). The glomerular filtration rate was assessed by creatinine clearance.
Statistical analysis
Serum sex steroids, bone turnover markers, and rates of bone loss were summarized using medians and interquartile (25th-75th percentile) ranges. The Spearman rank correlation was used to measure associations between the various continuous variables. The Wilcoxon rank sum test was used to compare the various end points between the age groups. Linear regression models were used to help determine the best split points between rates of bone loss and bioavailable E2 levels, where the split point was determined based on the maximum model r2 value. The resulting models, where slopes were allowed to vary before and after the split point, were compared with a one-slope model by F test. P < 0.05 was considered significant.
Results
Baseline variables
Table 1
shows the baseline
characteristics of the study subjects. As expected, there was a
progressive decline in BMD with age at the various skeletal sites.
Total T was slightly lower in the elderly compared with the young men,
whereas E2 and E1 values
were not different across the groups. Bioavailable T and
E2, however, did decline progressively with age,
principally due to a large age-related increase in SHBG levels. Of
note, bioavailable T levels were 46% lower in the elderly compared
with the young men, whereas bioavailable E2
levels were only 31% lower. This is primarily due to the fact that a
greater percentage of T is bound to SHBG compared with
E2, and SHBG levels were 88% higher in the
elderly compared with the young men. The sex steroid measures were also
correlated with each other; in particular, the Spearman
correlation coefficient between total T and E2
was 0.25 (P < 0.001), and that between bioavailable T
and bioavailable E2 was 0.55 (P
< 0.001). The bone turnover markers generally showed a biphasic
pattern, with the young and elderly men having higher values than the
middle-aged men.
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The annualized rates of change in BMD over 4 yr in the young,
middle-aged, and elderly men are shown in Table 2. As is evident, the young men had
significant increases in BMD at the radius, ulna, and total hip.
However, the midlateral spine BMD decreased even in the young men. The
elderly men lost bone at the radius and ulna and had even greater rates
of bone loss at the midlateral spine. In general, the changes in BMD in
the middle-aged men were intermediate compared with those in the young
and elderly men. Somewhat surprisingly, however, they continued to have
an increase in BMD at the total hip.
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Table 3 shows the correlation
between rates of change in BMD at the radius and ulna and serum sex
steroid levels in the three groups of men. Note that the associations
between the rates of change in BMD and E levels are in the expected
(positive) direction, as higher E levels in young men were associated
with more bone gain, and higher E levels in the elderly men were
associated with less bone loss. Changes in total hip and mid-lateral
spine BMD were not related to any of the measured parameters (except
for the total hip BMD rate of change in the middle-aged men, which was
inversely correlated to T levels; r = -0.20; P =
0.049) and hence are not included in Table 3. As is evident, the
increase in BMD at the radius and ulna in the young men was
significantly correlated to serum E levels (total
E2 and E1 and bioavailable
E2), but not T levels. In the middle-aged men,
these correlations were absent at the radius, but present at the ulna
with E1 and bioavailable E2
levels. By contrast, the decline in radius and ulna BMD in the elderly
men was correlated to total E2 as well as
bioavailable T and E2 levels, although the
strongest correlations were seen with bioavailable
E2 levels. After adjusting for bioavailable
E2 in the elderly men, none of the other sex
steroid variables remained significant predictors of bone loss (data
not shown).
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shows the correlation
coefficients relating urinary and serum NTx and serum osteocalcin to
the sex steroid levels in the three groups. Serum bone-specific
alkaline phosphatase did not show any significant correlations to these
parameters and hence is not included in Table 4. Total T was associated
with serum osteocalcin levels in the young and middle-aged, but not the
elderly, men. Bioavailable T was inversely correlated to urinary and
serum NTx in the elderly men. Bioavailable E2 was
consistently inversely correlated to urine NTx in all three groups and
also with serum NTx in the elderly men. Again, after adjusting for
bioavailable E2 in the elderly men, none of the
other sex steroid variables remained significant determinants of bone
turnover (data not shown).
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Figure 1 plots the rate of change in
radius and ulna BMD vs. bioavailable
E2, using a split-point of 40 pmol/liter (11
pg/ml). There was no relationship between the rate of change in BMD at
either site and bioavailable E2 levels above 40
pmol/liter. By contrast, rates of change in BMD at both sites were
significantly related to bioavailable E2 levels
less than 40 pmol/liter. Based on the serum SHBG levels in the elderly
men, we estimated that the total E2 level
required in these men to achieve a bioavailable
E2 level of 40 pmol/liter was 114 pmol/liter (31
pg/ml). A comparable analysis for rates of change in BMD at these sites
and total E2 using a split point of 114
pmol/liter gave identical results (data not shown).
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relates the rate of change in BMD
at the various sites and the bone resorption markers to bioavailable
E2 levels separately for the elderly men below
and above 40 pmol/liter. As is evident, there were significant
associations between these variables (except for the total hip and
midlateral spine) and bioavailable E2 levels when
bioavailable E2 values were below 40 pmol/liter,
but no associations were present in men with bioavailable
E2 levels above 40 pmol/liter. The analogous
analysis for elderly men below and above a total E2level of 114 pmol/liter was very similar (data not
shown).
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In the above analyses, we used the measured bioavailable
E2 for all of the correlations. The molar ratios
og E2/SHBG or (E1 +
E2)/SHBG are often used as surrogates for free E.
When the analyses were repeated substituting either one of these
indexes of free E, the results were comparable to those using the
measured bioavailable E2 values (data not shown).
The only exception was in the analysis shown in Table 5
, where using
(E1 + E2)/SHBG did not
produce any significant correlations. Thus, it appears that
E2/SHBG is a reasonable surrogate for actual
measured bioavailable E2.
Discussion
Although evidence from the ER-negative and aromatase-deficient
males (9, 10, 11, 12) had suggested that E played a key role in
the male skeleton, these findings left open the question of whether the
main effect of E was in the acquisition of peak bone mass in young
adulthood or whether it also had effects on age-related bone loss in
elderly men. Data from several cross-sectional observational studies
did, in general, show significant associations between E and BMD in
elderly men (14, 15, 16, 17, 18, 19, 20). However, as BMD in elderly men is a
function both of the acquisition of peak bone mass early in life and
bone loss with senescence, these studies could not dissociate the
possible effects of E on these two processes. By contrast, our
longitudinal findings demonstrating significant associations between E
levels and the increase in BMD in young men as well as bone loss in
elderly men clearly establish that E plays a significant role in the
male skeleton in both young and elderly men.
We also found that E levels correlated with bone resorption markers in both young and elderly men. These findings are consistent with our recent interventional study in which we directly tested the relative contributions of E vs. T in preventing the increase in bone resorption after the induction of hypogonadism and aromatase inhibition in normal elderly men (26). In that study we clearly demonstrated that E played the dominant role in regulating bone resorption in normal elderly men, although T may have made a smaller contribution that we lacked the statistical power to detect. The data from that study also indicated that both E and T contributed to the maintenance of bone formation. Consistent with this observation, serum osteocalcin levels were positively associated with T levels in the present study, at least in the young and middle-aged men. Osteocalcin levels were, however, negatively associated with E levels in the young men and were not associated with E levels in the middle-aged and elderly men. Thus, in the previous study in which we examined acute changes in bone formation (26), we were able to demonstrate a positive effect of E on bone formation markers, whereas in the present study the chronic reduction in bone turnover in men with higher E levels probably masked these associations.
Elderly men with bioavailable E2 levels below the 50th percentile [<40 pmol/liter (11 pg/ml), corresponding to a total E2 level of approximately 114 pmol/liter (31 pg/ml)], had higher bone resorption markers and rates of bone loss than comparable men with E2 levels above these values. Indeed, the elderly men with bioavailable E2 levels above 40 pmol/liter (or total E2 levels >114 pmol/liter) lost little or no bone, at least at the radius and ulna. By contrast, the elderly men with E2 levels below these values had progressively higher rates of bone loss with further decreases in E2 levels. These findings thus indicate that elderly men with total and bioavailable E2 levels below approximately 114 and 40 pmol/liter, respectively, are at risk for having increased bone resorption and rates of bone loss, whereas the men with E2 levels above these values are relatively protected against bone loss. Indeed, the latter men appear to be E sufficient so far as the skeleton is concerned. These findings are consistent with our recent observation that the selective ER modulator, raloxifene, actually increased bone resorption markers in elderly men with total E2 levels above approximately 96 pmol/liter (26 pg/ml), whereas it tended to decrease bone resorption markers in elderly men with E2 levels below this value (27). Similar to the findings from the present observational study, the data from the raloxifene study suggest that men with E2 levels above this value are relatively E sufficient; in these men raloxifene may compete with the more potent endogenous E, E2, thereby increasing bone resorption. By contrast, the men with E2 levels below this value appear to have skeletal E deficiency and may benefit the most from treatment with low doses of E or a selective ER modulator.
In an attempt to place these findings in a more global context of the
relationship between E2 levels and bone loss, we
compared the bioavailable E2 levels in the young,
middle-aged, and elderly men described here with bioavailable
E2 levels present in pre- and postmenopausal
women from a companion age-stratified sample of Rochester women who we
have previously described (16). As shown in Fig. 2, the majority of postmenopausal women
had bioavailable E2 levels below the threshold
value of 40 pmol/liter. In fact, approximately 90% of postmenopausal
women had bioavailable E2 values below this
level, and not surprisingly, they are the group with the greatest risk
of osteoporosis and fractures. Approximately 50% of elderly men,
however, had bioavailable E2 levels below 40
pmol/liter, and our data suggest that these are the individuals at
greatest risk for osteoporosis. In addition, approximately 25% of
middle-aged men had bioavailable E2 levels below
40 pmol/liter, and these individuals may also be at risk for developing
osteoporosis later in life. By contrast, few young men and women had
these low bioavailable E2 levels, although our
data suggest that those who do may well be at risk for bone loss.
Indeed, in a small study of 12 relatively young men with idiopathic
osteoporosis and age-matched controls, Gillberg et al.
(28) found that the osteoporotic men had significantly
lower E2/SHBG ratios than the control men. After
accounting for age- and gender-related differences in circulating SHBG
levels, we also estimated the total E2 levels
corresponding to a bioavailable E2 level of 40
pmol/liter in the various groups to be as follows: elderly men, 114
pmol/liter (31 pg/ml); middle-aged men, 84 pmol/liter (23 pg/ml); young
men, 73 pmol/liter (20 pg/ml); postmenopausal women, 140 pmol/liter (38
pg/ml); and premenopausal women, 132 pmol/liter (36 pg/ml).
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The major limitation of our study is that we found significant
associations between sex steroid levels and rates of change in BMD only
at the forearm sites, not at the total hip or mid-lateral spine. It is
possible that this was due to the better ability of the forearm
measurements to detect small longitudinal changes in BMD compared with
the central BMD measurements (29). Additional studies in
larger cohorts may be needed to assess whether the associations noted
in this study at the forearm are also present at other skeletal sites.
However, consistent with our findings, Szulc et al.
(20) recently reported in a cross-sectional study of men
aged 51–85 yr that men in the lowest quartile for bioavailable
E2 [
53 pmol/liter (14 pg/ml) in their assay]
clearly had lower BMD values at multiple skeletal sites than men with
bioavailable E2 levels above this value. Thus,
the combined data from the present longitudinal observational study,
our raloxifene study (27), and the above cross-sectional
analysis (20) provide fairly convincing evidence that the
male skeleton becomes relatively E deficient at bioavailable
E2 levels below 33–53 pmol/liter (9–14 pg/ml),
corresponding approximately to total E2 levels of
96–129 pmol/liter (26–35 pg/ml) in elderly men. Given the diverse
nature of the studies and the different assay methods used, this is a
remarkably narrow range, which could be refined further by
standardization of E2 and bioavailable
E2 measurements across investigators.
In summary, our longitudinal data indicate that E plays a
significant role in both bone mass acquisition in young adulthood and
bone loss in senescence. Combined with the previous findings from the
ER- and aromatase-negative males (9, 10, 11, 12), the
cross-sectional observational studies (14, 15, 16, 17, 18, 19, 20), and our
recent direct interventional study (26), the findings from
the present study now definitively establish E as the dominant sex
steroid regulating bone metabolism in men, both young and old. Although
total T and E2 levels do not change substantially
over life in men, bioavailable T and E2 levels
decrease to 30% and 50% of the levels in young men, respectively, due
principally to a greater than 2-fold increase in serum SHBG levels
(16). This decline in bioavailable
E2 levels may be the major cause of bone loss in
elderly men. Thus, the subset of aging men who develop serum
bioavailable E2 levels below the 50th percentile
[( 40 pmol/liter (11 pg/ml)] appear to be at the greatest risk for
increases in bone resorption and bone loss, whereas men with
E2 levels above this threshold are probably
protected against age-related bone loss. Although the available data
are consistent with this hypothesis, additional longitudinal studies in
larger cohorts are needed to further address this issue.
Acknowledgments
We thank Dr. B. Lawrence Riggs for helpful discussions, Ms. Vickie Gathje and Ms. Joan Muhs for their help in recruiting and studying the subjects, Ms. Roberta Soderberg for sampling handling, and Ms. Sara Achenbach for help with the statistical analyses.
Footnotes
This work was supported by Research Grant AR27065 from the NIAMSD, USPHS.
Abbreviations: BMD, Bone mineral density; CV, coefficient of variation; E, estrogen; E2, estradiol; E1, estrone; NTx, N-telopeptide of type I collagen; T, testosterone.
Received February 9, 2001.
Accepted April 16, 2001.
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A. Bjornerem, B. Straume, M. Midtby, V. Fonnebo, J. Sundsfjord, J. Svartberg, G. Acharya, P. Oian, and G. K. R. Berntsen Endogenous Sex Hormones in Relation to Age, Sex, Lifestyle Factors, and Chronic Diseases in a General Population: The Tromso Study J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6039 - 6047. [Abstract] [Full Text] [PDF]
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I. Van Pottelbergh, S. Goemaere, H. Zmierczak, and J. M. Kaufman Perturbed Sex Steroid Status in Men with Idiopathic Osteoporosis and Their Sons J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4949 - 4953. [Abstract] [Full Text] [PDF]
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M. Muir, G. Romalo, L. Wolf, W. Elger, and H.-U. Schweikert Estrone Sulfate Is a Major Source of Local Estrogen Formation in Human Bone J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4685 - 4692. [Abstract] [Full Text] [PDF]
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 A. Lipton Toward New Horizons: The Future of Bisphosphonate Therapy Oncologist, September 1, 2004; 9(suppl_4): 38 - 47. [Abstract] [Full Text] [PDF]
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V.-V. Valimaki, H. Alfthan, K. K. Ivaska, E. Loyttyniemi, K. Pettersson, U.-H. Stenman, and M. J. Valimaki Serum Estradiol, Testosterone, and Sex Hormone-Binding Globulin as Regulators of Peak Bone Mass and Bone Turnover Rate in Young Finnish Men J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3785 - 3789. [Abstract] [Full Text] [PDF]
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L. Gennari, L. Masi, D. Merlotti, L. Picariello, A. Falchetti, A. Tanini, C. Mavilia, F. Del Monte, S. Gonnelli, B. Lucani, et al. A Polymorphic CYP19 TTTA Repeat Influences Aromatase Activity and Estrogen Levels in Elderly Men: Effects on Bone Metabolism J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2803 - 2810. [Abstract] [Full Text] [PDF]
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C. Meier, P. Y. Liu, L. P. Ly, J. de Winter-Modzelewski, M. Jimenez, D. J. Handelsman, and M. J. Seibel Recombinant Human Chorionic Gonadotropin But Not Dihydrotestosterone Alone Stimulates Osteoblastic Collagen Synthesis in Older Men with Partial Age-Related Androgen Deficiency J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3033 - 3041. [Abstract] [Full Text] [PDF]
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C. Wang, G. Cunningham, A. Dobs, A. Iranmanesh, A. M. Matsumoto, P. J. Snyder, T. Weber, N. Berman, L. Hull, and R. S. Swerdloff Long-Term Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood, Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2085 - 2098. [Abstract] [Full Text] [PDF]
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S. Khosla, B. L. Riggs, E. J. Atkinson, A. L. Oberg, C. Mavilia, F. Del Monte, L. J. Melton III, and M. L. Brandi Relationship of Estrogen Receptor Genotypes to Bone Mineral Density and to Rates of Bone Loss in Men J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1808 - 1816. [Abstract] [Full Text] [PDF]
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J. K. Amory, N. B. Watts, K. A. Easley, P. R. Sutton, B. D. Anawalt, A. M. Matsumoto, W. J. Bremner, and J. L. Tenover Exogenous Testosterone or Testosterone with Finasteride Increases Bone Mineral Density in Older Men with Low Serum Testosterone J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 503 - 510. [Abstract] [Full Text] [PDF]
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, those with
values above 40 pmol/liter.