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Departments of Pediatric Endocrinology (N.M.M.L.S., B.J.O.), Nuclear Medicine (W.J.G.O.), Medical Technology Assessment (G.-J.v.d.W.), and Endocrinology (A.R.M.M.H.), University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands
Address all correspondence and requests for reprints to: Dr. B. J. Otten, 435 Department of Pediatric Endocrinology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: b.otten{at}cukz.umcn.nl.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsMethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsMethodsResultsDiscussionReferences |
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Glucocorticoid administration, even in substitution doses, may cause decreased bone mineral density (BMD) (2) and obesity (3). Previous reports on BMD in CAH patients showed increased (4, 5), decreased (6, 7, 8, 9), or normal (10, 11, 12) BMD. These reports differed with respect to age selections and glucocorticoid regimens. The conflicting results in the literature prompted us to investigate BMD in a group of CAH patients, homogeneous with respect to age (range, 17–25 yr) and glucocorticoid regimen (relatively low glucocorticoid doses). We hypothesized that BMD would result from the balance between glucocorticoids and excess androgens and that it could either be decreased, normal, or increased.
Body mass index (BMI) is found to be elevated in most (6, 7, 9, 11, 13, 14), but not all (8, 12), reports on CAH patients. From clinical observations, we hypothesized that, in our patients, BMI would be increased; but it was not clear whether this resulted from increased fat mass (as a result of glucocorticoid treatment, despite the low dose regimen) or increased lean mass (as a possible result of androgen excess) (7, 8).
So, the objectives of the present study were to assess BMD, lean mass, and fat mass, by dual-x-ray absorptiometry (DXA), in a group of young adult male (M) and female (F) CAH patients who had been treated with currently recommended low doses of glucocorticoids, to compare the results to those in age- and sex-matched controls and to establish a possible correlation between glucocorticoid dose and hormonal control on one hand, and BMD, lean mass, and fat mass on the other hand. In addition, we determined calcaneal ultrasonography parameters in CAH patients and controls, because calcaneal ultrasonography, which has been proposed as a nonradiation-based method for assessment of osteoporotic fracture risk (15), has been suggested to provide also information on bone quality (16).
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsMethodsResultsDiscussionReferences |
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All 30 patients with 21-hydroxylase deficiency who were younger than 30 yr old and had attained final height and regularly visited our center from the time of diagnosis participated in this study. There were 15 M and 15 F patients, 17–25 yr old, all Caucasian. Of these 30 patients, 24 (12 M and 12 F) had the classical salt-wasting form of CAH, characterized by both glucocorticoid and mineralocorticoid deficiency. They had been diagnosed in the first year of life and had been treated, from the time of diagnosis, with glucocorticoids and mineralocorticoids. They were followed up regularly with biochemical and anthropometrical measurements. In the other 6 patients, CAH was diagnosed later in childhood because of signs of androgen excess. Three M patients were diagnosed as classic simple virilizing patients at the ages of 3 (n = 2) and 6 yr. Three F patients were diagnosed as nonclassic CAH patients at the age of 0 (because of family history), 2, and 6 yr, respectively. Glucocorticoid therapy had been started from the time of diagnosis, with regular follow-up, as in the classic salt-wasting patients. In 28 of the 30 patients, DNA mutation analysis of the CYP21 gene had been performed, confirming the diagnosis in all cases.
The control group was recruited by advertisements in the region of the hospital. Inclusion criteria were: good health, no medication (except for oral contraceptives), and Caucasian race. Exclusion criteria were: any history of chronic illness; any history of glucocorticoid medication (also inhalation) or other regular medication intake; or a history of multiple fractures, diabetes mellitus, diseases of the liver, kidneys, adrenals, (para)thyroid, bone diseases, or muscular diseases. The control subjects were matched for age and sex (15 M and 15 F). The study was approved by the ethics committee of the University Medical Center Nijmegen. All subjects gave informed consent after explanation of the aims and methods of the study.
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Methods |
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TopAbstractIntroductionPatients and MethodsMethodsResultsDiscussionReferences |
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DXA.
All patients and control subjects underwent DXA using a QDR 4500 densitometer (Hologic, Inc., Waltham, MA). Standard procedures supplied by the manufacturer for scanning and analysis were followed. Calibration with the manufacturer’s spine phantom and quality control analysis was performed daily. Bone mineral content (BMC, g) and areal BMD (aBMD, g/cm2) were measured at the lumbar spine (L1–L4) and at the right femoral neck. Volumetric BMD was estimated using the formula for bone mineral apparent density (BMAD, g/cm3): BMAD-LS (lumbar spine) = BMC/A3/2; and BMAD-FN (femoral neck) = BMC/A2, where A is the projected bone area (18).
Total-body DXA was subsequently performed to assess total BMC, total aBMD, fat mass, and lean mass. To adjust for height, lean mass and fat mass were divided by (height)2 (kg/m2), analogous to the calculation of the BMI. Total body mass was calculated as follows: total body mass = total BMC + total fat mass + total lean mass. The percentage lean mass and percentage fat mass were calculated by dividing their absolute mass by the total body mass.
The total body was divided into four regions: head region (above the upper border of the ribs), both arms (from the glenoid cavity), both legs (from midcollum), and the trunk region (including spine and pelvis). Fat distribution (percentage of the total fat located in trunk, arms, and legs) was estimated by dividing truncal fat mass, arms fat mass, and legs fat mass by the total fat mass. The composition of the trunk (percent BMC, percent lean mass, and percent fat mass) was estimated by dividing the absolute mass (BMC, lean and fat mass) in the trunk by the total mass of the trunk (= trunk BMC + trunk lean mass + trunk fat mass). The same was done for the arms and legs.
Calcaneal ultrasound.
Calcaneal ultrasound measurements were performed with the ultrasound bone-imaging scanner UBIS 3000 (DMS, Montpellier, France) as previously described (19). Two acoustic properties, broadband ultrasound attenuation (BUA, decibel/MHz) and speed of sound (SOS, m/sec), were assessed; and the mean of two successive measurements was taken. Shoe size was noted, as a measure of foot length. In 56 participants (patients and controls), ultrasound was performed on the same day as DXA; and in 2 patients, it was performed 1 and 2 months later, respectively. In 2 other patients, ultrasound measurements had been performed 4 and 5 months, respectively, after DXA measurements. The ultrasound results of the latter 2 patients were excluded from the study.
Glucocorticoid treatment.
Glucocorticoid doses were expressed as cumulative dose per body surface (g/m2). Cumulative dose was calculated exactly over 0.5, 2, and 5 yr preceding the investigation: daily glucocorticoid dose, as reported in patient records, was multiplied by the number of days, adding up to 183, 730, and 1825 d, respectively, preceding the investigation. Doses of glucocorticoids were converted to hydrocortisone equivalents using: 1) antiinflammatory equivalents (30 mg hydrocortisone = 37.5 mg cortisone acetate = 7.5 mg prednisone = 0.75 mg dexamethasone) (3); and 2) growth-retarding equivalents (30 mg hydrocortisone = 37.5 mg cortisone acetate = 6 mg prednisone = 0.375 mg dexamethasone) (20).
Hormonal control.
Hormonal control was assessed by collecting all results of morning salivary levels of 17-hydroxyprogesterone (17-OHP) and androstenedione from the patient records in the preceding 5 yr (for assays of salivary 17-OHP and androstenedione, see Ref.21). Diurnal saliva sampling (three samples per day) is routinely used for the follow-up of our CAH patients, and the morning sample is taken before the morning medication intake. The normal range of morning (0800 h) salivary levels is, in males, 0.05–0.36 nmol/liter 17-OHP, 0.14–0.63 nmol/liter androstenedione (21); in females, 0.02–0.19 nmol/liter 17-OHP (follicular phase) and 0.06–0.32 nmol/liter 17-OHP (luteal phase), 0.18–1.1 nmol/liter androstenedione. The mean levels of morning 17OHP and androstenedione per patient in the last 5 yr were used to calculate the correlation between hormonal control and bone, and lean and fat mass.
Statistical analysis.
Normal distribution of the data was assessed by Shapiro-Wilk test. In normally distributed data, mean values ± SD are given. Otherwise, median (minimum-maximum) are given.
For comparison between the patient group and the control group, Student’s t test for unpaired observations (P denoted as P) or Mann-Whitney U test (P denoted as P*) were used, dependent on the normality of distribution and equality of variance (Levene’s test). Correlations between glucocorticoid dose and DXA and ultrasound results were calculated with Pearson correlation coefficient or Spearman rank correlation, dependent on normality of distribution (Shapiro-Wilk) and linearity (visual inspection of the data). Linear regression analysis was used to correct for confounding variables. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsMethodsResultsDiscussionReferences |
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In Table 1
, the characteristics of patients and controls are given. Height was significantly lower in patients, compared with controls: the mean height difference was -12.1 cm for males and -5.8 cm for females, which is equivalent to -1.7 and -0.9 SD score for the Dutch population (22). The mean weight of patients was not different from controls. BMI was significantly higher in patients, compared with controls, in both sexes. A BMI larger than 25 kg/m2 was found in half of the 30 patients (7 M and 8 F) and in 2 of the controls. Oral contraceptives were used by 8 F patients and 10 F controls (difference not significant, 
2 test). Among the patients, the 0.5-, 2-, and 5-yr cumulative glucocorticoid doses were significantly higher in males, compared with females, except for the 0.5-yr cumulative dose in antiinflammatory equivalents (Table 2).
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In males, DXA showed no difference between patients and controls in BMC, aBMD, and BMAD in the lumbar spine (L1–L4) and the right femoral neck (Table 3). Total body BMC was significantly lower in M patients, compared with the M control group. The total aBMD was not different between both groups.
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). When corrected for shoe size (as a measure of foot length) by linear regression, the difference remained significant. Shoe size was 40.6 ± 1.5 (patients) and 43.9 ± 1.0 (controls), P < 0.001.
In females, no difference between patients and controls was seen in bone parameters, measured by DXA or calcaneal ultrasound (Table 3).
Lean and fat mass in M patients and controls
In M patients, compared with controls, the total lean mass (kg) was lower, and the total fat mass (kg) was not different (Table 4). When adjusted for height, total lean mass was not different between patients and controls, and total fat mass was significantly higher in patients. The fat mass, expressed as a percentage of the total body mass, was significantly higher in patients. The distribution of the fat mass (in trunk, arms, and legs) was not different in patients and controls (Fig. 1).
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(kg) and Fig. 2A(%). In the trunk, patients had significantly less lean mass (kg); the fat mass (kg) was not different from controls. When adjusted for height, trunk lean mass was not different and trunk fat mass was significantly higher in patients. In the arms, lean and fat masses were not different in patients and controls, with and without adjustment for height. In the legs, patients had significantly less lean mass and more fat mass, compared with controls. When adjusted for height, legs lean mass was not different and legs fat mass was significantly higher in patients.
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In F patients, the total lean mass (kg) was not different and the total fat mass (kg) was significantly higher, compared with controls (Table 4). When adjusted for height, total lean mass was again not different between patients and controls; the difference in fat mass increased. The fat mass, expressed as a percentage of the total body mass, was significantly higher in patients. The distribution of the fat mass (in trunk, arms, and legs) was not different in patients and controls (Fig. 1).
Composition of trunk, arms, and legs is given in Table 5(kg) and Fig. 2B(%). In the trunk, lean and fat masses (kg) were not different in patients and controls. When adjusted for height, trunk lean mass was not different and trunk fat mass was significantly higher in patients. In the arms, lean and fat masses were not different in patients and controls. When adjusted for height, arms lean mass was not different and arms fat mass was significantly higher in patients. In the legs, patients had similar lean mass and more fat mass, compared with controls, with and without adjustment for height.
Glucocorticoid doses and morning saliva 17-OHP and androstenedione vs. bone parameters
In both M and F patients, no significant correlation was found between 0.5-, 2-, and 5-yr cumulative glucocorticoid doses (gram per body surface) on one hand and aBMD in lumbar spine or right femoral neck, calcaneal BUA, or SOS on the other hand (Tables 2 and 3). Also no significant correlation was found between 5-yr mean morning salivary levels of 17-OHP and androstenedione and the bone parameters.
Glucocorticoid doses and morning saliva 17-OHP and androstenedione vs. lean and fat mass
Only one significant correlation was found, namely a weak negative correlation between the 0.5-yr cumulative glucocorticoid dose (in growth-retarding equivalents) and the fat mass in females (r = -0.52, P = 0.048). The other correlations between 0.5-, 2-, and 5-yr cumulative glucocorticoid doses (gram per body surface) on one hand and lean mass or fat mass, either in kg or expressed as a percentage of the total body mass, on the other hand, in both M and F patients, were not statistically significant (Tables 2 and 4). Also no significant correlations were found between the 5-yr mean morning salivary levels of 17-OHP and androstenedione and the lean and fat mass parameters.
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Discussion |
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TopAbstractIntroductionPatients and MethodsMethodsResultsDiscussionReferences |
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In this study, we have shown that, in young adult M and F patients with 21-hydroxylase deficiency, DXA estimates of BMD in lumbar spine and right femoral neck are not different from healthy age- and sex-matched controls. In addition, in this patient population, no correlation was found between the 0.5-, 2-, and 5-yr cumulative glucocorticoid dose and the BMD of lumbar spine and femoral neck. Therefore, at this age and with prevailing glucocorticoid regimens, patients and healthy peers seem to have a similar risk for osteoporosis.
There was a significant difference in total body BMC between M patients and controls. Height is an important determinant of total body BMC (23): the larger the skeleton, the larger the two-dimensional DXA image, the larger the total body BMC. Our M patients were, on average, 12.1 cm shorter than controls; and total body BMC divided by bone surface (i.e. total body aBMD) showed no difference between patients and controls. Both observations suggest that the observed difference in total BMC between M patients and controls most likely results from the height difference.
Ultrasound measurement of bone has been proposed as a nonradiation-based method for quantitative assessment of osteoporosis (15). The calcaneus is one of the preferred sites to perform bone ultrasound, because it consists almost entirely of trabecular bone and mimics, in this respect, the spine and the femoral neck (24). In vitro studies have shown that the ultrasound parameter speed of sound (SOS) is a strong and independent predictor of bone stiffness and suggest that ultrasound also gives information about bone microarchitecture (16). The results of calcaneal ultrasound measurements were similar in our patients and controls, except that the M patients had a significantly higher SOS. Because SOS has previously been shown to correlate negatively with foot length in a population of healthy M children (independent of age) (19), we evaluated the influence of foot length, estimated by shoe size, on this finding. Despite the significant difference in shoe size between M patients and controls, the difference in SOS remained significant. This suggests that other characteristics (for example, differences in bone microarchitecture) may cause this specific difference between M patients and controls.
Normal BMD in CAH patients has been reported earlier by other authors (10, 11, 12). The results of our study correspond to those of Mora et al. (11), who found that adolescent and young adult CAH patients had BMD values comparable with controls, despite glucocorticoid treatment. These authors hypothesized that the negative effects of glucocorticoids on bone could be balanced by the positive effects of androgens. Obviously, this may be true as long as glucocorticoid doses in CAH patients are in the low, currently recommended range. In this study, however, we did not find support for this hypothesis, because no statistically significant correlations between BMD and the 5-yr mean salivary levels of 17-OHP and androstenedione were found.
When glucocorticoids are given at higher doses, this will cause increased bone resorption and inhibition of bone formation, leading to reduced BMD (25, 26). Both the reports of Jaaskelainen et al. (6) and Hagenfeldt et al. (7) showed decreased BMD in adult CAH patients that was associated with glucocorticoid overdosing. Cameron et al. (8) also found decreased BMD in a group of pre- and postpubertal CAH males but no correlation with glucocorticoid dose. There are only two reports showing increased BMD, both in prepubertal CAH patients with advanced bone ages; after adjusting for bone age, BMD was still increased (4, 5).
The normal BMD that we observed in our patients does not rule out that these patients may develop glucocorticoid- induced osteoporosis at an older age. In Addison patients, who are generally older than the CAH patients described in our study, low BMD is found especially in men with low testosterone levels and in postmenopausal women (2, 27, 28, 29, 30). This suggests that when gonadal sex steroid levels decrease in Addison patients, i.e. in case of hypogonadism or in postmenopause, the negative glucocorticoid effect on bone is no longer counteracted by the positive effect of sex steroids, resulting in a decline of BMD. This scenario may also apply for elderly CAH patients, in case of hypogonadism or postmenopause, if glucocorticoids are given in a dose that effectively suppresses adrenal androgen production. Therefore, follow-up BMD measurements are justified, even if a normal BMD is found in early adulthood.
Lean and fat mass
As in most previous studies, we found that BMI was significantly higher in CAH patients, compared with controls (13). Half of the patients were overweight (BMI > 25 kg/m2). DXA results showed that lean mass adjusted for height was not different in M patients, compared with controls, but fat mass adjusted for height was significantly higher in patients. Thus, the higher relative fat mass (i.e. fat mass divided by the total body mass) in M patients reflects increased fat mass and not decreased lean mass. This was also observed in females: lean mass was not different between patients and controls, but fat mass (with and without adjustment for height) was higher in the patients, as was the relative fat mass.
One previous study of body composition in CAH patients showed an increased fat/lean ratio in males but not in females (8). However, because these authors used fat/lean ratio and not relative fat and relative lean mass, no direct comparison with our study is possible. Hagenfeldt et al. (7) found increased body fat mass (kg) in F CAH patients but no different lean/fat ratio, compared with age-matched controls.
Treatment with glucocorticoids may lead to a Cushingoid syndrome with central obesity, resulting from redistribution of fat from peripheral to central depots (3, 31, 32). Therefore, the increased fat mass in both M and F patients could be the result of their long-term glucocorticoid use. However, in our patients, no abnormal fat distribution was seen, and no significant positive correlation was found between fat mass and the 0.5-, 2-, and 5-yr cumulative glucocorticoid dose. Still, we cannot exclude that, within the prevailing glucocorticoid dose range, there is a dose-independent effect of chronic glucocorticoid use. Other possible explanations for the increased fat mass could be hypogonadism in males or adrenal androgen excess in females (32). Furthermore, adrenomedullary dysfunction with decreased catecholamine secretion, as recently described in CAH patients (33), may be involved. In this respect, it is of interest that children with CAH have increased leptin levels and decreased insulin sensitivity, which has been ascribed to their adrenomedullary dysfunction (34). Finally, it must be noted that, although on average patients had more fat mass than controls, there were considerable differences in fat mass between patients. Clearly, other factors, such as genetic predisposition to develop overweight and differences in caloric intake, physical activity, and possibly tissue sensitivity to glucocorticoids, may also play a role.
In conclusion, young adult CAH patients using currently recommended low-dose glucocorticoid regimens have BMD values that are not different, compared with healthy, age-matched controls. This does not rule out that they may develop osteoporosis at an older age, especially when sex steroid levels become decreased. Young adult CAH patients have a larger BMI than controls, which is caused by increased fat mass. No positive correlation between fat mass and the 0.5-, 2-, and 5-yr cumulative glucocorticoid dose was found. Because overweight and increased fat mass are associated with the metabolic syndrome and increased cardiovascular risk, weight management should have appropriate attention in the follow-up of CAH patients, to prevent overweight-associated morbidity.
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Acknowledgments |
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Footnotes |
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Received July 10, 2002.
Accepted November 21, 2002.
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