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The Effects of Glucocorticoid Replacement Therapy on Growth, Bone Mineral Density, and Bone Turnover Markers in Children with Congenital Adrenal Hyperplasia

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada T6G 2R7

Address all correspondence and requests for reprints to: Rose Girgis, Pediatric Endocrinology Fellow, Division of Endocrinology and Metabolism, Department of Pediatrics 2C3 WMC, University of Alberta, 8440–112 Street, Edmonton, Alberta, Canada T6G 2R7.

	Abstract

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Even with current so called physiologic doses of glucocorticoid replacement therapy, children with congenital adrenal hyperplasia (CAH) often show relative short stature and delayed bone maturation, an observation that suggests possible long-term effects on bone metabolism of daily transient post-absorptive hypercortisolemia. In 28 patients with 21-hydroxylase or 17 -hydroxylase deficiency (16 females and 12 males, ages 4.9–22 yr) who had received oral cortisol 10–15 mg/M²/day for 4.7–22 yr, we studied cortisol bioavailability, growth, bone maturation, vertebral bone mineral density, and various markers of bone formation and resorption. Patients were grouped according to mean on-therapy serum 170H-progesterone or progesterone levels as tight control (170HP < 10 nmol/L), fair control (170HP 10–40 nmol/L or progesterone 1.0–1.5 nmol/L), or poor control (170HP > 40 nmol/L). There was no difference in peak post-absorptive serum cortisol or area under the concentration-time curve, and only three patients had a peak serum cortisol of more than 700 nmol/L. There was no difference in present height Z-score (-0.96; -0.24; -0.6), height Z-score at age 2 yr (-1.5; +0.4; -1.3), or current growth velocity Z-score (-0.1; +1.2; -2.2) between the groups, but bone maturation Z-score was significantly delayed (-1.63) in the tight control group and advanced (+0.8) in the poor control group. Present height was highly correlated (r = 0.8) with height at age 2 yr. Serum calcium, phosphorus, alkaline phosphatase, parathormone, and 25OH-vitamin D levels were all normal. There was no difference between the groups in age-corrected vertebral bone mineral density, and no difference in serum osteocalcin, procollagen peptide, or collagen C-terminal telopeptide, nor in urinary amino-terminal telopeptide. The data suggest that current methods of cortisol replacement do not significantly influence bone formation, resorption or density during childhood and therefore should not contribute to adult osteoporosis. The possibility remains that hypercortisolemia during infancy produces the short stature and delayed bone maturation that are present by the age 2 yr.

	Introduction

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CHILDREN WITH congenital adrenal hyperplasia (CAH) receive glucocorticoid therapy from the time of diagnosis, which may be at birth or even during fetal life. Current methods for monitoring this therapy have permitted considerable reduction in the doses of glucocorticoid used (1). Affected children are no longer overtly cushingoid, but there is evidence that even modern glucocorticoid replacement therapy impacts on skeletal growth and maturation. Thus patients typically show some degree of short stature and delayed bone maturation during childhood. In reported studies of adult survivors, the final height achieved is often 1.0–1.5 SD below average (2). As many as one third of CAH adults now have heights over 2 SD below the mean, although most of these did not benefit from modern methods of therapy (3, 4, 5).

Because of these observations, we have been concerned that oral glucocorticoid therapy, even in the so-called physiologic doses currently used in CAH, might expose these children to repeated transient periods of post-absorptive hypercortisolemia. Kehlet et al. (6) found in adult adrenalectomized patients that typical replacement doses of oral cortisol cause peak serum cortisol concentrations of 750-1700 nmol/L, levels as high as those in patients with Cushing’s disease. Perhaps such transient hypercortisolemia, repeated through infancy and childhood, could impact upon growth, skeletal maturation, and bone mineralization. Therefore we have studied cortisol bioavailability and various markers of bone growth and mineralization in a group of children with CAH who have received long-term glucocorticoid therapy under careful monitoring in our clinic.

	Materials and Methods

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The protocol was approved by the Ethics in Human Research Committee of the University of Alberta Hospital. Each child and the parents provided informed consent, and test results were discussed later with each family.

Subjects

There were 32 patients in our clinic with CAH who met the criterion of having received oral cortisol three times a day in a total dose of 10–15 mg/m²/day for at least 4 yr, under the supervision of a single endocrinologist. Four patients were unable to participate because of the expense and inconvenience of travel. Twenty-eight patients with either classical 21-hydroxylase deficiency or 17-hydroxylase deficiency (16 females, 12 males), ages 4.9–22 yr, were enrolled in the study. Twenty-three patients had salt-losing 21-hydroxylase deficiency and had received glucocorticoid and mineralocorticoid therapy since early infancy; one of these, now age 17 yr, had been treated elsewhere with excessive doses of prednisone for the first 2 yr of life. Three boys presented with simple virilizing 21-hydroxylase deficiency at 18–36 months of age; because their initial plasma renin values were elevated, they also received both glucocorticoid and mineralocorticoid replacement. The mineralocorticoid was oral 9-fluorohydrocortisone in amounts (0.1–0.2 mg/day) sufficient to maintain age-appropriate normal values of plasma renin and blood pressure. The final two patients were 46,XY male pseudohermaphrodites with 17-hydroxylase deficiency, who had been treated with oral cortisol since the ages of 3 and 5; they also received ethinyl estradiol at the time of puberty. No patient was taking other long-term medication, had any renal or nutritional disorder, or had a life style that would contribute to osteoporosis. At the time of the study, 11 patients were prepubertal, 7 were in early puberty (Tanner stage 2), four were stage 3, one was stage 4, and five were sexually mature (stage 5).

At least twice a year the dose of cortisol was adjusted on the basis of body size and the levels of serum 170H-progesterone (or progesterone in the two patients with 17-hydroxylase deficiency) drawn at 0830 before the morning cortisol dose and again at 1130. Growth and sexual maturation were assessed at each visit, and serum testosterone and plasma renin were measured. Wrist x-rays for bone age, using the standards of Greulich and Pyle (7), were obtained every 2 yr.

For this study the patients were grouped according to their metabolic control throughout the years of therapy with oral cortisol. In the 21-hydroxylase deficient subjects, tight control was defined as a mean serum 170H-progesterone value from all clinic visits of less than 10 nmol/L. Fair control was defined as a mean serum 170H-progesterone value of 10–40 nmol/L, together with normal levels of plasma renin. Poor control was defined as a mean serum 170H-progesterone value over 40 nmol/L; these were chronically noncompliant patients who also showed elevated levels of serum testosterone and plasma renin. In the two patients with 17-hydroxylase deficiency, mean serum progesterone values were 1.0–1.5 nmol/L, and blood pressure was normal on therapy; they were assigned arbitrarily to the fair control group. The mean coefficient of variance for 17OH-progesterone values from all clinic visits was ± 146% in the tight control group, ± 156% in the fair control group, and ± 156% in the poor control group.

Study protocol

All patients reported to the Clinical Investigation Unit at 0800, were examined and measured, and had blood drawn for their routine CAH monitoring and for serum calcium, phosphorus, alkaline phosphatase, parathormone, and 25OHD. Serum cortisol levels were measured before and at 30-min intervals for 2 h after ingestion of the usual morning dose of cortisol. At 1000 blood was drawn for analysis of osteocalcin, procollagen peptide, and collagen C-terminal telopeptide, and a urine sample was obtained for analysis of collagen amino-terminal telopeptide. All specimens were stored at -20 C until analysis.

Each patient had a wrist x-ray for bone age. Bone mineral density (BMD) of vertebrae L1 to L4, including intervertebral discs, was measured by dual energy x-ray absorptiometry (QDR 4500A Hologic, Waltham, MA) with in vivo precision value of 0.00806 g/cm² for the lumbar spine and a skin radiation dose less than 20 mrem. These results were compared with published standards for children (8, 9).

Calcium, phosphorus, and alkaline phosphatase were measured using a Boehringer Mannheim Hitachi 917 analyzer (Indianapolis, IN). Cortisol was measured by a competitive chemiluminescence immunoassay (ACS180, Ciba Corning, Medfield, MA). 25OH-Vitamin D was measured by RIA (Incstar, Stillwater, MN), with an interassay coefficient of variation of ± 14.9%. Intact PTH was measured by a chemiluminescent enzyme immunometric assay using the Immulite Automated Analyzer (Diagnostic Products, Los Angeles, CA).

Serum osteocalcin was assayed by RIA (Incstar) with an interassay coefficient of variance of ± 10.2%. Values were compared with levels in healthy children reported by Magnusson et al. (10) and Tarallo et al. (11). Serum procollagen peptide was measured by RIA (Incstar), with an interassay coefficient of variation of 5.2%; results were compared with the normal values of Saggese et al. (12) and of Triverdi and Risteli, University of Oulu, (personal communication).

As an index of bone resorption, fragments from osteoclastic degradation of the -chain of type I collagen were assayed as serum C-terminal telopeptide by RIA (Incstar) and as urinary amino-terminal telopeptide by ELISA (Ostex, Seattle, WA). These were compared with values for normal subjects (13; Triverdi and Risteli, personal communication).

Statistical analysis

Data were converted to standard deviation (Z) scores by comparison with age-appropriate normal standards. Differences between groups were assessed by two-way analysis of variance and Duncan’s test (14). Pearson’s correlation test was used to evaluate the relationship of growth and endocrine parameters to control.

	Results

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The mean duration of glucocorticoid replacement therapy in these patients was 11.4 ± 4.5 yr (range 4.7–22 yr). Fifteen patients, ages 4.9–22 yr, showed tight control, with a mean serum 170H-progesterone value during therapy of 2.9 ± 2.3 nmol/L. Eight 21-hydroxylase deficient patients ages 9.6–20.0 yr had fair control, with a mean serum 170H-progesterone value of 23.4 ± 10.9 nmol/L. To this group were added two 17-hydroxylase-deficient patients aged 14.4 and 16.2 yr. Three patients, ages 7.8–15.1 yr were in chronically poor control, with a mean serum 170H-progesterone value of 50.4 ± 8.5 nmol/L.

Post-absorptive serum cortisol

After the usual morning dose of oral cortisol, serum cortisol levels rose to a mean peak of 477 ± 212 nmol/L (range 95–838 nmol/L). There was no difference in cortisol bioavailability between the 3 patient groups as reflected in peak serum cortisol or area under the concentration-time curve. Only 3 of the 28 patients achieved a peak serum cortisol value greater than the morning normal range (>700 nmol/L). There were no differences in any of the parameters of the study in these 3 patients.

Growth

At the time of study the tight control group had a mean height Z-score of -0.96 ± 1.2 and a bone age Z-score of -1.63 ± 1.6. In these patients, the height Z-score at age 2 yr had been -1.48 ± 1.4, evidence that any growth impairment had occurred during infancy. Their mean height growth velocity Z-score during the most recent 2 yr of therapy was -0.1 ± 2.4, suggesting that tight control does not impair growth velocity later in childhood.

In the fair control group, the mean height Z-score was -0.24 ± 1.5, with a bone age Z-score of -0.1 ± 0.9. At age 2 yr, their height Z-score was 0.4 ± 2.0 and their mean height growth velocity Z-score during the last 2 yr was 1.2 ± 1.4.

The poor control group had a mean height Z-score of -0.6 ± 0.3, with a bone age Z-score of 0.8 ± 1.5. At age 2 yr, their height Z-score was -1.3 ± 1.1. Their current growth velocity Z-score was -2.2 ± 3.3.

There were no significant differences between the three groups in present height, height at age 2 yr, or current growth velocity. There was a strong correlation (r = 0.8; P < 0.0001) between present height and height at age 2 yr, further evidence that growth during infancy is a major determinant of height in later childhood and adolescence. By comparison with the fair control group, bone maturation was delayed with tight control (P < 0.05) and advanced by poor control (P < 0.05). In the 26 patients with 21-hydroxylase deficiency there was a significant correlation (r = 0.6; P < 0.01) between bone age and mean serum 170H-progesterone on therapy, and also between bone age and present height (r = 0.42; P < 0.05). The duration of glucocorticoid therapy showed a significant negative correlation (r = -0.46; P < 0.01) with present height Z-score, but had no relation to any other variables.

Bone mineral density

The tight control group had a mean bone mineral density (BMD) Z-score of -0.6 ± 1.0 (range -2.12 to +1.34). The fair control group had a BMD Z- score of -1.1 ± 0.7 (range -2.27 to +0.04), while the three poorly controlled patients had a BMD Z-score of 0.1 ± 0.5 (range -0.34 to +0.62). The differences in BMD Z-scores were not statistically significant, and there was no correlation with serum 170H-progesterone, height, or growth velocity.

Bone metabolism

Serum concentrations of calcium, phosphorus, alkaline phosphatase, parathormone, and 25-hydroxyvitamin D were within the normal range in all subjects, with no difference between treatment groups. Levels of the bone formation markers osteocalcin and procollagen peptide, and the bone resorption markers C-terminal telopeptide and aminoterminal telopeptide are summarized in Table 1. There was no significant difference between the groups for any of these markers and no correlation with serum 170H-progesterone levels.

	Discussion

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Although in past years children with congenital adrenal hyperplasia experienced significant mortality and morbidity even after diagnosis (15), recent improvements in management with more careful monitoring have permitted the goals of therapy to shift to the prevention of physical and psychological disability. Quite appropriately, concerns have been raised that glucocorticoid replacement therapy might reduce growth and final height and might predispose to later osteoporosis (2, 16). On the other hand, inadequate replacement therapy, with resulting androgen excess, is known to accelerate bone maturation and to impair growth potential.

For two decades we have applied in our clinic a protocol of regular monitoring of serum 170H-progesterone and plasma renin (1), an approach that has permitted doses of oral cortisol replacement to be reduced to 10–15 mg/m²/day. With such doses, children with CAH are never cushingoid, and they show normal growth velocity. However, there is increasing evidence that many of these children still show some degree of short stature and delayed bone maturation, which may result in reduced final height. Furthermore, reduced bone mineral accretion during childhood and ad-olescence might significantly increase the risk of later osteoporosis.

The present study shows that vigorous control of CAH, which reduces serum 170H-progesterone and androgen levels to the normal range, is associated with slightly reduced height and bone age Z-scores, even though current growth velocity is normal. While this situation is preferable to that of poor metabolic control with accelerated bone maturation, it is still unsatisfactory. Retrospective analysis demonstrates that short stature, if it occurs, is present by 2 yr of age and presumably results from hypercortisolemia during early infancy. It is important to recognize that, despite the lack of difference in present height found in the study, the group difference in bone age Z-score may influence final height.

Studies in adrenalectomized adults suggested that standard oral cortisol doses cause significant post-absorptive hypercortisolemia (6), perhaps sufficient to suppress growth hormone secretion and reduce bone growth. The present study indicates that currently used oral cortisol doses do not cause hypercortisolemia, at least in older children. Even patients under tight metabolic control for many years show normal growth velocity, normal BMD, and no evidence, using currently available markers, of either reduced bone mineral accretion or increased bone resorption. Our results confirm the conclusion of Cameron et al. (16) that replacement therapy does not lead to decreased BMD in the vertebrae, the most sensitive indicator of glucocorticoid effects. The relationship of long-term low-dose glucocorticoid therapy to the maintenance of BMD in adults must be the subject of another study.

It would appear, therefore, that current modes of therapy and monitoring are appropriate for children with CAH after age 2 yr. Provided these children continue to show normal growth velocity during late childhood and adolescence, it seems likely that bone mineral accretion will be normal and that their replacement therapy should not increase the risk of osteoporosis in later years. However, the observation in this and other studies (2, 4) that well-controlled children with CAH are often already short by age 2 suggests that inadvertent hypercortisolemia or sodium depletion during infancy can cause growth retardation that is not corrected by catch up growth in later years. Therefore, we should concentrate our attention on the pharmacodynamics of oral cortisol therapy during early infancy and the possible impact of even slight hypercortisolemia on growth velocity at this critical time.

	Acknowledgments

 
We thank Dr. Don Spady for helping with the statistical analysis of the data, Dr. Elizabeth Miller for reviewing the bone age x-rays, Mrs. Lorraine Hirsch for typing the manuscript, and the staff of the Clinical Investigation Unit of the University of Alberta Hospital.

Received March 24, 1997.

Revised June 18, 1997.

Accepted July 7, 1997.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Girgis, R. Articles by Winter, J. S.D. Search for Related Content PubMed PubMed Citation Articles by Girgis, R. Articles by Winter, J. S.D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Child Development Steroids Hazardous Substances DB HYDROCORTISONE