Growth in congenital adrenal hyperplasia
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《美国医学杂志》
1 ]Department of Endocrinology and Diabetes,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
2 Department of Endocrinology and Diabetes,Murdoch Children's Research Institute, Royal Children's Hospital,Parkville, Victoria, Australia
Abstract
Individuals with congenital adrenal hyperplasia (CAH) are shorter, on an average, than the general population. A recent meta analysis of final height in CAH indicated that the height deficit is typically 1 to 2 standard deviations below the mean in both males and females. Growth in CAH due to 21-hydroxylase deficiency is influenced by a number of factors, related both to the underlying disease and its treatment. In general, males with the simple virilising form have the poorest height prognosis. This relates in part to late diagnosis and treatment and the bone age advancement seen in individuals with untreated postnatal androgen excess. Obesity in CAH patients also appears to be correlated with reduced height potential. Glucocorticoid treatment which is vital for cortisol replacement, prevention of adrenal crises and androgen suppression, results in growth inhibition when administered in larger doses. Current evidence suggests that infancy and peripubertal periods are the time periods where height outcome is most sensitive to glucocorticoid dose. More recent estimates of physiological cortisol secretion rates indicate that standard cortisol replacement schedules may result in overtreatment. In addition, dose titration to achieve complete androgen suppression and normalization of 17-hydroxyprogesterone is likely to result in overtreatment and consequent growth impairment. Optimization of current treatment may lead to further improvements in height prognosis. The potential benefits of more complex treatment regimes, using aromatase inhibitors and antiandrogens, in combination with a reduced glucocorticoid dose remain uncertain.
Keywords: Congenital adrenal hyperplasia; Height; Obesity
Growth is a key concern in many chronic disease processes, and in this review the focus in on growth in congenital adrenal hyperplasia. In congenital adrenal hyperplasia (CAH), patients often fail to reach their target height. The literature on height outcome is reviewed in this paper on CAH, and factors related to diagnosis and treatment which are known to affect height outcome are considered. Current strategies to optimize height outcome are indicated and future treatment strategies are discussed.
Final height in CAH
FH in CAH 21OHD patients is often between -1 and -2 SD of normal height of control population. A meta-analysis of 18 studies conducted between 1977 and 1998 in a total of 561 CAH patients revealed that the means FH SDS of CAH patients were in the lower range of normal limits (-1.37 in all, 1.57 in males and -1.24 in females). There was no trend between the year of publication and final height outcomes in all the included studies. This meta-analysis only included studies which had at least 10 subjects with adequate information regarding height outcomes and diagnosis of CAH. The pooled population could be considered as a representative sample of CAH patients as the proportion of early diagnosed patients (in the 1st yr of life indicating they had the classical form) was at 72% (381/527 patients with stated time of diagnosis).[1]
Genetic factors and gender were also considered in the above analysis. The FH SDS was corrected for MPH in those whose target height data were available (204 out of 561 patients) and the corrected FH SDS (defined as mean FH SDS - TH SDS) slightly increased but still below the population mean (-1.21 SD). FH appeared to be slightly higher in females (-1.24 SD) than in males (-1.57 SD) although this difference was not significant.[1]
Factors correlated with height outcome other than corticosteroids
Type of CAH
FH appeared more severely affected in the SV form (FH SDS -1.05 +/- 1 in males and -1.4 +/- 1 in females) than in the SW form (FH-SDS -0.57 +/- 0.8 in males and -0.61 +/- 1 in females) although this was not always statistically significant in different studies.[2], [3] Reduced FH in the SV form may be related to late detection and consequent prolonged exposure to androgen excess, advanced bone age and early puberty in these patients. The NC group had significantly greater FH (0.3 +/- 1.4 in females) than the classical group although this was still slightly lower than that of normal population.[2], [3]
Timing of diagnosis and treatment
In general, a statistically significant difference was seen for patients identified early versus late with better height outcomes in early diagnosed and early treated patients.[1] Normal FH could be achieved if treatment was started early in infancy when bone age and chronological age were comparable. [4],[5],[6] Patients who had treatment starting before 1 year of age had significantly higher FH (up to 6.5cm) compared to later treated or untreated patients in both men[6] and women (up to 6.5cm of difference).[5] This could be the effect of androgen exposure although the types of CAH were not specified in the relating studies. Those with early diagnosis presumably had SW form with more androgen excess than late diagnosed patients who would be likely non-SW. However, one study in Finnish patients found that FH was only affected in men who were diagnosed late.[6] Men with simple virilising CAH are more likely to be diagnosed late and therefore more likely to have height outcomes impaired due to exposure to prolonged androgen excess. Virilisation is more easily recognised in female patients so those with late diagnosis are almost of non-classical type with minimal androgen excess and thus have better height outcomes.
Early treatment is not only important in infancy but also beneficial later in life for NC patients even in the absence of hyperandrogenism. Growth potential (comparison between height at the time of diagnosis and predicted height) appeared less reduced in NC patients with treatment than those without treatment while they were still growing.[3] Improved FH within normal range of MPH SDS was observed in NC patients treated with HC 7.5-15 mg/m2/d at least 1 yr before the onset of puberty, while patients starting treatment after this time almost did not attain their expected height.[7] Although the criteria of treatment for NC patients in previous reports were not clear, these findings raised the possibility that treatment during growing periods and before puberty could be beneficial to NC patients in terms of height outcomes especially if there is precocious or delayed puberty.
Although early treatment helps to improve FH by preventing the effect of growth acceleration, the glucocorticoid dose in infancy should be as low as possible as suggested from a study in Swedish patients (mostly SV patients) where there was no significant acceleration of growth in the first 18 months of life indicating that growth during infancy is less sensitive to androgens.[8] However, growth acceleration with an increase of +0.5 SDS during the first year of life without treatment was observed in patients who were diagnosed after one year of age.[6] While the benefit of glucocorticoid in terms of early growth remains inconsistent, treatment (including stress doses during acute illnesses) in this period should be kept to a minimum to avoid adverse effects on growth. In addition to cautious treatment during infancy, more rational dosing is also needed during puberty because retardation of growth pattern has been observed in infancy and during puberty in the early treated group (usually before the age of 1 yr). With dose adjusted to maintain normal 17OHP and PRA, growth velocity was retarded in infancy[6],[9],[10],[11] and during puberty while growth during childhood was normal.[9],[12] Decreased dose of steroids as age increased did not result in any catch-up growth.[9]
Compliance
Good compliance has generally been associated with improved height outcomes though this factor was assessed quite differently among different studies, based on the subjective assessment of the physicians of clinical visits, patient reports or laboratory results.[1]
Weight/Obesity
FH was negatively correlated with mean relative weight (% in relation to the mean) during childhood in patients diagnosed in infancy.[6] In girls with early treated CAH, high BMI also associated with loss of height potential (mean FH SDS - MPH SDS) during early childhood (3.2-4.6yr) and with over prediction of AH (decreased mean FH SDS- predicted FH) and early menarche in later childhood (7.2-9.1yr).[13] Although the relationship was not explained in those studies, it was possible that glucocorticoids which have been usually prescribed at high doses in infancy and childhood could be a reason for both overweight and reduced height. In a study in school age children, 75% of the children who had treatment with 30 mg/m2/d 30 mg/m GC in the first 2 yr of life had obesity compared to only 11% obesity in those who were treated with <30 mg/m2/d 30 mg/m2.[14]
Salt supplementation
Young infants with salt wasting CAH require supplementation of sodium chloride (1 to 2g or 17 to 34 mmol daily) in addition to steroid treatment because breast milk or formula milk do not contain enough sodium (8 mmol/l) to replace the urinary loss in the first few months of life when they are exclusively fed by milk.[15]
Adrenalectomy
Adrenalectomy has been tried as an alternative to medical treatment in patients with difficult control and helped to improve symptoms related to androgen excess (hirsutism, acne, menstrual abnormalities) while steroid replacement was subsequently reduced. [16],[17],[18] Whether this intervention can improve height outcomes was not demonstrated as all the patients were at or near final height.
Effects of steroid treatment on height outcome
Glucocorticoid (GC) doses
Height in CAH patients can be affected by different ways. In untreated or inadequately treated patients, androgen excess causes acceleration of growth and early fusion of the epiphyseal plates thus reduces height potential. In contrast, excessive corticosteroids in over-treated patients cause suppression of GH secretion which also reduces bone growth. Therefore, to maintain optimal linear growth in CAH, treatment should be adequate to replace the deficient hormones and inhibit the overproduction of adrenal androgens with the lowest dose of glucocorticoid possible.[15] The physiologic cortisol secretion is estimated between 4.8 and 8.7 mg/m2/day in children and adolescents,[19], [20] lower than the previous estimates and the usually prescribed doses of glucocorticoid (10-20 mg/m2/day of HC).[21]
Higher doses of GC have been shown to correlate with decreased height velocity although studies of the effect of GC dose on height velocity have been limited to short term treatment. The results, therefore, cannot be extrapolated to final height and any benefit of lower dose GC on FH has not been demonstrated. The effect of GC on adrenal suppression was dose dependent although GH secretion was not different between high (25mg/m2/d) and low dose GC (15mg/m2/d). In addition, increased adrenal precursors (17-OHP, testosterone, and androstenedione) have been found even with high dose GC treatment (25mg/m2/d) while height velocity positively correlates with 17 OHP as an indicator of GC excess.[22]
Most studies have not reported an association between GC dose and FH.[10] However, when different age intervals were analysed separately, there was a negative relationship between GC doses and height for age Z-score between the ages of 6-12m, 8-10yr, and 12-14y without any effect on weight in SW patients.[23] The same negative correlation was also reported between FH and GC doses between birth and 2 yr of age, as well as height at 2 yr of age[2], [24] which is the period when patients were most likely to receive high dose of steroids to prevent or treat adrenal crises. Height at 2 yr was also highly correlated to height in later periods.[25] Together with available data on growth patterns, this indicates that height outcomes are more vulnerable during infancy and puberty, and high doses of GC during these periods have a greater impact on potential height.
Aims of treatment
Different markers have been used to monitor treatment including levels of adrenal precursors and androgens. Androgen excess (androstenedione in infancy and childhood and testosterone in childhood) has been shown to be negatively correlated with FH and therefore treatment should aim to keep the androgen levels appropriate for the age and sex of the patients.[10] However, attempts to normalise all the adrenal markers (ie. 17 hydroxyprogesterone < 3nmol/l) usually require using glucocorticoid in supraphysiological doses. Corticosteroids sufficient to maintain normal levels of adrenal precursors (urinary pregnanetriol or plasma 17-OHP and PRA) did not help the patients to attain target height.[9] To avoid adverse effects of glucocorticoid including growth impairment, dosing should be adjusted to maintain 17-OHP at a level slightly higher than normal (between 3 and 30 nmol/l).[15] Assessment of adequate control based on normalisation of biochemical markers alone have been disappointing in terms of long term height outcome and it is therefore necessary to take into account other clinical factors including growth. Patients who are adequately treated with steroid doses adjusted based on both growth and biochemical markers had greater FH than those inadequately treated.[26]
Types of GC
Most patients had various regimes of GC during follow up making it difficult to compare different types of GC in terms of effect on height outcomes. Among different GC used in CAH, DXM have had a better effect on biochemical control (24h profile of ACTH, 17OHP, androstenedione, DHEAS) at 0.75 mg daily compared to HC (30mg daily) or CA (37.5mg daily) and no difference was seen between HC and CA.[27], [28] However, DXM also caused the greatest reduction in nocturnal GH secretion and a higher steroid dose in the evening had more inhibitory effect on nocturnal GH secretion.[29] This is the reason why HC with its shorter half life is the most commonly used GC in CAH.
Hydrocortisone
FH in patients treated with cortisone or HC generally ranged from less than 0 to -1.5 below the average.[3],[30],[31],[32] FH in the normal range could be achieved even with cortisone at 20-25 mg/m2[33] although the same dose could result in significant reduction of FH in other patients.[12]
Dexamethasone
With DXM, normal growth (FH -1 SD) could be achieved if patients started treatment early in infancy with the average dose of 0.27 +/- .01 mg/m2/d.[4] There is evidence that most patients only need <0.5 mg/d to eliminate adrenal insufficiency while avoiding GC excess.[34] However, in patients treated with DXM, doses should be finely adjusted to each patient as a 0.75mg daily regime could result in menstrual disturbances, Cushing's syndrome and hirsutism while reduction of the dose from 0.75 mg to 0.5 mg could lead to significant deterioration in control.[35] Side effects such as overweight were more common in patients with DXM treatment than patients with HC treatment (42.9% vs 38.1%).[36] Dosing of DXM also depends on the equivalent dose ratio in GC effects of DXM and HC which used to be 1:30 (compared to 1:80 recently) and could result in overdose in patients treated with DXM.[23]
Cortisone acetate
Long term follow up of children receiving CA for CAH showed a growth failure after the first year of life with relatively normal height during childhood and delay of pubertal growth spurt in females.[33]
Alternative regimen of reduced HC in combination with antiandrogens and aromatase inhibitors
Other drugs have been introduced in the treatment of CAH to reduce GC dose. The combination of reduced dose HC (8.7mg/m2/d) with antiandrogen (flutamide) and anti-aromatase (testolactone) also provided adequate control of CAH while maintaining normal linear growth rate over 2 yr (0.1 +/- 0.5 SD) compared to conventional regimen with higher dose GC at 13.3mg/m2/d and FC.[37] The benefits and risks of this new regimen in terms of height outcomes still need to be confirmed in more long term studies.
Mineralocorticoids
Although having significant glucocorticoid action (15 times that of HC), 9 alpha fludrocortisone (fludrocortisone) with its small dose (usually 50-200mcg/day) had much less GC effects on patients. However, fludrocortisone has been shown to have impact on growth. A significant decrease of height velocity (8.1 to 6.3 cm/y) occurred over 6 months after 9 alpha F had been increased from 68 to 98 mcg/m2/d in a controlled trial in SW patients aged from 2 to 12 yrs. The high dose decreased PRA from slightly higher than normal limits (10.4 +/- 1.6 ng/ml/h) to normal (3.9 +/- 1.1) suggesting that 9 alpha F needed to be adjusted but should not aim to normalise PRA to ensure good short term growth.[38]
MC has usually been prescribed for all patients with CAH regardless of their hormonal status based on the assumption that these patients may have some degree of aldosterone deficiency. MC can help to reduce GC dose by adding some adrenal suppression.[15] There has been evidence that fludrocortisone may not be beneficial in non salt losers as there has been withdrawal of 9 alpha F from 0.1mg daily in these patients did not result in any difference in short term height outcomes.[22]
Conclusion
Long term follow-up of children receiving CA for CAH patients generally achieve FH in the lower normal range (generally from -1 to -2 SD). Better height outcomes are seen in patients with non-classical CAH, early diagnosis, adequate treatment and good compliance. Growth velocity is retarded in patients in whom 17 OHP is normalised requiring careful titration of glucocorticoid with the use of short acting GC at the lowest dose possible. Reduced growth velocity, overweight and normal adrenal precursors should be considered as indicators of steroid excess. Growth is more affected during infancy and puberty implying that patients may benefit from closer monitoring during these periods.
Abbreviations
CAH = congenital adrenal hyperplasia
17-OHP = 17 hydroxyprogesterone;
FH = Final height
MPH = Mid parental height
GC = Glucocorticoid;
MC = mineralocorticoid
PRA = plasma renin activity
HC = hydrocortisone;
PP = precocious puberty
CPP = central precocious puberty
HPG = hypothalamo-pituitary-gonadal axis
DXM = dexamethasone
CA = cortisone acetate
NE = non classical
References
1. Eugster EA et al. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis.[see comment]. Journal of Pediatrics 2001. 138(1): 26-32.
2. Manoli I et al Early growth, pubertal development, body mass index and final height of patients with congenital adrenal hyperplasia: factors influencing the outcome. Clinical Endocrinology 2002; 57(5): 669-676.
3. New MI et al. Growth and final height in classical and nonclassical 21-hydroxylase deficiency. Journal of Endocrinological Investigation 1989. 12(8 Suppl 3): 91-95.
4. Rivkees SA, Crawford JD. Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth. Pediatrics , 2000; 106(4) : 767-773.
5. Klingensmith GJ et al. Glucocorticoid treatment of girls with congenital adrenal hyperplasia: effects on height, sexual maturation, and fertility. J Pediatrics 1977; 90(6) : 996-1004.
6. Jaaskelainen J, Voutilainen R. Growth of patients with 21-hydroxylase deficiency: an analysis of the factors influencing adult height. Pediatric Research 1997; 41(1): 30-33.
7. Weintrob N et al. Non-classical 21-hydroxylase deficiency in infancy and childhood: the effect of time of initiation of therapy on puberty and final height. European J Endocrinology 1997; 136(2): 188-195.
8. Thilen A et al. Early growth is not increased in untreated moderately severe 21-hydroxylase deficiency.[see comment]. Acta Paediatrica 1995; 84(8): 894-898.
9. Rasat R, Espiner EA, Abbott GD, Growth patterns and outcomes in congenital adrenal hyperplasia; effect of chronic treatment regimens. New Zealand Medical Journal 1995; 108(1005): 311-314.
10. Muirhead S et al. Indicators of adult height outcome in classical 21-hydroxylase deficiency congenital adrenal hyperplasia. J Pediatrics 2002; 141(2): 247-252.
11. Brook CG et al. Height correlations between parents and mature offspring in normal subjects and in subjects with Turner's and Klinefelter's and other syndromes. Annals of Human Biology 1977; 4(1) : 17-22.
12. Gussinye, M et al. Adult height, pattern of growth and pubertal development in patients with congenital adrenal hyperplasia, salt losing form]. Medicina Clinica 1997. 108(3): 87-90.
13. Yu, A.C. and D.B. Grant, Adult height in women with early-treated congenital adrenal hyperplasia (21-hydroxylase type): relation to body mass index in earlier childhood. Acta Paediatrica 1995; 84(8): 899-903.
14. Knorr, D. and S.G. Hinrichsen de Lienau, Persistent obesity and short final height after corticoid overtreatment for congenital adrenal hyperplasia (CAH) in infancy. Acta Paediatrica Japonica 1988. 30(Suppl): 89-92.
15. Speiser PW, White PC, Congenital adrenal hyperplasia. New England Journal of Medicine 2003; 349(8): 776-88.
16. Gmyrek GA et al . Bilateral laparoscopic adrenalectomy as a treatment for classic congenital adrenal hyperplasia attributable to 21-hydroxylase deficiency. Pediatrics 2002; 109(2): E28.
17. Warinner SA et al. Study of three patients with congenital adrenal hyperplasia treated by bilateral adrenalectomy. World Journal of Surgery 2000; 24(11): 1347-1352.
18. Scaroni C et al. Unilateral adrenal tumor, erectile dysfunction and infertility in a patient with 21-hydroxylase deficiency: effects of glucocorticoid treatment and surgery. Experimental and Clinical Endocrinology & Diabetes 2003; 111(1): 41-43.
19. Kerrigan JR et al. Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. Journal of Clinical Endocrinology & Metabolism 1993; 76(6): 1505-1510.
20. Linder BL et al. Cortisol production rate in childhood and adolescence.[see comment]. Journal of Pediatrics 1990. 117(6): 892-896.
21. Ten S, New M, Maclaren N, Clinical review 130: Addison's disease 2001. J Clinical Endocrinology & Metabolism 2001; 86(7): 2909-2922.
22. Silva IN et al. Randomised controlled trial of growth effect of hydrocortisone in congenital adrenal hyperplasia. Archives of Disease in Childhood 1997; 77(3): 214-218.
23. Stikkelbroeck NM et al. Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deficiency: in early infancy and (pre)puberty. Journal of Clinical Endocrinology & Metabolism 2003; 88(8): 3525-3530.
24. Ciaccio M et al. Effect of the dose of oral hydrocortisone on growth rate during long-term treatment of children with salt losing congenital adrenal hyperplasia. Medicina 2002; 62(6): 551-554.
25. Girgis R, Winter JS. The effects of glucocorticoid replacement therapy on growth, bone mineral density, and bone turnover markers in children with congenital adrenal hyperplasia.[see comment]. Journal of Clinical Endocrinology and Metabolism 1997; 82(12): 3926-3929.
26. Kirkland RT et al . The effect of therapy on mature height in congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 1978; 47(6): 1320-1324.
27. Horrocks PM, London DR. A comparison of three glucocorticoid suppressive regimes in adults with congenital adrenal hyperplasia. Clinical Endocrinology 1982. 17(6): p. 547-556.
28. Young MC, Hughes IA. Dexamethasone treatment for congenital adrenal hyperplasia. Archives of Disease in Childhood 1990. 65(3): 312-314.
29. Balsamo A et al. [Corticosteroid treatment regimes and growth hormone secretion in congenital adrenogenital syndrome]. Pediatria Medica Chirurgica 1993; 15(6): 585-587.
30. David M et al. [Final height in 69 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency]. Archives de Pediatrie 1994; 1(4): 363-367.
31. Brook CG et al . Experience with long-term therapy in congenital adrenal hyperplasia. Journal of Pediatrics 1974; 85(1): 12-19.
32. Young MC, Ribeiro J, Hughes IA. Growth and body proportions in congenital adrenal hyperplasia. Archives of Disease in Childhood 1989; 64(11): 1554-1558.
33. Clayton, G.W., Patterns of growth from birth to maturity in infants and children with congenital adrenal hyperplasia. Acta Endocrinologica. Supplementum 1986; 279: 295-304.
34. Li, HY, Dahir KM, Blevins LS, Jr. Treatment of adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a clinical practice audit. Endocrine Practice 2003; 9(5): 347-352.
35. Horrocks PM, London DR. Effects of long term dexamethasone treatment in adult patients with congenital adrenal hyperplasia. Clinical Endocrinology 1987; 27(6) : 635-642.
36. Nanbu A et al. [A clinical study of congenital adrenal hyperplasia]. Hinyokika Kiyo - Acta Urologica Japonica., 1989; 35(11): 1831-1837.
37. Merke DP et al. Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2000; 85(3): 1114-1120.
38. Lopes LA et al. Should we monitor more closely the dosage of 9 alpha-fluorohydrocortisone in salt-losing congenital adrenal hyperplasia Journal of Pediatric Endocrinology and Metabolism 1998; 11(6): 733-737.(Nguyen An TT, Brown Justi)
2 Department of Endocrinology and Diabetes,Murdoch Children's Research Institute, Royal Children's Hospital,Parkville, Victoria, Australia
Abstract
Individuals with congenital adrenal hyperplasia (CAH) are shorter, on an average, than the general population. A recent meta analysis of final height in CAH indicated that the height deficit is typically 1 to 2 standard deviations below the mean in both males and females. Growth in CAH due to 21-hydroxylase deficiency is influenced by a number of factors, related both to the underlying disease and its treatment. In general, males with the simple virilising form have the poorest height prognosis. This relates in part to late diagnosis and treatment and the bone age advancement seen in individuals with untreated postnatal androgen excess. Obesity in CAH patients also appears to be correlated with reduced height potential. Glucocorticoid treatment which is vital for cortisol replacement, prevention of adrenal crises and androgen suppression, results in growth inhibition when administered in larger doses. Current evidence suggests that infancy and peripubertal periods are the time periods where height outcome is most sensitive to glucocorticoid dose. More recent estimates of physiological cortisol secretion rates indicate that standard cortisol replacement schedules may result in overtreatment. In addition, dose titration to achieve complete androgen suppression and normalization of 17-hydroxyprogesterone is likely to result in overtreatment and consequent growth impairment. Optimization of current treatment may lead to further improvements in height prognosis. The potential benefits of more complex treatment regimes, using aromatase inhibitors and antiandrogens, in combination with a reduced glucocorticoid dose remain uncertain.
Keywords: Congenital adrenal hyperplasia; Height; Obesity
Growth is a key concern in many chronic disease processes, and in this review the focus in on growth in congenital adrenal hyperplasia. In congenital adrenal hyperplasia (CAH), patients often fail to reach their target height. The literature on height outcome is reviewed in this paper on CAH, and factors related to diagnosis and treatment which are known to affect height outcome are considered. Current strategies to optimize height outcome are indicated and future treatment strategies are discussed.
Final height in CAH
FH in CAH 21OHD patients is often between -1 and -2 SD of normal height of control population. A meta-analysis of 18 studies conducted between 1977 and 1998 in a total of 561 CAH patients revealed that the means FH SDS of CAH patients were in the lower range of normal limits (-1.37 in all, 1.57 in males and -1.24 in females). There was no trend between the year of publication and final height outcomes in all the included studies. This meta-analysis only included studies which had at least 10 subjects with adequate information regarding height outcomes and diagnosis of CAH. The pooled population could be considered as a representative sample of CAH patients as the proportion of early diagnosed patients (in the 1st yr of life indicating they had the classical form) was at 72% (381/527 patients with stated time of diagnosis).[1]
Genetic factors and gender were also considered in the above analysis. The FH SDS was corrected for MPH in those whose target height data were available (204 out of 561 patients) and the corrected FH SDS (defined as mean FH SDS - TH SDS) slightly increased but still below the population mean (-1.21 SD). FH appeared to be slightly higher in females (-1.24 SD) than in males (-1.57 SD) although this difference was not significant.[1]
Factors correlated with height outcome other than corticosteroids
Type of CAH
FH appeared more severely affected in the SV form (FH SDS -1.05 +/- 1 in males and -1.4 +/- 1 in females) than in the SW form (FH-SDS -0.57 +/- 0.8 in males and -0.61 +/- 1 in females) although this was not always statistically significant in different studies.[2], [3] Reduced FH in the SV form may be related to late detection and consequent prolonged exposure to androgen excess, advanced bone age and early puberty in these patients. The NC group had significantly greater FH (0.3 +/- 1.4 in females) than the classical group although this was still slightly lower than that of normal population.[2], [3]
Timing of diagnosis and treatment
In general, a statistically significant difference was seen for patients identified early versus late with better height outcomes in early diagnosed and early treated patients.[1] Normal FH could be achieved if treatment was started early in infancy when bone age and chronological age were comparable. [4],[5],[6] Patients who had treatment starting before 1 year of age had significantly higher FH (up to 6.5cm) compared to later treated or untreated patients in both men[6] and women (up to 6.5cm of difference).[5] This could be the effect of androgen exposure although the types of CAH were not specified in the relating studies. Those with early diagnosis presumably had SW form with more androgen excess than late diagnosed patients who would be likely non-SW. However, one study in Finnish patients found that FH was only affected in men who were diagnosed late.[6] Men with simple virilising CAH are more likely to be diagnosed late and therefore more likely to have height outcomes impaired due to exposure to prolonged androgen excess. Virilisation is more easily recognised in female patients so those with late diagnosis are almost of non-classical type with minimal androgen excess and thus have better height outcomes.
Early treatment is not only important in infancy but also beneficial later in life for NC patients even in the absence of hyperandrogenism. Growth potential (comparison between height at the time of diagnosis and predicted height) appeared less reduced in NC patients with treatment than those without treatment while they were still growing.[3] Improved FH within normal range of MPH SDS was observed in NC patients treated with HC 7.5-15 mg/m2/d at least 1 yr before the onset of puberty, while patients starting treatment after this time almost did not attain their expected height.[7] Although the criteria of treatment for NC patients in previous reports were not clear, these findings raised the possibility that treatment during growing periods and before puberty could be beneficial to NC patients in terms of height outcomes especially if there is precocious or delayed puberty.
Although early treatment helps to improve FH by preventing the effect of growth acceleration, the glucocorticoid dose in infancy should be as low as possible as suggested from a study in Swedish patients (mostly SV patients) where there was no significant acceleration of growth in the first 18 months of life indicating that growth during infancy is less sensitive to androgens.[8] However, growth acceleration with an increase of +0.5 SDS during the first year of life without treatment was observed in patients who were diagnosed after one year of age.[6] While the benefit of glucocorticoid in terms of early growth remains inconsistent, treatment (including stress doses during acute illnesses) in this period should be kept to a minimum to avoid adverse effects on growth. In addition to cautious treatment during infancy, more rational dosing is also needed during puberty because retardation of growth pattern has been observed in infancy and during puberty in the early treated group (usually before the age of 1 yr). With dose adjusted to maintain normal 17OHP and PRA, growth velocity was retarded in infancy[6],[9],[10],[11] and during puberty while growth during childhood was normal.[9],[12] Decreased dose of steroids as age increased did not result in any catch-up growth.[9]
Compliance
Good compliance has generally been associated with improved height outcomes though this factor was assessed quite differently among different studies, based on the subjective assessment of the physicians of clinical visits, patient reports or laboratory results.[1]
Weight/Obesity
FH was negatively correlated with mean relative weight (% in relation to the mean) during childhood in patients diagnosed in infancy.[6] In girls with early treated CAH, high BMI also associated with loss of height potential (mean FH SDS - MPH SDS) during early childhood (3.2-4.6yr) and with over prediction of AH (decreased mean FH SDS- predicted FH) and early menarche in later childhood (7.2-9.1yr).[13] Although the relationship was not explained in those studies, it was possible that glucocorticoids which have been usually prescribed at high doses in infancy and childhood could be a reason for both overweight and reduced height. In a study in school age children, 75% of the children who had treatment with 30 mg/m2/d 30 mg/m GC in the first 2 yr of life had obesity compared to only 11% obesity in those who were treated with <30 mg/m2/d 30 mg/m2.[14]
Salt supplementation
Young infants with salt wasting CAH require supplementation of sodium chloride (1 to 2g or 17 to 34 mmol daily) in addition to steroid treatment because breast milk or formula milk do not contain enough sodium (8 mmol/l) to replace the urinary loss in the first few months of life when they are exclusively fed by milk.[15]
Adrenalectomy
Adrenalectomy has been tried as an alternative to medical treatment in patients with difficult control and helped to improve symptoms related to androgen excess (hirsutism, acne, menstrual abnormalities) while steroid replacement was subsequently reduced. [16],[17],[18] Whether this intervention can improve height outcomes was not demonstrated as all the patients were at or near final height.
Effects of steroid treatment on height outcome
Glucocorticoid (GC) doses
Height in CAH patients can be affected by different ways. In untreated or inadequately treated patients, androgen excess causes acceleration of growth and early fusion of the epiphyseal plates thus reduces height potential. In contrast, excessive corticosteroids in over-treated patients cause suppression of GH secretion which also reduces bone growth. Therefore, to maintain optimal linear growth in CAH, treatment should be adequate to replace the deficient hormones and inhibit the overproduction of adrenal androgens with the lowest dose of glucocorticoid possible.[15] The physiologic cortisol secretion is estimated between 4.8 and 8.7 mg/m2/day in children and adolescents,[19], [20] lower than the previous estimates and the usually prescribed doses of glucocorticoid (10-20 mg/m2/day of HC).[21]
Higher doses of GC have been shown to correlate with decreased height velocity although studies of the effect of GC dose on height velocity have been limited to short term treatment. The results, therefore, cannot be extrapolated to final height and any benefit of lower dose GC on FH has not been demonstrated. The effect of GC on adrenal suppression was dose dependent although GH secretion was not different between high (25mg/m2/d) and low dose GC (15mg/m2/d). In addition, increased adrenal precursors (17-OHP, testosterone, and androstenedione) have been found even with high dose GC treatment (25mg/m2/d) while height velocity positively correlates with 17 OHP as an indicator of GC excess.[22]
Most studies have not reported an association between GC dose and FH.[10] However, when different age intervals were analysed separately, there was a negative relationship between GC doses and height for age Z-score between the ages of 6-12m, 8-10yr, and 12-14y without any effect on weight in SW patients.[23] The same negative correlation was also reported between FH and GC doses between birth and 2 yr of age, as well as height at 2 yr of age[2], [24] which is the period when patients were most likely to receive high dose of steroids to prevent or treat adrenal crises. Height at 2 yr was also highly correlated to height in later periods.[25] Together with available data on growth patterns, this indicates that height outcomes are more vulnerable during infancy and puberty, and high doses of GC during these periods have a greater impact on potential height.
Aims of treatment
Different markers have been used to monitor treatment including levels of adrenal precursors and androgens. Androgen excess (androstenedione in infancy and childhood and testosterone in childhood) has been shown to be negatively correlated with FH and therefore treatment should aim to keep the androgen levels appropriate for the age and sex of the patients.[10] However, attempts to normalise all the adrenal markers (ie. 17 hydroxyprogesterone < 3nmol/l) usually require using glucocorticoid in supraphysiological doses. Corticosteroids sufficient to maintain normal levels of adrenal precursors (urinary pregnanetriol or plasma 17-OHP and PRA) did not help the patients to attain target height.[9] To avoid adverse effects of glucocorticoid including growth impairment, dosing should be adjusted to maintain 17-OHP at a level slightly higher than normal (between 3 and 30 nmol/l).[15] Assessment of adequate control based on normalisation of biochemical markers alone have been disappointing in terms of long term height outcome and it is therefore necessary to take into account other clinical factors including growth. Patients who are adequately treated with steroid doses adjusted based on both growth and biochemical markers had greater FH than those inadequately treated.[26]
Types of GC
Most patients had various regimes of GC during follow up making it difficult to compare different types of GC in terms of effect on height outcomes. Among different GC used in CAH, DXM have had a better effect on biochemical control (24h profile of ACTH, 17OHP, androstenedione, DHEAS) at 0.75 mg daily compared to HC (30mg daily) or CA (37.5mg daily) and no difference was seen between HC and CA.[27], [28] However, DXM also caused the greatest reduction in nocturnal GH secretion and a higher steroid dose in the evening had more inhibitory effect on nocturnal GH secretion.[29] This is the reason why HC with its shorter half life is the most commonly used GC in CAH.
Hydrocortisone
FH in patients treated with cortisone or HC generally ranged from less than 0 to -1.5 below the average.[3],[30],[31],[32] FH in the normal range could be achieved even with cortisone at 20-25 mg/m2[33] although the same dose could result in significant reduction of FH in other patients.[12]
Dexamethasone
With DXM, normal growth (FH -1 SD) could be achieved if patients started treatment early in infancy with the average dose of 0.27 +/- .01 mg/m2/d.[4] There is evidence that most patients only need <0.5 mg/d to eliminate adrenal insufficiency while avoiding GC excess.[34] However, in patients treated with DXM, doses should be finely adjusted to each patient as a 0.75mg daily regime could result in menstrual disturbances, Cushing's syndrome and hirsutism while reduction of the dose from 0.75 mg to 0.5 mg could lead to significant deterioration in control.[35] Side effects such as overweight were more common in patients with DXM treatment than patients with HC treatment (42.9% vs 38.1%).[36] Dosing of DXM also depends on the equivalent dose ratio in GC effects of DXM and HC which used to be 1:30 (compared to 1:80 recently) and could result in overdose in patients treated with DXM.[23]
Cortisone acetate
Long term follow up of children receiving CA for CAH showed a growth failure after the first year of life with relatively normal height during childhood and delay of pubertal growth spurt in females.[33]
Alternative regimen of reduced HC in combination with antiandrogens and aromatase inhibitors
Other drugs have been introduced in the treatment of CAH to reduce GC dose. The combination of reduced dose HC (8.7mg/m2/d) with antiandrogen (flutamide) and anti-aromatase (testolactone) also provided adequate control of CAH while maintaining normal linear growth rate over 2 yr (0.1 +/- 0.5 SD) compared to conventional regimen with higher dose GC at 13.3mg/m2/d and FC.[37] The benefits and risks of this new regimen in terms of height outcomes still need to be confirmed in more long term studies.
Mineralocorticoids
Although having significant glucocorticoid action (15 times that of HC), 9 alpha fludrocortisone (fludrocortisone) with its small dose (usually 50-200mcg/day) had much less GC effects on patients. However, fludrocortisone has been shown to have impact on growth. A significant decrease of height velocity (8.1 to 6.3 cm/y) occurred over 6 months after 9 alpha F had been increased from 68 to 98 mcg/m2/d in a controlled trial in SW patients aged from 2 to 12 yrs. The high dose decreased PRA from slightly higher than normal limits (10.4 +/- 1.6 ng/ml/h) to normal (3.9 +/- 1.1) suggesting that 9 alpha F needed to be adjusted but should not aim to normalise PRA to ensure good short term growth.[38]
MC has usually been prescribed for all patients with CAH regardless of their hormonal status based on the assumption that these patients may have some degree of aldosterone deficiency. MC can help to reduce GC dose by adding some adrenal suppression.[15] There has been evidence that fludrocortisone may not be beneficial in non salt losers as there has been withdrawal of 9 alpha F from 0.1mg daily in these patients did not result in any difference in short term height outcomes.[22]
Conclusion
Long term follow-up of children receiving CA for CAH patients generally achieve FH in the lower normal range (generally from -1 to -2 SD). Better height outcomes are seen in patients with non-classical CAH, early diagnosis, adequate treatment and good compliance. Growth velocity is retarded in patients in whom 17 OHP is normalised requiring careful titration of glucocorticoid with the use of short acting GC at the lowest dose possible. Reduced growth velocity, overweight and normal adrenal precursors should be considered as indicators of steroid excess. Growth is more affected during infancy and puberty implying that patients may benefit from closer monitoring during these periods.
Abbreviations
CAH = congenital adrenal hyperplasia
17-OHP = 17 hydroxyprogesterone;
FH = Final height
MPH = Mid parental height
GC = Glucocorticoid;
MC = mineralocorticoid
PRA = plasma renin activity
HC = hydrocortisone;
PP = precocious puberty
CPP = central precocious puberty
HPG = hypothalamo-pituitary-gonadal axis
DXM = dexamethasone
CA = cortisone acetate
NE = non classical
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