PDF hosted at the Radboud Repository of the Radboud University
Nijmegen
The following full text is a publisher's version.
For additional information about this publication click this link.
http://hdl.handle.net/2066/50215
Please be advised that this information was generated on 2017-06-18 and may be subject to
change.
0021-972X/06/$15.00/0
Printed in U.S.A.
The Journal of Clinical Endocrinology & Metabolism 91(4):1205–1209
Copyright © 2006 by The Endocrine Society
doi: 10.1210/jc.2005-1701
EXTENSIVE CLINICAL EXPERIENCE
Absence of Increased Height Velocity in the First Year of
Life in Untreated Children with Simple Virilizing
Congenital Adrenal Hyperplasia
Hedi L. Claahsen-van der Grinten, Kees Noordam, George F. Borm, and Barto J. Otten
Departments of Metabolic and Endocrine Diseases (H.L.C.-v.d.G., K.N., B.J.O.) and Epidemiology and Biostatistics (G.F.B.),
Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
Context: In congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation
with compromised adult height.
Objective/Patients: The objective of the study was to analyze retrospectively early growth and bone maturation in 17 untreated simple
virilizing (SV) CAH patients.
Setting: The study was conducted at Radboud University Nijmegen
Medical Centre.
Interventions: Growth data were collected until time of diagnosis.
Height was expressed as height SD score and corrected for target
height. Bone maturation was determined and expressed as bone age
acceleration.
Results: In the term group (n ⫽ 11), there was no increase in height
SD score and corrected for target height in the first year of life [⫺0.1
SD/yr; 95% confidence interval (CI) ⫺0.5, 0.3] with a consecutive
significant (P ⬍ 0.001) increase up to 0.9 SD/yr (95% CI 0.7, 1.0). In
the premature group (n ⫽ 3), there was a catch-up growth of 1.6 SD/yr
(95% CI 0.9, 2.3) in the first year followed by a growth of 1.1 SD/yr (95%
CI 0.9, 1.5) in the following years. There was a positive linear correlation between bone age acceleration and age of diagnosis (r ⫽ 0.8).
Conclusions: Height velocity and bone maturation are not increased
in untreated children with mild forms of SV CAH in the first year of
life. After this period there is a progressive increase in height velocity
and bone maturation in strong relation to the duration of androgen
exposition. This observation has implications for the dose of glucocorticoids to be used in SV CAH patients in the first year of life. (J Clin
Endocrinol Metab 91: 1205–1209, 2006)
Main Outcome Measures: Growth pattern and bone maturation
were measured before the diagnosis.
C
ONGENITAL ADRENAL HYPERPLASIA (CAH) is
one of the most common autosomal recessive endocrine disorders with an incidence of the classical form at
1:10,000 (1, 2). In most cases, the disease is caused by 21hydroxylase deficiency. As a result of the enzyme deficiency,
the synthesis of cortisol and mostly also that of aldosterone
is impaired. Consequently, the secretion of ACTH by the
pituitary gland increases, leading to hyperplasia of the adrenal cortex and excess of androgen production. The gene
encoding for 21-hydroxylase is well known, and the diagnosis CAH can be easily confirmed by mutation analysis.
There is a strong genotype-phenotype correlation reported to
be up to 80 –90% (3–5).
The clinical symptoms of CAH depend on the degree of
enzyme deficiency. In the most severe form, the classic salt
wasting (SW) form, the enzyme activity is less then 1% leading to prenatal virilization in female patients and life-threat-
First Published Online February 7, 2006
Abbreviations: AR, Androgen receptor; BAc, bone age acceleration;
CAH, congenital adrenal hyperplasia; CI, confidence interval; HSDSTHSDS, height sd score and corrected for target height; SDS, sd score;
SV, simple virilizing; SW, salt wasting.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
ening SW in both sexes. An enzyme activity of 1–5% is
enough to preserve aldosterone synthesis leading to the classic simple virilizing (SV) form. In most of the male cases with
the SV form of CAH, patients are not detected in the neonatal
period but present after several years with signs of androgen
excess leading to pseudo-precocious puberty with increased
growth velocity, pubic hair development, and enlargement
of the external genitalia. The mildest form of CAH, the lateonset type, can present also with pseudo-precocious puberty,
irregular menstruation, hirsutism, and infertility. This form
of CAH can be easily missed, especially in male patients. The
treatment of CAH consists of substitution of cortisol to prevent Addison crisis and suppress the adrenal androgen overproduction. In the SW form, aldosterone also has to be substituted as well.
The growth pattern of treated children with SW or SV CAH
is described in several studies (6 –10). It is well known that
adrenal hypersecretion of androgens causes increased growth
velocity and bone age acceleration. Therefore, adequate suppression of androgens by treatment with glucocorticoids is important; however, oversuppression resulting in Cushing syndrome and growth retardation has to be avoided. Previous
reports on the growth pattern in children with CAH suggested
that the height velocity is not increased in the first years of life,
even in the untreated patient group (11–13).
1205
1206
J Clin Endocrinol Metab, April 2006, 91(4):1205–1209
Claahsen-van der Grinten et al. • Height Velocity in Untreated CAH Infants
We therefore investigated retrospectively our group of
patients with SV CAH retrospectively to define their growth
pattern before the diagnosis. Furthermore, we evaluated the
age of the onset of symptoms, the presence of associated
clinical features, and the bone maturation at the time of the
diagnosis.
Patients and Methods
Patients
We evaluated 17 patients with SV CAH (11 males and six females).
None of the patients was treated with glucocorticoids before the time of
diagnosis. Two patients (no. 12 and 13) are sisters.
The diagnosis SV CAH was based on clinical and biochemical criteria
(i.e. elevated levels of 17-hydroxyprogesterone and androstenedione,
abnormal urinary steroid profile, ACTH stimulation test) and was confirmed by mutation analysis (see Table 1). SW crisis has not been reported in any of the patients.
The I172N mutation, which is associated with the SV form of CAH,
was detected in all but one patient (no. 16) in at least one allele. Four
patients were homozygous for the I172N mutation. Patient 16 with the
clinical features of the SV form of CAH had a homozygous deletion/
conversion, which is typically associated with the SW form of CAH.
Three patients were born prematurely (no. 10, 13, and 14).
Clinical features and growth analysis
The age of diagnosis and clinical symptoms were obtained from the
patient’s medical records. The growth data from birth to the first presentation in our clinic were collected from the well-baby clinical reports.
Sufficient growth data were available in 14 patients (six females and
eight males): five to 15 growth measurements per patient were available
before the diagnosis, dependent on the age of the diagnosis. Height was
expressed as height sd score according to the national references (14) and
corrected for target height (HSDS-THSDS). Bone maturation at the time
of diagnosis was determined according to the atlas of Greulich and Pyle
and expressed as bone age acceleration (BAc ⫽ bone age ⫺ calendar age).
Statistical analysis
Because only limited data for the height (HSDS-THSDS) of untreated
patients were available for the age over 4 yr, we limited our analysis to
the period 0 – 4 yr. To account for the longitudinal character of the study,
linear mixed models with random factor patient were used for the
analysis of the growth
In a preliminary analysis, the statistical model was selected by including the fixed effects age, prematurity, sex, and the interaction between age and the other factors in the model. Because the relationship
between age and HSDS-THSDS may not be linear, age was included as
a spline function with knots at 1 and 2 yr of age. This analysis showed
a strong interaction between age and prematurity; therefore, the growth
of the premature and mature children was analyzed separately. It also
showed that a spline function with only one knot at 1 yr could adequately describe the data. Such a function consists of two straight lines,
one for the growth during the first year after birth and another one for
the growth between the age of 1 and 4 yr. As a result, in the final analysis,
the model included the fixed effects age up to 1 yr, age over 1 yr, and
sex. This model was used to derive estimates for the growth during and
after the first year.
Simple linear regression analysis was performed to evaluate the relationship between BAc and age at diagnosis. Ninety-five percent confidence intervals were calculated. The significance level for statistical
testing was set at P ⬍ 0.05 (two sided).
Results
Clinical presentation and growth analysis
The data on the clinical presentation are summarized in
Table 1. Fifteen of the 17 children presented with increased
growth velocity. The age of reported growth acceleration was
18 months or older. The other two patients (no. 16 and 17)
were detected at the age of 17 months and 23 months and
presented with clitoral hypertrophy and pubic hair development without a history of increased height velocity. Pubic
hair was noted in 11 children. At the time of the diagnosis,
enlargement of external genitalia was found in 11 children
(seven boys and four girls). Acne was detected in only two
patients. Axillary hair or hirsutism was not reported in any
of the patients.
The median age of onset of the first symptoms was 28
months (range 12– 46 months) in girls and 51 months (range
18 – 86 months) in boys.
Birth length corrected for gestational age was greater than
TABLE 1. Mutation analysis, clinical presentation, and BAc at time of diagnosis in 17 patients with SV CAH
Mutation analysis
Patient
no.
Sex
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
M
M
M
M
M
M
M
M
M
M
M
F
F
F
F
F
F
Allele 1
Allele 2
Intron2
I172N
Intron2
Del-Conv
I172N
Del-Conv
I172N
Del-Conv
I172N
I172N
I172N
I172N
I172N
Intron2
Del-Conv
Del-Conv
G110⌬nt
I172N
R356W
I172N
I172N
I172N
I172N
1235N,V237E,M239K
I172N
Del-Conv
Q318X
I172N
I172N
I172N
I172N
I172N
Del-Conv
I172N
Symptoms at
time of
diagnosisa
1,
2,
1,
1,
1,
1,
1,
1,
2,
2,
1,
1,
2,
1,
3
2
1
3
3
3
2,
3
2,
2,
3,
3
3
2,
2,
3
2,
3
3
3, 4
4
3
3
3
Age at first
symptoms
(yr:month)
6:2
1:6
6:2
3:10
4:0
3:1
2:11
5:10
3:5
3:0
7:2
3:10
2:8
1:6
3:4
1:0
1:11
BAcb at
diagnosis
(yr:month)
4:8
5:2
4:2
7:1
3:4
2:5
5:2
6:0
5:1
7:0
3:8
0:8
1:8
0:1
Birth weight (g)
with SDSc
Birth length (cm)
with SDSc
2880
2700
3380 (⫺0.6)
3975 (0.7)
3250 (⫺0.1)
3770 (0.05)
3500 (⫺0.3)
3940 (0.7)
3850 (0.5)
2350 (⫺1.3)
3500 (⫺0.03)
2100 (0.1)
2750 (⫺0.6)
3000 (⫺1.2)
3500 (⫺0.2)
3300 (⫺0.5)
M, Male; F, female.
a
Symptoms: 1, pubic hair; 2, enlarged external genital; 3, increased height velocity; 4, acne; 5, axillary hair.
b
BAc, Bone age ⫺ calendar age.
c
SDS was calculated according to Niklasson et al. (33).
49
48
50 (⫺0.6)
50 (⫺0.6)
50 (0.1)
57 (3.0)
53 (1.1)
52 (0.5)
48 (⫺0.1)
54 (2.2)
43 (⫺0.6)
47 (⫺0.7)
48 (⫺1.3)
54 (2.2)
Gestational
age (wk)
40
40
38
41
40
40
40
36
40
33
37
40
41
40
Claahsen-van der Grinten et al. • Height Velocity in Untreated CAH Infants
J Clin Endocrinol Metab, April 2006, 91(4):1205–1209
1207
⫺1.3 sd score (SDS) in all children except for one child (no.
15) with a birth length of ⫺1.3 SDS and early stunting in the
follow-up with weight and length decreasing to below ⫺2.0
SDS. Three patients had a birth weight greater than 2 SDS.
The growth data of 14 patients with sufficient growth data
are summarized in Fig. 1. In the term group (n ⫽ 11), there
was no significant increase in height velocity in the first year
[⫺0.1 sd/yr; 95% confidence interval (CI) ⫺0.5, 0.3] with a
consecutive significant (P ⬍ 0.001) increase up to 0.9 sd/yr
(95% CI 0.7, 1.0). In premature group (n ⫽ 3) there was a catch
up growth of 1.6 sd/yr (95% CI 0.9, 2.3) in the first year
followed by a growth of 1.1 sd/yr (95% CI 0.7, 1.5) in the
following years.
Bone maturation at time of diagnosis was determined in
14 of the 17 patients (Fig. 2). We found a strong positive linear
correlation between bone maturation and age of diagnosis
(Pearson’s correlation coefficient ⫽ 0.8). BAc increase was
1.06/yr (P ⫽ 0.01).
Discussion
In our group of patients with SV CAH, the most prominent
symptoms at time of diagnosis were increased height velocity, pubic hair, and enlargement of external genitalia. These
observations are similar to other studies. Surprisingly we did
not find any axillary hair development or hirsutism, suggesting a higher threshold for androgens in the axillary
region.
Increased height velocity is one of the most prominent
symptoms of androgen excess in childhood. In prepubertal
CAH patients, failure to suppress adrenal androgens leads to
accelerated growth and bone maturation with compromised
adult height. Treatment with glucocorticoids aims to suppress ACTH and androgens and to restore normal growth
and maturation (1, 6 –10).
The results of our study, demonstrating the absence of
FIG. 1. Growth pattern before diagnosis in 14 patients with SV CAH
in the first 4 yr of life. Height is expressed as height SD score and
corrected for target height (HSDS-THSDS). The solid lines represent
the term born group (n ⫽ 11), the dotted lines represent the premature
born group (n ⫽ 3). The thick solid line shows the estimated mean of
the HSDS-THSDS of the term group, thick dotted line of the P/SGA
group.
FIG. 2. BAc at age of diagnosis in 14 patients with SV CAH (r ⫽ 0.84).
increased height velocity in patients with SV CAH at least in
the first 12 months of postnatal life, suggests the presence of
relative resistance to androgen excess. After this period there
is a progressive increase of growth velocity and bone maturation in a strong relation to the duration of androgen
exposure. Several authors described the lack of growth acceleration in the first year of life as well. Aceto et al. (15)
described three girls with CAH and normal height and bone
age at time of diagnosis at 21, 24, and 42 months of age
without information about longitudinal growth data, parental height, or the type of CAH. Another study by Thilen et al.
(12) in 14 children with SV CAH showed no increase in height
velocity until the age of 18 months; however, height was not
corrected for target height, and no statistical analysis was
performed.
A similar growth pattern can be observed in other pathological conditions with high androgen levels like in familiar
testitoxicosis (16, 17). Also in normal males, the temporary
high levels of testosterone at the age of 6 wk to 6 months in
their minipuberty seem to have no effect on the growth
velocity in boys, compared with girls.
The reason for the lack of increased height velocity of CAH
patients in the early life is not well understood.
It is well known that androgens act on the bone mainly
after being aromatized to estrogens; however, direct effects
are described as well (18, 19). Van der Eerden et al. (20)
detected an androgen receptor (AR) in the tibial growth plate
of male and female rats with a significant higher expression
rate in male than female rats during sexual maturation with
increased testosterone levels. They found that testosterone
can either up-regulate or down-regulate AR mRNA in a
dose-dependent manner (20). The insensitivity of bone to
androgens in the first year of life can hypothetically be explained by temporary down-regulating or limited expression
of the AR in this period (21).
1208 J Clin Endocrinol Metab, April 2006, 91(4):1205–1209
Claahsen-van der Grinten et al. • Height Velocity in Untreated CAH Infants
Another possible explanation of increased growth velocity
by sex hormones might be the interference with the GH/IGF
axis. Sex hormones, mainly estrogens, increase pulse amplitude and the amount of GH secreted per pulse (22). It is
suggested in the infancy-childhood-puberty model that the
infancy growth in the first year of life seems to be relatively
independent of GH (23, 24). Therefore, in this period any
action of androgens by this pathway may not result in increased growth velocity. However, several studies (25, 26)
show that GH has some influence also in the first year of life
as demonstrated by growth failure of children with congenital GH deficiency.
There are not much data about the effect of androgen
excess in utero on prenatal growth and bone maturation.
Some studies (6, 27) show that the birth length in patients
with CAH is slightly elevated, independent of the degree of
virilization in girls or the postnatal androgen levels in boys.
Therefore, androgen excess in utero seems to have no strong
effect on the prenatal growth and bone maturation. In our
patients birth weight and length were mostly within the
normal range.
The absence of growth acceleration seems to be independent of the severity of the disease. Personal observations of
a patient with SW CAH and urethral valves who was treated
only with salt substitution in the first 3 yr of life showed no
increase in growth velocity or bone maturation (our unpublished data).
There is no evidence that higher androgens in the first year
of life can cause infertility in later years. It is well known that
fertility in women with CAH is impaired due to several
factors: mechanical factors after genital surgery, adrenal
overproduction with disturbing ovarian activity, polycystic
ovarian syndrome, or ovarian adrenal rests. It is not known
whether higher androgens in the first year of life can also
contribute to these factors. Behavioral problems are mostly
the result of prenatal exposure of androgens and not of
postnatal exposure (28, 29). A prospective study to analyze
reproductive problems in this group of patients could be very
helpful.
In our population the androgen levels in the first year were
not measured because the diagnosis was made in later life.
Therefore elevated androgens were not established. It is
known that in SV CAH patients androgen levels are elevated
in utero and after birth. The 21-hydroxylase activity in this
group is less than 5%, leading to elevated serum 17 hydroxyprogesterone and androstenedione levels. This becomes visible in girls with SV CAH, who present with signs
of virilization after birth. However, it is just possible that in
this situation the androgen levels are not high enough to see
any effect on the growth velocity in early life.
Although the reason for the absence of increased height
velocity in the first year of life in SV CAH patients is not
completely understood, our observations have important implications for the first year treatment of children with CAH.
In prepubertal children, the recommended cortisol replacement is hydrocortisone in doses of 10 –20 mg/m2䡠d in two or
three divided doses (30). This advice is based on the clinical
experience with the general premise to use the lowest possible dosage. However, the glucocorticoid dosages used in
daily practice in infancy are much higher (9 –37.5 mg/m2䡠d)
(31). These doses exceed physiological levels of cortisol secretion, which are 6 – 8 mg/m2䡠d in children and adolescents
and are necessary to adequately suppress adrenal androgens
and prevent growth acceleration.
However because of the absence of increased growth velocity and bone maturation in the first year of life as demonstrated in our study, suppression of androgens as required
in later years to prevent growth acceleration is not necessary,
and much lower doses of glucocorticoids are sufficient for
adequate treatment. Moreover, in an earlier study (32), we
demonstrated the high sensitivity of glucocorticoid with respect to growth retardation, especially in the first year of life.
These two arguments augment for a recommendation of
using more physiological glucocorticoid doses in early age.
Further prospective studies will be done to evaluate the effect
of this treatment on growth and fertility in later life.
Conclusion
Our study demonstrates the absence of increased growth
velocity and bone maturation in the first year of life untreated
children with mild forms of SV CAH. After this period there
is a progressive increase in height velocity bone maturation
with a strong correlation with the duration of androgen
exposure. This observation has implications for the dose of
glucocorticoids to be used in SV CAH patients in the first
year of life.
Acknowledgments
Received July 29, 2005. Accepted January 30, 2006.
Address all correspondence and requests for reprints to: H. L. Claahsen-van der Grinten, M.D., Radboud University Nijmegen Medical Centre, Department of Metabolic and Endocrine Diseases (435), P.O. Box
9101, 6500 HB Nijmegen, The Netherlands. E-mail: h.claahsen@
cukz.umcn.nl.
H.L.C.-v.d.G., K.N., G.F.B., and B.J.O. have nothing to declare.
References
1. Speiser PW, Whites PC 2003 Congenital adrenal hyperplasia. N Engl J Med
349:776 –788
2. White PC, Speiser PW 2000 Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291
3. Wedell A, Thilen A, Ritzen M, Stengler B, Luthman H 1994 Mutational
spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol
Metab 78:1145–1152
4. Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna MT,
Lesser M, New MI, White PC 1992 Disease expression and molecular genotype
in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin
Invest 90:584 –595
5. Stikkelbroeck MML, Hoefsloot LH, de Wijs IJ, Otten BJ, Hermus ARMM,
Sistermans EA 2003 Cyp21gene mutation analysis in 198 patients with 21hydroxylase deficiency in the Netherlands: six novel mutations and a specific
cluster of four mutations. J Clin Endocrinol Metab 88:3852–3859
6. Van der Kamp HJ, Otten BJ, Buitenweg N, de Muinck Keizer-Schrama
SMPF, Oostdijk W, Jansen M, Delmarre-de Waal, Vulsma T, Wit JM 2002
Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency
patients. Arch Dis Child 87:139 –144
7. Gasparini N, Di Maio S, Argenziano A, Franzese A 1997 Growth pattern
during the first 36 month of life in congenital adrenal hyperplasia (21-hydroxylase deficiency). Horm Res 47:7–22
8. Eugster EA, DiMiglio LA, Wright JC, Freidenberg GR, Seshadri R, Pescovitz
OH 2001 Height outcome in congenital adrenal hyperplasia caused by 21hydroxylase deficiency: a meta-analysis. J Pediatr 138:26 –32
9. Pena-Almazan SP, Buchlis J, Miller S, Shine B, Macgillivary M 2001 Linear
growth characteristics of congenitally GH-deficient infants from birth to one
year of age. J Clin Endocrinol Metab 86:5691–5694
10. Muirhead S, Sellers EAC, Guyda H 2002 Indicators of adult height outcome
Claahsen-van der Grinten et al. • Height Velocity in Untreated CAH Infants
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
in classical 21-hydroxylase deficiency congenital adrenal hyperplasia. J Pediatr
141:247–252
Thilen A, Larsson A 1990 Congenital adrenal hyperplasia in Sweden, 1969 –
1986. Acta Paediatr Scand 79:168 –175
Thilen A, Woods KA, Perry LA, Savage MO, Wedell A, Ritzen EM 1995 Early
growth is not increased in untreated moderately severe 21-hydroxylase deficiency. Acta Paediatr 84:894 – 898
Savage MO, Scommegna S, Carroll PV, Monson JP, Besser GM, Grossman
AB 2002 Growth disorders of adrenal hyperfunction. Horm Res 58(Suppl
1):39 – 43
Fredriks AM, Buuren van S, Burgmeijer RJF, Verloove-Vanhorick SP, Wit
JM 1998 Nederlandse groeidiagrammen 1997. In: Wit JM, ed. De vierde landelijke Groeistudie. Leiden, The Netherlands: Boerhaave Commissie; 69 –76
Aceto T, Macgillivray MH, Caprano VJ, Munschauer RV, Raiti S 1966 Congenital virilizing hyperplasia without acceleration of growth or bone maturation. JAMA 198:1341–1343
Kremer H, Mariman E, Otten BJ, Moll GW, Stoelinga GBA, Wit JM, Jansen
M, Drop SL, Faas B, Gopers HH, Brunner HG 1993 Co-segregation of missense mutations of the luteinizing hormone receptor gene with familial malelimited precocious puberty. Hum Mol Genet 11:1779 –1783
Boepple PA, Frisch LS, Wierman ME, Hoffman WH, Crowley WF 1992 The
natural history of autonomous gonadal function, adrenarche and central puberty in gonadotropin-independent precocious puberty. J Clin Endocrinol
Metab 75:1550 –1555
Frank GR 2003 Role of estrogen and androgen in pubertal skeletal physiology.
Med Pediatr Oncol 41:217–221
Arisaka O, Hoshi M, Kanazawa S, Numata M, Nakajima D, Kanno S, Negishi M, Nishikua K, Nitta A, Imataka M, Kuribayashi T, Kano K 2001 Effect
of adrenal androgen and estrogen on bone maturation and bone mineral
density. Metabolism 50:377–379
Van der Eerden BCJ, van Til NP, Brinkmann AO, Löwink CWGM, Wit JM,
Karperien M 2002 Sex differences in the expression of the androgen receptor
in the tibial growth plate and metaphyseal bone of the rat. Bone 30:891– 896
Van der Eerden BCJ, Gevers, EF, Löwink CWGM, Karperien M, Wit JM 2002
Expression of estrogen receptor ␣ and ␤ in the epiphyseal plate of the rat. Bone
30:478 – 485
Veldhuis JD, Metzger PM, Martha PM, Mauras N, Kerrigan JR, Keenan B,
Rogol AD, Pincus SM 1997 Estrogen and testosterone but not a non-aromatizable androgen, direct network integration of the hypothalamo-somatotrope
J Clin Endocrinol Metab, April 2006, 91(4):1205–1209
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
1209
(growth hormone) insulin-like growth factor I axis in the human: evidence
from pubertal pathophysiology and sex-steroid hormone replacement. J Clin
Endocrinol Metab 82:3414 –3420
Karlberg J 1989 On the construction of the infancy-childhood-puberty growth
standard. Acta Paediatr Scand (Suppl) 356:26 –37
Karlberg J, Engstrom I, Karlberg P, Fryer JG 1987 Analysis of linear growth
using a mathematical model. I. From birth to three years. Acta Paediatr Scand
76:478 – 488
Ogilvy-Stuart AL 2003 Growth hormone deficiency GHD) from birth to 2 years
of age: diagnostic specifics of GHD during the early phase of life. Horm Res
60(Suppl 1):2–9
Carel JC, Huet F, Chaussain JL 2003 Treatment of growth hormone deficiency
in very young children. Horm Res 60(Suppl 1):10 –17
Jaaskelainen J, Voutilainen R 1997 Growth of patients with 21-hydroxylase
deficiency: an analysis of the factors influencing adult height. Pediatr Res
41:30 –33
Beerenbaum SA, Duck SC, Bryk K 2000 Behavioral effects of prenatal versus
postnatal androgen excess in children with 21 hydroxylase-deficient congenital
adrenal hyperplasia. J Clin Endocrinol Metab 85:727–733
Hall CM, Jones JA, Meyer-Bahlburg HFL, Dolezal C, Coleman M, Foster P,
Price D, Clayton P 2004 Behavioral and physical masculinization are related
to genotype in girls with congenital adrenal hyperplasia J Clin Endocrinol
Metab 89:419 – 424
Joint ESPE/LWPES CAH Working Group 2002 Consensus statement on 21hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Paediatric Endocrine Society. Horm Res 58:188 –
195
Riepe FG, Krone N, Viemann M, Partsch C-J, Sippell WG 2002 Management
of congenital adrenal hyperplasia: results of the ESPE questionnaire. Horm Res
58:196 –205
Stikkelbroeck NMML, van’t Hof-Grootenboer BAE, Hermus ARMM, Otten
BJ, van’t Hof MA 2003 Growth inhibition by glucocorticoid treatment in salt
wasting 21-hydroxylase deficiency: in early infancy and (pre) puberty. J Clin
Endocrinol Metab 88:3525–3530
Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P 1991
An update of the Swedish reference standards for weight, length and head
circumference at birth for given gestational age (1977–1981). Acta Paediatr
Scand 80:756 –762
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.