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O R I G I N A L A R T I C L E
Adolescents with congenital adrenal hyperplasia because of21-hydroxylase deficiency have vascular dysfunction
Jennifer Harrington*, Alexia S. Pena*,†, Roger Gent‡, Craig Hirte† and Jennifer Couper*,†
*Department of Endocrinology and Diabetes, †Department of Pediatrics, University of Adelaide and ‡Medical Imaging Women’s and
Children’s Hospital, North Adelaide, SA, Australia
Summary
Context Patients with congenital adrenal hyperplasia (CAH)
because of 21-hydroxylase deficiency have multiple vascular risk
factors. Young adults with CAH have increased intima media
thickness, but there have been no studies of vascular function and
structure in children with CAH.
Objective To establish whether children with CAH have reduced
vascular function and increased carotid intima media thickness
(cIMT) when compared to healthy and obese children.
Design and Patients Cross-sectional study of 14 patients
(14Æ8 years ± 3Æ2, seven boys) with CAH secondary to 21-hydroxy-
lase deficiency compared to 28 obese and 53 healthy controls.
Measurements All subjects had assessment of endothelial func-
tion flow-mediated dilatation, (FMD), smooth muscle function
glyceryl tri-nitrate dilatation (GTN) and cIMT. Anthropometric
data, resting blood pressure and biochemical variables were also
measured.
Results Congenital adrenal hyperplasia subjects had significantly
reduced FMD (4Æ5 ± 3Æ0% vs 7Æ5 ± 5Æ2%; P = 0Æ04) and GTN
(17Æ2 ± 1Æ6% vs 28Æ4 ± 8Æ4%; P < 0Æ001) when compared to con-
trols and the impairment was comparable to the obese cohort.
There was no significant difference in cIMT between groups. CAH
subjects had increased homoeostasis model of assessment-insulin
resistance [HOMA-IR 2Æ5 (0Æ2–2Æ9) vs 1Æ8 (0Æ5–4Æ2); P = 0Æ04],
waist-to-height ratio (0Æ47 ± 0Æ05 vs 0Æ44 ± 0Æ04; P = 0Æ02) and
higher systolic blood pressure Z score (0Æ29 ± 0Æ9 vs )0Æ24 ± 0Æ64,
P = 0Æ01) compared to healthy controls but not when compared to
obese controls.
Conclusions Subjects with CAH have evidence of vascular dys-
function by adolescence.
(Received 13 September 2011; returned for revision 14 October
2011; finally revised 30 November 2011; accepted 1 December
2011)
Introduction
Congenital adrenal hyperplasia (CAH), because of 21-hydroxylase
enzyme deficiency, is an autosomal recessive condition that is
caused by mutations in CYP21A2. It is characterized by glucocorti-
coid and mineralocorticoid deficiency and androgen excess. The
goal of the treatment is to reduce adrenal androgens by replacing
the deficient hormones, and by doing so preventing adrenal
crisis and allowing normal growth and development.1 The bal-
ance between overtreatment leading to hypercortisolism and
under treatment leading to hyperandrogenism can be difficult to
manage.
There has been increasing evidence that patients with CAH have
multiple vascular risk factors that may put them at increased risk of
cardiovascular disease in adulthood. Adults with CAH have an
increased risk of elevated body mass index (BMI),2 fat mass3 and
insulin resistance.4,5 Vascular health may be particularly pertinent
to children with CAH, as the earliest stages of atherosclerosis first
appear in childhood and are accelerated in high-risk populations.6
Children and adolescents with CAH are at a greater risk of obesity
as measured by having a higher BMI and truncal fat mass,7
increased fasting serum insulin levels and insulin resistance,8 and
elevated ambulatory 24-h blood pressure measurements.9 The role
of hyperandrogenism as an independent risk factor is still not
known.
Endothelial and smooth muscle dysfunction as measured by
flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated
dilatation (GTN), respectively, as well as carotid intima media
thickness (cIMT) has been used as early surrogate markers of ath-
erosclerosis.10,11 Abnormal endothelial function as measured by
FMD correlates with abnormal coronary angiography in adults.12
Vascular dysfunction and increased cIMT occur in children with
accelerated atherosclerosis as in obesity, type 1 diabetes and hyper-
cholesterolemia.13,14
Adults with CAH were found to have increased cIMT in
one study,15 but there is no data on early markers such as
vascular function. Vascular dysfunction occurs early and is
independently associated with the progression of cIMT over
time.16 Our aim was therefore to determine whether there are
early changes in vascular function and structure in children
and adolescents with CAH secondary to 21-hydroxylase defi-
ciency.
Correspondence: Jennifer Harrington, Department of Endocrinology and
Diabetes, Women’s and Children’s Hospital, 72 King William Road, North
Adelaide, SA 5006. Australia. Tel.: 61 8 81616402; Fax: 61 8 81617759;
E-mail: [email protected]
Clinical Endocrinology (2012) 76, 837–842 doi: 10.1111/j.1365-2265.2011.04309.x
� 2012 Blackwell Publishing Ltd 837
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Subjects and methods
Subjects and controls
A total of 95 children [42 boys, mean age 15Æ1(3Æ0) years] were
studied. Fourteen children [seven boys] with CAH secondary to 21-
hydroxylase deficiency were recruited consecutively from the endo-
crinology clinic at the Women’s and Children’s Hospital (Adelaide,
Australia), three with simple virilizing and the remainder with salt-
wasting CAH. Exclusion criteria were subjects younger than 8 years
to ensure cooperation with ultrasound tests. They represented 14/
24 patients with CAH aged 9–20 years in South Australia. The diag-
nosis had been previously made by the presence of elevated 17-
hydroxyprogesterone. All of the salt-wasting patients were diagnosed
through the presence of virilization of the genitalia in girls at birth
and raised renin levels or with acute salt loss in the boys. All subjects
with CAH were being treated with hydrocortisone [mean dose 13Æ3(4Æ1) mg/m2 per day] and fludrocortisone [mean dose 108Æ3 (19Æ5)
lg/day]. Treatment had commenced within the first 2 and ½ weeks
of life in all subjects with salt-wasting CAH, and at 6 months and
4 years of age in the three patients with simple virilizing. Therapy
was monitored by regular assessment of clinical and laboratory data
in accordance with current guidelines.1 Reasons for not entering the
study were disinterest in the study, travelling distance from the
study centre and refusal to have additional blood testing.
Twenty eight children [14 boys] with mild to moderate obesity
[BMI Z score 1Æ5–3Æ3] and 53 healthy controls [21 boys] were used
as comparison groups. The obese children were recruited consecu-
tively from paediatric outpatient clinics at the Women’s and Chil-
dren’s Hospital (Adelaide, Australia). Diabetes, syndromal obesity
and/or endocrinological causes of obesity were exclusion criteria
and one subject with diabetes was excluded on this basis. The 53
healthy aged-matched controls were recruited from friends or sib-
lings of subjects who had participated in a previous study.17
The study was approved by the Children, Youth and Women’s
Health Service Human Research Committee. Written informed
consent was obtained from the parents/guardians of the subjects
and the subject if he/she was more than 16 years old.
Height was measured with a wall-mounted stadiometer to the
nearest 0Æ1 cm. Weight with minimal clothing was taken on an
electric digital scale to the nearest 0Æ1 kg. BMI [weight (kg)/height
(m)2] and BMI Z score were calculated using EpiInfo database ver-
sion 3Æ2Æ2 and Centers for Disease Control 2000 standardized refer-
ence charts. Waist circumference was measured at the mid-point
between the lower edge of the ribs in the mid-axillary line and the
top of the iliac crest, at minimal respiration. Blood pressure was
measured using an automated oscillometric device with an appro-
priately sized cuff three times and the mean of the measurements
was recorded. Systolic and diastolic blood pressure Z scores were
calculated as per the National High Blood Pressure Working Group
on high blood pressure in children and adolescents guidelines.18
Ultrasound assessment of vascular function and structure
Vascular endothelial and smooth muscle function and cIMT were
assessed using B mode ultrasound (Philips iU22; Philips, Bothell,
WA, USA) with a 17MHz linear array transducer after an over-
night fast in a quiet and stable temperature environment. The
ultrasound studies were performed by experienced ultrasono-
graphers who were unaware of the clinical characteristics of the
subject.
Vascular function was assessed using FMD and GTN-induced
dilatation as has been previously described using ultrasound of
the brachial artery to evaluate changes in blood vessel diame-
ter.19,20 Brachial artery diameter (2–15 cm above the elbow) was
measured in a longitudinal section from 2-dimensional ultra-
sound images. Each study included four scans. The first scan
was taken at rest. Reactive hyperaemia was then induced by
occluding arterial blood flow for 4 min using a sphygmoma-
nometer inflated to 250 mmHg. The second scan (reactive
hyperaemia or FMD) was recorded 30–90 s after cuff deflation,
with measurements between 45 and 75 s after deflation. Ten to
15 min were allowed for vessel recovery and then the third
(re-control) scan was taken. The final scan was taken 4 min
after sublingual administration of glyceryl trinitrate spray
(400 lg, Nitrolingual Spray, G. Pohl-Boskamp, Hohenlockstdet,
Germany).
Images were recorded onto VHS videotape and analysed sub-
sequently by a blinded observer. For each scan, measurements
were made incident with the electrocardiogram R-wave (i.e. at
end-diastole) over four cardiac cycles using ultrasonic calipers.
Then, the measurements were averaged and expressed as per-
centages of the first control (resting) scan. There were four final
measurements in total: resting, FMD, recontrol, and GTN. Reac-
tive hyperaemia was calculated as the flow in the first 15 s after
cuff deflation divided by the flow during the resting scan. The
coefficient of variation between 20 subjects is 3Æ9% for FMD and
4Æ0% for GTN.20
For cIMT, the left and right common carotid arteries were
imaged in a standardized magnification (2 · 2 cm) using images of
the posterior wall of the distal 10 mm of the common carotid
artery, just proximal to the carotid bulb. A minimum of four
images of each of the common carotid arteries were taken. All
images were taken at end-diastole, incident with the R-wave on a
continuously recorded ECG and then digitally stored for later anal-
ysis. The images were later analysed by two independent readers
who were blinded to the subjects’ clinical details. The greatest dis-
tance between the lumen-intima interface and media-adventitia
interface (intima media thickness – IMT) was measured at a mini-
mum of 100 points using a semi-automated edge detection and
measurement computer software package (Brian Bailey, Royal
Prince Alfred Hospital, Sydney, Australia). Three best quality
images were selected and analysed for mean and maximum IMT of
the right and left carotid arteries. The mean of the readings was
recorded to give the final result for each subject. The coefficient of
variation between 20 subjects is 1Æ2%.17
Laboratory tests
Overnight fasting venous blood samples were taken after the
subjects’ morning medication. High sensitive C-reactive protein
(hsCRP) was measured using a near infrared particle
838 J. Harrington et al.
� 2012 Blackwell Publishing Ltd
Clinical Endocrinology (2012), 76, 837–842
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immunoassay method using immage Immunochemistry Sys-
tems Reagent (Beckman Coulter Inc., Fullerton, CA, USA). Tri-
glycerides, total cholesterol, high-density lipoprotein, glucose
and insulin were measured using routine methods. Low-density
lipoprotein cholesterol was calculated using the Friedewald
equation. 17-hydroxyprogesterone and androstenedione were
measured using radioimmunoassay (Siemens Medical Solutions
Diagnostics, Los Angeles, CA, USA) and direct renin by
chemoluminescent immunoassay (Liaison, Vercelli, Italy). Insu-
lin resistance was estimated using the homoeostasis model of
assessment (HOMA-IR) method according to the formula
HOMA-IR = insulin (microunits per millilitre) · glucose (milli-
moles per litre)/22Æ5.
Statistical analysis
The data were analysed using spss software version 15.0 (SPPS Inc.,
Chicago, IL, USA). Comparisons of variables across the three
groups were made using a one-way anova and comparisons
between two groups were made using independent samples t-tests.
A log transformation was used in the analysis for HsCRP and
HOMA-IR as these variables were not normally distributed. The
strength of the linear association between a number of variables
with FMD and GTN was assessed using Spearman’s correlations.
Statistical significance was inferred with a P value <0Æ05.
Results
The characteristics of the study groups are shown in Tables 1 and
2. There was no significant difference with respect to age, BMI Z
score, waist–hip ratio, or lipids between the group with CAH and
healthy controls. Nor was there any significant difference with
respect to pubertal distribution across all three groups, with 28% of
the subjects in both the CAH and obese group being in early to
mid-puberty compared to 26% in the control group.
In comparison to the healthy control group, the CAH group had
a decreased height Z score ()0Æ7 ± 1Æ4 vs 0Æ8 ± 1Æ0, P < 0Æ001) and
greater waist-to-height ratio (0Æ47 ± 0Æ05 vs 0Æ44 ± 0Æ04, P = 0Æ02).
In addition, the CAH group had a higher insulin resistance com-
pared to the healthy controls [2Æ5 (0Æ2–2Æ0) vs 1Æ8 (0Æ5–4Æ2),
P = 0Æ04], but significantly less insulin resistance [2Æ5 (0Æ2–2Æ9) vs
6Æ8 (1Æ9–32Æ4), P < 0Æ001] and waist-to-height ratio (0Æ47 ± 0Æ05 vs
0Æ68 ± 0Æ14, P < 0Æ001) when compared to obese controls. The
CAH group had a significantly greater systolic blood pressure Z
score corrected for age, gender and height (0Æ29 ± 0Æ9 vs
)0Æ24 ± 0Æ64, P = 0Æ01).
Both endothelial (FMD) (4Æ5% ± 3Æ0 vs 7Æ5% ± 5Æ2, P = 0Æ04)
and smooth muscle function (GTN) (17Æ2% ± 6Æ0 vs 28Æ4% ± 8Æ4,
P < 0Æ001) were significantly decreased in the CAH cohort (Fig. 1).
This impairment was similar to that in the obese group (FMD
P = 0Æ5, GTN P = 0Æ4). We did not however find any difference
with respect to cIMT across all three groups (P = 0Æ27), nor any
difference in cIMT in the obese vs the CAH group (P = 0Æ17).
In the group with CAH, mean early am (0800–1000) hormone
levels were 17-hydroxyprogesterone 17Æ4 ± 12Æ8 nm, androstenedi-
one 9Æ0 ± 12Æ3 nm and renin 7Æ4 ± 12Æ9 ng/l. There were no signifi-
cant correlations between FMD or GTN with BMI Z score, blood
pressure, lipids, 17-hydroxyprogesterone, androstenedione, renin,
hydrocortisone dose, duration of treatment or HOMA-IR. There
was a positive trend between waist-to-height ratio and HOMA-IR
(r = 0Æ52, P = 0Æ05). Neither systolic blood pressure Z score
(r = )0Æ19, P = 0Æ51) or diastolic blood pressure Z score (r = 0Æ01,
P = 0Æ97) related to renin levels.
The calculated power at the 5% significance level to detect the
observed effect size for GTN and FMD between CAH and healthy
controls was 99Æ6% and 52Æ9%, respectively.
Discussion
This study demonstrated that children with CAH have significant
vascular endothelial and smooth muscle dysfunction when
compared to healthy controls, as measured by FMD and GTN. The
vascular dysfunction was comparable to the subjects with mild to
moderate obesity. Both the healthy control and obese children in
Table 1. Anthropometric data across three groupsControls
(n = 53)
Obese
(n = 28)
CAH
(n = 14)
anova
P-value
Age (years) 14Æ7 ± 3Æ1 16Æ2 ± 2Æ3 14Æ8 ± 3Æ2 0Æ08
Height Z score** 0Æ8 ± 1Æ0 0Æ75 ± 1Æ0 -0Æ7 ± 1Æ4 <0Æ001
Weight Z score 0Æ5 ± 0Æ8 2Æ6 ± 0Æ6 0Æ3 ± 1Æ4 <0Æ001
BMI (kg/m2) 20Æ6 ± 3Æ4 36Æ5 ± 6Æ9 23Æ0 ± 5Æ9 <0Æ001
BMI Z score 0Æ2 ± 0Æ9 2Æ3 ± 0Æ4 0Æ6 ± 1Æ3 <0Æ001
Waist (cm) 70Æ8 ± 8Æ6 103Æ8 ± 14Æ6 73Æ6 ± 10Æ6 <0Æ001
Waist–hip ratio 0Æ87 ± 0Æ05 0Æ9 ± 0Æ06 0Æ87 ± 0Æ04 0Æ04
Waist-to-height ratio* 0Æ44 ± 0Æ04 0Æ68 ± 0Æ1 0Æ47 ± 0Æ05 <0Æ001
Systolic blood pressure (mmHg) 108Æ8 ± 8Æ1 122Æ2 ± 10Æ5 112Æ0 ± 8Æ2 <0Æ001
Systolic blood pressure Z score* -0Æ24 ± 0Æ64 0Æ63 ± 0Æ9 0Æ29 ± 0Æ9 <0Æ001
Diastolic blood pressure (mmHg) 60Æ0 ± 6Æ4 62Æ8 ± 6Æ6 61Æ4 ± 5Æ9 0Æ17
Diastolic blood pressure Z score -0Æ52 ± 0Æ58 -0Æ42 ± 0Æ63 -0Æ27 ± 0Æ63 0Æ37
BMI, body mass index; CAH, congenital adrenal hyperplasia.
Values are given as mean ± SD.
CAH vs Controls: *P < 0Æ05, **P < 0Æ001.
Adolescents with congenital adrenal hyperplasia 839
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this study had comparable FMD and GTN measurements to previ-
ous published data in healthy and obese children of similar age.21,22
This is the first study to our knowledge detecting early changes of
atherosclerosis in adolescents with CAH. This has important impli-
cations as adolescence is a critical time in determining future vas-
cular risk.6
Possible risk factors causing vascular dysfunction in CAH are
overweight/obesity, insulin resistance, hypertension, dyslipida-
emia, hypercortisolism and hyperandrogenism. The impairment in
vascular function in our CAH subjects could not be explained by
any difference from controls in BMI Z score or fasting lipids. How-
ever, the CAH subjects had a significantly lower height Z score as
has been described23 and a greater waist-to-height ratio than the
healthy controls. Waist-to-height ratio is a comparable if not better
marker of cardiovascular risk than BMI Z score.24 It is strongly
associated with visceral adiposity as measured by dual X-ray
absorptiometry in children and correlates with insulin resistance,25
in accordance with our findings.
Children and adolescents with CAH have elevated 24-h ambula-
tory systolic blood pressure.9 Despite a limitation of our study being
that blood pressure was the mean of three measurements on a single
occasion, rather than a 24-h profile, we were still able to demonstrate
a significant increase in systolic blood pressure Z score in the group
with CAH. Only one of the subjects with CAH had an elevated
systolic blood pressure above the 95th percentile for age. Higher
blood pressures even in the normal range, however, relate to early
markers of atherosclerosis such as cIMT in healthy children.26,27
Whilst mineralocorticoid excess can elevate blood pressure,28 we
did not demonstrate an association between blood pressure and
renin levels in the CAH group consistent with other studies.9,29
The CAH subjects also had greater insulin resistance, as mea-
sured by HOMA-IR index, in comparison to the controls as previ-
ously described in paediatric and adult cohorts.4,5,8 Most studies,
like ours, have used HOMA-IR to assess insulin resistance in
patients with CAH, rather than the gold standard euglycemic
clamp. Insulin resistance as measured by clamp methods has been
shown to correlate strongly with HOMA-IR in children, and as
such is a good approximation.30 One explanation as to the cause of
insulin resistance in CAH is its association with long-standing
adrenomedullary hypofunction, with decreased catecholamines
leading to a loss of inhibition of insulin secretion.8 In addition,
periods of iatrogenic hypercortisolism may further contribute to
the insulin resistance.31 In our CAH subjects, hydrocortisone dose
range was within recommended guidelines1 and comparable to
other reported cohorts.7,9
The reduction in vascular function in our CAH subjects was
comparable to the obese group who had a significantly higher
BMI, waist-to-height ratio, systolic blood pressure Z score and
insulin resistance. This suggests that there may be other factors
Table 2. Vascular function and structure and
metabolic data across three groupsControls
(n = 53)
Obese
(n = 28)
CAH
(n = 14)
anova
P-value
FMD (%)* 7Æ5 ± 5Æ2 5Æ8 ± 4Æ1 4Æ5 ± 3Æ0 0Æ06
GTN (%)** 28Æ4 ± 8Æ4 19Æ1 ± 7Æ5 17Æ2 ± 6Æ0 <0Æ001
Mean cIMT (mm) 0Æ42 ± 0Æ05 0Æ44 ± 0Æ06 0Æ41 ± 0Æ06 0Æ27
HsCRP (mg/l)a 0Æ5 (0Æ1–7Æ8) 4Æ6 (0Æ6–30) 1Æ0 (0Æ2–3Æ5) <0Æ001
Triglycerides (mm) 0Æ7 ± 0Æ3 1Æ3 ± 0Æ6 0Æ8 ± 0Æ3 <0Æ001
Total cholesterol (mm) 4Æ2 ± 1Æ0 4Æ2 ± 0Æ9 4Æ1 ± 0Æ7 0Æ51
LDL cholesterol (mm) 2Æ5 ± 0Æ9 2Æ5 ± 0Æ7 2Æ3 ± 0Æ5 0Æ69
HDL cholesterol (mm) 1Æ4 ± 0Æ3 1Æ1 ± 0Æ2 1Æ4 ± 0Æ2 <0Æ001
HOMA-IRa* 1Æ8 (0Æ5–4Æ2) 6Æ8 (1Æ9–32Æ4) 2Æ5 (0Æ2–2Æ9) <0Æ001
CAH, congenital adrenal hyperplasia; cIMT, carotid intima media thickness; FMD, flow-mediated
dilatation; GTN, glyceryl tri-nitrate dilatation; HDL, high-density lipoprotein; HOMA-IR, homoeo-
stasis model of assessment insulin resistance; LDL, low-density lipoprotein; hsCRP , high sensitive
C-reactive protein.
Values are given as mean ± SD.aGeometric mean (range).
CAH vs Controls: *P < 0Æ05, **P < 0Æ001.
Fig. 1 Flow-mediated dilatation (%) and glyceryl tri-nitrate dilatation (%)
in healthy controls, obese and children with congenital adrenal hyperplasia.
The horizontal solid line is the median, and the edges of the box plots
represent the 25 and 75th percentiles, the bars represent values within 1Æ5times the interquartile range, and the circles are the outliers *P < 0Æ05 vs
controls, **P < 0Æ001 vs controls.
840 J. Harrington et al.
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specific to CAH that contribute to the vascular dysfunction,
including hyperandrogenism and hypercortisolism. We were not
able to demonstrate a direct association between androgen levels
and vascular function in CAH, but our study was not powered to
do this.
The close association between excess androgens and insulin
resistance in women is well known32, and insulin resistance is a
well-established independent cardiovascular risk factor.33 How-
ever, the role of hyperandrogenism as an independent cardiovascu-
lar risk factor remains uncertain. Women with polycystic ovarian
syndrome (PCOS) have endothelial and smooth muscle dysfunc-
tion.34 Several studies have demonstrated that the vascular dys-
function is independent of insulin resistance, weight and lipids.34,35
cIMT is associated with testosterone and androstenedione levels in
young women with PCOS.36 Whether there is a direct association
between androgen levels and vascular function is still unresolved,
as others have not found any independent effect of androgens on
vascular function in PCOS.37
A limitation of our study was that the sample was not large
enough to determine associations between vascular function and
cardiovascular risk factors, but we had adequate power to detect
differences between groups. The CAH subjects were representative
of our South Australia’s population of children under 18 years with
CAH, in terms of their hydrocortisone and fludrocortisone medi-
cation doses which were within published guidelines.1 In addition,
their androstenedione and 17-hydroxyprogesterone levels were
comparable with other published cohorts.9
We did not find any difference with respect to cIMT between the
group with CAH and healthy controls, unlike Sartorato et al.15
Given that our cohort was over a decade younger, changes in vascu-
lar structure may not yet have developed. Endothelial dysfunction
is a first critical step in the development of atherosclerosis,6 and
thus, the results that were seen in this study may simply represent
an earlier stage prior to any change in cIMT. Being able to identify
the early changes in vascular function is important as endothelial
dysfunction has been shown to be independently associated with
the progression of cIMT over time.16
Congenital adrenal hyperplasia is a lifelong condition that is
associated with multiple vascular risk factors, and we have shown
for the first time that endothelial and smooth muscle dysfunction
is present by adolescence. In addition to optimal hormonal treat-
ment of CAH according to current guidelines,1 all children should
have assessment of potential additional cardiovascular risk factors.
Monitoring and intervention for central adiposity, hypertension
and insulin resistance, as well as optimizing hormone replacement
to use the minimum hydrocortisone dose to adequately suppress
androgens in adolescence, may have an important role in decreas-
ing future cardiovascular disease.
Acknowledgements
We gratefully acknowledge Lino Piotto and Kelly Gaskin for their
help with the ultrasonography work. JH was supported by the MS
McLeod Medical Postgraduate Scholarship, Children, Youth and
Women’s Health Service and the study was supported by NHMRC
# 519245.
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