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Page 1: Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

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

Page 2: Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

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.

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Clinical Endocrinology (2012), 76, 837–842

Page 3: Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

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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Clinical Endocrinology (2012), 76, 837–842

Page 4: Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

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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Clinical Endocrinology (2012), 76, 837–842

Page 5: Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

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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