Reduced artery diameters in Klinefelter syndrome

ORIGINAL ARTICLE

Reduced artery diameters in Klinefelter syndromeC. Foresta,* N. Caretta,* P. Palego,* A. Ferlin,* D. Zuccarello,* A. Lenzi� and R. Selice*

*Department of Molecular Medicine, Section of Clinical Pathology and Center for Human Reproduction Pathology, University of Padova, Padova,

Italy, and �Department of Experimental Medicine, Section of Medical Pathophysiology and Endocrinology, Sapienza University of Rome, Rome,

Italy

Introduction

Klinefelter syndrome (KS) is the most common sex chro-

mosomal disorder, with a prevalence of 1:600 and it is a

frequent form of male hypogonadism and infertility

(Lanfranco et al., 2004; Bojesen et al., 2006). The KS is

characterized by the presence of one or more extra

X-chromosomes; about 80% of cases have 47, XXY karyo-

type, the remaining 20% have higher-grade chromosome

aneuploidies (48, XXXY, 48, XXYY, 49, XXXXY), mosa-

icisms (46, XY ⁄ 47, XXY) or structurally abnormal X

chromosomes (Lanfranco et al., 2004). The chromosome

aberration arises by maternal or paternal non-disjunction

during meiotic division in germ-cell development, or

rarely in early embryonic mitotic cell divisions (Lanfranco

et al., 2004).

The clinical features of KS commonly include hypergo-

nadotropic hypogonadism, gynecomastia, small testes and

azoospermia (Klinefelter et al., 1942), but Klinefelter syn-

drome may be associated also with an increased risk of

systemic diseases including malignancies, osteoporosis

(Kubler et al., 1992), venous thromboembolism (Camp-

bell & Price, 1981), diabetes and cardiovascular diseases

(CVDs) (Swerdlow et al., 2005; Bojesen & Gravholt,

2011). Various epidemiological studies in relatively large

cohorts of patients with KS described the increased mor-

bidity and mortality in KS. Focusing on CVDs, Bojesen

et al. in 2004 found that KS was associated with a signifi-

cant increase in mortality risk because of various causes,

including circulatory diseases (Hazard ratio: 1.41). Succes-

sively, Swerdlow et al., 2005found in KS a significantly

raised mortality for diseases of the circulatory system, in

Keywords:

artery diameter, brachial FMD, Klinefelter

syndrome, reproductive hormones

Correspondence:

Prof. Carlo Foresta, University of Padova,

Department of Histology, Microbiology and

Medical Biotechnologies, Section of Clinical

Pathology and Center for Human

Reproduction Pathology, Via Gabelli 63,

35121 Padova, Italy.

E-mail: [email protected]

Received 22 December 2011; revised 8

February 2012; accepted 21 February 2012

doi:10.1111/j.1365-2605.2012.01269.x

Summary

Various epidemiological studies in relatively large cohorts of patients with

Klinefelter syndrome (KS) described the increased morbidity and mortality in

these subjects. Our aim was to study the structure and function of arteries in

different districts to investigate in these subjects possible alterations. A total of

92 patients having non-mosaic KS, diagnosed in Centre for Human Reproduc-

tion Pathology at the University of Padova, and 50 age-matched healthy male

controls were studied. Klinefelter syndrome subjects and controls evaluation

included complete medical history, physical examination, measurement of con-

centrations of the reproductive hormones, lipidic and glycidic metabolism, AR

function and sensitivity, ultrasound examinations (diameters, carotid intima-

media thickness and brachial flow-mediated dilation) of brachial, common

carotid and common femoral artery and abdominal aorta. Klinefelter syndrome

patients showed significantly reduced artery diameters in all districts evaluated.

On the contrary no statistically significant difference was found in cIMT and

brachial FMD values between KS patients and controls. Furthermore, we found

no statistically significant correlation of artery diameters with reproductive hor-

mones, metabolic parameters, anthropometric measures and weighted CAG

repeats. To our knowledge, this is the first study finding a reduced artery diam-

eter in several districts in KS patients compared with that of normal male

subjects and overlapping to that of female subjects. We have not an explana-

tion for this phenomenon, even if a possible involvement of genes controlling

the development of vascular system might be hypothesized, and further

research is required to verify this hypothesis.

international journal of andrology ISSN 0105-6263

ª 2012 The Authors International Journal of Andrology, 1–6International Journal of Andrology ª 2012 European Academy of Andrology 1

particular for pulmonary embolism [Standardized Mortal-

ity Ratio (SMR): 5.7; 95% CI 2.5–11.3], cerebrovascular

disease (SMR: 2.2; 95% CI 1.6–3.0), peripheral vascular

disease (SMR: 7.9; 95% CI 2.9–17.2), subarachnoid haem-

orrhage (SMR: 3.1; 95% CI 1.2–6.8).

In recent years, a large body of data focused on the

possible role of diverse ultrasound measurements to

detect early signs of endothelial dysfunction, which in

turn has been considered as the primum movens with

respect to the onset and development of CVDs.

Several studies reported the predictive role of carotid

intima-media thickness (cIMT) in cardiovascular (CV)

risk stratification and future CV events (Chambless et al.,

1997; Lorenz et al., 2007) but such relationship is weak

and adds little to CVD prediction by traditional risk fac-

tors (Simon et al., 2010) and remains a topic of debate,

especially in young subjects.

Also flow-mediated dilation (FMD) has been consid-

ered as a predictor of CVD and other CV events, but its

value for risk stratification of CV events is still debatable

and further studies are needed to resolve such controversy

(Peters et al., 2011).

Recently, few reports documented the correlation

between brachial artery diameter (BAD) and CV risk fac-

tors and ⁄ or CV events in the general population (Yeboah

et al., 2007; Holewijn et al., 2009) and has been suggested

a more promising tool in CV risk prediction (Kullo et al.,

2007; Holewijn et al., 2009). On the basis of these recent

findings, considering that subjects affected by KS have an

increased risk of morbidity and mortality for CVD, we

studied the structure and function of arteries (diameter,

IMT and FMD) in different districts to investigate possible

alterations in these subjects and to correlate these mea-

sures with testosterone levels and function of the andro-

gen receptor (AR) CAG length and inactivation status.

Material and methods

Patients and clinical analysis

We studied, in a prospective study, a total of 92 patients

having non-mosaic KS (mean age 31.5 ± 8.7 years; range

15–52 years), diagnosed in Centre for Human Reproduc-

tion Pathology at the University of Padova and 50 age-

matched healthy male controls (mean age 30.8 ± 8.2 years;

range 19–49 years) from January 2010 to July 2011.

Patients had been referred to our centre for fertility prob-

lems, testicular hypotrophy, or referred to us for clinical

evaluation by other specialists. Healthy controls were

recruited through andrologic primary prevention check up

for fertility, premature ejaculation, erectile dysfunction

and lower urinary tract symptoms. The study was

approved by the Hospital Ethics Committee and each par-

ticipant gave his written informed consent.

All subjects (patients and controls) underwent periph-

eral karyotype analysis, evaluating al least 50 peripheral

blood lymphocyte metaphases. Each men had never

received testosterone substitution at the time of evalua-

tion.

Subjects evaluation included complete medical history

(pubertal history, lifestyle, physical activity, smoking, alco-

hol misuse), physical examination [weight, height, body

mass index (BMI), waist circumference, arm span, body

surface area calculated by the DuBois-DuBois formula;

0.007184 · height (cm)0.725 · weight (kg)0.425, blood pres-

sure] measurement of concentrations of the reproductive

hormones (LH, FSH, total testosterone, estradiol), lipidic

and glycidic metabolism (total cholesterol, HDL, triglyce-

rides, fasting glucose). Patients with more than one super-

numerary X chromosome, mosaicisms, or with any

endocrine dysfunction different from hypogonadism and

subjects assuming any drug were excluded from the study.

Blood pressure was measured in fasting conditions,

between 08.00 and 10.00 h, avoiding cigarette smoking

for a minimum of 12 h. Patients and controls reported a

regular lifestyle.

The AR function and sensitivity was studied through

the evaluation of the CAG repeat length and inactivating

status. The AR gene is located on the X chromosome and

therefore in KS is present in double copy. The inactiva-

tion rate of the two X chromosomes, and the effective

CAG repeat value in heterozygous KS men was calculated

as an X-weighted biallelic mean. This analysis was based

on Methylation-Specific PCR (MS-PCR) at the human

AR locus, with primers spanning the (CAG)n polymor-

phism region, as previously described (Kubota et al.,

1999).

Hormone assays

Blood was collected in the fasting state between 08.00 and

10.00 h. Serum FSH, LH, total testosterone (T) and estra-

diol (E) were evaluated by commercial electrochemilumi-

nescence immunoassay methods (Elecsys 2010; Roche

Diagnostics, Mannheim, Germany). For all parameters the

intra- and interassay coefficient of variation were <8%

and 10% respectively. Hypogonadism was defined as total

testosterone <10.4 nmol ⁄ L (Bhasin et al., 2006).

Ultrasound measurements

Ultrasound examinations of brachial, common carotid

and common femoral artery were performed in the

morning, after an overnight fasting, by the same experi-

enced operator (PP), blinded to patient clinical status,

with a high resolution Echo-Color-Doppler (Aplio XV

Toshiba, Tokyo, Japan) equipped with a 6–13 MHz

Reduced artery diameters in KS C. Foresta et al.

International Journal of Andrology, 1–6 ª 2012 The Authors2 International Journal of Andrology ª 2012 European Academy of Andrology

multifrequency linear probe. Intra-observer variability was

estimated to be less than 10%. Images were recorded and

measured in telediastole.

The inner to inner wall diameter (first echoic line in

the lumen, respectively, of near and far wall) of the bra-

chial artery was measured 4 cm above the antecubital

region using a dedicated semiautomatic software available

in the ultrasound machine. The arithmetic mean of six

consecutive measurements was considered for statistical

analysis.

The common carotid and common femoral artery were

measured with the same semiautomatic software and with

same procedure, both in the trait between 2 and 4 cm

before the bifurcation.

Abdominal aorta was measured using a high resolution

multifrequency convex probe 3–6 MHz: the mean of

three inner to inner wall measurements in the longitudi-

nal plan, from the infrarenal site to the aorto-iliac bifur-

cation, was considered for statistical analysis.

The IMT was measured in longitudinal scan, bilaterally,

in the distal tract, at 30 mm before the bifurcation of

common carotid artery, choosing the most linear tract of

arterial wall as by operator’s judgement. For each side

three semiautomatic measurements of the far wall IMT,

defined as the distance from the first echoic line between

lumen and wall vessel to the medio-adventitial margin,

were performed and the mean value of these measure-

ments was considered for statistical analysis.

Vascular endothelial function was evaluated with bra-

chial artery FMD (FMD) assessed in the morning, after an

overnight fasting. Longitudinal B-mode ultrasound images

of the brachial artery, 4–6 cm proximal to the antecubital

crease were taken. Images were obtained after 10 min of

supine relaxation during reactive hyperaemia, which was

induced by inflation for 5 min to suprasystolic pressure

(E20 mmHg) of an occlusion cuff placed around the fore-

arm. Increased blood flow and shear stress during hypera-

emia leads to NO-dependent FMD of the brachial artery.

End-diastolic images were stored and arterial diameters

were measured as the distance between the arterial wall

intima–media interfaces. The FMD was defined as the

maximum per cent change in arterial diameter from 10 to

120 s postdeflation of the occlusion cuff.

Statistical analysis

Differences between KS patients and controls were evalu-

ated using unpaired two-sided Student’s t-test. The same

test was used to evaluate differences between KS group

with hypogonadism and KS group with normal testoster-

one plasma levels. Relationships between continuous vari-

ables were assessed using non-parametric Spearman’s qcorrelation test.

The significance level was set to p < 0.05. Variables are

given as mean ± SD.

Results

Table 1 reports that KS patients had, as expected, signifi-

cantly higher weight, waist circumference, BMI, body sur-

face and gonadotropins with respect to controls and

significantly reduced levels of total testosterone.

Age, height, arm span, estradiol, weighted CAG repeat,

blood pressure, history of smoking and metabolic param-

eters (total and HDL cholesterol, triglycerides, glycaemia)

did not show statistically significant differences between

patients and controls.

Table 2 reports brachial, common carotid, common

femoral artery and abdominal aorta diameters in Klinefel-

ter patients and in controls. KS patients showed signifi-

cantly reduced artery diameters in all districts evaluated.

On the contrary no statistically significant difference was

found in cIMT and brachial FMD values between KS

patients and controls.

We then investigated in Klinefelter patients possible

associations between artery diameters, hormonal, meta-

bolic parameters and anthropometric measures. We found

Table 1 Clinical, metabolic, hormonal parameters and anthropomet-

ric measures in 92 Klinefelter patients compared with 50 controls

Variable

KS

(n = 92)

Controls

(n = 50) p

Age (years) 31.5 ± 8.7 30.8 ± 8.2 n.s.

Height (cm) 181.5 ± 7.5 179.9 ± 6.1 n.s.

Weight (kg) 84.3 ± 16.8 77.3 ± 12.0 <0.05

BMI (kg ⁄ m2) 25.6 ± 4.8 23.7 ± 3.8 <0.05

Body surface (m2) 2.04 ± 0.20 1.94 ± 0.15 <0.05

Waist (cm) 99.4 ± 16.1 84.5 ± 10.8 <0.0001

Arm span (cm) 182.5 ± 8.3 180.4 ± 7.3 n.s.

Total Testosterone

(nmol ⁄ L)

10.6 ± 4.9 17.3 ± 3.8 <0.0001

LH (IU ⁄ L) 21.2 ± 6.7 4.1 ± 2.1 <0.0001

FSH (IU ⁄ L) 34.9 ± 13.9 3.8 ± 1.7 <0.0001

Estradiol (pmol ⁄ L) 101.4 ± 35.8 95.8 ± 34.2 n.s.

LH ⁄ T 2.92 ± 3.5 0.3 ± 0.15 <0.0001

T ⁄ E 0.11 ± 0.06 0.2 ± 0.1 <0.0001

Weighted CAG repeats (n) 21.9 ± 3.1 21.0 ± 2.1 n.s.

Glycaemia (mg ⁄ dL) 80.1 ± 8.3 77.8 ± 7.1 n.s.

Total Cholesterol (mg ⁄ dL) 194.3 ± 36.4 188.4 ± 40.2 n.s.

HDL (mg ⁄ dL) 48.0 ± 11.7 51.1 ± 8.8 n.s.

Triglycerides (mg ⁄ dL) 107.3 ± 82.1 103.8 ± 45.2 n.s.

Systolic blood pressure

(mmHg)

123.1 ± 11.9 120.4 ± 9.1 n.s.

Diastolic blood pressure

(mmHg)

75.5 ± 7.8 73.0 ± 8.0 n.s.

Smoking history (n) (%) 48 (52) 23 (46) n.s.

n.s., not statistically significant.

C. Foresta et al. Reduced artery diameters in KS


no statistically significant correlation between artery

diameters (brachial, common carotid, common femoral

and abdominal aorta) and reproductive hormones (LH,

FSH, total testosterone, estradiol, LH ⁄ total T, T ⁄ E),

anthropometric measures (height, weight, BMI, body sur-

face, waist, arm span) and metabolic parameters. Further-

more, we found no statistically significant correlation

between artery diameters and weighted CAG repeats (data

not shown).

We then subgrouped KS patients in subjects with

reduced total testosterone plasma levels (<10.4 nmol ⁄ L)

and those with normal testosterone plasma levels

(‡10.4 nmol ⁄ L). Table 3 reports the data about artery

diameters in the two groups, showing no statistically

significant differences in brachial, common carotid,

common femoral artery and abdominal aorta diameters.

Also FMD and cIMT did not show any statistically signif-

icant difference between the two groups. As expected KS

subjects with low testosterone levels showed higher BMI

and body surface, whereas AR sensitivity and blood

pressure did not show statistically significant differences

between KS with low and normal testosterone levels.

Discussion

The aim of the present study was to analyse for the first

time the structure and function of arteries in Klinefelter

patients in different districts and to correlate the findings

with testosterone levels and AR function. The rationale

for this study has been suggested by various epidemiolog-

ical studies describing an increased morbidity and mortal-

ity in KS because of many causes, including circulatory

diseases. We found a reduced diameter in brachial, com-

mon carotid, common femoral artery and abdominal

aorta in KS subjects with respect to controls. Interestingly,

no relation with hormonal levels and AR CAG length was

found, and vascular diameters were similar in KS subjects

with low and normal testosterone levels. Furthermore,

cIMT and FMD were not different in KS subjects with

respect to controls. All together, these findings suggest an

altered morphological arterial structure in KS patients

with normal endothelial function.

It has been suggested that hypogonadism in KS subjects

might not be clearly defined by total testosterone levels.

Therefore, we correlated estradiol, LH, FSH, LH ⁄ total T

ratio and T ⁄ E ratio to vascular diameters, but we did not

find any correlation. These data further demonstrate that

the hypothalamus-pituitary-testicular axis function does

not seem to have a role in reduced artery diameters in KS

patients.

Previous studies have described associations of age

(Bonithon-Kopp et al., 1996; Crouse et al., 1996), gender

(Crouse et al., 1994, 1996; Bonithon-Kopp et al., 1996;

Jensen-Urstad et al.,1999; Jensen-Urstad & Johansson,

2001; Ruan et al., 2009) and height (Bonithon-Kopp

et al., 1996; Crouse et al., 1996; Jensen-Urstad et al.,1999)

with arterial diameters. It has been demonstrated that

women have lower lumen diameter than men, with differ-

ences that persist after adjustment for height, a variable

which differs between genders and which is known to

have a positive relation with the artery diameter. The

brachial artery diameter in women has been reported

between 3.1 and 3.6 mm (Jensen-Urstad & Johansson,

2001; Dengel et al., 2011; Montalcini et al., 2008 21, 23,

Table 2 Brachial, common carotid, common femoral artery and

abdominal aorta diameters, carotid intima-media thickness (cIMT), and

brachial flow-mediated dilatation (FMD) in 92 Klinefelter patients

compared with 50 controls

KS Controls p

Brachial arthery (mm) 3.21 ± 0.54 3.91 ± 0.52 <0.0001

Common femoral

artery (mm)

7.06 ± 0.87 7.78 ± 1.0 <0.0001

Common carotid (mm) 5.59 ± 0.55 5.96 ± 0.71 <0.01

Abdominal aorta (mm) 11.6 ± 1.8 14.0 ± 1.0 <0.0001

cIMT (mm) 0.52 ± 0,11 0.49 ± 0.13 n.s.

FMD (%) 21.0 ± 11.1 20.1 ± 12.4 n.s.


Table 3 Brachial, common carotid, common femoral artery and

abdominal aorta diameters, cIMT, and FMD, and clinical parameters in

KS patients with low T levels (total T <10.4 nmol ⁄ L) and normal T

levels

KS (46

patients)

Normal

T levels

KS (46

patients)

Low

T levels p

Brachial arthery (mm) 3.09 ± 0.54 3.29 ± 0.53 n.s.

Common femoral

artery (mm)

6.96 ± 0.87 7.14 ± 0.88 n.s.

Common carotid (mm) 5.50 ± 0.56 5.62 ± 0.56 n.s.

Abdominal aorta (mm) 11.50 ± 1.5 11.66 ± 1.5 n.s.

cIMT (mm) 0.50 ± 0.10 0.54 ± 0.11 n.s.

FMD (%) 20.1 ± 11.6 20.7 ± 11.2 n.s.

Total Testosterone

(nmol ⁄ L)

14.05 ± 3,7 6.9 ± 3.1 < 0.0001

BMI (kg ⁄ m2) 23.4 ± 3.5 27.6 ± 4.9 < 0.0001

Body surface (m2) 1.97 ± 0.18 2.11 ± 0.19 < 0.0005

Systolic blood

pressure (mmHg)

121.9 ± 11.4 124.5 ± 12.2 n.s.

Diastolic blood

pressure (mmHg)

74.6 ± 6.9 76.5 ± 8.0 n.s.

Weighted CAG

repeats (n)

22.1 ± 3.0 21.7 ± 3.1 n.s.




24) and the common carotid artery diameter between 5.4

and 5.7 mm (Jensen-Urstad et al., 1999; Ruan et al.,

2009; Dengel et al., 2011), Gonzales et al. report in young

women a diameter for femoral artery of 7.1 mm (Gonz-

ales et al., 2010). Our results showed that KS patients

have a diameter of brachial, common carotid and com-

mon femoral artery overlapping to women despite the

difference in height. Whether this is an effect of the extra

X-chromosome remains unknown, although intriguing. In

our study the height, as the other anthropometric mea-

sures, did not differ between KS patients and controls,

therefore the finding of smaller artery diameters is not

influenced by them.

Recently, few reports documented the correlation of

brachial artery diameter (BAD) with CV risk factors

and ⁄ or CV events in the general population (Yeboah

et al., 2007; Holewijn et al., 2009). Holewijn et al., 2009

showed a negative correlation between BAD and CVD in

337 subjects aged 50–70 years enrolled from general pop-

ulation, whereas Yeboah et al., 2007 found that the event-

free survival rate for CV events for subjects with BAD

below or equal to the median was higher than for those

with BAD above the median. Furthermore, Kullo et al.,

2007 studied asymptomatic subjects drawn from the com-

munity (mean age 61 years) finding that greater BAD was

associated with the presence and quantity of coronary

artery calcium, independent from coronary heart disease

risk factors, although this association was weak.

To our knowledge, this is the first study finding in KS

patients a reduced artery diameter in several districts

(brachial, common carotid, common femoral and

abdominal aorta) compared with that of normal male

subjects and overlapping to that of female subjects.

Furthermore, an involvement of hormone imbalance,

anthropometric measures, metabolic parameters, andro-

gen receptor sensitivity as causative for this difference has

been excluded.

We do not have an explanation for this phenomenon,

even if a possible involvement of genes controlling the

development of vascular system might be hypothesized.

Considering that in the opposite condition of KS, Turner

syndrome (45, X) there is a general dilatation of the same

arterial beds (Mortensen et al., 2011), we could hypothe-

size that a gene or genes on the X chromosome and a

possible paralogue on the Y needs to be present in two

copies to control normal growth of arteries, whereas hav-

ing only one gene leads to dilatation, while three copies

leads to insufficient growth. This of course especially

implicates pseudoautosomal genes like for instance the

SHOX gene, which has not so far been implicated in the

growth of arteries, but has BNP as one of its transcrip-

tional targets. Further research is required to verify this

hypothesis.

A limitation of our study is the lacking of echocardiog-

raphyc data to correlate our findings with cardiac func-

tion parameters. Recently Andersen et al. (Andersen et al.,

2008) found a higher left ventricular mass index in KS

subjects with respect to controls. This observation sug-

gests a possible increase of peripherical resistance related

to a reduced artery diameters. However, our patients

showed systolic and diastolic blood pressure levels not

statistically significant different with respect to controls,

probably as a consequence of a reduced resistance at

small arterial and arteriolar level.

In conclusion, our study provides new insight into rela-

tions between Klinefelter syndrome and CVD. For the

first time in KS patients we observed a reduced artery

diameter in several districts that should be implicated in

increased CV morbidity and mortality. Further studies are

necessary to clarify the pathogenesis and clinical implica-

tions of our findings.

Conflict of interest

The authors have nothing to disclose.

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Reduced artery diameters in Klinefelter syndrome