Biochemical and Biophysical Markers of Endothelial Dysfunction in Adults with Hypopituitarism and Severe GH Deficiency
T. A. Elhadd,
T. A. Abdu,
J. Oxtoby,
G. Kennedy,
M. McLaren,
R. Neary,
J. J. F. Belch and
R. N. Clayton
Department of Medicine (T.A.E., T.A.A., R.N.C.), School of
Postgraduate Medicine, Keele University, Staffordshire, United Kingdom;
Departments of Nuclear Medicine (J.O.) and Clinical Biochemistry
(R.N.), North Staffordshire Hospital, Stoke-on-Trent, United Kingdom;
and Section of Vascular Biology and Medicine (G.K., M.M., J.J.F.B.),
University Department of Medicine, Ninewells Hospital and Medical
School, Dundee, United Kingdom
Address all correspondence and requests for reprints to: Prof. R. N. Clayton, Department of Medicine, School of Postgraduate Medicine, University of Keele, Thornborow Drive, Stoke-on-Trent ST4 6QJ, United Kingdom. E-mail: r.n.clayton{at}keele.ac.uk
Abstract
Adult hypopituitarism is known to be associated with reducedlife
expectancy related to excess vascular events, and endothelial
dysfunctionis present in patients with this condition. We studied the
relationshipbetween biophysical and biochemical markers of endothelial
dysfunction,including E-selectin, intercellular cell adhesion
molecule-1,von Willebrand factor, and thrombomodulin in 52 adult
patientswith hypopituitarism and severe GH deficiency (<2 ng/ml
onprovocative testing) compared with 54 age-, sex-, and
smoking-matchednormal controls. We also examined
endothelium-dependent dilatationof the brachial artery to
postischemic occlusion and carotidartery morphology (intima-media
thickness) by high-resolutionultrasonography. The patients were stable
on conventional hormonereplacement therapy but not on GH therapy, and
none of the subjectshad a known risk factor for vascular disease.
Levels of E-selectin[57 ± 3 vs. 49 ± 2
ng/ml (mean ± SEM)](P <
0.043), intercellular cell adhesion molecule-1 (308± 11
vs. 266 ± 10 ng/ml) (P <
0.001), thrombomodulin(49 ± 3 vs. 35 ± 2
ng/ml) (P < 0.001), andvon Willebrand factor
(132 ± 7% vs. 105 ± 5%)
(P< 0.004) were significantly higher in patients
than in controls.Brachial artery endothelium-dependent dilatation was
significantlylower in patients than in controls [4.7% (0.00–9.77)
vs.10.5% (6.4–16.2) (median, interquartile range)]
(P <0.001). This difference in
endothelium-dependent dilatationwas more marked in female patients
than in controls (P <0.003), although it
disappeared when estrogen-sufficient femalepatients were compared with
controls (P = 0.31). However, thefemale patients
who were not replaced with estrogen continuedto show a striking
difference compared with estrogen-deficientcontrol females
(P < 0.004). There was no difference in carotid
intima-mediathickness between patients of either sex and controls. On
univariateanalysis, brachial artery endothelium-dependent dilatation
correlatedinversely with intercellular cell adhesion molecule-1
(r = -0.225,P < 0.033). Intercellular cell
adhesion molecule-1 correlatedpositively with E-selectin (r =
0.466, P < 0.0001) and negativelywith IGF-I
(r = -0.238, P < 0.016). E-selectin
correlatedwith thrombomodulin (r = 0.215, P
< 0.034) and von Willebrandfactor (r = 0.218,
P < 0.03) and negatively with IGF-I (r=
-0.255, P < 009). Thrombomodulin correlated
positivelywith von Willebrand factor (r = 0.422,
P < 0.0001) and inverselywith IGF-I (r =
-0.266, P < 0.008). These correlations persisted
aftercorrection for age, sex, body mass index, and waist to hip ratio,
withthe exception of IGF-I, which now correlated with thrombomodulin
only.These results confirm significant endothelial dysfunction in
hypopituitarismand provide insight into the relationship of
biochemical andbiophysical markers of early atherosclerosis in
hypopituitaryGH-deficient adults. The negative correlation of IGF-I
withsome biochemical markers of endothelial dysfunction and the
predictivenature of GH deficiency in stepwise regression analysis in
thisstudy supports the hypothesis that GH deficiency may play arole
in these abnormalities. Future studies will determine whetherGH
treatment can reverse these abnormalities. Furthermore, themore
significant endothelium-dependent dilatation abnormalityin the female
estrogen-deficient subjects compared with thosewho were estrogen
replete suggests that estrogen replacementin these patients is a
crucial element in protecting againstvascular disease.
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