Persistence of Increased Cardiovascular Risk in Patients with Cushing’s Disease after Five Years of Successful Cure
Annamaria Colao,
Rosario Pivonello,
Stefano Spiezia,
Antongiulio Faggiano,
Diego Ferone,
Mariagiovanna Filippella,
Paolo Marzullo,
Gaetana Cerbone,
Marcello Siciliani and
Gaetano Lombardi
Department of Molecular and Clinical Endocrinology and Oncology,
Federico II University (A.C., R.P., A.F., D.F., M.F., P.M., G.C., G.L.)
and Echo-Guided Surgery Unit, S. Maria del Popolo degli Incurabili
Hospital (S.S., M.S.), Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it
Patients with Cushing’s disease (CD) mainly die becauseof
cardiovascular accidents. The aim of this study was to evaluatewhether
patients with CD still have increased cardiovascularrisk and suffer
from premature atherosclerosis once cured.
Fifteen patients cured from CD for a long term period (5 yr),30 sex-
and age-matched controls, and 30 body mass index (BMI)-matchedcontrols
were included in this study. BMI; waist to hip ratio(WHR); systolic
(SBP) and diastolic (DBP) blood pressures; serumtotal, low density
lipoprotein (LDL), and high density lipoprotein(HDL) cholesterol;
serum triglycerides, fibrinogen, and lipoprotein(a)levels; prothrombin
time; activated partial thromboplastinetime; and basal and glucose
load-stimulated insulin and glucoselevels were measured in patients
and controls. By echo-Dopplerultrasonography, the intima media
thickness (IMT), systolicand diastolic media-media distances, blood
systolic (SPV) anddiastolic (DPV) peak velocity, systolic (SLD) and
diastolic(DLD) lumen diameter, and distensibility coefficient (DC)
weremeasured at both common carotid arteries where the presence,size,
and location of atherosclerotic plaques were also evaluated.
Compared with a sex- and age-matched control population, CDpatients
had BMI (P < 0.001), WHR (P <
0.001), SBP (P< 0.005), DBP
(P < 0.05), fasting glucose (P
< 0.001)and insulin (P < 0.05), glucose
load-stimulated glucose andinsulin levels (P <
0.05), total cholesterol (P < 0.05),LDL
cholesterol (P < 0.01), fibrinogen
(P < 0.01), andlipoprotein(a)
(P < 0.05) levels higher and HDL cholesterol
levels(P < 0.05) lower than controls. At
ultrasonography, in thepatients, IMT (P < 0.05),
SPV (P < 0.05) and DPV (P <
0.001)were significantly increased whereas SLD
(P < 0.001), DLD(P < 0.001),
and DC (P < 0.05) were significantly decreased
comparedto controls. In addition, CD patients had higher WHR
(P <0.05), DBP (P < 0.05),
glucose load-stimulated glucose andinsulin levels
(P < 0.05), and fibrinogen levels
(P <0.01) and lower HDL cholesterol
(P < 0.05) levels than BMI-matchedcontrols. At
ultrasonography, increased common carotid arteriesIMT
(P < 0.05) and DPV (P < 0.05)
and decreased DLD (P< 0.05) and DC
(P < 0.05) were measured in patients comparedto
those in BMI-matched controls. Atherosclerotic plaques werefound in
26.7% of patients, in none of the sex- and age-matchedcontrols, and
in 3.3% of the BMI-matched controls. In CD patients,a significant
correlation was found between both WHR and fastingserum insulin levels
and DBP (r = 0.52 and r = 0.55; P <
0.05),triglycerides levels (r = 0.56 and r = 0.77;
P < 0.05), andIMT (r = 0.64 and r =
0.56; P < 0.05). Right (r = -0.70;
P< 0.005) and left (r = -0.65;
P < 0.01) DC were inverselycorrelated to the
duration of CD in the patient group. At themultiple regression
analysis, WHR was the best predictor offasting insulin levels
(ß = 0.77; P < 0.05), and vice
versa,fasting insulin level was the best predictor of WHR
(ß= 1.20; P < 0.05).
In conclusion, patients cured from CD for a long term periodhave a
high prevalence of atherosclerosis and maintain increasedseveral
cardiovascular risk factors of the active disease, probablydue to a
residual abdominal obesity and/or insulin resistancesyndrome.
This article has been cited by other articles:
A. M Pereira, V. Delgado, J. A Romijn, J. W A Smit, J. J Bax, and R. A Feelders Cardiac dysfunction is reversed upon successful treatment of Cushing's syndrome
Eur. J. Endocrinol.,
February 1, 2010;
162(2):
331 - 340.
[Abstract][Full Text][PDF]
S. M. Webb, D. Mo, S. W. J. Lamberts, S. Melmed, F. Cavagnini, F. Pecori Giraldi, C. J. Strasburger, A. G. Zimmermann, W. W. Woodmansee, and on behalf of the International HypoCCS Advisory Bo Metabolic, Cardiovascular, and Cerebrovascular Outcomes in Growth Hormone-Deficient Subjects with Previous Cushing's Disease or Non-Functioning Pituitary Adenoma
J. Clin. Endocrinol. Metab.,
February 1, 2010;
95(2):
630 - 638.
[Abstract][Full Text][PDF]
A. F. Attanasio, D. Mo, E. M. Erfurth, M. Tan, K. Y. Ho, D. Kleinberg, A. G. Zimmermann, P. Chanson, and on behalf of the International Hypopituitary Contr Prevalence of Metabolic Syndrome in Adult Hypopituitary Growth Hormone (GH)-Deficient Patients Before and After GH Replacement
J. Clin. Endocrinol. Metab.,
January 1, 2010;
95(1):
74 - 81.
[Abstract][Full Text][PDF]
M.-J. Barahona, N. Sucunza, E. Resmini, J.-M. Fernandez-Real, W. Ricart, J.-M. Moreno-Navarrete, T. Puig, J. Farrerons, and S. M. Webb Persistent Body Fat Mass and Inflammatory Marker Increases after Long-Term Cure of Cushing's Syndrome
J. Clin. Endocrinol. Metab.,
September 1, 2009;
94(9):
3365 - 3371.
[Abstract][Full Text][PDF]
P. Anagnostis, V. G. Athyros, K. Tziomalos, A. Karagiannis, and D. P. Mikhailidis The Pathogenetic Role of Cortisol in the Metabolic Syndrome: A Hypothesis
J. Clin. Endocrinol. Metab.,
August 1, 2009;
94(8):
2692 - 2701.
[Abstract][Full Text][PDF]
M. B. Lodish, N. Sinaii, N. Patronas, D. L. Batista, M. Keil, J. Samuel, J. Moran, S. Verma, J. Popovic, and C. A. Stratakis Blood Pressure in Pediatric Patients with Cushing Syndrome
J. Clin. Endocrinol. Metab.,
June 1, 2009;
94(6):
2002 - 2008.
[Abstract][Full Text][PDF]
M. Sereg, A. Szappanos, J. Toke, K. Karlinger, K. Feldman, E. Kaszper, I. Varga, E. Glaz, K. Racz, and M. Toth Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study
Eur. J. Endocrinol.,
April 1, 2009;
160(4):
647 - 655.
[Abstract][Full Text][PDF]
M. Christ-Crain, B. Kola, F. Lolli, C. Fekete, D. Seboek, G. Wittmann, D. Feltrin, S. C. Igreja, S. Ajodha, J. Harvey-White, et al. AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome
FASEB J,
June 1, 2008;
22(6):
1672 - 1683.
[Abstract][Full Text][PDF]
L. K. Nieman, B. M. K. Biller, J. W. Findling, J. Newell-Price, M. O. Savage, P. M. Stewart, and V. M. Montori The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline
J. Clin. Endocrinol. Metab.,
May 1, 2008;
93(5):
1526 - 1540.
[Abstract][Full Text][PDF]
B. R Walker Glucocorticoids and Cardiovascular Disease
Eur. J. Endocrinol.,
November 1, 2007;
157(5):
545 - 559.
[Abstract][Full Text][PDF]
H. Holmer, J. Svensson, L. Rylander, G. Johannsson, T. Rosen, B.-A. Bengtsson, M. Thoren, C. Hoybye, M. Degerblad, M. Bramnert, et al. Nonfatal Stroke, Cardiac Disease, and Diabetes Mellitus in Hypopituitary Patients on Hormone Replacement Including Growth Hormone
J. Clin. Endocrinol. Metab.,
September 1, 2007;
92(9):
3560 - 3567.
[Abstract][Full Text][PDF]
A. A van der Klaauw, N. R Biermasz, E. J M Feskens, M. B Bos, J. W A Smit, F. Roelfsema, E. P M Corssmit, H. Pijl, J. A Romijn, and A. M Pereira The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term substitution with recombinant human GH
Eur. J. Endocrinol.,
April 1, 2007;
156(4):
455 - 462.
[Abstract][Full Text][PDF]
O. M. Dekkers, N. R. Biermasz, A. M. Pereira, F. Roelfsema, M. O. van Aken, J. H. C. Voormolen, and J. A. Romijn Mortality in Patients Treated for Cushing's Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma
J. Clin. Endocrinol. Metab.,
March 1, 2007;
92(3):
976 - 981.
[Abstract][Full Text][PDF]
D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism
Am J Physiol Endocrinol Metab,
March 1, 2007;
292(3):
E654 - E667.
[Abstract][Full Text][PDF]
F. Pecori Giraldi, M. Andrioli, L. De Marinis, A. Bianchi, A. Giampietro, M. De Martin, E. Sacco, M. Scacchi, A. Pontecorvi, and F. Cavagnini Significant GH deficiency after long-term cure by surgery in adult patients with Cushing's disease
Eur. J. Endocrinol.,
February 1, 2007;
156(2):
233 - 239.
[Abstract][Full Text][PDF]
P Haentjens, L De Meirleir, R Abs, J Verhelst, K Poppe, and B Velkeniers Glomerular filtration rate in patients with Cushing's disease: a matched case-control study
Eur. J. Endocrinol.,
December 1, 2005;
153(6):
819 - 829.
[Abstract][Full Text][PDF]
A. Faggiano, D. Melis, R. Alfieri, M. De Martino, M. Filippella, F. Milone, G. Lombardi, A. Colao, and R. Pivonello Sulfur Amino Acids in Cushing's Disease: Insight in Homocysteine and Taurine Levels in Patients with Active and Cured Disease
J. Clin. Endocrinol. Metab.,
December 1, 2005;
90(12):
6616 - 6622.
[Abstract][Full Text][PDF]
D. J. Brotman, J. P. Girod, M. J. Garcia, J. V. Patel, M. Gupta, A. Posch, S. Saunders, G. Y. H. Lip, S. Worley, and S. Reddy Effects of Short-Term Glucocorticoids on Cardiovascular Biomarkers
J. Clin. Endocrinol. Metab.,
June 1, 2005;
90(6):
3202 - 3208.
[Abstract][Full Text][PDF]
L.-A. Li and P.-W. Wang PCB126 Induces Differential Changes in Androgen, Cortisol, and Aldosterone Biosynthesis in Human Adrenocortical H295R Cells
Toxicol. Sci.,
May 1, 2005;
85(1):
530 - 540.
[Abstract][Full Text][PDF]
J. K. Schulman, P. R. Muskin, and P. A. Shapiro Psychiatry and Cardiovascular Disease
Focus,
April 1, 2005;
3(2):
208 - 224.
[Abstract][Full Text][PDF]
A. Colao, C. Di Somma, F. Rota, R. Pivonello, M. C. Savanelli, S. Spiezia, and G. Lombardi Short-Term Effects of Growth Hormone (GH) Treatment or Deprivation on Cardiovascular Risk Parameters and Intima-Media Thickness at Carotid Arteries in Patients with Severe GH Deficiency
J. Clin. Endocrinol. Metab.,
April 1, 2005;
90(4):
2056 - 2062.
[Abstract][Full Text][PDF]
L. Wei, T. M. MacDonald, and B. R. Walker Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease
Ann Intern Med,
November 16, 2004;
141(10):
764 - 770.
[Abstract][Full Text][PDF]
J. P. Girod and D. J. Brotman Does altered glucocorticoid homeostasis increase cardiovascular risk?
Cardiovasc Res,
November 1, 2004;
64(2):
217 - 226.
[Abstract][Full Text][PDF]
F. Orio Jr., S. Palomba, L. Spinelli, T. Cascella, L. Tauchmanova, F. Zullo, G. Lombardi, and A. Colao The Cardiovascular Risk of Young Women with Polycystic Ovary Syndrome: An Observational, Analytical, Prospective Case-Control Study
J. Clin. Endocrinol. Metab.,
August 1, 2004;
89(8):
3696 - 3701.
[Abstract][Full Text][PDF]
M. Terzolo, B. Allasino, S. Bosio, E. Brusa, F. Daffara, M. Ventura, E. Aroasio, G. Sacchetto, G. Reimondo, A. Angeli, et al. Hyperhomocysteinemia in Patients with Cushing's Syndrome
J. Clin. Endocrinol. Metab.,
August 1, 2004;
89(8):
3745 - 3751.
[Abstract][Full Text][PDF]
P C Souverein, A Berard, T P Van Staa, C Cooper, A C G Egberts, H G M Leufkens, and B R Walker Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study
Heart,
August 1, 2004;
90(8):
859 - 865.
[Abstract][Full Text][PDF]
R. Pivonello, D. Ferone, W. W. de Herder, J. M. Kros, M. L. Del Basso De Caro, M. Arvigo, L. Annunziato, G. Lombardi, A. Colao, L. J. Hofland, et al. Dopamine Receptor Expression and Function in Corticotroph Pituitary Tumors
J. Clin. Endocrinol. Metab.,
May 1, 2004;
89(5):
2452 - 2462.
[Abstract][Full Text][PDF]
G. Arnaldi, A. Angeli, A. B. Atkinson, X. Bertagna, F. Cavagnini, G. P. Chrousos, G. A. Fava, J. W. Findling, R. C. Gaillard, A. B. Grossman, et al. Diagnosis and Complications of Cushing's Syndrome: A Consensus Statement
J. Clin. Endocrinol. Metab.,
December 1, 2003;
88(12):
5593 - 5602.
[Abstract][Full Text][PDF]
M. L. Muiesan, M. Lupia, M. Salvetti, C. Grigoletto, N. Sonino, M. Boscaro, E. A. Rosei, F. Mantero, and F. Fallo Left ventricular structural and functional characteristics in Cushing's syndrome
J. Am. Coll. Cardiol.,
June 18, 2003;
41(12):
2275 - 2279.
[Abstract][Full Text][PDF]
A. Faggiano, R. Pivonello, S. Spiezia, M. C. De Martino, M. Filippella, C. Di Somma, G. Lombardi, and A. Colao Cardiovascular Risk Factors and Common Carotid Artery Caliber and Stiffness in Patients with Cushing's Disease during Active Disease and 1 Year after Disease Remission
J. Clin. Endocrinol. Metab.,
June 1, 2003;
88(6):
2527 - 2533.
[Abstract][Full Text][PDF]
A. Faggiano, R. Pivonello, D. Melis, M. Filippella, C. Di Somma, M. Petretta, G. Lombardi, and A. Colao Nephrolithiasis in Cushing's Disease: Prevalence, Etiopathogenesis, and Modification after Disease Cure
J. Clin. Endocrinol. Metab.,
May 1, 2003;
88(5):
2076 - 2080.
[Abstract][Full Text][PDF]
L. Tauchmanova, R. Rossi, B. Biondi, M. Pulcrano, V. Nuzzo, E.-A. Palmieri, S. Fazio, and G. Lombardi Patients with Subclinical Cushing's Syndrome due to Adrenal Adenoma Have Increased Cardiovascular Risk
J. Clin. Endocrinol. Metab.,
November 1, 2002;
87(11):
4872 - 4878.
[Abstract][Full Text][PDF]
J. Lindholm, S. Juul, J. O. L. Jorgensen, J. Astrup, P. Bjerre, U. Feldt-Rasmussen, C. Hagen, J. Jorgensen, M. Kosteljanetz, L. O. Kristensen, et al. Incidence and Late Prognosis of Cushing's Syndrome: A Population-Based Study
J. Clin. Endocrinol. Metab.,
January 1, 2001;
86(1):
117 - 123.
[Abstract][Full Text]
