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Original Studies |
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
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Abstract |
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Fifteen patients cured from CD for a long term period (5 yr), 30 sex- and age-matched controls, and 30 body mass index (BMI)-matched controls were included in this study. BMI; waist to hip ratio (WHR); systolic (SBP) and diastolic (DBP) blood pressures; serum total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol; serum triglycerides, fibrinogen, and lipoprotein(a) levels; prothrombin time; activated partial thromboplastine time; and basal and glucose load-stimulated insulin and glucose levels were measured in patients and controls. By echo-Doppler ultrasonography, the intima media thickness (IMT), systolic and diastolic media-media distances, blood systolic (SPV) and diastolic (DPV) peak velocity, systolic (SLD) and diastolic (DLD) lumen diameter, and distensibility coefficient (DC) were measured 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, CD patients 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 and insulin levels (P < 0.05), total cholesterol (P < 0.05), LDL cholesterol (P < 0.01), fibrinogen (P < 0.01), and lipoprotein(a) (P < 0.05) levels higher and HDL cholesterol levels (P < 0.05) lower than controls. At ultrasonography, in the patients, 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 compared to controls. In addition, CD patients had higher WHR (P < 0.05), DBP (P < 0.05), glucose load-stimulated glucose and insulin levels (P < 0.05), and fibrinogen levels (P < 0.01) and lower HDL cholesterol (P < 0.05) levels than BMI-matched controls. At ultrasonography, increased common carotid arteries IMT (P < 0.05) and DPV (P < 0.05) and decreased DLD (P < 0.05) and DC (P < 0.05) were measured in patients compared to those in BMI-matched controls. Atherosclerotic plaques were found in 26.7% of patients, in none of the sex- and age-matched controls, and in 3.3% of the BMI-matched controls. In CD patients, a significant correlation was found between both WHR and fasting serum 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), and IMT (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 inversely correlated to the duration of CD in the patient group. At the multiple regression analysis, WHR was the best predictor of fasting 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 period have a high prevalence of atherosclerosis and maintain increased several cardiovascular risk factors of the active disease, probably due to a residual abdominal obesity and/or insulin resistance syndrome.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The current study was designed to investigate the cardiovascular risk and vascular consequences in patients successfully cured of CD who had achieved a long term period of serum cortisol level normalization.
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Subjects and Methods |
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Among 65 patients followed up in our department for CD, 15 patients (3 males and 12 females, 20–50 yr of age) achieved stable cure of the disease for 5 yr and entered this study after their informed consent had been obtained.
The diagnosis of CD was based on 1) increase of daily urinary cortisol excretion with inappropriately high plasma ACTH concentrations, 2) increased basal serum cortisol concentrations with lack of the physiological circadian rhythm, and 3) failure of urinary and serum cortisol suppression after low dose but greater than 50% decrease after high dose dexamethasone test. After treatment, the criteria used to define cure of CD were 1) urinary daily cortisol excretion and plasma ACTH concentrations below or within the normal range, 2) serum cortisol concentrations below or within the normal range with restoration of physiological circadian rhythm, and 3) suppression of urinary and serum cortisol concentrations after low dose dexamethasone test.
All patients had undergone surgical selective resection of the
ACTH-secreting pituitary adenoma by the transsphenoidal approach; the
results of immunohistochemistry on surgically removed pituitary
adenomas confirmed the diagnosis of CD in all patients. After surgery,
4 of them had hypocortisolism and were given cortisone acetate at
standard doses (12.5–37.5 mg/day); 6 had normalization of serum and
urinary cortisol concentrations not requiring cortisone replacement
treatment. Two of these 6 patients had had a transient hypocortisolism
preceding the normalization of circulating cortisol levels. The
remaining 5 had persistent hypercortisolism and underwent pituitary
irradiation that induced normalization of serum and urinary cortisol
between 1–3 yr after radiotherapy. These latter patients had been
treated with adrenocortical-blocking drugs, which induced suppression
of serum and urinary cortisol levels, while awaiting the effects of
radiotherapy. No residual anterior pituitary deficiency was recorded
after treatment in the 15 patients, except for secondary hypogonadism
and diabetes insipidus in 1 woman (no. 4; Table 1
). This patient received an
estroprogestinic preparation and desmopressin at a dose of 15 µg/day
at the diagnosis of hormone insufficiency. Postthyroiditic
hypothyroidism occurred in 3 patients, 3–6 months after the cure of
the disease. These patients were replaced with T4 at doses
ranging 75–125 µg/day. The adequacy of replacement therapy was
periodically monitored during the follow-up by measuring free thyroid
hormone levels, daily water balance, blood pressure, serum electrolyte
levels, and regularity of menses. After cure, all patients had been
followed at least twice yearly to verify the persistent control of
cortisol secretion and the possible onset of other pituitary
insufficiencies. As GH deficiency was reported to cause premature
atherosclerosis (7), the GH response to insulin tolerance test (ITT)
and to arginine and GHRH (ARG+GHRH) test was evaluated in all 15
patients; a GH response above 3 µg/L (6.9 ± 0.3 µg/L) to ITT
and above 9 µg/L to ARG+GHRH (18.6 ± 1.2 µg/L) was
found in all cases, so excluding the coexistence of GH deficiency (8, 9). At the diagnosis, all patients (100%) had central obesity, 10
(66.7%) had arterial hypertension, 7 (46.7%) diabetes mellitus, and 6
(40%) had reduced glucose tolerance. Hypertension was classified (see
below) as mild in 5, moderate in 2, and severe in the remaining 3
patients. In patients with moderate or severe hypertension, treatment
with diuretics (in 1), calcium-antagonists (in 1), or
angiotensin-converting enzyme inhibitors (in 3) normalized blood
pressure. Two of the 7 patients with diabetes mellitus had taken
discontinuously oral glucose-lowering drugs, whereas the remaining 5
were subjected to only a low lipid/carbohydrate diet regimen.
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. The study of the hypothalamus-pituitary-adrenal axis in individual
patients is shown in Table 2.
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The study included two different control groups: 1) a sex- and age-matched group of healthy subjects, and 2) a body mass index (BMI)-matched group of subjects. The BMI-matched control group also included subjects with sex and age comparable to those of the patients. All control subjects agreed to participate to the study. None of these subjects had ever received chronic treatment with glucocorticoids or drugs known to interfere with glucose or lipid metabolism or influence blood pressure. All were nonsmokers, and none had familial or personal history of cardiovascular diseases. The comparisons between patients and the two different control groups were evaluated separately to estimate the role of BMI in the genesis of clinical, metabolic, and vascular features of the patients in the study.
Protocol of the study
All patients and controls were submitted to a three-step study.
Clinical study. Height, weight, BMI, waist to hip ratio (WHR), and measurements of heart rate and systolic (SBP) and diastolic (DBP) blood pressures were evaluated by standard methods. BMI was measured as the ratio between the weight and height squared. A BMI between 25–30 was considered as an index of overweight; a BMI above 30 was considered as an index of obesity (10). WHR was measured as the ratio between the waist, i.e. the smallest circumference of torso between the 12th rib and the iliac crest, and the circumference of the hip, i.e. the maximal extension of the buttocks. The measurements were performed with patients in a standing position with relaxed abdomen, arms at sides, and joined feet (11). Blood pressure was measured in the right arm, with the subjects in a relaxed sitting position. The average of six measurements (three taken by each of two examiners) with a mercury sphygmomanometer was used. Hypertension was diagnosed when DBP values were above 90 mm Hg and was graded as mild when DBP values were between 91–104 mm Hg, moderate when DBP values were between 105–114 mm Hg, and severe when DBP values were 115 mm Hg or greater, in line with WHO criteria (12). In patients treated with antihypertensive drugs, pretreatment blood pressure values were considered for diagnosis and evaluation of the severity of hypertension.
Biochemical study. Fasting glucose; triglycerides; total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol; prothrombin time (PT); activated partial thromboplastine time; lipoprotein(a) (Lpa) and fibrinogen levels were measured by standard procedures. The total/HDL cholesterol ratio, considered the index of severe cardiovascular risk (13), was also calculated. Hypertriglyceridemia was diagnosed when triglycerides levels were above 250 mg/dL (14), whereas hypercholesterolemia was diagnosed when total cholesterol levels were above 240 mg/dL (15). Impaired glucose tolerance was diagnosed after an oral glucose tolerance test (75 g glucose diluted in 250 mL saline solution, measuring blood glucose every 30 min for 2 h). In line with WHO criteria, diabetes mellitus was diagnosed when fasting blood glucose levels were higher than 140 mg/dL for two consecutive determinations or were 200 mg/dL or greater 2 h after oral glucose; reduced glucose tolerance was diagnosed when blood glucose levels were lower than 140 mg/dL at fasting and 140–200 mg/dL 2 h after oral glucose (16). Fasting and glucose load-stimulated insulin levels were measured in patients and controls to estimate insulin sensitivity. Plasma ACTH and serum and urinary cortisol levels were measured in patients and controls at study entry to verify the absence of hypercortisolism.
Vascular study. Carotid arteries ultrasound imaging was performed by echo-Doppler ultrasonography (US), carried out with a Vingmed Sound CMF 725 (Horten, Norway) using a 7.5-MHz annular phased array transducer. Right and left carotid arteries were scanned longitudinally, 2.5 cm proximal to the bifurcation. When satisfactory B-mode imaging was achieved, the volume sample was placed in the middle of the vessel lumen, and consequently M-mode images were taken for several cardiac cycles. The pictures were stored on magnetic media and analyzed later. US imaging studies were performed by one operator (S.S.) who was blind with respect to patient or control studies. Each measurement was repeated three times, and the mean was determined. Wall thickness, lumen, and distensibility of both carotid arteries were investigated by measuring the intima media thickness (IMT), systolic (SMM) and diastolic (DMM) media-media distance, systolic (SLD) and diastolic (DLD) lumen diameters, blood systolic (SPV) and diastolic (DPV) peak velocities, and distensibility coefficient (DC). The lumen diameter (LD) was calculated by the following equation: LD = MM - (2 x IMT). The DC was calculated using the following equation: (2d/SLD)/P, where d is the change in LD (peak systole to peak diastole) and P is the pulse pressure (17). In all subjects, the presence, location, and size of plaques were also evaluated at the levels of common, internal, and external carotid arteries.
Assays
Plasma ACTH, serum and urinary cortisol levels, and serum insulin levels were measured by RIA using commercially available kits.
Statistical analysis
Statistical analysis was performed using Student’s t
test for unpaired data and the 
2 test where appropriate.
The correlation study was performed using simple linear regression
analysis, considering the r coefficient, and multiple linear regression
analysis, considering the ß coefficient. Data were expressed as the
mean ± SEM. Significance was set at
5%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)
BMI was significantly higher in patients than in sex- and
age-matched controls (P < 0.001); overweight was
observed in five patients (33.3%) and six controls (20%), whereas
obesity was observed in six patients (40%) and none of the controls
(2 = 9.9; P < 0.005). WHR was
significantly higher in patients than in sex- and age-matched and
BMI-matched controls (P < 0.001 and P
< 0.05, respectively). DBP levels were significantly higher in
patients than in sex- and age-matched and BMI-matched controls
(P < 0.05) whereas SBP levels were significantly
higher in patients than in sex- and age-matched controls
(P < 0.05). Heart rates were similar in the three
groups. Hypertension was found in six patients (40%; mild in three,
moderate in two, and severe in one), in three sex- and age-matched
controls (10%; mild in two and moderate in one; 2
= 3.9; P < 0.05), and in six BMI-matched controls
(20%; mild in four and moderate in two; 2 =
1.2; P = NS).
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Biochemical study (Table 3)
Fasting blood glucose was higher in patients than in sex- and
age-matched controls (P < 0.005), and the glucose
response to glucose load was significantly greater in patients than in
both control groups (Fig. 1). Diabetes
mellitus was diagnosed in five patients (33.3%) and in two (6.7%)
BMI-matched controls, whereas reduced glucose tolerance was found in
four patients (26.7%), in three sex- and age-matched controls (10%;
2 = 15.2; P < 0.001), and in eight
BMI-matched controls (26.7%; 2 = 6.1;
P < 0.05). HDL cholesterol levels were lower
(P < 0.05) in patients than in either control group.
Total and LDL cholesterol levels were higher (P <
0.05) in patients than in sex- and age-matched controls, whereas
triglycerides levels were similar in the three groups.
Hypercholesterolemia was found in four patients (26.7%), in none of
the sex- and age-matched controls (2 = 5.8;
P < 0.05), and in seven (23.3%) BMI-matched controls
(2 = 0.02; P = NS). HDL cholesterol
levels lower than normal were found in four patients (26.7%), in none
of the sex- and age-matched controls (2 = 5.8;
P < 0.05), and in five (16.7%) BMI-matched controls
(2 = 0.16; P = NS).
Hypertriglyceridemia and serum LDL cholesterol levels higher than
normal were found in one patient (6.7%), in none of the sex- and
age-matched controls (2 = 0.13; P =
NS), and in three (10%) BMI-matched controls (2 =
0.04; P = NS). A total/HDL cholesterol ratio below 5
was found in four patients (26.7%) and none of the controls
(2 = 5.8; P < 0.05). Plasma
fibrinogen (P < 0.01) were higher in patients than in
either control group, whereas Lpa levels (P
< 0.05) were higher in patients than in sex- and age-matched controls.
PT and aPTT indexes were similar in the three groups. Fasting plasma
insulin levels were higher in patients than in sex- and age-matched
controls (P < 0.05), and the insulin response to a
glucose load was greater in patients than in either control group (Fig. 1). Plasma ACTH and serum and urinary cortisol were similar in the
three groups.
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Vascular study (Table 4)
Common carotid arteries IMT (P < 0.05) and DPV
(P < 0.001 and P < 0.05,
respectively) were significantly higher, and DLD (P <
0.001 and P < 0.05, respectively) and DC
(P < 0.05) were significantly lower in patients than
in sex- and age-matched and BMI-matched control groups; SPV
(P < 0.05) were significantly higher and SLD
(P < 0.001) were significantly lower in patients than
in sex- and age-matched control group; whereas MMS and MMD were similar
in the three groups. Well defined carotid wall plaques were detected in
four patients (26.7%) and in none of the sex- and age-matched controls
(2 = 5.8; P < 0.05). Three
patients had a plaque localized at the level of the left carotid
bifurcation with maximum diameters of 8, 25, and 27 mm and thicknesses
of 1.9, 2.3, and 1.5 mm, respectively, whereas one patient had a plaque
at the level of the right internal carotid artery with a maximal
diameter of 20 mm and a thickness of 2.0 mm. A well defined carotid
wall plaque with maximal diameter of 10 mm and a thickness of 1.8 mm
was detected in one BMI-matched control (3.3%) at level of the right
internal carotid artery (2 = 3.4; P
= NS).
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Figure 2 shows an example of IMT
measurement in one control and one patient (no. 6, Table 1), whereas
Fig. 3 shows an example of a plaque
detected at the origin of the internal carotid artery in another
patient (no. 9, Table 1).
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In CD patients, no significant correlation was found between BMI and any clinical, biochemical, or vascular parameter, whereas WHR was significantly correlated to DBP (r = 0.52; P < 0.05), glucose levels (r = 0.66; P < 0.01), triglycerides levels (r = 0.56; P < 0.05), total cholesterol levels (r = 0.62; P < 0.05), and right carotid artery IMT (r = 0.64; P < 0.05). Fasting insulin levels were significantly correlated to glucose levels (r = 0.75; P < 0.005), DBP values (r = 0.55; P < 0.05), triglycerides levels (r = 0.77; P < 0.005), and right (r = 0.56; P < 0.05) and left (r = 0.58; P < 0.05) carotid arteries IMT. Right (r = -0.70; P < 0.005) and left (r = -0.65; P < 0.01) DC were significantly and inversely correlated to the duration of CD in the patients’ group. At the multiple regression analysis, WHR was the best predictor of fasting 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). Neither WHR nor fasting insulin levels or any of the other clinical, biochemical, or hormonal parameters were predominantly predictive of common carotid IMT and DC.
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Discussion |
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Endogenous and exogenous hypercortisolism is known to be associated with an increased mortality rate for cardiovascular accidents, probably due to the obesity, hypertension, impaired glucose tolerance, hyperlipidemia, and hypercoagulability that characterize this clinical condition (4, 5, 6, 18). Today, the concept that all clinical and biochemical features of hypercortisolism reverse after its resolution is largely accepted. However, no data are available on the disappearance and/or the reduction of cardiovascular risk factors in patients with exogenous hypercortisolism who have withdrawn corticosteroid therapy or in patients with endogenous hypercortisolism after cure. On the other hand, the definition of cure of CD is still a matter of controversy. In fact, in different studies the achievement of normal, low, and unmeasurable urinary and/or serum cortisol levels as well as the suppressibility of cortisol levels after low dose dexamethasone administration have been alternatively considered as cure criteria after transsphenoidal surgery for CD (19, 20, 21, 22). The best long term results of transsphenoidal surgery were reported in those patients who had had unmeasurable circulating cortisol levels during the immediate postoperative period (23). The cure criteria adopted in the current study were the presence of low or persistently normal serum and urinary cortisol levels responsive to low dose dexamethasone administration together with the disappearance of pituitary adenoma documented at magnetic resonance imaging. Among our 15 patients, 4 had persistent hypo-cortisolism, whereas 2 others had transient hypocortisolism immediately after neurosurgery. The remaining 9 patients normalized their serum and urinary cortisol levels after surgery and/or radiotherapy. It might be postulated that these latter patients might be not truly cured from CD because they had not achieved the desirable postsurgical hypocortisolism. However, all patients were accurately and periodically monitored during the follow-up after their presumed cure, and none of them had relapse of hypercortisolism. In addition, analyzing separately the results of patients who had postsurgical hypocortisolism and those who did not, no significant difference was found, except for a lower BMI in the former group. These findings seem to suggest that the cure criteria adopted are reliable for the purpose of the current study.
After 5 yr of cortisol normalization, overweight or obesity was observed in 73% of patients, impairment of glucose tolerance was found in 60%, arterial hypertension was found in 40%, and hyperlipidemia was present in 26.7%. The prevalence of these disorders, although lower than that observed in the patients during the active phase of the disease, was still significantly higher than that observed in the sex- and age-matched control population. This finding indicates that the long term normalization of circulating cortisol levels is not followed by disappearance of the clinical and metabolic features of active CD; in other words, the hormonal cure is not paralleled by the clinical and metabolic cure. The only report in the literature concerning a similar finding is the isolated observation of the persistence of hypertension in 15% of patients with Cushing’s syndrome after the removal of adrenal tumors (24). These features together with the evidence in CD patients of increased levels of thrombotic risk factors, such as serum fibrinogen and Lpa levels (25, 26), determine an increased risk of developing and/or progression of atherosclerosis and cardiovascular accidents in the patients with a history of CD, although they may be cured from the endocrine point of view.
Today, the link between cortisol and atherosclerosis is suggested by fragments of information indicating that prolonged corticosteroid therapy accelerates the development of atherosclerosis. In animal experiments, ACTH and cortisone were shown to produce vascular injury (27) and to enhance experimentally induced atherosclerosis (28). In humans, the use of glucocorticoids caused significant changes in vascular connective tissue (29). In addition, a cause/effect relationship between corticosteroid treatment and premature atherosclerosis was hypothesized in patients with rheumatoid arthritis or systemic lupus erythematosus chronically treated with glucocorticoids (30, 31, 32). Furthermore, a significant association was found between coronary artery disease and serum cortisol concentrations in patients subjected to coronary angiography (33). However, in patients with endogenous hypercortisolism, the presence of atherosclerotic plaques or preatherosclerotic lesions at the level of coronary or carotid arteries has never been evaluated, although premature atherosclerosis was suggested.
In the current study, patients with previous CD were demonstrated to have a significant increase in IMT, SPV, and DPV and a decrease in LD and DC at the level of common carotid arteries compared to the sex- and age-matched control population, as documented by US. These findings suggested that these patients had significantly reduced caliber and significantly increased stiffness of carotid artery walls. As common carotid IMT is considered a marker of atherosclerosis (34), this further demonstrated the presence of premature atherosclerosis in these patients. In addition, an increased prevalence of carotid atherosclerotic plaques was found in patients compared to that in the sex- and age-matched control population. It is not possible to establish whether carotid atherosclerosis was already present during the active disease and whether the atherosclerotic process had advanced after cure. However, as cardiovascular risk factors persisted in these patients after 5 yr of disease cure, it is likely that the premature atherosclerosis was not arrested, but was even advanced, under their influence.
It is not known why the cardiovascular risk persists in patients cured of CD. One explanation is that the metabolic syndrome observed in our patients may depend on the persistence of obesity (35). At this concern, to estimate the role of obesity in determining the cardiovascular risk of patients with cured CD, we compared their clinical, biochemical, and vascular parameters with those of a BMI-matched control population. The patients were demonstrated to have a significant increase in DBP values, plasma fibrinogen levels, and common carotid artery IMT and DPV, and a significant decrease in HDL cholesterol levels and common carotid artery DLD and DC compared to the BMI-matched control group. Moreover, none of the clinical, biochemical, or vascular parameters was significantly correlated to BMI. These features suggested that obesity might play a role in the development of the metabolic syndrome of cured CD patients, but it is unlikely to be the main pathogenic factor. Nevertheless, the patients in this study had WHR values significantly higher compared to both sex- and age-matched and BMI-matched control populations. Moreover, WHR values were significantly correlated to several clinical, biochemical, and vascular parameters in patients with cured CD. WHR represents a reliable index of abdominal obesity (36, 37), and abdominal obesity was demonstrated to be strongly associated with increased cardiovascular risk (38). Therefore, it is likely that the persistence of altered body fat distribution with the accumulation of fat in abdominal viscera, which is typical of CD patients, rather than general obesity, plays the pivotal role in the genesis of the metabolic syndrome of patients with cured CD.
On the other hand, CD, as any other type of hypercortisolism, is known to be associated with insulin resistance, distinct from that occurring in obesity, and characterized by both decreased insulin responsiveness and clearance, probably due to a common defect at the distal level of glucose transport (39). Moreover, insulin resistance is presently considered as the primum movens of a metabolic syndrome, the X-syndrome, which includes hypertension, impairment of glucose tolerance, hyperlipidemia, and increased cardiovascular risk (40). In our CD patients, fasting and glucose-stimulated insulin levels were increased, suggesting a state of insulin resistance with hyperinsulinemia: fasting insulin levels were significantly correlated to blood pressure, serum triglycerides, and common carotid IMT. These data allow us to hypothesize the presence of an acquired X-syndrome that occurred in active CD and persisted after cure, because of the residual insulin resistance. This might be responsible for the persistent increased cardiovascular risk in patients cured of CD.
It is also known that a strong interrelationship exists between abdominal/visceral obesity and insulin resistance. In fact, abdominal obesity was demonstrated to be more closely associated with insulin resistance than peripheral obesity (41). Furthermore, abdominal obesity was demonstrated to be predictive of the onset of diabetes mellitus (42), and hyperinsulinemia was demonstrated to be predictive of the accumulation of visceral adipose tissue in the abdomen in nondiabetic humans (43). In this study, WHR was the best predictor parameter of fasting insulin levels, and fasting insulin levels were the best predictor parameter of WHR, confirming the strong relationship between these two parameters in patients with cured CD. Moreover, both were significantly correlated to several clinical, biochemical, and vascular parameters in these patients. This evidence strongly suggests that both insulin resistance and abdominal obesity, influencing themselves reciprocally, equally contribute to the persistence of the cardiovascular risk in patients with cured CD.
Finally, the significant correlation between the common carotid DC and the duration of CD suggested that disease duration might play a role in the severity of the metabolic syndrome responsible for the persistence of increased cardiovascular risk in patients cured of CD.
In conclusion, patients with a history of CD have a high prevalence of atherosclerosis and maintain increased several cardiovascular risk factors typical of the active phase of the disease even after normalization of circulating cortisol levels for 5 yr. This might be due to a persistent abdominal obesity and/or insulin resistance syndrome. Therefore, these patients have to be accurately investigated for atherosclerosis and cardiovascular risk. Furthermore, the results of this study suggest that an increased cardiovascular risk might also persist in patients who undergo treatment with exogenous glucocorticoids after therapy withdrawal. Taking into consideration the large number of patients subjected to corticosteroid treatment, this aspect could be of great clinical relevance and should be accurately investigated.
Received November 6, 1998.
Revised April 28, 1999.
Accepted May 3, 1999.
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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]
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 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]
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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]
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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]
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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]
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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]
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 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]
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 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]
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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]
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 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]
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 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]
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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]
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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]
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 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]
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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]
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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]
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 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]
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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]
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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]
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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]
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J. Lindholm, S. Juul, J. O. L. Jørgensen, J. Astrup, P. Bjerre, U. Feldt-Rasmussen, C. Hagen, J. Jørgensen, 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]
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), sex- and age-matched controls (•), and BMI-matched controls
(
). *, P < 0.05 compared to sex- and
age-matched controls; •, P < 0.05 compared to
BMI-matched controls.
