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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 574-584
Copyright © 2000 by The Endocrine Society

Original Studies

Hypopituitary Females Have a High Incidence of Cardiovascular Morbidity and an Increased Prevalence of Cardiovascular Risk Factors1

Birgitta Bülow, Lars Hagmar, Jan Eskilsson and Eva Marie Erfurth

Departments of Diabetology and Endocrinology (B.B., E.M.E.), Occupational and Environmental Medicine (L.H.) and Cardiology (J.E.), University Hospital, S-221 85 Lund, Sweden

Address all correspondence and requests for reprints to: Dr. Birgitta Bülow, Department of Diabetology and Endocrinology, University Hospital, S-221 85 Lund, Sweden.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We recently reported that female patients with hypopituitarism receiving controlled thyroid and steroid hormone substitution, but without GH replacement, had a more than 2-fold increase in cardiovascular mortality compared to the general population. In the present study we investigated the incidence of cardiovascular disease as well as the prevalence of cardiovascular risk factors in 33 females with hypopituitarism for 6–46 yr (median, 18) compared to those in 33 control subjects recruited from the general population in the same geographical area and matched for sex, age, smoking habits, educational level, and residence location. The patients were with a very high probability GH deficient, as 29 had subnormal serum insulin-like growth factor I levels, and the other 4 were GH deficient, as assessed by an insulin tolerance test.

The incidence of cardiovascular disease was significantly higher among the hypopituitary patients (incidence ratio, 3.7; 95% confidence interval, 1.2–11.3), and the consumption of cardioactive drugs was also significantly higher (P = 0.002). Hypopituitary patients had a lower degree of physical exercise during their spare time (P = 0.02), a higher waist/hip ratio (P = 0.01), lower high density lipoprotein cholesterol (P = 0.002), and higher low density/high density lipoprotein ratio (P = 0.009). Furthermore, the patients had a significantly increased left atrium size (P = 0.05), but no difference was observed for other cardiac measures. In the patients, serum insulin-like growth factor I levels significantly correlated with left ventricular mass index (r = 0.48; P = 0.006), suggesting that GH has a strong impact on cardiac size. More episodes of bradycardia (P = 0.05), but no increased occurrence of extrasystolies, were encountered in the patients during 24-h continuous electrocardiogram monitoring. Carotid artery intima-media thickness and plaque numbers did not differ between patients and controls.

In conclusion, hypopituitary females exhibit an increased incidence of cardiovascular disease, higher cardioactive drug consumption, and an increased prevalence of cardiovascular risk factors. The increased cardiovascular morbidity could not be ascribed to inadequate estrogen or thyroid hormone treatment, and unsubstituted GH deficiency is probably an important contributing factor.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HYPOPITUITARY patients receiving conventional hormone substitution, but without GH replacement, have an increased mortality from cardiovascular disease (1, 2). Inadequate hormone replacement is a possible cause of this increased mortality. GH deficiency (GHD) has in adult patients been associated with several cardiovascular risk factors, including hyperlipidemia (3, 4, 5), increased abdominal adiposity (6, 7), and impaired insulin sensitivity (8, 9). The incidence of nonfatal cardiovascular disease has, however, not been assessed in hypopituitary patients with GHD.

In a recent study we reported that hypopituitary females had a more than 2-fold increase in cardiovascular mortality compared to the general population and an even higher risk increase (5-fold) for cerebrovascular diseases (2). Although gender-related differences are encountered for cardiovascular risk factors (10), there is limited knowledge of the cardiovascular risk profile in female subjects with hypopituitarism (5).

The aim of the present study was to assess the incidence of cardiovascular morbidity and the prevalence of risk factors, especially for cerebrovascular disease, in females with hypopituitarism. To answer these questions patients were compared with controls randomly selected from the general population in the same catchment area and matched for sex, age, smoking habits, educational level, and residence location. Such a well matched control group has not previously been used in assessing cardiovascular risk or risk factors in patients with hypopituitarism.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients

Thirty-nine females, included in a cohort of hypopituitary patients operated for pituitary tumor (2), who were alive and did not have acromegaly or Cushing’s disease, were included in the study. Furthermore, 1 patient operated for a suprasellar meningioma and 4 patients without previous neurosurgery participated. Four subjects were unwilling to participate and were therefore excluded as were 4 patients with severe illnesses (status postcerebrovascular disease in 2 patients, dementia in 1 patient, and severe visual disturbances in 1 patient). Three patients treated with GH replacement were also excluded. The final group of patients consisted of 33 females, aged 39–77 yr (median, 64), with hypopituitarism for 6–46 yr (median, 18).

Twenty patients had been operated by the transcranial route, and 9 by the transsphenoidal route. Twenty-five of the patients received postoperative cranial radiotherapy (median, 40 Gy) at least 5 yr before the study. Characteristics of patients are shown in Table 1Go. With the exception of one patient (no. 24), with diagnosed TSH deficiency at the age of 12 yr but with normal growth, all patients had adult-onset hypopituitarism. Twenty-five of the patients were ACTH and TSH deficient and were treated with glucocorticoids (cortisone acetate, 25–37.5 mg/day) and thyroid hormones (levothyroxine, 0.075–0.25 mg/day), respectively. Treatment with an antidiuretic hormone analog (desmopressin, 0.1 µg/day, nasally, or 0.1–0.4 mg/day, orally) was given to five patients with diabetes insipidus. Five patients with hyperprolactinemia were treated with dopamine agonists (bromocriptine or quinagolide hydrochloride). In eight patients GH secretion had been evaluated with a stimulatory test before the present study.


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  		Table 1. Characteristics of 33 females with hypopituitarism participating in the study

 
Control subjects

For each patient, 10 potential control subjects matched for sex, age, and residence location (urban vs. rural area) were randomly selected from a computerized register comprising the population in the catchment area for the patients. These controls were then contacted by telephone, and complementary matching was made for educational level (6–9 yr of elementary school, high school, and university education) and smoking habits (life-long nonsmokers, exsmokers, and present smokers). The first eligible control, who agreed to participate in the study, was chosen. If none in the selected control set of 10 subjects was eligible, a new control set was selected. This process was repeated until an appropriate control subject was found. Fifty-three of 280 contacted controls declined to participate in the study, and 14 of them reported illness as a reason for nonparticipation.

Study design and interview

The clinical investigation was performed cross-sectionally, without any change in hormone substitutions. For each subjects, all investigations were performed in a single day. Through a structured interview, information was obtained for time of diagnosis of cardiovascular diseases. This latter information was confirmed by assessment of relevant medical records.

The study was performed between June 1996 and May 1997. The protocol was approved by the ethics committee of Lund University, and patients and controls gave their written informed consent to participate in the study.

Characteristics of matching factors

Twenty-one of the matched pairs consisted of life-long nonsmokers, 4 exsmokers, and 8 present smokers. Subjects in 20 of the matched pairs had only elementary school, 9 had a high school education, and 4 had a university education.

Family history and pharmacological treatment

A family history (i.e. parents or siblings) of cardiovascular disease was present in 14 of the patients and 14 of the controls. Five of the patients and 6 of the controls had a family history of diabetes mellitus. Prevalent pharmacological treatment for cardiovascular disease and hyperlipidemia is shown in Table 2Go. One patient, but no control, was being treated for diabetes mellitus.


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  		Table 2. Number of subjects receiving cardioactive drugs or lipid-lowering drugs in 33 female patients with hypopituitarism and 33 matched controls

 
Hormone levels, gonadal function, estrogen treatment, and other blood parameters

Serum free T4 was significantly higher in patients than in controls (Table 3Go), but serum free T3 levels did not differ. Serum cortisol and serum insulin-like growth factor I (IGF-I) levels (Fig. 1Go) were significantly lower in patients. Serum estradiol levels were similar in patients and controls. Twenty-nine of the patients had subnormal serum IGF-I levels for age, and the other four had normal levels, but had previously been found to be GH deficient, as assessed by an insulin tolerance test. Serum IGF-I was negatively correlated with the duration of pituitary insufficiency (r = -0.37; P = 0.04).


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  		Table 3. Serum hormone levels in 33 females patients with hypopituitarism and 33 matched controls

 


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  		Figure 1. Serum IGF-I in 33 female patients with hypopituitarism ({circ}) and 33 matched controls (•).

 
At the time of investigation 2 of the patients and 6 of the controls had normal menses. In 17 patients gonadotropin insufficiency started before 50 yr of age, and 8 of these patients had been without sex hormone substitution for 10–20 yr. At the time of the present investigation all gonadotropin-insufficient patients 50 yr or younger were given sex hormone replacement (conjugated estrogen plus medroxyprogesterone, estradiol plus noretisterone acetate, or estradiol plus levonorgestrel). Fourteen patients were diagnosed as gonadotropin insufficient after the age of 50 yr. None of the controls had premature menopause (median age, 50 yr; range, 45–56). Six of the patients were treated with sex hormones after the age of 50 yr, and five control subjects had postmenopausal treatment (estradiol plus noretisterone acetate or conjugated estrogen plus medroxyprogesterone).

All patients and controls had normal serum creatinine levels. Liver enzymes were also in the normal reference range, except in one patient who had slightly elevated levels.

Body mass index (BMI), waist/hip ratio (WHR), and body composition

Body weight was measured after a 12-h fast, and body height was measured while the subject was barefoot. BMI was calculated as kilograms per m2. Waist circumference was measured with a soft tape at the level of the umbilicus in the standing position, and hip circumference was measured over the widest part of the hip region enabling the calculation of the WHR. Body composition was measured in the supine position by bioelectric impedance analysis using the BIA 101-S technique (RJL-Systems, Detroit, MI). A 50-kHz, 800-µA current was applied.

Blood pressure

Blood pressure was measured to the nearest 5 mm Hg, and a mean of two measurements of the right arm was calculated. The measurements were made with the patient in the supine position after having rested for 5 min.

24-h ambulatory electrocardiographic (ECG) monitoring

Twenty-four-hour ECG monitoring (Del Mar model 423, Avionics, Irvine, CA) was performed to detect rhythm disturbances, and the tapes were analyzed with an automatic instrument (Strata Scan, Del Mar model 563) and visual supervision.

Doppler echocardiography

Doppler echocardiography was performed using a Hewlett-Packard Co. Sonos 500 (Palo Alto, CA). All echocardiographic examinations were performed by the same investigator, who was blinded to whether the subject was a patient or a control. Left ventricular end-diastolic (LVIDd) and end-systolic (LVIDs) cavity dimensions as well as interventricular septal wall thickness (IVSd), left ventricular posterior wall thickness (LVPWd), and left atrial dimension (LA) were measured. Left ventricular fractional shortening was used as an index of left ventricular systolic function and was calculated as: [(LVIDd - LVIDs)/LVIDd] x 100.

The left ventricular mass (LV-mass) was calculated as; 1.04[(LVIDd + IVSd + LVPWd)3 - LVIDd3] - 13.6 (11). LV-mass index was determined by dividing the LV-mass with the body surface area of the patient. Valvular structure and function were investigated. The early diastolic (E-wave) and the late diastolic (A-wave) peak velocities of the mitral flow were measured, and the E/A ratio was calculated as well as the time required for the E velocity to decline from its peak to its baseline (deceleration time). Diastolic function was characterized by the E/A ratio, the deceleration time, and the pulmonary venous blood flow pattern (12).

Carotid artery ultrasound

A high resolution 4-duplex ultrasound system, Acuson 128 XP/10, with a 7.5-MHz linear ultrasound probe, was used to measure intima-media thickness (IMT) and plaque of the carotid arteries of the far wall. IMT was defined as the distance between the luminal surfaces of the first and the second echogenic lines. Plaque was defined as a localized area of wall thickening over 1.2 mm, localized thickening 0.5 mm larger than the adjacent IMT, or diffuse wall thickening over 1.5 mm. The IMT of the common carotid artery was measured 1–2 cm from the carotid bifurcation, and the mean of three measurements was calculated. The maximum IMT of the bifurcation was also measured, as well as the IMT of the internal carotid artery 1 cm from the bifurcation. Measurements in all patients and controls were performed by two blinded, skilled operators. The mean of the right and left IMT values and the measurements of the two operators was calculated. The distal 5 cm of the common carotid artery, the carotid bifurcation, and the proximal part (at least 1 cm) of the internal carotid artery were viewed for plaque. Differences in measurements of the mean of the left and right common carotid arteries, the left and right bifurcations, and the left and right internal carotid arteries between the two operators were less than 0.02 mm.

Questionnaire of physical exercise

The degree of physical exercise during spare time was assessed by a self-rating questionnaire in which patients and controls classified their physical activity according to a four-grade scale (13) (Table 4Go).


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  		Table 4. Exercise habits during spare time, according to a four-grade scale assessed by a self-rating questionnaire, in 33 females with hypopituitarism and 33 matched controls

 
Biochemical assays

Blood samples were drawn in the morning after a 12-h fast and before administration of medication. Serum IGF-I levels were measured by a RIA after acid-ethanol extraction and cryoprecipitation. Truncated IGF-I was used as radioligand to minimize interaction of IGFBPs (14). The intra- and interassay coefficients of variation (CVs) were 4% and 11%, respectively. A reference range for serum IGF-I for patients older than 70 yr was obtained from a population-based study on subjects 80 yr old (15). All seven patients between 71–77 yr had serum IGF-I levels below the reference range of normal 80-yr-old subjects. Serum cortisol was measured by a radioimmunological method (Orion Diagnostica, Espoo, Finland). At serum cortisol levels of 95–800 mmol/L, the intraassay CV was 5% or less, and the interassay CV was 7% or less. The reference range for serum cortisol at 0800 h was 200–800 nmol/L. Serum FSH, LH, PRL, TSH, free T4, and free T3 were analyzed with an immunofluorometric technique (AutoDelfia, Wallac, Inc., Oy, Turku, Finland). The intraassay CVs for serum free T4 and serum free T3 were 5% and 9% or less, respectively, and the interassay CVs were 5% and 4% or less, respectively. The intra- and interassay CVs for serum TSH were 4% or less. The reference ranges for serum free T4 and serum free T3 were 9–22 and 4.0–7.8 pmol/L, respectively. Serum estradiol was analyzed by RIA (Diagnostic Products, Los Angeles, CA), and the intra- and interassay CVs were 15% or less with a sensitivity of 70 pmol/L. Serum insulin was measured by a competitive RIA (16), with intra- and interassay CVs of 7.1% or less. Blood glucose was measured with a HemoCue Blood Glucose Analyzer (Hemocue AB, Ängelholm, Sweden) (17). The SD between cuvettes was 0.3 mmol/L or less. Serum total cholesterol, serum triglycerides, and serum high density lipoprotein (HDL) cholesterol were analyzed enzymatically (Roche, Mannheim, Germany). Low density lipoprotein (LDL) cholesterol was calculated by Friedewald’s formula (18). Serum apolipoprotein A1 and B were analyzed with an immunoturbidimetric method. Plasma homocysteine was measured with a high performance liquid chromatograph method, and the intra- and interassay CVs were 4.0% or less for this method. Plasma fibrinogen was analyzed by use of a clotting method (Fibri-Prest Automate, Diagnostica Stago, Asnier-sur Seine, France), and the intra- and interassay CVs for this method were 3.0% or less.

Statistical analysis

Data are presented as the median and range. Patients and controls were compared with the Wilcoxon matched pair, signed rank test. The incidence of cardiovascular disease was calculated for patients and controls. The observation period for the patients and controls started at the date of diagnosed hypopituitarism and ended at the time of the present investigation. The incidence was calculated both with and without censoring observation time after the date of first diagnosis. Approximate 95% confidence intervals were calculated for the incidence ratio for cardiovascular diseases (19). McNemar’s test for correlated proportions was used for comparison of prevalent pharmacological treatment between patients and controls. Univariate correlations were assessed using Spearman’s rank order correlation test. To examine the influence of serum IGF-I on the IMT of the carotid arteries and on the LV-mass index in the hypopituitary patients, a multiple linear regression model was used. The level of significance was set at P <= 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Incidence of cardiovascular diseases

Hypopituitary patients had a significantly higher incidence of cardiovascular disease than control subjects (Table 5Go). Nine patients had 15 diagnosed cardiovascular diseases compared to 4 in 3 control subjects. The cause of pituitary insufficiency in these patients was in 6 cases pituitary adenomas, in 2 cases Sheehan’s postpartum necrosis, and in 1 case idiopathic hypopituitarism. Two of the 9 patients with cardiovascular disease had been insufficiently treated with sex hormones, and 6 were diagnosed as gonadotropin insufficient after the age of 50 yr.


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  		Table 5. Incidence ratio (IR) with 95% confidence interval (CI) for incidence of cardiovascular diseases in 33 females with hypopituitarism compared with 33 matched controls with and without censoring observation time after date of first diagnosis

 
Cardiovascular risk factors

According to a self-rating questionnaire, patients had a significantly lower degree of physical exercise during their spare time (Table 4Go). Diastolic blood pressure was significantly lower in patients compared to control subjects (Table 6Go), but systolic blood pressure did not differ. After exclusion of three patients and three controls receiving medical treatment for hypertension, diastolic blood pressure was still significantly lower in the patients (P = 0.03). BMI as well as whole body resistance and percentage of body fat mass did not differ between patients and controls. WHR was, however, significantly higher in patients and in the eight patients without corticosteroid replacement (P = 0.03). Neither serum IGF-I nor serum free T4 correlated to WHR (r = 0.01; P > 0.5 and r = -0.12; P > 0.5, respectively). Fasting blood glucose was significantly lower in patients, whereas serum insulin concentrations did not differ. Exclusion of one patient being treated for diabetes mellitus did not change this pattern. In patients, the correlations between serum IGF-I and blood glucose (r = 0.33; P = 0.14) and between serum cortisol and blood glucose (r = 0.26; P = 0.19), were not significant. There were no differences in the plasma levels of fibrinogen or homocysteine between patients and control subjects. Serum IGF-I was modestly, but significantly, negatively correlated to plasma fibrinogen (r = -0.37; P = 0.04). Total serum cholesterol, LDL cholesterol, and triglycerides did not differ between patients and controls. On the other hand, serum HDL cholesterol levels were significantly lower in the patients, and the LDL/HDL ratio was significantly higher in the patients. Exclusion of two patients and one control being treated for hyperlipidemia did not alter this pattern. In patients, serum free T4 or serum IGF-I did not correlate with HDL cholesterol (r = 0.21; P = 0.23 and r = -0.12; P > 0.5, respectively). Serum levels of apolipoprotein B did not differ between patients and controls, whereas serum apolipoprotein A1 was significantly lower in the patients.


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  		Table 6. Cardiovascular risk factors in 33 females with hypopituitarism and 33 matched controls

 
Ambulatory ECG monitoring

One patient had a left bundle branch block, and another had atrial fibrillation. All control subjects demonstrated sinus rhythm. The maximum heart rate was lower in the patients than in the controls; however, this was not significant (Table 7Go). The number of bradycardia episodes (pulse rate, <50 beats/min) was significantly higher in patients. Six patients had episodes of bradycardia during the 24-h ECG monitoring (1–90 episodes with a minimum rate of 38–42 beats/min) compared to 1 control (2 episodes with a minimum heart rate of 43 beats/min). After exclusion of 5 patients and 1 control receiving antiarrhythmics, the differences in maximum heart rate and episodes of bradycardia decreased (P = 0.3 and P = 0.07, respectively). Occurrence of ventricular and supraventricular extrasystolies did not differ between the 2 groups.


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  		Table 7. Results from a 24-h ambulatory electrocardiografic monitoring in 31 hypopituitary females and 31 controls

 
Doppler echocardiography

There were no differences in LVIDd, LVIDs, IVSd, and LVPWd between patients and controls (Table 8Go). The LA was slightly, but significantly, larger in patients than in controls. Serum IGF-I and serum free T4 did not significantly correlate with the LA, nor did systolic function (fractional shortening) and LV-mass index differ in patients and controls. Serum free T4 did not correlate with LV-mass index in patients, but there was a significant correlation between serum IGF-I and LV-mass index (r = 0.48; P = 0.006; Fig. 2Go). No age adjustment had to be made because age did not correlate with LV-mass index. Systolic blood pressure showed, however, a significant univariate correlation with LV-mass index (r = 0.39; P = 0.02), but the negative correlation with serum IGF-I was not significant (r = -0.20; P = 0.3). Adjusting for a potential negative confounding effect of systolic blood pressure in a multiple linear regression model slightly increased the effect of IGF-I on LV-mass index (P < 0.001). The total explanatory value (adjusted r2) for IGF-I and systolic blood pressure on LV-mass index was 0.52.


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  		Table 8. Results from the Doppler echocardiographic examination performed in 32 females with hypopituitarism and 32 matched controls

 


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  		Figure 2. Relationship between serum IGF-I and LV-mass index in 31 female patients with hypopituitarism (r = 0.48; P = 0.006). The results for 1 patient are missing due to poor compliance, and those for 1 patient are missing due to difficulties with the echocardiographic measurement.

 
One patient had a clearly restrictive left ventricle pattern. The E/A ratio was significantly higher in patients (Table 8Go), but the pattern of pulmonary venous blood flow did not support a pathological left ventricular diastolic function.

Two patients had moderate aortic valve insufficiency, and another patient had a moderate mitral insufficiency. None of the control subjects had significant aortic or mitral valve insufficiency, and neither patients nor controls had significant valvular stenosis.

Carotid artery ultrasound

The IMT from the right and left sides of the common carotid artery, the bifurcation, and the internal carotid artery did not differ between patients and controls (Table 9Go), nor was there a significant difference in plaque numbers. After adjustment for age in a multiple linear regression model, IGF-I did not correlate with the IMT parameters. The IMT of those eight patients, who previously had been insufficiently treated with estrogen, did not differ from the IMT of their controls.


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  		Table 9. Intima-media thickness of the common carotid artery (CCA), the bifurcation (BIF), and the internal carotid artery (ICA) and numbers of plaques in 32 females with hypopituitarism and 32 matched controls

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The hypopituitary females in the present study had a higher incidence of cardiovascular disease as well as an increased prevalence of cardiovascular risk factors compared to matched controls. We have recently shown that hypopituitary females had a higher risk for cardiovascular death than hypopituitary males (2). The female patients in the present study were mainly recruited from this cohort. A unique feature of the present study was that the controls were randomly selected from the general population in the same catchment area as the patients and matched not only for sex and age, but also for other important confounding factors, including smoking habits (20, 21), level of education before start of hypopituitarism (22), and residence location (23). An indication of a successful matching was that a family history of cardiovascular disease, which is an established risk factor in women (24), was found to the same extent in patients and controls.

Even though there was an overlap in serum IGF-I levels in patients and controls, there is a very high probability that all of the present patients were GH deficient. Twenty-nine patients had a serum IGF-I level below the normal range, which is strongly predictive of GHD in patients with pituitary disease (25). The 4 patients with normal serum IGF-I levels had all previously had a pathological evoked GH response to an insulin tolerance test. It has previously been shown that GHD develops at least 5 yr after radiotherapy (26). In the present study, all 25 of the 33 patients who had undergone radiotherapy received it more than 5 yr earlier, thus supporting the occurrence of GHD. Furthermore, the severity of GHD in adults relates to the degree of hypopituitarism (27). Of the 8 patients not irradiated, 6 had insufficiencies of three pituitary hormones, and the other 2 had GHD according to an insulin tolerance test. None of the patients suffered from malnutrition or liver or kidney disease, which are conditions that could contribute to a decrease in serum IGF-I.

Proper replacement therapy was given at diagnosis of TSH or ACTH insufficiency, but nevertheless the present investigation revealed significantly higher serum free T4 levels without any difference in serum free T3, suggesting a slight oversubstitution of levothyroxine. Furthermore, the patients had significantly lower morning serum cortisol levels, in agreement with a previous study (28). No difference in serum estradiol levels between the patients and the controls was found, as at the time of the investigation all gonadotropin-insufficient females of fertile age received sex hormone treatment and the prevalence of post-menopausal sex hormone treatment was similar in patients and controls. However, 8 of the 17 patients younger than 50 yr at diagnosis of gonadotropin insufficiency had previously not been sufficiently treated with sex hormones. The increased incidence of cardiovascular disease in the patients could not, however, be explained by estrogen deficiency alone, because 6 of the 9 patients with cardiovascular diseases became gonadotropin insufficient after the age of 50 yr. Thus, GHD seems to be a more important risk factor for the observed high incidence of cardiovascular diseases than the other hormone deficiencies.

No differences in BMI, whole body resistance, or body fat mass measured with bioimpedence analysis were evident. The WHR was, however, significantly higher in the hypopituitary females. In women, abdominal adiposity is an independent risk factor for myocardial infarction, angina pectoris, stroke, and overall mortality (29). No significant difference was found in the serum insulin levels between the patients and the controls, but the association between body fat distribution and the risk of ischemic heart disease might be independent of concomitant variations in plasma insulin concentrations (30). Overtreatment with glucocorticoids could possibly cause an increase in central body fat. In the present study the eight patients not receiving corticosteroid substitution had, however, a significantly higher WHR than their respective controls. Abdominal obesity is a characteristic clinical feature of GHD (6, 7), and after GH replacement therapy there is a decrease in visceral fat mass (6, 7, 31). Impaired GH secretion is therefore a probable explanation for the observed increase in WHR in the present study.

Diabetes mellitus is a stronger risk factor in females than in males for cardiovascular disease (32). In the present investigation only one patient was treated for diabetes mellitus and none of the controls. There is a well known association between insulin resistance and vascular disease (33). The patients had normal, but significantly lower, fasting blood glucose levels than the controls, which has been observed previously (28, 34) and has been suggested to be caused by either GHD or by low overnight circulating cortisol levels (28), which are also possible explanations in the present study. Measurements of insulin sensitivity were not performed in the present study. GHD patients have, however, previously been found to have impaired insulin sensitivity (8, 9) despite normal fasting levels of glucose and insulin.

Hypertension is an important risk factor for myocardial infarction and stroke (35, 36, 37) in both males and females. Previous studies of hypopituitary patients with GHD have revealed significantly lower systolic blood pressure (38, 39, 40) and unchanged systolic (4, 41, 42, 43) and diastolic blood pressure levels (4, 38, 39, 40, 41, 42, 43). Rosén and colleagues (1993; Ref. 4) did not find an increased prevalence of hypertension in hypopituitary females, in agreement with the results of our study in which the incidence of hypertension did not differ between patients and controls. Moreover, patients and control subjects had similar systolic blood pressure, and the patients had significantly lower diastolic blood pressure. Thus, increased blood pressure did not contribute to the enhanced cardiovascular risk in the present study.

Lipid alterations have been observed in both older and younger hypopituitary females with GHD and seem to be independent of sex hormone or glucocorticoid replacement (5). The female patients had significantly lower serum HDL cholesterol levels as well as a higher LDL/HDL ratio. Apolipoprotein A1 was also lower in the patients reflecting the lower HDL cholesterol (44). A low serum HDL cholesterol level seems to be a strong predictor of coronary heart disease (45, 46). The effects on HDL cholesterol after GH replacement have varied, with either increased (47, 48, 49) or unchanged levels (3, 50, 51). Thyroid hormones also influence serum lipids and lipoproteins (52), and HDL cholesterol has been reported to be normal (53) or decreased in hyperthyroidism (54). However, replacement therapy with different levothyroxine doses to hypothyroid subjects did not cause a significant decrease in HDL cholesterol levels even if the serum free T4 levels were slightly elevated above the normal reference range (55). In the present study five patients had slightly elevated serum free T4, but serum T3 levels were normal. No significant negative association was seen between serum free T4 and HDL cholesterol or the LDL/HDL ratio, which makes it unlikely that the thyroid hormone substitution had any influence on the lipoproteins.

Fibrinogen is an independent risk factor for stroke and ischemic heart disease (56). There was a significant negative correlation between serum IGF-I levels and plasma fibrinogen levels in the patients, but no difference in the plasma fibrinogen levels was seen between the hypopituitary women and the controls. This is in contrast to the results of a previous study, in which 10 adult hypopituitary women with GHD had higher levels of fibrinogen compared to controls (34). Abdominal obesity seems to be associated with an increase in fibrinogen levels (57). The more pronounced difference in WHR between patients and controls as well as the different selection criteria for the controls in the previous study (34) could explain the disparate results.

Elevated plasma homocysteine levels have been associated with an increased risk of atherosclerotic vascular disease (58), but have not heretofore been assessed in hypopituitary patients. Our results do not support a role for plasma homocysteine in the increased cardiovascular risk observed.

In both males and females there is a strong association between low physical activity and death from cardiovascular disease (59). The hypopituitary females in the present study had a significantly lower degree of physical activity during their spare time than the controls, which has not previously been reported. GHD patients have a reduced energy level (60), and an improvement has been reported after GH replacement (61). The observed low physical activity could have been the result rather than the cause of cardiovascular disease, but the patients who already had a cardiovascular diagnosis did not report lower physical activity than the other patients. This was also true for visual disturbances, which indirectly can affect the degree of physical activity.

Arrhythmias and morphological abnormalities of the heart are potential risk factors for stroke (62). A 24-h ambulatory ECG examination has not previously been performed in hypopituitary patients. In the present study there were no significant differences between patients and controls in supraventricular or ventricular extrasystolies, but one patient was treated for chronic atrial fibrillation and another had a history of paroxysmal atrial fibrillation, whereas all of the control subjects had normal sinus rhythm. Heart rate at rest has in previous investigations been similar in GHD patients and controls (39, 40, 41, 43, 63). In the present study the patients had more episodes of bradycardia during the 24-h ECG registration, which is a new observation that requires further investigations.

In the present investigation, patients had significantly larger left atria, previously associated with an increased risk of atrial fibrillation (64). LV-mass index and systolic function were similar in patients and controls. However, in adults with childhood-onset GHD, reduced LV-mass (38, 41) and impaired systolic function (38, 39, 41) have been reported. On the other hand, in patients with adult-onset GHD, the data have previously shown similar LV-mass (43, 63) and systolic function (43, 63, 65) or impaired systolic function (40). In the latter study, however, four of nine of the investigated patients with adult-onset GHD were 16 yr or younger at the diagnosis of GHD, which probably influenced the result (40). In the present investigation there was a significant correlation between serum IGF-I levels and LV-mass index in the patients, which is in agreement with previous results in patients with both childhood and adult-onset GHD (38, 66). Adjusting for systolic blood pressure in a multiple regression analysis, serum IGF-I had an effect on LV-mass index, which accords with a strong impact of GH on the heart. Slightly elevated serum T4 levels in patients treated for hypothyroidism have previously been associated with an increase in LV-mass compared to that in controls (67). In the present study there was, however, no association between serum levels of free T4 and the LV-mass index.

Abnormal left ventricular diastolic function with a low E/A ratio was previously observed in GHD patients (66); however, this study lacked a control group and also included patients with Cushing’s disease. A similar E/A ratio in adult-onset GHD patients and matched controls has also been found (43, 63). In the present study the E/A ratio was significantly higher in patients, consistent with a more pronounced diastolic dysfunction (restrictive filling), but the pattern of the pulmonary venous blood flow did not support such an impairment.

We could not detect differences in IMT between the patients and the controls, and after adjusting for age, no effect of IGF-I on IMT was evident. The IMT of the eight patients with insufficient estrogen treatment did not differ from the IMT of their respective controls. Markussis and colleagues (1992; Ref. 42), found an increased IMT of the common carotid artery as well as increased numbers of plaque in adult patients with GHD. We used the same definition for an atheromatous plaque as in the study by Markussis et al., but did not observe such a difference. However, the results of Markussis et al. were not presented separately for men and women. Increased IMT has also been found in adult patients with childhood-onset GHD (68); however, younger age (mean, 25 yr) and previous treatment with GH make a comparison difficult. The control subjects in the present study were randomly selected from the general population, whereas the controls in the previous two studies (42, 68), as a result of the inclusion criteria, were all healthy, which may have contributed to the observed discrepancy in results. An association between intima-media thickening and the risk of myocardial infarction and stroke has been shown (69, 70). The predictive value of a less pronounced intima-media thickening, as in the present and previous studies (42, 68), for the risk of cardiovascular disease has not been fully evaluated. A low degree of intima-media thickening may not reflect atherosclerosis, but could be an adaptive response to changes in blood flow and intraluminal pressure (71). None of the patients in the present study had stenosis of the carotids. Patients with ischemic stroke with concomitant significant carotid atherosclerosis have a much lower survival likelihood than the average ischemic stroke patient, leading to a survivor bias (72).

Thus, despite the observed increased incidence of cardiovascular disease in the present study, IMT was not increased in the patients. Some cardiac diseases, such as heart failure and atrial fibrillation, as well as cerebral hemorrhages (73) do not, however, always involve an atherosclerotic mechanism. Moreover, only about 10% of ischemic stroke is caused by extracranial carotid disease (74). In the present study, 25 of the patients had received radiotherapy, and 1 of these patients had undergone a cerebrovascular event. Cranial irradiation has been associated with cerebral ischemic disease due to radiation angiopathy (75), but the long term cerebrovascular impact of this treatment is still unknown.

In conclusion, hypopituitary females exhibit an increased incidence of cardiovascular disease, including both cardiac and cerebrovascular disease, higher drug consumption for these diseases, and an increased prevalence of cardiovascular risk factors, such as increased WHR, decreased HDL cholesterol, and less physical exercise. The increased cardiovascular morbidity could not be explained by inadequate estrogen or thyroid hormone treatment alone. Unsubstituted GHD is likely to be a more important contributing risk factor. The significance of corticoid replacement for the cardiovascular risk increase is still unknown and needs further investigation. The results from the study are consistent with those of two previous mortality studies (1, 2) and confirm the increased cardiovascular risk in patients with hypopituitarism. Thus, we believe it is important to establish adequate surveillance for cardiovascular disease in patients with pituitary deficiency.


   Acknowledgments
 
We thank R. N. Carina Borg for technical assistance, and Med. Lic. Vet. Zoli Mikoczy and B.Sc. Jonas Björk for statistical assistance.


   Footnotes
 
1 This work was supported by grants from the Medical Faculty, University of Lund (Lund, Sweden), Förenade Liv Mutual Group Insurance Co. (Stockholm, Sweden), and Pharmacia & Upjohn, Inc. (Uppsala, Sweden). Back

Received March 15, 1999.

Revised October 18, 1999.

Accepted October 25, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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