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Adults with hypothalamic‐pituitary disease have increased morbidity and mortality from cardiovascular disease (CVD). Therefore, the prevalence of CVD and adequacy of treatment of cardiovascular risk factors (according to current treatment guidelines) was studied in a large group of patients with hypothalamic‐pituitary disease.
In 2005, 152 consecutive adult patients with hypothalamic‐pituitary disease attending our neuro‐endocrine centre were clinically examined and blood pressure (BP), lipid profile, type 2 diabetes mellitus, body composition and smoking status were assessed.
Of the 152 patients, 36.8% had treated hypertension and 28.2% had treated dyslipidaemia. Many of these patients had inadequate BP control (BP >140/85 mm Hg, 44.6%) and undesirable lipid levels (total cholesterol >4.0 mmol/l, 69%). Also, many of the untreated patients had BP and lipid levels which should have been considered for treatment (26 patients (27%) and 83 patients (76%), respectively). Smoking was admitted in 18% of patients. Central adiposity was present in 86% and obesity (body mass index 30) was present in 50%.
Cardiovascular risk factors are highly prevalent and often inadequately treated in adult patients with hypothalamic‐pituitary disease. Aggressive treatment of these factors is essential to reduce mortality and morbidity from CVD in these patients.
Many of these patients have chronic growth hormone deficiency (GHD), which is associated with significant cardiovascular risk factors including centrally distributed adiposity, dyslipidaemia, reduced insulin sensitivity, hypertension and abnormal haemostatic factors.5 Patients with functioning pituitary tumours causing acromegaly and Cushing's disease have an increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus and hypertension, also causing an increased cardiovascular risk.6,7
The aims of this study were to determine the prevalence of macrovascular disease and adequacy of treatment of hypertension, dyslipidaemia and type 2 diabetes mellitus in a cohort of patients with hypothalamic‐pituitary disease. We also studied the prevalence of obesity and body composition in these patients. This information is obviously valuable in planning treatment strategies for the cardiovascular risk factors in these patients.
In 2005, the data were recorded in 152 consecutive patients with hypothalamic‐pituitary disease who attended the neuro‐endocrine clinic as described below.
Sitting blood pressure (BP) was measured according to the guidelines of the Joint British Societies (JBS)8 (hypertension was defined as sustained systolic BP (SBP) >140 mm Hg and/or diastolic BP (DBP) >90 mm Hg). The aim of BP treatment is to achieve a BP target of <140 mm Hg systolic and <85 mm Hg diastolic (<130/80 mm Hg in those with diabetes mellitus) in these patients in view of their cardiovascular risk.
In the non‐fasting state, the following were measured: random venous plasma glucose, glycated haemoglobin (HbA1c) and serum lipid profile (total cholesterol (TC), LDL‐cholesterol (LDL‐C), HDL‐cholesterol (HDL‐C) and triglycerides). In this study, we assessed if patients had achieved a target TC of <4.0 mmol/l and LDL‐C of <2.0 mmol/l as recommended in the JBS 2 guidelines.8
In most patients, body mass index (BMI, kg/m2), waist circumference (WC), hip circumference and waist hip ratio, and body fat percentage (assessed by whole body bio‐electrical impedance analysis; Tanita Systems, Stokie, IL) were also measured.
We also recorded the prevalence of established cardiovascular disease (CVD) in these patients, that is, ischaemic heart disease (IHD), cerebrovascular disease (cerebrovascular accident (CVA) or transient ischaemic attack (TIA)) and peripheral vascular disease (history of intermittent vascular claudication). Additionally, family history of premature CVD (coronary heart disease or stroke in male first degree relatives aged <55 years and female first degree relatives aged <65 years) and current smoking status were also recorded.
Regular endocrine assessments were made to identify and correct pituitary hormone deficiencies, including GHD. All patients had at least annual measurement of random serum hormones (free T4, free T3, prolactin, LH, FSH, testosterone or oestradiol, cortisol and insulin‐like growth factor 1 (IGF‐1)). Depending on the primary hypothalamic‐pituitary diagnosis, previous surgery and/or radiotherapy, dynamic pituitary testing of ACTH and GH secretion was carried out using the glucagon test.9
Patients received full appropriate pituitary hormone replacements. Over the last decade GH replacement has been offered, when appropriate, to patients with severe, symptomatic GHD (stimulated growth hormone level 9.0 mIU/l and poor quality of life as measured by the Assessment of Growth Hormone Deficiency in Adults (AGHDA) questionnaire).10
Table 11 shows details of the 152 patients. The most common disorder was non‐functioning pituitary adenoma (NFPA, 43.4%) followed by prolactinoma (14.4%).
The table also lists the prevalence of treated hypertension (36.8%), dyslipidaemia (28.2%), diabetes mellitus (9.2%), atherosclerotic CVD (11.1%), smoking history (current smokers 18.4%) and family history of premature CVD (14.4%) in these patients. The atherosclerotic CVD events included 12 IHD (myocardial infarction and stable angina pectoris), four patients with cerebrovascular episodes (two CVA and two TIA) and one patient with peripheral vascular disease.
The actual BP and serum lipid measurements are shown in table 22.. The mean (±SD) SBP and DBP in the group collectively were 136±22 and 82±11 mm Hg, respectively. Fifty six patients (36%) were already taking anti‐hypertensive medications and in this treated sub‐group mean (±SD) BP was 148±20/86±10 mm Hg. Despite treatment, 44.6% of these patients still had suboptimal measurements (>140 mm Hg systolic and/or >85 mm Hg diastolic). Of the 96 patients not on pharmacological treatment for hypertension, 27% had BP readings that would have warranted treatment. Of the 14 patients with type 2 diabetes mellitus, mean (±SD) BP among those with known hypertension was 143±11/82±8 mm Hg (target <130/80 mm Hg).
Results for the 42 patients (27%) who were taking lipid‐lowering therapy demonstrated mean (±SD) TC 4.8±0.9 mmol/l, LDL‐C 2.2±0.7 mmol/l and HDL 1.3±0.3 mmol/l. Despite lipid lowering therapy, 69% of treated patients had TC >4.0 mmol/l and 85% had LDL‐C >2.0 mmol/l, reflecting suboptimal treatment. Of the patients not taking lipid‐lowering therapy (n=110), mean TC was 5.6±0.9 mmol/l, LDL‐C 3.1±0.8 mmol/l and HDL‐C 1.3±0.4 mmol/l; many of these patients should be considered for pharmacological intervention.
Of the 14 patients with known type 2 diabetes mellitus, (mean) metabolic control was good (HbA1c 6.75±1.09%). Mean random plasma glucose among the “non‐diabetic” patients was 5.24±0.8 mmol/l and no patients were newly diagnosed with diabetes.
Obesity, defined as BMI 30,11 was prevalent in 50% of patients, 30.8% were overweight (BMI 25–29.9) and only 19% were of normal body weight. Of the 60 patients who were obese, 32 (26.6%) had class I obesity (BMI 30–34.9), 14 (11.6%) had class II obesity (BMI 35–39.9) and 14 patients (11.6%) were morbidly obese (BMI 40). The mean WC was 103.4±13.9 cm indicating the majority (86%) had central obesity (WC 94 cm for Europid men and 90 cm for Europid women).12
Male patients were more abdominally obese and had higher waist hip ratio than women, although women tended to have a higher proportion of total body fat (41.9±6.9% v 29.3±6.8%, p=not significant) (table 33).
There exists a large body of evidence confirming the substantial benefits of BP reduction,13,14,15 lipid lowering treatment16,17 and modest weight loss18 in the general population for reducing morbidity and mortality from major cardiovascular events such as IHD, stroke and heart failure.
Patients with hypothalamic‐pituitary disease are known to have increased cardiovascular risk. In this study, treated hypertension was prevalent in 36.8% of patients, dyslipidaemia in 28.2%, type 2 diabetes mellitus in 9.2% and CVD (mostly IHD) in 9.2%. BP was suboptimally treated in 44.6% of patients and lipid profiles were not to target in over two thirds of patients already on lipid lowering treatment. However, it should be noted that if the earlier JBS 1 guidelines, published in 1998, were applied, 52% of patients could be considered to have achieved lipid targets, that is, TC <5.0 mmol/l and LDL‐C <3.0 mmol/l. Also, many patients who were not on treatment for high BP or dyslipidaemia, had levels which would have warranted treatment according to current clinical practice guidelines.8
CVD was more prevalent amongst patients with non‐functioning pituitary adenoma, probably reflecting the greater age of the group. Hypertension and diabetes were common in patients with acromegaly and Cushing's disease, as expected.
A major finding in the patients studied in detail was the prevalence of obesity (BMI 30), which was present in 50%. This was predominantly central adiposity, particularly in men. This is similar to the prevalence of obesity (52%) in patients with type 2 diabetes attending the diabetes clinic at the same hospital19 and nearly double the prevalence of obesity among both sexes in the UK general population. According to the Health Survey for England, in 2004, 29.6% of men and 25.8% of women were obese (BMI 30) (data for middle aged men and women).20
The cause of obesity in these patients is multifactorial. Obesity is associated with lesions (congenital or acquired) of the hypothalamus due to damage to centres regulating appetite and feeding. In a recent study from this unit,21 78.5% of adult patients with structural hypothalamic damage were obese. Our present study had a heterogeneous mix of patients with various hypothalamic‐pituitary pathologies and only a minority had tumour involvement of the third ventricle or hypothalamus. Also, physical activity and mood can influence energy expenditure and body weight. Multiple aspects of quality of life, for example energy levels and psychological morbidity, are impaired in GHD patients and often these do not normalise in spite of growth hormone replacement.22
In the light of evidence for excess mortality from CVD in patients with hypothalamic‐pituitary disease,1,2,3,4 this study is important as it reveals a large number of potentially modifiable cardiovascular risk factors within this population which should be managed aggressively. This has resource implications and physicians managing these patients should actively screen and identify cardiovascular risk factors as well as manage the primary hypothalamic‐pituitary problem. This includes consideration of pharmacological treatments for hypertension and dyslipidaemia and treating these to target. In particular, this study highlights a major need for weight reduction strategies. Weight loss is difficult to achieve in many patients and more difficult to sustain in most. It is important that appropriate lifestyle advice is given to these patients and that drug therapies (eg, orlistat, sibutramine, rimonobant) to aid weight reduction are considered. Patients embarking on a weight loss regimen will require access to dietetic services. Also smoking cessation programmes must be instituted.
For patients with diabetes mellitus, there are national23,24,25 and international guidelines26 for management of hypertension and dyslipidaemia. However, despite the high cardiovascular burden in patients with hypothalamic‐pituitary disease, no such specific guidelines exist for cardiovascular risk factor management in this group of patients, although “reversal of increased long‐term mortality” is recommended as an objective of treatment in all patients with pituitary tumours.27
In summary, we have demonstrated a high prevalence of modifiable cardiovascular risk factors, including hypertension, dyslipidaemia, obesity and smoking, in patients with hypothalamic‐pituitary disorders, despite appropriate hormone replacement, including GH. A significant proportion also have established CVD and in this subgroup it is of even greater importance to identify and treat modifiable risk factors as a secondary prevention strategy. Obesity, with its association with type 2 diabetes and the metabolic syndrome, is a major problem for these patients. All these cardiovascular risk factors are easily identifiable and should be managed appropriately to reduce the burden of premature cardiovascular morbidity and mortality in this subgroup of patients.
BMI - body mass index
BP - blood pressure
CVA - cerebrovascular accident
CVD - cardiovascular disease
DBP - diastolic BP
GHD - growth hormone deficiency
HDL‐C - HDL‐cholesterol
IHD - ischaemic heart disease
JBS - Joint British Societies
LDL‐C - LDL‐cholesterol
SBP - systolic BP
TC - total cholesterol
TIA - transient ischaemic attack
WC - waist circumference
Competing interests: None.