Effect of 5 Years of GH Replacement on Atherosclerosis

Adult patients with hypopituitarism under adequate conventional hormone replacement therapy have reduced life expectancy due to excess vascular events (1-4). Deficiency in GH secretion (GHD) is likely to play a major role in determining the excess mortality, since it is associated with lipid abnormalities, visceral adiposity, glucose intolerance, insulin resistance, hypertension, cardiac abnormalities and increased intima-media thickness (IMT) at major arteries (5).

Beneficial effects of growth hormone (GH) replacement on cardiovascular risk factors have been demonstrated in several studies of hypopituitary GHD patients (5). GH replacement improves body composition and lipid profile (5): it is accepted that management of dyslipidaemia is crucial in primary and secondary prevention of cardiovascular disease and part of the excess vascular risk associated with hypopituitarism is likely to be due to dyslipidaemia (6). A meta-analysis of blinded, randomized, placebo-controlled trials with low doses and long-duration GH treatment showed that GH replacement has beneficial effects on cardiovascular risk by improving lean and fat body mass, total and LDL cholesterol levels, and diastolic blood pressure (7). Besides, GH replacement also induces improvement in cardiovascular markers (8), and cardiac performance (9). In small cohorts of GHD adults, beneficial effects of GH replacement for 6-24 mos have also been reported on surrogate parameters of atherosclerosis, such as intima-media thickness (IMT) at major arteries (10-13), while 6 months of GH deprivation is associated with an impairment of the cardiovascular risk profile (12). In a consistent series of men and women with hypopituitarism we reported, however, that two years of GH replacement is not adequate to normalize IMT levels at common carotid arteries (13).

To give further insights on the likelihood of reversal of early atherosclerosis in severe GHD patients after prolonged GH replacement, we designed this 5-yr prospective, controlled study. Only men aged ≤50 yrs and with severe GHD were enrolled to avoid gender and aging interference (13). Main outcome measure was IMT at common carotid arteries; secondary measure was prevalence of insulin-resistance syndrome according with the American College of Endocrinology (14).

This is an observational,5-yr prospective, controlled study. At study entry, all subjects underwent serum assay of IGF-I, systolic and diastolic blood pressure (SBP, DBP) measurement, total-, and HDL-cholesterol, triglycerides, glucose, and insulin level after an overnight fasting, and common carotid arteries ultrasonography. The oral glucose load (oGTT) was performed by measuring blood glucose every 30 minutes for 2 hours after the oral administration of 75 g of glucose diluted in 250 ml of saline solution. The conversion factors (mg/dl to mmol/l) for lipids and glucose were as follows: cholesterol 0.02586, triglycerides 0.01129, and glucose 0.05551. According with previous studies (13,19-21) blood pressure was measured at the right arm, with the subjects in relaxed sitting position. The average of six measurements (three taken by each of two examiners, in the same day, between 8.00-9.00 in the morning) with a mercury sphygmomanometer was used in all analysis.

In the patients, all parameters and carotid ultrasonography were re-evaluated after 12, 24, 36, 48 and 60 months while in controls they were re-evaluated after 60 months.

At study entry and at study end, in all of the patients and controls the prevalence of insulin-resistance syndrome (IRS) was evaluated according with the American College of Endocrinology (14) based on the presence of at least two criteria of the following: triglycerides levels ≥1.7 mmol/liter, HDL-cholesterol levels ≤1.0 mmol/liter, blood pressure above 130/85 mmHg, fasting glucose between 6.1 and 7 mmol/liter or 2 hr after oGTT between 7.7 and 11.1 mmol/liter.

Eligibility Criteria:
Inclusion Criteria:

* male gender
* age \<50 yrs to limit the effect of aging;
* body mass index \<30 Kg/m2;
* no familial or personal history of cardiovascular diseases;
* no concomitant treatment with drugs known to interfere with glucose or lipid metabolism or to influence blood pressure at the time of study entry;
* no previous GH treatment

Exclusion Criteria:

* female gender
* age \>50 yrs;
* body mass index ≥30;
* familial or personal history of cardiovascular diseases;
* previous and present treatments with drugs known to interfere with glucose or lipid metabolism or to influence blood pressure;
* previous GH treatment in adult age
* GHD of childhood onset
* GHD due to previous Cushing's disease