Growth Hormone Deficiency Clinical Trial
Official title:
Phase 4 Study of Recombinant GH on Intima-Media Thickness at Common Carotids and on Cardiovascular Risk Factors in Hypopituitary Patients
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.
;
Observational Model: Case Control, Time Perspective: Prospective
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