The effects of recombinant GH doses (10 micrograms/kg.day, 3 times a week for 6 months) lower than those previously used in the treatment of GH-deficient adults (GHDA) on body composition, bone mineral content, and heart structure and function were investigated in seven (six males and one female, aged 25-27 yr) GHDA. They were studied before treatment, after treatment, and 6 months after stopping therapy, and findings were compared with those for 20 sex-, age-, and body mass index-matched healthy controls. Before treatment, GHDA showed a significant reduction in insulin-like growth factor-I levels, an increase in bioimpedance and fat mass percentage, a reduction of bone density at both distal and proximal sites, a decrease in bone Gla-protein and procollagen III levels, and significant cardiac impairment supported by a reduction of left ventricular mass index and left ventricular systolic function with decreased fractional shortening and rate-adjusted mean velocity of circumferential fiber shortening. GH treatment normalized insulin-like growth factor-I levels, body composition and echocardiographic findings, but not bone density. Six months after stopping therapy, all parameters investigated returned to the pretreatment conditions. Our results suggest that prolonged GH deficiency induces alterations in body composition and bone metabolism and density, and impairment of cardiac structure and function in adult life. GH replacement therapy for 6 months, despite the low doses used by us, is able to improve all previously impaired biochemical and clinical features, except for bone density. This improvement disappears 6 months after the withdrawal of therapy.

In 70 healthy subjects with a large age range, the relationships between plasma tumor necrosis factor-α (TNF-α) and body composition, insulin action, and substrate oxidation were investigated. In the cross-sectional study ( n = 70), advancing age correlated with plasma TNF-α concentration ( r = 0.64, P < 0.001) and whole body glucose disposal (WBGD; r= −0.38, P < 0.01). The correlation between plasma TNF-α and age was independent of sex and body fat (BF; r = 0.31, P < 0.01). Independent of age and sex, a significant relationship between plasma TNF-α and leptin concentration ( r = 0.29, P < 0.02) was also found. After control for age, sex, BF, and waist-to-hip ratio (WHR), plasma TNF-α was still correlated with WBGD ( r = −0.33, P < 0.007). Further correction for plasma free fatty acid (FFA) concentration made the latter correlation no more significant. In a multivariate analysis, a model made by age, sex, BF, fat- free mass, WHR, and plasma TNF-α concentrations explained 69% of WBGD variability with age ( P < 0.009), BF ( P < 0.006), fat-free mass ( P < 0.005), and plasma TNF-α ( P < 0.05) significantly and independently associated with WBGD. In the longitudinal study, made with subjects at the highest tertiles of plasma TNF-α concentration ( n = 50), plasma TNF-α concentration predicted a decline in WBGD independent of age, sex, BF, WHR [relative risk (RR) = 2.0; 95% confidence intervals (CI) = 1.2–2.4]. After further adjustment for plasma fasting FFA concentration, the predictive role of fasting plasma TNF-α concentration on WBGD (RR = 1.2; CI = 0.8–1.5) was no more significant. In conclusion, our study demonstrates that plasma TNF-α concentration is significantly associated with advancing age and that it predicts the impairment in insulin action with advancing age.

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Although subclinical hypothyroidism is frequently diagnosed, the decision to institute a substitutive therapy with L-T4 remains controversial. Because the cardiovascular system is considered a main target for the action of thyroid hormone, we investigated whether subclinical hypothyroidism induces cardiovascular abnormalities. Twenty-six patients (mean age, 36 +/- 12 yr) were evaluated by Doppler-echocardiography, whereas a subgroup of 10 patients, randomly selected, were reevaluated after 6 months of L-T4 substitutive therapy (mean dose, 68 microg daily). Thirty subjects (matched for age, sex, and body surface area) served as controls. Mean plasma TSH was significantly higher in patients (P < 0.001), whereas mean serum free T4 and free T3 concentrations, although in the normal range, were significantly lower (P < 0.001 and P < 0.005, respectively). Blood pressure and heart rate did not differ from control values. Echocardiogram examination showed no abnormalities of the left ventricular morphology and a slight, but not significant, reduction in the systolic function in the patient group. In contrast, Doppler-derived indices of diastolic function showed significant prolongation of the isovolumic relaxation time (94 +/- 13 vs. 84 +/- 8 msec; P < 0.001), increased A wave (55 +/- 13 vs. 48 +/- 9 cm/sec; P < 0.05), and reduced early diastolic mitral flow velocity/late diastolic mitral flow velocity ratio (1.4 +/- 0.3 vs. 1.7 +/- 0.3; P < 0.001). In the subgroup of 10 patients, thyroid hormone profile was normalized by 6 months of L-T4 substitutive therapy, whereas no changes were observed in the left ventricular morphology. Systolic function was significantly enhanced, as compared with pretreatment values (P < 0.01) but did not differ from control values. Also, systemic vascular resistance was significantly decreased by L-T4 replacement therapy. Assessment of diastolic function showed significant shortening of isovolumic relaxation time (77 +/- 15 vs. 91 +/- 8; P < 0.05), reduction of A wave (51 +/- 13 vs. 60 +/- 12; P < 0.01), and increase of early diastolic mitral flow velocity/late diastolic mitral flow velocity ratio (1.7 +/- 0.4 vs. 1.3 +/- 0.3; P < 0.001). These indices, however, were comparable with those of control subjects. These findings indicate that subclinical hypothyroidism affects diastolic function and that this abnormality may be reversed by L-T4 substitutive therapy.