Comparative results of a 4-year study on cardiovascular parameters, lipid metabolism, body composition and bone mass between untreated and treated adult growth hormone deficient patients.

OBJECTIVE: To evaluate the long-term evolution of cardiovascular parameters, lipid metabolism, body composition and bone mass in untreated and treated adult growth hormone deficient patients (AGHD) comparing the differences between the two groups and within each group. DESIGN: Seventy-one AGHD-patients were enrolled; 48 received growth hormone (GH) therapy: treated group (TG) and 23 received no GH therapy: control group (CG). In the TG, 22 were childhood-onset (CO) GH-deficient patients, 18-44 years (12 males) and 26 were adult-onset (AO) GH-deficient patients, 27-66 years (10 males). In the CG, 10 patients were AGHD-CO, 20-43 years (8 males) and 13 were AGHD-AO, 25-70 years (8 males). For patients in the TG, GH was administered at a starting dose of 0.1mg/day, adjusted to maintain IGF-I levels between 0 and 2 SDS for gender and age. At baseline and during the 4th year of replacement therapy or follow-up, the following parameters were evaluated: body mass index, waist circumference, blood glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, total cholesterol/HDL-cholesterol ratio, systolic and diastolic blood pressure, 2-D echocardiogram with mitral Doppler, bone mineral density (total body, lumbar spine, and femoral neck), bone mineral content (BMC) and body composition. RESULTS: In the TG, there was a decrease in diastolic blood pressure (-4.0+/-1.8 mmHg, p<0.035) and an increase in blood glucose levels (0.58+/-0.19 mmol/L, p<0.025), bone mineral content (0.2+/-0.0 kg, p<0.015) and bone mineral density of lumbar spine (0.3+/-0.1 SDS, p<0.015) and femoral neck (0.4+/-0.1 SDS, p<0.001). All other variables did not show significant changes in any of the two groups. At year 4, changes (delta) differed between patients in the TG and those in the CG with regard to cholesterol levels (TG: -0.27+/-0.16 mmol/L, CG: 0.34+/-0.23 mmol/L, p<0.045), blood glucose (TG: 0.58+/-0.19 mmol/L, CG: -0.12+/-0.19 mmol/L, p<0.025) and BMC (TG: 0.2+/-0.0 g, CG: 0.0+/-0.0 g, p<0.015). An assessment of the changes in variables over time, with and without therapy, considering CO and AO separately, revealed a significant difference in total cholesterol levels during year 4 in CO patients CO (TG: -0.28+/-0.25 mmol/L and CG: 0.84+/-0.25 mmol/L, p<0.015). No differences related to the time of onset of GHD were found in changes in the remaining variables studied. There were no differences related to gender, GHD etiology or the presence of other pituitary hormone deficiencies in the evolution of the parameters analyzed. CONCLUSIONS: Our 4-year study in GH deficient adults showed significant beneficial effects on some cardiovascular risk parameters and BMC in treated patients. However, there are still unsettled issues regarding long-term benefits and these patients should be carefully monitored.

Medium and long-term outcome of growth hormone therapy in growth hormone deficient adults

We evaluated long-term replacement therapy outcomes in various subsets of patients with adult growth hormone (GH) deficiency (AGHD) as well as the patients' susceptibility to adverse events. Fifty-nine patients with AGHD were evaluated, 27 with childhood onset (CO) (18-44 years old, 12 females) and 32 with adult onset (AO) (27-70 years, 18 females). A significant improvement in HDL-cholesterol was observed in AGHD-AO males (basal: 41.3 +/- 12.9 mg/dl, intratreatment: 47.5 +/- 13.2 mg/dl, p = 0.009). However, individual analyses showed that total cholesterol decreased below 240 mg/dl in 33% of AGHD-CO patients and in 50% of AGHD-AO patients, and below 200 mg/dl in 67% of AGHD-CO patients and in 29% of AGHD-AO patients; in the AGHD-AO group, normalization of LDL-cholesterol (< or = 160 mg/dl) and triglycerides (< or = 200 mg/dl) was found in 100% and 50% of patients, respectively; the total cholesterol/HDL ratio decreased below 4.5 in 20% of AGHD-CO patients and in 25% of AGHD-AO patients. The cardiological evaluation showed a significant intra- and interindividual heterogeneity, but cardiac mass improved in patients with a baseline cardiac mass index below 60 g/m2. Markers of bone apposition increased significantly, while bone resorption markers were found to remain unchanged during treatment. A correlation was found between increased bone mineral content and lean body mass (p = 0.0009). Susceptibility to adverse events was not found to be dependent on gender or on the time of onset of the deficiency. Our findings would appear to confirm that a more severe metabolic impairment is correlated with a better therapeutic outcome.

Medium and long-term outcome of growth hormone therapy in growth hormone deficient adults

We evaluated long-term replacement therapy outcomes in various subsets of patients with adult growth hormone (GH) deficiency (AGHD) as well as the patients susceptibility to adverse events. Fifty-nine patients with AGHD were evaluated, 27 with childhood onset (CO) (18-44 years old, 12 females) and 32 with adult onset (AO) (27-70 years, 18 females). A significant improvement in HDL-cholesterol was observed in AGHD-AO males (basal: 41.3 +/- 12.9 mg/dl, intratreatment: 47.5 +/- 13.2 mg/dl, p = 0.009). However, individual analyses showed that total cholesterol decreased below 240 mg/dl in 33% of AGHD-CO patients and in 50% of AGHD-AO patients, and below 200 mg/dl in 67% of AGHD-CO patients and in 29% of AGHD-AO patients; in the AGHD-AO group, normalization of LDL-cholesterol (< or = 160 mg/dl) and triglycerides (< or = 200 mg/dl) was found in 100% and 50% of patients, respectively; the total cholesterol/HDL ratio decreased below 4.5 in 20% of AGHD-CO patients and in 25% of AGHD-AO patients. The cardiological evaluation showed a significant intra- and interindividual heterogeneity, but cardiac mass improved in patients with a baseline cardiac mass index below 60 g/m2. Markers of bone apposition increased significantly, while bone resorption markers were found to remain unchanged during treatment. A correlation was found between increased bone mineral content and lean body mass (p = 0.0009). Susceptibility to adverse events was not found to be dependent on gender or on the time of onset of the deficiency. Our findings would appear to confirm that a more severe metabolic impairment is correlated with a better therapeutic outcome.(AU)

Medium and long-term outcome of growth hormone therapy in growth hormone deficient adults

We evaluated long-term replacement therapy outcomes in various subsets of patients with adult growth hormone (GH) deficiency (AGHD) as well as the patients susceptibility to adverse events. Fifty-nine patients with AGHD were evaluated, 27 with childhood onset (CO) (18-44 years old, 12 females) and 32 with adult onset (AO) (27-70 years, 18 females). A significant improvement in HDL-cholesterol was observed in AGHD-AO males (basal: 41.3 +/- 12.9 mg/dl, intratreatment: 47.5 +/- 13.2 mg/dl, p = 0.009). However, individual analyses showed that total cholesterol decreased below 240 mg/dl in 33% of AGHD-CO patients and in 50% of AGHD-AO patients, and below 200 mg/dl in 67% of AGHD-CO patients and in 29% of AGHD-AO patients; in the AGHD-AO group, normalization of LDL-cholesterol (< or = 160 mg/dl) and triglycerides (< or = 200 mg/dl) was found in 100% and 50% of patients, respectively; the total cholesterol/HDL ratio decreased below 4.5 in 20% of AGHD-CO patients and in 25% of AGHD-AO patients. The cardiological evaluation showed a significant intra- and interindividual heterogeneity, but cardiac mass improved in patients with a baseline cardiac mass index below 60 g/m2. Markers of bone apposition increased significantly, while bone resorption markers were found to remain unchanged during treatment. A correlation was found between increased bone mineral content and lean body mass (p = 0.0009). Susceptibility to adverse events was not found to be dependent on gender or on the time of onset of the deficiency. Our findings would appear to confirm that a more severe metabolic impairment is correlated with a better therapeutic outcome.(AU)

Effect of two years of growth hormone and insulin-like growth factor-I suppression on prostate diseases in acromegalic patients.

The insulin-like growth factors (IGFs) have mitogenic effects on normal and tumoral prostate epithelial cells and have been suggested to be involved in prostate cancer. Moreover, chronic GH and IGF-I excess causes prostate overgrowth in patients with acromegaly. This study was designed to investigate whether the suppression of GH and IGF-I levels by surgery or pharmacotherapy could induce the regression of prostatic hyperplasia in acromegalic patients. To this end, prostate volume (PV) as well as the occurrence of prostatic diseases were studied by transrectal ultrasonography in 23 untreated acromegalic patients (with elevated GH and IGF levels). None of the patients reported symptoms due to prostatic disorders or obstruction. At study entry, prostate hyperplasia was found in half patients. After 2 yr, GH, IGF-I, and IGFBP-3 levels were decreased, whereas prostate-specific antigen levels did not change. PV was decreased in the 16 patients who were well controlled. Among the 6 patients with prostate hyperplasia at study entry who achieved disease control, 4 regained a normal PV at the end of the 2 yr of treatment, whereas none of the 5 patients with prostate hyperplasia at study entry and not achieving disease control normalized their PV. When patients were divided according to age, prostate volume decreased after 2 yr only in the 8 controlled patients aged below 50 yr, but not in those controlled and with age above 50 yr despite similar decrease in GH, IGF-I, and IGFBP3 levels. No clinical, transrectal ultrasonography, or cytological evidence of prostate cancer was detected during the study period. These data suggest that hyperplasia, but not cancer, is frequent in acromegalic men, and that the GH-IGF axis and age are independently associated with the development of this process.

Peripubertal prolactinomas: clinical presentation and long-term outcome with different therapeutic approaches.

UNLABELLED: The evolution of prolactinomas in children and adolescents continues to be controversial. We report on the long-term evolution (2-20 yr) of prolactinomas in 40 patients (29 F, 11 M). In females, the age for the onset of symptoms ranged between 8 and 16 yr and the age at which diagnosis was made ranged from 15 to 19 yr; in males, ages ranged from 8 to 17 yr and from 13.8 to 19 yr, respectively. In females, there was predominance of microprolactinomas (22/ 29) and the symptomatology resulted from functional disorders, whereas in males there was predominance of macroprolactinomas (8/11) and symptoms were caused by tumor mass disorders. Surgery was used as primary therapy in nine patients and as supplemental therapy in six patients. Twenty-four patients were treated primarily with bromocriptine and seven with cabergoline. Of the nine patients treated primarily with surgery, only one achieved gonadotropic axis restoration; in 25/31 patients receiving drug therapy gonadotropic function was restored to normal. Fifteen patients showed complete resolution or substantial shrinkage of tumor. CONCLUSION: In pediatric and adolescent age, there seem to be age- and sex-dependent differences in the clinical presentation of prolactinomas that cannot be accounted for only in terms of time of evolution. Drug therapy can control the disease, normalize prolactin levels and achieve gonadotropic axis restoration in most patients.

Ultrasonographic evidence of joint thickening reversibility in acromegalic patients treated with lanreotide for 12 months.

BACKGROUND: A major cause of morbidity and functional disability in acromegaly is represented by axial and peripheral arthropathy. OBJECTIVE: The effect of a 12-month treatment with lanreotide (LAN) on arthropathy in 12 untreated acromegalic patients has been evaluated. Twelve healthy subjects served as controls. STUDY DESIGN: Open prospective. STUDY PROTOCOL: Articular cartilage thickness of shoulder, wrist and knee, as well as the size of the heel tendons, was measured by ultrasonic (USG) examination before, monthly for the first 3 months and quarterly thereafter, during treatment with 60-90 mg/month of LAN. The achievement of safe GH and IGF-I levels was considered when fasting GH was below 5 mU/l and IGF-I levels were normalized for age. RESULTS: Before treatment, thickening of shoulder, wrist and knee cartilages, and of heel tendons, was found in all patients compared with controls (P < 0.01). During the first 3 months of LAN treatment, a significant decrease in circulating GH (from 86.8 +/- 19.8 to 25.6 +/- 9.8 mU/l) and IGF-I levels (from 624 +/- 47.8 to 412.2 +/- 44.5 microg/l) was observed. Overall, a slight decrease was noted in all the articular sites examined, but it reached statistical significance only at the right shoulder (P < 0. 001). However, a notable improvement of joint pain and active and passive articular mobility were recorded in all patients, as well as of weakness, soft tissue swelling, hyperhydrosis and headache. After 6 months of LAN treatment, a further significant decrease was observed at the level of the right shoulder (P < 0.01) and the right knee (P < 0.01). Eight patients achieved safe GH and IGF-I levels. After 12 months of LAN treatment, a significant decrease was observed at the level of all the articular sites examined (P < 0.01), as well as at the level of both heel tendons (P < 0.01). Safe GH and IGF-I levels were achieved in all but one of the patients who, similarly, had a significant decrease in shoulder, wrist and both heel tendon thicknesses. The thickness reduction of right shoulder cartilage, a non-weight-bearing joint, was significantly greater than that observed at the level of the right and left knee cartilages and heel tendons (37.4 +/- 4.4% vs. 18 +/- 6.1%, 19.3 +/- 4.4%, 16.5 +/- 4.2%, and 13.7 +/- 5.5%, respectively, P < 0.01). No difference was found in thickness decrease of all sites examined between the eight patients achieving safe GH levels after 3-6 months, and the remaining four patients, or between patients with estimated disease duration below (n = 6) or above 10 years (n = 6). CONCLUSIONS: Improvement in articular and periarticular soft tissue hypertrophy of the shoulder and wrist, two non-weight-bearing joints, but also of the knees, two weight-bearing joints, and heel tendons, was obtained by suppressing GH and IGF-I levels for 12 months with LAN treatment, although complete reversal of joint thickening was not achieved. Since no difference in the response to treatment, in terms of joint size decrease, was found between patients with short or long disease duration, treatment longer than 12 months may be needed to reverse the acromegalic arthropathy completely.

Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects.

The role of insulin-like growth factor I (IGF-I) in prostate development is currently under thorough investigation because it has been claimed that IGF-I is a positive predictor of prostate cancer. To assess the effect of GH and IGF-I levels on prostate pathophysiology, 46 acromegalic (30 in active disease, 10 cured from acromegaly, and 6 affected from GH deficiency) and 30 age-matched male controls, free from previous or concomitant prostate disorders, underwent pituitary, androgen, and prostate hormonal assessments and transrectal ultrasonography. Compared to control values, GH (P < 0.0001), IGF-I (P < 0.0001), and IGFBP-3 (P < 0.001) levels were increased, whereas testosterone (P < 0.0001) and dihydrotestosterone levels (P < 0.0001) were reduced in active acromegalic patients. Hypogonadism was present in 28 of the 46 acromegalic patients (60.8%). The anteroposterior (P < 0.05), and transverse (P < 0.0001) prostate diameters and the transitional zone volume (P < 0.05) were increased in acromegalic patients compared to those in controls. Prostate volume (PV) was significantly higher in untreated acromegalic patients than in controls (41.7 +/- 3.2 vs. 21.9 +/- 1.4 mL; P < 0.0001), cured patients (23.6 +/- 1.6 mL; P < 0.0001), and GH-deficient patients (17.5 +/- 1.1 mL; P < 0.0001). In the patients, PV was correlated with disease duration (r = 0.606; P < 0.0001) and age (r = 0.496; P < 0.0001), whereas in controls it was correlated with age (r = 0.476; P < 0.01) and IGF-I levels (r = -0.448; P < 0.05). Benign prostate hyperplasia (PV > or = 30 mL) was found in 58% of the acromegalics and 26.6% of the controls. When grouped by age (<40, 40-60, and >60 yr), PV was increased in elderly patients compared to younger patients (P < 0.05) and to controls (P < 0.01). The prevalence of structural abnormalities, including calcifications, nodules, cysts, and vesicle inflammation, was significantly increased in patients compared to controls (78.2% vs. 23.3%; chi2 = 5.856; P < 0.05). No clinical, transrectal ultrasonography, or cytological evidence of prostate cancer was detected in acromegalic or control subjects. In conclusion, chronic excess of GH and IGF-I cause prostate overgrowth and further phenomena of rearrangement, but not prostate cancer.

Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly.

This single-center open sequential study aimed at comparing the efficacy of a 6-month treatment with lanreotide (LAN) (60-90 mg/month i.m.), to that of octreotide (OCT) (0.3-0.6 mg/day s.c.) in 45 patients with active acromegaly (GH, 63.2+/-12.1 ng/ml, IGF-I, 757+/-67.1 ng/ml). After 6 months of OCT treatment, safe GH (fasting <2.5, glucose suppressed <1 ng/ml) and IGF-I (normalized for age) levels were achieved in 23 patients. After treatment withdrawal, GH levels significantly increased in all patients, though remaining slightly lower than pre-OCT therapy (39.2+/-5.8 ng/ml) while plasma IGF-I levels were unchanged (654+/-59.4 ng/ml). After 6 months of LAN treatment, safe GH and IGF-I levels were achieved in 26 patients (57.7%). After OCT or LAN treatments, no significant difference was found between nadir GH (6+/-1 vs 5.9+/-1.1 ng/ml) and IGF-I levels (281+/-23.3 vs 262+/-20.6 ng/ml). Four out of the 20 patients poorly responsive to OCT achieved safe GH and IGF-I levels after LAN treatment. Among the 20 non-operated patients, a significant tumor shrinkage was documented by CT and/or MRI in 5 patients after OCT and in 1 patient after LAN treatment. All patients referred a notable improvement of soft tissue swelling, arthralgia, headache and weakness, both after OCT and LAN treatments. During the first days of OCT treatment, abdominal discomfort was referred by 12 patients and steatorrhea by 5 patients: side effects disappeared spontaneously in 6 cases while during treatment with pancreatic enzymes in the remaining ones. After the first injections of LAN, abdominal discomfort was referred by 10 patients and steatorrhea by 2 of them. No difference in the prevalence of both early and late side effects was noted after treatment with OCT and LAN (chi2, 0.49). The majority of these poorly tolerant patients had side effects with both compounds. During LAN treatment, side effects were mild and spontaneously disappeared but recurred after the injection of the drug in six patients. Gallstones were detected in one patient during OCT and in another during LAN, sludge was noted in 6 patients after OCT and in 2 after LAN treatment. In conclusion, the treatment with LAN allowed to achieve safe GH and IGF-I levels in 57.7% of acromegalics with an excellent patients' compliance. LAN treatment possessed similar efficacy and caused side effects with a similar incidence of OCT treatment. The recurrence of side effects after LAN injection suggests the necessity of a careful monitoring of adverse reactions.