C. Di Somma

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 im), to that of octreotide (OCT) (0.3-0.6 mg/day sc) 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 (χ2, 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.

Circulating insulin-like growth factor-I levels are correlated with the atherosclerotic profile in healthy subjects independently of age

To investigate the relationships between the GH-IGF-I axis and the atherosclerotic profile, we designed this open, observational, prospective study. Peak GH after GHRH+arginine (ARG) test, serum IGF-I and IGF binding protein-3 (IGFBP-3), lipid profile, homeostasis model assessment (HOMA) index and intima-media thickness (IMT) at common carotid arteries were measured in 174 healthy individuals (92 women, 82 men, aged 18–80 yr). Exclusion criteria for this study were: 1) body mass index (BMI) ≥30 kg/m2; 2) personal history of cardiovascular diseases; 3) previous or current treatments of diabetes or hypertension; 4) previous corticosteroids treatment for longer than 2 weeks or estrogens for longer than 3 months; 5) smoking of more than 15 cigarettes/day and alcohol abuse. Subjects were divided according to age in decade groups from <20 to >70 yr. BMI increased with age, as did systolic and diastolic blood pressures, although they remained in the normal range. The GH peak after GHRH+ARG test was significantly higher in the subjects aged <20 yr than in all the other groups (p<0.01), but was similar in the remaining groups. An inverse correlation was found between the IGF-I z-score and total/HDL-cholesterol ratio (p=0.02) and mean IMT (p=0.0009); IGFBP-3 z-score and mean IMT (p=0.043); IGF: IGFBP-3 molar ratio and total/HDL-cholesterol ratio (p<0.0001) and mean IMT (p<0.0001). Atherosclerotic plaques were found in 7 out of 12 subjects (53.8%) with a z-IGF-I score from ≤−2 to −1, in 4 out of 63 (6.3%) with a z-IGF-I score from −0.99 to 0.1 out of 66 (1.5%) with a z-IGF-I score from 0.1 to 1 and none of the 33 subjects with an IGF-I z-score >1 (p=0.006). At multi-step regression analysis, age was the best predictor of HDL-cholesterol levels and mean IMT, IGF-I level was the best predictor of total cholesterol and total/HDL-cholesterol ratio, the IGF-I/IGFBP-3 molar ratio was the best predictor of triglycerides levels. The z-scores of IGF-I and IGFBP-3 were the second best predictors of mean IMT after age. In conclusion, IGF-I and IGFBP-3 were negatively correlated with common cardiovascular risk factors, studied as total/HDL-cholesterol ratio, and/or early atherosclerosis, studied as IMT at common carotid arteries. The prevalence of atherosclerotic plaques, though not hemodinamically significant, was higher in the subjects having a z-score of IGF-I of ≤−2 to −1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.

Estrogens and health in males

Estrogen receptor concentrations are higher in the male reproductive tract than in other organs. Brain structure, neuronal organization and behavioral sex differences result from brain conversion of testosterone into estradiol within the brain. Estrogens modulate hormonal secretion at pituitary level and immune function at thymus level. Estrogens promote vasodilatatory and protective effects on the cardiovascular system by acting on the vascular smooth muscle and endothelium. Adult men with mutations in genes for estrogen receptor or aromatase are affected by osteopenia and tall stature, open epiphysis, which is corrected by estrogen treatment. Over the past few years there has seen a decline in sperm concentration, which has been attributed to exposure of fetal testes to estrogens. Many substances have estrogen-like properties and inhibit the action of estradiol or testosterone action. In conclusion, estrogens play a pivotal role in men also. In particular, taking in account their prevalent origin from testosterone aromatization at tissue and peripheral levels the presence and the distribution of the two receptors (ERalpha and ERbeta) are responsible for different responses in physiological and pathological conditions.

Hypopituitarism induced by traumatic brain injury in the transition phase

Traumatic brain injury (TBI) has been associated with hypopituitarism in general and GH deficiency (GHD) in particular; the consequences of this on growth and development are likely to be critical in children and adolescents in the so-called “transition phase”. In order to verify the consequences of TBI on pituitary function in the transition phase, we studied a population of adolescents and young adults 3 and 12 months after brain injury [no.=23, 9 females, 14 males; age: 16-25 yr; body mass index (BMI): 21.9±0.6 kg/m2]. At 3 months, hypopituitarism was present in 34.6%. Total, multiple and isolated deficits were present in 8.6, 4.3 and 21.7%, respectively. Diabetes insipidus (DI) was present in 8.6% patients and mild hyperprolactinemia in 4.3%. At 12 months, hypopituitarism was present in 30.3%. Total, multiple and isolated deficits were present in 8.6, 4.3 and 17.4%, respectively. DI was present in 4.3% of patients and mild hyperprolactinemia in 4.3%. Total hypopituitarism was always confirmed at retesting. Multiple and isolated hypopituitarism were confirmed in 0/1 and 2/5, respectively. Two/23 patients showed isolated hypopituitarism at 12 months only; 1 patient with isolated at 3 months showed multiple hypopituitarism at retesting. GHD and secondary hypogonadism were the most common acquired pituitary deficits. These results show the high risk of TBI-induced hypopituitarism also in the transition age. Thus it is recommended that pediatric endocrinologists follow-up pituitary function of children and adolescents after brain injuries.

Impairment of GH secretion in adults with primary empty sella

Primary empty sella (PES) is generally not associated with overt endocrine abnormalities, although mild hyperprolactinemia and, in children, deficient GH secretion have been reported. The aim of this multi-center collaborative study was to evaluate basal and stimulated GH secretion in a large series of adult PES patients. The study group consisted of 51 patients [41 women and 10 men, age range: 20–78 yr; (mean±SD) 47±11 yr]; results were compared with those in normal subjects (Ns) (Ns: no.=110, 55 women, age: 20–50 yr, 37±14 yr), and in hypopituitaric patients (HYP) with GH deficiency (HYP: no.=44, 17 women, age: 20–72, 49±16 yr). Baseline IGF-I levels and GH responses to insulin-induced hypoglycemia (insulin tolerance test, ITT) and/or GHRH+arginine (ARG) stimulation tests were evaluated. PES patients were also subdivided according to BMI in lean (BMI <28 kg/m2 no.=22) or obese (BMI >28 kg/m2 no.=29). PES patients had serum total IGF-I concentrations (mean±SE: 142.2±9.6 ng/ml) higher than HYP patients (77.4±6.4 ng/ml, p<0.001), but lower than Ns (213.3±17.2 ng/ml, p<0.005), with no differences between lean and obese PES subjects. The increase in serum GH concentrations following ITT and/or GHRH+ARG stimulation tests, although higher than that observed in HYP patients, was markedly reduced with respect to Ns. No difference was observed in the GH response to provocative tests between lean and obese PES patients. When individual GH responses to ITT or GHRH+ARG were taken into account, a large proportion of PES patients (52% after ITT, 61% after GHRH+ARG) showed a GH peak increase below the 1st centile of normal limits. Serum IGF-I levels in PES patients with blunted GH responses to provocative tests were significantly (p<0.001) lower in PES patients with normal GH responses, and a positive correlation was observed between IGF-I levels and serum GH peak concentrations after GHRH+ARG. In conclusion, the results of the present study provide evidence that adult PES patients often have an impairment of GH secretion, as indicated by the blunted GH response to ITT and GHRH+ARG provocative tests, and by the reduction in serum IGF-I levels. These changes are independent of body mass.

Failure of long-term therapy with sodium valproate in Cushing’s disease

The aim of the current study was to evaluate the effectiveness of a long-term treatment with sodium valproate in 19 patients with Cushing’s disease. Before therapy beginning, the patients were subjected to acute test with 600 mg sodium valproate. Then, they were subjected to a 3-month therapy with sodium valproate at the dose of 600 mg/day before surgery (presurgical study). The 7 patients not surgically cured were subjected again to a 3-month therapy with sodium valproate at the dose of 600 mg/day after surgery (postsurgical study). Circulating ACTH and cortisol and urinary free cortisol levels were evaluated before and monthly after the beginning of the therapy. A decrease of plasma ACTH and serum cortisol levels greater than 50% of baseline was considered as positive response to acute test whereas the normalization of plasma ACTH, serum cortisol and urinary free cortisol levels and the clinical remission were considered as positive response to the long-term treatment. At acute test, 8 patients were considered responders and 11 patients non-responders. In no patient plasma ACTH, serum cortisol and urinary free cortisol were normalized during the long-term treatment. Urinary free cortisol levels significantly decreased (483.2±33.8 vs 699.4±67.0 ug/24 h), whereas plasma ACTH (302.8±17.7 vs 183.3±25.0 ng/l) and serum cortisol (466.5±23.2 vs 356.7±19.6 µg/l) significantly increased during sodium valproate administration in the 19 patients enrolled in the presurgical study. Plasma ACTH (247.7±22.3 vs 168.6±15.0 ng/l), serum cortisol (387.4±35.8 vs 282.0±16.0 µg/l) and urinary free cortisol (370.9±70.6 vs 261.3±37.8 µg/24 h) levels significantly increased in the 7 patients enrolled in the postsurgical study. No patient had clinical remission of Cushing’s disease. In conclusion, the current study showed that long-term therapy with sodium valproate is not useful in the therapeutic management of Cushing’s disease neither as alternative nor as adjunctive therapy to surgery.

Treatment of skeletal impairment in patients with endogenous hypercortisolism: when and how?

Guidelines for the management of osteoporosis induced by endogenous hypercortisolism are not available. Both the American College of Rheumatology and the International Osteoporosis Foundation recommend to modulate the treatment of exogenous glucocorticoid-induced osteoporosis (GIO) based on the individual fracture risk profile (calculated by FRAX) and dose of glucocorticoid used, but it is difficult to translate corticosteroid dosages to different degrees of endogenous hypercortisolism, and there are no data on validation of FRAX stratification method in patients with endogenous hypercortisolism. Consequently, it is unclear whether such recommendations may be adapted to patients with endogenous hypercortisolism. Moreover, patients with exogenous GIO take glucocorticoids since suffering a disease that commonly affects bone. On the other hand, the correction of coexistent risk factors, which may contribute to increase the fracture risk in patients exposed to glucocorticoid excess, and the removal of the cause of endogenous hypercortisolism, may lead to the recovery of bone health. Although the correction of hypercortisolism and of possible coexistent risk factors is necessary to favor the normalization of bone turnover with recovery of bone mass; in some patients, the fracture risk could not be normalized and specific anti-osteoporotic drugs should be given. Who, when, and how the patient with endogenous hypercortisolism should be treated with bone-active therapy is discussed.

Bone mineral density and circulating cytokines in patients with acromegaly

Acromegalic patients present an increase of osteoblastic and osteoclastic activity, showing a different effect on the axial and appendicular skeletal structures. At this regard controversial data about bone mineral density (BMD) have been published in literature. In fact an increase of BMD levels in femoral neck and Ward’s triangle without any difference in lumbar spine has been described. On the other hand normal BMD levels at forearm and reduced BMD levels at lumbar spine were found. These patients seem to have a reduction of trabecular BMD similar to postmenopausal osteoporotic patients despite normal or slightly elevated cortical BMD. Recently, it has been described that cytokines, in particular tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), are implicated in the pathogenetic mechanism of postmenopausal osteoporosis. Taking into account that growth hormone (GH) can increase TNF-α and IL-1 secretion by mononuclear blood cells, the evaluation of possible relationship between the reduced BMD at lumbar spine and circulating cytokines levels was carried out in acromegalic patients. In addition we evaluated the effect of acute octreotide administration on serum TNF-α and IL-I concentrations. Eleven patients with active acromegaly and eleven healthy age-, sex-, weight- and heightmatched subjects were enrolled in this study. BMD was significantly reduced at lumbar spine (0.80±0.29 g/cm2vs 1.02±0.11 g/cm2; p<0.01), but not at femoral neck level or at Ward’s triangle level (0.92+0.15 g/cm2vs 0.97+0.11 g/cm2, p=NS; and 0.74±0.16 g/cm2vs 0.85±0.1 g/cm2, p=NS) when compared to controls. Baseline serum levels of TNF-α and IL-1 were in the normal range both in patients and controls. After acute octreotide administration, no differences in circulating TNF-α and IL-1 levels were found. In conclusion, acromegalic patients present a reduced BMD at lumbar spine but not at femoral neck level and Ward’s triangle. Circulating cytokines such as TNF-α and IL-1 are in the normal range. These data suggest that cytokines are not involved in the pathogenesis of GH-excess induced osteoporosis. The possibility that the GH excess might affect bone turnover inducing an increase of cytokines acting by a paracrine/autocrine mechanism cannot be ruled out.

The cardiovascular system in growth hormone excess and growth hormone deficiency.

The clinical conditions associated with GH excess and GH deficiency (GHD) are known to be associated with an increased risk for the cardiovascular morbidity and mortality, suggesting that either an excess or a deficiency in GH and/or IGF-I is deleterious for cardiovascular system. In patients with acromegaly, chronic GH and IGF-I excess commonly causes a specific cardiomyopathy characterized by a concentric cardiac hypertrophy associated with diastolic dysfunction and, in later stages, with systolic dysfunction ending in heart failure if GH/IGF-I excess is not controlled. Abnormalities of cardiac rhythm and anomalies of cardiac valves can also occur. Moreover, the increased prevalence of cardiovascular risk factors, such as hypertension, diabetes mellitus, and insulin resistance, as well as dyslipidemia, confer an increased risk for vascular atherosclerosis. Successful control of the disease is accompanied by a decrease of the cardiac mass and improvement of cardiac function and an improvement in cardiovascular risk factors. In patients with hypopituitarism, GHD has been considered the under-lying factor of the increased mortality when appropriate standard replacement of the pituitary hormones deficiencies is given. Either childhood-onset or adulthood-onset GHD are characterized by a cluster of abnormalities associated with an increased cardiovascular risk, including altered body composition, unfavorable lipid profile, insulin resistance, endothelial dysfunction and vascular atherosclerosis, a decrease in cardiac mass together with an impairment of systolic function mainly after exercise. Treatment with recombinant GH in patients with GHD is followed by an improvement of the cardiovascular risk factors and an increase in cardiac mass together with an improvement in cardiac performance. In conclusion, acromegaly and GHD are associated with an increased risk for cardiovascular morbidity and mortality, but the control of GH/IGF-I secretion reverses cardiovascular abnormalities and restores the normal life expectancy.

Prevalence of the metabolic syndrome in moderately-severely obese subjects with and without growth hormone deficiency

Background and aim: There is a considerable heterogeneity in metabolic phenotype among equally obese subjects. Impaired GH secretion is frequent in obese patients, with GH secretion reduced up to levels that are comparable to those found in adult patients with organic GH deficiency (GHD). Low GH status exerts detrimental effects on metabolic abnormalities in organic GHD patients. The aim of this observational, retrospective study was to investigate the prevalence of the metabolic syndrome (MetS) in moderately-severely obese subjects who met criteria for GDH (GHD) and in those with normal GH status (GH sufficient: GHS). Methods and results: One-hundred and ninety-five moderately-severely obese individuals partecipated, 149 women and 46 males [body mass index (BMI) 43.0±4.4 kg/m2 aged 34.3±11.8 yr]. Main outcome measures were: GH peak after GHRH plus arginine test, IGF-I, MetS parameters according to National Cholesterol Education Program criteria. Fifty-five subjects (27.3%) were GHD (49 females and 6 males). The prevalence of MetS parameters was 70.9% in GHD subgroup vs 52.9% in GHS (χ2=5.281; p=0.02) and the likelihood of MetS was highest in GHD subgroup (odds ratio: 2.174; 95% confidence interval 1.113 to 4.248). At the multiple regression analysis either GH peak or IGF-I were the major determinants of waist circumference (β=-0.380, t=−6.110 and β=-0.326, t=−4.704, respectively; p<0.001), while age and IGF-I were the major determinants of MetS (β=0.255, t= 3.342, and β=−0.282, t=−3.270; p=0.02, respectively). Conclusions: Among moderately-severely obese individuals the prevalence of the MetS was higher in GHD than in GHS subjects. Thus, in obese subjects, GH status investigation might be considered in the clinical evaluation of their metabolic risk profile.