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L. Cantalamessa, E. Reschini, A. Catania and G. Giustina

ABSTRACT

The pituitary reserve of GH, prolactin, TSH, LH, and FSH has been studied in a group of 13 acromegalic patients with the aim of evaluating the pituitary function and the activity of the disease. Plasma GH, TSH and prolactin were determined after thyrotrophin releasing hormone (TRH) administration, plasma gonadotrophins and GH after luteinizing hormone releasing hormone (LH-RH) administration.

The plasma TSH response to TRH was generally blunted in the patients treated with pituitary irradiation; however, none of the patients with diminished TSH reserve had signs of hypothyroidism. Six acromegalics showed prolactin basal levels higher than controls; none had galactorrhoea; 4 of them complained of impairment of the gonadal function. The prolactin response to TRH was variable and not related to prolactin basal levels. A subnormal LH reserve after LH-RH stimulation was observed in 5 out of 10 patients; 4 of them had also clinical signs of hypogonadism. A normal FSH response to LH-RH was present in all patients.

A non-specific GH response to TRH and/or LH-RH was obtained in about half of the acromegalics studied. The GH responsiveness to TRH and/or LH-RH was not related to the activity of the disease or to a specific derangement of the hypothalamo-pituitary function. A concordant response was observed only between GH and prolactin response to TRH; the highest prolactin responses to TRH were obtained in the GH responsive patients. Each patient showed a constant GH pattern of response on repeated testing. Even after pituitary irradiation the pattern of GH response was unchanged in spite of lowered GH plasma levels.

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G Mazziotti, A M Formenti, S Frara, E Roca, P Mortini, A Berruti and A Giustina

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

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GD Rio, A Velardo, C Mascadri, G Zalteri, G Papi, R Menozzi and A Giustina

OBJECTIVE: Alterations in catecholamine plasma levels may contribute to the cardiovascular complications of acromegaly. Since few data are available on the catecholamine secretory dynamics in active acromegaly and no evidence exists on catecholamine variations during GH decrease, we studied acromegalic patients before and during octreotide administration. METHODS: We evaluated the catecholamine responses to upright posture and a cold pressure test (CPT) in 11 acromegalic (A) patients before and during continuous administration of octreotide (500 microgram/24h by s.c. pump) compared with 11 normal (N) subjects. RESULTS: All the acromegalic patients showed left ventricular cardiac hypertrophy. The cardiovascular responses to upright posture were similar between normal subjects and acromegalics both before and during octreotide treatment. The basal levels of norepinephrine (NE) were significantly higher in A patients compared with N subjects (423+/-45 vs 264+/-32pg/ml, P<0. 05) and decreased during therapy (291+/-32pg/ml; P<0.01). The increase in plasma NE during upright posture was significantly lower in A than in N subjects (P<0.01), but was restored to normal during octreotide treatment. CPT increased systolic and diastolic blood pressure, pulse rate and NE plasma levels in N (P<0.05) but not in A subjects both before and during octreotide treatment. CONCLUSIONS: Our data demonstrate the presence of increased basal NE levels in acromegalic patients with a defective sympathetic response to stimuli. Short-term octreotide infusion is able to induce a reduction in the basal levels of NE and a normalization of the catecholamine response to posture.

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Andrea Giustina, Mauro Doga, A Rosa Bussi, Massimo Licini and Maurizio Schettino

Galanin elicits growth hormone (GH) secretion in normal man but may cause a paradoxical fall of GH in acromegaly. The aim of our study was to investigate the effects of long-term treatment with bromocriptine on the galanin-induced GH decrease in acromegalic subjects. Six acromegalic patients (5F, 1M) chronically treated with bromocriptine underwent in randomized order: (i) iv infusion of 100 ml saline from 0 to 45 min and (ii) iv infusion of synthetic porcine galanin (0.5 mg in 100ml saline) from 0 to 45 min. In acromegalic patients, GH values fell from baseline (10.5±2.7 μg/1) to a mean nadir of 6.9±2.2 μg/1 after galanin infusion (57.8±9.4% vs basal levels). Saline infusion did not cause any change in circulating GH levels. The mean change in GH values with respect to baseline after galanin in these subjects significantly differed from that observed after saline from time 15 to 90 min. Serum prolactin levels were not significantly affected by galanin. Our results confirm that the dose of galanin capable of increasing plasma GH levels in normal subjects can decrease GH values in patients with acromegaly. Moreover, our data show that this paradoxical GH decrease induced by galanin can also be observed in patients chronically treated with bromocriptine. Therefore, the paradoxical decreasing effect of galanin on plasma GH levels in acromegaly seems not to be mediated via dopaminergic pathways.

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G Mazziotti, M Baracca, M Doga, T Porcelli, P P Vescovi and A Giustina

Objective

Heart failure (HF) has been associated with increased risk of fragility fractures. Indeed, most literature data on fractures were based on an historical and clinical approach focused on the identification of peripheral fractures, whereas the risk of vertebral fractures in this clinical setting is still unclear.

Design

Cross-sectional study.

Aim

To evaluate the prevalence and determinants of radiological thoracic vertebral fractures in patients with HF.

Methods

The study includes 1031 elderly hospitalized patients (491 females and 540 males; median age, 75 years; range, 65–90; 430 patients with HF) who were evaluated for the presence of thoracic vertebral fractures by quantitative morphometric analysis, using chest X-ray routinely performed in the diagnostic work-up of HF.

Results

Vertebral fractures were found in 166 patients (16.1%), the prevalence being significantly higher in patients with HF as compared with those without HF, both in females (30.9 vs 15.8%; P<0.001) and in males (16.4 vs 7.4%; P=0.001). The association between HF and vertebral fractures remained statistically significant (odds ratio, 2.14; 95% CI, 1.25–3.66; P=0.01) even after adjustment for age, sex, loop diuretic therapy, anticoagulant therapy, proton pump therapy, coexistent chronic obstructive pulmonary disease, diabetes mellitus, renal insufficiency, and chronic liver diseases. In patients with HF, vertebral fractures were positively correlated with female sex, duration of HF, ischemic heart disease, cigarette smoking, and treatment with anti-osteoporotic drugs, and inversely correlated with left ventricular ejection fraction.

Conclusions

Hospitalized patients suffering from HF are at higher risk of vertebral fractures than patients without HF in the same clinical context.

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Marilda Mormando, Luigi A Nasto, Antonio Bianchi, Gherardo Mazziotti, Antonella Giampietro, Enrico Pola, Alfredo Pontecorvi, Andrea Giustina and Laura De Marinis

Objective

Acromegaly is associated with an increased prevalence of vertebral fractures (VFs) in close relationship with GH hypersecretion. Two isoforms of the GH receptor (GHR) have been identified; the two isoforms differ or not by the expression of the protein fragment encoded by exon 3 of the GHR gene. Deletion of the exon 3 may influence the functional properties of the GHR and affect fracture risk in acromegalic patients.

Design

A cross-sectional study was designed to investigate the association between the d3-GHR isoform and the prevalence of VFs in patients with acromegaly.

Methods

In this study, 109 acromegalic patients were included (M/F, 48/61): 73 with controlled/cured acromegaly and 36 with active disease. GHR genotype was assessed in each patient. All patients were evaluated for VFs and bone mineral density at lumbar spine and hip. Serum IGF1 levels and bone metabolism markers were measured. A multivariate analysis was performed to establish risk factors for VFs in our population.

Results

d3-GHR carriers showed an increased prevalence of VFs when compared with patients expressing full-length GHR (35/55 vs 12/54; P<0.001). The association between GHR deletion and VFs was demonstrated both in patients with active disease and in those with controlled/cured disease. Out of 35 patients who were prospectively evaluated, 13 (37.1%) developed incident VFs. The incidence of VFs was significantly higher in patients for whom the GHR gene has been deleted when compared with those harboring the fl gene (P=0.04). In multivariate analysis, male sex (odds ratio (OR), 3.250; P=0.041), IGF1 levels (OR, 1.183; P=0.031), length of active diseases (OR, 1.038; P=0.001), and d3-GHR genotype (OR, 3.060; P=0.015) were all confirmed as risk factors of VFs in our population.

Conclusions

This study suggests for the first time that exon 3 deletion of GHR may predispose patients with active and controlled acromegaly to a higher risk of VFs.

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G Mazziotti, M Mormando, A Cristiano, A Bianchi, T Porcelli, A Giampietro, F Maffezzoni, V Serra, L De Marinis and A Giustina

Objective

In this study, we aimed at evaluating the association between radiological vertebral fractures and levo-thyroxine (l-T4) replacement doses in adult patients with hypopituitarism.

Design

Cross-sectional study.

Methods

We studied 74 adult hypopituitary patients (males, 43; females, 31; mean age, 57 years; and range, 23–79) with central hypothyroidism treated with l-T4 (median daily dose: 1.1 μg/kg). All patients also had severe GH deficiency (GHD) and 38 of them were replaced with recombinant GH. Vertebral fractures were assessed by a quantitative morphometric analysis performed on thoracic and lumbar spine lateral X-ray.

Results

Radiological vertebral fractures were found in 23 patients (31.1%) in association with untreated GHD (P=0.02), higher serum free T4 levels (P=0.03), a higher daily dose of l-T4 (P=0.005), and a longer duration of hypopituitarism (P=0.05). When GHD was treated, the prevalence of vertebral fractures was more frequent (P=0.03) in patients receiving high l-T4 doses (third tertile: >1.35 μg/kg per day) as compared with patients who were treated with lower drug doses (first tertile: <0.93 μg/kg per day). Such a difference was not observed in patients with untreated GHD who showed a higher prevalence of vertebral fractures regardless of l-T4 daily doses. Multivariate analysis showed that untreated GHD (odds ratio: 4.27, 95% CI 1.27–14.33; P=0.01) and the daily dose of l-T4 (odds ratio: 4.01, 95% CI 1.16–14.39; P=0.03) maintained a significant and independent association with vertebral fractures in patients with central hypothyroidism.

Conclusions

Our data suggest for the first time that a relative overtreatment with l-T4 may influence the fracture risk in some patients with hypopituitarism.

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G Mazziotti, T Porcelli, A Bianchi, V Cimino, I Patelli, C Mejia, A Fusco, A Giampietro, L De Marinis and A Giustina

Objective

GH deficiency (GHD) and glucocorticoid excess are associated with increased risk of fragility fractures. We aimed to evaluate whether the prevalence of vertebral fractures may be influenced by glucocorticoid over-replacement in hypopituitary males with GHD.

Design

Cross-sectional study.

Methods

Fifty-one adult hypopituitary patients (all males; mean age 55 years, range: 23–81) with severe adult-onset GHD (replaced in 21 patients and untreated in 30 patients) and glucocorticoid deficiency on replacement treatment were studied for vertebral fractures using a radiological and morphometric approach.

Results

Vertebral fractures were observed in 31 patients (60.8%) in correlation with untreated GHD, urinary cortisol values, and cortisone doses. Patients were stratified according to treatment of GHD, and current and cumulative cortisone doses. In untreated GHD, vertebral fractures occurred more frequently in patients who had received higher (greater than median) cumulative and current doses of cortisone compared with patients who had received lower (less than median) drug doses (95.2 vs 50.0%, P=0.009 and 90.5 vs 55.6%, P=0.04 respectively). In untreated GHD, fractured patients had significantly higher urinary cortisol values compared with patients without vertebral fractures (84 μg/24 h, range: 24–135 vs 49 μg/24 h, range: 30–96; P=0.04). In treated GHD patients, by contrast, the prevalence of vertebral fractures was not influenced by cumulative and current cortisone doses and urinary cortisol values.

Conclusions

Glucocorticoid over-replacement may increase the prevalence of vertebral fractures in patients with untreated GHD. However, treatment of GHD seems to protect the skeleton from the deleterious effects of glucocorticoid overtreatment in hypopituitary patients.

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P R Ebeling, R A Adler, G Jones, U A Liberman, G Mazziotti, S Minisola, C F Munns, N Napoli, A G Pittas, A Giustina, J P Bilezikian and R Rizzoli

Objective

The central role of vitamin D in bone health is well recognized. However, controversies regarding its clinical application remain. We therefore aimed to review the definition of hypovitaminosis D, the skeletal and extra-skeletal effects of vitamin D and the available therapeutic modalities.

Design

Narrative and systematic literature review.

Methods

An international working group that reviewed the current evidence linking bone and extra-skeletal health and vitamin D therapy to identify knowledge gaps for future research.

Results

Findings from observational studies and randomized controlled trials (RCTs) in vitamin D deficiency are discordant, with findings of RCTs being largely negative. This may be due to reverse causality with the illness itself contributing to low vitamin D levels. The results of many RCTs have also been inconsistent. However, overall evidence from RCTs shows vitamin D reduces fractures (when administered with calcium) in the institutionalized elderly. Although controversial, vitamin D reduces acute respiratory tract infections (if not given as bolus monthly or annual doses) and may reduce falls in those with the lowest serum 25-hydroxyvitamin D (25OHD) levels. However, despite large ongoing RCTs with 21 000–26 000 participants not recruiting based on baseline 25OHD levels, they will contain a large subset of participants with vitamin D deficiency and are adequately powered to meet their primary end-points.

Conclusions

The effects of long-term vitamin D supplementation on non-skeletal outcomes, such as type 2 diabetes mellitus (T2DM), cancer and cardiovascular disease (CVD) and the optimal dose and serum 25OHD level that balances extra-skeletal benefits (T2DM) vs risks (e.g. CVD), may soon be determined by data from large RCTs.

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S Melmed, F Casanueva, F Cavagnini, P Chanson, L A Frohman, R Gaillard, E Ghigo, K Ho, P Jaquet, D Kleinberg, S Lamberts, E Laws, G Lombardi, M C Sheppard, M Thorner, M L Vance, J A H Wass and A Giustina

In November 2003, the Pituitary Society and the European Neuroendocrine Association sponsored a consensus workshop in Seville to address challenging issues in the medical management of acromegaly. Participants comprised 70 endocrinologists and neurosurgeons with international expertise in managing patients with acromegaly. All participants participated in the workshop proceedings, and the final document written by the scientific committee reflects the consensus opinion of the interactive deliberations. The meeting was supported by an unrestricted educational grant from Ipsen. No pharmaceutical representatives participated in the program planning or in the scientific deliberations.