Roberto Attanasio

Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: Efficacy and lack of predictive value of prolactin status

background  Somatostatin analogues (SA) are currently the mainstay in the medical treatment of acromegaly. However, even high doses of depot SA for prolonged periods do not achieve GH–IGF‐I normalization in some patients. Even though some data were reported about the addition of cabergoline, a long‐acting dopamine agonist (DA), to SA in resistant patients, definite data are still lacking.

Efficacy and tolerability of gamma knife radiosurgery in acromegaly: a 10‐year follow‐up study

Objective  The long‐term efficacy and safety of stereotactic radiosurgery by gamma knife (GK) still remain unknown. The aim of the study was to investigate the long‐term efficacy and tolerability of GK in acromegalic patients.

Effects of lanreotide autogel on growth hormone, insulinlike growth factor 1, and tumor size in acromegaly: A 1-year prospective multicenter study

OBJECTIVE To evaluate the safety and effectiveness of lanreotide Autogel on growth hormone and insulinlike growth factor 1 (IGF-1) concentrations and tumor size in patients with acromegaly. METHODS Between September 2004 and March 2006, patients with active acromegaly who had not previously been treated with somatostatin analogues or received irradiation were enrolled in a 1-year, prospective, open, multicenter study. Lanreotide Autogel was injected subcutaneously starting with 90 mg every 4 weeks for 2 cycles and then individually titrated, aiming for safe growth hormone concentrations (<2.5 ng/mL) and normal age-matched IGF-1 concentrations. Tumor shrinkage, clinical score, pituitary function, and safety parameters were evaluated. RESULTS Twenty-seven patients (15 women, 12 men) were enrolled. One patient withdrew because of treatment intolerance, and 5 proceeded to neurosurgery 6 months into the study. Lanreotide Autogel was the primary treatment in 19 patients (4 with microadenoma, 15 with macroadenoma) and the adjuvant treatment in 8 patients in whom it followed a previous unsuccessful neurosurgery. In the 26 patients, safe growth hormone values were achieved in 11 (42%), normal IGF-1 values in 14 (54%), and both targets were achieved in 10 (38%). Tumors shrank in 16 of the 22 patients (73%) in whom tumor shrinkage could be evaluated. The maximal vertical diameter of the tumor decreased by a mean of 24% (range, 0% to 50%), from 14.4 +/- 8.4 mm to 10.4 +/- 7 mm, and tumor volume decreased by a mean of 44% (range, 0% to 76%), from 2536 mm3 (range, 115-7737 mm(3)) to 1461 mm(3) (range, 63-6217 mm(3)) (both P<.015). Symptom scores and lipid levels significantly improved. In the 26 patients, glucose metabolism deteriorated in 3 (12%) and improved in 4 (15%). New biliary alterations appeared in 26%. Pituitary function and safety parameters did not change. CONCLUSIONS Lanreotide Autogel treatment, titrated for optimal hormonal control, effectively controls IGF-1 and growth hormone levels, shrinks tumors, reduces acromegalic symptoms, and is well tolerated.

GH/IGF-I normalization and tumor shrinkage during long-term treatment of acromegaly by lanreotide

New depot somatostatin analogs such as lanreotide-slow release (LAN) represent a significant improvement in the medical treatment of acromegaly. Seventy-three consecutive acromegalic patients, treated by LAN, were evaluated in a retrospective monocentric study. Sixteen were excluded from further evaluation due to combined treatment with dopamine agonist drugs, early LAN withdrawal for persistence of headache, or gastrointestinal side-effects. Fifty-seven patients (aged 20–82 years, 16 males) were thus evaluated. Thirty-two patients had been previously treated by neurosurgery (Tx) and/or radiotherapy (Rx). After washout, LAN (30 mg) was administered im at 10–14-day intervals. Time intervals between injections were then individually tailored to normalize IGF-I levels. LAN was administered for 12 (6–36) [median (range)] months. GH and IGF-I levels decreased from 13 (7–20) [median (interquartile)] μg/l to 3.2 (1.7–6.2) μg/l (p<0.0001) and from 780 (596–1000) μg/l to 264 (180–530) μg/l (p<0.000001), respectively. Seven patients were resistant to treatment. Among the 50 sensitive patients, GH levels fell below 2.5 μg/l in 52% (and below 1 μg/l in 18%), IGF-I levels normalized in 72% and both results were obtained in 46%. IGF-I values normalized in 87% of patients treated every 14 days, in 100% every 21–28 days, in 69% every 10 days and in 22% every 7 days. No different control of GH/IGF-I hypersecretion was evidenced between patients previously treated or not by Tx and/or Rx. Patients with the lowest basal hormonal levels and those over 55 years showed greater responsiveness (both p<0.05). The maintenance of LAN schedule up to 18 months determined a further suppression (p=0.04 for IGF-I). A reduction of tumor size was shown in 60% of evaluated patients (6/10). HbA1c slightly increased in 42% of patients and gallstones were observed in 16%. LAN is a very effective tool in the treatment of acromegaly: its chronic administration normalizes GH/IGF-I levels in most patients, shrinks the tumor in a high percentage of patients and seems to control hormonal hypersecretion as primary treatment as well as neurosurgery.

Lanreotide 60 mg, a Longer-Acting Somatostatin Analog: Tumor Shrinkage and Hormonal Normalization in Acromegaly

Background: Somatostatin analogues are nowadays the milestone in the medical treatment of acromegaly. We evaluated the effects of a new 60 mg longer-acting formulation of lanreotide (LAN60) on GH/IGF-I levels and tumor size. Patients: Twenty-one acromegalics entered a prospective monocentric open study. Eight were consecutive “de novo” patients (group I). Thirteen patients sensitive to SA (GH levels < 2.5 μg/l and/or IGF-I normalization on chronic LAN 30 mg (LAN30) treatment) were switched to LAN60 (group II). Protocol: LAN60 was administered IM for 6 cycles at 28 day intervals. In group I when GH/IGF-I remained pathological, the intervals were shortened to 21 days for the last three cycles. Controls: GH/IGF-I at the end of the 1st, 3rd and 6th cycle; MRI at the end of the study in all patients in group I bearing an adenoma. Results: Group I. GH (p = 0.00638, below 2.5 μg/l in two patients) and IGF-I (p = 0.0289, normalized in 5) significantly decreased. In one of two patients shortening the LAN60 schedule was more effective in suppressing GH/IGF-I. Group II. No change in GH and IGF-I levels was observed with the administration of LAN60, instead of LAN30. On LAN60 GH remained below 2.5 μg/l in 8/10 patients and IGF-I normal in 11/11 patients that had attained those values on LAN30. Tumor markedly shrank (23% to 64% vs basal), from 1400 (664–1680) mm3 to 520 (500–960) mm3 (median, interquartile, p = 0.0218) in all the 5 evaluable patients. Conclusion: LAN60 is a very effective and longer-lasting formulation for the treatment of acromegaly. A closer administration schedule might achieve greater efficacy. Its effectiveness in shrinking tumor opens new perspectives in the therapy of acromegaly.

Effects of tamoxifen on GH and IGF-I levels in acromegaly

Tamoxifen (TAM), a non steroid partially competitive antagonist to the estrogen receptors, has been reported to decrease plasma GH and IGF-I levels both in vitro and in vivo. These data prompted us to evaluate GH and IGF-I changes in acromegaly after acute and chronic TAM administration. Nineteen acromegalic patients (6 M, 13 F, aged 30–70 years) were studied in a prospective open study. Acute TAM test (20 mg po) did not induce any significant change in GH and IGF-I levels. Chronic TAM treatment (20 mg/day for a month and 40 mg/day for another month) induced a transient increase in GH levels (from 9 [3–139] µg/l [median, range] to 12 [3-188] µg/l, p=0.0025) and a persistent decrease in IGF-I levels (from 785 [500-1200] µg/l to 553 [209-1420] µg/l, p=0.0034). Individual IGF-I values decreased in 13 patients and reached the normal range in 4 of them. At TAM withdrawal hormonal levels increased up to pretreatment values. There was no correlation between GH and IGF-I changes and results were not influenced by age, sex or gonadal status. In this setting it is likely that the observed decrease in plasma IGF-I levels is dependent on TAM activity at the hepatic level.

Estroprogestinic pill normalizes IGF-I levels in acromegalic women

In some acromegalic patients medical treatment does not succeed in normalizing GH/IGF-I values. Data showing IGF-I suppression in acromegaly by estrogen and by tamoxifen use prompted us to reevaluate the effects of estro-progestins (EP) supplementation on GH/IGF-I levels in acromegalic women resistant or only par-tially sensitive to medical treatment. Eight active acromegalic women (30–52 yr, 4 with regular menses) entered a prospective open pilot study. Three of them, resistant to medical treatment, were off therapy; the remaining five, partially sensitive, maintained it at the maximally effective dosages throughout the study. Patients were treated with a triphasic pill (ethynil-estradiol 30–40–30 μg/day and desogestrel 50–70–100 mg/day) for 13±7 months. IGF-I levels fell from 512 (median, interquartile 436–657) μg/l to 282 (244–526) μg/l (p=0.0414); the decrease was observed in 6 patients (75%), and normal values were reached in 4 (50%). GH levels did not change [basal 7.6 (6.2–8.6) μg/l, final 7.6 (6.5–8.3) μg/l]. Effectiveness of treatment was not dependent on concomitant anti-GH treatment or gonadal status. In all patients IGF-I levels re-increased after EP withdrawal. This pilot study shows a marked IGF-I lowering effect of pill in acromegalic women, and warrants a prospective randomized study in patients resistant or partially sensitive to other medical treatments.

Perioperative Cortisol can predict hypothalamus-pituitary-adrenal status in clinically non-functioning pituitary adenomas

Background: Peri-operative steroids are administered routinely to patients with pituitary adenoma undergoing transsphenoidal adenomectomy (TSA). Aim: To evaluate hypothalamic-pituitary-adrenal (HPA) axis before and after programmed endoscopic TSA (E-TSA) in patients with clinically non-functioning pituitary macroadenoma (NFPA). Design: Open prospective. Setting: Tertiary referral hospitals. Patients: Seventy-two consecutive patients (20–87 yr, 37 males). Interventions: Adrenal steroid replacement therapy (ASRT) was given only in patients with hypocortisolism [08:00 h cortisol (F) <8 µg/dl]. Main outcome measurements: After E-TSA, achieving wide (>90%) selective resection of the adenoma in all, F and clinical picture were checked at day 2. The low-dose (1 µg) ACTH test (LDACTH) was performed at 6 weeks and repeated at 12 months. Results: Hypocortisolism was present pre-operatively in 14 patients (19.4%), persisted post-operatively in all but one, and was detected de novo at the post-operative day 2 control in 6 (10.3%). In all but one the post-operative day 2 basal F and peak F during LDACTH test were concordant. No patient whose F was > 8 µg/dl was treated with ASRT or developed symptoms of adrenal failure during the follow-up (1–11 yr, median 5). Conclusions: HPA function is usually preserved in NFPA and is infrequently impaired after complete tumor removal by E-TSA. The 08:00 h. plasma cortisol evaluation before and 2 days after surgery, using as cut-off the value of 8 µg/dl, allows full evaluation of HPA status. Peri-operative steroid treatment should be given only in patients with hypocortisolism.

Silent renal stones in primary hyperparathyroidism: prevalence and clinical features.

OBJECTIVE (1) To evaluate the prevalence of silent nephrolithiasis in patients with primary hyperparathyroidism (PHPT) compared with controls, and (2) To characterize clinically PHPT patients with silent renal stones. METHODS We reviewed clinical data for 141 patients with PHPT and without symptoms or history of nephrolithiasis in whom renal ultrasonography was performed at diagnosis. A total of 141 sex- and age- matched subjects with abdomen ultrasonography obtained for reasons different from urinary symptoms served as controls. RESULTS Silent nephrolithiasis was more prevalent in PHPT patients than in controls (11.35% vs. 2.13%; P = .003). Among patients with PHPT, those with silent renal stones showed higher serum calcium and parathyroid hormone levels and met surgical criteria, regardless of nephrolithiasis, more frequently than those without renal stones. CONCLUSION The prevalence of silent nephrolithiasis is increased in patients with PHPT as compared with controls. Moreover, it seems likely that silent renal stone disease could identify a subset of PHPT patients with more severe disease. Accordingly, we suggest ultrasonographic screening of nephrolithiasis in all PHPT patients. Further studies are needed to better characterize this clinical entity.

Vitamin D status in primary hyperparathyroidism: a Southern European perspective

Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one‐third of the patients.