Real-life data of Pasireotide LAR in acromegaly: a long-term follow-up.

OBJECTIVE: Pasireotide LAR (PAS-LAR) was released in Italy in 2017 to treat acromegaly patients resistant to SRLs (Somatostatin Receptors Ligands). The long-term follow-up data of PAS-LAR therapy in Italy are limited. This study aimed to evaluate the efficacy and safety of PAS-LAR in acromegaly. DESIGN: Patients with acromegaly in PAS-LAR treatment were enrolled in three tertiary Italian endocrinological centers and evaluated by a retrospective observational real-life multicentre study. METHODS: Patients have been studied before (baseline) and 1, 6, 12, 24 and > 36 months after PAS-LAR start. Clinical, biochemical, and pituitary magnetic resonance data were collected, along with information on adverse events. Acromegaly disease activity was classified according to the IGF-1 index (normal value < 1.0). RESULTS: Fifty patients (female 23) were enrolled. PAS-LAR treatment (mean follow-up 24 ± 16 months) significantly decreased IGF-1 levels (IGF-1 index baseline vs last visit: 1.9 ± 0.6 vs 1.2 ± 0.6, p < 0.0001). At the last visit, 67% of patients had controlled disease, and 44% showed a decrease in tumor volume. Clinical and biochemical efficacy was observed as early as after 1-month of PAS-LAR treatment (IGF-1 index baseline vs 1-month: 1.9 ± 0.6 vs 1.4 ± 0.7, p < 0.0001). Also, 50% of patients referred headache improvement or disappearance. Fifteen patients discontinued PAS-LAR due to failure of treatment and poor glycaemic control. The prevalence of diabetes increased from 33% at the baseline to 54% at the last visit (p = 0.0072). CONCLUSION: In real-life settings, PAS-LAR significantly decreases symptoms, IGF-1 levels, and the size of adenoma in patients with acromegaly resistant to SRLs. Beneficial effects may occur early after the first injection.

Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity.

OBJECTIVE: Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. DESIGN: Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. RESULTS: For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P < 0·001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18·3 ± 8·10 vs 37·3 ± 6·48 bursts/min, P < 0·0001, respectively in patients and controls). A reduction in plasma leptin (1·6 ± 1·04 vs 6·5 ± 2·01 µg/l, P < 0·0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0·0001). CONCLUSIONS: Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia.

Control of ion transport by mitochondrion-rich chloride cells of eurythermic teleost fish: Cold shock vs. cold acclimation.

Seawater-acclimated eurythermic mummichogs (Fundulus heteroclitus L.) were acclimated to cold and warm conditions (5 and 20 °C, 4 weeks). Opercular epithelia (OE) from 20 °C-acclimated animals, containing numerous mitochondrion-rich chloride cells were mounted in Ussing-style membrane chambers, cooled to 16, 13, 10, 5 and 2.5 °C, then subjected to hypotonic shock that normally inhibits Cl(-) secretion (as short-circuit current, I(sc)). Cold exposure to 10 °C slowed Cl(-) secretion (Q(10)=1.62 ± 0.204 95% CI) and OEs responded rapidly and reversibly to hypotonic shock, but below 8.0 °C a sharp decrease (Q(10)=5.63 ± 0.736) occurred and the tissue was unresponsive to hypotonicity. By immunocytochemistry, Focal Adhesion Kinase (FAK) phosphorylated at tyrosine-407 (pY(407)) colocalized with CFTR in apical membrane and dephosphorylated with hypotonic shock at 20 °C but failed to dephosphorylate at 5 °C, while opercular epithelia from cold-acclimated fish at 5 and 20 °C responded normally to hypotonic shock. Cold-shock of warm-acclimated OEs also stimulated covering over of mitochondrion- rich cell apical crypts, detected by SEM. Cold-acclimation increased C18:1 and decreased C18:0 fatty acids in liver, indicating homeoviscous adaptation. Eurythermic fish acclimate osmoregulatory systems to cold by maintaining membrane fluidity and preserving complex transport regulation pathways.

Levodopa therapy reduces DNA damage in peripheral blood cells of patients with Parkinson's disease.

Oxidative stress seems to play a major role in the pathogenesis of neurodegeneration. In Parkinson's disease (PD) patients, the dopaminergic neurons are subjected to oxidative stress resulting from reduced levels of antioxidant defenses such as glutathione and high amount of intracellular iron. Levodopa (LD) is widely used for the symptomatic treatment of PD, but its role in oxidative damage control is still unclear. The aim of this study was to analyze the presence of DNA damage in peripheral blood lymphocytes (PBL) of PD patients, during a washout and a controlled LD dosage and to evaluate the oxidative damage fluctuation after LD intake. The standard and the Fpg-modified version of Comet assay were applied in analyzing DNA damage in PBL from blood samples of nine PD patients and nine matched controls. Due to the limited number of patients we cannot reach definite conclusions even if our data confirm the accumulation of DNA lesions in PD patients; these lesions decrease after LD intake.

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 microg/dl]. MAIN OUTCOME MEASUREMENTS: After ETSA, achieving wide (>90%) selective resection of the adenoma in all, F and clinical picture were checked at day 2. The low-dose (1 microg) 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 microg/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 microg/dl, allows full evaluation of HPA status. Peri-operative steroid treatment should be given only in patients with hypocortisolism.

Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in somatostatin analogue-naive patients with acromegaly.

OBJECTIVE: To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4-8 weeks in somatostatin analogue-naïve patients with acromegaly. DESIGN: Open, non-comparative, phase III, multicenter clinical study. METHODS: Fifty-one patients (28 women, aged 19-78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if 5 microg/l every 4 weeks (group C, 19 patients). Treatment duration was 48-52 weeks. The primary objective was to control GH and IGF-I levels (GH

Somatostatin analogs and gallstones: a retrospective survey on a large series of acromegalic patients.

CONTEXT: Development of gallstones (GS) is reported during the use of somatostatin analogs (SA) that are at present the mainstay for the medical treatment of acromegaly. OBJECTIVE: To review the prevalence and clinical and biochemical correlates of GS in acromegalic patients. DESIGN AND SETTING: Retrospective survey on hospital records in acromegalic patients followed up in the last 20 yr in tertiary referral centers. PATIENTS: Four hundred and fifty-nine patients (272 females). MAIN OUTCOME MEASURES: According to SA use and GS occurrence, patients were divided in 4 groups: 1) treated with SA without GS (SA+GS-), 2) GS developed while on SA (SA+GS+), 3) GS without SA use (SA-GS+), 4) neither GS nor SA (SA-GS-). RESULTS: Patients were unevenly distributed in the 4 groups: 232, 125, 38, 64, respectively, pointing to a prevalence of GS in acromegaly of 8.3% at diagnosis with an additional 35% developing GS during SA. GS occurred after 3 months-18 yr (median 3 yr) of SA treatment, were diagnosed after symptoms in 17.6%, were associated to steatosis, ultrasound biliary dilation, and biochemical cholestasis, in 25.6%, 12.8%, and 4% of patients, respectively. Ursodehoxicolic acid was administered after GS occurrence, causing their dissolution in 39% of patients after 3-48 months (median 12). Cholecystectomy was performed in 16.8%of patients in group 2. At multivariate analysis obesity, dyslipidemia, and SA treatment were independent predictors of GS onset, whereas gender and age were not. CONCLUSIONS: GS are a frequent occurrence in acromegalic patients treated with SA, may occur at any time, but are seldom symptomatic or prompt acute surgery. Obesity and dyslipidemia appear to play a major role in the occurrence of GS in acromegalic patients on SA treatment.

Focal adhesion kinase and beta1 integrin regulation of Na+, K+, 2Cl- cotransporter in osmosensing ion transporting cells of killifish, Fundulus heteroclitus.

Focal adhesion kinase (FAK), also known as PYK2, is a tyrosine kinase that functions in integrin-mediated signaling in mechanosensitive cells but its role in osmosensing cells is unknown. Antibodies directed against phosphorylated FAK, whose epitopes are conserved among vertebrates, were used to follow phosphorylation patterns in an osmosensing ion secreting epithelium, the killifish (Fundulus heteroclitus) opercular membrane. At the electron microscopic level, a unique combination of integrin beta1, the phosphorylated form of FAK at tyrosine 407 (pY407) and Na(+), K(+), 2Cl(-) cotransporter (NKCC1) were all colocalized only on the basolateral membrane in chloride cells. The three proteins were also coimmunoprecipitated with each other in isotonic conditions, suggesting an osmosensing complex involving the three proteins. Only FAK pY407 was sensitive to hypotonic shock and became dephosphorylated with hypotonic shock, while FAK pY576 in the apical membrane and pY861 in cell-cell adhesions were insensitive to hypotonicity. NKCC1 contributes to NaCl secretion in seawater and previous reports showed that hypotonic shock (-60 mOsm/kg) rapidly inhibits Cl(-) secretion. These results indicate that chloride cells respond to hypotonic shock using integrin beta1 as an osmosensor that is connected to dephosphorylation of FAK pY407 which leads to NKCC1 deactivation in the basolateral membrane and the inhibition of NaCl secretion by these epithelial cells.

Human protective response induced by meningococcus B vaccine is mediated by the synergy of multiple bactericidal epitopes.

4CMenB is the first broad coverage vaccine for the prevention of invasive meningococcal disease caused by serogroup B strains. To gain a comprehensive picture of the antibody response induced upon 4CMenB vaccination and to obtain relevant translational information directly from human studies, we have isolated a panel of human monoclonal antibodies from adult vaccinees. Based on the Ig-gene sequence of the variable region, 37 antigen-specific monoclonal antibodies were identified and produced as recombinant Fab fragments, and a subset also produced as full length recombinant IgG1 and functionally characterized. We found that the monoclonal antibodies were cross-reactive against different antigen variants and recognized multiple epitopes on each of the antigens. Interestingly, synergy between antibodies targeting different epitopes enhanced the potency of the bactericidal response. This work represents the first extensive characterization of monoclonal antibodies generated in humans upon 4CMenB immunization and contributes to further unraveling the immunological and functional properties of the vaccine antigens. Moreover, understanding the mechanistic nature of protection induced by vaccination paves the way to more rational vaccine design and implementation.

WNK1 and p38-MAPK distribution in ionocytes and accessory cells of euryhaline teleost fish implies ionoregulatory function.

Ionocytes of euryhaline teleost fish secrete NaCl, under regulation by serine and threonine kinases, including with-no-lysine kinase (WNK1) and p38 mitogen-activated protein kinase (MAPK). Mummichogs (Fundulus heteroclitus L.) were acclimated to freshwater (FW), full strength seawater (SW) and hypersaline conditions (2SW). Immunocytochemistry of ionocytes in opercular epithelia of fish acclimated to SW and 2SW revealed that WNK1-anti-pT58 phosphoantibody localized strongly to accessory cells and was present in the cytosol of ionocytes, close to cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane and the sodium potassium 2 chloride cotransporter (NKCC) in the basolateral membrane. In FW acclimated fish, WNK1 localized to a sub-apical zone, did not colocalize with apical membrane-located sodium chloride cotransporter (NCC), and typically was present in one cell of paired ionocytes and in some single ionocytes. Forskolin treatment (10 µM, 30 min) increased WNK1 immunofluorescence in SW ionocytes only, while hypertonicity had little effect, compared to controls. Anti-p38-MAPK antibody localized to the cytosolic compartment. The distribution of WNK1 and p38MAPK is consistent with a proximal position in regulatory cascades, rather than directly affecting transporters. The strong staining of accessory cells by WNK1 phosphoantibody infers an osmoregulatory function for WNK.

Aberrations induced in chromosomes of somatic cells of Drosophila melanogaster irradiated in C-metaphase.

Experiments conducted on the X irradiation of neural ganglia of Drosophila melanogaster are described. The ganglia were placed in saline containing colchicine. After two hours, they were irradiated and then samples were fixed at 5,15,25,35 minutes from the beginning of irradiation. The results obtained show that the aberration level increases with time subsequent to fixing. This increase takes place first for chromatid deletions and then for isochromatid deletions and chromatid exchanges. Gaps and subchromatid exchanges do not, on the contrary, show any increase with time. We did not observe a difference in radiosensitivity between the sexes. Some hypotheses are put forth in an attempt to explain these results.

A multi-biomarker analysis of DNA damage in automobile painters.

The genotoxic effects associated with automobile painting were analyzed using a panel of biomarkers. Chromosomal aberrations (CAs), sister chromatid exchange (SCE), and micronuclei were evaluated in 25 car painters (12 smokers, 13 nonsmokers) working in different automobile paint-shops in Italy and in 37 control subjects. The controls were healthy blood donors (14 smokers, 23 non-smokers) that were matched with the experimental population for gender and age. Air samples were analyzed regularly at the work places, and elevated concentrations of benzene and toluene were detected consistently. The exposed group had higher frequencies of CAs (both chromosome- and chromatid-type), micronuclei, and SCE (P < 0.5 - P < 0.001). Furthermore, exposed and control subjects were also genotyped for GSTM1 and GSTT1 polymorphism. No significant associations were detected between the biomarker responses and either the GSTM1 or GSTT1 genotype of the subjects, but the small sample size does not allow definite conclusions on the relationship between the genetic polymorphism and the biomarkers. The results indicate that automobile painters have increased levels of clastogenic and possible aneugenic damage and that smoking may be a confounding factor for the responses.

Relationship between somatomedin-C and growth hormone levels in acromegaly: basal and dynamic evaluation.

The relationship between basal and stimulated plasma GH and somatomedin-C (SmC) levels in acromegalic patients was evaluated. The basal plasma SmC levels of 66 patients were significantly correlated (P less than 0.01) with mean daily plasma GH levels, but not with the percent GH increase after GH-releasing hormone or TRH or the GH decrease after acute bromocriptine administration. Bromocriptine (7.5-15 mg/day) administration for 9.2 +/- 0.9 (+/- SD) months in 20 patients significantly (P less than 0.05) decreased GH levels. SmC decreased significantly [from 9.8 +/- 1.9 to 5.1 +/- 0.7 U/ml (mean +/- SE)] only in the 10 patients who had the more marked GH inhibition. The administration of a somatostatin analog, SMS 201-995 (100 micrograms twice daily), to 12 patients for 16 weeks significantly decreased plasma GH and SmC levels beginning on the second day of therapy; normal SmC levels were achieved in 5 of 12 patients. Pituitary adenomectomy resulted in normal GH and SmC levels in 10 of 12 and 8 of 12 patients, respectively. Our data indicate an overall dependency of plasma SmC levels on plasma GH levels in acromegaly, although similar GH levels may have differing somatomedin-stimulating activities. A derangement in the feedback mechanisms controlling GH secretion is indicated by the failure of elevated SmC levels to influence the GH responsiveness to releasing hormones. In evaluating pharmacological or surgical treatments of acromegaly, a single plasma SmC value can reliably replace several plasma GH determinations.

Serum type III procollagen propeptide levels in acromegalic patients.

Serum type III procollagen propeptide (PIIIP) is a reliable index of tissue collagen synthesis. Since in acromegaly there is increased collagen production, we measured serum PIIIP in acromegalic patients before any treatment (basal), during medical treatment with the somatostatin analog SMS 201-995, and after pituitary adenomectomy. In all patients, serum GH and plasma somatomedin-C (SmC) levels were also measured. Basal serum PIIIP levels were significantly (P less than 0.01) higher in acromegalic patients (mean +/- SEM, 22.7 +/- 2.1 ng/ml) than in normal subjects (n = 30; 9.7 +/- 0.5 ng/ml), and they were significantly correlated with plasma SmC values (r = 0.31; P less than 0.05). A significant (P less than 0.01) reduction in PIIIP levels occurred in patients treated with SMS 201-995 or surgery (from 24.3 +/- 2.7 to 12.4 +/- 1 ng/ml) as well as in GH and SmC levels. The maximum percent decrease in serum PIIIP was significantly correlated with those in GH (r = 0.65; P less than 0.01) and SmC (r = 0.60; P less than 0.01). Serum PIIIP levels did not change in those patients in whom neither GH nor SmC were decreased by treatment. In conclusion, serum PIIIP levels are elevated in acromegalic patients, and they decline in parallel with GH and SmC during medical or surgical treatment. Serum PIIIP measurements may be useful in the evaluation of acromegalic patients to gain information on the biological activity of GH and in monitoring the course of the disease.

Bromocriptine does not alter growth hormone (GH) responsiveness to GH-releasing hormone in acromegaly.

GHRH (100 micrograms) and TRH (200 micrograms) were administered to 24 active acromegalic patients before and during chronic bromocriptine (Br) treatment (Br, 10-15 mg/day for 3-5 months) to evaluate the possible effects of the dopamine agonist on GH release induced by these releasing hormones. Mean daily plasma GH levels were reduced by Br treatment from 34 +/- 40 (SD) to 16 +/- 19 ng/ml (P less than 0.01). No significant changes were found when comparing the GH response to GHRH as mean area under the response curve (nanograms per min/ml above the basal) (pretreatment, 5453 +/- 7843; during Br, 7017 +/- 12763 ng/ml . min), and as mean individual peak GH values (pretreatment, 130 +/- 148; during Br, 126 +/- 187 ng/ml) before and during treatment. The percentage GH increase (pretreatment, 340 +/- 354; during Br, 617 +/- 539%) was however significantly higher during Br. Br treatment significantly reduced the GH response to TRH in terms of mean of individual peak levels (from 136 +/- 134 to 60 +/- 52 ng/ml; P less than 0.01) and area under the response curve (from 3142 +/- 3998 to 1331 +/- 1646 ng/min . ml; P less than 0.01). However, the percentage GH increase was not significantly different (pretreatment, 486 +/- 729; during Br, 1059 +/- 1862%). When the patients were divided into Br responders, i.e. mean daily GH reduction during Br of at least 50% below baseline, and nonresponders, the initial response to GHRH was significantly higher in the latter group, but was unaffected by Br treatment in either group. On the contrary, the response to TRH, statistically significant initially only in the Br responder group, was reduced by Br treatment. We suggest that cells sensitive to Br and TRH but not to GHRH (lactotroph-like) and cells sensitive to GHRH but not to Br (pure somatotrophs) may coexist in GH-secreting adenomas.

Homogeneity in the growth hormone-lowering effect of dopamine and somatostatin in acromegaly.

We have studied the effect of maximally inhibiting doses of dopamine (DA) or somatostatin on GH levels in 39 acromegalic patients. The GH-lowering effects of the two drugs were highly variable in different patients. A significant correlation (r = 0.45; P < 0.01) was found between the percent changes obtained during the infusions of DA (500 microgram/min) and somatostatin (3.33 microgram/min). Pretreatment with L-sulpiride markedly blunted the inhibitory effect of DA but did not affect the response to somatostatin. We conclude that the GH-secreting cells of acromegalic patients contain separate receptors for DA and somatostatin. We hypothesize that the partial or total lack of responsiveness to DA or somatostatin may be due to the loss of receptors for these agents on the GH-secreting neoplastic cells.

Chronic treatment of pathological hyperprolactinemia and acromegaly with the new ergot derivative terguride.

The long term effectiveness and tolerance of terguride, a new ergot derivative, as initial therapy were evaluated in 20 patients with pathological hyperprolactinemia (PHP; group A) and 7 patients with acromegaly. We also studied 10 patients with PHP whose treatment was changed from bromocriptine or lisuride to terguride (group B). Terguride, given for at least 6 months in divided doses ranging from 0.25-1.50 mg/day to group A patients, resulted in normal (11 patients) or markedly reduced plasma PRL levels. Gonadal function was restored in all but 2 patients in this group, and the tumors shrank in 3 of 5 patients with a macroprolactinoma and in 1 of 3 patients with a microprolactinoma. In group B patients, positive effects of the previous treatment on PRL levels, gonadal function, and tumor growth were maintained by terguride. Terguride suppressed plasma GH levels below 50% of baseline in 4 of the 7 acromegalic patients. Two of the 27 patients initially treated with terguride complained of mild nausea and postural hypotension only after the first dose (0.25 mg) of the drug. No patient in group B had any side-effects during terguride, with the exception of 1 patient who was also intolerant to bromocriptine. We conclude that terguride is an effective well tolerated dopaminergic agent in PHP.

Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine.

We studied the effects of acute and chronic sc administration of SMS 201-995 (SMS), a long-acting somatostatin analog, in acromegalic patients. The results were compared with those obtained in the same patients treated with oral bromocriptine (Brc). A single dose of 50 micrograms SMS administered to 28 patients induced a more rapid, greater, and more prolonged reduction in plasma GH levels than did 2.5 mg Brc. Chronic treatment [60-330 days; mean 208 +/- 23 (+/- SEM)] with SMS (100-300 micrograms/day) induced in 16 patients a significantly greater decrease in mean plasma GH and somatomedin-C levels than did 20 mg Brc. Combined treatment with the 2 agents had an additional effect. The clinical and metabolic parameters of acromegaly dramatically improved in all patients whose plasma GH and somatomedin-C levels decreased even if they were not normalized by SMS. Reduction in tumor size occurred in 3 of the 10 patients examined by computed tomography before and during SMS treatment. We conclude that SMS is more effective than Brc and that the 2 drugs may be complementary in the medical treatment of acromegaly.

Size reduction of macroprolactinomas by bromocriptine or lisuride treatment.

We have administered to 29 patients with macroprolactinoma the dopamine agonists bromocriptine and lisuride for 1-50 months (mean +/- SE, 12.7 +/- 1.8) in order to assess the effects of these drugs on tumor size. Fourteen patients were treated with bromocriptine (dose range, 7.5-20 mg/day), 12 patients were treated with lisuride (0.6-2 mg/day), and 3 patients were given both drugs. Computed tomography performed before and during treatment showed the occurrence of tumor shrinkage in 18 patients (62%), but in no case was a complete disappearance of the tumor observed. In 5 of these patients, it was even possible to document tumor shrinkage within the first month of treatment with low doses of the dopamine agonists, whereas in other patients, tumors shrank only after prolonged treatment with higher doses. Visual field and acuity improved or normalized in 8 of the 13 patients with visual defects; in some cases, the improvement was reported as early as 2 days after the treatment was started. Plasma PRL levels fell in all patients who showed a reduction in tumor size; in 2 other patients, PRL levels were only poorly suppressed, and tumor size remained unchanged. In the remaining patients, PRL levels were lowered without convincing evidence of tumor shrinkage. In considering the high percentage of patients showing tumor shrinkage under medical treatment, we propose a course with dopamine agonists as the first step in the management of patients with macroprolactinomas regardless of the presence of visual impairments.