A. Di Sarno

Revised Guidelines for Neonatal Screening Programmes for Primary Congenital Hypothyroidism

Since the first guidelines for neonatal screening for congenital hypothyroidism (CH) were issued by ESPE in 1993 [1], there have been considerable advances in our understanding of CH and our appreciation of the various geographical and logistic difficulties involved. Therefore, an updating of the guidelines is overdue. Experience from countries where screening began in the late 1970s and early 1980s has indicated that treatment should be started no later than the first 2 weeks of life using a ‘high’ dosage regime of L-thyroxine (10–15 Ìg/kg/day). It has also been shown that the quality of long-term outcome is closely related to the quality of follow-up. In Eastern Europe, screening programmes for CH have either been started or will start soon in almost all countries, and although many programmes are operating satisfactorily, it is important to standardise screening procedures and management of suspected cases as much as possible in order to optimise outcome. A degree of uniformity throughout Europe would not only facilitate early detection and treatment of individual patients but give insight into the economic and epidemiological aspects of the screening programmes as well as the epidemiological aspect of CH.

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.

Power Doppler Improves the Diagnostic Accuracy of Color Doppler Ultrasonography in Cold Thyroid Nodules: Follow-Up Results

The usefulness of a recent color Doppler (CD) ultrasonography technique, named power Doppler (PD), was evaluated in the diagnosis of thyroid nodules showing low or absent uptake of 99mTc-pertechnetate, in order to investigate the possibility to improve the diagnostic accuracy of ultrasonography. The rationale was the evidence that at PD the color map displays the total integrated Doppler power in color, while CD generally displays an estimate of the mean Doppler shift. The vascular patterns recorded at PD and CD evaluation of 322 thyroid nodules were compared to the results of cytology and/or histology, when surgery was performed. In respect to the results of cytology, PD has a higher sensitivity (100 vs. 91%) and specificity (95.1 vs. 86.2%) than CD. A similar result was found when PD and CD were compared to the results of histology, sensitivity being 100 vs. 89% and specificity 98.1 vs. 93.7%, respectively. During the follow-up the 2 nodules considered false positive at PD resulted to be tumoral lesions. On this basis, the final specificity of PD in our series was 100%. In conclusion, in the current series including 322 thyroid nodules characterized by a low or absent uptake of 99mTc-pertechnetate, PD seems to provide a better characterization of thyroid nodules, possibly allowing a more accurate selection of the patients to subject to fine-needle biopsy.

Cabergoline-induced CSF rhinorrhea in patients with macroprolactinoma. Report of three cases

Three cases of cerebrospinal fluid (CSF) leak, in subjects with an invasive macroprolactinoma under treatment with cabergoline (CAB), are reported. The patients underwent surgical treatment by means of an endoscopic endonasal transsphenoidal approach, which allowed removal of the lesion and sealing of the fistula. Many cases of CSF rhinorrhea are described in literature after bromocriptine therapy in invasive prolactinomas, but only one report has been recently published of such condition after CAB treatment. The complication is likely due to the brisk cessation of the so-called “stopper effect”, i.e. the tumor mechanically blocking the CSF leak in spite of its previous erosion of the skull-base, when CAB induces the macroprolactinoma shrinkage. Endoscopic transsphenoidal surgery offers a safe, minimally invasive and efficient management of this complication, which allows to regularly perform the following steps of the therapeutical strategy against the prolactinoma.

Effects of a Chronic Treatment with Octreotide in Patients with Functionless Pituitary Adenomas

The effects of a chronic treatment with octreotide were evaluated in 19 patients affected with functionless pituitary adenomas. Octreotide caused a significant decrease of GH and IGF-I levels in all the patients and no significant change in thyroid, adrenal and gonadal function. In contrast, during the therapy, the glucose response to an oral glucose tolerance test considerably increased and was delayed, while the insulin response decreased and was delayed. Serum alpha-subunit (alpha-SU) was above normal in 10 of 16 patients in which this evaluation was performed: octreotide caused a significant decrease (p < 0.01) of alpha-SU levels in 6 of these 10 patients. Octreotide did not induce any significant change in visual fields except in 1 patient, who had a great improvement of visual perimetry and a decrease of alpha-SU levels but unmodified CT scan features. In our series of patients, octreotide was ineffective in reducing tumor mass. The efficacy of octreotide might rely on the presence of somatostatin receptors on adenoma-cell membranes. Therefore patients with functionless adenomas to be treated with octreotide might be identified with pituitary scintiscan using the recently available labeled 111In-octreotide.

Comparison among Different Dopamine-Agonists of New Formulation in the Clinical Management of Macroprolactinomas

BACKGROUNDnIn the last decade, the treatment of macroprolactinomas has been significantly improved by the introduction in the clinical practice of new drugs with dopamine-agonist properties. In particular, the availability of different forms of bromocriptine (BRC) with long duration of action and slow absorption, suitable for injectable (BRC-LAR) or oral (BRC-SRO) administration, has allowed one to obtain a more constant bromocriptinemia than with standard BRC, thus reducing adverse reactions. Moreover, a selective action on dopamine D2 receptors has been achieved using a new non-ergot derivative: the quinagolide (CV 205-502). The aim of this study was to evaluate the effects of BRC-LAR, BRC-SRO and CV 205-502 in 34 patients with macroprolactinoma. PROTOCOL OF THE STUDY: BRC-LAR was given at the monthly dose of 50-100 mg for 6-24 months to 8 patients whose PRL levels were 150-700 micrograms/l. BRC-SRO was given at the daily dose of 5-20 mg for 1-24 months to 10 patients whose PRL levels were 120-900 micrograms/l. CV 205-502 was given at the daily dose of 0.075-0.6 mg for 6-12 months to 16 patients whose PRL levels were 250-2,050 micrograms/l. CT and/or MRI scans were performed before and during treatment to evaluate tumor shrinkage. Data are presented as Mean +/- SD.nnnRESULTSnSerum PRL levels normalized in 8/8 with BRC-LAR, 7/10 with BRC-SRO and 12/16 patients with CV 205-502. A significant shrinkage of tumor mass was obtained in 7/8 with BRC-LAR, 9/10 with BRC-SRO and 16/16 patients with CV 205-502, with consequent improvement of visual-field defects. Overall, the drugs were rather well tolerated: no patient stopped BRC-LAR or BRC-SRO and only 2 stopped CV 205-502. In particular, nausea, vomiting, headache, hypotension that disappeared spontaneously were observed in 5/8 with BRC-LAR, 4/10 with BRC-SRO and 4/16 with CV 205-502.nnnCONCLUSIONSnThe medical approach with long-acting BRC preparations and CV 205-502 which selectively binds D2 receptors allows one to obtain rapid normalization of PRL levels and shrinkage of macroprolactinomas in a large series of patients. These drugs are rather well tolerated also by patients proven to be untolerant to standard BRC.

Positive response to compound CV 205-502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine

The clinical effects of CV 205-502, a potent and non-ergot-derived dopamine agonist, were investigated in 24 selected patients with hyperprolactinemia previously treated with standard oral bromocriptine, the slow-release oral form of bromocriptine (BRC-SRO) and/or the long-acting injectable form of bromocriptine (BRC-LAR); 14 were chosen because of their resistance to treatment and ten because they were intolerant of the different forms of bromocriptine. A macroprolactinoma was present in seven patients and a microprolactinoma in ten, whereas seven had no radiological images of a pituitary tumor and were classified as having non-tumoral hyperprolactinemia. All the 24 patients were treated with CV 205-502 at a daily dose of 0.075-0.6 mg for 3-12 months. All the patients had gonadal dysfunction and galactorrhea. Basal serum prolactin values ranged from 70 to 1677 ng/ml. CV 205-502 was effective in 11 of the 14 patients resistant bromocriptine, BRC-SRO and BRC-LAR; serum prolactin levels became normal within 6 months and a tumor shrinkage was obtained in five of the seven macroprolactinomas. In general, the drug was effective and well tolerated. Only three patients (two resistant and one intolerant) manifested nausea, vomiting and postural hypotension. In conclusion, this study shows that CV 205-502 is effective in bromocriptine-resistant hyperprolactinemic patients. Furthermore, CV 205-502 has insignificant and tolerable side-effects in patients intolerant of bromocriptine. CV 205-502 can, therefore, be considered a useful and effective drug, and an interesting therapeutic alternative to the ergot-derived dopamine-agonist drugs in use today.

Impaired luteinizing hormone responsiveness to gonadotropin-releasing hormone in the inferior petrosal sinuses of hyperprolactinemic patients

The aim of this study was to evaluate serum baseline and gonadotropin-releasing hormone (GnRH)-stimulated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations in the inferior petrosal sinuses and in peripheral blood in nine normoprolactinemic and eight hyperprolactinemic patients who were being subjected to perihypophyseal phlebography for diagnostic purposes or neurosurgical indications. Serum FSH and LH concentrations were significantly higher in both inferior petrosal sinuses than in peripheral blood (p < 0.001 and p < 0.05, respectively) in normoprolactinemic but not in hyperprolactinemic patients. Additionally, in normoprolactinemic patients, the LH response to intravenous bolus GnRH in the inferior petrosal sinuses (evaluated as peak/basal) was significantly greater than in hyperprolactinemic patients (p < 0.01). No difference was found as far as FSH response to GnRH was concerned. In conclusion, these findings suggest that the hypogonadism of hyperprolactinemic patients may depend on the impaired release of LH at the pituitary level.

CV 205–502 in the treatment of tumoral and non-tumoral hyperprolactinemic states

CV 205-502 (octahydrobenzol[g]quinoline), a non-ergot dopamine agonist drug, was administered to 40 patients with hyperprolactinemic syndrome: 16 patients with macroprolactinoma, 14 with microprolactinoma and 10 with non-tumoral hyperprolactinemia. Twenty-four out of 40 patients had previously been treated by surgery and/or bromocriptine, with variable results. All had gonadal dysfunction and 22 patients had galactorrhea. Eight patients with macroprolactinoma had defects of the visual field. Pre-treatment serum PRL levels ranged from 60 to 2050 micrograms/l. The daily dose of CV 205-502 used in this trial ranged from 0.075 to 0.600 mg. After 6-12 months of treatment, serum PRL level decreased in all the patients reaching normoprolactinemia in 31 of them (77.5%) who demonstrated restoration of menses and disappearance of galactorrhea. The remaining nine patients (22.5%) had only a decrease of PRL levels without reaching normoprolactinemia and without any clinical effect. In 12 out of 16 patients with macroprolactinoma not previously surgically treated, a significant tumor shrinkage was shown by means of Computed Tomography and/or Magnetic Resonance Imaging. The disappearance of visual defects was obtained in four out of eight patients. CV 205-502 was tolerated satisfactorily: mild side-effects occurred in four patients in the first week of treatment and spontaneously disappeared, whereas six patients (15%) needed to withdraw the therapy after 6 months because of side-effects. In conclusion CV 205-502 is a potent and well-tolerated drug in the treatment of tumoral and non-tumoral hyperprolactinemic states and is an effective alternative to other dopamine agonists in use today.

Different sensitivity to sodium valproate in healthy, non-tumoral and tumoral hyperprolactinemic subjects

GABAergic drugs affect PRL secretion in both rat and man. Sodium valproate (SV) inhibits GABA transaminase so increasing the endogenous GABAergic tone. The aim of this study was to evaluate the effects of SV at low and high doses on PRL release in healthy subjects and hyperprolactinemic patients. Fifteen patients with prolactinomas, 8 patients with non-tumoral hyperprolactinemia and 10 healthy subjects were studied: in non consecutive days, all subjects received placebo and SV at the dose of 400 and 800 mg po. Serum PRL levels were assessed 30, 15 and 5 min before and every 30 min for 4 hours after administration. SV at the dose of 400 mg induced a significant decrease of serum PRL in healthy subjects (p<0.05), whereas no effect was noted in both tumoral and non-tumoral hyperprolactinemia. The administration of 800 mg SV induced a significant decrease of PRL levels in healthy subjects and in patients with non-tumoral hyperprolactinemia (p<0.05). Conversely, in prolactinomas a paradoxical increase of serum PRL concentration (p<0.05) was observed 120 min after the administration of the drug. These data confirm the inhibitory activity of SV on PRL release in healthy subjects, and suggest the existence of a partial resistance to GABA in non-tumoral hyperprolactinemia. In prolactinomas, the paradoxical PRL increase after high dose of SV suggests the existence of a complete pituitary resistance to GABA. This finding might be explained by the appearance of the stimulatory effect of GABA at hypothalamic level that could have been unmasked by the lack of pituitary GABA effects on adenomatous lactotrophs.