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Secondo Lastoria, Annamaria Colao, Emilia Vergara, Diego Ferone, Paola Varrella, Bartolomeo Merola, Gaetano Lombardi, and Marco Salvatore

Lastoria S, Colao A, Vergara E, Ferone D, Varrella P, Merola B, Lombardi G, Salvatore M. Technetium-99m pentavalent dimercaptosuccinic acid imaging in patients with pituitary adenomas. Eur J Endocrinol 1995;133:38–47. ISSN 0804–4643

We studied the tumor-seeking agent technetium-99m-labeled pentavalent dimercaptosuccinic acid ([99mTc](V)DMSA) to visualize 21 growth hormone (GH)-, nine prolactin (PRL)-, two mixed GH/PRL-, six adrenocorticotropin (ACTH)-secreting and 15 clinically non-functioning pituitary adenomas, three craniopharyngiomas and one dysgerminoma of the sella. All non-adenomas and 31 out of 53 adenomas were studied before treatment: 22 after surgery and/or radiotherapy. Eight cases of acromegaly were studied before and after chronic treatment with octreotide, whereas three cases of acromegaly, one of prolactinoma and two of non-functioning adenoma were imaged before and after adenomectomy. As a control group, 27 patients without any clinical evidence of pituitary adenoma were studied: 10 of them were operated on previously and treated with iodine-131 for metastatic thyroid carcinoma, 10 had brain tumors and the remaining seven patients had functional pituitary hypersecretion (four Klinefelter's syndrome, two primary hypothyroidism and one Addison's disease). The scintigraphy was repeated after testosterone in Klinefelter's syndrome, l-thyroxine in primary hypothyroidism and cortisone administration in Addison's disease. Seventeen GH-secreting (81%), seven PRL-secreting (78%), three ACTH-secreting (50%), 15 non-functioning (100%) and one (50%) mixed adenoma significantly concentrated [99mTc](V)DMSA, showing elevated tumor-to-background (T/B) ratios. The T/B ratios were similar in untreated and surgically treated adenomas (11.2 ± 5.6 vs 11.8 ± 6.2). Radiotherapy significantly lowered the [99mTc](V)DMSA uptake to 5.1 ± 2.8 (p < 0.1 vs untreated patients). Non-adenomatous lesions of the sella turcica did not concentrate [99mTc](V)DMSA in the pituitary as well as brain tumors and 8 out of 10 metastatic thyroid cancers. The treatment with octreotide normalized GH and insulin-like growth factor I levels and reduced [99mTc](V)DMSA from 15.7 ± 4.8 to 13.5 ± 3.9 (p < 0.05). Conversely, adequate substitutive therapy completely inhibited the uptake of the radiotracer in Klinefelter's syndrome, in primary hypothyroidism and in Addison's disease. The [99mTc](V)DMSA scintigraphy showed an overall sensitivity of 81% (43/53) in detecting pituitary adenomas, which was increased to 95% for lesions greater than 10 mm in size. High-quality images with minimal total body radiation were obtained, enabling a good in vivo characterization of viable adenomatous tissue as well as an accurate monitoring of the effects of different therapeutic regimens.

Secondo Lastoria, Department of Nuclear Medicine, National Cancer Institute, Fondazione G Pascale, via M Semmola, 80131 Napoli, Italy

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Pietro Ameri, Andrea Giusti, Mara Boschetti, Marta Bovio, Claudia Teti, Giovanna Leoncini, Diego Ferone, Giovanni Murialdo, and Francesco Minuto


Previous studies suggested that vitamin D modulates circulating IGF1. We investigated this effect in adults and its clinical relevance in the management of GH deficiency (GHD).

Design and methods

IGF1 levels were prospectively measured before and after 12 weeks of treatment with oral vitamin D3 (5000 or 7000 IU/week) vs no intervention in 39 subjects 61.9±7.9 years old. The frequency of IGF1 values ≥50th age- and sex-specific percentile in relation to vitamin D status, as determined by the concentration of 25-hydroxyvitamin D (25(OH)D), was retrospectively assessed in 69 GHD patients (57.4±16.6 years) on stable hormone replacement and with 25(OH)D and IGF1 concurrently measured.


Treatment with 5000 and 7000 IU vitamin D3/week significantly raised 25(OH)D by 12.7±8.4 and 13.1±6.5 ng/ml respectively (both P<0.001 vs baseline). In the 7000 IU group, IGF1 levels also significantly increased by 31.3±36.7 ng/ml (P=0.01). Neither 25(OH)D nor IGF1 significantly varied in controls. IGF1 was ≥50th percentile more frequently in GHD patients with 25(OH)D levels ≥15 than <15 ng/ml (65.9 vs 40.0%, P<0.05). Logistic regression with adjustment for recombinant human GH (rhGH) dose, vitamin D supplements, gender, use of thyroid hormones, corticosteroids or estrogen/testosterone, and season revealed a significant positive association between ≥15 ng/ml 25(OH)D and IGF1 ≥50th percentile (OR 4.4, 95% CI 1.0–18.8, P<0.05). A significant negative correlation between 25(OH)D concentrations and rhGH dose was found after correcting for age and IGF1 (β −0.042, P<0.01), but not after further adjusting for sex, thyroid, adrenal or gonadal replacement, and season (β −0.037, P=0.06).


Vitamin D increases circulating IGF1 in adults. As a result, a better vitamin D status may ease the achievement of normal IGF1 values in GHD.

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Annamaria Colao, Bartolomeo Merola, Diego Ferone, Maria Rosaria Calabrese, Salvatore Longobardi, Renato Spaziante, Gianfranco Di Renzo, Lucio Annunziato, and Gaetano Lombardi

Colao A, Merola B, Ferone D, Calabrese MR, Longobardi S, Spaziante R, Di Renzo G, Annunziato L, Lombardi G. Effect of corticotrophin-releasing hormone administration on growth hormone levels in acromegaly: in vivo and in vitro studies. Eur J Endocrinol 1994;131:14–19. ISSN 0804–4643

The ability of CRH to cause a paradoxical response of GH in acromegaly is still under debate. In this study, the effect of CRH administration on GH release was evaluated in a large series of patients with active acromegaly, both in vivo, compared to that of TRH and GnRH, and in vitro. The study was organized as follows. In vivo study: 30 acromegalic patients were submitted to TRH, GnRH, and CRH tests on non-consecutive days: blood samples were collected before and 10, 20, 30, 45, 60, 90, and 120 min after bolus. In nine patients the CRH test was repeated after a 3-month therapy with octreotide and at the dose of 300–600 μg sc thrice daily. In vitro study: CRH (10 nmol/l, 100 nmol/l, and 1 μmol/l) was tested on pituitary tumor tissue obtained in eight patients during transsphenoidal adenomectomy and immediately placed in sterile Ca2+ and Mg2+ free buffer phosphate. A paradoxical GH response to TRH (evaluated as a GH increase over 50% of basal values) was recorded in 19 patients (63.3%), whereas 7 patients (23.3%) responded to GnRH and 4 others to CRH (13.3%). TRH administration induced a maximal percent GH increase significantly greater than that induced by GnRH and CRH (p < 0.05). Octreotide caused the normalization of GH and insulin-like growth factorI levels in all the patients, as well as the disappearance of the GH paradoxical response to CRH in 3/4 patients. All four CRH responders and four CRH non-responders, used as controls, were surgically treated and adenomatous tissue was used for the in vitro study. No significant GH increase was found in the CRH non-responders and in the three CRH responders in whom the GH paradoxical response to CRH disappeared during octreotide treatment. Conversely, a significant GH increase (over 250% of pre-incubation values) after CRH administration was found in the remaining case. In conclusion, the results of the present study show that CRH is rarely able to stimulate paradoxical GH response in patients with active acromegaly and that the in vivo recorded GH release after CRH is in vitro reproducible only in extremely rare cases.

Annamaria Colao, Corso Europa 63, 80127 Napoli, Italy

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Gaetano Lombardi, Annamaria Colao, Diego Ferone, Francesca Sarnacchiaro, Paolo Marzullo, Antonella Di Sarno, Emanuela Rossi, and Bartolomeo Merola

Lombardi G, Colao A, Ferone D, Sarnacchiaro F, Marzullo P, Di Sarno A, Rossi E, Merola B. CV 205-502 treatment in therapy-resistant acromegalic patients. Eur J Endocrinol 1995;132:559–64. ISSN 0804–4643

The growth hormone (GH) inhibitory effect of CV 205-502 was evaluated during acute and 3-month administration, alone or in combination with octreotide, in 12 therapy-resistant acromegalic patients. Although these patients previously had undergone surgery and received chronic therapy with octreotide at 0.3–0.6 mg/day, they still had high GH and insulin-like growth factor I (IGF-I) levels. CV 205-502 (0.15 mg), octreotide (0.1 mg) and placebo were tested acutely. CV 205-502 at the dose of 0.15 mg caused a decrease of GH level (from 34.9 ± 15.1 to 2.7 ± 0.3 μg/l) in 4/12 (33.3%) and completely inhibited prolactin (PRL) secretion in all the patients. Octreotide caused a decrease of GH level (from 37 ± 6.7 to 15.9 ± 3.0 μg/l) without any change of PRL level. The GH and PRL levels were not changed during placebo administration. CV 205-502 at the dose of 0.3 mg/day (chronic test) normalized GH and IGF-I levels in five patients (41.6%: the four responders to the acute test and an additional patient who was a poor responder to acute CV 205-502 administration). The remaining seven patients were subjected to CV 205-502 (0.6 mg/day) and octreotide (0.6 mg/day) in combination for 3 months. In 2/7 patients the combined therapy induced a greater inhibition of GH and IGF-I levels than did each drug when administered alone. The drug was well-tolerated by the 12 patients. In conclusion, CV 205-502 is able to normalize GH and IGF-I levels and to improve clinical symptoms in certain acromegalic patients resistant to other therapeutic approaches. CV 205-502 can, therefore, be considered an effective alternative in the medical management of acromegaly when the first choices, surgery and octreotide, fail to resolve GH hypersecretion.

Gaetano Lombardi, via G. Santacroce 40/a, 80129 Napoli, Italy

Free access

Alberto Tagliafico, Massimo Calabrese, Giulio Tagliafico, Eugenia Resmini, Carlo Martinoli, Alberto Rebora, Annamaria Colao, Rosario Pivonello, and Diego Ferone


Mammographic density is a strong independent risk factor for breast cancer, whose prevalence in acromegaly is still controversial.


To compare breast density in premenopausal acromegalic patients and controls and to determine whether density correlated with disease duration, GH, and IGF1 levels.

Design, setting and participants

A prospective study involving 30 patients and 60 controls matched for age and body mass index.


A quantitative computer-aided mammographic density estimation (MDEST) and a qualitative blind evaluation by two experienced radiologists using the breast imaging reporting and data system (BI-RADS) was performed. Totally, 60 (acromegaly) and 120 (controls) craniocaudal and mediolateral oblique mammograms were evaluated in both patients and controls.

Main outcome measures

Breast density.


Patients showed a significantly (P<0.01) increased mammographic breast density with both methods (MDEST: 0.33±0.21% and BI-RADS category: 2.81±0.78) in comparison with controls (MDEST: 0.26±0.19% and BI-RADS category: 2.35±0.61). The agreement between the two methods and inter-observer agreement between the two radiologists were excellent (k=0.63 and k=0.85). In patients grouped according to disease activity (17 controlled and 13 uncontrolled) and medical therapy (15 treated and 15 untreated), no differences were found. All these groups had significantly increased mammographic breast density compared with controls (P<0.01).

A positive correlation was found between mammographic breast density, IGF1 values and disease duration (r=0.29 and r=0.39), whereas it was not found with GH (r=−0.02).


Mammographic breast density in premenopausal acromegalic patients is significantly higher than controls and positively correlated with IGF1 and disease duration.

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Annamaria Colao, Bartolomeo Merola, Diego Ferone, Paolo Marzullo, Gaetana Cerbone, Salvatore Longobardi, Carolina Di Somma, and Gaetano Lombardi

Colao A, Merola B, Ferone D, Marzullo P, Cerbone G, Longobardi S, Di Somma C, Lombardi G. Acute and chronic effects of octreotide on thyroid axis in growth hormone-secreting and clinically non-functioning pituitary adenomas. Eur J Endocrinol 1995;133:189–94. ISSN 0804–4643

The effect of somatostatin on thyroid function was studied in 12 patients with growth hormone (GH)-secreting and eight patients with clinically non-functioning adenomas (NFA) and normal pituitary/ thyroid axis; the patients were subjected to the administration of octreotide (OCT), which is a longacting somatostatin analog. All the patients received an acute test with 100 μg of OCT, both short term (1 month) and long term (6 months), with doses ranging from 300 to 600 μg/day, Serum thyroxine (T4). triiodothyronine (T3), free T4, free T3, thyroglobulin and basal and thyrotropin (TSH)-releasing hormone (TRH)-stimulated TSH were evaluated before and after 1 and 6 months of therapy. Circulating GH and insulin-like growth-factor I (IGF-I) in acromegalics and GH, IGF-I and α-subunit in NFA were assessed at baseline and every month. The acute administration of 100 μg of OCT significantly reduced the TSH response to TRH (p < 0.01) in both acromegalics and NFA. In all the patients OCT administration caused a significant decrease of GH, IGF-I and α-subunit levels (p < 0.01). In addition, after 1 month of therapy both baseline and TRH-induced TSH secretion were decreased significantly in acromegalics and NFA. After 6 months of therapy, baseline and TRH-induced TSH was still reduced in NFA. Conversely, in acromegalics, baseline TSH levels were increased while TSH response to TRH was inhibited. No change of T4, T3, free T4 and free T3 was observed in NFA, whereas a slight but significant increase of T4 and decrease of T3 was recorded in acromegalics. In conclusion, OCT does seem to possess long-term suppressive effects on TSH response to TRH, both in acromegalics and NFA. The lack of basal TSH level inhibition in acromegalics could depend on the restored peripheral conversion of T4 into T3 due to the normalized GH levels during long-term OCT administration.

Annamaria Colao, Corso Europa 63, 80127 Napoli, Italy

Open access

Diego Ferone, Alexandru Saveanu, Michael D Culler, Marica Arvigo, Alberto Rebora, Federico Gatto, Francesco Minuto, and Philippe Jaquet

Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells and pituitary adenomas. Indeed, initially several dopaminergic drugs, and lately somatostatin analogs, have been developed for the treatment of pituitary adenomas. Recently, it has been demonstrated that subtypes of somatostatin and dopamine receptors may form homo- and hetero-dimers at the membrane level, as part of their normal trafficking and function. Interestingly, a specific ligand for a given receptor may influence the activity of an apparently unrelated receptor, and the association between the two different receptors could be induced by addition of either dopamine or somatostatin. The new properties of these families of G-protein coupled receptors (GPCRs) offer a potential explanation for the apparent conflicting results observed both in vivo and in vitro in human cell systems treated with the presently available analogs. Moreover, this observation not only increases the possibilities of modulating the activities of these receptors, but also raises new questions on the role of associations of specific receptors in the control of cell functions. In fact, results from preclinical studies have shown that receptor activation may not only trigger different intracellular signaling pathways, but also induce a distinct response depending upon the specific cell type. Recently, a number of new interesting compounds (subtype selective analogs and antagonists, as well as bi-specific and hybrid somatostatin/dopamine compounds) have been developed. The effects of these new molecules have been explored in few animal and human cell lines and primary cultures from human tumors, revealing a heterogeneous, but broader, profile of activities. Further studies are certainly needed to fully elucidate the complex interplay between the GPCRs and consequent biological effects, to identify suitable therapies for controlling hormonal secretion of pituitary tumors. However, these recent observations form the basis for the application of new interesting strategies for the treatment of not only pituitary tumors but also other human malignancies.

Free access

Alberto Tagliafico, Eugenia Resmini, Raffaella Nizzo, Lorenzo E Derchi, Francesco Minuto, Massimo Giusti, Carlo Martinoli, and Diego Ferone


Acromegalic patients may complain of sensory disturbances in their hands. Cubital tunnel syndrome, the ulnar nerve neuropathy at the cubital tunnel (UCT), in acromegalic patients has never been reported.


To describe and assess the prevalence of UCT in acromegalic patients and the effects of 1 year of therapy on UCT.


We examined prospectively 37 acromegalic patients with no history of polyneuropathy, acute trauma at the elbow, no diabetes or hypothyroidism with clinical examination, nerve conduction studies (NCS), and high-resolution ultrasound (US). A control group was made by 50 volunteers. The local ethics committee approved the study and written informed consent was obtained from all subjects involved in the study.


Clinical history, physical examination, NCS, and US were used to diagnose UCT at the beginning of the study and after 1 year.


In 8 of 37 patients, a diagnosis of UCT was made at the beginning of the study reflecting a prevalence of 21%. After 1 year, 5 of 8 (62.5%) patients reported clinical and NCS improvements and evident US reduction of nerve cross-sectional area (CSA; 16.7±2.9 mm2 vs 12.2±3.1 mm2; P<0.001). In 3 of 8 (37.5%) patients, the UCT was unchanged. Ulnar nerve CSA was significantly increased in acromegalic patients with UCT (16.7±2.9 mm2 vs 11.1±2.3 mm2; P<0.047).


Ulnar neuropathy could occur in acromegalic patients and can improve in 62% of cases with disease control. Due to the different management and therapeutic approach, it would be important to make differential diagnosis between cubital and carpal tunnel syndrome in acromegaly.

Open access

Rosario Pivonello, Diego Ferone, Gaetano Lombardi, Annamaria Colao, Steven W J Lamberts, and Leo J Hofland

The dopaminergic system has a pivotal role in the central nervous system but also plays important roles in the periphery, mainly in the endocrine system. Dopamine exerts its functions via five different receptors, named D1–D5, belonging to the category of G protein coupled membrane receptors. Dopamine receptors are heterogeneously expressed in different cells, tissues and organs, where they stimulate or inhibit different functions, including neurotransmission and hormone synthesis and secretion. In particular, the dopamineric system has a pivotal role in the physiological regulation of the hypothalamus–pituitary–adrenal axis. Recent data have demonstrated the expression and function of dopamine receptors not only in endocrine organs but also in endocrine tumors, mainly those belonging to the hypothalamus–pituitary–adrenal axis, and also in the so-called ‘neuroendocrine’ tumors. These data confirm the important role of the dopaminergic system in this endocrine axis, as well as in the neuroendocrine system. This review summarizes the main structural and functional characteristics of dopamine receptors, emphasizing the most recent novelties, and focused on the physiological and pathological regulation of the hypothalamus–pituitary–adrenal axis by the dopaminergic system. In addition, the recent findings on the relationship between dopamine receptors and neuroendocrine tumors are summarized.

Open access

Diego Ferone, Rosario Pivonello, Eugenia Resmini, Mara Boschetti, Alberto Rebora, Manuela Albertelli, Valeria Albanese, Annamaria Colao, Michael D Culler, and Francesco Minuto

Pituitary tumors can cause symptoms of mass effect and hormonal hypersecretion that can be reversed with surgical resection or debulking of the adenoma, radiotherapy, or medical treatment. Medical treatment is the primary choice for prolactinomas because dopamine agonists are very effective in the treatment of these tumors, with rates of control (tumor size reduction and hormone suppression) as high as 80–90% for microprolactinomas and 60–75% for macroprolactinomas. The function of dopamine receptors in other histotypes of pituitary adenoma is still debated. However, new insights into receptor physiology and the introduction of new clinically available, as well as experimental, compounds have reopened a potential role of dopaminergic drugs in the medical treatment of pituitary tumors. The differences between the effectiveness and the resistance to different dopaminergic agents, the new challenging results from clinical and experimental studies, as well as the future of dopamine agonists in the therapy of pituitary tumors are discussed.