Pituitary tumours express both somatostatin and dopamine receptors. Medical treatment with somatostatin analogues is a cornerstone of GH- and TSH-secreting tumours, while treatment with dopamine agonists is a cornerstone of prolactin-secreting tumours. Dopamine agonists have also demonstrated some efficacy in patients with GH- and TSH-secreting adenomas. Neither ACTH-secreting nor clinically non-functioning tumours have a well-established medical treatment. Nevertheless, some recent results have indicated a potential usefulness of the dopamine agonist cabergoline in patients with pituitary-dependent Cushing’s disease. Combination treatment with both somatostatin analogues and dopamine agonists has been poorly investigated. Some studies conducted in small series have documented an additive effect of both drugs in patients with GH-secreting adenomas. Of mention is that none of the studies were randomised and cross-sectional so that the results should be confirmed by other well-designed studies. No data are available in other pituitary tumour histotypes. Preliminary observations in patients with clinically non-functioning adenomas are very promising.
Annamaria Colao, Mariagiovanna Filippella, Rosario Pivonello, Carolina Di Somma, Antongiulio Faggiano and Gaetano Lombardi
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
Bartolomeo Merola, Annamaria Colao, Emanuela Rossi, Giuseppe La Tessa, Renato Spaziante and Gaetano Lombardi
The aim of this retrospective study was to evaluate the existence of a multihormonal gradient between the inferior petrosal sinuses in various pituitary diseases: Cushing's disease (8 cases), acromegaly (4 cases), prolactinomas (7 cases), GH, PRL-secreting adenoma (1 case), functionless adenoma (2 cases), empty sella (3 cases) and in non-tumoral hyperprolactinemia (5 cases). A significant intersinus gradient (more than 1.4:1) was recorded for GH, ACTH and PRL in 16 patients (80%), but in only 9 patients (45%) out of the 20 with hormone-secreting tumors for TSH, FSH and LH. Moreover, of the 10 patients in the remaining groups, only in two cases was a significant intersinus gradient present: one for GH and one for LH. In conclusion, the finding of a multihormonal release in the inferior petrosal sinus ipsilateral to the adenoma is reported, for the first time, in patients with GH- and PRL-secreting adenomas. The possible explanation for such a finding may be either an increased blood flow in this site of sampling or a pituitary multihormone release through a paracrine mechanism primed by the tumoral hypersecreted hormone. In addition, the pulsatile secretory pattern and the short half-life of polypeptide hormones may contribute to better demonstrate this phenomenon in respect to glycoprotein hormones.
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.
Annamaria Colao, Rosario Pivonello, Renata S Auriemma, Mariano Galdiero, Silvia Savastano and Gaetano Lombardi
To evaluate the efficacy of dose escalation of Octreotide-long-acting repeatable (LAR) up to 40 mg/month we studied 56 newly diagnosed patients with acromegaly (24 women, 32 men; age 20–82 years).
Analytical, observational, open and prospective.
Three months after LAR treatment beginning with a dose of 20 mg /q28d (every 28 days), 24 patients maintained the same dose (Group A), while 32 required a dose of 30 mg/q28d (Group B). The dose was further increased to 40 mg/q28d in 17 out of the 32 patients of Group B for another 12 months (Group C).
After 24 months, serum GH and IGF-I levels decreased by 93.1±8.6% (95% confidence limit (CL) 90.8–95.4%) and 62.7±13.4% (95% CL 59.1–66.3%) respectively. Control of GH and IGF-I levels was achieved in 45 patients (80.3%). Tumor shrinkage after 12 months was 49.8±23%; the relative tumor shrinkage during the second 12 months of treatment was 35.3±13.1% and overall tumor volume was 68.1±16.5% (95% CL 63.7–72.5%). Glucose tolerance impaired in eight patients (14.3%): four in Group A and four in Group C (16.7% vs 36.4%, P=0.39).
The final dose was predicted by the patient's age at diagnosis (t=−2.2; P=0.032) and baseline tumor volume (t=2.1; P=0.043).
An increase of the LAR dose up to 40 mg/q28d in patients resistant to 30 mg/q28d is followed by greater suppression of GH and IGF-I levels and tumor shrinkage without further significant impairment of glucose tolerance when compared with lower doses. These results suggest that a new dosage schedule of 40 mg every 28 days is applied in patients with acromegaly mostly of young age and with bigger tumors who are likely to be poorly responsive to standard doses of Octreotide-LAR.
Renata S Auriemma, Mariano Galdiero, Ludovica F S Grasso, Pasquale Vitale, Alessia Cozzolino, Gaetano Lombardi, Annamaria Colao and Rosario Pivonello
Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months.
A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence.
This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal.
Aart-Jan van der Lely, Ignacio Bernabeu, Jan Cap, Philippe Caron, Annamaria Colao, Josef Marek, Sebastian Neggers and Pascal Birman
To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40–120 mg/week) in acromegaly.
This is a 28-week, multicenter, open-label, single-arm sequential study.
Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40–80 mg once weekly or 40 or 60 mg twice weekly).
In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (−0.6±1.6) and soft tissue swelling (−0.6±1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related – thrombocytopenia, urticaria; not treatment related – abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5×upper limit of normal with normalization after withdrawal).
In patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.
Bartolomeo Merola, Salvatore Longobardi, Matteo Sofia, Rosario Pivonello, Assunta Micco, Francesca Di Rella, Vincenzo Esposito, Annamaria Colao and Gaetano Lombardi
Merola B, Longobardi S, Sofia M, Pivonello R, Micco A, Di Rella F, Esposito V, Colao A, Lombardi G. Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency. Effect of 12 months' growth hormone replacement therapy. Eur J Endocrinol 1996;135:553–8. ISSN 0804–4643
We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study. For each subject, evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, record of flow–volume curves, measurement of static lung volumes and lung diffusing capacity. Childhood-onset GH-deficient patients had a significant reduction of maximal inspiratory (p < 0.01) and maximal expiratory (p < 0.05) mouth pressures. Total lung capacity, vital capacity and functional residual capacity were significantly reduced compared to healthy subjects (p < 0.05). Conversely, residual volume and diffusing lung capacity did not show any significant change. No significant change of the ratio between the percentage forced expiratory volume in 1 s and the forced vital capacity was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. Adult-onset GH-deficient patients had only a significant reduction of maximal expiratory pressure compared to healthy subjects (p < 0.05). After 6 months of treatment no significant differences in any of the evaluated parameters were found. After 12 months of treatment patients with childhood-onset GH deficiency show a significant improvement of lung volumes (p < 0.01) and maximal respiratory mouth pressures (p < 0.005), whereas adult-onset GH-deficient patients show a significant improvement of maximal expiratory pressure (p < 0.05). In conclusion, the results of this study showed that adult patients affected with childhood-onset GH deficiency suffer from an impairment of the ventilatory function due to a reduction of lung volumes and a decrease of respiratory pressures probably due to a reduction of respiratory muscle strength. This impairment was reversed after 12 months of treatment with recombinant GH. Conversely, adult-onset GH-deficient patients had only an impairment of the maximal expiratory pressure, probably due to respiratory muscle weakness re-established after 12 months of GH therapy.
Gaetano Lombardi, Via G. Santacroce 40/a, 80129 Naples, Italy
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
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