Microprolactinomas: why requiem for surgery?
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Dopamine Agents↗
Biomedical subjects
A Liuzzi
Publications and source records attributed to A Liuzzi.
Nonfunctioning adenomas of the pituitary.
The term "nonfunctioning" pituitary adenomas (NFPA) implies heterogeneity, since it relies on a clinical definition that is mainly related to tumor mass. The first complaint is often of impaired visual function, and despite the secretion of gonadotropins, hypogonadism is frequent. NFPA must be differentiated from prolactinomas, because of the therapeutic implications, but although prolactin (PRL) levels greater than 200 ng/mL indicate prolactinoma, PRL levels of 100 to 150 ng/mL are equivocal. An assessment of gonadotropin response to gonadotropin-releasing hormone (GnRH) is of no use, but the thyrotropin-releasing hormone (TRH) test is invaluable. NFPA are monoclonal in origin, but genetic mutations data have not clarified their etiology, which remains largely unknown. Proliferating cell nuclear antigen expression is increased in recurrent adenomas, as is abnormality and overexpression of the protein kinase C family in aggressive tumors. Mutations of tumor-suppressor genes, such as the p53 and Rb genes, and of the metastasizing suppressor gene nm23, have been found in invasive tumors. Immunohistochemistry data confirm that most NFPA originate from gonadotroph cells; many NFPA are negative for all anterior pituitary hormones tested, although isolated or clustered cells are often positive for glycoprotein hormones or their subunits. Silent gonadotroph and also silent growth hormone (GH) or corticotroph tumors can constitute the anatomical basis for clinical NFPA. The heterogeneity of the immunohistochemistry data is reflected in the receptor complex of these tumors. Dopaminergic receptors have recently been visualized in vivo and there are also receptors for TRH or GnRH, since levels of alpha or beta subunits and intact gonadotropins increase after TRH or GnRH stimulation. As a result, three second-line pharmacological approaches have been tried: dopamine agonists, octreotide, and GnRH superagonists or antagonists, with tumor shrinkage of up to 11% to 20%. However, surgery should be tried first.
Adenoma↗
Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?
OBJECTIVE: A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with 'burned-out' disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse. DESIGN: Longitudinal prospective study of previously untreated patients with GD. PATIENTS: Thirty-nine consecutive patients aged 10-72 years were treated with methimazole (MMI) for 12-24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal. MEASUREMENTS: Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal. RESULTS: Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1 +/- 1.1 vs 2 +/- 0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month. CONCLUSIONS: Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.
Adolescent↗
Percutaneous ethanol injection of large thyroid cystic nodules.
To evaluate the effect of percutaneous ethanol injection (PEI) in the treatment of large compressive thyroid cystic nodules (TCN), we studied 20 patients, potential candidates for surgery (tracheal displacement, nodule volume over 10 mL at ultrasonography) and not cured by aspiration alone: 14 experienced a recurrence after two complete evacuations of cystic fluid (watery nodules, WN); in six an aspiration was impossible because the cystic fluid was very thick (viscous nodules, VN). To exclude malignancy, both cytocentrifugate from WN and the smears from VN were examined. WN were treated with 1-4 sessions of conventional PEI; in VN a first PEI session was performed with the purpose of reducing the density of cystic fluid; then if cystic fluid was successfully aspirated, one or more PEI sessions were performed. Thyroid palpation, ultrasonography with nodule volume assessment, and assays for FT3, FT4, and TSH were performed 1 and 6 months after the last PEI. At month 6, 17 patients (85%) had volume reduction of more than 90% of the initial nodule volume; in 2 patients (10%) there was a reduction between 50 and 90%, and in one patient (5%) an appreciable swelling persisted after 3 injections. Nodule volume was significantly decreased below baseline at month 1 (10.9 +/- 13.3 vs 39 +/- 24 mL, p < 0.001), with a further reduction at month 6 (5 +/- 11.7 mL, p < 0.01 vs 1st month value). In most of the nodules the cystic portion completely disappeared; the residual tissue showed fibrous features, often with calcifications. In 11 patients follow-up was prolonged over the sixth month (15 +/- 4 months); the nodule volume did not significantly differ from the sixth month (3 +/- 2.2 mL) and the end of the follow-up (2.8 +/- 2.3 mL). In conclusion, we demonstrate that PEI may be a safe and effective procedure in the treatment of large TCN.
Adult↗
Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study versus placebo.
In a randomized double-blind study, 20 parkinsonian patients (suffering from the disease for 2-18 years), chronically treated with levodopa (500-750 mg/day for 0.5-12 years), received terguride (1 mg b.i.d.) or placebo for 4 weeks. Growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-I) secretions were studied before and after the morning dose of levodopa (250 mg p.o.), both before and at the end of study period. At the beginning of the study, basal hormonal levels were within normal limits, and levodopa administration induced a significant suppression in PRL and TSH levels (both p < 0.01)) and a significant increase in GH (p < 0.01). The same results were observed at the end of the study period in the placebo group. Addition of terguride induced a significant suppression in basal PRL levels (p < 0.01), whereas levodopa-induced hormonal changes were unaffected. These data suggest that the hypothalamic dopaminergic function that controls anterior pituitary hormones is preserved in parkinsonian patients, regardless of both the duration of the disease and the long-term treatment with levodopa. The strong additional prolactin-lowering effect of terguride indicates long-lasting dopaminergic effects, as is already known from hyperprolactinemic conditions. The dopaminergic effects of levodopa on TSH, GH, and IGF-I secretion were unchanged by terguride treatment. The anti-dopaminergic effects of terguride observed in the motor system in animal studies, as well as in levodopa-induced dyskinesias in parkinsonian patients, could not be observed in the case of the dopaminergic control of anterior pituitary hormones under the conditions of this study.
Aged↗
Thyroperoxidase microsatellite polymorphism in thyroid diseases.
Autoimmune thyroid diseases (AITD) cluster in families, although the nature of this phenomenon is still poorly understood. One possible approach to the identification of genetic factors contributing to the pathogenesis of AITD is the study of association between polymorphic markers and AITD themselves. In the present study we have analyzed the allelic distribution of sRA-1, a TPO tetranucleotide repeat, among patients with AITD, in comparison with patients with nonautoimmune thyroid diseases and the general population. The polymorphic marker was analyzed by PCR followed by electrophoresis on polyacrylamide denaturant gel. Our data show that no association exists between AITD and any of sRA-1 alleles, despite the important role that TPO plays as a thyroid autoantigen.
Adult↗
TSH receptor antibodies and ultrasonography in Graves' disease.
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Autoantibodies↗
In vivo visualization of pituitary dopaminergic receptors by iodine-123 methoxybenzamide (IBZM) correlates with sensitivity to dopamine agonists in two patients with macroprolactinomas.
We performed in two patients with macroprolactinoma, pituitary scintigraphy with 123 iodine-methoxybenzamide (IBZM), a dopaminergic antagonist that specifically binds to the D2 dopaminergic receptors. In a 34-yr-old woman with basal PRL levels of about 2000 ng/mL, 7.5 mg/day of Bromocriptine (Br) for a month neither reduced PRL levels nor affected tumor size; in this patient single photon emission tomography SPECT failed to show any pituitary accumulation of the tracer. In the other patient, a 27-yr-old man presenting with cerebrospinal fluid rhinorrhea, basal PRL levels were at 5000 ng/mL; magnetic resonance imaging (MRI) demonstrated a huge pituitary tumor, and SPECT showed a very intense concentration of IBZM at the level of the adenoma. PRL levels fell dramatically to 530 ng/mL with only 2.5 mg/day of Br after 4 days; after 6 days with 7.5 mg/day Br, PRL levels were 63 ng/mL, and the patient underwent surgery to correct cerebrospinal fluid leakage. We conclude that, in these two patients, the pituitary scintigraphy with IBZM has given information on the density of dopamine receptors on the adenoma and has correlated with the inhibitory effect of Br on PRL secretion. Whether this tool might be of value in identifying patients with pituitary tumors potentially responsive to Br treatment is still to be investigated.
Adult↗
Persistence of somatostatinergic tone in acromegaly.
It is a matter of debate whether hypothalamic somatostatin (SRIH) secretion in acromegaly is preserved and still regulated by the physiological feedback mechanisms of growth hormone (GH) and insulin-like growth factor I. To gather further information on this, the reproducibility of plasma GH changes induced by growth hormone-releasing hormone (GHRH) administration was evaluated in 15 acromegalic patients. There was a highly significant correlation between the peak/basal ratio (P/B) GH response in the 15 patients administered GHRH on two separate occasions (r = 0.99, p < 0.001). The test was performed also before and after the administration of drugs able to inhibit or stimulate hypothalamic SRIH release, by activating (pyridostigmine) or inhibiting (pirenzepine) cholinergic pathways, respectively. The GHRH-induced GH response (P/B = 2, range 1.1-26.1) was increased significantly by pyridostigmine pretreatment in 30 patients (P/B = 2.6, range 1.3-34.8; p = 0.0045). In nine out of 30 patients an increase of greater than 2 SD of within-subject GHRH variability was observed in response to GHRH plus pyridostigmine when compared to GHRH alone. An inverse correlation (r = -0.37, p < 0.05) was observed between GH response to GHRH alone and after pyridostigmine pretreatment. On the contrary, no change of GHRH-induced GH response was observed in 12 patients after pirenzepine pretreatment (P/B = 1.9, range 1.1-5 and P/B = 2, range 1.3-6 without and after pirenzepine pretreatment, respectively). These data suggest that in acromegaly the somatostatinergic tone does not seem to fluctuate, and that it can be inhibited often by cholinergic pathway activation but not increased further by cholinergic suppression.
Acromegaly↗
A thyroid hormone receptor beta gene polymorphism associated with Graves' disease.
Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EA beta H) intragenic to c-erbA beta, which codes for the thyroid hormone beta receptor, and Graves' disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n = 120) from the same area was also analysed. The distribution of EA beta H alleles was significantly different (P < 0.001) in Graves' disease (n = 94) but not in autoimmune thyroiditis (n = 60), as compared with controls. Also the distribution of the EA beta H genotypes was significantly different in Graves' patients (P = 0.003), as compared with controls, the homozygous state EA beta H+/EA beta H+ being more frequent in Graves' patients than in all the other groups. We did not find any association between EA beta H genotypes and clinical parameters in Graves' patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves' disease is a genetically distinct group within the AITDs.
Adult↗
Effect of octreotide on neuroenolase levels in patients with small cell lung cancer.
AIMS AND BACKGROUND: The somatostatin analog octreotide has an antiproliferative effect on small cell lung cancer lines in vitro and in experimental xenograft transplantation systems in vivo. Thus it is worth investigating octreotide activity in the clinical setting. METHODS: We studied the effect of octreotide (200 micrograms three times a day subcutaneously for seven days) on serum levels of the tumor marker neuroenolase in 13 patients with small cell lung cancer. RESULTS: A decrease in neuroenolase levels was observed at day 7 during octreotide treatment, with a mean +/- SD of 32.6 +/- 42.0 ng/ml compared to basal values of 44.4 +/- 57.7 ng/ml and to washout values of 50.3 +/- 65.7 ng/ml (P < 0.03). CONCLUSIONS: Our results indicate that octreotide is effective in reducing neuroenolase levels in small cell lung cancer patients. These data suggest a possible role for octreotide in the treatment of this kind of tumor.
Adult↗
CV 205-502 in acromegaly.
In a series of acromegalic patients the effects of CV 205-502, a new long-acting dopamine-agonist drug, on growth hormone (GH), insulin-like growth factor I (IGF-I) and prolactin (PRL) levels were evaluated in an open study. After acute administration of CV 205-502 (0.0375 mg, po) in 12 patients. GH levels did not change, whereas PRL values significantly decreased and remained suppressed for 24 h. In the 14 patients who underwent chronic CV 205-502 treatment (at daily doses of 0.150-0.600 mg/day given at bedtime or b.i.d. for up to 12 months). GH and IGF-I levels fell significantly from 60 +/- 17 (mean +/- SEM) micrograms/l to 28 +/- 10 micrograms/l and from 1127 +/- 84 micrograms/l to 738 +/- 57 micrograms/l, respectively (p < 0.05). A retrospective comparison with the results obtained for the same patients during a previous chronic bromocriptine treatment (at daily doses of 5-20 mg given t.i.d. or q.i.d.) did not show any significant difference in the suppression of GH levels between the two treatments; no bromocriptine-resistant patient was CV 205-502 sensitive, even at the highest CV 205-502 dose used. We conclude that in acromegaly chronic treatment with this new dopaminergic drug has a GH- and PRL-lowering effect that is similar to but more prolonged than that of bromocriptine, and normal or near-normal GH and IGF-I levels may be obtained in a few patients with b.i.d. administration. However, no GH-lowering effect is observed in bromocriptine-resistant patients.
Acromegaly↗
Proceedings of the workshop, "Practical approaches to the diagnosis and treatment of acromegaly".
Practical approaches to the management of acromegaly are discussed. The roles of surgery, radiotherapy, and medical treatment with oral dopamine agonists such as bromocriptine or the long-acting somatostatin analogue octreotide given subcutaneously are reviewed. Most cases need surgery, but cure is rare in patients with macroadenomas, although common with microadenomas. Radiotherapy should be considered in surgical failures, but takes several years to be effective. Medical treatment with octreotide is effective in the majority, for whom it represents a major advance, but it needs to be administered subcutaneously and the development of gallstones and gastritis in long-term treatment are problems. Bromocriptine is usually less effective, but occasionally still plays a role in the therapeutic program. Combinations of the different modalities are usually required in the management of acromegalic patients.
Acromegaly↗
The brain as a target for adrenocortical steroids: cognitive implications.
It is well established that a reciprocal control exists between the brain and glucocorticoid hormones. The brain regulates adrenocortical function via hypothalamic corticotrophin releasing hormone-41 (CRH-41), glucocorticoids act at specific receptors in the hippocampus, thus promoting negative feedback mechanisms. Because the hippocampus is a major site for memory processes, a role for excessive/long-lasting plasma glucocorticoid levels has been suggested in conditions of mental impairment. Major depression, Cushing's disease, and dementia of the Alzheimer type are disorders which share hyperactivity of the hypothalamo-pituitary-adrenal axis, as well as symptoms of cognitive decline. Although the mechanisms leading to hypercortisolemia appear to be different in each case, the neuropsychological features of these three disorders accord with the hypothesis of glucocorticoid-associated brain damage. It therefore is important to find pharmacological strategies that will avert or reduce these potential consequences on brain function.
Adrenocorticotropic Hormone↗
Doxorubicin for acromegaly: a case report.
We report the case of an acromegalic woman, aged 35 years, with a huge GH-secreting tumor, repeatedly treated with neurosurgery and radiotherapy, not responsive to bromocriptine (Br) and octreotide (SMS), whose clinical picture evolved to coma due to endocranic hypertension. Since remnant size was too large to be further treated by surgery, chemotherapy with doxorubicin (DOX) (100 mg i.v. every three weeks up to 0.5 mg/m2 over 7 months) was started. Treatment was followed by a rapid improvement of clinical picture with resumption out of coma, progressive decline of GH levels (from 800 ng/ml to 15 ng/ml) and a slight shrinkage of tumor. No side effects were observed during DOX administration. We suggest that in those few acromegalic patients resistant both to SMS and Br, and with poor prognosis, DOX may be effectively used.
Acromegaly↗
Prolactin response to growth hormone-releasing hormone during chronic thyrotropin-releasing hormone infusion in the treatment of amyotrophic lateral sclerosis.
In six patients suffering from amyotrophic lateral sclerosis we evaluated changes of T4, T3, TSH, PRL, and GH during treatment by continuous iv infusion of TRH for at least 15 days. No clinical improvement was detected. A significant rise of thyroid hormone levels was observed, as well as an upward trend of basal TSH levels and no change of basal PRL and GH levels. TRH acute test-induced TSH and PRL responses became blunted. Treatment provoked also the onset of a responsiveness of PRL to GHRH. The reduced TSH and PRL responses to acute TRH test during treatment could be explained by a down-regulation of TRH pituitary receptors. On the contrary, the onset of PRL responsiveness to GHRH is at present without a satisfactory explanation.
Amyotrophic Lateral Sclerosis↗
Resistance to a long-acting somatostatin analog (SMS 201-995) reversed by surgery in acromegaly.
A 42-year-old woman had acromegaly and a large macroadenoma with supra- and parasellar extension. Her GH levels (median 85 ng/ml, range 63-170 ng/ml) were not responsive to TRH (200 micrograms iv), GHRH (100 micrograms iv) and bromocriptine (Br 2.5 mg po) acute tests; Sm-C level was 8 U/ml. She was treated with octreotide (SMS) (up to 1500 micrograms daily) for 3 months. No changes of clinical, biochemical and radiological findings were seen, therefore she underwent transsphenoidal surgery. After surgery, hypopituitarism and diabetes insipidus appeared: GH levels remained high (median 45 ng/ml; range 37-56 ng/ml), but became responsive to Br acute test. The patient was given SMS again, and this resulted in clinical improvement, marked reduction of GH and Sm-C levels and slight shrinkage of the residual tumor. Speculative hypotheses about this previously unreported phenomenon might be either an excess of both GHRH and somatostatin, caused by a primary increase of dopaminergic tone, or a primary excess only of GHRH; in both cases the surgical lesion of the hypothalamic-pituitary region might have impaired the neurohormones inflow to the residual pituitary and so let SMS and Br exert their inhibitory actions on GH secretion.
Acromegaly↗
Clinical use of the somatostatin analog SMS 201-995 in endocrinology.
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Acromegaly↗