Biomedical subjects
Publications and source records attributed to F Massara.
Primary pigmented micronodular disease is a peculiar form of ACTH-independent Cushing's syndrome characterized by the familial occurrence, the frequent association with malformations and the pathological adrenocortical picture consisting in micronodules with cellular deposition of lipofuscinic pigment. We describe here a case occurring in a 14-year-old girl.
In the treatment of hyperprolactinemia bromocriptine is generally administered in 3 daily doses during the day. Due to the limited compliance of patients under this long term regimen, in 16 hyperprolactinemic patients we investigated the efficacy and tolerability of the treatment with this dopaminergic drug administered as a single evening dose. This dose was the same which the patients had been assuming previously on a tid basis. Chronic treatment (4-12 months) with an oral single evening dose of bromocriptine is able to control plasma PRL at least as well as the traditional tid regimen (2.8-21.6 ng/ml vs 1.2-31.8 ng/ml). Furthermore, during this single dose regimen the side effects were of lesser intensity and extent. Since the compliance of the patients with the single dose regimen was very good and the efficacy the same in reducing plasma PRL and controlling the clinical manifestations with a lower rate of side effects, we suggest to extend this regimen to all patients with hyperprolactinemia treated with bromocriptine after successful reduction of plasma PRL levels is obtained.
Recently, a new long-acting form of bromocriptine (Parlodel LA, Sandoz) has been developed and it has already been found to be effective in lowering plasma PRL levels in normal volunteers and postpartum women. This work reports the clinical, hormonal and radiological effects of a single 50 mg dose of long-acting bromocriptine in 10 patients with tumorous hyperprolactinemia (2 microprolactinomas, 6 macroprolactinomas, 1 acromegaly and 1 nonsecreting macroadenoma). A rapid and long-lasting (28 days) normalization of PRL levels was observed in patients with microprolactinoma, acromegaly and nonsecreting adenoma. None of the 6 patients with macroprolactinoma underwent normalization of plasma PRL, but the latter was markedly reduced (61-80% of basal levels). A second injection of the drug in 5 macroprolactinoma patients induced a further reduction of plasma PRL levels in 2 of them. No changes in the tumor size were observed either after the first or the second injection of long-acting bromocriptine in any of the patients. This injectable form of bromocriptine induced nausea and/or mild hypotension lasting a few h in 4 of the 10 patients and was better tolerated than the oral form as regards both the duration and intensity of the side effects. Thus, as this drug has proved to be efficacious and well tolerated by the patients, this long-acting form of bromocriptine may be a valid therapeutical approach for initiating medical treatment of patients with prolactinoma.
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There is evidence indicating that the cholinergic system positively modulates GH release probably by inhibiting somatostatinergic tone. In the present study, the effects of cholinergic enhancement by pyridostigmine, (PD), a cholinesterases inhibitor, on GH release in normal adults (n = 14) (NA) and in both normal (n = 5) (NC) and short children (n = 19) (SC) with familial short stature (n = 7) or constitutional growth delay (n = 12) were studied. In SC the insulin hypoglycaemia (IH)-induced GH increase was also studied. In both NC and SC 60 mg orally PD induced a significant GH increase with mean peak at 90 min (mean +/- SEM 11.0 +/- 2.2 ng/ml in NC and 11.2 +/- 2.3 ng/ml in SC). The GH areas under response curve (AUC) were 379.3 +/- 76.6 and 327.8 +/- 43.2 ng/ml/h in NC and SC respectively. In NA 120 mg orally PD induced a significant GH increase with mean peak at 120 min (5.1 +/- 1.1 ng/ml) which was significantly lower (P less than 0.05) than that observed in both NC and SC. This statistical difference was strengthened by evaluating AUC (NA:205.6 +/- 33.7 ng/ml/h, P less than 0.05 vs NC and SC). The correlation of drug dosage with body area ruled out that this difference could be related to the different PD dose in adults and children. In SC, IH induced a GH increase significantly lower than that observed after PD (GH peak 7.8 +/- 0.6 vs 16.4 +/- 1.9 ng/ml P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Increased cholinergic tone induced by pyridostigmine (PD) increases basal plasma GH levels and potentiates the GH response to GHRH in normal adults. In this study the effects of PD (60 mg, orally) on both basal and GHRH (1 microgram/kg)-induced GH secretion in seven children with familial short stature (FSS), six with GH deficiency (GHD) and 10 with constitutional growth delay (CGD) were studied and compared with results obtained by stimulation with insulin-induced hypoglycemia (IH) and GHRH alone. The mean peak plasma GH levels were variable, but individual values were frequently low in all groups after both IH [FSS, 9.7 +/- 1.3 (+/- SEM) ng/mL; GHD, 1.6 +/- 0.4 ng/mL; CGD, 7.0 +/- 0.8 ng/mL] and GHRH (FSS, 23.8 +/- 6.6 ng/mL; GHD, 11.1 +/- 5.8 ng/mL; CGD, 15.1 +/- 4.5 ng/mL) administration. PD induced GH responses (FSS, 14.5 +/- 1.6 ng/mL; GHD, 3.8 +/- 0.8 ng/mL; CGD, 18.3 +/- 3.2 ng/mL) that in many children in the FSS and CGD groups were higher than those after IH and GHRH treatment. PD clearly increased the GH response to GHRH in all children [FSS, 69.5 +/- 9.4 ng/mL (P less than 0.01 vs. other stimuli); GHD, 18.0 +/- 7.5 ng/mL; CGD, 50.0 +/- 8.5 ng/mL (P less than 0.01 vs. other stimuli)]. We conclude that in children with short stature, as in adults, enhancement of cholinergic tone increases both basal and GHRH-induced GH secretion, and that PD plus GHRH is the best provocative stimulus for evaluating the somatotroph response.
To throw light onto the mechanism(s) by which the cholinergic system influences growth hormone (GH) release, the effects of two muscarinic receptor blockers, pirenzepine and atropine, and of an acetylcholinesterase inhibitor, pyridostigmine bromide, on the GH response to GHRH-44 were studied in 19 normal volunteers. Moreover, the effects of pirenzepine administration on plasma GH levels both in basal conditions and after stimulation by GHRH-44 and TRH were studied in 9 acromegalics. Both pirenzepine (0.6 mg/kg i.v., 5 min before GHRH) and atropine (1 mg i.m., 15 min before GHRH) blunted the GH response to GHRH (1 microgram/kg i.v. bolus) (area under the response curve, AUC: 81.3 +/- 17.3 vs. 481.2 +/- 211.3 ng/ml/h for pirenzepine and 100.2 +/- 27.0 vs. 364.7 +/- 81.0 ng/ml/h for atropine; p less than 0.01). Pyridostigmine (120 mg orally, 30 min before GHRH) induced a variable but significant (p less than 0.02) rise in basal plasma GH levels and, furthermore, an unequivocal potentiation of the GH response to GHRH (AUC: 1044.6 +/- 245.3 vs. 481.2 +/- 211.3 ng/ml/h; p less than 0.01). In all but one acromegalics 0.6 mg/kg i.v. pirenzepine was unable to modify the basal GH levels whilst it showed a variable inhibitory effect on the GH response to GHRH. The GH response to TRH (200 micrograms i.v. bolus) was instead unmodified by pirenzepine. In conclusion, muscarinic receptor blockade inhibits while cholinergic potentiation seems to positively modulate the GH response to GHRH. Therefore, the cholinergic system seems to positively modulate the GHRH effect on somatotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)
To verify the diagnostic capacity of some dynamic tests of the prolactin (Prl) secretion, the findings obtained by high-resolution computed tomography (CT) were compared with results obtained from tests using nomifensine (NOM) domperidone (DOM) and thyrotrophin-releasing hormone (TRH) in 72 patients with pathological hyperprolactinaemia. None of the patients with tumours had a positive Prl response to NOM or to DOM administration; however, a positive response to these tests was present in only 24 and 41%, respectively, of the patients with normal CT picture. The results of TRH testing were similar to those obtained with DOM. Different neuroendocrine patterns were disclosed by comparing pituitary Prl and thyrotrophin (TSH) responses to DOM: 1) some subjects had a reduced Prl response together with an exaggerated or normal TSH response to DOM; they comprised patients with tumour, empty sella, and normal CT picture; 2) other patients with normal CT picture had a positive Prl and a normal TSH response to DOM. These results demonstrate that a negative Prl response to NOM and DOM characterizes all patients with adenoma; however, the tumour-like responses in patients with no visible tumours seem to reduce the diagnostic value of these tests, unless the latter may predate the radiological appearance of an adenoma. On the other hand, a positive Prl and a normal TSH response to DOM exclude the presence of a pituitary tumour. This diagnostic finding is strengthened by the positive response also to NOM. Whatever may be the diagnostic validity of dynamic tests, they provide sound information on the functional state of dopamine neurotransmission.
It is known that in normal subjects repeated administration of the growth hormone-releasing factor (GRF) induces a state of partial refractoriness of the somatotropes to GRF. Studies were conducted to verify whether the cholinergic system plays a role in the mechanism(s) underlying the reduced GH responsiveness to the neuropeptide. In five healthy men, the GH response to three consecutive injections of GRF (50 micrograms iv), administered at 2 h intervals, was considerably blunted after the second and third GRF bolus. Administration of the inhibitor of cholinesterase, pyridostigmine bromide (120 mg orally) 30 min before the second GRF bolus, not only restored but greatly potentiated the GH responsiveness to the second GRF bolus. The GH response to the third GRF bolus was not apparently influenced by pre-treatment with pyridostigmine. These data reinforce the view that cholinergic neurotransmission plays an important role in the control of GH secretion in human.
In order to evaluate whether glucagon-induced hyperkalemia is due to mobilization of potassium from the splanchnic region, we measured potassium changes in the hepatic veins following a glucagon injection into the ascending aorta. Twenty-seven subjects undergoing routine cardiac catheterization for diagnostic purposes were studied. Hepatic venous and aortic blood samples were withdrawn simultaneously under basal condition and 30, 60, 120, 180, 300, 600 s after a bolus injection of either saline, glucagon (100 ng/kg body weight) or glucagon +somatostatin (100 micrograms). After the intra-aortic injection, plasma glucagon in the hepatic veins reached levels comparable to those observed under pathophysiological conditions. Plasma potassium increased promptly with a peak at 60 s (delta max: 0.79 +/- 0.12 mmol/l, mean +/- SEM; p less than 0.01). The glucose increment peaked at 300 s (delta max: 2.36 +/- 0.20 mmol/l, mean +/- SEM; p less than 0.01). Potassium increment was potentiated by the addition of somatostatin, despite the abolition of insulin and C-peptide rises (potassium delta max: 0.56 +/- 0.10 mmol/l; p less than 0.05). In conclusion, these data demonstrate that glucagon induces a transient mobilization of potassium from the splanchnic region in man. This effect of glucagon on potassium is not antagonized by glucagon-induced insulin secretion.
A study was performed on eight subjects with Klinefelter's syndrome to assess the relation between gonadal hormones and opioid inhibition of gonadotropin secretion through comparison of their gonadotropin response to naloxone (NAL) (0.3 mg/kg; 1/3 bolus iv. at time 0 and 2/3 iv. for 120 min) before and after testosterone propionate (TP) 100 mg/day im. for 5 days. Under basal conditions, NAL failed to induce a significant change in LH levels. After TP, however, despite unchanged basal LH levels (mean +/- S.E.M.: 27.0 +/- 3.4 vs 21.2 +/- 3.21 microU/ml), LH significantly increased in response to NAL. FSH did not respond to NAL either before or after TP administration, though FSH levels were significantly reduced by TP. These findings suggest that in man, as in animals, gonadal hormones regulate opioid inhibition of LH secretion. The negative feedback of testosterone and its ability to activate opioid inhibiting tone may be dissociated, in keeping with the view that gonadal hormones control gonadotropin secretion through the activation of distinct, albeit concomitant, mechanisms.
A study of the effect of alpha-methyl-1-tryosine (metyrosine) blockade (2 g/d for 2 d) of dopamine (DA) synthesis on the PRL and TSH response to domperidone (DOM) and TRH in normal women and subjects with pathological hyperprolactinaemia is reported. In the normal subjects, there was a marked increase in basal PRL (51.7 +/- 11.1 vs 5.7 +/- 1.0 ng/ml) and the PRL and TSH responses to DOM were abolished. The PRL response to TRH was also reduced. In the hyperprolactinaemic subjects, metyrosine had no effect on basal PRL nor on the virtually non-existent PRL response to DOM, whereas it abolished the exaggerated TSH response. The conclusion is drawn that the response of both PRL and TSH to DA receptor blockers is really dependent upon DA inhibitory tone. A fall in this tone can also be postulated as responsible for the hyporesponsiveness of PRL to DOM frequently observed in pathological hyperprolactinaemia. In addition, the fact that metyrosine also abolished the exaggerated TSH response to DOM shows that the latter is totally dependent on enhanced DA inhibition of the thyrotrophs. Lastly, the reduced PRL response to TRH after metyrosine indicates that DA partly determines the ability of the lactotrophs to respond to TRH.
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The way in which the dopaminergic system controls GH secretion in infancy and adolescence was investigated by studying the effects on GH of a specific dopaminergic agonist apomorphine, and two antagonists, metoclopramide (MC), which can and domperidone (DOM), which cannot cross the blood-brain-barrier, (BBB), in 14 males and 6 females aged 8-17 years. Treatment with both antagonists was followed by a marked increase in Prl, whereas only MC stimulated GH secretion, suggesting that this action must occur inside the BBB if it is linked to antidopaminergic properties. GH secretion was also stimulated by apomorphine, which acts at the central level. The paradox posed by the presence of a central effect on GH secretion derived from both an agonist and an antagonist of the dopaminergic receptors is discussed.
To verify if the low estrogen regimen could condition the TSH hyperresponsivity and PRL hyporesponsivity to antidopaminergic drugs seen by us and others in patients bearing prolactinoma, the effect of ethynilestradiol treatment (50 micrograms/day/14 days) on TSH and PRL responses to domperidone in 6 women with tumoral hyperprolactinemia and hypoestrogenemia were studied. Estrogenic treatment was unable to modify the TSH and PRL responsiveness either to domperidone and TRH. These data do not support the hypothesis that hypoestrogenemia could cause the peculiar TSH and PRL pattern in response to antidopaminergic drugs, in patients bearing prolactinoma. Also the TRH releasable pool of TSH and PRL in these patients seems to be unaffected by estrogenic treatment.
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In five healthy young men, pretreatment with the cholinergic muscarinic antagonist pirenzepine (0.6 mg/kg iv) almost completely abolished the rise in plasma growth hormone (GH) elicited by an iv bolus injection of 1 microgram/kg human pancreatic GH-releasing factor 1-40 (hp-GRF-40). These data demonstrate that cholinergic receptor sites involved in GH-releasing mechanisms do not interact with GRF-secreting structures in the central nervous system. A mechanism mediated via hypothalamic release of somatostatin or, alternatively, a direct pituitary site of action, can be postulated for the blocking effect of pirenzepine.
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