Oral Administration Of Levodopa Research Articles

Effect of oral administration of L-dopa on the plasma levels of growth hormone-releasing hormone (GHRH) in normal subjects and patients with various endocrine and metabolic diseases

The responses of plasma growth hormone-releasing hormone (GHRH) and growth hormone (GH) to oral administration of L-dopa were studied in normal subjects and patients with various endocrine and metabolic diseases to clarify the pathophysiological role of the GHRH-GH axis. In normal subjects, the plasma GHRH concentration was increased from the basal value of 9.8 +/- 1.4 pg/ml (mean +/- SE) to 34.8 +/- 3.1 pg/ml at 30 approximately 90 min after oral administration of 500 mg L-dopa, followed by a rise of GH release (plasma GH level from less than 1 ng/ml to 21.7 +/- 4.7 ng/ml) in most cases, indicating that L-dopa stimulates GH secretion via hypothalamic GHRH. On L-dopa administration, no apparent increases in both plasma GHRH and GH concentrations were observed in patients with hypothalamic hypopituitarism, whereas GHRH administration induced almost normal GH response. In patients with acromegaly, the plasma levels of GHRH remained stationary after the L-dopa administration and did not correlate with plasma GH levels. In subjects with simple obesity, the responses of plasma GHRH (peak 13.2 +/- 1.2 pg/ml) and GH (peak 4.3 +/- 1.7 ng/ml) to L-dopa were significantly lower than those in normal subjects (p less than 0.01). In patients with primary hypothyroidism, peak levels of plasma GHRH (12.6 +/- 1.3 pg/ml) and GH (2.4 +/- 0.6 ng/ml) were significantly lower than those in normal subjects (p less than 0.01). In patients with non-insulin dependent diabetes mellitus (NIDDM), the responses of GHRH and GH were divided into 2 groups; in the responder the peak values of GHRH and GH were 19.4 +/- 8.6 pg/ml and 12.2 +/- 1.4 ng/ml and in the low or non responder 14.7 +/- 1.5 pg/ml and 2.0 +/- 0.6 ng/ml, respectively. Between both groups, there was a significant difference in the values of fasting blood sugar and HbA1 and mean suffering period. These findings suggest that GH secretion evoked by the L-dopa administration is induced by GHRH released from the hypothalamus, and impairment of GH secretion associated with simple obesity, primary hypothyroidism, or NIDDM may be in part attributed to insufficiency of GHRH release from the hypothalamus, and indicate that L-dopa test is clinically useful for evaluating the ability of intrinsic GHRH release in such diseased states.

O-103 - Plasma levels of dopamine, sulfo-conjugated dopamine and oilier dopamine metabolites in dogs after oral administration of L-dopa

O-103 - Plasma levels of dopamine, sulfo-conjugated dopamine and oilier dopamine metabolites in dogs after oral administration of L-dopa

Levodopa-induced regional cerebral blood flow changes in normal volunteers and patients with Parkinson's disease. Lack of correlation with clinical or neuropsychological improvements.

Single photon emission computed tomography was used to measure regional cerebral blood flow in six normal subjects and 12 patients with Parkinson's disease, before and after acute oral administration of levodopa. The drug induced a significant increase in cerebral blood flow both in controls and patients. Before levodopa, there was no significant difference between the groups, either in flow values or in their pattern. The clinical effects of levodopa were not related to the hemodynamic changes. The results suggest that measuring the flow response to levodopa is not appropriate to demonstrate variations in central dopaminergic receptor sensitivity in man.

L-dopa stimulates release of hypothalamic growth hormone-releasing hormone in humans.

A sensitive RIA for human GH-releasing hormone-(1-44)-NH2 [hGHRH-(1-44)-NH2] was developed which allows its measurement in human plasma extracts. The assay did not detect hGHRH-(1-37)-OH or hGHRH-(1-40)-OH. A method to extract hGHRH from plasma was developed using silicic acid and acid-acetone, by which recovery of synthetic hGHRH-(1-44)-NH2 from plasma averaged 74.3%. Serial dilutions of plasma extracts gave an inhibition curve parallel with that of synthetic hGHRH-(1-44)-NH2 in the RIA system. On Sephadex G-50 columns, hGHRH-like immunoreactivity (hGHRH-LI) in plasma extracts eluted as a single peak corresponding to hGHRH-(1-44)-NH2. This hGHRH-LI peak, when subjected to reverse phase HPLC, emerged at the position where hGHRH-(1-44)-NH2 was eluted. hGHRH-LI was detectable in the peripherally circulating plasma of all subjects tested. The mean basal level of plasma hGHRH-LI in normal subjects was 9.4 +/- 0.7 (+/- SE) pg/ml (n = 22; range, 2.8-18.1 pg/ml), comparable to the basal plasma hGHRH-LI concentration in patients with hypothalamic lesions (11.3 +/- 1.1 pg/ml; n = 7). Oral administration of L-dopa (0.5 g) caused a significant increase in both plasma hGHRH-LI and GH levels in normal subjects, and the plasma hGHRH-LI peak slightly preceded or coincided with that of plasma GH in individual subjects. There was also a significant correlation between plasma hGHRH-LI and the GH rises after L-dopa administration when their net increments were compared. All of the patients with hypothalamic lesions had significant increases in plasma GH after hGHRH-(1-44)-NH2 injection (1 microgram/kg BW, iv), indicating the presence of functioning somatotrophs in their pituitaries. When L-dopa was orally administered to these patients, neither plasma hGHRH-LI nor GH concentration changed throughout a 120-min observation period. These findings suggest that 1) hGHRH, immunologically and chromatographically indistinguishable from synthetic hGHRH-(1-44)-NH2, is detectable in peripheral plasma in humans; 2) L-dopa stimulates the release of hypothalamic hGHRH, alterations of which are reflected in changes in peripheral levels; and 3) the source of circulating hGHRH is not restricted to the hypothalamus, since hGHRH-LI is present in the peripheral plasma of patients with hypothalamic lesions in amounts similar to those found in normal subjects.

Plasma growth hormone response to oral l-dopa in infantile autism.

In order to assess further the occurrence of hypothalamic dysfunction in infantile autism and its possible relationship to dopaminergic abnormalities, the l-dopa provocative test was performed in 22 patients fulfilling DSM-III criteria for this disorder. The results indicate a high incidence (at least 30%) of blunted plasma growth hormone (GH) responses following oral administration of l-dopa in this sample. These data suggest an alteration of hypothalamic dopamine receptor sensitivity in the patients with blunted responses. Thus, a subgroup of autistic patients within a descriptively homogeneous diagnostic category shows evidence of hypothalamic dysregulation and dopaminergic abnormalities.

Growth hormone release in response to human pancreatic tumor growth hormone-releasing hormone-40 in children with short stature.

Forty children with short stature were evaluated for GH reserve after pharmacological tests and after a single iv injection of human pancreatic tumor GH-releasing hormone [hpGRH-40). These children were grouped into four diagnostic categories: 1) idiopathic GH deficiency (n = 10); 2) organic hypopituitarism (n = 7); 3) intrauterine growth retardation (n = 5); and 4) constitutional delay of growth and/or familial short stature (n = 18), by standard clinical criteria and physiological and pharmacological tests of GH reserve. Venous blood was sampled for GH concentrations on 2 consecutive days: on day 1, after the iv administration of L-arginine (0.5 g/kg for 30 min) and oral administration of L-dopa (9 mg/kg), and on day 2, after the administration of hpGRH-40, 3.3 micrograms/kg, as an iv bolus. No GH-deficient patient in categories 1 or 2 increased his/her circulating GH concentration to more than 7 ng/ml after the arginine-L-dopa test; however, six children had marked GH responses after hpGRH-40 administration. As a group the lowest peak responses (mean +/- SE) to GRH were found in the organic hypopituitary (3.4 +/- 1.1 ng/ml) and in the idiopathic GH deficiency (8.2 +/- 2.4 ng/ml) categories. All children in the intrauterine growth retardation and constitutional delay of growth (controls for the GH-deficient children) responded briskly to hpGRH-40, although there was wide variation of the peak GH levels (5-51 ng/ml). Circulating concentrations of somatomedin-C did not differ in subjects in any category 24 h after hpGRH-40 injection when compared to basal values. These data indicate that hpGRH-40 can be employed to evaluate GH reseve in short children and may be useful in the diagnosis of hypothalamic-pituitary disorders.

Beneficial Hemodynamic Effects of Oral Levodopa in Heart Failure

Among the positive inotropic drugs available to improve myocardial contractility in congestive heart failure, only digitalis glycosides are suitable for oral administration. In this study, we administered oral levodopa (1.5 to 2.0 g), which is decarboxylated to form dopamine, to 10 patients with severe congestive heart failure. Peak hemodynamic responses occurred one hour after the ingestion of levodopa, with the mean (+/- S.E.M.) cardiac index increasing from 1.8 +/- 0.1 to 2.4 +/- 0.2 liters per minute per square meter of body-surface area (P less than 0.01) and systemic vascular resistance declining from 1905 +/- 112 to 1513 +/- 121 dyn X sec X cm-5 (P less than 0.01). These effects persisted for four to six hours. Left ventricular filling pressure, heart rate, and mean arterial pressure were unchanged. Plasma concentrations of dopamine rose to a peak level of 34 +/- 5 ng per milliliter one hour after drug ingestion and decreased toward base line over the ensuing five hours. A significant correlation was observed between plasma dopamine levels and changes in cardiac index (r = 0.8; P less than 0.02). Five patients enrolled in a trial to evaluate the effectiveness of long-term therapy with levodopa had similar hemodynamic responses to the drug after 6.8 +/- 1.7 months of treatment. Thus, oral administration of levodopa to patients with severe heart failure produced a sustained improvement in cardiac function. The hemodynamic responses observed can be attributed to the activation of beta 1-adrenergic, dopamine, and dopamine receptors by dopamine derived from levodopa.

Depending on the stimulus, central serotoninergic activation by fenfluramine blocks or does not alter growth hormone secretion in man.

The role of serotonin (5-HT) in the hypothalamic regulation of human growth hormone (GH) was reassessed through the use of fenfluramine, which selectively releases 5-HT from presynaptic terminals. Oral administration of L-dopa plus propranolol induced a potent and sustained GH release in the subjects tested (26 +/- 6 ng/ml). The administration of fenfluramine (20 mg i.v. as bolus plus 20 mg/30 min i.v.) completely suppressed the L-dopa-induced GH secretion (2 +/- 09.5 ng/ml). On the other hand, when arginine (30 g/30 min i.v.) was used as a GH stimulant of medium intensity (12.7 +/- 2.8 ng/ml), fenfluramine at the same dose was not able to alter the pattern of pituitary secretion (11.5 +/- 4.2 ng/ml). Fenfluramine alone induced a slight nonsignificant decrease in GH values with a parallel and significant increase in prolactin (PRL) secretion in accordance with the proposed serotoninergic activity of the drug. Rat PRL secretion by pituitaries incubated in vitro was inhibited by dopamine. Fenfluramine added to the system did not counteract the dopaminergic reduction of PRL release, making unlikely the possibility of an antagonism at the dopaminergic receptor as mechanism of action of fenfluramine on PRL secretion. In conclusion, depending on the stimulus under study, serotoninergic activation by fenfluramine either inhibits or does not alter GH secretion in man. No proof of a serotoninergic stimulatory component on GH regulation has been detected in this study. Fenfluramine is a valuable tool in neuroendocrinological studies, dealing with serotoninergic mechanisms.

Failure of inhibition by TRH of L-Dopa stimulated GH secretion in patients with alcoholic cirrhosis of the liver.

We have investigated the effects of a single oral dose of L-Dopa (500 mg) or of an i.v. infusion of TRH (1 mg dissolved in 400 ml of saline solution) or both administered together, on GH release in men with alcoholic cirrhosis of the liver, and compared them with responses in normal subjects. The results obtained in normal subjects confirm that TRH does not modify plasma GH levels, L-Dopa elevates GH concentrations, while the administration of these two drugs together significantly inhibits GH release induced by oral L-Dopa. In contrast, in patients with alcoholic cirrhosis of the liver, the following results were obtained: 1 TRH infusion significantly increased plasma GH levels which were steadily elevated throughout the experiment; 2 oral administration of L-Dopa provoked a significant rise in blood GH over the basal values similar to that observed in normal subjects; 3 when TRH and L-Dopa are administered at the same time a GH increase like that observed after L-Dopa alone was obtained. These results clearly demonstrate that in patients with alcoholic cirrhosis of the liver the normal inhibitory effect of TRH on L-Dopa induced GH release is completely lost.

Age related changes in the control of prolactin secretion in the female rat

The purpose of this investigation was to evaluate the effects of advancing age on the control of pituitary prolactin secretion. The effects of dopaminergic inhibition and estrogen stimulation of pituitary prolactin secretion were tested both in vivo and in vitro. Estrogen stimulated prolactin secretion in both old and young animals, and elevated estrogen levels in old rats may be partially responsible for elevated prolactin levels. Oral L-DOPA administration induced cycles in old rats but had no effect on prolactin levels in either old or young rats. Injections of L-DOPA lowered prolactin in young but not in old rats, while apomorphine reduced prolactin levels in both groups. The pituitaries of young rats secrete more prolactin in vitro than old pituitaries, further supporting a decrease in hypothalamic DA turnover as a cause for elevated prolactin levels in old rats.

Serum prolactin concentrations in mangabey (Cercocebus atys lunulatus) and patas (Erythrocebus patas) monkeys in response to stress, ketamine, TRH, sulpiride and levodopa.

An homologous radioimmunoassay for human serum prolactin was validated to measure serum prolactin in 10 mangabey and 7 patas monkeys. Mean basal levels of serum prolactin were almost identical in the males of both species and in immature and mature males. However, basal levels were higher in females than in males. Serum prolactin was enhanced by stress, i.v. injection of TRH and intramuscular injection of a potent dopamine antagonist (sulpiride). The rise in serum prolactin observed after i.m. injection of ketamine hydrochloride used as anaesthetic was of small amplitude and short duration. Oral administration of levodopa was followed by a significant fall in serum prolactin. Sexual maturity did not influence the responses to TRH or sulpiride. The mangabeys were more sensitive to sulpiride but less sensitive to levodopa than were the patas monkeys. The variations in serum prolactin levels observed in these monkeys under the influence of stress, TRH, sulpiride and levodopa are similar to those observed in man to the same stimuli, although the experimental conditions were quite different.

Effects of increased central dopaminergic tonus on gonadotropin secretion.

Gonadotropin secretion was investigated in 10 healthy volunteers (5 men and 5 women in the early follicular phase of cycle) by the following procedures: i) infusion of saline over 4 1/2 h period; ii) infusion of dopamine (DA) 4 microgram/kg bw/min over 4 h period; iii) oral administration of L-dopa (D) 100 mg plus carbidopa (C) 35 mg after 24 h pretreatment with C 50 mg every 6 h. This last pharmacological approach selectively enhances the central dopaminergic tonus. Blood samples were withdrawn every 15 min over 4 1/2 h period. No ultradian periodicity in LH and FSH secretion was observed. No significant modification in serum FSH levels was induced by any treatment at any time, while a significant decrease in serum LH concentration was observed from 45 to 240 min during DA infusion (-46.8%; p less than 0.005) and from 60 to 240 min after D + C administration -41.5%; p less than 0.05). These data demonstrate that, in humans, acute dopaminergic stimuli have an inhibitory action on LH release and suggest that this inhibition is exerted at the central level.

Interaction between the thyrotrophin-releasing hormone-induced growth hormone rise and dopaminergic drugs: studies in pathologic conditions of the animal and man.

A rise in plasma growth hormone (GH) after thyrotrophin-releasing hormone (TRH) and a striking reduction after dopaminergic drugs is present in acromegalic ('responder') patients. We have investigated the GH response to dopaminergic stimuli in two conditions of animals and man, which, like acromegaly, are characterized by a TRH-induced GH rise, i.e. rats with electrolytic lesions of the median eminence (ME) and patients with hepatic cirrhosis. In addition, we have studied the TRH-induced GH rise in rats with ME lesions, in the cirrhotic patients and in a group of 'responder' acromegalics before and after administration of dopaminergic drugs. In rats with ME lesions an infusion of dopamine (DA) neither modified baseline GH levels nor the TRH-induced GH rise. In five out of six cirrhotic patients oral administration of L-Dopa was followed by the usual rise in plasma GH. infusion of DA increased plasma GH levels in three out of seven cirrhotic patients and in four out of five subjects an earlier GH rise after TRH was seen. However, in the 'responder' acromegalics, the infusion of DA, besides lowering baseline plasma GH, was capable of reducing the TRH-induced GH rise. Collectively these data indicate that the TRH-induced GH rise emphasizes defects in the neurohormonal links between the central nervous system and the anterior pituitary. Instead, the paradoxical fall of GH after dopaminergic drugs appears to be a prerequisite of acromegaly and may be attributable to receptors for DA located on the tumorous tissue.

Disordered growth hormone and prolactin secretion in primary disorders of sleep.

Growth hormone (GH) and prolactin (PR) secretion were evaluated in 28 patients who had sleep apnea or narcolepsy but no other primary neurologic or endocrine disorders. Eighty-one percent of subjects with impaired alertness failed to demonstrate serum GH concentrations in excess of 5 ng per milliliter following oral administration of L-DOPA, 500 mg. Diminished GH responses to sleep and intravenous arginine were observed in 57 percent and 44 percent, respectively, of patients tested. Sleep-related PRL release was less than normal in women with narcolepsy, with or without sleep apnea. All patients had at least one abnormality in GH or PRL secretion.

TESTS OF PROLACTIN SECRETION IN DIAGNOSIS OF PROLACTINOMAS

Prolactin-secreting tumours of the pituitary were identified and treated by transsphenoidal microsurgery in fourteen infertile females with hyperprolactinæmia. Resting prolactin levels were 590-9000 mU/1 (mean 3400). In seven patients, tomography of the pituitary fossa was normal and resting prolactin levels were 590-6000 mU/1 (mean 3400). In these patients the pre-operative diagnosis of prolactinoma in these patients was made by demonstrating loss of the normal circardian prolactin profile and impaired prolactin response to intravenous thyrotrophin-releasing hormone (T.R.H.) and metoclopramide stimulation. Prolactin response to the acute oral administration of L-dopa and bromocriptine was of less diagnostic value. Preoperative assessment of anterior pituitary function identified abnormalities other than hyperprolactinæmia in four patients (28%). Post-operative assessment indicated that microsurgery was curative in twelve patients (86%), selective in all, and without significant aide-effect. It is concluded that dynamic tests such as T.R.H. and metoclopramide stimulation have considerable value in identifying hyperprolactinæmic patients with prolactin-secreting adenomas, particularly those which are radiologically occult.

Regional cerebral blood flow in parkinsonism: Measurement before and after levodopa

Data from recent studies in experimental animals suggest that central dopaminergic mechanisms may be involved in regulation of the regional cerebral blood flow (rCBF) in the mammalian brain. In order to evaluate possible effects of dopaminergic stimulation on human cerebral circulation, rCBF was measured by the 133Xenon inhalation technique in 26 patients with Parkinson's disease before and after the chronic oral administration of levodopa combined with a peripheral Dopa-decarboxylase inhibitor. Treatment with levodopa did not induce significant alterations in the mean brain, mean hemispheric or regional flow values in these patients. These findings suggest that the dopaminergic system does not play an important role in modulation of the rCBF in man.

Effect of hyperglycemia on the growth hormone response to L-dopa in diabetic subjects.

Plasma growth hormone (GH) levels were measured before and after oral administration of L-dopa in 8 insulin-dependent juvenile diabetic patients, and in 6 non insulin-dependent maturity-onset diabetics, while they were hyperglycemic, and values were compared with those of normal children and adult subjects. Maturity-onset diabetics failed to show an increase in serum GH levels after L-dopa administration, while serum peak GH values of juvenile diabetic patients were not significantly different from those of normal adults and children. Hyperglycemia thus failed to prevent L-dopa induced growth hormone response in insulin-dependent juvenile diabetic patients.

Sequential use of insulin and levodopa to provoke pituitary secretion of growth hormone.

More than one method of stimulating human growth hormone (hGH) release is necessary to adequately evaluate the secretory capacity of pituitary somatotropes. In this study, sequential insulin-induced hypoglycemia (ITT) and oral administration of levodopa were used to study hGH release in 30 short normal children and adolescents and in five children with hypopituitarism. In the normal subjects, hGH levels greater than 5 ng/ml were achieved in 26 of 30 with the ITT and in 28 of 30 following administration of levodopa. Each of the normal children responded to at least one test. None of the children with hypopituitarism demonstrated hGH secretion during the study. We conclude that sequential administration of insulin and levodopa is a reliable, convenient, and safe method of assessing the release of hGH by the pituitary somatotropes during childhood.

Central dopaminergic receptor supersensitivity and its relevance to Parkinson's disease

The degeneration of the substantia nigra that characterises Parkinson's disease may cause an alteration in sensitivity of striatal dopamine receptors. The development of denervation supersensitivity has been held to be responsible for some of the effects of chronic levodopa therapy. The rotating rodent is an animal model commonly used to study the phenomenon of striatal dopamine receptor supersensitivity, and to investigate drugs which may prove to be beneficial in the treatment of Parkinson's disease. We have investigated as to whether long-term oral administration of levodopa to mice with unilateral destruction of striatal dopaminergic nerve terminals influences dopaminergic receptor denervation supersensitivity as judged by the circling response following systemically administered levodopa. It does not do so and the relevance of these findings to the treatment of Parkinson's disease is discussed.

Effects of long-term L-dopa therapy on carbohydrate metabolism in patients with Parkinson's disease.

Carbohydrate metabolism and insulin secretion were investigated in 26 patients with Parkinson's disease before and during L-dopa treatment. Oral glucose tolerance tests were performed on 13 patients treated with L-dopa alone and on 7 patients treated with L-dopa combined with Carbidopa. Intravenous glucose tolerance tests were performed on additional 6 patients treated with L-dopa alone. Results indicate that chronic L-dopa administration does not modify glucose metabolism. It was observed only a significant decrease of insulin secretion after oral glucose in the early phase (15th day) of treatment with L-dopa alone. This temporary effect may be related to the peripheral conversion of L-dopa to dopamine since insulin secretion during combined therapy was normal. The mechanism by which L-dopa transiently inhibits insulin release is not clear. Perhaps the oral administration of L-dopa alone causes an alteration in some gastrointestinal functions which are involved in the handling of oral glucose.