Patients with pituitary adenomas were examined with positron emission tomography (PET) with the administration of the 11C-labelled dopamine-D2 antagonists N-methylspiperone and raclopride. The studies were repeated after protection of the D2-receptors with Haloperidol to enable a separation of specific and unspecific receptor binding. The receptor binding was evaluated by visual inspection and with the application of a kinetic model. The results showed marked specific dopamine-D2 receptor binding in the prolactinomas and minimal or no such binding in the hormonally inactive adenomas. The two tracers 11C-raclopride and 11C-N-methylspiperone showed qualitatively the same result although raclopride resulted in a higher tumor to normal brain ratio. In conclusion, PET is a valuable complement to other radiologic techniques like computed tomography and magnetic resonance imaging in the evaluation of pituitary adenomas. An assessment of the dopamine-D2 receptors in the adenomas has a direct influence on the choice of treatment because adenomas with high amounts of receptors are in most cases effectively treated with dopamine agonists like bromocriptine.
PRL receptors have been previously identified in purified rat liver plasma membrane and Golgi vesicle preparations. In this study, we report on PRL receptors located in highly purified lysosome preparations. These lysosomal PRL receptors were characterized using Scatchard analysis and compared to other intracellular and cell surface receptors. We have identified two classes of lysosomes. Lighter lysosome-like vesicles, which are greatly enriched in acid phosphatase activity (the marker enzyme of lysosomes), contain a great deal of binding activity. This PRL binding was only slightly increased by pretreatment of animals with the lysosomotropic agent chloroquine. In contrast, mature lysosomes showed very little binding activity in control animals, but chloroquine treatment increased binding 7- to 8-fold in these mature lysosomes. We suggest that the lysosome-like structures are immature lysosomes (namely prelysosomes) toward which the hormone-receptor complex is internalized: they appear to bear little proteolytic activity. These structures could play a role in PRL receptor recycling. Lysosomal PRL receptors showed curvilinear Scatchard plots, in contrast to plasma membrane and Golgi counterparts, which were linear over the same range of hormone concentrations. The high affinity site in lysosomes had a Kd comparable to the cell surface and Golgi receptors. The number of binding sites per mg protein in prelysosomes and lysosomes was 3 times greater than that in the homogenate, but Golgi preparations were 3 times as rich as lysosomes. The great number of PRL receptors in prelysosomes could be attributed, in large part, to the low affinity sites. The internalization of PRL into rat liver was examined after in vivo injection of [125I]iodoovine PRL. The labeled hormone was found initially in the plasma membrane fraction, after which it localized preferentially in the Golgi fraction, with maximum incorporation 15 min postinjection. Substantial radioactivity was observed in both classes of lysosomes (L-1 and L-2). In contrast to the Golgi fraction, maximum incorporation of [125I]iodoovine PRL in lysosomes occurred at 30 min. This suggests either that during internalization, PRL first reaches Golgi elements and is then transferred to the lysosomal compartment, or that there are two independent pathways of internalization, one rapid toward the Golgi complex (may be a path of receptor recycling) and the other toward lysosomes (probably leading to receptor degradation).
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Hyperprolactinemia is one of the causes of sterility. Cabergoline is indicated in cases resistant to bromocriptine, but, usually, its administration is interrupted at the beginning of the pregnancy. A case of prolonged treatment with cabergoline during pregnancy is reported, without teratogenic effects on the fetus.
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After single doses (100 to 400 microgram orally), pergolide, a synthetic ergot, reduced basal plasma prolactin levels in normal subjects in a dose-related manner. This effect persisted for more than 24 hr. Multiple doses of pergolide (150 to 250 microgram daily for 7 days) resulted in a plasma prolactin decrease of more than 80%. A single dose of pergolide (150 microgram orally) suppressed plasma prolactin and abolished the plasma prolactin diurnal rhythm, i.e., suppression of sleep-induced elevation in plasma prolactin during a 40-hr period. Perphenazine (5 mg intramuscularly)-induced plasma prolactin elevation was inhibited by pergolide; the effect was dose dependent. After single or multiple doses, pergolide had no effect on plasma follicle-stimulating hormone, luteinizing hormone, cortisol, growth hormone, and thyroid-stimulating hormone. Pergolide appears to have specificity at the pituitary level for the dopamine receptors that mediate prolactin secretion.
Pituitary and testicular hormone secretion and sex-hormone binding globulin (SHBG) level were investigated in 15 males with active acromegaly in normal and hyperprolactinemic state. Basal serum folitropin (FSH) and lutropin (LH) levels did not change before and after the administration of bromocriptine and remained in normal range compared with those in healthy men. Serum total testosterone concentration and SHBG were decreased particularly in hyperprolactinemic patients, but their levels were significantly increased to the normal limits following bromocriptine application. Although slight changes in serum concentration of free testosterone (fT) and circadian rhythm of fT in saliva was observed before and following bromocriptine treatment, the statistical differences were not significant. The results of the present study suggest that in acromegaly the alterations in peripheral metabolism of sexual steroids may exist.
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Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease emerging toward the end of pregnancy or in the first postpartal months in previously healthy women. Recent data suggest a central role of unbalanced peri-/postpartum oxidative stress that triggers the proteolytic cleavage of the nursing hormone prolactin (PRL) into a potent antiangiogenic, proapoptotic, and proinflammatory 16-kDa PRL fragment. This notion is supported by the observation that inhibition of PRL secretion by bromocriptine, a dopamine D2-receptor agonist, prevented the onset of disease in an animal model of PPCM and by first clinical experiences where bromocriptine seem to exert positive effects with respect to prevention or treatment of PPCM patients. Here, we highlight the current state of knowledge on diagnosis of PPCM, provide insights into the biology and pathophysiology of 16-kDa PRL and bromocriptine, and outline potential consequences for the clinical management and treatment options for PPCM patients.
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Pergolide mesylate ((8 beta)-8-[(methylthio)methyl]-6-propylergoline monomethanesulfonate, LY 127,809, CAS 66104-23-2) is a novel and potent dopamine agonist marketed for treating the symptoms of Parkinson's disease. The potential secondary pharmacological effects of this agent on the cardiovascular, respiratory, and the autonomic nervous systems were examined. Pergolide exhibited significant pharmacological effects in cardiovascular and autonomic tests at high oral or intravenous doses. The reference dopamine agonist, bromocriptine, exhibited effects qualitatively similar to, but at doses generally higher than, pergolide, in parallel with its lower therapeutic potency relative to pergolide. In summary, these studies confirm the pharmacological selectivity of pergolide at low doses, and indicate the potential for secondary pharmacological side effects upon cardiovascular function at significant multiples of the clinical dose.
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After 1 month, 63% of the patients in both groups had normal PRL and 43% had menses. Side effects were similar. After 1 year all patients except one had normal PRL levels, and 89% were ovulating.
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The markedly increased well being in patients treated with CV 205-502 cannot be explained by its better tolerability and is probably caused by a specific central activity of CV 205-502. Further research into the antidepressive properties of this compound is warranted.
In a 21-year-old woman with McCune-Albright syndrome, acromegaly and hyperprolactinemia with hypopituitarism developed secondary to a large pituitary tumor. Bromocriptine suppressed the secretion of growth hormone and prolactin, with a reduction in tumor size. However, at the age of 8, she already showed evidence of biochemical acromegaly, with a paradoxical rise of growth hormone levels during two glucose tolerance tests, in the presence of a radiologically normal pituitary fossa. These data support the hypothesis that long-standing hypothalamic stimulation may have been responsible for the later development of a pituitary tumor.
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Rats with a unilateral 6-hydroxydopamine lesion of substantia nigra were treated with the dopamine agonists SKF-82958 (D1 receptor selective) or bromocriptine (D2 receptor-selective) and their circling response recorded. Both of the compounds induced an acute episode of rotation directed away from the lesioned side. Consecutive daily treatments with either compound usually resulted in a significantly increased average response (sensitization) over a 3- to 6-day treatment period. But nearly all animals treated with low doses of either SKF-82958 or bromocriptine exhibited one or more days when they were totally unresponsive to drug treatment. Response fluctuations thus were not exclusively associated with D1 or D2 receptor agonist treatment. When subsequently tested, undrugged, in the drug-associated environment, 2, 4 and 10 weeks after their last drug treatment, rats that had previously been treated with SKF-82958 exhibited rapid contralateral rotation while rats that had previously been treated with bromocriptine showed no such undrugged rotation. This result is consistent with previous findings that the D1 receptor agonist, SKF-38393, but not the D2 receptor agonist, quinpirole, had long-term behavioral effect in nigral rats, and suggests that persistent motor consequences of limited treatment with dopamine receptor agonists are D1 receptor-related.
The problem of hyperprolactinaemia is dominated by the search for an active pituitary adenoma, which, if it is at all large, requires neuro-surgical operation. In cases where a microadenoma is responsible or where the pathological secretion of prolactin is istrogenic, the most serious consequence is sterility. Hyperprolactinaemia in fact works at two levels: on cyclical gonadotrophic activity and on luteal function. Whatever the cause is, bromocriptine allows hyperprolactinaemia to be corrected together with the disturbances of ovulation resulting from it.
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Twenty-three patients with microprolactinoma (basal serum PRL levels 1620-18750 mU/l) and 16 patients with macroprolactinoma (basal serum PRL levels 4110-111000 mU/l), previously shown to be intolerant of bromocriptine. All patients had gonadal failure and 11 patients with macroprolactinoma had visual field defects. Five patients with macro- and one with microprolactinoma had previously undergone surgery.
Results in 136 hyperprolactinaemic women who presented with infertility, amenorrhoea, menstrual irregularities and/or galactorrhoea are reported. There was radiographic evidence of pituitary microadenoma in 21 (15.4%) patients and 5 (3.7%) had macroadenoma. Four patients were taking antidepressants, 2 antihypertensive drugs and 7 had taken oral contraceptives for a period of 6 months to 5 years. The remaining patients had no obvious cause for elevated prolactin levels. Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy. The patients without an adenoma required a significantly smaller dose of bromocriptine (2.5-5.0 mg) (p less than 0.005) than those with an adenoma. Galactorrhoea disappeared in all 64 patients within 2-4 months of treatment, sixty-six (71%) of the 93 patients who desired pregnancy achieved it within 3 to 8 months of bromocriptine therapy; 32 of these patients received additional treatment with clomiphene and human chorionic gonadotrophins for induction of ovulation. In the remaining 70 patients menstruation became regular and ovulation was evident in 40% of them. There was no significant difference in the pregnancy rate between the patients with or without pituitary adenoma. Similarly, presence of galactorrhoea or a high level of prolactin did not influence the pregnancy rate. No complications were observed during pregnancy related to pituitary adenomas; 8 (12%) pregnancies ended in first trimester abortion. No lethal congenital fetal abnormalities were observed in the patients treated with bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)
Eleven patients with prolactin-producing pituitary adenomas were treated with the new non-ergot, long-acting dopamine agonist, CV 205-502, for a period of 2-18 months (mean 11 months). Tumour volumes ranged from 1.9 to 64 ml in seven patients who were newly diagnosed, and from 0.1 to 3.1 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3.5 to 360 U/l before institution of CV 205-502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once-daily doses of CV 205-502 between 0.075 and 0.300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205-502 treatment and/or during several days after a dose increase were observed in three patients. We conclude that CV 205-502 in a once daily dose is an effective and safe alternative in the long-term treatment of macroprolactinomas.
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In patients with early Parkinson's disease, ropinirole monotherapy was more efficacious than bromocriptine with regard to improvement in activities of daily living, and need for supplemental levodopa. Ropinirole recipients had a higher requirement for levodopa supplementation than levodopa recipients in a 5-year study, but the incidence of dyskinesia was significantly lower with ropinirole than with levodopa (markedly so in the one third of ropinirole recipients who were able to remain on monotherapy with no levodopa supplementation). Thus available data suggest that ropinirole may provide a means of treating early Parkinson's disease while minimising the risk of dyskinesia and delaying the need for supplemental levodopa in some patients. In addition, ropinirole is also efficacious in the management of more advanced Parkinson's disease in patients who are experiencing motor complications after long term levodopa use.
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The effects of intravenous infusions of dopamine (0.1 to 1 mg kg-1h-1) and bromocriptine (10 to 40 micrograms kg-1h-1) on colonic motility were investigated in fasted dogs fitted with permanent strain gauges on the ascending, transverse and descending colon. Infused at rates of 0.5 and 1 mg kg-1h-1 during 1 h, dopamine immediately stimulated the motility of the descending colon; after a delay of 40 to 60 min this effect was balanced by an inhibition of the motility of the ascending and transverse colon. Bromocriptine infused intravenously at doses of 10 to 40 micrograms kg-1h-1 stimulated the motility of the whole colon but these effects were limited to the duration of the infusion (60 min). Both propranolol (0.5 mg kg-1) and tolazoline (2 mg kg-1) failed to block the effects of dopamine and bromocriptine whereas phentolamine (0.1 mg kg-1) and prazosin (0.2 mg kg-1) partially reduced the inhibitory effects of dopamine on the proximal colon. Haloperidol at doses higher than 0.2 mg kg-1 and domperidone blocked the bromocriptine-induced stimulation of colonic motility which was unaffected by previous treatment with alpha- and beta-adrenoceptor blocking agents. These results suggest that in the dog, dopamine and bromocriptine stimulate colonic motility through specific dopamine receptors. However, they suggest that the inhibitory effects of dopamine on the proximal colon which are blocked by dopamine antagonists are also partially due to an effect on alpha 1-adrenoceptors.
Administration of 4 mg of the antiprogestagen RU486 to 4-day-cyclic rats over 8 consecutive days starting on the day of estrus (Day 1) induced and anovulatory cystic ovarian condition with endocrine and morphological features similar to those exhibited in polycystic ovarian disease (PCO). To determine whether the RU486-treated rat responds in an analogous fashion to therapies similar to those that have been used to treat human PCO, RU486-treated rats were injection on Days 5 and 7 with 1) 1 mg of an LHRH antagonist (LHRHa), 2) 5 IU of human FSH (hFSH), 3) 2 mg of the antiandrogen flutamide (FLU), 4) 1 mg of the antiestrogen tamoxifen (TMX), or 5) 1 mg of the dopamine agonist bromocriptine (BRC). Controls were intact cyclic rats decapitated on estrus and rats injected with RU486 and the corresponding vehicles (saline or 70% ethanol) used with LHRHa, hFSH, FLU, TMX, and BRC injections. RU486-treated rats were decapitated on Day 9, and the serum concentrations of LH, FSH, prolactin (PRL), testosterone (T), and estradiol-17 beta (E2) were determined. Pituitary and ovary weight, number of follicular cysts, size of the corpora lutea, and rates of follicular growth and atresia were also noted. Finally, the ovulatory response to ovine LH (oLH) in rats treated with RU486 and injected with various doses of hFSH (5, 10, or 20 IU) was evaluated. While administration of LHRHa and of TMX decreased the serum concentrations of LH, T and E2 and the LH/FSH and T/E2, ratios, and injections of BRC and of FLU increased the serum concentration of LH and T, the administration of hFSH (10 IU) to RU486-treated rats increased only the serum levels of E2. All treatments decreased, though in different degrees, both the number of cysts and the rate of follicular atresia, and stimulated follicular growth. The positive effects on follicular growth and atresia were significantly higher in those rats injected with hFSH. Moreover, RU486-treated rats injected with different doses of hFSH ovulated in a dose-dependent manner in response to oLH. Rates deprived of the actions of progesterone through the administration of the antiprogestagen RU486 had 1) endocrine and morphologic alterations comparable to those observed in women with PCO, 2) analogous responses to therapies similar to those that have been used to treat human PCO, and 3) an ovulatory response to combined treatment with FSH and LH. These results establish the fundamental adequacy of using the RU486-treated rat as a PCO model.
Twenty hyperprolactinemic women (median prolactin [PRL] 2,989 mU/L, range 1,149 to 11,910 mU/L), previously unsuccessfully treated with bromocriptine, were treated in a prospective study, for 3 to 24 months with the new, nonergot, long-acting, dopamine agonist, CV 205-502. Treatment resulted in normalization of PRL in 14 patients, in one daily dose of 0.075 to 0.150 mg of the drug. Three patients were treated in doses above 0.150 mg up to 0.300 mg, but PRL was not normalized during the study. Menstrual function was restored in 15 of 18 amenorrheic patients. Galactorrhea, present in 7 patients, disappeared in 5. Four patients became pregnant and gave birth to healthy children. In conclusion, we found CV 205-502 effective in one daily dose, with good tolerability; it is safe and provides a valuable alternative to the dopamine agonist drugs in use today.
Forty migraineurs (10 males, 30 females) were randomized according to a two-period (3-month), two-treatment, crossover design. Efficacy was assessed using quantitative data recorded in the patient's headache diary. Data were evaluated using the Wallenstein's method.
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In normal rats, before Day 12 of pseudopregnancy, minimal levels of 20 alpha-HSD activity were detected in functional CL whereas those in the residue were 3-5 times higher. When ovulation was blocked for more than 2 weeks by placing rats in a continuously lit environment before the induction of pseudopregnancy, only minimal levels of 20 alpha-HSD activity were detectable in the functional CL and residue before Day 12. In normal pseudopregnant rats, there was a linear increase in 20 alpha-HSD activity from Day 12 to 15 in the functional CL and residue, but the rate of elevation was much higher in functional CL. This tendency was much more clear-cut in rats in the continuous lighting. In immature rats in which pseudopregnancy was induced by PMSG and hCG treatment, 20 alpha-HSD activity peaked twice. The first small peak was attributed to the early regression of some of the large number of corpora lutea, and the changes in 20 alpha-HSD activity in most of the corpora lutea paralleled those in rats in continuous lighting. Bromocriptine abolished the prolactin surges, and in normal pseudopregnant rats an increase in 20 alpha-HSD activity in functional CL started from 12 h and the rate of the increase was accelerated from 36 h afterwards, while a relatively small increase was observed in the residue at 18 h and later.(ABSTRACT TRUNCATED AT 250 WORDS)
Two review authors independently assessed a single trial for inclusion, evaluated trial quality and extracted data. Data were checked for accuracy.
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Bilateral Vim stimulation suppressed both extremity and orolingual tremors which interfered with daily living activities such as eating and swallowing.
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The Cochrane Subfertility Review Group specialised register of controlled trials was searched.
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Secondary diabetes mellitus is known to occur in acromegaly due to insulin resistance caused by growth hormone excess. However, diabetes in acromegaly usually does not lead to ketosis. We describe an unusual case of a patient that presented with diabetic ketoacidosis in the emergency room with thirst, polyuria and dyspnoea. The patient was subsequently diagnosed with a growth hormone-secreting pitutary macroadenoma as the underlying pathology; after initial stabilisation with insulin and fluids, the patient was successfully treated with trans-sphenoidal surgery.
Extracellular single-cell recording and microiontophoretic techniques were used to characterize the presynaptic dopamine (DA) receptors (autoreceptors) on A10 DA neurons in the rat ventral tegmental area. Thus, the ability of various agonists to inhibit the activity of A10 DA neurons was compared. DA and the DA agonists N-n-propylnorapomorphine (NPA), apomorphine, lisuride, pergolide, LY141865 and bromocriptine all suppressed the activity of A10DA neurons. NPA was the most potent exogenous agonist, exerting effects that were similar to an equimolar concentration of DA (0.01 M). When ejected at equimolar concentrations (0.01 M) and equivalent ejection currents, the rank order of potency for these agonists was DA = NPA greater than LY141865 greater than pergolide = lisuride = apomorphine greater than norepinephrine greater than bromocriptine. The alpha-2 adrenoceptor agonist clonidine, the beta adrenoceptor agonist isoproterenol, the D-1 specific DA agonist SKF 38393 and the hallucinogenic ergot lysergic acid diethylamide exerted only weak effects or were inactive. The D-2 specific DA antagonist sulpiride completely blocked the rate-suppressant effects of DA and DA agonists but not those of gamma-aminobutyric acid. The purported D-1 specific DA antagonist SCH 23390 failed to block the effects of either DA or the D-2 specific DA agonist LY141865. These results indicate that DA agonists suppress the activity of the majority of A10 DA neurons by acting directly on somatodendritic DA autoreceptors which exhibit the pharmacological characteristics of D-2 receptors.
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Using the MEDLINE and Cochrane Library Central databases, we selected clinical trials that allowed paired comparisons of bromocriptine with the most frequently prescribed dopamine receptor agonists in PD (ie, pergolide, piribedil, pramipexole, and ropinirole). From these data, we calculated dose equivalents of optimal daily doses for each pair of dopamine receptor agonists.