Effects of bromocriptine on central dopaminergic receptors.

Bromocriptine injected to rats induces an increase of cAMP levels in the striatum in vivo. The time course of this increase is very similar to that of apomorphine. However bromocriptine does not stimulate striatal dopamine-sensitive adenylate cyclase but surprisingly antagonized the activation of this enzyme elicited by dopamine. Possible hypotheses on various sites of action of the drug are discussed.     

Effects of chronic bromocriptine treatment of an estrone-induced, prolactin-secreting rat pituitary adenoma

Bromocriptine (BROM), a dopamine (DA) agonist, is commonly and successfully used for long-term treatment of human prolactinomas. We have studied the effects of chronic BROM administration to female 344 Fisher/Lis rats bearing an estrone-induced, prolactin (PRL)-secreting pituitary tumor recently characterized as a model for human prolactinoma. The animals were injected twice daily with BROM (2.5 mg/kg) or with diluent. After 1 month of treatment, the animals were sacrificed, and plasma collected and stored at -20 degrees C for PRL radioimmunoassay. The pituitary tumors were removed and tumoral mammotrophs dispersed enzymatically for studies of DA receptor binding and PRL release in vitro. BROM treatment significantly reduced tumor weight, cell size, rough endoplasmic reticulum, Golgi complexes and plasma PRL levels. [3H]-spiroperidol binding to tumoral mammotrophs was also evaluated. BROM induced a significant decrease in the number of DA binding sites without any changes in affinity. These results indicate that chronic BROM treatment of an animal model of prolactinoma induces tumor involution, reduction of PRL release and probably synthesis, and down regulation of dopaminergic binding sites.     

Serum growth hormone levels and size of pituitary tumour in untreated acromegaly

Serum levels of growth hormone were measured in 84 untreated acromegalic patients. The range of mean level during a glucose tolerance test was 8 to 1,860 ng./ml. and was lognormally distributed. Mean level was reproducible and correlated moderately well with maximum sellar area on lateral tomography. The hormone level was more responsive to oral glucose and insulin-induced hypoglycaemia in patients with smaller tumours. Attention is drawn to limitations of plain radiographs in assessing the size of a pituitary tumour. Suprasellar tumour extensions may be present in patients without visual field defects.     

Reduction of pituitary tumor size with clinical and biochemical improvement with bromocriptine in a normoprolactinemic Cushing's disease

We report a 37-year old Japanese female patient with Cushing's disease who was treated with a large daily dose of bromocriptine, which resulted in the reduction of the pituitary tumor size with clinical and biochemical improvements. On admission, the pituitary tumor size detected by magnetic resonance imaging (MRI) was 12.4 x 11.1 x 6.2 mm. Both the basal plasma prolactin level and its response to TRH test were normal. The patient was treated with bromocriptine at 5 to 35 mg/day. With 35 mg daily, 24-h urinary free cortisol started to decrease and eventually became normal. Four months after initiation of treatment with the drug, there was clinical remission with normalization of suppressibility of plasma cortisol with 1 mg dexamethasone. Repeated examination of the pituitary fossa by MRI showed a marked reduction in the tumor size (6.3 x 6.2 x 2.4 mm). This is a very rare case in which treatment with bromocriptine resulted in a reduction of the pituitary tumor size as well as clinical and biochemical improvements in a patient with normoprolactinemic Cushing's disease.     

DNA synthesis in lactotrophs of primary rat anterior pituitary cell cultures. Effects of thyroliberin, bromocriptine and somatostatin

Prolactin immunostaining in combination with thymidine autoradiography was used to characterize changes in the DNA-synthesizing activity of lactotrophs in primary monolayer cultures of the rat anterior pituitary gland treated for 3 days with thyroliberin (TRH), somatostatin (SRIF) and bromocriptine (CB 154). The number of lactotrophs labelled with 3H-thymidine within the total pool of labeled pituitary cells was used to estimate DNA synthesis in prolactin-producing cells. TRH (10 ng/ml) stimulated DNA synthesis in the whole population of cultured cells but not in lactotrophs. TRH only weakly counteracted the noticeable inhibitory effect of CB 154 (0.75 microM/l) on thymidine incorporation into lactotrophs. SRIF (20 ng/ml) inhibited DNA synthesis in lactotrophs to a lesser extent than CB 154. The combination of methods used in this paper may be useful for studying the selective effects of regulators on the proliferative activity of various pituitary cell types in vivo and in culture.     

Mixed pituitary tumours--effects of bromocriptine treatment: Parlodel MR and Parlodel LAR.

Majority of pituitary tumours secrete one of the named hormones: PRL, GH, ACTH, proopiomelanocortine, alpha and beta subunit of TSH, LH, and FSH. Some of those tumours secrete two or more hormones. The aim of this study was to determine the effect of bromocriptine (Parlodel MR and LAR) upon secretion of hormones and tumour size in 10 patients with mixed pituitary tumours. In all patients pituitary and peripheral hormones, CT scan and visual fields were examined before and after treatment with bromocriptine: Parlodel MR and LAR. Bromocriptine treatment decreased PRL secretion in all 10 patients; GH--in all 6 in whom it was increased; TSH--in 2, FSH--in 2 and alpha-subunit in all 6 in whom they were increased. In 5 patients treatment resulted in shrinkage of the tumour mass by 20 to 35%. In all examined subjects clinical improvement was achieved. Our results demonstrate that bromocriptine (Parlodel MR and LAR) is very effective and well tolerated in the treatment of patients with mixed pituitary tumours particularly those with hyperprolactinemia.     

Effects of fibroblast growth factor and bromocriptine on the mitotic activity of the anterior pituitary gland in organ culture

Summary Effects of fibroblast growth factor (FGF) and of bromocriptine, a dopaminergic receptor agonist, on the mitotic index in the organ-cultured anterior pituitary gland of the rat were investigated, using the colchicine metaphase-arrest technique. It has been found that FGF increases the mitotic index in the anterior pituitary explants. By contrast bromocriptine inhibits the mitogenic effect of FGF.     

Isolated thyrotropin deficiency due to a pituitary tumour.

Hypothyroidism due to isolated deficiency of thyrotropin (TSH) associated with an enlarged sella turcica, presumably the result of a nonfunctioning pituitary adenoma, occurred in a 58-year-old man. Low serum concentrations of TSH and thyroid hormones, together with the lack of TSH response to administration of thyroid releasing hormone, indicated a pituitary deficiency of TSH. Serum values of other pituitary hormones were normal.     

Regulation of interleukin-1 receptors on AtT-20 mouse pituitary tumour cells.

To study the cellular mechanisms of interleukin-1 (IL-1) in the pituitary corticotroph, we studied the properties of IL-1 receptors on a mouse pituitary ACTH-producing cell line, AtT-20. Scatchard plot analysis revealed a single type of receptor with a Kd (dissociation constant) of 93 pM, and 482 binding sites/cell. [125I]IL-1 alpha binding competed with IL-1 alpha and IL-1 beta in an equimolar fashion. A 24 h pre-incubation with either CRH, epinephrine or nor-epinephrine increased the [125I]IL-1 alpha binding sites in the AtT-20 cells and conversely, a similar pre-incubation with either dexamethasone or tumour necrosis factor-alpha (TNF alpha) decreased them without affecting the affinity of the receptors in either case.     

Dopamine receptors in rat pituitary and estradiol-induced pituitary tumor: effect of chronic treatment with bromocriptine

We have investigated dopamine (DA) receptors in estradiol-induced PRL-secreting pituitary tumors and intact pituitary tissue. Female rats were injected at 3-week intervals with 2 mg estradiol valerate (EV) or with diluent. After 21 weeks, adenomatous changes in the pituitary gland of EV-treated rats were seen and plasma PRL concentrations reached 2 micrograms/ml. Bromocriptine (2.5 mg/kg) was then administered for 1 month to half of the control rats and half of the rats bearing tumors. Anterior pituitary weight was increased in EV-treated rats compared to controls while the affinity and the density of DA receptors as assessed by [3H]spiperone binding remained unchanged. Bromocriptine (CB-154) induced a 70% decrease in the density of DA receptors without any change in affinity both in normal pituitaries and in tumors. Concurrently, the elevated plasma concentrations of PRL in the tumor bearing rats were decreased to control values following the CB-154 treatment. Our data suggest that rats with primary estrogen-induced PRL secreting tumors have normal pituitary DA receptors.     

Effects of bromocriptine and alpha-flupenthixol on sleep in REM sleep deprived rats.

Administration of bromocriptine mesylate (5 mg/kg, i.p.), a dopamine receptor stimulant, to rats which were deprived of REM sleep for 24 hours resulted in a significant increase in wakefulness as well as significant reduction of REM sleep during the first 5 hours of EEG recording. These effects were completely abolished by pretreatment with α-flupenthixol (0.2 mg/kg, i.p.), a dopamine receptor blocker. The loss of REM sleep has not been regained during the next 25 hours of EEG recording suggesting that the stimulation of dopamine receptors reduced REM sleep without causing subsequent REM rebound. These data raise questions on the negative dopamine control of REM sleep and on the potential use of dopamine stimulants in clinical situations characterized by excessive REM or by REM sleep dysfunction (narcolepsy).     

Effects of LH-RH on isolated pituitary gonadotropic cells.

Rat anterior pituitary glands were dissociated with Pronase and the cells were separated by velocity sedimentation at unit gravity. After 30 min of incubation of the enriched gonadotropic cells with LH-RH, there was a significant increase in LH and FSH in the incubation medium. LH-RH (100 ng/ml) and 10(-3) M cAMP both caused significant increases in LH in the incubation medium after 24 hr of incubation.     

Effects of bromocriptine on sweat gland function during heat acclimatization

This study examined the involvement of the hormones aldosterone and prolactin in sweat gland function during heat acclimatization. Two groups of male subjects (n = 8) were tested - one receiving a placebo (control), the other receiving bromocriptine. Both groups performed cycle ergometer exercise at 50% of maximal oxygen uptake over 10 consecutive days in an environmental chamber maintained at 39 degrees C and 30% relative humidity. Duration of exercise was 90 min on days 2-4 and 6-9, and 45 min on test days 1, 5 and 10. Electrolyte concentrations were determined by total body washdown. Prolactin increased (p less than 0.001) during exercise on day 1 in the control group but not on days 5 and 10. In contrast, prolactin was suppressed by bromocriptine and did not rise in response to exercise or heat exposure. Plasma aldosterone increased during exercise in both groups, showing no differences between groups. The sodium concentration in sweat decreased significantly (p less than 0.05) in the control group from day 1 to 10 but was unchanged in the treatment group. These data suggest that acclimatization-related changes in sweat gland function may be attenuated by increases in central dopaminergic activity and implicate prolactin in control of sweat gland function.     

Caveolin-1 sensitizes rat pituitary adenoma GH3 cells to bromocriptine induced apoptosis

Background  

Prolactinoma is the most frequent pituitary tumor in humans. The dopamine D₂ receptor agonist bromocriptine has been widely used clinically to treat human breast tumor and prolactinoma through inhibition of hyperprolactinemia and induction of tumor cell apoptosis, respectively, but the molecular mechanism of bromocriptine induction of pituitary tumor apoptosis remains unclear. Caveolin-1 is a membrane-anchored protein enriched on caveolae, inverted flask-shaped invaginations on plasma membranes where signal transduction molecules are concentrated. Currently, caveolin-1 is thought to be a negative regulator of cellular proliferation and an enhancer of apoptosis by blocking signal transduction between cell surface membrane receptors and intracellular signaling protein cascades. Rat pituitary adenoma GH3 cells, which express endogenous caveolin-1, exhibit increased apoptosis and shrinkage after exposure to bromocriptine. Hence, the GH3 cell line is an ideal model for studying the molecular action of bromocriptine on prolactinoma.     

Validity of radioimmunoassay for blood and pituitary prolactin in the male rat. Effect of bromocriptine and thyrotropin-releasing hormone

Validity of a radioimmunoassay for rat prolactin (PRL) in serum and pituitary is analysed in adult male rats. Data are presented bearing on the accuracy, precision and sensitivity of the method. Serum levels and pituitary content are respectively ranged from 2.56 to 28.03 ng PRL RP2 ml-1 and from 7.36 to 21.44 microgram PRL RP2 per gland in intact animals. Treatment with bromocriptine (10 days) results in a decrease of serum PRL levels and pituitary PRL contents. In progesterone-estradiol benzoate pretreated rats, serum PRL levels are increased 20 min after the injection of TRH.     

Effects of morphine on tumour growth

Endogenous opiate alkaloids, such as morphine, and their peptide counterparts have been implicated in a wide variety of pharmacological and physiological functions. In addition to their use in the treatment of pain, opioids, appears to be important in the growth regulation of normal and neoplastic tissue. This review will focus on the influence of endogenous and exogenous opioids on tumour growth, with emphasis on immunoregulatory and antiproliferative mechanisms.