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The effect of the somatostatin analog SMS 201-995 on normal growth hormone secretion in the rat. A comparison with the effect of bromocriptine on normal prolactin secretion.

The somatostatin analog SMS 201-995 was recently shown to be effective in suppressing GH secretion and in causing tumour shrinkage in patients with GH-secreting pituitary tumours. In this respect, the action of SMS 201-995 seems similar to that of the dopamine-agonist bromocriptine in patients with PRL-secreting pituitary tumours. In the present study we compared the respective effects of SMS 201-995 and bromocriptine on normal rat GH and PRL release in vivo and in vitro. Both in vitro and in vivo, repeated administration of SMS for up till 6 days suppressed circulating GH concentrations, and the ability of the pituitary glands to release GH in vitro. A dose-dependent diminution occurred of the total pituitary GH content in rats treated in vivo with SMS 201-995 for 4-6 days. During short-term in vitro incubation for only 4 h, the total amount of GH measured in the medium + gland was also diminished. Chronic administration with SMS 201-995 (2 micrograms/kg twice daily for 15 days), however, resulted in a complete desensitization of its inhibitory effect on GH synthesis and release. In similar experiments it was shown that the dopamine agonist bromocriptine affects normal PRL secretion in a different manner. Both in vitro (10 nmol/l) and in vivo administration for 6 days (0.2 mg/kg twice daily) greatly inhibited circulating PRL levels and the ability of the pituitary glands to release PRL in vitro. This is, however, in all instances accompanied by an accumulation of PRL within the pituitary gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Direct effects of bromocriptine on the steroidogenic capability of porcine granulosa cells.

The direct effects of bromocriptine on steroidogenesis were examined in cultured porcine granulosa cells. The following observations were made with bromocriptine: (1) It significantly increased the basal or FSH-stimulated secretion of progesterone in cultured porcine granulosa cells at concentrations exceeding 10(-7) mol/l; (2) its inhibitory effect on basal estradiol secretion was demonstrated; (3) it did not influence cell number in cultured porcine granulosa cells; (4) it increased the extracellular accumulation of cAMP in a concentration-dependent manner; and (5) it did not induce a change in cytosolic free Ca2+ concentration. These findings suggest that bromocriptine exerts a direct effect on steroidogenesis in ovarian granulosa cells.

Animals↗

Effect of long-term treatment with bromocriptine on the growth hormone response to galanin in patients with acromegaly.

Galanin elicits growth hormone (GH) secretion in normal man but may cause a paradoxical fall of GH in acromegaly. The aim of our study was to investigate the effects of long-term treatment with bromocriptine on the galanin-induced GH decrease in acromegalic subjects. Six acromegalic patients (5F, 1M) chronically treated with bromocriptine underwent in randomized order: (i) iv infusion of 100 ml saline from 0 to 45 min and (ii) iv infusion of synthetic porcine galanin (0.5 mg in 100 ml saline) from 0 to 45 min. In acromegalic patients, GH values fell from baseline (10.5 +/- 2.7 micrograms/l) to a mean nadir of 6.9 +/- 2.2 micrograms/l after galanin infusion (57.8 +/- 9.4% vs basal levels). Saline infusion did not cause any change in circulating GH levels. The mean change in GH values with respect to baseline after galanin in these subjects significantly differed from that observed after saline from time 15 to 90 min. Serum prolactin levels were not significantly affected by galanin. Our results confirm that the dose of galanin capable of increasing plasma GH levels in normal subjects can decrease GH values in patients with acromegaly. Moreover, our data show that this paradoxical GH decrease induced by galanin can also be observed in patients chronically treated with bromocriptine. Therefore, the paradoxical decreasing effect of galanin on plasma GH levels in acromegaly seems not to be mediated via dopaminergic pathways.

Acromegaly↗

Plasma calcitonin, IGF-I levels and vertebral bone mineral density in hyperprolactinemic women during bromocriptine treatment.

Hyperprolactinemia is associated with decreased bone mineral density, which may be caused by the hypogonadism and hypoestrogenicity noticed in patients with hyperprolactinemia. Since calcitonin inhibits the bone resorption, and insulin-like growth factor I (IGF-I) has important anabolic effects on the skeleton, lack of one or both peptides may contribute to the development of osteopenia. We therefore measured the plasma calcitonin and IGF-I levels in nine women with hyperprolactinemia caused by a prolactin-producing pituitary tumor. The calcium-stimulated C-cell reactivity was studied by measuring calcitonin in plasma during a calcium clamp before and after normalization of serum prolactin during treatment with bromocriptine. Basal CT levels were measurable but lower than in healthy controls. Basal IGF-I levels and calcium-stimulated plasma calcitonin were normal in the hyperprolactinemic state and similar to the calcitonin and IGF-I levels during bromocriptine treatment. The serum prolactin levels decreased (p < 0.001) and the serum estradiol levels increased (p < 0.001). The bone mineral density of the lumbar spine increased significantly during treatment. Thus, basal plasma CT levels are slightly reduced in hyperprolactinemic women. However, the reversible osteopenia in hyperprolactinemic women is less likely to be caused by inhibited IGF-I secretion or by deficient CT levels since the CT response to calcium is normal. In addition, bromocriptine treatment with normalization of prolactin levels is beneficial for the bone mineral content in this condition.

Adult↗

Suppression of luteal function in dogs by luteinizing hormone antiserum and by bromocriptine.

Beagle bitches were treated with equine anti-LH serum (ALHS) or the dopamine agonist bromocriptine at selected times during the 2-month luteal phase of the ovarian cycle or pregnancy. After a single injection of ALHS (10 ml, i.m.) at Day 42 of pregnancy (N = 2) or the ovarian cycle (N = 3), progesterone was reduced (P less than 0.05) to 7-24% of preinjection values within 1-2 days, and by 4-8 days returned to levels not different from those in control bitches treated with normal horse serum. Injections of bromocriptine (0.1 mg/kg, i.m.) daily for 6 days caused abrupt declines in progesterone which lasted 6-8 days in bitches treated at Day 8 or 22 of pregnancy (N = 5). In bitches treated at Day 42 of pregnancy (N = 3) or in non-pregnant cycles (N = 4) the bromocriptine treatment caused declines (P less than 0.05) in progesterone which were permanent, extensive (less than 2 ng/ml), and therefore abortive. The declines in progesterone in response to immunoneutralization of LH and to prolactin-lowering doses of a dopamine agonist demonstrate that normal luteal function in dogs requires both LH and prolactin.

Animals↗

Mammary growth during pregnancy in hypophysectomized or bromocriptine-treated goats.

Mammogenesis in primiparous hypophysectomized goats has been assessed between days 60 and 120 of gestation and compared with that found in untreated goats and goats treated with 5 mg bromocriptine/day. There were fivefold increases in the weight of lobulo-alveolar tissue in the hypophysectomized and bromocriptine-treated goats and a tenfold increase in the untreated goats. Histological examination of the mammary glands at 120 days showed normal structure, and determinations of lactose, lactose synthetase, cytosol enzymes, protein, DNA and RNA indicated qualitatively normal initiation of milk synthetic capabilities in both the hypophysectomized and bromocriptine-treated goats. Bromocriptine treatment lowered the plasma concentration of placental lactogen as well as that of prolactin. The results indicate that placental lactogen has important mammogenic effects during pregnancy.

Animals↗

Effect of bromocriptine on DNA synthesis, growth and hormone secretion of spontaneous pituitary tumours in the rat.

The 'spontaneous' development of pituitary tumours has been studied in the Wistar-Furth strain of rat. In females aged 64--135 weeks the incidence was as high as 69% whereas in males aged 72--116 weeks only 6% developed tumours. Hyperprolactinaemia was invariably associated with these spontaneous pituitary tumours but excessive secretion of growth hormone (GH) was found in one animal only. Bromocriptine inhibited secretion of prolactin and DNA synthesis of the tumours. In a mixed GH- and prolactin-secreting tumour transplanted to a peripheral site, bromocriptine reduced the size of the tumour as well as the secretion of both hormones. Oestradiol reversed the inhibitory action of bromocriptine on prolactin secretion and tumour growth but failed to influence the reduction in GH secretion caused by the drug.

Animals↗

Effects of chronic long-acting bromocriptine treatment on liveweight, voluntary food intake, coat growth and breeding season in non-pregnant red deer hinds.

Seventeen red deer hinds were housed in individual pens and from 28 February until 11 November were injected each week with vehicle (group A; n = 6) or 5 (group B; n = 6) or 12.5 mg (group C; n = 5) of a long-acting formulation of bromocriptine. Liveweight and voluntary food intake (VFI) were recorded for each hind, and blood was collected for determination of progesterone, prolactin, tri-iodothyronine (T3) and cortisol concentrations by radioimmunoassay. Treatment with the high dose of bromocriptine was associated with a significant (P less than 0.05) reduction in VFI, with the effect being greatest between March and July. There was no treatment effect on liveweight, but there was a significant (P less than 0.01) interaction between time and treatment due to the faster rate of weight gain in control animals at the beginning of the experiment. Changes in liveweight could be explained by changes in VFI rather than by changes in the efficiency of utilization of intake. Termination of the breeding season was significantly (P less than 0.01) delayed by 54 days in group C hinds. Growth of the summer coat and subsequent winter coats was delayed by 1 and 3 months respectively in group C hinds, and in groups B and C the duration that animals were in summer coat was increased by about 1 month. The seasonal increase in prolactin concentrations was seen in all groups, but levels were significantly (P less than 0.05) lower in group C hinds. Concentrations of T3 and cortisol were not affected by bromocriptine.

Animals↗

Photoperiod and bromocriptine treatment effects on expression of prolactin receptor mRNA in bovine liver, mammary gland and peripheral blood lymphocytes.

Recent evidence suggests that photoperiod influences immune function. Interestingly, photoperiod has profound effects on concentrations of prolactin (PRL), a hormone also known to be involved in fluctuations of the immune system. However, the impact of photoperiod on PRL receptor (PRL-R) expression is poorly understood, particularly in tIssues of the immune system. Two experiments were performed to increase the general understanding of how photoperiod interacts with the immune system. Our first objective was to determine the effects of photoperiod on PRL-R mRNA expression and cellular immune function. Lymphocytes were isolated from blood collected from calves (n=10) and PRL-R mRNA expression of both long and short forms was quantified using real-time PCR. Lymphocytes expressed PRL-R mRNA, suggesting that PRL could act directly on these cells. To determine the relationship between photoperiod and PRL-R mRNA expression in other tIssues, hepatic and mammary biopsies were collected after calves were exposed to long days (LDPP; 16 h light:8 h darkness) or short days (SDPP; 8 h light:16 h darkness). Relative to LDPP, SDPP decreased circulating PRL, but increased expression of both forms of PRL-R mRNA in liver, mammary gland and lymphocytes. Short days also increased lymphocyte proliferation compared with long days. Reversal of photoperiodic treatments reversed the effects on circulating PRL, PRL-R mRNA expression and lymphocyte proliferation. Our second objective was to manipulate PRL concentration in photoperiod-treated animals, using bromocriptine. Concentrations of PRL in LDPP animals injected daily with bromocriptine for 1 week were decreased compared with LDPP controls, to a level similar to SDPP animals. Receptor expression was increased in LDPP+bromocriptine-treated animals relative to LDPP controls, as was lymphocyte proliferation. Overall, our results indicate that photoperiodic effects on PRL-R mRNA expression were inverse to those on circulating PRL, with short days stimulating expression of both forms of PRL-R mRNA. Expression of PRL-R mRNA changed in the same direction as lymphocyte proliferation with regard to photoperiod treatment, suggesting a link between photoperiodic effects on PRL sensitivity and immune function. Thus, PRL signaling may mediate photoperiodic effects on immune function.

Animals↗

Use of bromocriptine in hyperprolactinaemic anovulation and related disorders.

Bromocriptine has been successfully used to treat hyperprolactinaemic disorders of ovulation; treatment with 5.0 to 7.5 mg daily results in normalisation of serum prolactin concentration and restoration of ovulatory menstruation in most patients with hyperprolactinaemic amenorrhoea or oligomenorrhoea. It is equally effective in hyperprolactinaemic patients with pituitary tumours as in those with normal pituitary x-rays, but the choice of bromocriptine as primary treatment in the former group (especially in those patients who desire pregnancy) is a matter of some controversy and requires careful judgement. Bromocriptine has also been used, with reported success, in infertility associated with luteal insufficiency, the polycystic ovary syndrome, normoprolactinaemic amenorhoea and ovulatory infertility. However, its role in the treatment of these disorders will remain uncertain until more extensive, adequately controlled clinical trials are availabe.

Amenorrhea↗

Bromocriptine in the treatment of parkinsonism.

Bromocriptine alters the motor behaviour of animals and improves the motor defect of parkinsonism. Changes in movement are accompanied by biochemical changes in the central nervous system, consistent with the idea that bromocriptine has a dopamine agonist action in the basal ganglia and also in the mesolimbic system and hypothalamus. The overall anti-parkinsonian effect of bromocriptine is similar to that of l-dopa alone or with benserazide (a decarboxylase inhibitor) when optimum doses are used, although individual patients may respond better to 1 drug than to the other.

Apomorphine↗

Cyclic Cushing's disease in long-term remission with a daily low dose of bromocriptine.

A 56-year-old male patient with cyclic Cushing's disease remained in a state of remission for more than one year with a relatively low dose of bromocriptine (2.5-3.75 mg/day). It has been reported that bromocriptine treatment for cyclic Cushing's disease induces only a transient remission; in the most effective cases, a relatively high dose (40 mg/day) was necessary. In the hypercortisolemic state, plasma adrenocorticotropic hormone (ACTH) and serum cortisol were not suppressed by dexamethasone and did not respond to corticotropin-releasing factor (CRF). An antehypophysectomy was not effective, even though the resected tissue contained ACTH-positive microadenomas. The present observations thus indicate the effectiveness of bromocriptine for some patients with this rare disorder.

Adenoma↗

Bromocriptine-induced morphological changes in cultured growth hormone-producing pituitary adenoma cells.

Tumor tissues obtained from two patients with growth hormone-producing pituitary adenomas were cultured and treated with bromocriptine, then examined for morphological changes. Untreated tumor cells (controls) were morphologically well preserved and in terms of growth hormone secretion. Tumor cells exposed to bromocriptine for 7 days contained many vacuoles, which, after 14 days of exposure, grew larger and more numerous. These vacuoles appeared to be extensions of endoplasmic reticulum: some were connected to rough or smooth endoplasmic reticulum or, occasionally, to Golgi apparatus, and there were ribosomes on their surfaces. Bromocriptine apparently has cytocidal effects on growth hormone-producing pituitary adenoma in vitro.

Adenoma↗

Bromocriptine given orally to periparturient of lactating sows inhibits milk production.

Gilts were assigned as controls (CTL, n = 6) or received orally 10 mg of bromocriptine thrice daily from d 110 of gestation until farrowing, (BRPP, n = 7), from d 1 to 6 postpartum (PP) (BRL1, n = 6), from d 7 to 13 PP (BRL2, n = 7), from d 14 to 20 PP (BRL3, n = 6), or from d 21 to 27 PP (BRL4, n = 6). Weights of pigs were recorded at birth, 24 h later, and on d 7, 14, 21, 28, 31 (weaning), 42, and 56 PP. Jugular blood samples were collected from sows on d 109 of gestation and every other day until farrowing, as well as on d 1, 6, 13, 20, and 27 PP. Behavioral observations of sows and litters were taken every 3 min for a 24-h period beginning 48 h after the onset of the treatments. In experimental sows, bromocriptine induced marked reductions in prolactin levels during treatment (P < .001). Compared to CTL sows, concentrations of IGF-I were higher at d 21 (P = .01) and 28 (P = .003) PP in BRL3 and BRL4 sows, respectively. In bromocriptine-treated sows, weight gain of litters was either drastically reduced or abolished (P < .001) during the week of treatment. Treatments also altered significantly the suckling behavior of pigs at all stages studied. Therefore, the present results strongly suggest that prolactin is essential for the initiation and the maintenance of milk production in sows. Results also indicate that prolactin does not seem to be involved in the maintenance of lactational anestrus during a 4-wk lactation.

Administration, Oral↗

Inhibition of puerperal lactation. A double blind study of bromocriptine and placebo.

Bromocriptine and placebo were randomly allocated for three weeks to 52 postpartum patients requiring lactation suppression. Bromocriptine significantly lowered plasma prolactin levels and suppressed breast milk, breast pain and engorgement quicker than placebo. No side-effects were noted and rebound lactation did not occur. Menstruation appeared to re-start sooner when Bromocriptine was given.

Bromocriptine↗

Treatment of hyperprolactinemic luteal insufficiency with bromocriptine.

Twelve patients with infertility and insufficent luteal function were studied during a control cycle, and during a cycle when 2.5 mg of bromocriptine was given twice daily. Serum levels of prolactin, progesterone, estradiol-17-beta, FSH and LH were determined during both cycles. Endometrial biopsies were taken from most patients during the late luteal phase. Two patients had persistent hyperprolactinemia, approximately 35-45 ng/ml, and both had repeated insufficient luteal function, which completely reverted to normal during treatment. Five of the 10 normoprolactinemic patients achieved a normal luteal function during bromocriptine therapy. No pregnancies were achieved during the study but one patient later conceived during bromocriptine therapy.

Adult↗

Gynecological follow-up of parkinsonian patients on long-term bromocriptine treatment.

Bromocriptine given for prolonged times at high doses has been found to induce tumors in the uterus in aged rats. To elucidate the possible tumorigenic effect of long-term treatment with bromocriptine in humans, 35 women treated with this drug for chronic parkinsonism were studied. For each patient a gynecological anamnesis and examination were performed; one or several cervicovaginal smears and endometrial samples were also taken, by jetwash. No evidence of malignant changes was seen. Thus, in this respect bromocriptine would appear to be a safe drug, even for long-term use.

Adult↗

Bromocriptine for treatment of benign breast disease. A double-blind clinical trial versus placebo.

Over the last few years bromocriptine has been used for treatment of mastodynia and benign breast disease, but with contradictory results. This double-blind clinical trial was performed to determine the efficacy of this prolactin inhibitor as compared with placebo. Subjective discomfort, clinical examination of the breast lesions, echomammography and breast thermography were evaluated before, during and after 3 months of treatment and in a further follow-up. Plasma levels of estradiol, progesterone and prolactin were measured over the same time. Significant reduction of mastodynia and significant improvement of the breast lesions were observed in the group given bromocriptine, though echomammography and breast thermography did not reveal any significant differences between the two groups. Plasma prolactin levels were significantly reduced by bromocriptine administration.

Adult↗