Bromocriptine Withdrawal Research Articles

Worsening of Migraine Associated with Hyperprolactinemia

A 45-year-old woman presented with worsening of migraine without aura. Laboratory test revealed hyperprolactinemia, but brain magnetic resonance imaging was normal. She had no known etiologies of hyperprolactinemia. Headache improved together with normalization of serum prolactin level after administration of bromocriptine. However, withdrawal of bromocriptine caused elevation of serum prolactin level and worsening of migraine headache. She repeated similar pattern of improvement and aggravation two times more. We suggest that hyperprolactinemia may cause aggravation of migraine headache.

Withdrawal of dopamine agonist therapy in prolactinomas: In which patients and when?

The aim of the study was to assess the effect of dopamine agonist (DA) withdrawal, the current recurrence rate of hyperprolactinemia, and possible factors that predict recurrence in patients with prolactinoma. We evaluated DA withdrawal in 67 patients with prolactinoma (50 female/17 male) who received DA treatment for at least 2years and showed normalization of prolactin (PRL) levels and tumor disappearance or ≥50% tumor shrinkage, retrospectively. Accordingly, patients were divided into two groups as remission and recurrence groups, and factors that predict recurrence were evaluated. The overall remission rate was 46%; the remission ratios were 65% in microprolactinomas and 36% in macroprolactinomas. Remission rates were 39% in the bromocriptine withdrawal group and 55% in the cabergoline withdrawal group. The maximum tumor diameter and baseline PRL levels were significantly higher in the recurrence group (p=0.001 and p=0.003, respectively). The mean duration of DA therapy was significantly longer in the remission group (88.7±48.1 and 66.7±30.4months, respectively, p=0.026).The mean time to recurrence was 5.3±3.2months. The mean PRL levels at recurrence time were significantly lower than baseline PRL levels (p=0.001). The most important predictors of recurrence were maximum tumor diameter and baseline PRL levels in this study. The remission rate in our study group was higher, which was thought to be associated with the longer duration of DA treatment and that our patients were selected according to certain criteria. Despite these positive results, close monitoring is necessary for detection of early and late recurrence, especially within the first year after DA withdrawal.

Bromocriptine withdrawal

Bromocriptine withdrawal

Neuroleptic malignant syndrome associated with bromocriptine withdrawal in Parkinson's disease — a case report

A 74-year-old man had 15-year history of Parkinson's disease and received bromocriptine monotherapy for 3 years. We present the first case report of neuroleptic malignant syndrome associated with the withdrawal of bromocriptine. The symptoms were alleviated by adequate replenishment of intravenous fluid, temperature reduction and replacement of bromocriptine. Clinicians need to be aware of this potential complication and that a thorough history of current medications is crucial to its identification.

Long-Term Follow-Up of Prolactinomas: Normoprolactinemia After Bromocriptine Withdrawal

Long-term bromocriptine (BRC) therapy has been considered necessary in patients with prolactinoma, with discontinuance often followed by recurrent hyperprolactinemia and, at least after short-term treatment, regrowth of tumor. There are, however, some reports that these adverse effects are not inevitable. The present study examined the effects of BRC withdrawal in a series of 350 patients, 280 females and 70 males aged 10 to 70 years, with prolactinomas. Prolactin levels were followed after withdrawal of BRC in this retrospective study. Primary treatment was with BRC in 301 patients, the median dose being 5 mg. Seventy-two patients who continued having high serum prolactin despite surgery received BRC in a median dose of 7.9 mg. Of 131 patients with prolactinoma who achieved normal prolactin levels during BRC therapy, 27(20.6%) continued to have normal levels after withdrawal of the drug when followed for a median time of 44 months. No macroprolactinoma was seen to reexpand when monitored by CT and/or MR imaging. Persistently normal prolactin levels after drug withdrawal could not be predicted by patient age or gender, tumor size, the pretreatment prolactin level, the initial dose of BRC, or the time of treatment. Pregnancy, past surgery, and radiotherapy also failed to influence the course after withdrawal of BRC. About one in five prolactinoma patients in this study who received BRC maintained normal serum prolactin levels after withdrawal of the drug. The investigators believe that gradual dose reduction is worthwhile in patients with prolactinoma whose serum prolactin becomes normal during treatment with BRC or another dopamine agonist.

Long-term follow-up of prolactinomas: normoprolactinemia after bromocriptine withdrawal.

Bromocriptine (BRC) and other dopamine agonist drugs are the first-choice treatment for prolactinomas. However, the major disadvantage is the need for prolonged therapy. We retrospectively studied 131 patients [62 microprolactinoma (MIC), 69 macroprolactinoma (MAC)], who achieved serum prolactin (PRL) normalization during BRC use. Twenty-seven percent of them (31% MIC and 69% MAC) underwent previous surgery. Twenty-seven patients (20.6%: 25.8% MIC and 15.9% MAC) persisted with normoprolactinemia after a median time of 44 months of BRC withdrawal. The median time of BRC use was 47 months. There were no statistically significant differences regarding age, gender, BRC initial dose, length of BRC use, tumor size, pregnancy during treatment, previous surgery, or radiotherapy among patients who persisted with normoprolactinemia and those who did not, using both univariate and multivariate analysis. BRC-induced prolactinoma cell alterations are highly controversial; and so, whether the mechanism of PRL normalization after BRC withdrawal is related to BRC use or whether it is attributable to natural history is a matter for debate. A periodic assessment of PRL levels during BRC (and other dopamine-agonist drugs) withdrawal is recommended to avoid the unnecessary maintenance of therapy in a subset of patients with prolactinomas.

Long-Term Follow-Up of Prolactinomas: Normoprolactinemia after Bromocriptine Withdrawal

Long-Term Follow-Up of Prolactinomas: Normoprolactinemia after Bromocriptine Withdrawal

Questioning the Cardioprotective Effect of Bromocriptine Treatment

To the Editor: I read with interest the paper “Centrally Mediated Effects of Bromocriptine on Cardiac Sympathovagal Balance” by Drs Franchi, Lazzeri, Barletta, Ianni, and Mannelli, which was published in July 2001.1 The authors cite a report by Przuntek et al2 published in 1992 that suggested that bromocriptine treatment lessened mortality in patients with Parkinson disease. The authors presumed that this putative cardioprotective effect can be related to withdrawal of cardiac sympathetic activity leading to fewer life-threatening ventricular arrhythmias. Unfortunately, the authors failed to mention that since 1992, long-term studies in Australia3 and France4 have failed to replicate the findings cited in the Przuntek paper. The Australian and French studies were of 10-year durations and found no evidence of a cardioprotective effect from bromocriptine. Over the past 25 years, bromocriptine has been studied in the treatment of clinical indications such as acromegaly, hyperprolactinemia, postpartum lactation suppression, cocaine craving, and diabetes mellitus, in addition to Parkinson disease. Rather than a cardioprotective effect, bromocriptine shares with other ergot alkaloids the property of vasoconstriction, with the potential for serious tissue injury. Hypertension5 and cardiac injury6 have been reported in association with bromocriptine use in lactation suppression. Seizures and myocardial infarction were reported in association with bromocriptine use in the treatment of cocaine craving, which led the Italian Health Ministry to request the withdrawal of bromocriptine for use in cocaine craving.7 Finally, in clinical trials of bromocriptine for the treatment of Type 2 diabetes presented to the Food and Drug Administration, a relative risk of myocardial infarction of 2.9 after bromocriptine treatment was found.8 In the design of the study by Franchi and colleagues, the investigators used single oral doses of bromocriptine with measurements at baseline and 180 minutes after bromocriptine administration. It has long been …

Effects of chronic bromocriptine treatment on tyrosine hydroxylase (TH) mRNA expression, TH activity and median eminence dopamine concentrations in ageing rats.

The purpose of this study was to investigate the age-related changes in the responsiveness of tuberoinfundibular dopamine (TIDA) neurones to chronic hypoprolactinemia induced by treatment with bromocriptine, a dopamine receptor agonist. In one experiment, TIDA neuronal activity after acute hypoprolactinemia or exogenous prolactin was monitored by measuring tyrosine hydroxylase (TH) activity in the stalk median eminence of middle-aged cycling female rats (10-12 months), old constant oestrous rats (18-20 months) and old pseudopregnant rats (22-24 months). In another experiment, middle-aged cycling (10-12 months) rats were treated with bromocriptine for 6 or 12 months. TH activity was measured in the stalk median eminence, TH mRNA levels were measured in the arcuate nucleus and dopamine concentrations were measured in the arcuate nucleus and median eminence. Responsiveness of TIDA neurones to exogenous prolactin and to the withdrawal of bromocriptine in these rats was also tested. While the TIDA neurones in all three age groups responded to acute hypoprolactinemia by showing a reduction in TH activity, older rats failed to respond to exogenous prolactin administration. In contrast, chronic hypoprolactinemia for 12 months enabled the rats to retain TIDA neuronal responsiveness to exogenous prolactin. It also decreased TIDA neuronal function as measured by dopamine concentrations in the median eminence, TH activity in the stalk median eminence and TH mRNA in the arcuate nucleus of ageing rats. The restoration of the responsiveness of these neurones to prolactin stimulation in older rats demonstrates for the first time that hypoprolactinemia produced by chronic bromocriptine treatment indeed provides a neuroprotective effect on TIDA neurones. These results indicate that maintaining a low level of neuronal activity by lowering prolactin levels may be a contributing factor in retaining the plasticity of TIDA neurones.

Bromocriptine-induced cerebrospinal fluid fistula in patients with macroprolactinomas: Report of three cases and a review of the literature

Bromocriptine therapy for macroprolactinoma induced cerebrospinal fluid (CSF) rhinorrhea in three patients. The tumor had extended well beyond the sella turcica and caused bony erosion in all the cases. All three patients responded to bromocriptine therapy rapidly. CSF fistula occurred concomitantly with the reduction of tumor size and caused meningitis in two of the patients. Withdrawal of bromocriptine resulted in cessation of the leakage. One of the patients underwent transsphenoidal repair. Two patients refused surgery. This potentially lethal complication encountered in these three cases demonstrates the need for close supervision of macro-prolactinoma patients with skull base erosion placed under bromocriptine therapy.

Macroprolactinomas with suprasellar extension: Effect of bromocriptine withdrawal during one or more pregnancies

Macroprolactinomas with suprasellar extension: Effect of bromocriptine withdrawal during one or more pregnancies

Bromocriptine withdrawal

Bromocriptine withdrawal

Macroprolactinomas with suprasellar extension: effect of bromocriptine withdrawal during one or more pregnancies

To investigate the effects of bromocriptine withdrawal during one or more pregnancies in patients who presented with pituitary macroprolactinomas with suprasellar extension. Four infertile patients presenting with a macroprolactinoma with suprasellar extension conceived during treatment with bromocriptine on 10 occasions resulting in eight full-term normal deliveries. Treatment was withheld shortly after conception in each pregnancy. Serum prolactin (PRL) levels fell initially from a mean of 2,776 (range 1,682 to 4,515) to 27 micrograms/L (range 1 to 71) with the development of a partially empty sella in all patients. Recovery of visual field defects occurred in the only affected individual. In case 1, PRL levels remained within the normal range, after bromocriptine withdrawal in the first pregnancy, with the development of an empty sella. Prolactin levels, however, increased substantially in cases 2 to 4. An asymptomatic suprasellar tumor extension returned in cases 2 and 3. After two or more pregnancies (cases 1, 3, and 4), there was a progressive decline in the serum PRL levels. Although still elevated in cases 3 and 4, the PRL levels were considerably below those obtained at presentation or in the first pregnancy. Tumor regression with the development of an empty sella was observed in both these patients as well in their pregnancy or postpartum period. Bromocriptine may be safely withdrawn during pregnancy in patients presenting with a macroprolactinoma. With multiple bromocriptine induced pregnancies, PRL levels and tumor size may progressively decrease with the eventual development of an empty sella.

Bromocriptine treatment over 12 years in acromegaly: effect on growth hormone and prolactin secretion.

It is not known whether bromocriptine treatment in acromegaly can be implemented for a life-long period. To elucidate this problem, the secretory GH and PRL states of 12 patients with acromegaly were determined, before bromocriptine treatment, under therapy (15.0 +/- 6.8 mg/day for 12 +/- 3 years; mean +/- SD) and during two-weeks long drug withdrawal after long-term treatment, respectively. Before therapy, all patients showed a non-sufficient GH suppression after oral glucose load (greater than 2 micrograms/l), whereas under dopaminergic treatment the post-glucose GH levels of three patients fell below 2 micrograms/l; normal IGF-I concentrations were found in five patients. However, under bromocriptine, only two patients showed GH suppressions below 2 micrograms/l following glucose, accompanied with normal IGF-I levels. During bromocriptine withdrawal, GH secretion at 60 min in the oral glucose tolerance test increased significantly (17.0 +/- 15.5 vs 5.7 +/- 5.2 micrograms/l; p less than 0.01); the mean IGF-I level rose from 2.1 +/- 0.8 to 4.9 +/- 2.2 kU/l (p less than 0.01). IGF-I was normal during bromocriptine cessation in only one patient; none of the 12 patients showed a GH suppression below 2 micrograms/l after oral glucose load. Under dopaminergic treatment hyperprolactinemia could not be detected. In conclusion, bromocriptine led to a stable suppression of both GH hypersecretion and--if present--concomitantly elevated PRL levels. Severe side effects or a further tumor growth could not be observed. Thus, the data of the longest follow-up investigation that has so far been published indicate that effective life-long bromocriptine therapy seems to be possible in selected patients with acromegaly.

Effect of bromocriptine withdrawal in acromegaly on body composition as assessed by bioelectrical impedance analysis

To evaluate the effect of bromocriptine withdrawal after dopaminergic long-term treatment (15.0 +/- 6.8 mg/day, mean +/- SD) in 12 acromegalic patients on body composition, bioelectrical impedance was measured before and at the end of two weeks of drug withdrawal. During withdrawal basal hGH and IGF-I increased from 2.5 +/- 1.9 micrograms/l and 2.1 +/- 0.8 kU/l to 9.1 +/- 11.7 micrograms/l and 4.9 +/- 2.2 kU/l, respectively, and the hGH secretion deteriorated significantly both after oral glucose load and in the TRH test, indicating recurrence of active acromegaly. Reactance and resistance decreased by 5 +/- 4 and 23 +/- 19 omega, respectively (p less than 0.01), whereas body weight remained constant (+0.4 +/- 2.1 kg). Bioelectrical impedance analysis indicated evident shifts in body composition, i.e. a significant reduction of body fat (-2.0 +/- 1.7 kg) and a simultaneous increase in both lean body mass (+2.4 +/- 2.2 kg) and total body water (+1.8 +/- 1.6 l). The changes in body composition were related to a combined effect of unsuppressed hypersomatotropism and the lack of bromocriptine actions other than inhibition of hGH secretion (for example stimulation of the renin-angiotensin-aldosterone system by both the recurred hypersomatotropism and the absence of dopaminergic bromocriptine effects). We conclude that bioelectrical impedance analysis is a good additional tool to assess the pathophysiological effects of bromocriptine withdrawal in long-term treated acromegalic patients.

Long-term effects of radiotherapy and bromocriptine treatment in patients with previous surgery for macroprolactinomas

The long-term effect of radiotherapy and bromocriptine treatment was retrospectively evaluated in 25 patients who had previously undergone transsphenoidal surgery for treatment of macroprolactinomas. Surgery had reduced the median serum prolactin (PRL) value from 613 micrograms/l, a reduction of 53%. Postoperative bromocriptine was administered to 21 of the 25 patients. In 14 of these patients, serum PRL values became normal or almost normal with medication. There were no radiological or ophthalmological signs of progressive tumor growth during bromocriptine treatment. Fourteen patients received postoperative radiotherapy. After withdrawal of bromocriptine in 13 of these patients an average of 7 years after radiotherapy, the median serum PRL value had further decreased by 95%. The PRL reduction was similar for all doses applied, 38 to 52 Gy. After withdrawal of bromocriptine in 8 patients not receiving radiotherapy an average of 7 years after operation, the median serum PRL level had further decreased by 75%. At follow-up, 18 additional instances of pituitary insufficiency had developed in the group receiving radiotherapy, compared with 8 cases of insufficiency in the group not receiving radiotherapy. Thus, because bromocriptine has a long-standing effect on prolactin secretion, and radiotherapy is associated with a notably high incidence of pituitary insufficiency, we propose that photon irradiation should be considered mainly for patients who are not candidates for surgical or medical treatment.

Long-Term Effects of Radiotherapy and Bromocriptine Treatment in Patients with Previous Surgery for Macroprolactinomas

Abstract The long-term effect of radiotherapy and bromocriptine treatment was retrospectively evaluated in 25 patients who had previously undergone transsphenoidal surgery for treatment of macroprolactinomas. Surgery had reduced the median serum prolactin (PRL) value from 613 Mg/l to 291 Mg/l, a reduction of 53%. Postoperative bromocriptine was administered to 21 of the 25 patients. In 14 of these patients, serum PRL values became normal or almost normal with medication. There were no radiological or ophthalmological signs of progressive tumor growth during bromocriptine treatment. Fourteen patients received postoperative radiotherapy. After withdrawal of bromocriptine in 13 of these patients an average of 7 years after radiotherapy, the median serum PRL value had further decreased by 95%. The PRL reduction was similar for all doses applied, 38 to 52 Gy. After withdrawal of bromocriptine in 8 patients not receiving radiotherapy an average of 7 years after operation, the median serum PRL level had further decreased by 75%. At follow-up, 18 additional instances of pituitary insufficiency had developed in the group receiving radiotherapy, compared with 8 cases of insufficiency in the group not receiving radiotherapy. Thus, because bromocriptine has a long-standing effect on prolactin secretion, and radiotherapy is associated with a notably high incidence of pituitary insufficiency, we propose that photon irradiation should be considered mainly for patients who are not candidates for surgical or medical treatment.

Withdrawal of Bromocriptine after Long-Term Therapy for Macroprolactinomas

Withdrawal of Bromocriptine after Long-Term Therapy for Macroprolactinomas

Withdrawal of bromocriptine after long‐term therapy for macroprolactinomas; effect on plasma prolactin and tumour size

The present study describes the effect on plasma prolactin values and tumour size of bromocriptine withdrawal in 12 patients who had been treated for macroprolactinomas for a period of 3.5-7 (mean 4.9) years. Pretreatment plasma prolactin values ranged from 12,000 to 210,000 (mean: 66,000) mU/l. Immediately before bromocriptine withdrawal plasma prolactin values were in the normal range (less than 350 mU/l for men; less than 450 mU/l for women). Bromocriptine treatment was associated with tumour reduction in all cases. The following observations were made upon withdrawal of bromocriptine: (1) In 11 patients hyperprolactinaemia redeveloped although plasma prolactin levels remained below 600 mU/l in two of these patients during a follow-up period of 1 year. In the other nine patients bromocriptine treatment was reinstituted after 4-12 weeks. (2) Hyperprolactinaemia was associated with tumour reexpansion in one case and increased density of the tumour in two cases. (3) In one patient plasma prolactin remained undetectable during a follow-up period of 1 year and no tumour re-expansion was found. It is concluded that tumour regrowth is uncommon and of small extent after cessation of long-term bromocriptine treatment for macroprolactinomas.

Bromocriptine Increasingly Suppresses thein VitroGonadotropin andα-Subunit Release from Pituitary Adenomas during Long Term Culture

Prolonged treatment with bromocriptine may lead to a decrease in tumor size in patients with a gonadotroph, alpha-subunit-secreting, or clinically nonfunctioning pituitary adenoma. The effectiveness of the treatment, however, may depend on its duration. We investigated the effects of prolonged incubation with bromocriptine on the release and intracellular hormone and alpha-subunit concentrations in 10 such adenomas in vitro. The release of FSH, LH, alpha-subunit, or a combination of these was demonstrated in 7 tumors. Bromocriptine significantly suppressed this release in 6 tumors. In 5 tumors bromocriptine had an inhibitory effect on gonadotropin and/or alpha-subunit release which increased with duration of culture. Withdrawal of bromocriptine during the culture period led to a recovery of gonadotropin or alpha-subunit release in the 2 tumors in which it was tested. Intracellular hormone and alpha-subunit concentrations in 3 of 4 tumors cultured for 4 or more weeks were significantly lower in bromocriptine-treated than in untreated cells. We conclude that 1) bromocriptine can suppress the in vitro release of gonadotropins and alpha-subunit from the majority of clinically nonfunctioning, gonadotroph, and alpha-subunit-secreting pituitary adenomas; 2) during prolonged incubation of these tumors with bromocriptine, this drug has a time-dependent increasing inhibitory effect on the release and synthesis of gonadotropins and alpha-subunit, which eventually may lead to decreased intracellular concentrations of these glycoproteins.