Bromocriptine in management of large pituitary tumours.

Bromocriptine has an accepted place in the management of small pituitary tumours that secrete either prolactin or growth hormone. The treatment of large tumours with extrasellar extensions is more difficult, however: though surgery is the standard treatment, it is often unsuccessful in returning excessive hormone secretion to normal and may cause hypopituitarism. A prospective trial was undertaken to assess the frequency with which changes in pituitary function and size of large tumours occurs. Nineteen patients were studied before and during treatment with bromocriptine (7.5 to 60 ml/day) for three to 22 months, using contrast radiology and a detailed assessment of pituitary function. Eighteen patients had hyperprolactinaemia and two of these also had raised concentrations of growth hormones; one patient had an apparently non-functioning tumour. In 12 patients (63%) tumour size decreased with bromocriptine and no tumour enlarged. Nine patients had visual-field defects, which improved in seven, becoming normal in five. Pituitary function improved in nine patients (47%) becoming entirely normal in three. Bromocriptine should be the treatment of choice in patients with large pituitary tumours with extrasellar extensions, provided close supervision is maintained.     

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.     

Effect of the GABAA agonist muscimol on prolactin secretion from human prolactin-secreting adenomas and GH3 rat pituitary tumour cells.

The effect of muscimol, a specific potent GABAA receptor agonist, on prolactin release from human prolactin-secreting tissue was investigated using a perifusion system. Perifusion studies on normal rat anterior pituitary tissue, which has identical GABA receptors to those found in normal human pituitary glands, show that muscimol has a specific biphasic effect on prolactin release. This is characterized by an initial transient stimulation (222.3 +/- 21.6% of basal) lasting for 5-10 min followed by a more prolonged inhibitory phase (63.9 +/- 3.1% inhibition of basal). Five human prolactin-secreting adenomas were studied, and in none of the tumours could a biphasic response be demonstrated. One of the prolactin-secreting adenomas had a blunted inhibitory response, but the other 4 showed no inhibitory effect of muscimol on prolactin release. Muscimol had no significant effect on basal or thyrotropin-releasing-hormone (TRH)-stimulated prolactin secretion from GH3 rat pituitary tumour cells. These studies suggest that the GABAergic effect on prolactin secretion is absent or altered in both rat and human prolactin-secreting tumour cells.     

Expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in pituitary tumours

The present study was performed to investigate HIF-1alpha (hypoxia-inducible factor-1alpha) expression in a large number of immunohistochemically and ultrastructurally characterized surgically removed pituitary tumours. The potential relation of HIF-1alpha with outcome variables as well as the presence of HIF-1alpha expression in the tumours treated with dopamine agonists and octreotide, a long-acting somatostatin analogue was also investigated. HIF-1alpha immunoreactivity was confined to the nucleoplasm whereas the nucleoli were unconspicuous. The distribution of HIF-1alpha was evident in the tumours whereas normal adenohypophysial cells showed no HIF-1alpha staining. HIF-1alpha expression was detected not only in the tumour cells but also in endothelial cells lining the blood vessels within the tumour. ACTH producing adenomas showed the lowest level of HIF-1alpha expression whereas pituitary carcinomas and GH producing adenomas had the highest counts. The statistical study demonstrated no significant correlation between HIF-1alpha expression, patient age, gender, tumour, size, invasiveness, cell proliferation rate and vascularity. These results suggest that the behaviour of pituitary tumours does not primarily depend of HIF-1alpha expression. Our study demonstrated an increase HIF-1alpha expression in bromocriptine treated PRL producing pituitary adenomas compared with untreated tumours but no increase in octreotide treated tumours.     

Pregnancy,prolactin, and pituitary tumours

Nine pregnancies are described in patients with pituitary tumours. All patients had definite radiological evidence of a pituitary tumour and no evidence of acromegaly or Cushing''s disease. In seven patients serum prolactin levels were estimated before pregnancy and found to be raised.Seven patients had been treated with pituitary implantation of yttrium-90. The remaining two developed complications of the tumour during pregnancy. One developed a bitemporal visual field defect in the second trimester which was successfully treated by emergency yttrium-90 implantation. The other developed diabetes insipidus in the third trimester which resolved spontaneously after delivery.Six patients were treated with drugs to achieve pregnancy. Four took bromocriptine to suppress raised prolactin levels, one was treated with human menopausal gonadotrophin, and one was treated with clomiphene.     

The role of the GH/IGF system in pituitary tumorigenesis.

Pituitary adenomas are mostly benign tumours that originate from differentiated anterior pituitary cells. Altered expression of growth factors or their receptors could enhance clonal expansion of pituitary adenoma cells. GHRH overstimulation or an activating point mutation in the Gs a-subunit leads to increased GH secretion and tumour formation. In contrast, IGF-I suppresses basal and GHRH-stimulated GH secretion in pituitary adenoma cells, whereas prolactin secretion is unaffected. Somatostatin analogues and pegvisomant, a novel growth hormone-receptor antagonist, results in a reduction of serum IGF-I levels and clinical improvement in patients suffering from pituitary adenoma. Thus, this review focuses on the role of the growth hormone/insulin-like growth factor system in pituitary tumorigenesis with particular focus on the genetic alterations described in pituitary adenomas up to now.     

Pregnancy in patients presenting with hyperprolactinaemia.

Ninety-two pregnancies occurred in 76 hyperprolactinaemic patients treated with bromocriptine. Half conceived within three months of attempted conception. There was no evidence of an increased rate of spontaneous abortion, fetal abnormality, or multiple pregnancy; the three twin pregnancies occurred in women who were additionally treated with clomiphene and human chorionic gonadotrophin. Thirty-one patients had radiological evidence of a pituitary tumour; 14 with major radiograph changes in the pituitary fossa or serum prolactin concentrations greater than 100 ng/ml received pituitary irradiation before conception. None of the latter showed evidence of enlargement of the tumour during pregnancy. In contrast two of the four patients with similar tumours but who were not irradiated developed visual field defects, one with gross destruction of the pituitary fossa. Prophylactic treatment to limit subsequent tumour expansion during pregnancy in patients with prolactinomas is indicated, and pituitary irradiation before conception appears to be a safe and effective method to achieve this goal.     

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.     

New long-acting bromocriptine (Parlodel MR and Parlodel LAR) in the treatment of pituitary tumours with hyperprolactinemia.

In order to assess the efficacy and tolerability of new long acting bromocriptine: Parlodel MR (oral form) and Parlodel LAR (injectable form suitable for repeatable administration) 40 patients (29 women and 11 men) with pituitary tumours with hyperprolactinemia (PRL 70 micrograms/l) were investigated in a double blind study. Patients were divided into 2 groups of 20. In the first group Parlodel R or Parlodel MR in equivalent doses was given, the other group was administered Parlodel R or Parlodel LAR. During the next 6 months 20 patients were treated with Parlodel MR and the other 20 with Parlodel LAR. In all patients pituitary and peripheral hormones, CT scan and visual fields were examined before and after 28 days of bromocriptine treatment. During the next six months 20 patients were treated with Parlodel MR while the other 20 with Parlodel LAR. Serum PRL fell in all patients and values in the normal range were obtained in 36 patients. In 30 out of 35 patients with signs of pituitary tumour in CT scan, a significant tumour shrinkage was observed. Most patients achieved considerable clinical improvement: disappearance of galactorrhoea, resumed menses in women, increased potency in men. There were no difference in efficacy in Parlodel R, Parlodel MR and Parlodel LAR, but in the case of Parlodel LAR the least number of side effects was found. Treatment with long acting bromocriptine-Parlodel MR and LAR of patients with pituitary tumours with hyperprolactinemia is an efficacious, safe and better tolerated method than Parlodel R treatment.     

Value of computed tomography of the abdomen and chest in investigation of Cushing's syndrome.

Computed tomography (CT) scans were performed on 37 patients with biochemically proved Cushing''s syndrome to evaluate the role of CT in the investigation of this condition. CT rapidly and correctly identified all 15 adrenocortical tumours, distinguishing five carcinomas from the 10 adenomas. In ACTH-dependent Cushing''s syndrome appreciable bilateral adrenal enlargement was common in patients with an ectopic source (6 of 10 cases), while those with a pituitary source usually had normal sized adrenals (9 of 10). Two patients with a history of over seven years had bilateral adrenal nodules. CT was more accurate in locating a primary ectopic source of ACTH (5 of 12 cases) than any other technique and was particularly valuable in detecting small (less than 1.5 cm) peripheral lung carcinoid tumours which may be undetectable by conventional x-ray techniques. Its speed, accuracy, and simplicity make CT the technique of choice both to show the adrenal anatomy and to locate a suspected ectopic ACTH-secreting tumour in patients with proved Cushing''s syndrome.     

A giant prolactinoma and the effect of chronic bromocriptine therapy on basal and TRH-stimulated serum prolactin levels.

The role of bromocriptine as primary therapy for prolactin-producing tumors is currently well accepted in the literature. Bromocriptine decreases the concentration of serum prolactin and this decrease precludes tumor shrinkage, despite the lack of correlation between amount of decrease in tumor size and baseline serum prolactin. We submit the case of a patient on chronic bromocriptine therapy followed by measuring baseline and thyrotropin-releasing hormone (TRH)-stimulated serum prolactins. Bromocriptine affects both release and storage of prolactin. The literature has suggested that the effects of bromocriptine on storage and synthesis may be responsible for its effects on tumor size. It was felt that TRH stimulation would more accurately reflect storage and synthesis, and thus correlate better with tumor size. The pituitary was initially debulked via a right frontal approach; then the patient was placed on bromocriptine therapy and postoperatively followed with baseline and TRH-stimulated serum prolactins. The size of the pituitary was measured by computed tomography. Baseline serum prolactin levels rapidly decreased, but despite the slow decrease in TRH-stimulated prolactins no change was noted in tumor size. Because of the time difference between the baseline and TRH-stimulated prolactin levels, we conclude that clinically bromocriptine affects primarily secretion of prolactin and secondarily storage and synthesis. We also show that TRH-stimulated prolactin does not correlate with size of prolactin-secreting pituitary tumors and therefore tumor size should be independently measured. The literature has shown that prolactinomas do not respond well to TRH stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolactin-secreting pituitary adenomas in males: transsphenoidal microsurgical treatment.

Fifteen male patients with prolactin-secreting pituitary adenomas were studied before and after transsphenoidal microsurgical treatment. Loss of libido and sexual impotence were the most frequent symptoms, being present in 12. Visual defects were present in seven patients, gynecomastia was observed in four and galactorrhea was noted in three. Most of the tumours were large; only one was a microadenoma. Four patients were cured by the operation. In all the other patients the plasma levels of prolactin were significantly lowered and the visual defects corrected or lessened, but sexual impotence was not modified. No important deficiency of the pituitary gland was induced by the operation. The results indicate that in males loss of libido and sexual impotence are frequent and early manifestations of prolactinomas, and that transsphenoidal resection is a safe therapeutic approach.     

Treatment of Cushing's disease with low dose radiation therapy.

Nineteen patients with Cushing''s disease were treated with low dose external pituitary irradiation (20 Gy (2000 rad) in eight fractions over 10 days). While awaiting the effects of pituitary irradiation all patients were treated with metyrapone. Seven patients had a complete remission of their disease within six to 12 months of irradiation. They did not require any further treatment and were followed up for a mean of three and a half (range one to eight) years. Another patient had a complete remission after a second course of pituitary irradiation. A further two patients showed a significant biochemical improvement after irradiation, although they were not rendered eucorticoid. There were no complications after this dose of irradiation. These results compare favourably with those reported after pituitary irradiation at conventional doses (40-50 Gy (4000-5000 rad) over four or five weeks) but were not associated with any complications. It is therefore recommended that low dose external pituitary irradiation be used as definitive first line treatment for Cushing''s disease.     

Beneficial effects of high daily dose bromocriptine treatment in Cushing's disease.

Treatment with a high daily dose bromocriptine was evaluated in 6 Cushing's disease patients (4 females and 2 males; aged 23 to 56 years). The highest doses administered were 40 mg to patient 1, 55 mg to patient 2, 35 mg to patient 3, 25 mg to patient 4, 25 mg to patient 5, and 17.5 mg to patient 6. The former 3 cases, 2 (patients 1 and 2) of whom were previously reported and further followed up, showed clinical and biochemical improvement with the regimen. Patient 1 who obtained remission with 40 mg/day has been on remission for further 14 months with a total of 36 months. Patient 2, who had a reduction in pituitary tumor size with 35 mg daily, relapsed thereafter. The therapy, however, resolved the paradoxical responses of plasma ACTH and cortisol to arginine. Readministration of bromocriptine resulted into another clinical and biochemical improvement with 45 to 55 mg/day. Patient 3, a relapsed case after a remission with reserpine plus pituitary irradiation, showed an improvement in the 24-h urinary free cortisol excretion with 35 mg/day. Patient 4 was the only case who had a marked decrease in plasma cortisol (basal; 16.3, nadir; 1.9 micrograms/dl) after a single-dose bromocriptine test among the 5 cases tested. The patient had favorable response with 25 mg/day for 2 months but the dose was not increased after an escape. Patient 5 received the drug in 4 occasions, 7.5 to 25 mg/day, in combination with several agents, which failed to induce clinical remission. The last patient did not respond to a maximum dose of 17.5 mg/day. These observations suggest that, regardless of the result of a single-dose bromocriptine test, treatment with a high daily dose of bromocriptine, 35 mg or more, may be necessary to obtain a favorable clinical response and normal cortisol secretion.     

Rapid improvement of visual defects with parenteral depot-bromocriptine in a patient with a non-functioning pituitary adenoma

The management of non-functioning pituitary adenomas with bromocriptine is controversial, and surgical treatment is usually prescribed when the visual field is affected. Here we report, what we believe to be the first case of a patient with a non-functioning pituitary adenoma who experienced normalization of visual field defects and a substantial improvement in visual acuity after the parenteral administration of depot-bromocriptine. The patient's tolerance to the drug was excellent. The results of the immunohistochemical study of the surgically removed tumor were negative for PRL, GH, LH, FSH, TSH and ACTH. In our opinion, the use of depot-bromocriptine may represent an alternative to surgery in patients with non-functioning pituitary adenomas associated with visual lesions.     

Light microscopical morphometry of prolactin secreting adenomas under treatment with dopamine agonists

In order to study the light microscopical alterations of pituitary tumours under dopamine agonist treatment, three groups of a total of 18 large or small cell chromophobe adenomas were analysed by light microscopical, immunohistological and morphometrical methods. They were all removed by transsphenoidal surgery. 6 of them were treated preoperatively with dopamine agonists, bromocriptine and/or lisuride, for various periods of time. 8 adenomas remained preoperatively untreated. 4 additional untreated tumors were small cell inactive adenomas for comparison. One case was excluded from the final evaluation of the data because it appeared to be a typical non-responder, clinically as well as histologically. Immunohistological positivity for prolactin was to be found in all cases in various degrees. Clinically active adenomas contained many prolactin positive cells, whereas in inactive adenomas only scattered cells were prolactin positive. The morphometric analysis revealed a reduction of the cytoplasmic area in a statistically significant degree in the group of adenomas under treatment, which explains adequately the shrinkage of the entire adenoma and the reduction of prolactin plasma levels. The morphometric data of treated adenomas resembled those of untreated inactive adenomas.     

Bromocriptine treatment of acromegaly.

The effects of oral bromocriptine in acromegaly have been studied. A dose of 5 mg six-hourly suppressed circulating growth hormone (GH) levels in nine out of 11 patients treated for seven to 11 weeks. This was associated with considerable clinical improvement in all patients, with abolition of excessive sweating, reduction in soft-tissue thichening, loosening of rings, decrease in shoe size, improvement in facial features, and loosening of dentures. Metabolic changes included improvement in glucose tolerance and reduction in hydroxyproline excretion. Unlike the actions of growth hormone release inhibiting hormone the suppression of GH was not accompanied by a reduction in insulin or glucagon secretion, though prolactin levels were suppressed. Side effects other than mild constipation were not seen when the full dose regimen was reached by slowly increasing the dose from 2-5 mg once daily. Bromocriptine holds promise as a safe and orally effective medical treatment to augment surgical or radiotherapeutic measures directed at the pituitary tumour. Its efficacy during longterm administration remains to be established.     

Effectiveness of pergolide mesylate in long term treatment of hyperprolactinaemia.

Twenty five patients with hyperprolactinaemia were treated with pergolide mesylate, a new dopamine receptor agonist. Twenty three received treatment for six to 20 months, and in all serum prolactin concentrations were considerably reduced. In most patients prolactin concentrations were maintained in the normal range by a low, once daily dose of pergolide and reversal of associated reproductive disorders was observed. Tumour volume as assessed by computed tomography decreased considerably during treatment in three out of four patients with a pituitary tumour. The drug was well tolerated. Side effects were similar to those of bromocriptine, but four out of eight patients who had been forced to stop taking bromocriptine because of untoward effects were subsequently able to tolerate treatment with pergolide. Pergolide mesylate promises to be a useful addition to the currently available long acting dopamine agonists in the management of hyperprolactinaemia.     

E‐cadherin expression is associated with somatostatin analogue response in acromegaly

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin‐like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E‐cadherin expression by immunohistochemistry in fifty‐five GH‐producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E‐cadherin levels exhibit a worse response to SSAs. E‐cadherin levels are associated with GH‐producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E‐cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.     

Prevalence of hypothalamic-pituitary tumours - retrospective analysis of 20-year own material

OBJECTIVES: The prevalence of pituitary tumours has recently been identified to be higher than previously thought. The aim of our study was to assess the occurrence of hypothalamic-pituitary tumours in 20-year material of the Department of Endocrinology and Metabolic Diseases, Polish Mother`s Memorial Hospital - Research Institute, Lodz, Poland. Methods: We analyzed medical data of 845 patients, hospitalized from 1990 to 2009 due to presumptive diagnosis of hypothalamic-pituitary tumour. Among 340 cases with confirmed diagnosis, 278 tumours were classified as micro- or macroadenomas. Tumour type and size, as well as patient gender and age, were evaluated. In 252 tumours the exact volume was calculated, and 4 volume subgroups were assessed for each aforementioned parameter separately. Results: Prolactinomas and - at the next place - non-functioning adenomas were the most frequent, followed by pituitary tumors of non-epithelial origin, and - finally, the rarest - other secreting adenomas. Prolactinomas were found mostly in females (p=0.028), while non-functioning adenomas in males (p=0.045). Prolactinomas and non-functioning adenomas were found to be predominantly microadenomas (p<0.0001 and p=0.0003, respectively), while mixed-type adenomas were mostly macroadenomas (p=0.028). In females microadenomas were the most frequent (p<0.0001). Moreover, in persons under 50 years of age microadenomas predominated, whereas in older adults macroadenomas mostly occurred. Conclusion: To conclude, our retrospective, single-centre study provides relevant estimates of prevalence of hypothalamic-pituitary tumours in the era of modern diagnostic tools and indicates that our data are comparable with results regarding other populations worldwide.