Extrasellar prolactinomas: successful management of 24 patients using bromocriptine

24 patients with an extrasellar prolactinoma (mean prolactin 4,722 ng/ml), 8 of whom had previously had surgery, received 5-40 mg bromocriptine daily for 13-252 weeks. The mean prolactin level had fallen 89% at 2 days, 95% at 6 weeks, and 15 patients achieved normal values. Tumor shrinkage occurred in all 9 patients rescanned within 2 weeks and later was documented in 23; in 18 the extrasellar tumour disappeared. 12 patients had visual abnormalities; 7, including 2 who had been completely blind, improved within 1 week. 2 patients had normal prolactin levels after withdrawal of bromocriptine, 1 following radiotherapy and the other during two uncomplicated pregnancies. Bromocriptine is safe and effective. We conclude that medical treatment should always precede surgery unless pituitary apoplexy causes sudden deterioration of vision. Most patients will subsequently require radiotherapy or surgery for permanent cure.     

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 bromocriptine on pituitary tumour size.

In a prospective study designed to assess the influence of bromocriptine on pituitary tumour size 12 patients with pituitary tumours, eight of whom had suprasellar extensions, were treated for three months with 20 mg of bromocriptine daily after a gradual increase to this dose. The group comprised eight women and four men, five with prolactin-secreting adenomas, four with acromegaly, two with functionless adenomas, and one with Nelson''s syndrome. All five patients with prolactin-secreting adenomas showed a reduction in pituitary tumour size as assessed by computerised tomography and metrizamide cisternography accompanied by a fall in prolactin concentrations and clinical and biochemical improvement in their hypopituitarism. One patient in this group had a visual-field defect before treatment, and this resolved. There was no radiological evidence of reduction in tumour size in the remaining seven patients, though this might refect the fairly short duration of treatment, particularly in view of the ancillary evidence of clinical, biochemical, and visual-field improvement in some of the patients. These results emphasise the potential value of bromocriptine in treating patients with large prolactinomas or recurrences of such tumours after previous chiasmal decompression and conventional external megavoltage irradiation on the pituitary.     

Long-term Treatment of Galactorrhoea and Hypogonadism with Bromocriptine

Seventeen women and four men with galactorrhoea and associated hypogonadism have been treated with bromocriptine for 2 to 28 months. In 18 patients the gonadal status became normal as the galactorrhoea improved. The gonadally unresponsive patients had either pituitary tumours or premature menopause. Prolactin levels fell with treatment; withdrawal of the drug was associated with an increase in serum prolactin and a recurrence of the galactorrhoea and hypogonadism. Two patients tried to become pregnant on treatment and both succeeded. Raised prolactin levels appear to block the actions of the gonadotrophins at a gonadal level rather than prevent their synthesis or release; lowering prolactin secretion with bromocriptine allows resumption of normal gonadal function. Bromocriptine appears to be the treatment of choice for inappropriate lactation in association with hypogonadism on a long-term basis.     

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.     

Effects of hypersecretion of growth hormone and prolactin on plasma levels of glucagon and insulin in GH3-cell-tumor-bearing rats, and the influence of bromocriptine treatment

Plasma levels of prolactin, growth hormone, glucagon insulin and glucose were measured in non-treated control rats, bromocriptine-treated control rats and GH3-cell-tumor-bearing rats with and without bromocriptine treatment. Bromocriptine treatment increased plasma levels of glucagon, insulin and glucose in control rats. Tumor-bearing rats had increased body weight and increased plasma levels of prolactin, growth hormone, glucagon, insulin and glucose. Bromocriptine treatment reduced body weight and decreased the plasma levels of prolactin, glucagon and insulin, as compared to non-treated tumor-bearing rats. The drug had no effect on plasma levels of growth hormone and glucose. These results indicate that, in GH3-cell-tumor-bearing rats, prolactin, glucagon and insulin are more sensitive to the action of bromocriptine than growth hormone.     

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.     

Spontaneous endocrine cure of gigantism due to pituitary apoplexy.

An 11 year old, tall boy presented with symptoms typical of pituitary apoplexy. A large necrotic and haemorrhagic tumour was removed, which was shown to be an adenoma secreting growth hormone and prolactin. Subsequent treatment comprised cranial irradiation and hormone replacement. Eighteen months after operation growth was static and plasma growth hormone and prolactin concentrations were undetectable. Treatment of pituitary apoplexy should comprise excision of the tumour and postoperative irradiation; such treatment after early recognition of the condition offers the best chance of preserving normal pituitary function in children with gigantism.     

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)     

Hyperprolactinemia in nonpregnant women due to pituitary tumors

The human prolactin molecule has been isolated and its structure characterized. This anterior pituitary hormone plays an important function in the induction and maintenance of lactation in the post-partum nursing mother. Prolactin-producing tumors cause inappropriate lactation in the nonpregnant woman. Bromocriptine, an ergot derivative, mimics the action of dopamine in the anterior pituitary gland and does not cure the underlying pathology. Prior to the development of bromocriptine, there was no effective treatment for the symptoms of amenorrhea and galactorrhea. Although the methods of therapy are more sophisticated today, there remain a number of unanswered questions. The unknown long-term risks of bromocriptine therapy must be balanced against the potential risk of osteopenia.     

Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly.

A highly specific and sensitive radioimmunoassay was developed for measuring circulating growth hormone releasing factor (GRF) in human plasma. Before measuring immunoreactive GRF plasma samples were extracted on to Vycor glass. Immunoreactive GRF concentrations in plasma samples from 37 fasting normal subjects ranged from less than 10 to 60 ng/l (mean 21 ng/l). Fasting concentrations in 76 out of 80 acromegalic subjects were within the normal range, but the remaining four patients had values of 92 to 25 000 ng/l. Of these, only the patient with the highest concentration had evidence of ectopic GRF secretion from a disseminated carcinoid tumour. Two of the others had longstanding pituitary tumours, and the fourth patient had a pituitary growth hormone (GH) secreting tumour proved by its removal and subsequent remission of acromegaly. There was no correlation between serum GH and plasma immunoreactive GRF concentrations, irrespective of whether the patients were untreated or had been given radiotherapy or dopamine agonists. The assay should help elucidate the physiological role(s) of GRF and may also prove useful in differentiating between pituitary and hypothalamic defects in patients with acromegaly.     

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.     

Treatment of prolactinomas with megavoltage radiotherapy.

The outcome of treatment of 36 women with prolactinomas using megavoltage radiotherapy combined with interim dopamine agonists (bromocriptine, lysuride, pergolide) was reviewed; 16 of the women showed radiological evidence of a macroadenoma. The most common presenting symptom was secondary amenorrhoea; 26 of the patients had galactorrhoea. In 29 patients who wished to conceive the ovulation rate (as indicated by circulating progesterone concentrations) was 97% and the successful fertility rate 86%. No patient had enlargement of the tumour during pregnancy and there were no complications of radiotherapy. No further tumour enlargement was detected in serial skull radiographs, and an improvement in size of the fossa was noted in 45% of those assessed. When medical treatment was withdrawn a mean of 4.2 years (range 1-11) after radiotherapy in the 27 patients who had completed their families the serum prolactin concentration had fallen appreciably in 26 of them and later became normal in eight. The incidence of growth hormone deficiency rose from 24% of the whole group before radiotherapy to 79% afterwards. Only one patient required thyroxine, and one was receiving gonadotrophin. No patient became deficient in adrenocorticotrophic hormone. A regimen of megavoltage radiotherapy and interim bromocriptine allows women with prolactinomas safely to undergo pregnancy and results in the long term prospect of tumour shrinkage and control of hyperprolactinaemia.     

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.     

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.     

Management of pituitary tumours: strategy for investigation and follow-up

Investigation of a patient presenting with evidence of a pituitary tumour has three main objectives: investigation of any hormonal hypersecretion; assessment of residual pituitary function, and examination of any mass effect of the tumour. A prolactin-secreting adenoma is often easily diagnosed by performance of a basal prolactin level. Biochemical assessment to exclude acromegaly or Cushing's disease should only be performed if clinically indicated. The standard investigations for acromegaly consist of establishing the degree of growth hormone (GH) suppression following a glucose load and estimating the basal insulin-like growth factor-I level. Before detailed investigation for Cushing's disease is initiated, the presence of Cushing's syndrome must be established. The second requirement is to determine the presence of any pituitary hyposecretion. Whilst the remainder of pituitary function can be assessed by baseline hormonal estimations, the evaluation of ACTH and GH secretion necessitates dynamic function testing. Lastly, the impact of the mass itself requires careful examination. Both neuroradiology, preferably magnetic resonance imaging at a centre specialized in examination of the pituitary fossa, and careful detailed clinical examination of the visual fields should be performed. The follow-up requirements in an individual patient are affected by a number of factors including the size and nature of the underlying tumour and any treatment administered. In patients with a hormone-secreting tumour, the hormone levels themselves provide a 'tumour marker' to aid follow-up. An important caveat, however, is that on some occasions tumour size and hormone levels do not change in parallel. Patients who have undergone pituitary surgery should have dynamic assessment of pituitary function performed approximately 6 weeks after surgery. There is no reason to suspect any further impairment of pituitary function after this date. In direct contrast, pituitary hormone deficiencies after radiotherapy are unlikely less than 6 months after treatment. Patients should undergo testing of pituitary reserve at 6 months, and then at yearly intervals for at least 10 years after radiotherapy, if they have not already developed panhypopituitarism. Even after this period, if patients develop new symptoms the possibility of further pituitary hormone deficits should be considered. Neuroradiology should be performed approximately 6 weeks to 3 months after surgery. If radiotherapy is not administered, neuroradiology should be performed yearly for at least 10 years. If the patient has received radiotherapy, tumour recurrence is much less likely and therefore in these individuals neuroradiology does not need to be performed with such regularity. In conclusion, when planning the investigation and follow-up of an individual patient, one should take into account the size and characteristics of the tumour, as well as the treatment modalities.     

Aneurysms of the Internal Carotid Artery Simulating Pituitary Tumours: Report of Two Cases

Two patients suffering from aneurysms of the internal carotid artery simulating pituitary tumours are reported. One of these was a 17-year-old boy with a mycotic aneurysm of the right internal carotid artery causing failure of growth and pubertal maturation. The second was a 53-year-old woman with a left internal carotid artery aneurysm, probably of atherosclerotic origin, who had evidence of anterior pituitary insufficiency.In both cases there was paresis of extraocular muscles and one patient had bitemporal hemianopsia. While lateral radiographs of the skull suggested intrasellar calcification in each case, further roentgenological investigation established that this calcification was actually extrasellar, and carotid arteriograms demonstrated the presence of an internal carotid aneurysm in each case. Investigations of the endocrine system confirmed the presence of anterior pituitary insufficiency in both patients, and diabetes insipidus became evident in one patient after cortisone therapy was commenced.This lesion, while rare, may be difficult to differentiate from a pituitary tumour. It is likely that this syndrome depends on aneurysmal expansion to the region of the sella turcica with compression of the pituitary gland itself, as well as the optic fibres.     

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.     

Lysosomal enzymes in the rat harderian gland are altered by either bromocriptine treatment or hypophysectomy and hormone replacement therapy

Four groups of adult male hypophysectomized rats were injected subcutaneously twice daily between 0800-0900 hr and 1600-1700 hr with either saline diluent, 150 micrograms sheep prolactin and/or growth hormone (GH); intact rats received either saline or 150 micrograms bromocriptine twice daily. After 4 days of treatment, lysosomal enzyme assays revealed significant elevations in both acid phosphatase and alpha-mannosidase enzyme activities in the Harderian glands of saline-injected hypophysectomized rats compared to those in intact controls. beta-Glucuronidase levels were depressed and hexosaminidase activity unaffected by hypophysectomy treatment alone compared to intact controls. Lysosomal enzyme activities in hypophysectomized animals treated with prolactin were not different from the hypophysectomized control animals. However, treatment with GH alone or in combination with prolactin had a significant inhibitory effect on beta-glucuronidase, hexosaminidase, and alpha-mannosidase enzyme activities in the Harderian gland of hypophysectomized animals. Bromocriptine treatment in intact rats only elevated acid phosphatase activity. In summary, the patterns of responses did not reveal a role for prolactin in the control of Harderian gland lysosomal enzyme activities by the pituitary. However, some of the influence on this target system may be exerted by growth hormone.     

Verification of NB2 lymphoma cell bioassay for the measurement of plasma and pituitary prolactin in the Mongolian gerbil (Meriones unguiculatus)

Serum and pituitary glands were taken from male Mongolian gerbils which had received bromocriptine implants, ether stress or no treatment (controls). Pituitary prolactin (Prl) and growth hormone (GH) mRNA were analyzed by Northern hybridization using rat cDNA probes. Pituitary and plasma Prl content were analyzed with the Nb2 lymphoma cell growth bioassay. These assays were sensitive to the decreases in Prl caused by bromocriptine and the elevation of Prl caused by ether stress. The inhibition of pituitary and plasma Prl levels by bromocriptine correlated with a marked inhibition of pituitary Prl mRNA content. In contrast, levels of GH mRNA did not change with treatment, indicating that gerbil GH does not contribute to the lactogenic activity measured in the Nb2 lymphoma cell bioassay. The results indicate that this bioassay is suitable for the measurement of gerbil pituitary and plasma Prl.