Progesterone receptor synthesis in human meningiomas: relation to the estrogen-induced proteins pS2 and cathepsin-D and influence of epidermal growth factor, Forskolin and phorbol ester in vitro.

Autonomous expression of progesterone receptors (PR) in human meningiomas is well established. To evaluate whether, similar to progesterone receptors, other estrogen-inducible proteins are also autonomously expressed in meningiomas, concentrations of pS2 and cathepsin-D (Cath-D) were measured in 52 meningiomas. No pS2 protein was detectable in 52/52 tested meningiomas. The Cath-D protein was measurable in all 52 meningiomas, but the mean concentration of Cath-D in meningioma cytosols was 2.4-fold lower than that of a group of 54 breast tumors (p < 0.001). These results indicate that autonomous expression is a PR-related rather than an estrogen receptor-related phenomenon and, consequently, that estradiol is probably not responsible for PR synthesis in human meningiomas. To evaluate the role of other, non-estradiol-dependent signalling pathways in PR synthesis, the effects of EGF, Forskolin and phorbol ester on PR synthesis were tested in vitro. No PR was detectable after the addition of EGF to six different primary cultures. Forskolin and TPA addition caused a morphological change in meningioma cells, but did not induce PR or pS2 synthesis in two different primary meningioma cultures. We conclude that PR synthesis in human meningiomas cannot be triggered by switching on the signalling pathways activated by these growth factors.

Transsphenoidal hypophysectomy in beagle dogs: evaluation of a microsurgical technique.

OBJECTIVE: Assessment of a microsurgical technique for transsphenoidal hypophysectomy in dogs. STUDY DESIGN: Prospective study using physical examination, pituitary function testing, computed tomography (CT), and histological examination at autopsy. ANIMALS OR SAMPLE POPULATION: Eight laboratory beagle dogs. METHODS: Pituitary function was assessed before and at 10 weeks after hypophysectomy by combined administration of four releasing hormones (anterior pituitary), administration of haloperidol (pars intermedia), and infusion of hypertonic saline (posterior pituitary). RESULTS: CT imaging enabled accurate preoperative localization of the pituitary. Appropriate positioning and surgical technique facilitated exposure of the pituitary and its extraction without hemorrhage. Postoperative recovery was generally uncomplicated. None of the eight dogs had somatotropic, gonadotropic, lactotropic, melanotropic, or posterior pituitary responses to stimulation at 10 weeks after hypophysectomy. Four dogs (ACTH nonresponders) also had no corticotropic response and four (ACTH responders) had small but significant responses in the combined anterior pituitary function test. Adrenocortical atrophy was more pronounced in the ACTH nonresponders than in the responders. No residual pituitary tissue was found along the ventral hypothalamic diencephalon but nests of pituitary cells were found embedded in fibrous tissue in the sella turcica. CONCLUSIONS: The surgical technique proved to be safe and effective. Microscopic nests of pituitary cells in the sella turcica may be responsible for residual corticotropic response to hypophysiotropic stimulation after hypophysectomy. CLINICAL RELEVANCE: The surgical technique may be used in the treatment of dogs with pituitary-dependent hyperadrenocorticism. The corticotropic response is the most sensitive criterion in assessing completeness of hypophysectomy in dogs.

Oestrogen receptor independent expression of progestin receptors in human meningioma--a review.

Human meningiomas are rich in progestin receptors (PR), which are expressed in this tissue in an oestrogen independent fashion. In the search for an explanation of this observation, the existence of a protein in human meningioma cytosol which is capable of binding to a synthetic oestrogen responsive element (ERE) has been demonstrated. Using reverse transcriptase, PCR mRNA encoding for the wild-type oestrogen receptor (ER) was found. In addition, several splice variants of ER mRNA have been identified in human meningioma tissue, including variants lacking exons 4, 5 and 7. We found the ER delta 4 protein to have no transcriptional activity and the ER delta 7 protein reportedly is dominant negative. These mutants therefore probably are not responsible for the autonomous PR synthesis in human meningioma. The ER delta 5 protein, by contrast, has been reported to have oestrogen independent transcriptional activity and it is tempting to speculate that this protein is similar or identical to the ERE binding protein we have found in human meningioma. The role of wild type ER mRNA is presently unclear. Activation of other signal transduction pathways in meningioma does not lead to an increased PR concentration. The promoter area of the meningioma PR gene should be investigated for the possible sensitivity to other transcription factors.

The use of surgery for the treatment of prolactinomas.

Success with trans-sphenoidal surgery for microprolactinomas is good (57 to 93% cure rate) but tumours can recur. Conversely, the results of surgery for macroprolactinomas are not so good (14 to 39% cure rate) and cure is rarely effected when plasma prolactin levels are > 10 U/l. Surgical therapy for prolactinoma should be reserved for patients with dopaminergic resistance or intolerance and complications (e.g. haemorrhage and rhinorrhoea) to dopamine agonist therapy. Trans-sphenoidal surgery was used to treat 11 microprolactinoma patients who had compliance problems to dopaminergic therapy. Postoperative plasma prolactin levels were normal in all patients. During follow-up (range 0.5 to 8 years, mean 3.9 years) six patients remained normoprolactinaemic, four patients developed slightly elevated plasma prolactin levels ( < 0.7 U/l), and one patient developed a macroadenoma resistant to bromocriptine and CV 205-502. He underwent a second operation, followed by radiotherapy and bromocriptine. His plasma prolactin was reduced to 3.3 U/l. One patient with a prolactinoma extending into the left cavernous sinus had a tumour cyst in the left temporal lobe. During treatment with CV 205-502 he developed a haemorrhage in the tumour cyst necessitating craniotomy.

Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro.

We have studied seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary macroadenoma, four of whom received long term, high dose octreotide treatment. We have attempted to correlate the presence of somatostatin receptors (SS-R) in the adenomas and the outcome of octreotide treatment, as measured by tumor size, improvements in visual field defects, and hormonal response. The presence of SS-R in the pituitary adenomas was demonstrated in vivo using [111indium]octreotide scintigraphy and in vitro by autoradiography of tissue fragments obtained after transsphenoidal surgery. Adenomas from six of the seven subjects were SS-R positive. High dose (1200 micrograms, sc, daily) octreotide treatment was given to four subjects, three of whom were SS-R positive. Improvement of the visual field defects was observed in three of four patients (including the SS-R-negative subject), although no computed tomographic scan-assessed tumor size reduction was found. Two of four patients showed small but significant reductions in serum FSH concentrations (to 83% and 93% of initial values) with treatment. These in vivo responses to high dose octreotide treatment could not be predicted by pretreatment responses to 200 micrograms TRH or 100 micrograms octreotide. Tissue fragments for cell culture were obtained from six patients, and in vitro release of gonadotropins and/or alpha-subunit could be demonstrated in five cultures. In vitro, octreotide (10 nmol/L) significantly decreased gonadotropiin or subunit release in three of five cultures, whereas bromocriptine (10 nmol/L) significantly reduced the release in four of five cultures and to a significantly greater extent than octreotide. In conclusion, in six of seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary adenoma, SS-R were demonstrated in the tumor. In vitro incubation of adenoma cells with octreotide resulted in mild inhibition of gonadotropin or alpha-subunit release. Although in vivo long term treatment with high doses of octreotide did not result in substantial tumor size reduction, improvement of visual field defects was observed in three of four subjects.

Sellar granulomatous mass in a pregnant woman with active Crohn's disease.

At the end of her third pregnancy, a woman with a history of chronic active proctocolitis which had been diagnosed as Crohn's disease complained of deterioration of visual acuity. The patient was found to have hypopituitarism and progressive bitemporal hemianopia caused by an intrasellar mass with suprasellar extension. At transsphenoidal surgery an intrasellar granuloma was found without remnants of pituitary tissue. This sellar granuloma could have been an extra-intestinal granuloma of Crohn's disease. However, the possibility that giant cell granulomatous hypophysitis had been present was considered more likely. The occurrence of this disorder in the postpartum period has not been reported before.

Prolactinoma and body weight: a retrospective study.

Body weight and weight history in association with hormone levels were studied retrospectively in 47 patients with prolactinoma; macroprolactinoma was diagnosed in 36, microprolactinoma in 11 patients. At the time of diagnosis a weight history could be traced in 14 patients, 9 patients having gained weight (11.8 +/- 2 kg), 1 with a weight loss of 5 kg, and 4 reporting unaltered body weight. Body weight and Body Mass Index before treatment were 83 +/- 2.4 kg and 27.3 +/- 0.6 kg/m2, respectively. In the male patients the prevalence of BMI greater than or equal to 25 was greater than in the average Dutch male population (p less than 0.001). After 6 months of treatment, mainly with bromocriptine, patients with macroprolactinoma had lost 5.5 +/- 1.6% (p less than 0.002) of initial body weight. No significant weight change occurred in patients with microprolactinoma. Weight loss did not correlate with degree of hyperprolactinemia, nor with decrease of prolactin levels during treatment, in either group of patients. Thyroid or gonadal function were not associated with weight loss either. It appears that prolactinoma is associated with a higher frequency of overweight, as far as patients with macroprolactinoma are concerned.

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.

Treatment of macroprolactinomas with a new non-ergot, long-acting dopaminergic drug, CV 205-502.

Eleven patients with prolactin-producing pituitary adenomas were treated with the new non-ergot, long-acting dopamine agonist, CV 205-502, for a period of 2-18 months (mean 11 months). Tumour volumes ranged from 1.9 to 64 ml in seven patients who were newly diagnosed, and from 0.1 to 3.1 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3.5 to 360 U/l before institution of CV 205-502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once-daily doses of CV 205-502 between 0.075 and 0.300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205-502 treatment and/or during several days after a dose increase were observed in three patients. We conclude that CV 205-502 in a once daily dose is an effective and safe alternative in the long-term treatment of macroprolactinomas.

Results of primary treatment with bromocriptine of prolactinomas with extrasellar extension.

Nineteen patients, seven women and twelve men, with macroprolactinomas characterized by extrasellar extension and basal prolactin levels above 6 U/l were treated with 10-20 mg bromocriptine daily in four divided doses for a mean period of 3.4 years (range 1.5-5.5 years). Plasma prolactin levels fell dramatically in all patients and values in the low normal range were obtained in sixteen patients. Tumor size was reduced by more than 75% in seventeen patients and by 50-75% in two patients. Tumor reduction was associated with the development of a partial empty sella in fourteen cases. In seventeen cases the pituitary became visible. Diminished visual acuity (six patients), bitemporal hemianopia (nine patients), unilateral and bilateral central scotomas (three patients) and oculomotor palsy (two patients) improved or normalized in all cases. Hypogonadism (all patients), hypothyroidism (nine patients) and hypocorticism (four patients) improved or normalized in most cases. It is concluded that in the medical treatment of macroprolactinomas 10-20 mg bromocriptine in four divided doses effectively reduces both plasma prolactin level and tumor size. The good results in this study may be related to the continued use of a fixed dose regimen of bromocriptine regardless of the plasma prolactin lowering effect.

Primary hypothyroidism mimicking pituitary adenoma.

The case history is presented of a woman with secondary amenorrhoea, mild hyperprolactinaemia and pituitary enlargement with suprasellar extension, mimicking a pituitary adenoma. It appeared that she had primary hypothyroidism. After L-thyroxine treatment, all abnormalities disappeared. The literature on the combination of primary hypothyroidism, hyperprolactinaemia and pituitary enlargement is reviewed and the pathophysiology is discussed. It is concluded that determination of thyrotropin is essential in all patients with pituitary enlargement and hyperprolactinaemia.

Bromocriptine-responsive Cushing's disease associated with anterior pituitary corticotroph hyperplasia or normal pituitary gland.

Cushing's disease may originate from either the anterior pituitary lobe or the neurointermediate lobe, a major characteristic of the latter group being bromocriptine responsiveness. This study of two patients with Cushing's disease demonstrates that bromocriptine responsiveness also may be associated with anterior pituitary corticotroph hyperplasia or a normal pituitary gland. The two patients were a 14-yr-old boy (patient 1) and a 29-yr-old woman (patient 2); their cortisol production rates were 121 and 234 mumol/24 h (normal values, less than 80 mumol/24 h), respectively. A single oral dose of 2.5 mg bromocriptine resulted in a gradual decrease in plasma cortisol from 680 to 130 nmol/L after 6 h in patient 1 and from 640 to 170 nmol/L after 4 h in patient 2. Both patients then received medical treatment for a period of 2 yr. Whereas sodium valproate was ineffective, bromocriptine (5 mg/day) abruptly decreased the cortisol production rate to 60 mumol/24 h in patient 1 and to 138 mumol/24 h in patient 2, and both patients had a partial clinical remission. Despite an increase in bromocriptine dosage to 30 mg daily and 24 mg/day cyproheptadine, the clinical and biochemical remission was not sustained in patient 1, and no further improvement occurred in patient 2. Total hypophysectomy then was performed in both patients. Sections of the pituitary from patient 1 showed diffuse anterior pituitary corticotroph hyperplasia, with early nodule formation in some areas. The sections from patient 2 showed normal numbers and distribution of corticotrophs. We conclude that the heterogeneous nature of Cushing's disease cannot be explained on the basis simply of anterior vs. intermediate lobe origin of the disease.

Primary treatment of macroprolactinomas with Parlodel LAR.

Five patients, 3 women and 2 men, with macroprolactinomas characterized by extrasellar extension and basal plasma prolactin levels ranging from 4.6 to 102 U/l received six monthly injections of 50-100 mg Parlodel LAR, an injectable long-acting repeatable form of bromocriptine. The following observations were made: 1. Plasma prolactin levels fell dramatically in all patients and values in the normal range were obtained in 3 patients. 2. In all patients, the onset of tumour reduction was visible on CT scans made one week after the first Parlodel LAR injection. After six Parlodel LAR injections, tumour size was reduced by more than 75% in 3 patients and by 50-75% in two patients. 3. Diminished visual acuity (one patient), bitemporal hemianopia (2 patients), and oculomotor and trochlear nerve dysfunction (one patient) were restored to normal after the first Parlodel LAR injection. 4. Hypogonadism normalized in 2 patients and improved in one patient, whereas plasma gonadotropins remained low in the 2 postmenopausal women. In one patient with hypothyroidism and hypocorticism, thyroid and adrenal functions normalized. It is concluded that bromocriptine retard (50-100 mg monthly) is a useful alternative for oral treatment of patients with prolactinomas, especially in those patients with compliance problems on oral bromocriptine therapy.

Response of luteinizing hormone secreting pituitary adenoma to a long-acting somatostatin analogue.

A large pituitary tumour was discovered in a 20 year old man who came to medical attention because of grand-mal seizures. The tumour produced biologically active LH as demonstrated by supranormal plasma LH and plasma testosterone values. Free alpha-subunit values were also elevated. In contrast, plasma FSH was in the lower normal range. Transsphenoidal operation failed to remove all tumour tissue. Detailed studies were carried out in the postoperative period. TRH and GnRH administration were associated with a rise of plasma LH and alpha-subunit, whereas plasma FSH was low and unresponsive. Bromocriptine treatment was ineffective. In contrast, both during and after treatment with SMS 201-995 for 6 weeks, a decrease of basal plasma LH values was observed. Furthermore, the administration of a single dose of SMS 201-995 reproducibly induced a decrease of plasma LH lasting for a period of about 6 h. The study suggests that SMS 201-995 may be useful in the treatment of patients with gonadotrope cell adenomas.

An inverted papilloma with intracranial extension.

Inverted papilloma can be found in the lateral wall of the nose, the ethmoidal sinus, the maxillary sinus, the sphenoidal sinus and the frontal sinus. To our knowledge there are no reports of papillomas with intracranial extension. This case report describes the history of a patient with long-standing inverted papillomas, which eventually grew intracranially. The treatment of this patient and the treatment of inverted papilloma in general are discussed.

Transsphenoidal microsurgery as primary treatment in 25 acromegalic patients: results and follow-up.

Twenty-five patients with acromegaly were treated by transsphenoidal microsurgery. Fourteen patients (56%) were considered cured according to the following criteria: a. basal plasma GH less than 10 mU/l; b. glucose suppressed plasma GH less than or equal to 4 mU/l, and c. disappearance of TRH responsiveness if present preoperatively. Thirteen of the cured patients were re-evaluated after a mean follow-up period of 3.5 years (range 1.5 to 5.5 years). At that time, basal plasma GH was still less than 10 mU/l and glucose suppressed plasma GH was still less than or equal to 4 mU/l in all patients, indicating the practical value of our criteria. The remaining 11 patients (44%) received additional treatment by external pituitary irradiation and bromocriptine. Owing to surgery, 5 patients (20%) developed partial or panhypopituitarism.

Bromocriptine treatment of prolactin secreting macroadenomas: a radiological, ophthalmological and endocrinological study.

Twelve patients, six women and six men, with macroprolactinomas characterized by extrasellar extension and basal plasma prolactin levels greater than 6 U/l were treated with 10-20 mg bromocriptine daily in four divided doses for a mean period of 2.4 years (range 0.5-3.5 years). The following observations were made: Plasma prolactin levels fell dramatically in all patients and values in the low normal range were obtained in 10 patients. Tumour size was reduced by more than 75% in 11 patients and by 50-75% in one patient. Tumour-reduction was associated with the development of a partial empty sella in eight cases. In four cases the pituitary became visible. Diminished visual acuity (three patients), bitemporal hemianopia (three patients), unilateral or bilateral central scotomas (three patients) and oculomotor palsy (two patients) restored to normal. Hypogonadism (all patients), hypothyroidism (six patients) and hypocorticism (three patients) improved or normalized in most cases. It is concluded that in the medical treatment of macroprolactinomas 10-20 mg bromocriptine in four divided doses effectively reduces both plasma prolactin level and tumour size.