The pituitary megatest: outdated?
Explore the source record for details and available documents.
Adrenocorticotropic Hormone↗
Biomedical subjects
C W Burke
Publications and source records attributed to C W Burke.
Dopamine agonists and pituitary tumor shrinkage.
The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.
Adenoma↗
Vasopressin antagonist in early postoperative diabetes insipidus.
23 patients without diabetes insipidus before transfrontal (hypothalamic) or trans-sphenoidal (pituitary) surgery were studied prospectively to investigate the pathogenesis of early postoperative diabetes insipidus. 12 patients who underwent trans-sphenoidal surgery and who did not develop diabetes insipidus were used as controls. All received prophylactic corticosteroid replacement. Blood samples were obtained immediately after operation, at the onset of diabetes insipidus, and 24 h later. Immediately after trans-sphenoidal pituitary surgery, plasma vasopressin (AVP) was raised but had fallen to subnormal concentrations by the onset of diabetes insipidus. After transfrontal hypothalamic surgery diabetes insipidus occurred sooner and was associated with high plasma AVP immunoreactivity--but the plasma showed no antidiuretic bioactivity and greatly attenuated the antidiuretic response to standard AVP. Early diabetes insipidus after hypothalamic surgery is associated with release of a substance, presumably an analogue, from the damaged hypothalamo-neurohypophyseal system, which acts as an antagonist to normal AVP activity; after trans-sphenoidal operations diabetes insipidus seems to be caused by failure of AVP release.
Adolescent↗
Transsphenoidal surgery for Cushing's disease: does what is removed determine the endocrine outcome?
Fifty-seven patients with pituitary-dependent Cushing's syndrome and eight with Nelson's syndrome underwent transsphenoidal pituitary exploration, with removal of macroscopically abnormal tissue in 64 patients and detailed histology of this in 63. The cure rate by stringent criteria 1 month later was 48 (83%) of the 58 with assessable data, who were followed for 225 patient-years. Two patients relapsed later, a rate of one per 112 patient-years of follow-up. In 27% of patients, the macroscopically abnormal tissue removed was histologically indistinguishable from normal pituitary gland but the cure rate was 82%, and a quarter of the patients in this group assessable for recovery of normal ACTH function gained it. Another 53% of biopsies showed corticotroph adenomas, and the cure rate in these was 89% though rather more (69%) recovered normal ACTH function. The remaining 20% of biopsies were consistent with corticotroph hyperplasia. The cure rate varied little whether the lesion was diffuse or localized, whether or not it was in the invasion zone/interlobar cleft, whether or not there was pituitary enlargement, or whether the surgery was radical or selective. Six patients, of whom three are cured, showed surgical or radiological evidence of invasion outside the pituitary fossa. The data are consistent with the idea that pituitary adenoma is merely the end stage of some other process in the corticotrophs, and cure often follows removal of a lesion other than adenoma. Of patients who were permanently cured, 47% regained normal ACTH function within 3 years of operation (none later), 53% remaining ACTH-deficient at 3 years or more. Of all patients 48% acquired gonadotrophin deficiency, 28% have TSH deficiency and 25% permanent diabetes insipidus. All these pituitary function deficits were more common after radical surgery and in patients with normal histology, The literature contains so little objective data on these functions that we cannot say whether the endocrine damage in our patients is exceptional or not.
Adenoma↗
The anterior pituitary, snakebite and Sheehan's syndrome.
Explore the source record for details and available documents.
Female↗
Perifusion studies of bromocriptine-treated and untreated macroprolactinomas: effects of dopamine, bromocriptine and TRH.
There have been no detailed in-vitro studies of PRL secretion by human macroprolactinoma cells exposed to bromocriptine (BC) to within a few days of surgical removal. We have studied cells from four such tumours (serum PRL 7.05-247 U/l) and six untreated tumours (serum PRL 4-80.35 U/l) using a perifusion technique. The BC-treated tumours had shown tumour shrinkage and were treated until 40-96 h before surgery, but in one patient serum PRL had not suppressed below 15 U/l despite chronic treatment. Pretreatment serum PRL responses to TRH were blunted in all 10 patients. During perifusion with dopamine (DA, 5 mumol/l) untreated prolactinomas had a higher PRL secretion rate (19.3 +/- 2.7 microU/mg tissue/min, mean +/- SEM) than BC-treated (3.9 +/- 0.7, P = 0.005). When DA was removed, PRL secretion from untreated tumours increased to 129.7 +/- 18.7 microU/mg/min, but in three of the BC-treated, little increase occurred. In the fourth (from the patient whose serum PRL had not fully suppressed) PRL secretion increased from 4.4 to 25.6 microU/mg/min after DA withdrawal, and DA and BC dose-related inhibition of PRL was similar to that observed in untreated tumours. TRH (10 ng/ml), without DA, provoked increased PRL release from both untreated (266% basal secretion, n = 3) and BC-treated (298%, n = 3) tumours; this effect was completely inhibited by DA (5 mumol/l). The absence of hormones other than PRL following potassium (55 mmol/l) excluded contaminating normal pituitary. We conclude: (1) The effects of BC on prolactinoma PRL secretion may persist for at least 4 days; (2) partial in-vivo BC resistance can be due to factors other than DA receptor malfunction; (3) the apparent discrepancy between in-vivo and in-vitro TRH responses was consistent with the presence of increased hypothalamic DA tone in vivo; and (4) BC may have differential effects on TRH and DA-controlled PRL pools in the tumourous lactotroph.
Bromocriptine↗
Studies of two thyrotrophin-secreting pituitary adenomas: evidence for dopamine receptor deficiency.
Of 22 previously reported patients with TSH-secreting pituitary adenomas challenged with dopamine agonists, 18 showed no decrease in serum TSH. There have been few in-vitro studies of these rare tumours so the mechanism of the dopaminergic resistance has remained obscure. We describe two further patients with thyrotrophinomas; the first was thyrotoxic (T3 6.1 nmol/l, TSH 7 mU/l) and the second was diagnosed after radioiodine for presumed Graves' disease. The second patient had an alpha-subunit: TSH molar ratio less than unity (0.27). In-vivo TSH responses to TRH, bromocriptine and domperidone were compared with those of the resected tumour cells in vitro, the latter studied using a continuous perifusion system. Dopamine receptors were sought in membranes from each tumour using a radioreceptor assay employing 3H-spiperone. Patient 1 showed significant increases in serum TSH (7 to 13 mU/l) and alpha-subunit (18.7 to 385 ng/ml) after 200 micrograms TRH (i.v.) but patient 2 showed no such increases (TSH: 69 to 72 mU/l, alpha-subunit: 4.9 to 5.2 ng/ml). Neither patient showed a change in serum TSH following bromocriptine 2.5 mg (orally) or domperidone 10 mg (i.v.), though serum PRL responded normally. Serum TSH from patient 1 was of apparently normal molecular size but increased bioactivity (B/I ratio 3.8) and that from patient 2 was of increased molecular size but reduced bioactivity (B/I ratio 0.1). Tumour cells from each patient immunostained for TSH beta and alpha-subunit, and secreted TSH in vitro. The first showed dose-dependent TSH release after TRH (1-100 ng/ml) which could not be inhibited by dopamine (5 mumol/l) but the second was unresponsive to TRH in vitro. Neither tumour showed inhibition of TSH release by dopamine (5 mumol/l) or bromocriptine (0.01-10 nmol/l) and neither contained membrane-bound dopamine receptors. The results suggest that the dopaminergic resistance typical of most TSH-secreting pituitary adenomas may be due to altered or absent membrane-bound dopamine receptors.
Adenoma↗
Intrasellar gangliocytoma containing gastrin and growth hormone-releasing hormone associated with a growth hormone-secreting pituitary adenoma.
A 74-year-old acromegalic found to have an intrasellar gangliocytocytoma and GH-secreting pituitary adenoma is described. The gangliocytoma contained immunoreactive gastrin and, to a lesser extent, GHRH, and the adenoma immunostained for GH. Gastrin has not been previously reported in hypothalamic gangliocytomas. Since this peptide has been demonstrated in normal hypothalamus and pituitary, and provokes GH release when administered intraventricularly, it may have caused GHRH release from the gangliocytoma by a local paracrine action and led to adenoma formation and acromegaly.
Adenoma↗
The human leucocyte sodium pump in Cushing's syndrome.
Because corticosteroids have important effects on sodium homeostasis, we studied leucocyte 22Na efflux in patients with Cushing's syndrome. The ouabain-sensitive 22Na+ efflux rate constant was raised in Cushing's syndrome (mean +/- SD 2.84 +/- 0.32 vs 2.35 +/- 0.53/h, P less than 0.001, n = 15). This efflux rate constant correlated with the urinary free cortisol (rs = 0.61, P less than 0.02), but less significantly with the 0900 h plasma cortisol (rs = 0.46, P less than 0.08). There was no correlation with the supine plasma aldosterone. Intracellular sodium content was significantly lower in Cushing's syndrome (21.1 +/- 4.6 vs 27.8 +/- 9.5 mmol/kg dry weight, P less than 0.01), with a raised intracellular potassium to sodium content ratio (16.1 +/- 3.3 vs 12.9 +/- 3.6, P less than 0.01). After treatment of the Cushing's syndrome by trans-sphenoidal adenomectomy or adrenalectomy, these defects in cellular sodium balance were corrected. Thus, the distribution of sodium between intra- and extracellular fluid may be affected by adrenal corticosteroids via an action on the sodium pump.
Adult↗
Body fat topography in women with androgen excess.
The relationship between body fat distribution and androgen excess was determined in 168 premenopausal women of varying degrees of androgen excess. In 84 women with the polycystic ovary syndrome or idiopathic hirsutism, the waist:hips girth ratio (WHR) was 0.81 +/- 0.01 (mean +/- s.e.m.) and was significantly greater (P less than 0.001) than in an age- and weight-matched group of 84 non-hirsute women (0.77 +/- 0.01), indicating upper body fat predominance in the hirsute subjects. Plasma testosterone was directly correlated with the WHR (r = 0.55, P less than 0.001) and this relationship was independent of obesity level, supporting the hypothesis that plasma androgens are an important determinant of body fat topography in premenopausal women.
Adipose Tissue↗
Acute and chronic pituitary failure resembling Sheehan's syndrome following bites by Russell's viper in Burma.
Pituitary function was investigated in 9 patients in shock after Russell's viper bites and in 24 individuals who had been severely envenomed 2 weeks to 24 years previously. 3 out of 9 patients had hypoglycaemia and inappropriately low serum cortisol, plasma growth hormone, and plasma prolactin concentrations. 4 who died had pituitary haemorrhage and 1 had adrenal haemorrhage as well. Of the 24 who had apparently recovered from bites, 7 had clinical features of hypopituitarism and no response in plasma growth hormone or prolactin concentrations to symptom-producing insulin-induced hypoglycaemia. 4 of these 7 had a sluggish serum cortisol response to 'Synacthen Depot' and 5 had an abnormal cortisol response to hypoglycaemia. 4 men with symptoms who were tested had low serum testosterone concentrations; serum thyroxine was also low in these men but not in 2 women with menstrual disturbances and impaired insulin responses. Of the 17 individuals without clinical evidence of endocrine disease, 4 had pituitary hormonal abnormalities. Russell's viper envenoming may thus produce a disorder resembling Sheehan's syndrome.
Acute Disease↗
Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement.
Serum prolactin concentrations and clinical features were correlated with the histopathologic diagnosis in 128 patients, without acromegaly or Cushing's syndrome, referred for surgical treatment of a presumed pituitary adenoma. A serum prolactin concentration of more than 8,000 mU/liter was always due to a prolactin-secreting adenoma. Prolactin levels of less than 8,000 mU/liter occurred with a variety of pathologic diagnoses. Fifteen patients had lesions other than pituitary adenomas, most commonly intrasellar craniopharyngioma; 10 of these had modest hyperprolactinaemia (maximum, 5,260 mU/liter) and four had received inappropriate bromocriptine therapy. Adenomas that were not prolactinomas frequently caused mild hyperprolactinaemia, although this was usually less than 3,000 mU/liter; three of these patients, however, had serum prolactin concentrations greater than this (maximum, 8,000 mU/liter). If the serum prolactin concentration is less than 3,000 mU/liter in the presence of significant pituitary enlargement, surgical removal is essential for both diagnosis and treatment since only prolactin-secreting adenomas are likely to shrink with dopamine agonist therapy. A serum prolactin concentration between 3,000 and 8,000 mU/liter is consistent with any diagnosis, whether the fossa is greatly enlarged or not, and great care must be taken with dopamine agonist therapy in such patients.
Adenoma↗
Factors in the outcome of transsphenoidal surgery for prolactinoma and non-functioning pituitary tumour, including pre-operative bromocriptine therapy.
Radical transsphenoidal surgery in 58 patients with large non-functioning pituitary tumours relieved pressure symptoms and disconnection hyperprolactinaemia without loss of pituitary function, and verified the diagnosis. Pre-operative bromocriptine did not cause any shrinkage of non-functioning tumours (n = 8), even up to 48 weeks. Thirty-two patients not given postoperative radiotherapy are being followed-up, and although two show minor CT scan evidence of tumour regrowth, for the others the delay in radiotherapy is enabling reproduction where required. In 20 patients with non-invasive macroprolactinomas radical surgery caused no loss of pituitary function but cured eight, of whom one has relapsed; none of eight invasive prolactinomas was cured by surgery. Pre-operative bromocriptine caused marked size reduction in seven of seven macroprolactinomas, but if continued beyond 6 weeks induced tumour fibrosis and uneven shrinkage which made surgery dangerous and unproductive. Selective transsphenoidal surgery relieved hyperprolactinaemia in 70% of patients with meso- (n = 15) or microprolactinoma (n = 24) usually without loss of pituitary function: the relapse rate was 1 per 88 patient years of follow-up. Invasive prolactinomas, and macroprolactinomas showing uneven shrinkage with a short (up to 4 weeks) course of bromocriptine should have radiotherapy rather than surgery, while the patients most suited to surgery are those with mesoprolactinomas, or some macroprolactinomas with compact intrasellar shrinkage after short-term bromocriptine. Microprolactinomas generally did not benefit from surgery as compared to conservative therapy. In none of the tumour groups were the surgical findings an accurate predictor of postoperative pituitary function.
Adenoma↗
Cushing's syndrome in pregnancy: the timing of definitive treatment.
Cushing's syndrome in pregnancy is rare but associated with a high fetal loss rate, premature labour and excessive maternal morbidity. There has been controversy regarding the safety and efficacy of surgical treatment during pregnancy. We describe two further cases, both due to adrenal adenomas, in whom the diagnosis was made at 28 and 31 weeks gestation. Both cases suffered from severe myopathy. The first case was not treated during pregnancy and developed wound and urinary infections after caesarean section and subsequent adrenalectomy. An incisional hernia in the caesarean section scar has been repaired twice. The second had an adrenalectomy when 29 weeks pregnant with rapid resolution of the features of Cushing's syndrome, particularly the myopathy, and had an uneventful vaginal delivery. The second case, and a review of those previously described, indicates that surgical treatment during pregnancy is safe and significantly reduces fetal losses, premature labour and maternal morbidity.
Adenoma↗
The human leucocyte sodium pump in adrenocortical insufficiency.
In view of the known effects of cortisol and related compounds on sodium balance, we examined leucocyte 22Na+ efflux in patients with adrenocortical insufficiency. The ouabain-sensitive 22Na+ efflux rate constant, which reflects sodium pump activity, was lowered in secondary hypoadrenalism (mean 1.95 +/- SD 0.25 vs 2.33 +/- 0.45 h-1, P less than 0.002, n = 6). Patients with hypoadrenalism also had higher intracellular sodium content (mean 34.9 +/- SD 3.5 vs 27.8 +/- 9.5 mmol/kg dry weight, P less than 0.008) and lower intracellular potassium to sodium ratios (mean 9.7 +/- SD 0.7 vs 12.9 +/- 3.6, P less than 0.001). These defects in cellular sodium balance were corrected following replacement therapy with cortisol, prednisolone or dexamethasone. In-vitro incubation of normal leucocytes with 5-20 nmol/l dexamethasone led to an increase in the Na+/K+-ATPase activity. The effect of cortisol and related compounds on the distribution of sodium between intra- and extra-cellular fluid may be mediated by their action on the sodium pump.
Adrenal Insufficiency↗
Pituitary apoplexy following isosorbide administration.
Explore the source record for details and available documents.
Humans↗
Non-functioning pituitary adenomas do not regress during bromocriptine therapy but possess membrane-bound dopamine receptors which bind bromocriptine.
Dopaminergic binding to membranes from 20 well-characterized non-functioning pituitary tumours was investigated using the radioligand [3H]spiperone; nine had failed to regress during pre-operative bromocriptine therapy. Five macroprolactinomas and six normal pituitaries were similarly investigated. High affinity dopaminergic binding sites were defined in all tissues studied. Mean dissociation constants were similar for the three groups (0.92, 0.55 and 0.51 nmol/l, respectively) but mean site numbers were greater in the prolactinomas (698) than in non-functioning tumours (131) or normal pituitaries (136 fmol/mg protein). In a pool of non-functioning tumour membranes ligand competition experiments confirmed that binding was dopaminergic. Stereospecificity was demonstrated using the (+) and (-)isomers of butaclamol. Bromocriptine was present in three non-functioning tumours that had been exposed to the drug within 24 h of surgery and it largely prevented [3H]spiperone binding; membrane washing restored [3H]spiperone binding to control values. We conclude that non-functioning tumours possess high affinity membrane-bound dopaminergic binding sites similar to those in normal pituitary and macroprolactinomas, but apparently fewer in number than in the latter. Though bromocriptine binds to dopamine receptors on non-functioning tumours in vivo, this does not result in tumour regression.
Adenoma↗