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J S Bevan

Publications and source records attributed to J S Bevan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Impaired processing of proopiomelanocortin in corticotroph macroadenomas.

The regulation and secretion of the ACTH precursors POMC and pro-ACTH were assessed directly using a 2-site immunoradiometric assay in six patients with pituitary macroadenomas (> or = 1.2 cm in diameter) and 27 patients with Cushing's disease due to a microadenoma. ACTH precursor levels were elevated in patients with macroadenomas (150-3690 pmol/L; normal range, < 5-40 pmol/L) and significantly higher than those in microadenoma patients (median, 29 pmol/L; range, 9-104 pmol/L; P < 0.001). Patients with macroadenomas also had increased ACTH precursor/ACTH ratios (15-181:1) compared with microadenoma patients (median, 5:1, range, 0.7-18.5:1; P < 0.001). ACTH precursors were unresponsive to high dose dexamethasone in patients with macroadenomas, whereas ACTH and cortisol responses varied. After CRH administration, ACTH precursors were unchanged, whereas cortisol increased significantly, suggesting the release of biologically active ACTH. This study clearly demonstrates reduced processing of POMC to ACTH in large pituitary tumors, a characteristic usually associated with tumors causing the ectopic ACTH syndrome, and provides evidence for differential regulation of ACTH precursors and ACTH by glucocorticoid and CRH. Variation in the clinical symptoms of patients with corticotroph macroadenomas may be attributable to differences in biological potency between the ACTH precursors and ACTH.

Adenoma↗
PubMed1995

Acute pre-tibial myxoedema following radioiodine therapy for thyrotoxic Graves' disease.

A 54-year-old woman was treated with an oral dose of 555MBq of 131I radioiodine for thyrotoxicosis. She had no clinically detectable extrathyroidal manifestations of Graves' disease at the time, but within two months developed moderately severe ophthalmopathy and very extensive thyroid dermopathy affecting her face, arms, hands and feet, in addition to the classic pre-tibial area. Although she developed mild post radioiodine hypothyroidism, this was detected at an early stage and its treatment had no effect on the extrathyroidal signs. Thyrotrophin receptor antibodies (TRAb) were positive before treatment (22% inhibition of TSH binding in neat serum), rose to very high levels following radioiodine (97.6% inhibition), and fell progressively over the following year during treatment with prednisolone. Thyroglobulin autoantibodies became detectable following radioiodine but thyroid peroxidase antibodies were undetectable throughout. Serum and purified IgG from blood samples obtained prior to steroid therapy and over the subsequent year were tested on a dermal fibroblast cell line in vitro for the stimulation of synthesis of glycosaminoglycans, protein and DNA, but no increase in radiolabel incorporation was apparent for any sample when compared to controls. The temporal relation between the radioiodine and the acute onset of dermopathy and ophthalmopathy, together with the abrupt rise in TRAbs, indicates a probable causal association. However, the absence of in-vitro fibroblast stimulation would suggest that the pathogenesis of Graves' dermopathy is not dependent solely on any simple humoral factor.

Autoantibodies↗
PubMed1995

Nesidioblastosis in an elderly patient.

We report an 84-year-old woman with hypoglycaemia and hyperinsulinaemia caused by diffuse nesidioblastosis. This is the oldest case of nesidioblastosis so far recorded. The case illustrates some of the difficulties in diagnosing inappropriate hyperinsulinaemia and the benefits of surgery, even in old age. Hypoglycaemia should be considered in patients with variable mental function.

Aged↗
PubMed1995

Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families.

Familial glucocorticoid deficiency is an autosomal recessive syndrome of adrenal unresponsiveness to ACTH characterized by glucocorticoid deficiency, high plasma ACTH levels, and a normal renin-aldosterone axis. Defects of the ACTH receptor have been suggested as a possible cause, and we have previously reported a number of novel mutations of the ACTH receptor gene in some, but not all, cases, suggesting that familial glucocorticoid deficiency may have a heterogeneous molecular etiology. Here we report the clinical features and ACTH receptor gene analysis in four patients from different families. We found that two patients were compound heterozygotes for the S74I and R128C mutations (patient A) and I44M and L192fs frame shift mutations (patient B). The other two patients (C and D) were of different ethnic ancestry, but were both homozygous for a R146H mutation. Segregation studies within families revealed heterozygosity in the parents and several other family members. Human CRH tests in the parents of patients A and B showed normal cortisol and ACTH responses in the S74I, R128C, and I44M heterozygotes and exaggerated cortisol and ACTH responses in the L192fs heterozygote, suggesting that the physiological ACTH increment induced in this test did not reveal evidence of subclinical ACTH resistance, and that this test may not be of value in ascertaining heterozygosity.

Adrenocorticotropic Hormone↗
PubMed1992

Low recurrence rate after partial hypophysectomy for prolactinoma: the predictive value of dynamic prolactin function tests.

OBJECTIVE: To determine the factors influencing the outcome of transethmoidal partial hypophysectomy for suspected prolactinoma and the predictive value of pre and post-operative dynamic PRL function tests. DESIGN: A retrospective study of patients undergoing surgery for a suspected prolactinoma in Cardiff between 1979 and 1989. PATIENTS: Eighty-two hyperprolactinaemic patients (75 women, seven men) diagnosed as having a prolactinoma on the basis of dynamic PRL function tests, radiological investigation and exclusion of other causes. MEASUREMENTS: TSH and PRL responses to domperidone (10 mg i.v.) and TRH (200 micrograms i.v.) measured preoperatively, 2 months post-operatively, and annually thereafter. CT scan performed preoperatively in 58 patients. Operative findings, including adenoma size, documented in each case. RESULTS: Forty-two patients (51%) had microadenomas (less than 10 mm), 37 (46%) had macroadenomas and in three no tumour was found at operation. Preoperatively, normal responses of both TSH (incremental rise less than 2.0 mU/l) and PRL (greater than 100% rise) to domperidone were observed in two patients only: both had an abnormal vascular supply to the pituitary rather than an adenoma. Serum PRL was normalized in the early post-operative period (less than 72 h; 'early cure') in 65 patients (79%). The highest early cure rate (96%, n = 26) was in patients with adenomas of 5-9 mm, lower rates being achieved for lesions of 10-19 mm (80%, n = 30), less than 5 mm (63%, n = 19) or greater than or equal to 20 mm (57%, n = 7). The early cure rate was strongly correlated with preoperative PRL, ranging from 100% in patients with PRL less than 1000 mU/l (n = 13) to zero in those with PRL greater than 10,000 mU/l. Dopamine agonist therapy of between 5 weeks and 4 years duration prior to surgery was associated with a significantly reduced early cure rate (60 vs 94%, P less than 0.02) in macroadenoma but not microadenoma patients. Recurrent hyperprolactinaemia during mean follow-up of 51.7 months occurred in eight patients (12%), in five cases within 2 months of surgery and in the others at 26, 48 and 50 months. Recurrence could not be predicted from any preoperative parameter, but a serum PRL greater than 150 mU/l 1-3 days following microadenomectomy was associated with early recurrence and probably indicates failed surgery. An abnormal response of TSH to domperidone was documented 2 months post-operatively in 11/60 patients with normal basal PRL, and preceded all three late recurrences. Of four patients with abnormal responses of both PRL and TSH at this time, two have relapsed to date. CONCLUSIONS: In carefully selected patients, partial hypophysectomy is an acceptable alternative to medical treatment for prolactinoma. Preoperatively, dynamic tests accurately identified those patients whose hyperprolactinaemia was non-adenomatous in origin and, post-operatively, identified a subgroup of patients at increased risk of late recurrence.

Adult↗
PubMed1992

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↗
PubMed1992

Reversible adrenocorticotropin deficiency due to probable autoimmune hypophysitis in a woman with postpartum thyroiditis.

The natural history and pathogenesis of lymphocytic hypophysitis remain poorly understood. We describe a 34-yr-old woman with postpartum thyroiditis and ACTH deficiency, studied at monthly intervals for 18 months after pregnancy. A significant titer of thyroid peroxidase autoantibodies was detected at 16 weeks gestation, and she was recruited into a prospective study of postpartum thyroid function. Four months postpartum she developed mild hyperthyroidism [free T4 (fT4), 27 pmol/L; TSH, less than 0.2 mU/L] and showed a rise in thyroid peroxidase and thyroglobulin autoantibodies. At 9 months postpartum, serum fT4 and fT3 levels were low normal (8.0 and 1.7 pmol/L, respectively), but TSH was not raised (0.4 mU/L). Subsequent investigation showed a low basal plasma cortisol level (28 nmol/L) in association with undetectable ACTH, and subnormal cortisol responses to depot Synacthen (535 nmol/L at 6 h) and hypoglycemia (peak, 145 nmol/L). FSH, LH, GH, and PRL function and computerized tomography of the pituitary were normal. Retrospective analysis of serum samples taken throughout the postpartum year showed developing hypocortisolemia between 3-9 months postpartum. Each sample was also tested for pituitary autoantibodies using a specific indirect immunofluorescent assay; none was detected. The ACTH deficiency recovered spontaneously, with normal cortisol responses to depot Synacthen (greater than 1380 at 6 h) and hypoglycemia (peak, 590) 14 and 18 months postpartum, respectively. This case illustrates that postpartum pituitary deficiencies are potentially reversible. The pattern of pituitary deficit and postpartum thyroiditis supported a diagnosis of autoimmune hypophysitis.

Adrenocorticotropic Hormone↗
PubMed1992

Quinine-induced cutaneous vasculitis.

We report a 60-year-old woman who developed severe cutaneous vasculitis three weeks after commencing quinine sulphate (300 mg at night) for nocturnal cramps. The patient died despite immunosuppressive treatment with prednisolone and cyclophosphamide. We review three previous cases and conclude that cutaneous vasculitis is a rare but life-threatening complication of treatment with this widely-prescribed drug. Quinine sulphate is prescribed frequently for nocturnal cramps, although its efficacy is unsupported by stringently controlled clinical trials. Adverse reactions to the drug are unusual. We describe a 60-year-old woman with fatal cutaneous vasculitis related to quinine treatment.

Female↗
PubMed1991

Cholinergic blockade with pirenzepine induces dose-related reduction in glucose and insulin responses to a mixed meal in normal subjects and non-insulin dependent diabetics.

OBJECTIVE: The aim of the study was to assess the effects of cholinergic blockade with pirenzepine on glucose and insulin responses to a mixed meal in normal subjects and patients with non-insulin dependent diabetes (NIDDM). Further, to assess in normal subjects the relative importance of nocturnal GH suppression by pirenzepine. DESIGN: Placebo, 100 or 200 mg pirenzepine were given to the normal subjects 1 hour before a standard mixed meal. The effects of placebo or 200 mg pirenzepine at night on nocturnal GH secretion and subsequent breakfast carbohydrate tolerance were also studied. NIDDMs were given placebo or 200 mg pirenzepine before the meal. SUBJECTS: We studied six healthy male volunteers (ages 20-22, body mass indices 20.3-23.3) and ten NIDDMs (eight men, ages 42-74); five obese (BMI 25.5-31.8) and five non-obese (BMI 21.2-24.8). MEASUREMENTS: Serial plasma glucose and insulin concentrations were measured for 3 hours after a standard mixed meal. RESULTS: Acute pretreatment of normal male volunteers with pirenzepine produced a dose-related improvement in carbohydrate tolerance. Peak post-prandial plasma glucose levels were delayed and significantly reduced following 200 mg orally (6.5 +/- 0.1 mmol/l), but not following 100 mg (7.3 +/- 0.3), compared with placebo (7.6 +/- 0.3). Peak insulin levels were similarly delayed and reduced by the 200 mg dose only (36.5 +/- 6.1 mU/l, compared with 49.8 +/- 8.7). Suppression of nocturnal GH by 200 mg pirenzepine at night produced a small reduction in fasting plasma glucose (5.0 +/- 0.1 mmol/l, compared with 5.3 +/- 0.1, P less than 0.02) but did not improve subsequent breakfast carbohydrate tolerance. Peak plasma glucose in NIDDMs was reduced following pirenzepine (12.4 +/- 0.9 mmol/l) compared with placebo (14.3 +/- 1.0, P less than 0.01). This reduction was equally significant in obese and non-obese groups. Peak plasma insulin was also reduced by pirenzepine (22.4 +/- 3.9 mU/l) compared with placebo (42.4 +/- 5.3, P less than 0.01). Insulin suppression was quantitatively greater in obese than in non-obese patients. CONCLUSIONS: Improvement in carbohydrate tolerance after pirenzepine in normal subjects is dose related and largely independent of GH suppression. Cholinergic blockade can also improve meal carbohydrate tolerance with simultaneous reduction in plasma insulin concentrations in non-insulin dependent diabetics, particularly those with obesity.

Adult↗
PubMed1991

Preliminary characterization of growth factors secreted by human pituitary tumors.

To investigate the secretion of mitogenic factors by human pituitary tumors we have cultured cells from 54 adenomas in serum-free medium. Conditioned media from 28 (52%) elicited dose-dependent stimulation of [3H]thymidine incorporation into rat GH3 cells (22-338% above control), while 14 (26%) inhibited GH3 proliferation. Stimulating activity was observed more frequently in nonfunctional tumor-conditioned medium (73%; n = 22) than in secretory tumor-conditioned medium (37%; n = 32). Of 10 tumour-conditioned media with mitogenic activity for GH3 cells, only 4 produced modest stimulation of HEp2 (human laryngeal carcinoma) cells. In contrast, [3H]thymidine incorporation into A431 (human squamous carcinoma) and PC12 (rat adrenal pheochromocytoma) cells was enhanced by each of 15 tumor-conditioned media (up to 342% and 275%, respectively), 8 of which had shown stimulatory and 2 inhibitory effects on GH3 cells. Gel filtration of pooled conditioned media from 10 nonfunctional tumors showed significant growth-promoting activity for GH3 cells in fractions corresponding to mol wt of 2-3 and 11-18 kDa. Proliferative activity on A431 cells also eluted in two positions; one corresponded to the higher mol wt peak seen with GH3 cells, while the other, not observed with GH3 cells, was in the 3- to 6-kDa range. These findings suggest that cells derived from human pituitary adenoma tissue synthesize and secrete several growth factors, each of which may have its own target cell specificities. These factors have yet to be characterized, but we suggest that they may have a role in stimulating the development or maintenance of human pituitary adenomas.

Adenoma↗
PubMed1990

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↗
PubMed1990

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↗