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Biomedical subjects

P J Trainer

Publications and source records attributed to P J Trainer.

At least 73 records · Page 4Linked to original sources
PubMed1994

Treatment with GHRH(1-29)NH2 in children with idiopathic short stature induces a sustained increase in growth velocity.

OBJECTIVE: Therapy with GHRH in patients with mild GH insufficiency appears to be more effective than in those with severe insufficiency. We, therefore, studied the clinical response of children with idiopathic short stature to treatment with GHRH(1-29)NH2 (GHRHa) for a period of 12 months. DESIGN: Eighteen short pre-pubertal children (aged 4.3-11.0 years, 17 male) with idiopathic short stature (height < 3rd centile, peak GH to provocative testing > 20 mU/l) were recruited to receive GHRHa 20 micrograms/kg by twice daily s.c. injection for one year. One patient was non-compliant and was withdrawn prior to 3 months of therapy. Pretreatment height velocity was calculated for 12 months and subjects were measured 3-monthly during therapy. Overnight GH profiles and s.c. GHRH tests (20 micrograms/kg) were performed at 0, 3, 6 and 12 months of therapy. In addition, an i.v. GHRH test (1 microgram/kg) was performed at the start and after 1 month of therapy. MEASUREMENTS: Overnight GH profiles were analysed using the Pulsar program. RESULTS: Mean (SD) height velocity (HV) increased from 4.8(0.9)cm/year pre-treatment to 7.2(1.6)cm/year after 12 months of therapy (P = 0.001). The children growing slowly (HV < 25th centile) before treatment had a greater growth response than those growing normally (HV > or = 25th centile) before treatment. Final height prediction increased by a mean (SD) of 3.4(2.6)cm. Overnight GH levels and GH responses to GHRH testing fell during the 12 months of therapy. Fasting blood glucose and insulin levels increased during therapy, as did IGF-I. Cessation of GHRHa was followed by catch-down growth during the first 3 months off therapy: mean (SD) HV 3.89(1.82)cm/year (P < 0.04), although the HV after 6 months (4.9(1.0))cm/year) and 12 months (4.4(1.0)cm/year) was not different from pretreatment values. CONCLUSIONS: Short-term therapy with twice-daily s.c. injection of GHRHa (20 micrograms/kg) promoted linear growth in short children who were not GH-insufficient. The improved height velocity was sustained throughout the 12 months of treatment, followed by catch-down growth, and returned to pretreatment velocity after cessation of therapy.

Blood Glucose↗
PubMed1994

The effect of recombinant IGF-I on anterior pituitary function in healthy volunteers.

OBJECTIVE: Insulin-like growth factor-I is the mediator of many of the actions of GH and is a potent metabolic regulator. Recombinant IGF-I (rhIGF-I) is of potential value in the treatment of syndromes associated with either GH or insulin resistance. This study was designed to assess the effects of subcutaneous (s.c.) rhIGF-I on anterior pituitary function. DESIGN: Double-blind, placebo controlled, randomized cross-over study. The interval between investigations was 2 weeks. SUBJECTS: Twelve normal volunteers received on one occasion a single s.c. dose of 40 micrograms/kg rhIGF-I and on the other, placebo. MEASUREMENTS: Circulating levels were measured, over 24 hours, of GH, LH, FSH, PRL, TSH, cortisol, ACTH, glucose, IGF-I, IGF-II, insulin, C-peptides; IGF binding proteins by Western ligand blotting; total IGF bioactivity using FRTL-5 thyroid cells; and glucose by the glucose oxidase method. RESULTS: Recombinant IGF-I increased AUC for plasma IGF-I, measured by radioimmunoassay (rhIGF-I mean 7065 +/- SEM 33 vs 3895 +/- 204 micrograms/l, P < 0.0001) and IGF bioactivity (22.5 +/- 3.4 vs 14.2 +/- 1.8 U/ml, P < 0.001) but plasma IGF-II fell (9308 +/- 403 vs 11052 +/- 451 micrograms/l, P < 0.0001). There was no biochemical or clinical evidence of hypoglycaemia and no difference in mean glucose levels. No difference existed in AUC for GH, LH, FSH, ACTH and cortisol between rhIGF-I and placebo; additionally, pulse number and amplitude for GH and LH were unaffected. TSH fell following rhIGF-I (33.0 +/- 3.36 vs 42.5 +/- 5.98 mU h/l, P = 0.01). Both mean plasma C-peptide (0.73 +/- 0.06 vs 0.91 +/- 0.05 nmol/l, P = 0.03), and insulin (10.81 +/- 1.02 vs 15.36 +/- 1.18 mU/l, P = 0.03) were lower following rhIGF-I. There was no change in IGFBPs. CONCLUSION: A single injection of 40 micrograms/kg of subcutaneous rhIGF-I does not cause hypoglycaemia. IGF bioactivity was increased without inhibition of GH secretion. The only change observed in anterior pituitary function was a fall in plasma TSH.

Adrenocorticotropic Hormone↗
PubMed1994

An audit of the insulin tolerance test in adult subjects in an acute investigation unit over one year.

OBJECTIVE: We audited our practice of insulin tolerance testing (ITT) in terms of safety and technical success. We reviewed the results of those tests performed over a 12-month period. By relating peak cortisol response to 0900 h screening cortisol level, we determined whether we could reduce the number of tests performed. DESIGN: The results of all ITTs performed on our unit between 1 January and 31 December 1991 were reviewed. PATIENTS AND MEASUREMENTS: Patients were prescreened by measurement of serum cortisol and thyroxine, and recording of an electrocardiogram. A subnormal serum thyroxine (< 58 nmol/l), 0900 h serum cortisol (< 100 nmol/l) or an abnormal ECG were taken as contraindications to the test. Minimum glucose and maximum cortisol levels were recorded, along with peak GH responses when measured. The peak cortisol response was compared to the screening and basal cortisol levels. RESULTS: A total of 161 tests were performed, 135 of which fulfilled our inclusion criteria. The test was technically successful in all but 5 of these; a significant adverse event occurred in one patient with full recovery after reversal of hypoglycaemia. Thirty-two patients had a suboptimal serum cortisol response to hypoglycaemia: screening cortisol level ranged from 128 to 493 nmol/l and 0900 h serum cortisol measured prior to the ITT from 97 to 431 nmol/l. The lowest level of screening cortisol above which all patients would be expected to achieve the normal peak cortisol of 580 nmol/l or over is therefore 494 nmol/l. If this cut-off level had been adopted, 10 (8%) ITTs need not have been performed if their only purpose had been to assess cortisol reserve. Altering the criterion for the necessary peak cortisol to 500 nmol/l did not affect the number of ITTs required. Our lower limit for testing could not be revised upwards from 100 nmol/l. Adequacy of cortisol reserve did not predict a normal GH response to insulin-induced hypoglycaemia. CONCLUSIONS: When performed in an experienced endocrine unit with adequate supervision, the insulin tolerance test is a safe procedure. According to the current sample, fewer tests would be performed without detriment to patient care if those with a screening cortisol of greater than 500 nmol/l did not proceed to testing, unless the purpose of the test was also to exclude GH deficiency. A lower limit of 100 nmol/l appears reasonable and need not be revised upwards.

Acromegaly↗
PubMed1994

Opioid peptide and alpha-adrenoceptor pathways in the regulation of the pituitary-adrenal axis in man.

Opioid peptides are well established as potent inhibitors of the pituitary-adrenal axis, while alpha 1-adrenoceptor drugs have recently been shown to stimulate this axis: both classes of agents appear to work principally above the level of the pituitary, most probable directly on the hypothalamus. There is also evidence that these drugs interact in their control of pituitary-adrenal function, although the specific hypothalamic releasing hormone involved has remained unclear. We have therefore carried out a study into the interaction of methoxamine, an alpha 1-adrenoceptor agonist and naloxone, an opioid antagonist, together with human corticotrophin-releasing hormone (CRH), in a group of healthy volunteers in order to establish the mode of action of these drugs. The following drugs were administered to a group of seven healthy male subjects in a randomized double-blind manner: methoxamine (6 micrograms/kg per min over 3 h); naloxone (10 mg bolus); human CRH (100 micrograms bolus); methoxamine plus CRH; naloxone plus CRH; methoxamine plus naloxone; saline (control). Plasma ACTH and serum cortisol were measured at intervals in each subject, and blood pressure and pulse rate recorded with each sample. Both CRH and naloxone produce a marked rise in ACTH and cortisol, peaking at approximately 45 min after infusion. In combination, the drugs produced a peak response in plasma ACTH at the same time, but its magnitude was greater than that after either drug alone. Methoxamine produced a rise in plasma ACTH which was maximal at approximately 75 min, as well as a peak rise in serum cortisol at 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Cushing's syndrome. Therapy directed at the adrenal glands.

Establishing the exact etiologic diagnosis of Cushing's syndrome is fundamental to the management of the disease. It allows for specific therapy, such as pituitary microsurgery. In cases where the adrenal gland is the cause, treatment can be either surgical or medical. This article explores both types of treatment and their respective results.

Adenoma↗
PubMed1994

Bilateral phaeochromocytomas in von Hippel-Lindau disease: diagnosis by adrenal vein sampling and catecholamine assay.

Three unrelated patients with von Hippel-Lindau disease had phaeochromocytomas diagnosed as a result of screening in their third decade. All had raised 24-h urinary noradrenaline levels and obvious unilateral adrenal tumours on ultrasound scanning and computed tomography. The contralateral adrenal appeared either normal or equivocally abnormal using the same imaging techniques. Radiolabelled meta-iodo-benzylguanidine uptake and enhanced T2-weighted magnetic resonance signals confirmed the ipsilateral lesion, but showed no abnormality in the contralateral adrenal. Nevertheless, venous sampling demonstrated abnormally elevated noradrenaline:adrenaline ratios (normal < 1) in blood draining both adrenals in all three patients. All underwent bilateral adrenalectomy: histological examination confirmed bilateral phaeochromocytomas in all three patients, with the smaller adrenal showing tumours between 3 and 11 mm in diameter. A fourth patient with von Hippel-Lindau disease was also evaluated because of a left 'suprarenal' mass discovered by ultrasound scanning. Urinary and plasma catecholamines were normal. Computed tomography showed a normal right adrenal, with a left para-aortic mass lying superior to the left adrenal. Magnetic resonance scanning showed an enhanced T2 signal from the mass, which also showed positive uptake with radiolabelled mIBG. At operation, a non-secretory left para-aortic paraganglioma was found. Venous sampling suggested that the left adrenal was normal, and this was confirmed on histology. Venous sampling for catecholamine assays is effective in locating small bilateral phaeochromocytomas and defining a normal adrenal gland, and can be useful in preventing unnecessary or repeat operations in patients with non Hippel-Lindau disease.

Adrenal Gland Neoplasms↗
PubMed1993

The radiological investigation of occult ectopic ACTH-dependent Cushing's syndrome.

The radiological features of 14 patients with Cushing's syndrome due to 'occult' ectopic ACTH syndrome have been reviewed. In 11 of the 14 patients (79%), the ACTH-producing tumour was located in the thorax. Bronchial carcinoid tumours (eight patients) were the single most common source of 'occult' ectopic ACTH production with thymic carcinoid tumours (two patients) and mediastinal metastases from a medullary carcinoma of the thyroid gland (one patient) accounting for the other intrathoracic tumours. The tumours were usually small with five of the eight bronchial carcinoid tumours measuring between 4 and 10 mm in diameter. Since it remains difficult to distinguish between pituitary-dependent Cushing's disease and 'occult' ectopic ACTH-dependent Cushing's syndrome both clinically and biochemically, the role of radiology remains vital.

ACTH Syndrome, Ectopic↗
PubMed1993

Urinary free cortisol in the assessment of hydrocortisone replacement therapy.

Glucocorticoid replacement therapy should be tailored to individual patients' requirements to avoid the risks of over and under treatment. Serum and urinary free cortisol profiles over 24 hours were compared as a means of assessing replacement therapy in nine patients on long-term twice daily hydrocortisone. Both indices varied in relationship to the timing and dose of hydrocortisone and there was a close correlation between individual measurements of serum and urinary free cortisol (r = 0.885, p < 0.0001). Collection of urine samples offers certain advantages over repeated serum sampling and urinary free cortisol measurement may have a role in the assessment of hydrocortisone replacement therapy.

Adrenal Insufficiency↗
PubMed1993

Malignant prolactinoma with extracranial metastases: a report of three cases.

OBJECTIVE: Prolactin-secreting tumours of the pituitary almost never metastasize extracranially. However, we have recently seen three such patients, whose presentation, clinical course and response to treatment are reviewed in order to determine whether they possess unique clinical features, and to assess optimum therapy. DESIGN AND PATIENTS: Three patients with extracranial metastases from prolactinomas have been retrospectively reviewed. MEASUREMENTS: Clinical courses, biochemical parameters and imaging modalities (CT, MR and radiolabelled somatostatin analogue scanning) and histopathology were assessed before and during different therapeutic regimens. RESULTS: All three patients' presentations were initially unremarkable, but later each had persistent and relentlessly increasing serum prolactin concentrations and evidence of distant spread of their tumours. The first patient presented aged 32 and was treated with repeated transsphenoidal resections of the tumour, pituitary radiotherapy, high dose bromocriptine therapy, the somatostatin analogue octreotide and chemotherapy. Nine years after the original diagnosis a liver biopsy revealed carcinoma cells positively immunostaining for prolactin. At autopsy further microscopically similar metastases were seen in both lungs and the left hilar lymph nodes. The second patient presented aged 48 and was treated with external beam pituitary radiotherapy, bromocriptine, transsphenoidal hypophysectomy and chemotherapy. Fifteen years after the original diagnosis bone biopsy revealed carcinoma cells positively immunostaining for prolactin; the patient developed interstitial nephritis and died in renal failure. The third patient presented aged 48 with hypogonadism and bitemporal hemianopia due to a macroadenoma. This was removed transfrontally and followed by external beam radiotherapy. After recurrence, further surgery and radiotherapy were undertaken, but the tumour continued to grow and the patient died suddenly of a pulmonary embolus. At autopsy, tumour was found in thoracic lymph nodes and lung capillaries. CONCLUSIONS: These three patients may be added to the previous two reported cases of malignant prolactinoma with extracranial spread. Several different therapies were tried but were of limited value in controlling the progression of the disease, although chemotherapy is an important modality to be considered. No particular factor or combination of factors at presentation differentiated these patients from more typical patients whose disease is much less aggressive.

Adult↗
PubMed1993

Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successful treatment.

OBJECTIVE: We tested the hypothesis that in Cushing's disease, ACTH secretion from the normal pituitary surrounding an ACTH-secreting adenoma is inhibited and hence removal of the entire adenoma should result in an undetectable serum cortisol in the immediate post-operative period. DESIGN: A retrospective study of patients undergoing transsphenoidal selective adenomectomy, hemi-hypophysectomy or total hypophysectomy for Cushing's disease at St Bartholomew's Hospital between 1985 and 1990. PATIENTS: Forty-eight consecutive patients (33 women, mean age 43, range 7-69 years) undergoing transsphenoidal hypophysectomy for Cushing's disease. Ten patients who underwent a second operation were re-evaluated; the patients were followed for a median time of 40 months after operation (range 15-70). MEASUREMENTS: Post-operatively, serum cortisol was measured daily at 0900 h. Serum TSH, T4, prolactin, LH, FSH, testosterone or oestradiol plus plasma and urine osmolality were measured. RESULTS: After initial surgery, post-operative serum cortisol was undetectable (< 50 nmol/l) in 20 out of 48 patients (42%) and < 300 nmol/l in 32 out of 48 patients (67%). Re-exploration of the pituitary fossa in 10 patients found undetectable cortisol levels in 25 (52%) and levels < 300 nmol/l in 39 (81%) patients. Cushing's syndrome has not recurred, clinically or biochemically, in any patient in whom the post-operative cortisol was < 50 nmol/l. Post-operatively, hypothyroidism was present in 40% of patients and hypogonadism in 53% of men and 30% of premenopausal women. Diabetes insipidus, persisting for at least six months, occurred in 46% of patients. CONCLUSIONS: Cushing's disease has not recurred in any patient with an undetectable serum cortisol (< 50 nmol/l) post-operatively. Serum cortisol should be regarded as a tumour marker in Cushing's disease and the aim of transsphenoidal hypophysectomy for Cushing's disease should be to render the immediate post-operative serum cortisol undetectable.

Adenoma↗
PubMed1993

The relationship between cortisol production rate and serial serum cortisol estimation in patients on medical therapy for Cushing's syndrome.

OBJECTIVE: The aim was to determine the target range into which mean daily serum cortisol should be lowered in patients on medical therapy for Cushing's syndrome, using isotopically estimated cortisol production rates as 'gold standard'. DESIGN: Patients with Cushing's syndrome on medical treatment were given 12 ng of tritiated cortisol intravenously and a 24-hour urine collection was made in a single day. On the same day, serum cortisol was measured at 0900, 1200, 1500, 1800, 2100, and at 2400 h in in-patients. In addition, serum cortisol was measured at the same times as above in a group of healthy volunteers. SUBJECTS: Twenty-two patients on medical therapy for Cushing's syndrome were studied on a total of 29 occasions. In addition, serum cortisol profiles were obtained in 12 healthy volunteers. RESULTS: The median serum cortisol in patients with Cushing's syndrome was 400 (range 66-839) nmol/l, and in the healthy volunteers 178 (range 137-299) nmol/l. The median isotopic cortisol production rate in the patients with Cushing's syndrome was 84 mumol/24 h, range 10-343 (normal range 22-83) mumol/24 h. In the patients with Cushing's syndrome, the correlation of mean serum cortisol to cortisol production rate was +0.77 (P < 0.001). Normal rates were found when mean serum cortisol levels were between 150 and 300 nmol/l. CONCLUSIONS: The aim of drug therapy for Cushing's syndrome should be to lower the mean serum cortisol through the day into the range 150-300 nmol/l.

Cushing Syndrome↗
PubMed1992

A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG).

Radiolabelled meta-iodobenzylguanidine (MIBG) is widely used in the diagnosis, follow-up and treatment of patients with tumours of neural crest origin. Some commonly prescribed and readily available over-the-counter medicines interfere with the uptake and biodistribution of this radiopharmaceutical. This may lead to poor concentration of radiolabelled MIBG within the target organs and tissues. The clinical implications are a potentially inaccurate assessment of tumour burden during diagnostic studies and a suboptimal radiation dose when MIBG is employed for targetted radiotherapy. In order to avoid false negative results a comprehensive list of prescribed and over-the-counter medicines that have the potential to inhibit uptake of MIBG has been compiled. It is hoped that this will help nuclear medicine physicians to avoid this pitfall.

3-Iodobenzylguanidine↗
PubMed1992

Pyridostigmine partially reverses dexamethasone-induced inhibition of the growth hormone response to growth hormone-releasing hormone.

The GH response to insulin-induced hypoglycaemia and growth hormone-releasing hormone (GHRH) has been shown to be impaired in subjects with Cushing's syndrome and in healthy volunteers given oral glucocorticoids. Pyridostigmine is an anticholinesterase that stimulates GH secretion, probably by inhibition of hypothalamic somatostatin secretion. This work was designed to study the site of action of glucocorticoids in inhibiting the secretion of GH. Eight healthy male volunteers were studied on three occasions in random order. They took 2 mg oral dexamethasone or placebo at precisely 6-hourly intervals for 48 h before receiving 120 mg oral pyridostigmine or placebo, followed 60 min later by GHRH (100 micrograms) i.v. Samples for measuring GH were obtained at 15 min intervals for 2 h. The 'area under the curve' (AUC) for each of the treatments was significantly different: dexamethasone-pyridostigmine-GHRH (mean +/- S.E.M., 1938 +/- 631 mU/min per l), dexamethasone-placebo-GHRH (634 +/- 211) and placebo-placebo-GHRH (4267 +/- 1183) (P < 0.02, Wilcoxon test). In conclusion, dexamethasone given for 48 h significantly inhibited the AUC for GH following treatment with GHRH. However, pretreatment with pyridostigmine significantly reversed the inhibition although this was still partial. Our data suggested that this short-term suppressive effect of dexamethasone was independent of GHRH, and most probably relates to stimulation of the release of somatostatin.

Depression, Chemical↗
PubMed1992

Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia.

Ortho,para,dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane (Roussell)) is used as an adrenolytic drug to reduce adrenocortical mass and circulating cortisol levels in Cushing's syndrome but has the unwanted side-effect of inducing hypercholesterolaemia. This paper examined the mechanism of that effect in 30 patients with Cushing's syndrome treated with o,p'DDD during the past 10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly by increasing LDL-cholesterol. The latter effect was not due to impaired binding of LDL to its receptor, as shown in vitro using cultured fibroblasts. Increases in plasma mevalonic acid during o,p'DDD administration were suggestive of increased cholesterol synthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemia by increasing cholesterol synthesis. It is proposed that this effect is due to the drug's known ability to block cytochrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for down-regulating hepatic cholesterol synthesis. Treatment with simvastatin, an inhibitor of cholesterol synthesis, reverses the hyperlipidaemia and enables o,p'DDD therapy to be maintained without increasing cardiovascular risk.

Adult↗
PubMed1991

Pyridostigmine fails to increase either spontaneous or GHRH-stimulated GH secretion during day or night in growth hormone-insufficient children.

OBJECTIVE The aim of the study was to investigate whether pyridostigmine, a cholinesterase inhibitor which is thought to act at the hypothalamus to inhibit somatostatin secretion, would augment spontaneous or GHRH-stimulated serum GH levels in patients with GH-insufficiency. DESIGN Oral pyridostigmine 60 mg or placebo was administered at the start of a 9-h subcutaneous infusion of either GHRH (1-29)NH2 10 micrograms/kg/h or saline control. Studies were performed during the daytime (0900-1800 h) in five patients, and the night-time (2100-0600 h) in a further five. PATIENTS Ten short, pre-pubertal children (aged 6-11 years; eight boys) with growth hormone insufficiency were studied. MEASURES Blood for serum GH was sampled every 20 min, and analysed using the PULSAR program. RESULTS The subcutaneous infusion of GHRH 10 micrograms/kg/h increased mean serum GH levels (+/- SEM): by day 17.7(+/- 6.8) vs placebo 2.2(+/- 0.4) mU/l (P less than 0.01), and by night 26.9(+/- 3.3) vs 5.5(+/- 1.3) mU/l (P less than 0.05). There was a significant rise in mean 'baseline' GH concentration: by day 5.5(+/- 1.7) vs 1.0(+/- 0.0) mU/l (P less than 0.05); and night 8.2(+/- 2.7) vs 1.3(+/- 0.3) mU/l (P less than 0.05). Pyridostigmine failed to produce a significant overall increase in either spontaneous or GHRH-stimulated GH secretion by day or night, although there was a significant rise in mean GH levels during the 3 h following pyridostigmine administration in the morning: 4.4(+/- 1.1) vs 2.4(+/- 0.5) mU/l (P less than 0.001). GHRH or pyridostigmine given singly or in combination had no significant effect on the number of pulses. Side-effects attributable to pyridostigmine occurred in seven children. CONCLUSIONS Pyridostigmine, either on its own or as an adjuvant therapy in combination with GHRH, acts for only a brief time and does not offer any potential benefit in the management of children with short stature.

Abdominal Pain↗