Anterior pituitary response to thyrotrophin-releasing hormone during open-heart surgery.

The anterior pituitary response to thyrotrophin-releasing hormone has been studied in 20 patients submitted to elective open-heart surgical procedures, and in six control patients submitted to closed mitral valvotomy. Standard non-pulsatile normothermic perfusion was used in all the open-heart cases. 400 microgram thyrotropin-releasing hormone was administered by intravenous injection during bypass, at 30 min post-bypass, and at 60 min post-bypass. The same dose (400 microgram) was given during closed mitral valvotomy (Control Group). Thyrotrophin-releasing hormone administration during bypass failed to produce a normal response from the anterior pituitary, in contrast to the normal response pattern seen in the control group (P less than 0.01). Thyrotrophin-releasing hormone given after the period of bypass produced responses within the normal range in the majority of patients. These results suggest that anterior pituitary hypofunction may exist during the period of extracorporeal circulation using non-pulsatile perfusion and that recovery of pituitary function is evident within the first hour post-extracorporeal circulation.

Calcium antagonists and hormone release: effect of nifedipine on luteinizing hormone-releasing hormone and thyrotropin-releasing hormone-induced pituitary hormone release.

In vitro evidence suggests that calcium is involved in the release of anterior pituitary hormones. Therefore, we studied the effect of the slow calcium channel blocker or calcium antagonist nifedipine on the FSH and LH responses to LRH and the TSH and PRL responses to TRH in vivo. Nine normal male subjects were studied on two occasions, and nifedipine (20 mg, by mouth, or matching placebo) was administered in a randomized single blind manner. Blood pressure and heart rate were measured at 0 and 30 min. The patients then received TRH (200 micrograms) and LRH (100 micrograms) iv. Blood levels of FSH, LH, TSH, and PRL were measured by RIA at 0, 30, 50, 60, and 120 min. Nifedipine lowered diastolic blood pressure significantly (--12 +/- 8 mm Hg; P less than 0.005) and increased heart rate (+ 17 /*- 10 beats/min; P less than 0.005), but had no effect on either baseline hormone levels or the incremental response of any hormone to its secretagogue. In contrast to the results of previous studies with verapamil, nifedipine does not inhibit the release of pituitary hormones. More information is required on the precise intracellular actions of these drugs before they can be used to study the role of calcium in hormone release. Nifedipine, however, may be less likely to influence pituitary function than verapamil.

Sleep shift dissociates the nocturnal peaks of parathyroid hormone (1-84), nephrogenous cyclic adenosine monophosphate, and prolactin in normal men.

The secretion of PTH(1-84) and PRL over a 24-h period in normal subjects has been shown to be highly correlated, with changes in PRL occurring approximately 2 h after those in PTH(1-84). It has been postulated that there may be neuroendocrine control common to PTH(1-84) and PRL. As the secretion of PRL is known to be strongly influenced by sleep we investigated the effect of a 7-h acute sleep shift on the nocturnal secretion of PTH(1-84), PRL, and nephrogenous cAMP, a marker of PTH(1-84) bioactivity. Six normal male subjects were studied on two occasions (study A sleep, 0100-0800 h; study B, 0800-1400 h) with samples withdrawn at 30-min intervals. Sleep shift produced the expected shift in PRL secretion to new time of sleep. The overall timing of the PTH(1-84) nocturnal peak (0200-0600 h) was not altered by sleep shift. However, the start of the rise in PTH(1-84) (0200-0300 h) was blunted (P less than 0.05), and the peak of nephrogenous cAMP, coincident with the nocturnal rise in PTH(1-84) in study A, was markedly attenuated (P less than 0.01). Thus whereas the results of this study argue against a direct neuroendocrine link between PTH(1-84) and PRL, it is postulated that sleep shift disrupts a high degree of temporal organization which, under normal conditions, may allow concerted metabolic effects between PTH(1-84) and other hormones over a 24-h period.

The circadian rhythm of intact parathyroid hormone-(1-84): temporal correlation with prolactin secretion in normal men.

Serum PTH-(1-84), PRL, and adjusted calcium concentrations were determined at 30-min intervals for a 24-h period in six normal adult men. PTH-(1-84) and PRL both exhibited two peaks of increased secretion [1600-1900 and 0200-0600 h for PTH-(1-84); 2000-2200 and 0400-0800 h for PRL]. For each subject there was a striking similarity in the magnitude of secretion of the two hormones and a consistent temporal relationship. Thus, the maximum correlation coefficients of 0.62-0.83 were obtained for the six subjects when the PRL surge lagged that of PTH-(1-84) by 0.5-3.5 h. In contrast, the correlation between PTH-(1-84) and adjusted calcium was weaker (r = -0.36 to -0.66) and showed no consistent temporal relationship (0.0-10.5 h). These data support the concept of higher center control of PTH-(1-84) secretion with the possible involvement of factors common to the control of PRL secretion.

Serum and urine phosphate during short-term beta-adrenergic blockade in healthy men.

Treatment of 6 healthy adult men with a beta-blocker, timolol, resulted in a rise in serum phosphate which was maintained for the 5 days of therapy. This rise was accompanied by a transient fall in urine phosphate and a rise in the tubular maximum for phosphate reabsorption per unit glomerular filtration rate (TmPO4/GFR). No change in circulating parathyroid hormone or growth hormone could be demonstrated.

Production and characterisation of monoclonal antibodies to parathyroid hormone (1-34).

Monoclonal antibodies to the biologically active N terminal region of parathyroid hormone (PTH) suitable for use in the measurement of circulating PTH concentrations have proved difficult to produce. In this study, no serum PTH antibody titres could be detected in mice using synthetic human PTH (1-34) (free or coupled to albumin) or PTH (1-10) (coupled to keyhole limpet haemocyanin) as immunogen. A consistent response to PTH (1-34) peptide was obtained in DA rats. We have produced five monoclonal antibodies to PTH (1-34) derived from the fusion of DA rat spleen cells and the mouse myeloma line X63 Ag.8.653. Bulk production of the antibodies was achieved using congenitally athymic mice for ascites production. Antibody assessment studies revealed the antibodies to be sensitive to the oxidation state of the methionine residues in PTH (1-34). Two of the antibodies, 3B3 and 6E3, were shown to be of potential use in measuring circulating PTH (1-84) when used in combination with available antibodies to C terminal PTH. A third antibody, 4G3, which failed to recognise PTH (1-84) when used in combination with 3B3, formed the basis of a specific assay for PTH (1-34).

The circadian rhythm of intact parathyroid hormone (1-84) and nephrogenous cyclic adenosine monophosphate in normal men.

A pronounced circadian rhythm has been demonstrated for intact parathyroid hormone (1-84) in the serum of normal male adults. The broad nocturnal rise of parathyroid hormone (1-84) secretion appears to be of physiological significance, for it is accompanied by a significant rise in nephrogenous cyclic adenosine monophosphate. The rate of return of parathyroid hormone (1-84) to baseline concentrations varies between individuals, an observation which has implications for the optimal time of sampling for the investigation of possible mild hyperparathyroidism.

Neonatal screening for congenital adrenal hyperplasia: a programme based on a novel direct radioimmunoassay for 17-hydroxyprogesterone in blood spots.

We have assessed the feasibility of screening newborn babies for congenital adrenal hyperplasia (CAH) by the direct measurement of 17-hydroxyprogesterone (17-OHP) in blood spots collected on filter paper (Guthrie cards) for the phenylketonuria, hypothyroidism and galactosaemia screening programmes run in Scotland. The procedure described for CAH uses an iodinated 17-OHP tracer and a specific 17-OHP antiserum sheathed within semipermeable nylon microcapsules. The method does not require a solvent extraction step, is inexpensive, precise, efficient and, therefore, practical for large-scale use. With this system the value of a neonatal screening programme was assessed in a retrospective analysis and a prospective trial. The retrospective study of 15 paediatric cases of CAH illustrated that at least half were not diagnosed within 3 weeks of birth. Analysis of the original Guthrie card samples revealed increased levels of 17-OHP in all cases. The prevalence of CAH as calculated in the retrospective study was 1 in 20 907 with a range (within 95% confidence limits) of from 1 in 12 675 to 1 in 32 604 (n = 301 450). In the prospective trial a total of 92 051 consecutive samples was screened. Five cases of CAH were correctly identified with a current false positive rate of 0.042%. Analysis of urinary steroids confirmed defective adrenal 21-hydroxylase activity in all positive cases. In the prospective trial the prevalence was 1 in 18 401 with a range of from 1 in 7422 to 1 in 50 006. We conclude that mass screening for CAH is both feasible and desirable.

Comparative studies of pulsatile and nonpulsatile flow during cardiopulmonary bypass. III. Response of anterior pituitary gland to thyrotropin-releasing hormone.

Previous studies have indicated that, during nonpulsatile cardiopulmonary bypass, the anterior pituitary gland fails to respond to the tropic stimulus of thyrotropin-releasing hormone (TRH). This is in contrast to the normal response seen during closed cardiac and general surgical procedures. The Stöckert pulsatile pump system described in Part I has been employed in a comparative study of TRH responses in 20 patients subjected to pulsatile or nonpulsatile perfusion during open-heart surgery. In the nonpulsatile group, a consistently subnormal response to TRH injection was again found. In the pulsatile group, however, the pituitary response to TRH was normal in nine patients out of 10. The quantitative difference between the groups was statistically highly significant (p less than 0.005). These results indicate that the subnormal pituitary function seen with nonpulsatile bypass may be prevented by the use of pulsatile perfusion.

ACP Broadsheet No 141: September 1993. Role of endocrine biochemistry laboratories in the investigation of infertility.

The staff and services of the endocrine biochemistry laboratory are essential to the efficient investigation of infertility. Each centre should adopt a detailed strategy for the investigation of the infertile couple which specifies the hormone analyses required at each stage. Appropriate first-line hormone tests should be selected after a thorough clinical history and physical examination of both partners. Second-line hormone testing should be determined from the results of the initial investigation and should be restricted to requests that either confirm or clarify an endocrine basis to infertility or monitor the response to treatment. The clinical biochemist should advise on specimen timing and collection, have responsibility for guaranteeing time and valid hormone results, and be part of the team that audits the overall strategy and the outcome for individual patients.

Insulin-like growth factor-I in Helicobacter pylori gastritis and response to eradication using bismuth based triple therapy.

AIMS: To measure insulin-like growth factor-I (IGF-I) concentrations in the presence and absence of Helicobacter pylori infection and in response to eradication of the organism. METHODS: An enzyme linked immunosorbent assay was used to measure gastric and fasting serum concentrations of IGF-I in 17 patients with and 11 without H pylori infection. Repeat assessments were performed in the infected patients six weeks after they received a two week course of bismuth chelate, metronidazole, and amoxycillin. RESULTS: IGF-I was detected at very low concentrations in gastric juice and in mucosal incubates. The median serum IGF-I concentration was 88 micrograms/l in the patients infected with H pylori compared with 90 micrograms/l in the non-infected controls; IGF-I concentrations dropped to 77 micrograms/l following eradication therapy (p = 0.014). CONCLUSION: The similarity in baseline IGF-I concentrations in the presence and absence of H pylori suggests that their subsequent drop after treatment is more likely to be due to the treatment.

Hyperinsulinism associated with primary renal cell carcinoma.

A case is reported of a patient with symptomatic hyperinsulinism associated initially with a renal cell carcinoma and then later, with secondary deposits from the same tumor. Evidence points to a strong possibility of renal tumor involvement in the production of insulin hypersecretion.

Effects of growth hormone, glucose and insulin on the factor VIII complex.

The relationship of growth hormone (GH) to the factor VIII complex (VIIIC, VIIIRAg and VIIIRRCo) was investigated. No correlation between basal levels of GH and factor VIII assays was found in 23 subjects. No significant change in factor VIII assays was observed after GH suppression by oral glucose or bromocriptine. After insulin-induced hypoglycaemic all three factor VIII assays rose and fell in parallel with GH. However, after exercise the rise in VIIIC and VIIIRAg preceded the rise in GH; and no changes in factor VIII assays were observed after administration of thyrotrophin releasing hormone (TRH) (releasing endogenous GH) or exogenous GH. These findings do not support a role for GH in the regulation of plasma levels of VIIIC, VIIIRAg or VIIIRRCo.

Insulin-dependent ketosis-resistant diabetes in Ethiopia.

Anthropometric, clinical and biochemical findings were compared in 30 rural (group A), 18 urban insulin-requiring (group B) and 45 urban oral-agent-responsive (group C) newly diagnosed diabetics. Mean ages at onset were 28.3 +/- 12.0, 25.6 +/- 14.5 and 42.1 +/- 10.5 years respectively. The differences between A and C and between B and C were significant. Group A were poor and malnourished, with body mass index (BMI) 15.9 +/- 1.9 and 17.2 +/- 3.7 kg/m2 for males and females respectively, presented with a long history of classical diabetes without ketoacidosis and required insulin in modest doses. 3 of 10 cases had excess stool fat but none of 13 unselected cases had pancreatic calcification. Group C were better nourished, with BMI 22.6 +/- 2.8 and 22.4 +/- 4.5 kg/m2, and responded to oral agents. Group B, with BMI 17.2 +/- 2.6 and 18.6 +/- 3.1 kg/m2, required insulin for control but had C-peptide levels above 0.02 nmol/1 in 10 of 15 cases. Anthropometric indices for males, but not for females, were significantly lower in group A than in group B or C. There were significant differences in levels of glucose between A and B and A and C, free fatty acids between A and C and B and C, insulin between A and B and A and C and C-peptide between A and C and B and C. Of the 3 groups the rural type most closely resembled the tropical variants.

Endocrine and protein response to elective surgery: effect of nursing at two different environmental temperatures.

Twenty male patients undergoing elective abdominal surgery were studied on one control day pre-operatively and for the first 4 days postoperatively at an environmental temperature of either 20 degrees C or 28 degrees C. Glucose, insulin, growth hormone and urinary catecholamine levels all rose significantly on the first postoperative day returning to within normal limits by day 4. Urine nitrogen excretion also increased significantly postoperatively in both groups. Environmental temperature did not influence these responses. Concentrations of C-reactive protein and a1-antichymotrypsin increased significantly on the first postoperative day and were returning to normal by day 4 while concentrations of haptoglobin, a1-antitrypsin and a1-acid glycoprotein, which also showed a significant increase, remained elevated at the end of the study. Concentrations of albumin, transferrin, a2-macroglobulin, prealbumin and retinol binding protein all decreased significantly following operation. Elevated environmental temperature did not affect the protein response to surgery. Urine cortisol and 17-hydroxycorticosteroid excretion rose significantly postoperatively and remained elevated throughout the study. Patients nursed at 28 degrees C showed significantly lower postoperative excretion of both hormones than patients nursed at 20 degrees C.

Concentrations of sodium, potassium and cortisol in saliva, and self-reported chronic work stress factors.

One hundred and fifteen electronics factory employees completed questionnaires relevant to work stress, and gave unstimulated saliva samples. As previously found, Perceived Coping Incapacity correlated very significantly with self-reported emotional upset and psychosomatic complaints. Salivary [Na+] correlated significantly with Perceived Coping Incapacity (rho = -0.30, p < 0.01), and also with emotional upset (rho = -0.19, p < 0.05). Raised [K+] tended to be associated with reduced fatigue (rho = -0.21, p < 0.05) and lower self-medication (rho = -0.21, p < 0.05) together with a greater perceived personal work responsibility (rho = 0.19, p < 0.05)-all consistent with the perception of work demands as positive challenges rather than stressors. Self-reported fatigue and emotional upset at work gave higher correlations with [K+] and [Na+] than either did on its own. Salivary [cortisol] was uncorrelated with self-reported work stress indices, and with [K+] and [Na+].

Organon OD 14 (tibolone) and menopausal dynamic hormone profiles.

Hormonal profiles were studied in 15 post-menopausal women, 7 of whom had been treated with Organon OD 14 (Tibolone) and 8 with placebo tablets for 3 yr. In the Tibolone-treated group, the sex hormone binding globulin (SHBG) levels were significantly lower, while the estimated free testosterone levels, the testosterone/SHBG ratio and the thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) were significantly higher than in the placebo group. Prolactin and triiodothyronine (T3) concentrations were lower in the actively treated group, although the differences were not statistically significant. No significant differences were observed with respect to thyroxine (T4), TSH, basal cortisol or cortisol response to synacthen.

Sex steroid replacement in post-menopausal women: effects on thyroid hormone status.

We have measured serum thyroxine (T4), triidothyronine (T3), thyroid-stimulating hormone (TSH) free thyroxine (FT4) and thyroxine-binding globulin (TBG) levels in a total of 5 post-menopausal women who were receiving oestrogen alone (Premarin, n = 19), progestogen alone (Primolut-N, n = 12), a combination of oestrogen and progestogen (Prempak C, n = 14) or no treatment (control group, n = 12). No differences were observed between the Premarin and Prempak C groups; both exhibited elevated T4 and TBG levels, although free thyroxin (FT4) and T4/TBG concentrations were normal relative to those in the control group. The Primolut-N subjects showed subnormal T3 and FT4 levels relative to the controls. It was concluded that it is not possible to make general statements regarding the effects of sex steroids on FT4 levels.

A review of the role of established tumour markers.

Increasing numbers of commercial assays for the established tumour markers are available which are capable of excellent analytical performance. Whilst all these assays are useful as research tools, their clinical value is more limited and should be appreciated before any decision is taken to offer a tumour marker assay service. 1. Calcitonin (medullary carcinoma of thyroid), alphafetoprotein (hepatoma) and human chorionic gonadotrophin (choriocarcinoma) are the only tumour markers that can be used for screening for malignancy in high risk populations. 2. Hormones, paraproteins, alphafetoprotein, human chorionic gonadotrophin and prostate specific antigen are valuable in establishing the diagnosis of certain tumour types. 3. Alphafetoprotein and human chorionic gonadotrophin concentrations at the time of diagnosis are of value in predicting prognosis in specific tumour types. 4. Although their sensitivity for a particular tumour type may be poor, most tumour markers can be used for monitoring the therapy and follow-up of selected marker positive patients. Optimal clinical results of the management of patients with malignancy are usually obtained by specialist centres, and laboratory tumour marker services should be established so that they are appropriate to local oncology specialities.

Development and evaluation of a direct immunofluorimetric assay for urinary growth hormone.

We describe a two-site immunofluorimetric assay for urinary growth hormone that is resistant to interference from a wide range of urinary constituents and therefore eliminates the need for sample pre-treatment. A microtitre plate format is used with specific orientation of capture antibody on a polystyrene surface carrying a hydrazide group. Europium-labelled F(ab)2 is the fluorophore and time-resolved fluorimetry with co-fluorescence enhancement the signal detection system. Inter-assay precision was 11.3% at 5.2 ng/L and 10.3% at 44.3 ng/L, minimum detection limit (22% coefficient of variation, CV) was < 1.0 ng/L, working range (< 10% CV) was 0-100 ng/L and quantitative recovery and good parallelism were demonstrated. This convenient and sensitive assay is suitable for the routine measurement of human growth hormone (hGH) in urine.