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Search for other papers by G. C. KENNEDY in
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SUMMARY
Electrolytic lesions in the posterior part of the median eminence of rats caused diabetes insipidus, and aldehyde-fuchsin-positive material disappeared from the infundibular process but not from the hypothalamus. The lesions were consistently followed by infarction of the central pars distalis and depression of the thyroid uptake of radioactive iodine, but the effects on the gonads and adrenal cortex were very variable. Chronic adrenal atrophy occurred in some females in association with recurrent pseudopregnancy, atrophic but hyperluteinized ovaries, and cytological changes in the pituitary similar to those in ectopic grafts. After a short post-operative period of pseudopregnancy other rats recovered normal cycles and had, in general, adrenals of normal weight; their pituitaries resembled ectopic grafts returned to the median eminence. It is suggested that the difference between the two groups of rats with chronic lesions depended on the permanence or otherwise of the damage to the long portal veins. No evidence could be found of a separate corticotrophin-releasing mechanism in the median eminence, nor of any dependence of the secretion of corticotrophin on the release of vasopressin.
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Search for other papers by A Kennedy in
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Search for other papers by AM McNicol in
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Inhibins and activins are dimeric proteins of the transforming growth factor-beta superfamily which have been shown to be expressed in the adrenal cortex. Recent studies have suggested a role for these peptides in the pathogenesis and/or function of adrenal tumours. To investigate further their physiological and pathological roles, we have documented immunoreactivity for inhibin alpha, betaA and betaB subunits in normal adult and fetal human adrenals, in hyperplastic adrenals and in adrenal tumours. In the normal and hyperplastic adult gland, diffuse immunopositivity was demonstrated for beta subunits, suggesting that activins (beta beta dimers) can be expressed in all zones. Inhibin alpha was limited to the zona reticularis and the innermost zona fasciculata in the normal gland, extending centripetally into the zona fasciculata in hyperplasia, supporting a role for ACTH in the regulation of expression, and suggesting that expression of inhibins (alpha beta dimers) is restricted. Immunopositivity for all three subunits was seen in both fetal and definitive zones of the fetal cortex, indicating that both inhibins and activins could be expressed in both. Immunopositivity for all three subunits was seen in most adrenocortical tumours. Loss of immunopositivity for inhibin alpha in a subgroup of carcinomas might indicate a role in tumour progression. The greater intensity of staining for inhibin alpha in tumours associated with Cushing's syndrome again suggests a link with cortisol production.
Search for other papers by J A Kennedy in
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Search for other papers by R Nicolson in
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Search for other papers by M L Wellby in
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Abstract
Elevation of non-esterified fatty acids (NEFA) in vivo is associated with abnormal control of TSH. To determine whether TSH secretion is directly inhibited by NEFA, as has been reported for GH, cultured rat anterior pituitary cells were exposed for 20 h to oleic acid in medium containing 77 × 10−5 mol/l bovine serum albumin (BSA). In a molar ratio with albumin of 1·2 (total oleic acid 9× 10 mol/l), or greater, oleic acid inhibited basal GH secretion (maximum inhibition to 40% of control) while basal TSH was less affected, a ratio of 3 (2·3 × 10−4 mol/l oleic acid) or greater causing a smaller degree of inhibition (maximum inhibition to 80% of control). In the presence of 10−9 mol/l growth hormone-releasing hormone or 108 mol/l TRH, inhibition was achieved at a ratio of 12 (9 × 10−4 mol/l oleic acid) or greater. Basal TSH was less sensitive to inhibition by thyroxine (T4) in the presence of oleic acid/albumin at a ratio of 6 or greater, and inhibition by oleic acid was less than additive with T4 at a ratio of 6 or greater. Responses to tri-iodothyronine (T3) were unaffected at a ratio of 6 (4·6 × 10−4 mol/l oleic acid), but a ratio of 12 inhibited the effects of both T3 and T4 on TSH. Oleic acid had less effect in the presence of TRH, a ratio of 12 causing a small increase in the threshold concentration of T3 and T4 for TSH inhibition. Further studies are required to determine the mechanism by which oleic acid inhibits the response of basal TSH to T4 as well as the reason for a reduced effect of oleic acid in the presence of TRH. In some critically ill patients, total serum NEFA/albumin ratios from 1·5 to 6 have been reported, indicating that the direct inhibitory effects on TSH observed in vitro occur at free NEFA concentrations achieved in vivo. However, the direct inhibitory effect on TSH may be offset to some extent by reduced responsiveness to T4 at higher oleic acid concentrations. Hence other sites of action of NEFA in vivo may also be important in limiting TSH secretion. Further studies should examine the hypothalamic hormones like TRH and somatostatin, which control the thyrotrophs, as potential sites of action of NEFA.
Journal of Endocrinology (1994) 143, 557–564
Search for other papers by A. M. Wallace in
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Search for other papers by G. H. Beastall in
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Search for other papers by B. Cook in
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Search for other papers by A. J. Currie in
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Search for other papers by A. M. Ross in
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Search for other papers by R. Kennedy in
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Search for other papers by R. W. A. Girdwood in
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ABSTRACT
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 7 422 to 1 in 50006.
We conclude that mass screening for CAH is both feasible and desirable.
J. Endocr. (1986) 108, 299–308
Search for other papers by H. N. COHEN in
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Search for other papers by J. A. FYFFE in
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Search for other papers by W. A. RATCLIFFE in
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Search for other papers by A. M. McNICOL in
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Search for other papers by H. McINTYRE in
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Search for other papers by J. S. KENNEDY in
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Search for other papers by J. A. THOMSON in
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The effects on pituitary–thyroid function of the commonly prescribed anti-bacterial preparations co-trimoxazole and co-trifamole, and their component drugs, have been studied in the rat and compared to the changes caused by propylthiouracil.
Co-trimoxazole and co-trifamole, in doses 20-fold in excess of a pharmacological dose administered for 10 days, produced marked changes in hormone levels consistent with blocking of thyroidal activity. Significant increases in thyroid gland weight, with histological evidence of hyperplastic goitre formation, were also demonstrated. Propylthiouracil produced less marked changes of thyroid hormone levels but higher levels of thyroid-stimulating hormone. Pharmacological doses of co-trimoxazole and co-trifamole and sulphamoxole, the sulphonamide component of co-trifamole, caused significant changes in thyroid hormone levels consistent with anti-thyroidal activity. In contrast, there was no evidence that trimethoprim, which is common to both preparations, or sulphamethoxazole, the sulphonamide component of co-trimoxazole, had an anti-thyroidal action, indeed, serum thyroxine levels were significantly increased at pharmacological dosage. We have concluded that the new commonly prescribed combination preparations retain the goitrogenic properties of the earlier sulphonamides.
Search for other papers by R. A. Prysor-Jones in
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Search for other papers by J. J. Silverlight in
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Search for other papers by S. J. Kennedy in
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Search for other papers by J. S. Jenkins in
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ABSTRACT
Treatment with a high dose of oestradiol for 6 months caused hyperprolactinaemia and pituitary hyperplasia in female Wistar–Furth rats. Changes in the vasoactive intestinal peptide (VIP) and dopamine content of the hypothalamus and pituitary were also found. The hypothalamic dopamine concentration was only slightly reduced and, although the concentration of dopamine in the pituitary was less in treated animals, the total pituitary content was increased. The concentration of VIP in the pituitary was increased by oestradiol treatment but decreased in the non-median eminence hypothalamus. In the median eminence the VIP content was increased by oestradiol treatment and the amount present correlated positively and significantly with pituitary wet weight in animals treated with both oestradiol and fluphenazine. In Fischer 344 rats, oestradiol produced greater incremental changes in pituitary wet weight and plasma concentrations of prolactin than in Wistar controls and the increase in the pituitary concentration of VIP was five times greater. Although peptide turnover has not been measured, these results suggest that oestradiol, as well as having a direct action, stimulates pituitary lactotrophs by increasing pituitary concentrations of VIP.
J. Endocr. (1988) 116, 259–265
Search for other papers by S. A. BARKER in
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Search for other papers by C. J. GRAY in
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Search for other papers by J. F. KENNEDY in
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Search for other papers by W. R. BUTT in
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SUMMARY
A procedure for the purification of human pituitary follicle-stimulating hormone (FSH) is outlined. Various methods of protein determination were applied to the preparation (CP 150), and the results obtained compared with those of amino acid analysis. The composition of CP 150 with respect to amino acid and carbohydrate components is reported, and is suggested as the most suitable basis for expression of biological activity and stability. CP 150 sedimented as a single boundary with S20,w = 2·8s. The composition of various reported FSH preparations including CP 150 are compared, and attention is drawn to some striking similarities.
Search for other papers by Yewei Xing in
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Search for other papers by Michael A Edwards in
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Search for other papers by Clarence Ahlem in
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Search for other papers by Mike Kennedy in
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Search for other papers by Anthony Cohen in
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Search for other papers by Celso E Gomez-Sanchez in
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Search for other papers by William E Rainey in
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The adrenal glands are the primary source of mineralocorticoids, glucocorticoids, and the so-called adrenal androgens. Under physiological conditions, cortisol and adrenal androgen synthesis are controlled primarily by ACTH. Although it is well established that ACTH can stimulate steroidogenesis in the human adrenal gland, the effect of ACTH on overall production of different classes of steroid hormones has not been defined. In this study, we examined the effect of ACTH on the production of 23 steroid hormones in adult adrenal primary cultures and 20 steroids in the adrenal cell line, H295R. Liquid chromatography/tandem mass spectrometry analysis revealed that, in primary adrenal cell cultures, cortisol and corticosterone were the two most abundant steroid hormones produced with or without ACTH treatment (48 h). Cortisol production responded the most to ACTH treatment, with a 64-fold increase. Interestingly, the production of two androgens, androstenedione and 11β-hydroxyandrostenedione (11OHA), that were also produced in large amounts under basal conditions significantly increased after ACTH incubation. In H295R cells, 11-deoxycortisol and androstenedione were the major products under basal conditions. Treatment with forskolin increased the percentage of 11β-hydroxylated products, including cortisol and 11OHA. This study illustrates that adrenal cells respond to ACTH through the secretion of a variety of steroid hormones, thus supporting the role of adrenal cells as a source of both corticosteroids and androgens.
