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SUMMARY
The changes in plasma ACTH concentration of pregnant sheep and their foetuses during the latter half of pregnancy and during labour were studied. Before 140 days of gestation the mean concentration in foetal arterial plasma was 117 ± 19 (s.e.m.) pg/ml which rose to a mean of 286 ± 63 pg/ml. The rise in ACTH occurred at about the same time as, but not before, the rise in corticosteroid concentration in foetal plasma. The maternal plasma ACTH concentration did not change during the latter half of pregnancy and had a mean concentration of 64 ± 9 pg/ml. During labour there was a progressive rise in the ACTH concentration in foetal plasma which was not associated with any corticosteroid changes. Ethanol did not suppress labour but reduced the ACTH concentration in foetal plasma.
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SUMMARY
The effect of incubating the hypothalamus of adult male rats with various neurotransmitters upon the release of corticotrophin-releasing hormone (CRH) was studied. The CRH activity in the incubation medium was assayed in 48 h median eminence-lesioned rats and the corticosteroidogenesis of excised adrenals in vitro was used as the end-point. 5-Hydroxytryptamine (100 pg/ml–10 ng/ml) caused a dose-dependent release of CRH which was antagonized by methysergide (30–100 ng/ml). The response to 5-hydroxytryptamine was also inhibited by hexamethonium and atropine which indicated that it was acting through a cholinergic interneurone. Melatonin (10 ng) did not alter the basal release of CRH but inhibited the action of both 5-hydroxytryptamine (10 ng) and acetylcholine (3 pg). Thus it appears that both 5-hydroxytryptamine and melatonin play a role in the control of CRH release. Noradrenaline blocked the release of CRH induced by both acetylcholine and 5-hydroxytryptamine and presumably this inhibition was caused by direct action on the CRH neurone. γ-Aminobutyric acid (GABA) also inhibited the release of CRH and may also be involved in the regulation of CRH secretion. The inhibitory neurotransmitters, noradrenaline, GABA and melatonin, act via independent receptor mechanisms. A model based on the above data is presented.
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Recent in-vivo studies made by Deshpande, Jensen, Carson, Bulbrook & Doouss (1970) concerned with the synthesis of androgens by the human adrenal gland have again emphasized the equivocal nature of the results available on this subject. The present communication describes how results contrary to those obtained in vivo were derived from investigations in vitro: this prompts us to suggest that further studies are necessary on the control of androgen production. Evidence has been obtained (Ichii, Forchielli, Cassidy, Rosoff & Dorfman, 1962; Kase & Kowal, 1962; Ward & Grant, 1963) for the presence in various pathological types of human adrenal tissue of the enzyme systems necessary for the conversion of progesterone to adrenal androgens, while Deshpande et al. (1970) showed that in vivo, 17α-hydroxyprogesterone rather than dehydroepiandrosterone (DHA) is the more important precursor of androstenedione. On the other hand Cohn & Mulrow (1963) showed in both hyperplastic and neoplastic adrenal tissue
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SUMMARY
Corticosterone was administered intraperitoneally to rats, and the consequent changes in plasma corticosterone concentration traced. Stress (sham bilateral adrenalectomy) was applied at various times when the plasma corticosterone concentration was changing at different rates, and it was shown that there was a critical rate of rise of plasma corticosterone concentration of about 1·3 μg/100 ml plasma/min in excess of which the stress response was inhibited. Rates of rise less than this did not affect the stress response. A state of ' saturation' of the control system was also demonstrated to result from high plasma corticosterone concentrations when the response to stress was not inhibited as above. A model of the system is suggested to explain these and other data.
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SUMMARY
Corticosteroid feedback mechanisms were investigated at the hypothalamic level using the rat hypothalamus in vitro and at the pituitary level using basal hypothalamic-lesioned rats. Both fast and delayed corticosteroid feedback effects were demonstrated at the level of the hypothalamus and pituitary gland with doses of corticosteroids within or near the physiological range. These two phases of feedback were separated temporally by a 'silent period' during which no feedback was apparent.
Studies on the mechanism of action of corticosteroids at the hypothalamic level showed that the fast feedback mechanism acts by inhibition of release whilst the delayed feedback mechanism acts by inhibition of both synthesis and release. The fast feedback action of corticosterone does not appear to act by excitation of neuroinhibitory pathways since neither picrotoxin nor phentolamine prevented the feedback action of corticosteroids in vitro.
Corticosterone inhibition of corticotrophin releasing factor release was overcome by depolarization of the membrane with K+ suggesting that the mechanism of action of the fast feedback of corticosteroids is by membrane stabilization.
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SUMMARY
Structure–activity studies on the corticosteroid fast and delayed feedback receptor mechanisms controlling the secretion of corticotrophin releasing factor (CRF) were carried out with the rat hypothalamus in vitro. The secretion of CRF was induced by acetylcholine (3 pg/ml).
The fast feedback receptor appears highly specific, and the structure essential for efficacy involves an 11β-hydroxyl group and an unblocked 21-hydroxyl group. Several steroids showed antagonism and so the binding site is not very specific. 18-Hydroxy,11-deoxycorticosterone, progesterone, 17α-hydroxyprogesterone and 11-deoxycorticosterone were antagonists of fast feedback.
The delayed feedback receptor required either an 11β- or a 21-hydroxyl group for efficacy. The binding site required a 17-hydroxyl group when the 11β- or 21-hydroxyl groups were absent. Binding also involved the 3-oxo,4,5-ene structure since steroids in which these are absent were inactive.
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The effect of various steroids on the functional activity of the rat hypothalamus in vitro was investigated. The addition of corticosterone (10−7 mol/l) for 30 min to the incubation medium inhibited immediately the release of bioactive corticotrophin releasing factor (CRF) by tissue induced by serotonin (2·6×10−8 mol/l). This was followed by a period lasting from 30 min (coincident with removal of the steroid from the medium) to 60 min when no inhibition was seen. Finally a second period of suppression of hypothalamic CRF activity in vitro was shown to be fully established 120 min after addition of the steroid. In more detailed investigations the latter inhibition was shown to occur when the tissue was exposed to the steroid (3×10−7 mol/l) for 5 or 30 min, but not for 1 min, and it was dose-related. Of other steroids investigated, progesterone in high concentrations (3 × 10−6 mol/l) suppressed to a small extent the functional activity of the hypothalamus in vitro but 17α-hydroxyprogesterone, 11α-hydroxyprogesterone, 11α,17α-dihydroxyprogesterone and 11-epicortisol had no effect on the delayed inhibition. Progesterone (10−7 mol/l) potentiated the ability of corticosterone (10−8 mol/l) to induce the delayed suppression of hypothalamic CRF activity in vitro. In contrast, 17α-hydroxyprogesterone, 11α-hydroxyprogesterone, 1 1α,17α-dihydroxyprogesterone and 11-epicortisol competitively antagonized this inhibitory action of corticosterone (3 × 10−7 mol/l) in a dose-related manner (1·5 × 10−8–3 × 10−8 mol/l). The action of the antagonist 11-epicortisol was similar whether it was added to the tissue in vitro before corticosterone or antagonist and agonist were added together. The functional characterization of steroid action on the hypothalamus may lead to a clearer understanding of the mechanism by which the compounds influence hormone release.
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ABSTRACT
The effect of six hypothalamic peptides on the basal release of ACTH and that induced by arginine vasopressin (AVP) or by ovine corticotrophin releasing factor (oCRF) from fragments of the rat anterior pituitary gland incubated in vitro was investigated. Dose–response curves to AVP and to oCRF were obtained, and the response to a low dose of oCRF was potentiated by a low dose of AVP. Basal release of ACTH was not affected by any of the peptides in concentrations in the range 10−12 to 10−6 mol/l, and only substance P (SP) and somatostatin (SRIF) inhibited significantly the response to oCRF in a dose-related manner. The responses to a range of doses of oCRF or AVP were reduced by 10−8 and 10 − 6 mol SP or SRIF/1, and to a greater extent by the higher dose. Except in the case of 10−6 mol SRIF/1 on the response to AVP, the response was not further diminished by preincubation of the tissue with the peptide before the stimulating agent was added. The inhibition of the responses to AVP or oCRF by 10−9 mol SP/1 was not potentiated by its combination with either 5 × 10−10 or 10−8 mol SRIF/1; the inhibitory effects were merely additive. The results suggest that although SRIF and SP are able to modulate the release of ACTH from the anterior pituitary gland, they do so only at a high concentration. In the case of SRIF these concentrations are several orders of magnitude higher than those reported to be present in the hypophysial portal blood and therefore a physiological role for this peptide in the control of ACTH secretion is unlikely.
J. Endocr. (1984) 100, 219–226
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ABSTRACT
Male Wistar-derived rats (200–250 g) were treated for 14 days with prednisolone 21-sodium succinate at a concentration of 1035 μmol/l in their drinking water. The drug was then replaced with normal tap water and groups of animals were killed at various times during recovery, trunk blood being collected after decapitation. At the same time, hypothalamic slices, anterior pituitary gland fragments and adrenals were removed and their responsiveness assessed by exposure to appropriate stimuli in vitro. Tissues were also extracted to measure changes in content of hormones during recovery. Treatment with prednisolone produced marked reductions in body weight gain, adrenal weight and pituitary ACTH content, but no significant change in hypothalamic corticotrophin-releasing factor (CRF) bio- or immunoreactivity. The ACTH content was restored by 5 days after withdrawal but adrenal weight remained significantly reduced after 9 days of recovery. The responsiveness of the hypothalamus to acetylcholine in vitro was markedly inhibited and was still significantly reduced 7 days after withdrawal. The responsiveness of the anterior pituitary gland to synthetic CRF or arginine vasopressin and that of the adrenal gland to ACTH added in vitro were restored simultaneously after 7 days of withdrawal. In vivo, recovery was assessed by measurement of the response to laparotomy stress. Treatment with prednisolone prevented the increase in the plasma concentrations of ACTH and corticosterone produced by stress, and these responses recovered by 5 days (corticosterone) and 7 days (ACTH) after withdrawal. The abolition of the circadian rhythms of ACTH and corticosterone by treatment was also reversed by 5 days after withdrawal. This pattern of recovery is different from that which we observed after long-term treatment with dexamethasone, where the responsiveness of the hypothalamus and adrenal gland in vitro recovered before that of the anterior pituitary gland.
J. Endocr. (1987) 113, 239–247
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ABSTRACT
Immunoreactive tissue kallikrein was co-localized with prolactin in all the eleven prolactin-secreting adenomas of the human anterior pituitary gland examined in this study. The intracellular distribution of immunoreactivity in the prolactin-secreting cells suggests that tissue kallikrein is located within the Golgi complex of these cells. Both the intracellular hormone-processing action and the kininogenase activity of tissue kallikrein may be of functional importance in human prolactinomas.
Journal of Endocrinology (1990) 124, 327–331