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Plasma cortisol is largely bound to corticosteroid-binding globulin (CBG), which regulates its bioavailability by restricting exit from capillaries. Levels of CBG may be altered by several factors including stress and this can influence the amount of cortisol reaching cells. This study investigated the effect of social instability on plasma concentrations of CBG, total and free (not protein bound) cortisol in horses. Horses new to our research herd ('newcomers') were confined in a small yard with four dominant resident horses for 3-4 h daily for 3-4 (n = 5) or 9-14 (n = 3) days. Jugular blood was collected in the mornings from newcomers before the period of stress began ('pre-stress'), and then before each day's stress. Residents were bled before stress on the first and thirteenth day. Residents always behaved aggressively towards newcomers. By the end of the stress period, all newcomers were subordinate to residents. In newcomers (n = 8) after 3-4 days of social stress, CBG binding capacity had fallen (P = 0.0025), while free cortisol concentrations had risen (P = 0.0016) from pre-stress values. In contrast, total cortisol did not change. In residents, CBG had decreased slightly but significantly (P = 0.0162) after 12 days of stress. Residents and newcomers did not differ in pre-stress CBG binding capacity, total or free cortisol concentrations. However, by the second week of stress, CBG binding capacity was lower (P = 0.015) and free cortisol higher (P = 0.030) in newcomers (n = 3) than in residents. Total cortisol did not differ between the groups. In conclusion social stress clearly affected the adrenal axis of subordinate newcomer horses, lowering the binding capacity of CBG and raising free cortisol concentrations. However, no effect of stress could be detected when only total cortisol was measured. Therefore, to assess adrenal axis status accurately in horses, it is essential to monitor the binding capacity of CBG and free cortisol concentrations in addition to total cortisol levels.
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ABSTRACT
The role of sex steroids in the programming of the level of serum corticosteroid-binding globulin (CBG) in the rat has been studied at different stages of ontogenesis.
The CBG content in the serum of mature female rats was 2·5 times higher than that in male rats. Sexual dimorphism of CBG content was absent in immature animals of 3–4 weeks of age. Castration of mature rats led to a 40–50% increase in CBG content. The CBG concentration in mature females or castrated adult males treated with testosterone propionate (TP; 3 mg/day for 4 days) was decreased by 40–50% compared with vehicle-treated rats. Oestradiol injection (1 μg/day for 4 days) had no influence on CBG levels in mature male and ovariectomized adult female rats.
Immature rats were castrated on days 1, 7, 14, 21, 28 or 35 of age and the CBG level was determined at 10–12 weeks of age. The CBG content of rats castrated up to day 28 of age was 2·5 times higher than that in mature males and did not differ from that in mature females. The CBG content of male rats castrated on day 35 of age was the same as that of adult castrated males. The CBG level in castrated rats treated with TP (1·25 mg for days 1–3 or 300 μg/day for 5 days after castration at day 7 up to day 26) did not differ from that in controls (i.e. vehicle-treated rats). TP injection into castrated rats on days 29–33 of age (300 μg/day) led to a 40–50% decrease in CBG level when compared with controls.
Ovariectomy of rats at different ages (on days 1 or 28 or 3 months) did not affect CBG concentration. TP injection (300 μg/day) into ovariectomized rats on days 29–33 had the same effect on CBG concentration as in males.
Gonadectomized rats treated with diethylstilboestrol on days 29–33 (100 μg/day) had the same CBG concentrations as TP-treated rats.
It was concluded that there is a short period during ontogenesis, from days 29 to 35 of age, which is critical for irreversible masculinization of the CBG concentration in male rats.
Journal of Endocrinology (1992) 132, 235–240
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Abstract
Synthetic glucocorticoids stimulate the production of corticosteroid-binding globulin (CBG) by the liver of the sheep fetus near term (day 145). We have examined whether physiological changes in plasma cortisol alter plasma CBG concentrations, patterns of glycosylation and the amount of hepatic CBG mRNA at earlier times during pregnancy (day 100), prior to the activation of fetal hypothalamic-pituitary-adrenal function. Cortisol was infused into chronically catheterized sheep fetuses in amounts that raised the plasma cortisol concentration by about 15 nmol/l. This treatment resulted in a significant increase in the plasma corticosteroid-binding capacity and in the amount of CBG mRNA in the fetal liver, but did not alter the proportion of CBG retained using Concanavalin A chromatography. We conclude that the CBG gene in the liver of fetal sheep responds to physiological changes in plasma concentration of cortisol and we speculate that the rise in plasma CBG concentration is important in diminishing the negative feedback effect of circulating cortisol on the fetal pituitary and hypothalamus.
Journal of Endocrinology (1994) 140, 425–430
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ABSTRACT
The effects of the activation of protein kinase A (PKA), protein kinase C (PKC) and corticosteroids were investigated on the release of corticotrophinreleasing factor-41 (CRF), arginine vasopressin (AVP) and oxytocin from rat fetal hypothalamic cells in culture. Both forskolin and PMA (phorbol 12-myristate 13-acetate) increased CRF, AVP and oxytocin release, while dexamethasone and aldosterone only reduced basal secretion of CRF. Both steroids also inhibited forskolin-induced CRF, AVP and oxytocin responses to PMA. These data provide direct evidence for a role for both PKC- and PKA-mediated mechanisms in the regulation of CRF, AVP and oxytocin release and for differential effects of both glucocorticoids and mineralocorticoids on PKA- and PKC-stimulated responses.
Journal of Endocrinology (1992) 132, 57–65
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SUMMARY
The rat hypothalamus in vitro preparation was used to investigate the effect of bilateral adrenalectomy, with and without replacement therapy, on the release of corticotrophin-releasing factor (CRF). Corticotrophin-releasing factor was estimated using 48 h basal hypothalamic lesioned assay rats and corticosterone production of excised adrenals was used as the end point.
Bilateral adrenalectomy resulted in depletion of hypothalamic CRF content within the first 2 h after the operation but this effect was prevented by replacement therapy with corticosterone. Thereafter, the hypothalamic CRF content returned to values not significantly different from the intact control level. Bilateral adrenalectomy caused an increase in both basal and acetylcholine-induced release of CRF and it is suggested that corticosteroids exert a negative feedback effect on the hypothalamus.
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SUMMARY
Incubation of the adrenocortical tissue of Xenopus with labelled steroidal precursors gave aldosterone, corticosterone, 11-deoxycorticosterone and 18-hydroxycorticosterone as the major products. Kinetic studies indicated that the major biosynthetic pathway in Xenopus is the same as that in the duck, cobra and frog, and follows the sequence: pregnenolone → progesterone → 11-deoxycorticosterone → corticosterone → aldosterone + 18-hydroxycorticosterone.
The effects of adenohypophysectomy and of injection of mammalian corticotrophin (ACTH) on the corticosteroidogenetic capacity of Xenopus were also studied. The production of both aldosterone and corticosterone increased after ACTH administration and decreased markedly after adenohypophysectomy. Some of the evidence suggests that ACTH was effective at biosynthetic stages following the formation of pregnenolone. The present studies on corticosteroid production were done in conjunction with parallel investigations on osmoregulation and electrolyte and water changes in Xenopus (Edwards, 1969).
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al . 2004 ). We propose that corticosteroid receptors also play a role in cardiac enlargement in the fetal heart, although by mechanisms independent of cardiac injury and fibrosis. The purpose of this study was to test the hypothesis that increase in
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Abstract
Plasma cortisol levels increase in fetal sheep during late gestation and this is associated with an increase in plasma corticosteroid-binding globulin (CBG) concentrations. However, the relative tissue sources of plasma CBG, the ontogeny of its biosynthesis and glycoform composition have not been established in the ovine fetus. Therefore we examined whether changes in plasma corticosteroid binding capacity (CBC) in fetal sheep during late gestation were associated with different patterns of glycosylation and reflected changes in tissue CBG expression. Since free cortisol is considered the bioactive fraction, we measured changes in the percent and absolute free cortisol in fetal plasma during late gestation. In order to examine whether CBG alters cortisol negative feedback at the level of the fetal pituitary, we also examined the effect of exogenous CBG in mediating the glucocorticoid-induced suppression of basal and corticotrophin-releasing hormone (CRH)-stimulated ACTH release from fetal pituitary cells in culture.
The mean free cortisol concentration in plasma was not different between days 15 and 20 prior to parturition, and between 5 and 10 days prepartum, although it did rise between these times. Plasma CBC in chronically catheterized fetuses rose from 23·3 ± 4·6 ng/ml at day 115 to 86·5 ± 20·8 ng/ml at term and then decreased rapidly after birth. Between day 125 and day 140 of pregnancy approximately 10% of fetal plasma CBG was retarded by Concanavalin-A chromatography. This proportion increased at birth and attained adult values of >70% by one month of age. By Northern blotting the relative levels of CBG mRNA in the fetal liver did not change between days 100 and 125, then increased significantly at day 140, but declined at term and in newborn lambs. CBG mRNA was undetectable in total RNA from lung, kidney, hypothalamus and placentomes, but was present in the fetal pituitary at days 125 and 140. Reverse transcription-PCR was used to confirm the presence of CBG mRNA in pituitary tissue from term fetuses. In cultures of term fetal pituitary cells, added CBG attenuated the cortisol- but not the dexamethasone-mediated suppression of basal and CRH-stimulated ACTH release.
We conclude that in fetal sheep there is an increase in the corticosteroid binding capacity of plasma during late pregnancy which regulates, in part, free cortisol levels in the circulation. The liver is the major site of CBG biosynthesis in the fetus and at least until day 140 of gestation the rise in plasma CBC is associated with an increase in hepatic CBG mRNA levels. The fetal pituitary was also established as a site of CBG production. Output of ACTH by cultured pituitary cells was inhibited by cortisol and this effect was diminished in the presence of added CBG. This study supports a role for systemic CBG in modulating the availability of cortisol to the fetal pituitary and suggests an additional way of modifying feedback effects of cortisol at the pituitary through its own production of CBG.
Journal of Endocrinology (1995) 146, 121–130
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SUMMARY
The quantities of nine corticosteroids in 24 h urine samples collected by pregnant women (nine with normal foetuses and nine with anencephalic foetuses) were measured after hydrolysis with β-glucuronidase and separation by paper chromatography. The excretion (μmol/24 h, mean ± s.d.) of pregnanetriol (0·85 ± 0·17), 3α,17α-dihydroxy-5β-pregnan-20-one 17α-hydroxypregnanolone, 0·55 ± 0·17), 3α,17α,21-trihydroxy-5β-pregnan-20-one (tetrahydro-11-deoxycortisol, 0·17 ± 0·14) and tetrahydrocorticosterone (0·65 ± 0·26) by women with an anencephalic foetus was significantly lower (P < 0·01 or <0·05) than the excretion of these compounds by women with a normal foetus (pregnanetriol, 2·42 ± 0·62; 17α-hydroxypregnanolone, 2·72 ± 0·69; tetrahydro-11-deoxycortisol, 0·56 ± 0·37; tetrahydrocorticosterone, 1·95 ± 0·94). These differences suggest that the adrenal of the normal foetus contributes to the quantity of pregnanetriol, 17α-hydroxypregnanolone, tetrahydro-11-deoxycortisol and tetrahydrocorticosterone in maternal urine. The excretion of tetrahydrocortisol, tetrahydrocortisone, tetrahydrodeoxycorticosterone, cortol and cortolone were similar in both groups of subjects.
No evidence was obtained therefore to indicate the secretion of cortisol or deoxycorticosterone by the foetal zone of the adrenal of the undisturbed human foetus in late gestation.
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This report concerns the tetrahydrometabolites of cortisol and corticosterone excreted as glucuronides in the urine of 20 normal children up to the age of 8 yr. There are numerous papers on the total urinary 17-hydroxycorticosteroid excretion in children, but few on the qualitative and quantitative fractionation of the individual urinary steroids (Guignard-De Maeyer, Crigler & Gold, 1963; Visser & Cost, 1964; Teller, 1967; Tanner & Gupta, 1968).
Our method, which incorporates several new features, has been adapted from those described by Birchall, Cathro, Forsyth & Mitchell (1963) and by Gupta (1965), the former having been used previously in this Department in a study of newborn infants. Assays are made on two consecutive pooled 24 hr. specimens of urine. After extraction and hydrolysis of the urinary conjugates both glucuronide and sulphate fractions are assayed separately, final separation of the individual steroids being achieved on paper using Bush systems (Bush, 1961). Any
