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1.
B R Carr C R Parker J C Porter P C MacDonald E R Simpson 《The Journal of clinical endocrinology and metabolism》1980,50(5):870-873
ACTH-stimulated adrenal tissue of a human anencephalic fetus, when maintained in organ culture, secreted appreciable quantities of cortisol but little dehydroisoandrosterone sulfate or pregnenolone sulfate. In the absence of ACTH, cortisol secretion was severely attenuated. Arginine vasopressin or alpha MSH, when added to the culture medium, did not stimulate steroid secretion. When whole human serum was present in the culture medium bathing the adrenal tissue of the anencephalic fetus, the rate of cortisol secretion was similar to that attained when lipoprotein-poor serum was in the medium. Based on these findings, it is concluded that in the presence of ACTH, the adrenals of the anencephalic fetus secrete principally cortisol, and the failure of dehydroisoandrosterone sulfate and pregnenolone sulfate secretion is due to the absence of the fetal zone. The lack of stimulation of cortisol secretion by lipoprotein is probably due to a reduced number of low density lipoprotein receptors resulting from diminished ACTH stimulation before birth. 相似文献
2.
Primary monolayer cultures of human fetal adrenal cells maintained in either lipoprotein-depleted or lipoprotein-supplemented media responded chronically to ACTH treatment with similarly increased steroid secretion. The principal steroid secreted into each medium was dehydroepiandrosterone sulfate. The presence of human low density lipoprotein (hLDL) in the medium enhanced the secretion of nonsulfoconjugated steroids, especially dehydroepiandrosterone. The secretion rate of 11 beta-hydroxyandrostenedione was similar to that of cortisol. In the absence of hLDL, ACTH increased cholesterologenesis to maintain the high rates of steroid secretion. After ACTH treatment, increased accumulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-determining enzyme of cholesterol biosynthesis, was found. Immunoblot analysis demonstrated that this enzyme was a 97K protein in human fetal adrenal cells. Interestingly, the content of this enzyme in cells treated with ACTH in lipoprotein-depleted medium was similar to that in adrenal fetal zone tissue. This finding suggests that cholesterologenesis de novo in addition to plasma LDL is important as a source of steroid precursor in vivo in the human fetal adrenal gland. 相似文献
3.
The role of lipoproteins as a source of the cholesterol utilized for steroidogenesis by human fetal adrenal (HFA) tissue was investigated previously. It was found that low density lipoprotein (LDL) was the lipoprotein preferred as a source of cholesterol for steroidogenesis by the HFA. [125I]Iodo-LDL was taken up and degraded by HFA tissue in organ culture, and the degradation of [125I]iodo-LDL was stimulated when ACTH (1 microgram X ml-1) was present in the culture medium. Others have shown that high density lipoprotein (HDL) is utilized as a source of cholesterol for steroidogenesis by rat adrenocortical cells in vitro and by the adrenals of the adult rat in vivo. In the present investigation we evaluated the metabolism of [125I]iodo-HDL by HFA tissue. [125I]iodo-HDL uptake by the HFA tissue increased in a linear manner with time and as the concentration of [125I]iodo-HDL in the culture medium was increased. However, there was little degradation of [125I]iodo-HDL by HFA. Moreover, preincubation of HFA tissue in medium containing ACTH (1 microgram X ml-1) or HDL, in various concentrations, did not affect the rate of uptake and degradation of [125I]iodo-HDL. The rate of degradation of [125I]iodo-LDL was found to decrease to low levels as the concentration of nonradiolabeled LDL in the culture medium was increased, whereas nonradiolabeled HDL had little effect on the degradation of [125I]iodo-LDL. HFA tissue fragments were incubated in medium containing ACTH plus lipoprotein-poor serum (LPPS) alone or LPPS plus HDL in various concentrations (50-1000 microgram X ml-1). The medium was changed daily and assayed for dehydroisoandrosterone sulfate and cortisol. In the presence of HDL, steroid secretion rates were no greater than those attained by HFA maintained in medium containing LPPS. It is concluded that the HFA utilizes cholesterol derived from LDL for steroidogenesis and that HDL is not metabolized efficiently by the human fetal adrenal. 相似文献
4.
Steroidogenesis in dispersed cells of human fetal adrenal 总被引:1,自引:0,他引:1
J I Mason P G Hemsell K Korte 《The Journal of clinical endocrinology and metabolism》1983,56(5):1057-1062
Steroidogenesis in dispersed fetal zone cells of midtrimester human fetal adrenal was stimulated acutely by ACTH. Polypeptide hormones such as hCG, alpha MSH, ovine PRL, and LH did not produce a similar stimulation of steroidogenesis. The principal steroid products of ACTH-stimulated fetal adrenal cells were dehydroisoandrosterone sulfate, pregnenolone, pregnenolone sulfate, and 17 alpha-hydroxypregnenolone. Only minimal production of the delta 4-3-ketosteroids, cortisol, corticosterone, and progesterone, was observed. Cyanoketone (2 alpha-cyano-4,4,17 alpha-trimethyl-17 beta-hydroxyandrost-5-en-3-one; an inhibitor of 3 beta-hydroxysteroid dehydrogenase activity) treatment of the cells caused only a minor increase in 3 beta-hydroxysteroid formation, confirming that 3 beta-hydroxysteroid formation is the principal steroidogenic fate of cholesterol in these cells. SU-10603 [7-chloro-3,4-dihydro-2-(3-pyridyl)naphthalen-1-(2H)one; a steroid 17 alpha-hydroxylase inhibitor] treatment of the cells caused a marked accumulation of pregnenolone sulfate, indicating that the C-19 steroids are produced from C-21 steroids in this tissue and possibly that dehydroisoandrosterone sulfate is synthesized directly from pregnenolone sulfate. ACTH-stimulated pregnenolone synthesis was inhibited by AY-9944 [trans-1,4-bis-(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride; an inhibitor of cholesterol biosynthesis]. Thus, cholesterol synthesized de novo was the likely steroidogenic precursor in the acute hormonally stimulated fetal adrenal cells. 相似文献
5.
6.
The control of steroidogenesis by human fetal adrenal cells in tissue culture. I. Responses to adrenocorticotropin 总被引:2,自引:0,他引:2
K Fujieda C Faiman F I Reyes J S Winter 《The Journal of clinical endocrinology and metabolism》1981,53(1):34-38
A technique of monolayer tissue culture of human fetal adrenal cells was developed in order to study steroidogenic responses to factors such as ACTH. The daily production of 12 steroids [pregnenolone, 17-hydroxy pregnenolone, dehydroepiandrosterone (DHA), DHA sulfate, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, corticosterone, 11-desoxycortisol, cortisol, and aldosterone) was measured by RIA. Initially, fresh fetal adrenal cells produced DHA, DHA sulfate, 17-hydroxypregnenolone, and small amounts of cortisol, but in the absence of ACTH, the production of all steroids declined during culture to low levels. The addition of physiological amounts (1-10(4) pg/ml) of either alpha ACTH-1(1-24) or alpha ACTH-(1-39) or coculture with fetal pituitary cells elicited a progressive rise in steroid production during the first 4-6 days of incubation. The lowest ACTH doses elicited a proportionately greater adrenal androgen response (as reflected in the DHA to cortisol ratio), but with increasing ACTH dosage, there was greater stimulation of cortisol production, which equalled or exceeded that of DHA. The data demonstrate that fetal adrenal cells may be maintained in short term culture and can respond to physiological amounts of ACTH. The progressive increase in the production of cortisol and other delta 4, 3-ketosteroids in vitro suggests that the characteristic fetal pattern of steroidogenesis may result from the interaction of ACTH with some circulating inhibitor of adrenal 3 beta-hydroxysteroid dehydrogenase. 相似文献
7.
The action of phorbol ester on steroidogenesis in cultured human fetal adrenal cells 总被引:1,自引:0,他引:1
The potent mitogen and tumor promoter, phorbol 12-myristate 13-acetate (PMA), has a primary action via activation of calcium-dependent protein kinase C. The treatment of monolayer cultures of human fetal adrenal neocortex (HFA) cells with PMA (50-250 nM) stimulated basal dehydroepiandrosterone sulfate (DS) secretion 2-3 fold. ACTH-treated HFA cells secreted amounts of DS and cortisol (F) 10-50 fold greater than basal secretions. PMA (250 nM) addition with ACTH to HFA cells decreased DS and F secretions at least 75% on days 2 and 3 of treatment. Treatment of HFA cells with 4 alpha-phorbol, which does not activate calcium-dependent protein kinase C, did not inhibit steroidogenesis. The attenuated rates of steroidogenesis after PMA treatment correlated with the decreased amounts of steroid 11 beta, 17 alpha- and 21-hydroxylase cholesterol side-chain cleavage steroid dehydrogenase and sulfotransferase activities. The decrease of steroid 17 alpha-hydroxylase activity correlated with the decreased amount of cytochrome P-450(17) alpha as determined after protein immunoblotting of NaDodSO4 cell lysates. After PMA treatment the ACTH-promoted increases of hydroxysteroid sulfotransferase and dehydrogenase activities of HFA cells were suppressed. PMA (50 nM) inhibited cAMP accumulation in ACTH-treated HFA cells, while 4 alpha-phorbol had no effect. Importantly, dibutyryl cAMP (0.2 mM) treatment of HFA cells did not reverse phorbol ester-promoted attenuation of steroidogenesis. We conclude that, in the presence of ACTH, phorbol ester chronically inhibits both cAMP synthesis and cAMP-dependent protein kinase action with resultant decreased steroidogenic enzyme synthesis and steroid production. This may be a consequence of activation, migration and a slow degradation of protein kinase C activity. These multifaceted actions of phorbol ester and associated protein kinase C activation may have critical effects on the ontogeny of fetal adrenal function. 相似文献
8.
The role of protein kinase-C-dependent mechanisms in steroidogenic enzyme gene expression was studied in primary cultures of human fetal and adult adrenals. Cells were first cultured for 7-10 days and then stimulated with ACTH or 12-O-tetradecanoyl phorbol-13-acetate (TPA), a protein kinase-C activator, for 1-2 days. Cytoplasmic RNA was extracted and analyzed by Northern and dot blotting with 32P-labeled cDNA probes for P450scc (cholesterol side-chain cleavage enzyme/20,22-desmolase), P450c17 (17 alpha-hydroxylase/17,20-lyase), and P450c21 (21-hydroxylase); for P450c11 (11 beta-hydroxylase/18-hydroxylase/18-methyl oxidase), a 30-mer oligonucleotide was used as a probe. ACTH (200 ng/ml) increased the accumulation of all of the studied steroidogenic enzyme mRNAs in both fetal and adult cultures by several-fold. TPA inhibited this accumulation in a dose-dependent manner (0.01-100 ng/ml), whereas the inactive phorbol ester 4 alpha-phorbol-12,13-didecanoate was without effect. On the other hand, in the absence of ACTH, TPA slightly increased all steroidogenic P450 mRNAs in adult cultures. In fetal cultures TPA slightly increased P450scc, P450c11, and P450c21 mRNA levels, whereas it decreased P450c17 mRNA. (Bu)2cAMP and cholera toxin increased steroidogenic enzyme mRNAs such as ACTH. TPA down-regulated (Bu)2cAMP- and cholera toxin-induced P450mRNAs in the same way as ACTH-induced mRNAs. The secretion of ACTH-stimulated cortisol, dehydroepiandrosterone sulfate, and aldosterone was decreased by TPA in both fetal and adult cultures. The basal steroid production was slightly increased by TPA in both culture types. The changes in steroid production correlated well with the alterations in the steroidogenic enzyme gene expression. Our results show that the inhibitory effect of TPA on ACTH-stimulated adrenal steroidogenesis is mediated at the mRNA level of steroidogenic enzymes. Thus, it seems likely that both protein kinase-C- and cAMP-dependent mechanisms are involved in the long term maintenance of steroidogenic enzymes and hormone production in adrenocortical cells. 相似文献
9.
B R Carr M Ohashi C R Parker E R Simpson 《The Journal of clinical endocrinology and metabolism》1981,52(6):1124-1128
In the present investigation we studied the role of cAMP as a mediator of ACTH action in human fetal adrenal (HFA) tissue. We have characterized the response to ACTH, dibutyryl adenosine 3',5'-cyclic monophosphoric acid (dbcAMP), and cholera toxin (CT) with respect to steroidogenesis, low density lipoprotein (LDL) binding, degradation of LDL, and the rate of de novo synthesis of cholesterol. The rate of dehydroisoandrosterone sulfate secretion was similar in HFA tissue maintained in the presence of ACTH, dbcAMP, or CT. In contrast, cortisol secretion by HFA tissue was more sensitive to dbcAMP and CT than to ACTH. In membrane preparations obtained from HFA tissue maintained in the presence of ACTH, dbcAMP, or CT, there was a 2 to 3-fold increase of specific binding of [125I]iodo-LDL. In HFA tissue maintained in the presence of ACTH or CT, the rate of degradation of LDL was significantly increased compared to tissue maintained in the lipoprotein-poor serum alone. Finally, in HFA tissue maintained in the presence of ACTH, dbcAMP, or CT there was a 6- to 10-fold stimulation of the rate of incorporation of [14C]acetate into cholesterol. We conclude that steroidogenesis, LDL binding, and degradation, as well as de novo synthesis of cholesterol, are probably stimulated in HFA tissue via a cAMP-mediated pathway. 相似文献
10.
H D Colby 《Endocrinology》1979,104(5):1299-1303
Studies were carried out to determine the actions of PRL on adrenocortical function in hypophysectomized female rats in the presence and absence of ACTH. PRL administration alone decreased 5 alpha-reductase activity but did not significantly affect the rates of corticosterone secretion or peripheral plasma corticosterone concentrations. The activities of several steroidogenic enzymes (cholesterol desmolase, 11 beta-hydroxylase, and 21-hydroxylase) were also unaffected by PRL. Adrenal steroidogenesis was increased by ACTH treatment, as expected, resulting in an increase in corticosterone secretion. However, since adrenal 5 alpha-reductase activity was higher in ACTH-treated hypophysectomized rats than in normal animals with intact pituitary glands, large amounts of 5 alpha-dihydrocorticosterone (DHB) and 3 beta, 5 alpha-tetrahydrocorticosterone (THB) were also secreted. PRL, when administered in combination with ACTH, potentiated the effecte levels. PRL did not affect cholesterol side chain cleavage, 11 beta-hydroxylation, or 21-hydroxylation in ACTH-treated rats. However, administration of PRL to ACTH-treated rats lowered adrenal 5 alpha-reductase activity, decreasing DHB and THB secretion. The decrease in DHB and THB secretion approximated the increase in corticosterone output. The results indicate that, in the presence of ACTH, PRL increases corticosterone secretion by decreasing intraadrenal degradation of corticosterone and not by enhancing steroidogenesis. 相似文献
11.
A model proposed for regulation of steroidogenesis, lipoprotein utilization and cholesterol metabolism in HFA tissue is presented in Fig 17. We envision that the role of ACTH and cAMP in steroidogenesis and cholesterol metabolism is as follows. ACTH binds to specific receptors on the surface of the cells of the HFA gland and as a consequence, adenylate cyclase is activated, leading to increased formation of cAMP. cAMP causes activation of protein kinase that leads, presumably, to phosphorylation of specific proteins. This leads to the initiation of reactions that give rise to increased activity of key enzymes and levels of proteins involved in adrenal cholesterol metabolism. Presumably, the action of ACTH causes an increase in the activity of cholesterol side chain cleavage, the rate-limiting step in the conversion of cholesterol to steroid hormones. We suggest that once the mitochondrial cholesterol side-chain cleavage system is fully activated by ACTH, the supply of cholesterol to the mitochondria becomes rate-limiting for steroidogenesis. To meet this demand for cholesterol, a further action of ACTH results in an increase in the number of LDL receptors. LDL binds to specific receptors on the cell surface that are localized in coated pits. LDL is internalized by a process of adsorptive endocytosis and the internalized vesicles fuse with lysosomes and the protein component of LDL is hydrolyzed by lysosomal proteolytic enzymes to amino acids. The cholesteryl esters of LDL also are hydrolyzed to give rise to fatty acids and cholesterol. The liberated cholesterol is available for utilization in the biosynthesis of steroid hormones and other cellular processes. In addition, ACTH stimulates the activity of HMG CoA reductase and, thus, the rate of de novo cholesterol biosynthesis. In this way sufficient cholesterol is obtained to provide for precursor cholesterol to maintain the high rate of steroid synthesis by the HFA. HDL is not utilized as a source of cholesterol by the HFA. Because of the rapid rate of utilization of LDL by the HFA, fetal plasma levels of LDL are low and the activity of the HFA is a primary determinant of these levels. Thus, in the case of anencephaly, in which the activity of the adrenal is very low, plasma levels of LDL are 2--3 times higher than in normal fetuses, whereas plasma HDL levels are similar. In addition, in the normal neonate plasma LDL levels rise rapidly after birth, and this event is coincident with the involution of the fetal zone of the adrenal. The fetal liver is likely to be the major source ultimately of the LDL-cholesterol utilized by the HFA. Consequently, factors that regulate cholesterol and lipoprotein synthesis in the fetal liver may, in turn, affect the steroidogenic activity of the HFA through regulation of the supply of cholesterol precursor. Thus, if trophic factors for the HFA other than ACTH exist, an important site of their action might be the fetal liver, rather than a direct action to influence the rate of synthesis of steroids by the fetal adrenal. 相似文献
12.
Monolayer cultures have been prepared from both definitive and fetal zones of the human fetal adrenal cortex. Cultures from each zone consist predominately of adrenocortical cells, as determined by a specific morphological retraction response to ACTH, and by ACTH-induced inhibition of DNA synthesis and cell proliferation. Cell growth was stimulated by fibroblast growth factor. ACTH stimulated steroidogenesis in cells from each zone with an ED50 of 0.4--1.0 nM and at a maximal concentration of 5 nM. Short term stimulation of less than 24 h with ACTH produced a pattern of steroid secretion that was characteristic of the zone of origin. Definitive zone cultures produced both cortisol and dehydroepiandrosterone plus its sulfate (DHA/S), with cortisol production exceeding DHA/S production. Fetal zone cultures produced more DHA/S than cortisol. 3 beta-Hydroxysteroid dehydrogenase, delta 4,5-isomerase enzyme activity was 3-fold less in fetal than in definitive zone cultures. Long term stimulation of 1--4 days with ACTH, 8-bromo-cAMP, or cholera toxin increased steroidogenic capacity in cultures from both zones. The pattern of steroid production by definitive zone cells remained constant, but cortisol production was preferentially increased in fetal zone cells. Forty-eight-hour treatment of fetal zone cells with ACTH increased 3 beta-hydroxysteroid dehydrogenase, delta 4,5-isomerase activity 5-fold. alpha-, beta-, gamma 1-, gamma 2-, and gamma 3-MSH were not effective steroidogenic agents for either zone. These studies indicate that steroidogenic agents induce in fetal zone cells steroid production characteristic of definitive and adult adrenocortical cells. 相似文献
13.
S Midorikawa H Sanada S Hashimoto T Suzuki T Watanabe H Sasano 《Endocrine journal》2001,48(2):167-174
Adrenal incidentalomas have recently increased in incidence, and thus it has become important to establish clinical management of these patients. It is also important to evaluate whether these tumors are different from preclinical or overt Cushing's syndrome in their steroidogenesis. In this study, we therefore examined steroidogenesis of hormonally inactive adrenal incidentalomas via short-term culture of tumor specimens, in addition to an immunohistochemical study of steroidogenic enzymes. Five patients (two men and three women) diagnosed with adrenocortical incidentaloma without any clinical signs of adrenocortical hormonal excess except for hypertension and disturbed glucose tolerance, were recruited for this study. Hormonal findings, including circadian rhythms for cortisol and ACTH secretion, the response of ACTH to CRH infusion and results of dexamethasone suppression test were all within normal limits in these patients. Immunoreactivity for all steroidogenic enzymes involved in cortisol production was detected in tumor cells in all cases examined. Results of in vitro steroidogenesis analysis using short-term culture revealed that levels of cortisol secretion varied among the cases. There were no differences in the immunolocalization of steroidogenic enzymes and/or the levels of cortisol secretion between these hormonally inactive tumors and preclinical and/or overt Cushing's syndrome. Dehydroepiandrosterone-sulfotransferase (DHEA-ST) immunoreactivity in nonneoplastic regions was suppressed in one case in which the tumor secreted cortisol similar to preclinical and/or overt Cushing's syndrome. These results demonstrate that the levels of in vitro steroid production and/or the immunolocalization of steroidogenic enzymes in hormonally inactive adrenocortical tumors vary markedly and are not overtly different from those of preclinical and/or overt Cushing's syndrome. 相似文献
14.
Studies were carried out to define the mechanism of action of growth hormone on adrenocortical steroidogenesis in hypophysectomized female rats. ACTH administration for 7 days increased corticosterone secretion in vivo and corticosterone production by adrenal tissue in vitro. Adrenal mitochondrial and microsomal cytochrome P-450 concentrations as well as the activities of cytochrome P-450-dependent enzymes (cholesterol sidechain cleavage, 11beta-hydroxylase, 21-hydroxylase) were also increased by ACTH. Administration of bovine growth hormone alone to hypophysectomized rats had no effect on any of the parameters evaluated. However, when given in combination with ACTH, growth hormone synergistically enhanced the effects of ACTH on cholesterol sidechain cleavage activity and corticosterone secretion. The magnitude of the pregnenolone-induced difference spectrum in adrenal mitochondria, indicative of cholesterol binding to cytochrome P-450, was also increased by growth hormone, but neither cytochrome P-450 content nor the activities of other steroidogenic enzymes were affected. The results indicate that growth hormone interacts with ACTH to promote corticosterone secretion by increasing the association of cholesterol with adrenal mitochondrial cytochrome P-450, thereby increasing the activity of cholesterol sidechain cleavage, the rate-limiting step in steroidogenesis. 相似文献
15.
The adrenal gland of the human fetus (HFA) is relatively large compared to that of the adult and exhibits an extremely high rate of steroidogenesis both in vivo and in vitro. The fetal zone cells make up 80-85% of the volume of the HFA and are the major site of steroid production during fetal development. We have recently demonstrated that calcium is involved in the regulation of steroidogenesis in fetal zone cells of the HFA. There is considerable evidence that many actions of calcium within cells are mediated by the calcium-binding protein calmodulin. The purpose of the present investigation was to determine if calmodulin also plays a role in HFA steroidogenesis. To investigate this possibility, the fetal zone was dissected from fetal adrenals of first and second trimester human abortuses. After collagenase digestion of the tissue, dispersed fetal zone cells were maintained in a Krebs-Ringers medium at 37 C for a 3-h incubation. Cells were incubated with and without ACTH (10(-8) M) in the presence of the calmodulin inhibitors trifluoperazine (TFP), chlorpromazine (CPZ), and calmidazolium (CAL) at concentrations of 5-100 microM. The media were assayed for contents of dehydroepiandrosterone sulfate (DS), cortisol (F), pregnenolone, and cAMP by RIA. The addition of ACTH stimulated F secretion 5- to 10-fold compared to that in control fetal zone cells. DS secretion increased up to 5-fold and pregnenolone about 2-fold in the presence of ACTH compared to values in control cells. ACTH also stimulated cAMP secretion by 10-fold compared to that in control cells. The addition of TFP, CPZ, and CAL significantly inhibited ACTH-stimulated DS, F, and pregnenolone secretion in a dose-related fashion to near-control levels. We observed that TFP, CPZ, and CAL inhibited cAMP accumulation as well as Bu2cAMP-stimulated steroid secretion. The metabolism of 22R-hydroxycholesterol to pregnenolone was inhibited by TFP and CPZ, but not by CAL. These studies suggest that calmodulin plays a role in regulating steroidogenesis in fetal zone cells of the HFA. 相似文献
16.
Steroid secretion and ultrastructural differentiation of human fetal adrenal cortical cells were analyzed in tissue culture with and without ACTH. The unconjugated and sulfated endogenous neutral steroids were analyzed by gas-liquid chromatography and gas chromatography-mass spectrometry. A fetal pattern of neutral steroids, including high concentrations of sulfate conjugates, was found during the first five days of the cultivation. At 6 to 11 days of cultivation, a decrease was seen in concentrations of these steroids. However, when stimulated with ACTH, an increasing amount of steroids was secreted during days 6 to 11 and their pattern was transformed into the adult type with a 30-200 times higher secretion rate of cortisol. Cortical cells capable of proliferation in the culture had the ultrastructure of the permanent zone cells of the fetal adrenal or adult zona glomerulosa type. ACTH stimulation induced a differentiation of these cells into zona fasciculata type. The results suggest that ACTH is the main hormonal regulator in the genesis of the adult human adrenal cortex and that there is a factor during fetal life which inhibits the synthesis of the 3beta-hydroxysteroid dehydrogenase system. 相似文献
17.
D P Lotshaw R Franco-Saenz P J Mulrow 《The American journal of the medical sciences》1991,301(1):15-20
The authors examined the effects of the alpha 2-adrenergic agonist guanabenz and other alpha-adrenergic ligands on aldosterone secretion and cyclic nucleotide content in isolated rat adrenal glomerulosa cells. Guanabenz inhibited aldosterone secretion stimulated by potassium, angiotensin II (AII), and adrenocorticotropic hormone (ACTH), exhibiting IC50 values of 35 microM, 43 microM, and 58 microM for stimulation by 10 mM K+, 1 nM AII, and 10 pM ACTH, respectively. Guanabenz did not affect the cGMP content of purified adrenal glomerulosa cells but inhibited ACTH stimulation of cAMP accumulation. Guanabenz inhibition of ACTH-induced cAMP may represent a mechanism for inhibition of aldosterone secretion, however, guanabenz also inhibited aldosterone secretion stimulated by the cAMP analog dibutyryl cAMP. The effect of guanabenz on the early and late pathways of steroidogenesis was tested in the isolated rat glomerulosa cells using 25-OH cholesterol and steroid precursors to aldosterone. Guanabenz inhibited the steroidogenic response to 25-OH cholesterol stimulation of aldosterone secretion but induced a much smaller inhibition of the steroidogenic response to exogenous pregnenolone, progesterone, and 11-deoxycorticosterone. These results suggested that guanabenz inhibited aldosterone secretion primarily through inhibition of the early component of the steroidogenic pathway prior to pregnenolone formation. The effects of guanabenz were not mimicked by other alpha-adrenergic ligands suggesting that these effects of guanabenz were not mediated through activation of alpha-adrenergic receptors. 相似文献
18.
Corticotropin-releasing hormone stimulates steroidogenesis in cultured human adrenal cells 总被引:3,自引:0,他引:3
The effects of corticotropin releasing hormone (CRH) on steroid production by cultures of human fetal adrenal cells was investigated. We found that CRH, at concentrations that have been reported to exist in human fetal serum, stimulated dehydroepiandrosterone sulfate (DS) and cortisol production by cultured fetal zone and neocortical zone cells. A dose-dependent increase in secretion of both steroids was noted, with the cortisol pathway being preferentially enhanced by CRH at high concentrations. Pretreatment of adrenal cells for 3 days made them more responsive to ACTH stimulation and such effects were dose-dependent also. Inclusion of the antagonist, alpha-helical CRH (9-41) blocked CRH-induced stimulation of DS and cortisol over a broad dose range and also interfered with the augmentation of cortisol secretion noted after ACTH in CRH treated cells. CRH had no effects on adrenal cell proliferation or total cell protein. These studies are suggestive that CRH, either of systemic origin or else produced within the adrenal itself, has the potential to be a modulator of adrenal steroid production in the human. 相似文献
19.
Chamoux E Narcy A Lehoux JG Gallo-Payet N 《The Journal of clinical endocrinology and metabolism》2002,87(4):1819-1828
The specific development of the human fetal adrenal gland requires cell proliferation, migration, apoptosis, and zone-specific steroidogenic activity. The present work was designed to determine the physiological significance of the previously identified spatial distribution of extracellular matrix components in the fetal gland. Primary cultures of human fetal adrenal cells grown on collagen IV, laminin, or fibronectin revealed that cell morphology was affected by environmental cues. Matrices also modulated the profile of steroid secretion by the fetal cells. Collagen IV favored cortisol secretion after ACTH or angiotensin II stimulation and increased dehydroepiandrosterone production when the AT(2) receptor of angiotensin II was specifically stimulated. These effects were correlated by changes in the mRNA levels of 3beta-hydroxysteroid dehydrogenase and cytochrome P450C17. In contrast, fibronectin and laminin decreased cell responsiveness to ACTH in terms of cortisol secretion, but enhanced ACTH-stimulated androgen secretion. Finally, extracellular matrices were able to orchestrate cell behavior. Collagen IV and laminin enhanced cell proliferation, and fibronectin increased cell death. This study is the first to demonstrate that the nature of extracellular matrix coordinates specific steroidogenic pathways and cell turnover in the developing human fetal adrenal gland. 相似文献
20.
Impaired cortisol secretion in abetalipoproteinemia 总被引:2,自引:0,他引:2
D R Illingworth E S Orwoll W E Connor 《The Journal of clinical endocrinology and metabolism》1980,50(5):977-979
In the adrenal gland cholesterol for steroid biosynthesis is derived from both de novo biosynthesis and receptor mediated uptake of plasma low density lipoproteins (LDL). In the present study we have compared ACTH stimulated adrenal production of cortisol in four control subjects and one adult male patient with abetalipoproteinemia, a disorder in which LDL is absent. Basal morning cortisol levels in the plasma in the control subjects (13.3 +/- 1.6 microgram/dl) and abetalipoproteinemic patient (14.6 micrograms/dl) were similar. During infusion of alpha 1, 24 ACTH however, plasma cortisol levels were higher in the control subjects than in the abetalipoproteinemic patient and this difference was significant at times after 4 hours. Urinary excretion of both 17-hydroxy and 17-ketosteroids over the 24 hour infusion period was also significantly lower in the abetalipoproteinemia patient indicating that cortisol production rates were reduced. Our results suggest that in the absence of plasma low density lipoproteins, as occurs in abetalipoproteinemia, the maximal production of adrenal corticosteroids is impaired. By inference, these findings lend in vivo support to the view that plasma low density lipoproteins serve as an important source of cholesterol for adrenal steroidogenesis in man. 相似文献