Steroidogenesis in human aldosterone-secreting adenomas and adrenal hyperplasias: effects of hypoxia in vitro

The synthesis of adrenal steroids requires molecular oxygen. Because arterial hypoxemia is a common clinical condition, the purpose of the present study was to examine steroidogenesis in vitro under physiological changes in O2 tension (Po2) in cells from human adrenal glands with aldosterone-secreting adenomas (ASA; n = 3) or with bilateral adrenal hyperplasia causing Cushing's syndrome ( n = 4). A decrease in Po2 from 150 mmHg (mild hyperoxia) to 80 mmHg had minimal effect on steroid production. A reduction to 40 mmHg (still well within the physiological range) significantly inhibited cAMP- and ACTH-stimulated aldosterone, cortisol, and dehydroepiandrosterone (DHEA) production from ASA. Furthermore, cortisol and DHEA production in cells from histologically normal tissue, adjacent to ASA and from bilateral adrenal hyperplasias, was also inhibited under a Po2 of 40 mmHg. We conclude that physiological decreases in Po2 to levels typical for adrenal venous Po2 under mild hypoxia inhibit steroidogenesis. These studies may have implications for oxygen therapy in critically ill patients with functional adrenal insufficiency, as well as for therapeutic options in patients with adrenal neoplasms.

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Neonatal hypoxic hyperlipidemia in the rat: effects on aldosterone and corticosterone synthesis in vitro

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.3.r663 ◽

2000 ◽

Vol 278 (3) ◽

pp. R663-R668 ◽

Cited By ~ 14

Author(s):

Hershel Raff ◽

Eric D. Bruder ◽

Barbara M. Jankowski ◽

Theodore L. Goodfriend

Keyword(s):

Fatty Acids ◽

Adrenal Glands ◽

Plasma Lipids ◽

Plasma Cholesterol ◽

Neonatal Rat ◽

Nonesterified Fatty Acids ◽

Aldosterone Production ◽

Old Rats ◽

In Cells

Neonatal hypoxia increases aldosterone production and plasma lipids. Because fatty acids can inhibit aldosterone synthesis, we hypothesized that increases in plasma lipids restrain aldosteronogenesis in the hypoxic neonate. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Plasma was analyzed for lipid content, and steroidogenesis was studied in dispersed whole adrenal glands untreated and treated to wash away lipids. Hypoxia increased plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rat only. Washing away lipids increased aldosterone production in cells from 7-day-old rats exposed to hypoxia, but not in cells from normoxic 7-day-old rats or from normoxic or hypoxic 35-day-old rats. Addition of oleic or linolenic acid to washed cells inhibited both aldosterone and corticosterone production, although cells from hypoxic 7-day-old rats were less sensitive. We conclude that hypoxia induces hyperlipidemia in the suckling neonate and that elevated nonesterified fatty acids inhibit aldosteronogenesis.

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Effects of Thyroid Hormones on Ring A Reduction of Cortisone by Liver

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1958.195.2.373 ◽

1958 ◽

Vol 195 (2) ◽

pp. 373-380 ◽

Cited By ~ 35

Author(s):

F. Eugene Yates ◽

John Urquhart ◽

Arthur L. Herbst

Keyword(s):

Thyroid Hormones ◽

Adrenal Glands ◽

Close Correlation ◽

Female Rats ◽

Adrenal Steroids ◽

Acth Secretion ◽

Liver Size ◽

Thyroid State ◽

Male And Female Rats

Triiodothyronine increases total hepatic capacity for in vitro reduction of ring A of cortisone by 38% in both male and female rats. Thyro-parathyroidectomy decreases it 56% in males and 48% in females. These alterations in thyroid state influence hepatic reduction of corticosteroids in several ways: a) the total amount of Δ4-steroid hydrogenases in the liver may be altered, both by changes in liver size and by changes in amount of enzyme per gram of liver; and, b) the activity per gram of liver can also be altered through variations in coenzyme (TPNH) availability. These effects of thyroid hormones provide an enzymatic basis for the alterations in biological half-life of adrenal steroids observed in hyper- and hypothyroidism. A very close correlation ( r = 0.97) between total hepatic capacity to inactivate cortisone and the size of the adrenal glands was found. It is suggested that the rate of ring A reduction of corticosteroids by liver determines the rate of ACTH secretion in unstressed animals.

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STEROID PRODUCTION IN VITRO BY THE OVARIES AND ADRENAL GLANDS OF THE THIRTEEN-LINED GROUND SQUIRREL (CITELLUS TRIDECEMLINEATUS MITCHELL)

Journal of Endocrinology ◽

10.1677/joe.0.0320401 ◽

1965 ◽

Vol 32 (3) ◽

pp. 401-402 ◽

Cited By ~ 4

Author(s):

G. P. VINSON

Keyword(s):

Ground Squirrel ◽

Adrenal Glands ◽

Steroid Production

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COMPARISON BETWEEN SEASONAL AND THERMAL ACCLIMATION IN WHITE RATS: III. STUDIES OF THE ADRENAL CORTEX

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y59-140 ◽

1959 ◽

Vol 37 (1) ◽

pp. 1255-1261 ◽

Cited By ~ 1

Author(s):

O. Héroux ◽

E. Schönbaum

Keyword(s):

Adrenal Glands ◽

Cold Resistance ◽

Adrenal Weight ◽

Similar Degree ◽

Zona Fasciculata ◽

Steroid Production ◽

White Rats ◽

Number Of Cells ◽

Indoor And Outdoor

The rate of production of corticosteroids in vitro as well as the histological picture of the adrenal glands was studied in white rats exposed to cold for 3 months, either indoors at 6 °C in individual cages or outdoors during the winter in groups of 10.Under the indoor cold conditions, the adrenals hypertrophied within 1 week and their weight then remained constant for the following 11 weeks. The hypertrophy was due to an increase in the number of cells in the zona fasciculata. Relative to adrenal weight, the production of corticosteroids in vitro was less in the 6 °C rats than in the 30 °C controls. Under the outdoor cold conditions, the adrenal weight as well as the number of fasciculata cells remained normal, but the steroid production "in vitro" was greater than in the "summer controls". Since both "indoor" and "outdoor" cold-exposed rats have been shown previously to develop a similar degree of cold resistance as well as a similar capacity for elevating their metabolism through a non-shivering heat production mechanism, it appears that similar degrees of adaptation to cold can exist with different requirements of adrenocortical hormones.

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CUSHING'S SYNDROME WITH ATYPICAL BIOCHEMICAL RESULTS

Acta Endocrinologica ◽

10.1530/acta.0.0460256 ◽

1964 ◽

Vol 46 (2) ◽

pp. 256-264 ◽

Cited By ~ 12

Author(s):

R. McG. Harden ◽

A. P. M. Forrest

Keyword(s):

Cushing’S Syndrome ◽

Adrenal Glands ◽

Cushing's Syndrome ◽

Adrenal Hyperplasia ◽

Normal Range ◽

Bilateral Adrenal Hyperplasia

ABSTRACT A case of Cushing's syndrome is described with bilateral adrenal hyperplasia. Basal excretion of urinary total 17-OHCS and 17-KS were within the normal range, but the excretion of 17-OHCS was not suppressed by 16 mg dexamethasone daily in divided doses for five days. The adrenal glands were stimulated normally by corticotrophin and the hypophysis by cortisol lack. The blood corticotrophin was estimated to be not significantly different from the levels found in normal persons. It is concluded that the failure of suppression indicates either that the adrenal glands were functioning in part autonomously or more likely that the pituitary corticotrophin regulating mechanism was more completely disturbed than is usually found in Cushing's syndrome, due to bilateral adrenal hyperplasia.

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COMPARISON BETWEEN SEASONAL AND THERMAL ACCLIMATION IN WHITE RATS: III. STUDIES OF THE ADRENAL CORTEX

Canadian Journal of Biochemistry and Physiology ◽

10.1139/o59-140 ◽

1959 ◽

Vol 37 (11) ◽

pp. 1255-1261 ◽

Cited By ~ 6

Author(s):

O. Héroux ◽

E. Schönbaum

Keyword(s):

Adrenal Glands ◽

Cold Resistance ◽

Adrenal Weight ◽

Similar Degree ◽

Zona Fasciculata ◽

Steroid Production ◽

White Rats ◽

Number Of Cells ◽

Indoor And Outdoor

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METABOLISM OF [4-14C]CHOLESTEROL BY HUMAN ADRENAL GLANDS IN VITRO AND ITS INHIBITION BY METYRAPONE

Acta Endocrinologica ◽

10.1530/acta.0.0760689 ◽

1974 ◽

Vol 76 (4) ◽

pp. 689-702 ◽

Cited By ~ 5

Author(s):

Andres Carballeira ◽

Su Chiau Cheng ◽

Lawrence M. Fishman

Keyword(s):

Steroid Hormones ◽

Normal Tissue ◽

Adrenal Glands ◽

Fold Increase ◽

Hydroxylase Activity ◽

Steroid Biosynthesis ◽

Clinical Observations ◽

Substrate Conversion ◽

Rate Limiting

ABSTRACT The in vitro conversion of [4-14C] cholesterol1) to steroid hormones was studied in 1 normal, 1 adenomatous and 2 hyperplastic, surgically resected, human adrenals. The degree of overall conversion per gram of tissue was similar (4.4–5.6 %) in NADPH-supplemented homogenates from normal or moderately hyperactive adrenals; a 2-fold increase was found in a markedly hyperfunctioning gland. Only labelled cortisol, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone and androstenedione were isolated from incubations with [4-14C] cholesterol, but cortisol accounted for slightly more than 50 % of overall substrate conversion in the normal adrenal, while 11-deoxycortisol and androstenedione predominated in the abnormal glands. "Apparent 11β-hydroxylase activity" was considerably lower in the abnormal glands than in normal tissue when assessed using [4-14C] cholesterol as substrate, but this deficit was not observed in comparable incubations with 14C-labelled pregnenolone, progesterone or 11-deoxycorticosterone. [4-14C] Cholesterol was a more efficient precursor of androstenedione than either [4-14C] pregnenolone or [4-14C] progesterone. In parallel studies, metyrapone (1.0 mm) depressed the formation of both 11-oxy and 11-deoxymetabolies from [4-14C] cholesterol, overall inhibition ranging from 66 to 86%. The conversion of [4-14C] 11-deoxycorticosterone to corticosterone was inhibited by 93 % under identical conditions. Metyrapone did not, however, impair the overall transformation of either [4-14C]pregnenolone or [4-14C]progesterone, since the inhibition of cortisol and corticosterone biosynthesis was associated with an increment in 11-deoxycortisol (with [4-14C] pregnenolone) or 11-deoxycorticosterone (with [4-14C]progesterone). From these studies it appears likely that the additional site of metyrapone inhibition of steroid biosynthesis suggested by others on the basis of clinical observations involves the rate-limiting, ACTH-regulated conversion of cholesterol to pregnenolone.

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CONTRIBUTION TO THE EXISTENCE OF REGULATORY MECHANISMS AT THE ADRENAL LEVEL

Acta Endocrinologica ◽

10.1530/acta.0.0700741 ◽

1972 ◽

Vol 70 (4) ◽

pp. 741-757

Author(s):

Otto Linèt

Keyword(s):

Orotic Acid ◽

Adrenal Glands ◽

Actinomycin D ◽

Delay Period ◽

Regulatory Mechanisms ◽

Leucine Incorporation ◽

Total Period ◽

Free Media

ABSTRACT Rat adrenal glands atrophied by the administration of cortisol acetate in vivo were used as a model for the study of early metabolic processes occurring in vitro. Atrophied adrenals incubated in the presence of 14C-leucine incorporated subnormal quantities of this amino acid per mg of protein for the first 120 min. When the incubation lasted for a total period of 180 or 240 min a supranormal rise in the 14C-leucine incorporation was observed. Similar changes occurred with some delay with regard to corticosterone production as expressed per 100 mg of tissue. No differences in 14C-leucine incorporation were observed between the control and atrophied adrenals in vivo. Homogenates from atrophied glands incorporated 14C-leucine to a greater extent than the control homogenates. The in vitro incorporation of 14C-orotic acid into the RNA was also higher in atrophied adrenals. The in vitro use of actinomycin D, cycloheximide and amphenone indicated that corticosterone production depended on the incorporation of 14C-leucine. The addition of cortisol to the incubation media markedly decreased the enhancement of 14C-lysine incorporation into the protein of atrophied adrenals. These, as well as additional results suggest rebound phenomena: once atrophic adrenals are transferred to cortisol-free media, reparative processes begin after a delay period. Such phenomena seem to be mediated by regulatory mechanisms at the adrenal level.

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