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PubMed1977

Interactions of corticosterone, 5alpha-dihydrocorticosterone and dexamethasone with proteins in rat-liver cytosol.

The intracellular binding of [3H]corticosterone and [3H]dexamethasone and their metabolites to macromolecules in rat liver cytosol was studied in vivo and in vitro. The macromolecules binding corticosterone and its metabolites were characterized as (a) a steroid conjugate-binding (Stokes radius 2.5 nm and sedimentation coefficient 4.1 S in high ionic strength; pI 8.7, (b) transcortin and (c) a glucocorticoid "receptor". Competition experiments indicate that corticosterone and dexamethasone bind to the same site of the glucocorticoid receptor molecule. Different Stokes radii between the corticosterone-receptor and the dexamethasone-receptor complexes (6.9 and 6.3 nm, respectively, in high ionic strength) indicate that the two ligands induce different conformations of the receptor protein. This may be of importance when explaining the qualitative differences between the cellular effects of natural and synthetic glucocorticoids. 5alpha-Dihydrocorticosterone, on the other hand, competed to a very limited extent with dexamethasone for binding sites on the receptor. An assay of the inductive effect on liver tyrosine aminotransferase and tryptophan oxygenase indicated that 5alpha-dihydrocorticosterone was practically devoid of glucocorticoid activity. It is concluded that 5alpha-dihydrocorticosterone probably does not act as the mediator of corticosterone action in rat liver.

Adrenalectomy↗
PubMed1982

Antibodies against progesterone receptor from chick oviduct. Cross-reactivity with mammalian progesterone receptors.

The highly purified, molybdate-stabilized '8-9-S' form of the chick oviduct progesterone receptor complexed with [3H]progesterone (Specific activity approximately equal to 10-12 nmol bound steroid/mg protein) was prepared according to the three-step method [Renoir et al. (1982) Eur. J. Biochem. 127,71-79] and 50-90 micrograms samples were injected into a goat and a rabbit. Specific antibodies were observed as early as 2 weeks following the first booster injection and increased considerably 12 weeks later after further booster injections. Results were similar in the two animals, with higher titers observed in the goat. Antibodies cross-reacted with the 'transformed' 4-S form of the chick oviduct progesterone receptor. They also cross-reacted with molybdate-stabilized 8-9-S progesterone receptors of mammalian species (obtained from MCF-7 human breast cancer cells and from rabbit and mouse uteri), suggesting some evolutionary conservation of steroid hormone receptors. No cross-reaction was observed with chick oviduct oestradiol receptor and with chick plasma transcortin (a non-receptor progesterone-binding protein).

Animals↗
PubMed1998

Aldosterone action: fact, failure and the future.

1. It is now 45 years since aldosterone was isolated and 25 years since its genomic action, via mineralocorticoid receptors (MR), was first described. 2. Although the classic physiological role of aldosterone is to promote unidirectional transepithelial sodium transport, our ignorance of the mechanisms involved remains profound. 3. Unanswered questions include: (i) the physiological significance of the equivalent, high affinity of MR for aldosterone, progesterone, corticosterone and cortisol; (ii) the protein(s) induced as a direct transcriptional response to aldosterone; (iii) the physiological roles of MR in non-epithelial tissues where aldosterone, in concert with salt loading, produces direct pathophysiological effects; (iv) how aldosterone occupies epithelial MR, despite the 100-fold 'advantage' it enjoys over cortisol/corticosterone due to transcortin binding/11 beta-hydroxysteroid dehydrogenase activity, as plasma glucocorticoid levels are approximately 2000-fold higher; and (v) how epithelial MR, normally overwhelmingly occupied by glucocorticoids, are not transcriptionally active under normal circumstances in vivo, in contrast with transfection systems or the syndrome of apparent mineralocorticoid excess. 4. Possible avenues for consideration of the last two of these questions are briefly proposed.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1987

Adrenocortical steroids and the brain.

In summary, a wide variety of effects of adrenal steroids on the brain have been reported and have been recently and exhaustively reviewed. From the viewpoint of endocrine physiology, however, what is often forgotten is the extraordinary difference in signal level between the two unique products of the adrenal cortex, the mineralocorticoid and glucocorticoid hormones. Levels of cortisol or corticosterone are 2-3 orders of magnitude higher than those of aldosterone, a difference that is tempered by perhaps one order of magnitude by the much higher binding of glucocorticoids to plasma protein. The signal-detecting mechanisms for the lower-intensity signal, i.e. the mineralocorticoid receptor, must therefore have powerful specificity-conferring mechanisms to enable it to recognize, bind, and respond to aldosterone. In vitro studies from a number of laboratories have shown that Type I receptors, in both classic mineralocorticoid target tissues (kidney, parotid, gut) and nontarget tissues (pituitary, hippocampus), cannot distinguish between aldosterone and corticosterone. This finding highlights the problem of aldosterone-selectivity in the kidney (Na+ transport) or the brain (Na+ appetite). In vivo studies, in contrast, show that corticosterone is very poorly taken up and/or retained in kidney, colon, parotid, and pituitary (but not in hippocampus) in mature and 10-day-old (minimal transcortin) rats, whereas aldosterone is well taken up and/or retained by all tissues, evidence for tissue-specific aldosterone selectivity in vivo. Two nonexclusive (i.e. possibly additive) models for such aldosterone selectivity are proposed, one "prebinding" and the other "postbinding". Both models accommodate the experimental findings of the nonselectivity of cytosol preparations in vitro and the stringent specificity seen in in vivo receptor and effector studies. In any real sense, the action of adrenal steroids on the brain is still largely an area of unconnected phenomenology, despite the efforts of a number of talented individuals and groups over the past two decades. Without descriptions of phenomena, even of the most basic ablation and replacement type, we have no chance of making physiological statements. It is equally important, in the attempt to make a coherent physiology, to erect a scaffolding of hypothesis that can be tested against the existing experimental findings and that can serve to suggest further studies in a logical sequence. These hypotheses themselves, and the models used to reify them, may be validated, altered, or rejected by the studies over the next few years.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1994

Type I (mineralocorticoid) receptors in the guinea pig.

The affinity, capacity, and specificity of type I receptors (mineralocorticoid receptors, MR) in the guinea pig are indistinguishable from similar values determined in parallel studies in the rat. In both epithelial (kidney, colon) and nonepithelial (hippocampus, heart) cytosol preparations, aldosterone binds with a dissociation constant at 4 degrees C of 1-2 nM in both species; for both guinea pig and rat the tissue concentrations of MR are an order of magnitude higher in hippocampus and colon than in kidney or heart. In both species, aldosterone and cortisol appear to have equivalent affinity for MR, and corticosterone appears to have two- to fourfold higher affinity. Given the wide variety of differences between the guinea pig and other species in other components of the pituitary-adrenal axis (superagonist adrenocorticotropic hormone, high circulating cortisol, low levels of transcortin, low-affinity glucocorticoid receptors) the unexpected finding of pristine type I receptors in the guinea pig suggests powerful specificity-conferring mechanisms to allow aldosterone occupancy of MR in epithelia and the possibility of further definition of the roles of such type I receptors in nonepithelial tissues.

Aldosterone↗
PubMed1996

Progesterone binding to mineralocorticoid receptors: in vitro and in vivo studies.

In previous studies using expressed recombinant human mineralocorticoid receptors (MR), progesterone was reported to have widely divergent affinity, from approximately 10 nM to < 10 pM. In the present studies, cytosol preparations of colon or hippocampus were incubated with [3H]aldosterone or [3H]progesterone, alone or with excess RU-486, and the ability of each steroid to compete for MR was determined. In guinea pigs, progesterone has equivalent affinity to aldosterone for MR in vitro, and in rats three times of that aldosterone, with no differences between tissues. In vivo, in both epithelial (kidney, colon) and nonepithelial tissues (heart, hippocampus), progesterone was 10- to 100-fold less potent a competitor than aldosterone for MR, both in the absence of transcortin (8-day-old rats) and in adult mice. Bolus injection of [3H]progesterone was not specifically bound in any of the four tissues. Whether progesterone at steady state may bid for MR occupancy under conditions of high circulating free levels (in utero, luteal phase, pregnancy), presumably to act as an antagonist to cortisol/corticosterone in unprotected nonepithelial receptors, thus remains to be determined.

Adrenalectomy↗
PubMed1989

Vascular responsiveness in adrenalectomized rats with corticosterone replacement.

To determine under resting, unstressed conditions the circulating glucocorticoid concentrations that best maintain sensitivity of the vascular smooth muscle and baroreceptor responses to vasoactive agents, rats with vascular cannulas were sham-adrenalectomized (sham) or adrenalectomized (ADRX) and provided with four levels of corticosterone replacement (approximately 100 mg fused pellets of corticosterone: cholesterol 0, 20, 40, and 80% implanted subcutaneously at the time of adrenal surgery). Changes in vascular and baroreflex responses were determined after intravenous injection of varying doses of phenylephrine and nitroglycerin with measurement of arterial blood pressure and heart rate in the conscious, chronically cannulated rats. Vascular sensitivity was decreased, and resting arterial blood pressure tended to be decreased in the adrenalectomized rats; both were restored to normal with levels of corticosterone (40%), which also maintained body weight gain, thymus weight, and plasma corticosteroid binding globulin concentrations at normal values. The baroreflex curve generated from the sham group was different from the curves generated from the ADRX+0, 20, and 40% groups, but not different from that of the ADRX+80% group, suggesting that the baroreflex is maintained by higher levels of corticosterone than are necessary for the maintenance of the other variables. These data demonstrate that physiological levels of corticosterone (40% pellet) restore vascular responsiveness, body weight, thymus weight, and transcortin levels to normal in ADRX rats, whereas higher levels (80% pellet) are necessary for restoration of the baroreflex.

Adrenalectomy↗
PubMed1982

Regulation of glucocorticoid receptors in brain by corticosterone treatment of adrenalectomized rats.

Binding of (3H)-corticosterone in cytosol of hippocampus and hypothalamus has been measured in adrenalectomized (ADX) rats in the presence or absence of corticosterone replacement therapy (suspended shortly before receptor analysis). Corticosterone pellet implantation into female rats or oral corticosterone administration in salinized drinking water given to males for 3 weeks reduced (3H)-corticosterone binding by half in the hippocampus. This reduction was observed whether corticosterone or dexamethasone was employed as competitor to determine nonspecific binding, thus eliminating transcortin as the cause of the corticosterone effect on binding. Scatchard analysis of binding data revealed that the reduction was mostly due to decreased number of receptors. Animals pretreated with corticosterone had a reduction in thymus weight, indicating further the biological effectiveness of the treatment. Further, serum corticosterone in ADX rats pretreated with corticosterone (but with therapy suspended for 24 h) was very low and similar to that of untreated ADX rats. Uptake studies after injection of (3H)-corticosterone intravenously into ADX rats showed that the injected hormone was absent from blood and brain tissues 1 day later, ruling out (in addition to the measurement of serum corticosterone) that the reduction in binding was due to occupation of receptor sites by exogenous corticosterone remaining after withdrawal from therapy. It is suggested that down-regulation of glucocorticoid receptors in brain follows the chronic corticosterone administration. These data are discussed in relation with evidence for down-regulation of other classes of steroid receptors in several tissues, and the consequence that changes in receptor binding in brain may have on the feedback mechanism of corticoids at the central level.

Adrenalectomy↗
PubMed1995

Ventromedial hypothalamic lesions inhibit corticosteroid feedback regulation of basal ACTH during the trough of the circadian rhythm.

We have determined the effects of bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) on activity in the hypothalamo-pituitary-adrenal (HPA) system. Acutely, during the first 5 days, lesions of the anterior-medial VMH caused loss of the diurnal rhythms in food intake and plasma corticosterone (B) levels. Plasma B concentrations were elevated during the time of the normal trough of the basal diurnal rhythm in HPA axis activity and the diurnal rhythm in food intake was abolished, in agreement with the results of others. Consistent with hyperactivity in the HPA axis, lesioned rats had increased adrenal weight, decreased thymus and body weights and decreased plasma transcortin concentrations. To determine how lesions of the VMH provoke these increases in activity of the HPA system, the sensitivity of ACTH in adrenalectomized, lesioned rats to replacement with exogenous B was determined under basal conditions during the trough (morning-AM) and peak (evening-PM) of the diurnal rhythm in HPA axis activity. ACTH in lesioned rats in the AM was insensitive to feedback over the very low range of plasma B of 1-4 micrograms/dl, whereas sham-lesioned controls exhibited the normal, high sensitivity of ACTH to B at this time of day. There was no difference between the sensitivity of ACTH to this low range of B in the PM in VMH- and sham-lesioned rats. Two to 5 weeks after VMH lesions, as found by others, mean daily plasma B levels did not differ from sham-lesioned controls; however, plasma B during the AM was still mildly elevated in these rats. Inhibition of plasma B in the PM by dexamethasone was less effective in lesioned rats. Although HPA system responses to hypoglycemia, corticotropin-releasing factor and ACTH were normal, the lesioned rats exhibited obesity, hyperinsulinemia, hyperglycemia, hypertension and tachycardia, all signs consistent with mild hyperactivity of the PHA axis. Occupancy of type I, high-affinity corticosteroid receptors is known to control basal activity of the HPA system during the trough of the diurnal rhythm and to interact with glucocorticoid receptors to affect basal activity during the peak of the diurnal rhythm and during AM stress. We conclude that VMH lesions disrupt transmission of inhibitory signals, mediated by occupancy of type I corticosteroid receptors, that are initiated by a B feed-back site.

Adrenal Cortex Hormones↗
PubMed1976

The renin-angiotensin-aldosterone system in mother and fetus at term.

Plasma renin activity, renin substrate, angiotensin II, aldosterone and cortisol were measured concurrently and renin concentration calculated in plasma from mothers during labor and delivery, from cord and from newborn infants. The renin-angiotensin-aldosterone system was found strongly stimulated in both mother and fetus. The high values of plasma renin activity in fetus were due exclusively to the high renin concentrations the substrate concentration being normal. In the mother, however, the markedly elevated renin substrate resulted in a doubling of relative values of renin activity compared to renin concentration. Therefore gradients of renin and renin substrate across the placenta are established, but the resulting renin activity is similar on both sides and the levels of generated angiotensin II are also nearly indentical with a good correlation between these last parameters. Aldosterone is as elevated in mother as in fetus whereas cortisol, due to its binding to transcortin, is twice as high in mother as in fetus. No correlation was found between renin activity or concentration of angiotensin II and aldosterone or cortisol indicating that other factors controlling aldosterone are involved.

Adult↗
PubMed1983

Relation between diurnal changes in peripheral plasma progesterone, cortisol, and estriol in normal women at 30-31, 34-35, and 38-39 weeks of gestation.

To determine the relation of diurnal changes in plasma progesterone to those in cortisol and estriol we measured the concentrations of progesterone, cortisol and estriol in samples of plasma taken at 30- to 60-min intervals throughout 24 h from women at 30-31, 34-35, and 38-39 weeks of gestation. Plasma progesterone showed a significant diurnal rhythm at 30-31 and at 34-35 weeks of pregnancy, with troughs at 04.30-10.00 h. Major peaks occurred between 15.30 and 02.30 h. There was no diurnal rhythm in progesterone at 38-39 weeks. Plasma progesterone showed a significant negative correlation with plasma cortisol at 30-31 and 34-35 but not at 38-39 weeks. Plasma progesterone showed a significant positive correlation with estriol at 34-35 and at 38-39 weeks. We suggest that daily fluctuations in plasma progesterone may be related to the concentration of plasma cortisol, either directly by competition for binding sites on transcortin, or indirectly after modulation of fetal pituitary-adrenal function by maternally derived glucocorticoid.

Circadian Rhythm↗
PubMed1983

Abnormal dexamethasone suppression test in normal females.

Eighty women taking part in a population study were subjected to a dexamethasone suppression test (DST) intended as a diagnostic aid for melancholia. The women were selected systematically from two age strata, 38 and 50 years. Fifteen subjects (19 per cent) were found to be non-suppressors. High post-dexamethasone serum cortisol concentrations were not the result of elevated concentrations of the main cortisol binder, transcortin. There were no differences between suppressors and non-suppressors as regards depressive symptoms, strain experience, body mass, gynaecological history, drug use, smoking, erythrocyte sedimentation rate, number of leucocytes, activity of serum aminotransferases and gamma-glutamyltransferase, serum iron, bilirubin, ferritin content, serum growth hormone or serum prolactin. However, the nonsuppressors reported a significantly lower (P less than 0.01) orgasmic capacity in a questionnaire inquiry about two weeks before the DST. The outcome of the study indicates that DST as the presently recommended procedure for out-patients has a lower specificity for melancholia than has been reported previously.

Adult↗
PubMed1995

Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence.

The carbohydrate-deficient glycoprotein (CDG) syndrome type 1 is a genetic multisystem disorder, characterized by hypoglycosylation of glycoproteins and presenting with neurologic impairment. In 12 girls and 14 boys, we confirmed the diagnosis of CDG syndrome type 1 by immune-isoelectric focusing of serum sialotransferrins, and we examined the endocrine status singly or sequentially, including a 16-y follow-up of the index cases, a pair of monozygotic girls. Serum FSH levels were normal in newborns and prepubertal children, but elevated in female toddlers and teenagers, as well as in adolescent males. Serum LH concentrations displayed an analogous age-dependent pattern. In adolescent girls, serum estradiol remained low. FSH bioactivity was low normal, as was the bioactive/immunoreactive FSH ratio. However, exogenous gonadotropins evoked an estradiol response and induced ovarian follicular growth. Male patients virilized at puberty; however, testicular volume was subnormal. The thyroid axis was hallmarked by thyroid-binding globin deficiency and, during infancy, increased serum TSH concentrations. A subgroup of female patients presented hypersomatotropism and/or hyperprolactinemia. During adolescence, the index cases responded to glucagon with normal glycemic, but exaggerated insulin and paradoxically augmented growth hormone responses. The hypothalamo-pituitary area appeared intact on magnetic resonance imaging. Circulating IGF-1 levels were in the lower normal range and transcortin concentrations decreased. In conclusion, a study of endocrine aspects of a major glycosylation disorder revealed an age-dependent constellation, including hypergonadotropic hypogonadism with deficient FSH rather than LH action; transient hyperthyrotropinemia; inconsistent hyperprolactinemia; hyperglycemia-induced growth hormone release; deficiencies of hormone-binding glycoproteins and possibly decreased insulin sensitivity, thus pointing to the importance of glycoprotein glycosylation for pediatric endocrinology.

Adolescent↗
PubMed1984

Corticosteroid inhibition of ACTH secretion.

Corticosteroid feedback inhibits the brain-hypothalamo-pituitary units of the adrenocortical system. Naturally occurring corticosteroids may have their primary actions in vivo at brain and hypothalamic sites of feedback, whereas synthetic glucocorticoids that do not bind to transcortin may act primarily on corticotropes and regions of brain outside the blood-brain barrier. There appear to be three major time frames of corticosteroid action: fast, intermediate and slow. These time frames probably are the consequence of three separate mechanisms of corticosteroid action at feedback-sensitive sites. The rapidity of occurrence of fast feedback is not compatible with a nuclear site of corticosteroid action, and protein synthesis is not required. The action of CRF on ACTH release may be inhibited by a rapid effect of corticosteroids at the cell membrane. Since stimulated, but not basal, ACTH and CRF release are inhibited in vitro, the corticosteroids may inhibit some event in stimulus-secretion coupling (e.g., cAMP production). Intermediate feedback also decreases ACTH release in response to stimulation of the corticotrope, but does not affect ACTH synthesis; CRF synthesis and release both appear to be affected by the intermediate corticosteroid action. The mechanism of intermediate feedback requires the presence of a protein whose synthesis is corticosteroid-dependent; however, the role of this protein is unknown. Intermediate feedback, like fast feedback, apparently does not involve inhibition of total ACTH stores or the releasable pool of ACTH since basal secretion of ACTH is also not inhibited in vitro within this time domain. On the other hand, slow feedback apparently involves the classical genomic steroid mechanism of action; slow feedback reduces pituitary ACTH content by decreasing levels of mRNA encoding for POMC, the ACTH precursor molecule. Slow feedback, therefore, inhibits basal as well as stimulus induced ACTH secretion. Corticosteroid-induced inhibition of basal ACTH secretion has been shown to occur within 2 h in vivo but not in vitro. The time course and sensitivity of this feedback effect is different than that demonstrated for stimulus induced secretion. This difference suggests that basal secretion is activated by different pathways to (CRF and) ACTH secretion. There is some evidence that suggests that whereas comparator elements are not reset during stress, a comparator element is reset during the course of the circadian rhythm so that different basal levels of steroid are achieved.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1980

Heterogenetiy of glucocorticoid binders: a high affinity triamcinolone acetonide binder in bovine serum.

While investigating glucocorticoid-binding proteins in bovine tissues, a new binder was found in fresh bovine serum which exhibited high affinity for certain synthetic glucocorticoids. This serum binder was characterized using [3H]triamcinolone acetonide (TA) as the ligand. On sucrose gradients, the [3H]TA peak sedimented at 8S, which was easily distinguishable from the [3H]cortisol-transcortin peak at 4S. Unlike the tissue receptor, which showed ionically dependent transformation from 8S in equilibrium or formed from 4S, the serum binder sedimented at 8S in both hypo- and hypertonic gradients. Binding properties were evaluated employing sephadex G-50 chromatography to separate bound from free steroid. Scatchard analysis of specific [3H]TA binding data revealed a straight line. The apparent equilibrium dissociation constant (Kd) was 7.8 +/- 0.7 X 10(-8) M, and the binding capacity was 772 +/- 70 fmol/mg serum protein. Hormonal specificity was determined by a competitive binding assay and revealed the following sequence: TA (100%) > betamethasone (47%) > triamcinolone (33%) > dexamethasone (2%) = cortisol = progesterone; aldosterone, estradiol, and testosterone exhibited negligible competitive activity. The serum binder was very stable, withstanding heating to 37 C for 60 min and long term storage in the frozen state. However, binding was significantly destroyed by trypsin. The binder was absent from fresh samples of chicken, mouse, rat, rabbit, dog, monkey, and human sera and frozen horse and porcine sera, but was clearly present in commercially available frozen calf, fetal calf, and lamb sera. At this time, we are unable to define the function of this binder, although its existence in both ovine and bovine sera suggests a possible role in ruminants. However, since bovine serum is routinely employed in tissue culture studies, the presence of this glucocorticoid binder might significantly influence many experiments.

Animals↗
PubMed1981

Ontogenesis of glucocorticoid receptors in anterior pituitary gland: transient dissociation among cytroplasmic receptor density, nuclear uptake, and regulation of corticotropic activity.

The present investigation was undertaken to define the developmental pattern of glucocorticoid binding to the anterior pituitary gland and ascertain whether that binding correlated to modulation of corticotropin-releasing factor-induced release of ACTH. Scatchard analysis of data revealed the presence in cytosol (besides classical receptor sites interacting with both [3H]dexamethasone and [3H]corticosterone) of a transcortin-like component binding only the natural steroid. Whereas the number of sites of the former binder was not significantly altered during maturation and remained close to the adult value (276 +/- 12 fmol/mg protein), that of the latter declined dramatically after birth and rose again after postnatal day 10. The apparent Kd, however, remained unchanged. Transfer of te [3H]dexamethasone-receptor complex to nuclei of pituitary cells from neonates 2-6 days of age was found to be 20% that of adults despite the presence of comparable concentrations of receptor sites. Mixing experiments carried out with cytosol and nuclear fractions from different origins pointed to the cytoplasmic compartment as being implicated in this discrepancy. It was not until after postnatal day 10 that nuclear transfer reached mature levels. Although the extent of nuclear uptake and the magnitude of inhibition of ACTH secretion, as judged by means of a perifusion system, correlated well in hypophyses from 10- to 30-day-old neonates and adults, steroid binding and induction of biological response at earlier time points were less closely related. The results indicate the existence during development of a transient dissociation between cytosol and nuclear binding of corticosteroids by the anterior pituitary as well as between the latter process and blockade of ACTH release. These data are discussed in connection with the postnatal period nonresponse to stress. (Endocrinology 108: 591, 1981)

Adrenocorticotropic Hormone↗
PubMed1982

Search for a progesterone-binding protein in secretory granules of the ovine corpus luteum.

The hypothesis that electron-dense granules present in the corpus luteum contain progesterone in a protein-bound form was examined using differential and sucrose gradient centrifugation. Ovine luteal tissue was fractionated by differential centrifugation at 1,000 X g (P1 pellet), 10,000 X g (P2), and 82,000 X g (P3; supernatant S3). Samples of P2, P3, and S3 were further fractionated o 20-40% (P2 and P3) or 5-25% (S3) sucrose gradients and examined for progesterone-binding activity by measuring the progesterone content and/or the specific binding of [3H]progesterone of sucrose gradient samples. In addition, saturation binding assays were performed with steroid-free samples of P2 and S3. Saturable binding of progesterone was not found in P2, the fraction containing electron-dense granules. In S3, two progesterone-binding proteins with sedimentation rates of 3.2S and 8.6S and an affinity of 7.1 X 10(5) M-1 for progesterone were detected. The sedimentation behavior of these proteins was distinct from that of ovine plasma transcortin, a 4S protein. The view that a binding protein is released into the interstitial fluid during the exocytosis of granules was examined by measuring the progesterone-binding activity of protein released by slices of corpus luteum in vitro. No binding activity was found. The results of this investigation do not support the hypothesis that putative progesterone-secreting granules observed in luteal tissue contain a binding protein

Alpha-Globulins↗
PubMed1983

Aldosterone-binding sites in pregnant and lactating rat mammary glands.

We have identified and characterized aldosterone-binding sites in the mammary gland of pregnant and lactating rats by using the highly specific glucocorticoid RU26988 (11 beta, 17 beta-dihydroxy-17 alpha-propynyl-androsta-1,4,6-triene-3-one) to eliminate aldosterone binding to classical glucocorticoid (type II)-binding sites. The hierarchy of affinity of steroids competing for aldosterone in the presence of RU26988 was similar in mammary glands of pregnant and lactating rats and kidneys of lactating rats: deoxycorticosterone greater than aldosterone greater than or equal to corticosterone greater than dexamethasone; this pattern is similar but not identical to that for the mineralocorticoid (type I) receptor of a classical mineralocorticoid target organ, the kidney of the virgin female rat, where aldosterone has a higher affinity than corticosterone. This pattern (aldosterone greater than corticosterone) was also found in renal cytosols of pregnant rats. To define these aldosterone-binding sites in terms of dissociation constant and number of sites, it was necessary to pretreat cytosols with charcoal. Without this treatment, curvilinear Scatchard plots were obtained. After pretreatment with charcoal, subsequent Scatchard analysis indicated a single class of site with low capacity (3-33 fmol/mg protein) and dissociation constants of about 1-3 nM in kidneys and mammary glands of pregnant and lactating rats. The occupancy of this site in vivo may depend on the relative tissue concentrations of aldosterone or corticosterone, which, in turn, are modulated by the levels of extravascular transcortin.

Aldosterone↗