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N J MacLusky

Publications and source records attributed to N J MacLusky.

At least 127 records · Page 7Linked to original sources
PubMed1982

Progestin receptor levels in rat hypothalamic and limbic nuclei.

We have utilized a method to minimize cytosol progestin receptor loss during freezing in order to localize the quantify estrogen-inducible progestin receptors in individual nuclei of the female rat brain. Ovariectomized females received estradiol benzoate (20 micrograms for 3 days) or vehicle prior to sacrifice. All animals were perfused with cold distilled H2O containing the cryoprotective compound, dimethyl sulfoxide (DMSO; 10% (v/v)). Thirty-one nuclei or brain regions were removed from frozen sections (300 micrometers) according to the method of Palkovits (Palkovits, M. (1973) Brain Res. 59: 449-450) and were assayed in vitro using a synthetic radioligand, [3H]R5020. In ovariectomized animals perfused with DMSO, a basal level (1 to 8 fmol/mg of protein) of progestin receptors was observed in a variety of preoptic, hypothalamic, and limbic structures. Moreover, estrogen treatment induced high levels (24 to 49 fmol/mg of protein) of progestin receptors in regions of the preoptic area of hypothalamus which contain high levels of estrogen receptors. These regions included the medial, periventricular, and superchiasmatic nuclei of the preoptic area, the periventricular anterior hypothalamus, the ventromedial nucleus, and the arcuate-median eminence. Moderate levels (2 to 8 fmol/mg of protein) of progestin receptors were induced by estrogen in other hypothalamic and limbic structures, including the anterior and lateral hypothalamus, the bed nucleus of the stria terminalis, the cingulate cortex, the medial amygdaloid nucleus, and the CA subfield of the hippocampus. By contrast, some areas, such as the caudate-putamen and the supraoptic nucleus, were devoid of both estrogen-inducible and uninduced progestin receptors. These results support the hypothesis that progesterone action in the central nervous system is mediated by cytosol receptors in discrete brain regions and provide the first quantitative map of progestin binding in a vertebrate brain.

Animals↗
PubMed1982

Estrogen receptors in ovarian epithelial carcinoma.

Specimens from 53% (16 of 30) of patients with untreated ovarian epithelial cancers between October 1976 and February 1979 had estrogen binding levels greater than 30 fmoles/mg of cytosol protein (receptor rich). The likelihood of a specimen being receptor rich appeared to be independent of patient age, histologic grade of tumor, clinical stage, and amount of residual tumor left after surgery. For 20 patients with previously untreated advanced disease a life-table analysis showed no significant difference when receptor-rich and -poor groups were compared in terms of either survival or time to first progression of disease. Analysis of more recent specimens (predominantly obtained after February 1979) indicates high-affinity binding of the estrogen consistent with receptor; occasional substantial heterogeneity in estrogen binding results between different sites of tumor involvement; and progestin-specific binding in some specimens. In an analogy to breast cancer, patients whose tumors are cytosol estrogen receptor rich might theoretically be responsive to the administration of antiestrogens.

Aged↗
PubMed1982

Aromatase in the central nervous system.

Central (central nervous system and pituitary) aromatization appears to be a fundamental process for endocrine control and development. Metabolism of androgens to estrogens and the subsequent metabolism of estrogens have been proven in many species, including humans, and linked to estrogen action. Thus, aromatization appears to initiate or to be involved in activities of importance to endocrine function at the central level and their effects peripherally. In the context of breast cancer, central aromatization relates to the control of gonadotrophins and other pituitary-brain hormones which may effect metabolism at the level of the breast. For example, follicle-stimulating hormone can increase aromatization and may be a factor in the control of such metabolism in breast tissue.

Androgens↗
PubMed1982

Estradiol receptor levels in rat hypothalamic and limbic nuclei.

The amount of cytoplasmic receptor for the steroid hormone, estradiol (E2), was determined in 46 nuclei and subdivisions of rat brain. Individual nuclei were removed from 300-micrometers frozen sections according to the punch-out method of Palkovits (Palkovits, M. (1973) Brain Res. 59: 449-450), and the content of E2 receptor was measured with a sensitive radioligand binding method. Cytoplasmic receptors for E2 were distributed heterogeneously throughout the rat brain. The highest level of receptor (40 fmol/mg of protein) was found in the periventricular nucleus of the preoptic area, while low (1 fmol/mg) but detectable levels of receptors were found in such limbic regions as the nucleus of the diagonal band, the olfactory tubercle, and the cingulate cortex. Regions that were devoid of detectable receptor included the medial septum, the parietal cortex, and the ventral thalamus. Our results support the notion that E2 influences reproductive behavior and neuroendocrine function by binding to receptors in discrete areas of the brain and provide the first quantitative map of E2 receptors in individual rat brain nuclei.

Animals↗
PubMed1981

Sexual differentiation of the central nervous system.

Sexual differentiation of reproductive and behavior patterns is largely effected by hormones produced by the gonads. In many higher vertebrates, an integral part of this process is the induction of permanent and essentially irreversible sex differences in central nervous function, in response to gonadal hormones secreted early in development.

Androgens↗
PubMed1981

Steroid receptor levels in intact and ovariectomized estrogen-treated rats: an examination of quantitative, temporal and endocrine factors influencing the efficacy of an estradiol stimulus.

Cell nuclear estrogen receptors and cytosol progestin receptors were measured in the pituitary gland, preoptic area and hypothalamus throughout the estrous cycle of the rat. Cell nuclear estrogen receptor levels paralleled changes in serum estradiol concentrations with highest values on proestrus and lowest on diestrus. Proestrous values were 50-60% of capacity for each tissue. Cytosol progestin receptor number in these tissues was also highest on proestrus and lowest on diestrus. With these data as a guide, Silastic capsules filled with estradiol-cholesterol mixtures were used to generate physiologic levels of estrogen receptor occupation within the brain-pituitary complex of ovariectomized rats and to examine the kinetics of estradiol stimulation of lordosis behavior and cyclic gonadotropin release. Our results indicate that the effectiveness of an estradiol stimulus to elicit lordosis or luteinizing hormone release depends on at least three factors: the magnitude of the increment in serum estradiol and brain and pituitary cell nuclear estradiol receptor levels; the duration over which these increments area maintained; and the interval from previous exposure to estrogen.

Animals↗
PubMed1981

Actions of catechol oestrogens on concentrations of serum luteinizing hormone in the adult castrated rat: various effects of 4-hydroxyoestradiol and 2-hydroxyoestradiol.

The pharmacological effect of 2-hydroxyoestradiol (2-OHE2) and 4-OHE2 on concentrations of LH in the chronically castrated rat have been compared with that of oestradiol in order to determine whether the in-vivo activity is altered by insertion of a hydroxyl group at position 2 or 4 of the aromatic A ring; these derivatives are naturally occurring oestrogen metabolites. Four groups of six adult male rats were used 4 weeks after bilateral orchidectomy. The right jugular vein was exposed under ether anaesthesia and a basal blood sample taken (10.00 h) immediately before an intravenous injection of vehicle alone (0.1 ml ethanol with 0.01% ascorbic acid), oestradiol, 2-OHE2 or 4-OHE2 (10 micrograms of each in 0.1 ml vehicle). Blood was taken from each animal at 2, 4, 6, 8 and 24 h after treatment and serum assayed for LH. Baseline LH levels were similar in the four groups. At 2 h there was no change in 2-OHE2-treated rats but there was a significant decrease of serum levels of LH in rats treated with oestradiol and 4-OHE2 compared with vehicle-treated controls. The decrease in LH was quantitatively similar in oestradiol- and 4-OHE2-treated groups and was sustained at 4, 6 and 8 h, returning to control values at 24 h. In subsequent experiments the effects of lower doses of these two steroids were compared and the potency of 4-OHE2 was estimated to be about 25% that of oestradiol. In a further experiment, 2-OHE2 (100 micrograms) had no effect when given alone, but when injected i.v. immediately before treatment with 1 microgram oestradiol, it was able to inhibit the suppression of LH by oestradiol. In conclusion, 4-OHE2 had a potent effect in lowering plasma LH levels whereas 2-OHE2, even at a high dose (100 micrograms), did not suppress LH but it was able to inhibit the effect of oestradiol. These differences in biological activity may reflect more rapid metabolism of 2-OHE2 or differences in binding properties of these catechol oestrogens to the oestrogen receptor.

Animals↗
PubMed1980

Comparative properties of the catechol estrogens, I: methylation by catechol-O-methyltransferase and binding to cytosol estrogen receptors.

Five catechol estrogens and two 2-methoxyestrogens were compared for their relative affinity of binding to hypothalamic, pituitary, and uterine cytosol estrogen receptors; and for the kinetics of the catechols' methylation by hepatic catechol-0-methyltransferase. All of the catechol estrogens tested have similar Km's for 0-methylation (9-14 muM). Estrogen receptor affinities, however, differ widely. In hypothalamus, for example, where estradiol-17 beta has a Kd of 0.039 +/- 0.008 nanomolar, 4-hydroxyestradiol also binds tightly (0.12 +/- 0.02 nM), 2-hydroxyestradiol and 4-hydroxyestrone with intermediate affinity (0.26 +/- 0.06 and 0.28 +/- 0.07 nM, respectively), and 2-hydroxyestrone and 2-hydroxyestriol much less well (1.68 +/- 0.79 and 1.27 +/- 0.26 nM, respectively). The binding of the 2-methoxyestrogens is extremely weak. These receptor affinities roughly parallel the potencies of these compounds in altering gonadotropin secretion.

2-Methoxyestradiol↗
PubMed1980

2-hydroxyestradiol-17 alpha and 4-hydroxyestradiol-17 alpha, catechol estrogen analogs with reduced estrogen receptor affinity.

2-Hydroxyest radiol-17 alpha and 4-hydroxyestradiol-17 alpha, the catechol derivatives of estradiol-17 alpha, have reduced affinity for hypothalamic, pituitary, and uterine estrogen receptors, but retain a potency for interaction with catechol-0-methyltransferase equal to that of the natural, 17 beta-hydroxy catechols. This dissociation of receptor binding and catecholamine interactions may allow the use of the 17 alpha catechols as a probe for the mechanism of action of the catechol estrogens.

Amygdala↗
PubMed1980

Progestin receptors in rat brain: distribution and properties of cytoplasmic progestin-binding sites.

Putative progestin receptors have been characterized in brain and pituitary tissue from untreated and estrogen-primed ovariectomized-adrenalectomized rats. The properties of these sites appear indistinguishable from those of cytoplasmic progestin receptors from the uterus: 1) sedimentation coefficient of 7S, which is reduced by half in the presence of 0.3 M KCl; 2) specificity of binding which strongly favors synthetic and natural progestins as opposed to glucocorticoids, androgens, and estrogens; 3) a dissociation constant for binding the synthetic progestin [3H]R5020 (17 alpha, 21-dimethyl-19-norpregna-4, 9-diene-3,20-dione) of 0.3 nM; and 4) similar rates of formation and dissociation of the [3H]R5020-receptor complexes. In these respects, the estrogen-inducible and noninducible receptors of the brain also appear to be indistinguishable from each other. Estrogen induction of progestin receptors is apparent in uterus (6-fold), pituitary (8-fold), mediobasal hypothalamus (4-fold), and preoptic area (4-fold), all estrogen receptor-containing areas. The corticomedial amygdala does not show an estrogen effect on progestin receptor levels even though it contains estrogen receptor sites. The midbrain of the rat doeogen-insensitive receptors in the brain is relatively low and of the same order of magnitude as in nonstimulated hypothalamus, preoptic area, and pituitary, yet variations are seen among the estrogen-insensitive structures, with lowest levels occurring in cerebellum (6-7 fmol/mg protein) and highest levels occuring in cerebral cortex (approximately 25 fmol/mg protein). These findings are discussed in relation to the actions of progesterone which do and do not require estrogen priming and in relation to intracranial progesterone implantation studies.

Adrenalectomy↗
PubMed1979

The development of estrogen receptor systems in the rat brain: perinatal development.

The estrogen receptor system of the rat brain is not detected at 15 and 19 days of gestation, even though estrogen receptors can be measured in the maternal hypothalamus. Estrogen receptors are first detected around the 21st day of gestation after which they increase rapidly in the perinatal period and reach a plateau around postnatal day 6. Estrogen receptors are found predominantly in the limbic brain (hypothalamus, preoptic area, amygdala) and in the cerebral cortex, and they are present in very low levels in a sample consisting of the midbrain, brain stem and cerebellum. Development of cortical estrogen receptors is retarded by a few days compared to those in the limbic brain, but then is extremely rapid so that cortical receptor levels are equal to those in the limbic block on or about postnatal day 6. As early as estrogen receptors can be detected in the fetus (day 21 of gestation), they are occupied by endogenous estradiol in male but not in female fetuses. This is measured by the occurrence of cell nuclear estrogen receptor complexes which can be detected by an exchange assay. The presence of such complexes in male limbic brain tissue is consistent with the presence of testicular androgen in the circulation and with the existence in the brain of aromatizing enzymes capable of converting testosterone to estradiol. The absence of such complexes from the female limbic brain is consistent with the protective role of alpha-fetoprotein in scavenging circulating maternal estradiol and keeping it from reaching intracellular receptor sites. The results are discussed with respect to the timing of the critical period for brain sexual differentiation and related maturational events.

Adrenalectomy↗
PubMed1979

The development of estrogen receptor systems in the rat brain and pituitary: postnatal development.

The postnatal development of the estrogen receptor system of the rat brain is described by means of data from in vitro cytosol binding assays and from in vivo cell nuclear experiments using 3H-labeled estrogens. Cytosol and nuclear measures give a similar picture of the changes in estrogen receptor levels from day 2--3 up to day 25 of postnatal life. Pituitary receptor levels reach a peak at day 10 and then decline slightly. A similar, though less pronounced, peak was seen in hypothalamus between days 8 and 15. In the amygdala, the concentration of receptors remains relatively constant apart from a slight increase around day 10. In the preoptic area, receptor levels increase throughout the entire period studied. In the cortex receptor levels increase between days 3 and 10 and then decline precipitously and remain low from day 15 onwards. In the midbrain and brain stem receptor levels remain low throughout the entire period. Occupation of estrogen receptors by estradiol in cell nuclei was investigated by means of an exchange assay. No occupation was seen in either cortex or limbic structures (hypothalamus, amygdala, preoptic area) of female pups on postnatal days 2--3; low level occupancy amounting to around 5% of capacity was seen in limbic structures but not in cortex of females on postnatal days 10--11 and 25--26. The possibility is discussed that this estrogen arises from testosterone via aromatization. The apparent absence of receptor occupation by endogenous circulating estradiol is discussed in relation to the presence and progressive disappearance of alpha-fetoprotein in the neonatal period. Data is presented showing that injected estrogens have a longer half-life in newborn rats than in 3-week-old animals and that estrogens such as diethylstilbestrol and moxestrol, which do not bind strongly to alpha-fetoprotein, gain access to brain estrogen receptors at lower doses compared to estradiol-17 beta.

Aging↗