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PubMed1980

Reversal of ethinyl estradiol-induced bile secretory failure with Triton WR-1339.

The effects of Triton WR-1339 and phenobarbital on ethinyl estradiol bile secretory failure were examined to determine the mechanism responsible for decreased bile salt excretion. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored bile salt independent bile flow and maximum taurocholate transport, whereas phenobarbital corrected bile flow only. Ethinyl estradiol decreased the activities of Na(+)-K(+)-ATPase, 5'-nucleotidase, while increasing the activities of Mg(++)-ATPase and alkaline phosphatase. In contrast to these heterogeneous changes in surface membrane enzyme activities, the number and affinity of [(14)C]cholic acid carriers were not altered. When administered in vivo or added directly to surface membrane fractions Triton WR-1339 restored the activities of Na(+)-K(+)-ATPase and Mg(++)-ATPase of rats treated with ethinyl estradiol through a process that did not require protein synthesis (unaffected by cycloheximide). Phenobarbital also restored the activity of Na(+)-K(+)-ATPase to control levels, but, unlike Triton WR-1339 it did not correct the defect responsible for reduced bile salt secretion. Ethinyl estradiol increased the concentration of cholesterol esters in surface membrane fractions. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored cholesterol ester concentrations to normal, whereas phenobarbital did not. These combined data suggest that decreased or altered bile salt carriers or reduced sodium driving forces resulting from impaired activity of Na(+)-K(+)-ATPase are not responsible for decreased bile salt excretion in ethinyl estradiol-treated rats. It is proposed that the diverse changes in surface membrane function, which are associated with ethinyl estradiol bile secretory failure, may be the result of a generalized alteration in membrane lipid structure.

Animals↗
PubMed2002

An evaluation of bioequivalence of two 7-day 17beta-estradiol transdermal delivery systems by anatomical site.

An open-label, randomized, crossover study was conducted to assess the bioequivalence of two 7-day transdermal 17beta-estradiol delivery systems following application to the buttock in 42 postmenopausal women. The systems tested were a generic Estradiol Transdermal System (Mylan Pharmaceuticals, Inc.) and Climara (Berlex Laboratories, Inc.), the reference product. Each system was labeled to deliver 17beta-estradiol 0.1 mg/day and was applied for 7 days. Serial serum samples were assayed for estradiol, estrone, and estrone sulfate using validated assays. The bioequivalence confidence intervals for the ratio of log-transformed 17beta-estradiol Cmax values for the Estradiol Transdermal System and Climara were outside the interval of 0.80 to 1.25, indicating that the products were not bioequivalent. Application site reactions and skin irritation were more common with the Estradiol Transdermal System than with Climara. The odds of patch lifting or detachment were 6.95 times higher with the Estradiol Transdermal System than with Climara. Because these two transdermal delivery systems had been previously shown to be bioequivalent after application to the abdomen, the findings of this study suggest that bioequivalence at one anatomical site is not indicative of bioequivalence at another.

Administration, Cutaneous↗
PubMed2002

Targeted brain delivery of 17 beta-estradiol via nasally administered water soluble prodrugs.

The utility of the nasal route for the systemic delivery of 17beta-estradiol was studied using watersoluble prodrugs of 17beta-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17beta-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17beta-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17beta-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17beta-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17beta-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.

Administration, Intranasal↗
PubMed2003

Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms.

We systematically characterized the oxidative metabolites of 17beta-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17beta-estradiol 2-hydroxylation, followed by 15alpha-, 6alpha-, 4-, and 7alpha-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15alpha- or 6alpha-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17beta-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9-13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16alpha- and 16beta-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone with CYP3A4 was 0.22 or 0.51, respectively. CYP3A5 had similar catalytic activity for the formation of 2- and 4- hydroxyestrogens. Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone (0.53 or 1.26, respectively). CYP3A4 and 3A5 also catalyzed the formation of nonpolar estrogen metabolite peaks (chromatographically less polar than estrone). CYP3A7 had a distinct catalytic activity for the 16alpha-hydroxylation of estrone, but not 17beta-estradiol. CYP4A11 had little catalytic activity for the metabolism of 17beta-estradiol and estrone. In conclusion, many human CYP isoforms are involved in the oxidative metabolism of 17beta-estradiol and estrone, with a varying degree of catalytic activity and distinct regioselectivity.

Aryl Hydrocarbon Hydroxylases↗
PubMed1981

The effects of 17 beta-estradiol and progesterone on the metabolism of free fatty acid by perfused livers from normal female and ovariectomized rats.

To determine whether any interaction occurs between progesterone and 17 beta-estradiol in the regulation of FFA metabolism by the liver, normal female rats were injected sc daily for 14 days with 7.5, 15, 50, or 100 microgram 17 beta-estradiol/kg, 25 mg progesterone/kg, 15 microgram 17 beta-estradiol plus 25 mg progesterone/kg, or vehicle (sesame oil) alone. To determine the effects of these hormones in the absence of endogenous estradiol and progesterone, ovariectomized rats were treated with the steroids. Livers were removed from the variously treated rats and perfused in vitro in a recycling system. An albumin-oleate complex was infused into the perfusate, providing a steady state concentration of 0.3--0.5 nM oleate. The uptake of FFA and output of ketone bodies and glucose by the livers were generally not altered by any of the steroid treatments. Neither these parameters nor triglyceride secretion was altered by ovariectomy. The administration of 15, 50, and 100 microgram estradiol/kg to normal, but not ovariectomized rats, increased triglyceride secretion. Progesterone alone had no effect on the secretion of triglyceride, but did antagonize the estradiol-mediated stimulation of triglyceride secretion in normal rats. The molar ratios of phospholipid to triglyceride and cholesterol to triglyceride of the very low density lipoprotein secreted by livers from normal females treated with estradiol were not altered, suggesting that the livers secreted more very low density lipoprotein particles of the same size. Based on the same criteria, livers from ovariectomized rats secreted smaller very low density lipoprotein particles compared to livers from control animals, an effect which was reversed by the administration of estradiol. We conclude that progesterone antagonizes the stimulation of hepatic triglyceride secretion by estradiol in normal female rats and that ovariectomy prevents this effect of progesterone.

Animals↗
PubMed1981

The endocrine basis of the synergistic suppression of luteinizing hormone by estradiol and progesterone.

The basis of the synergism between estradiol and progesterone in suppressing tonic (pulsatile) LH secretion was examined in the ewe, making use of the observation that progesterone exerts its inhibition selectively on LH pulse frequency, while estradiol decreases only pulse amplitude. To accomplish this, we analyzed changes in LH pulse patterns produced by a low level of progesterone in ovariectomized ewes treated with Silastic estradiol implants from the time of gonadectomy. A serum progesterone level of about 1 ng/ml was chosen because it inhibits LH only in the presence of estradiol. Under these circumstances, a decrease in LH pulse amplitude during progesterone treatment would suggest that progesterone increased the response to the existing level of estradiol; a decrease in pulse frequency would suggest that estradiol increases the effectiveness of progesterone. It was found that the low level of progesterone produced a decrease in LH pulse frequency in estradiol-treated ovariectomized ewes without altering pulse amplitude. These results are consistent with the hypothesis that the synergism of these two steroids reflects, at least in part, an estradiol-induced increase in the sensitivity of the central nervous system to the negative feedback action of progesterone.

Animals↗
PubMed1984

Hormonal regulation of immunoglobulins in the rat uterus: uterine response to multiple estradiol treatments.

The present studies explored the processes by which estradiol regulates the accumulation or immunoglobulins A (IgA) and G (IgG) in the uterus. Levels of IgG in uterine secretions increased rapidly within 3 h after either two or three daily estradiol (1 microgram) treatments of ovariectomized rats and then declined. These levels, however, were only a small fraction of the total IgG content measured in uterine tissue. In contrast, luminal IgA levels increased gradually, with maximal amounts occurring 6 to 25 h after the third estrogen injection. Moreover, concentrations of IgA in uterine secretions at this time were significantly greater than those found in uterine tissue. Therefore, under the influence of estradiol, IgA moves from tissue to lumen against an apparent concentration gradient, whereas IgG movement is consistently down a gradient. Estradiol also rapidly increased the levels of IgA and IgG in uterine tissue. These increases, in contrast to the luminal pattern, occurred in parallel. Tissue content of both IgA and IgG were highest within 6 h after the second or third estradiol injection and then decreased. Of particular interest was our finding that, whereas the form of IgA in uterine tissue was both monomeric and polymeric, only polymeric IgA accumulated in the uterine lumen. Analysis of the effect of nafoxidine on the uterine Ig response indicated that this compound significantly increased the amount of uterine tissue IgA and IgG. The Ig levels in uterine secretions, however, were significantly less than those measured after estradiol treatment. Nafoxidine's stimulatory effect on luminal Ig concentrations was equal to that of estradiol when uteri were ligated to prevent fluid loss through the cervix. Utilization of this ligation procedure was also instrumental in demonstrating that chronic estrogen exposure (8 days) resulted in greater quantities of uterine luminal Ig. The role of T cells in the estrogen control of uterine luminal Igs was also examined. In rats that had been neonatally thymectomized, luminal levels of both IgA and IgG were significantly reduced, when compared to those measured in sham-operated or intact estrogen-treated controls. Thymic absence, however, did not prevent the estradiol-induced movement of IgA from tissue to lumen against a concentration gradient.

Animals↗
PubMed1984

Estradiol-induced changes in progesterone secretion by rabbit corpora lutea are associated with quantitative ultrastructural changes in luteal cells.

In this study, we examined changes in luteal cell structure that accompany estradiol-altered progesterone production by the rabbit corpus luteum. To stimulate progesterone production, polydimethylsiloxane (Silastic) capsules containing 17 beta-estradiol were inserted sc into superovulated New Zealand White rabbits. Luteal progesterone production, assessed by measurement of progesterone in peripheral serum, was high after the estradiol-filled capsules were inserted, declined within 24 h after the capsules were removed, and increased within 32 h after reinsertion of the capsules. Stereological analyses at the light microscopic level revealed that the number of luteal cells and the volume of an average luteal cell did not differ significantly between estradiol-stimulated and estradiol-deprived rabbits over the time period employed. In contrast, stereological analyses at the electron microscopic level demonstrated that the surface areas of smooth endoplasmic reticulum and inner mitochondrial membrane declined with estradiol deprivation, but were restored by reimposition of estradiol stimulation. These changes in the surface area per cell of smooth endoplasmic reticulum and inner mitochondrial membrane were strongly correlated (r = 0.94 and r = 0.88, respectively) with changes in progesterone concentrations in peripheral serum. Changes in the surface area of lipid droplets per luteal cell also occurred, but were inversely correlated (r = -0.87) with progesterone levels. No significant changes were seen in the surface areas per cell of outer mitochondrial membrane or rough endoplasmic reticulum. These results demonstrate that estradiol stimulation and deprivation cause reversible quantitative changes in the rabbit luteal cell organelles known to be directly involved in progesterone biosynthesis. This leads to the conclusion that the steroidogenic activity of the luteal cell is tightly coupled to its subcellular structure.

Animals↗
PubMed1985

Estradiol acts as a competitive inhibitor of the 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase enzyme of cultured Leydig tumor cells.

To study the local regulatory mechanisms involving steroid hormones in steroidogenic cells, the effect of estradiol on steroidogenesis was investigated using MA-10 Leydig tumor cells. Estradiol inhibited progesterone biosynthesis in MA-10 cells in a dose-dependent manner. Inhibition of progesterone biosynthesis by estradiol was associated with a concomitant accumulation of pregnenolone in the incubation medium. Estradiol inhibited the activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase by a chemical mechanism which is not mediated through the cellular estrogen receptor. Thus, the estrogen receptor agonist diethylstilbestrol did not inhibit this enzyme activity, nor could this agent block the effect of estradiol on the enzyme. Furthermore, estradiol inhibited enzyme activity in isolated microsomes which do not contain estradiol receptor protein. Kinetic analysis of the inhibitory effect of estradiol on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase revealed that this steroid hormone functions as a competitive inhibitor of the enzyme, with an average apparent Ki of 1.8 microM.

3-Hydroxysteroid Dehydrogenases↗
PubMed1986

Estradiol secretion by granulosa cells from rats with four- or five-day estrous cycles: the development of responses to follicle-stimulating hormone versus luteinizing hormone.

The relative importance of LH vs. FSH in stimulating estradiol secretion by granulosa cells during follicular development was assessed in Sprague-Dawley rats with regular 4- or 5-day estrous cycles. At various times during diestrus (D-1200 h, D-2000 h) and proestrus (P-0800 h, P-1400 h, P-2000 h) granulosa cells were isolated from the presumptive preovulatory follicles. The cells were cultured with 0.5 microM testosterone and various doses of LH or FSH (0, 0.1, 1, 10, or 100 ng/ml). Media were collected and replaced daily for 3 days and measured for estradiol by RIA. Estradiol secretion in the absence of gonadotropins (endogenous aromatase activity) increased progressively with stage of the cycle. At earlier times of cell isolation (D-1200, D-2000, P-0800) secretion by cells from 5-day rats was greater relative to 4-day rats. Since estradiol production in the absence of gonadotropins declined progressively over each 3-day culture period, effects of the gonadotropins were most evident on the third day of culture when endogenous aromatase activity was low. On this day FSH consistently increased estradiol secretion above control levels. Sensitivity to FSH, as measured by the 50% maximally effective dose (ED50; approximately 1-3 ng FSH/ml), did not vary with cycle type or stage of the cycle and the response to FSH, in terms of 50% maximal estradiol secretion, was also relatively constant. In contrast, the effects of LH varied with cycle type and time of cell isolation. As follicles developed, cells from both 4- and 5-day rats became more sensitive to LH, as evidenced by a decline in the ED50 from approximately 32 ng LH/ml to approximately 3 ng/ml. This increase in sensitivity to LH is consistent with previous reports that the number of LH receptors on granulosa cells increases progressively during the final stages of follicular development. However, the increase in sensitivity to LH occurred earlier in cells from 5-day rats, relative to the expected next estrus (later, relative to the preceding estrus). Responsiveness to LH (50% maximal estradiol production) was relatively constant, except that it was lower in cells from 4-day rats isolated at D-1200. These results indicate that the LH receptors acquired by granulosa cells during diestrus and proestrus are functionally linked with aromatase activity and may, therefore, be important to the production of estradiol levels sufficient to elicit the LH surge.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Estrogen regulation of prolactin gene transcription in vivo: paradoxical effects of 17 beta-estradiol dose.

We investigated in male rats the effects of a range of doses of 17 beta-estradiol on PRL gene transcription, the level of circulating estradiol, and the levels of nuclear and cytosolic forms of the anterior pituitary estrogen receptor. One hour after 17 beta-estradiol injection, transcription of the PRL gene was significantly stimulated by 0.1 micrograms and maximally stimulated by 1.0 microgram/animal. Lesser stimulatory effects were observed 1 h after injection of 10 or 100 micrograms. At this 1 h point, the level of circulating estradiol was linearly increased relative to the 17 beta-estradiol dose. The level of nuclear form estrogen receptor was increased from 8% of the total receptor content in control rats to 12%, 28%, 50%, and 64% of the total receptor content in rats that received 0.1, 1.0, 10.0, and 100 micrograms, respectively. The anterior pituitaries of rats injected with 100 micrograms 17 beta-estradiol contained 30% fewer measurable estrogen receptors than control rats. Thus, dose-dependent losses of transcriptional responsiveness and measurable estrogen receptor were observed 1 h after injection of the larger doses of 17 beta-estradiol. Twenty-four hours after injection of the various doses of 17 beta-estradiol, PRL gene transcription was stimulated 1.3-fold in response to 0.1 microgram and approximately 2-fold in response to 1.0, 10, and 100 micrograms. At the 24 h point the circulating level of this hormone and the levels of nuclear and cytosolic forms of the estrogen receptor had returned to near their control values. This differing dose responsiveness at 1 and 24 h supports our previously reported observation that estrogen regulates PRL gene transcription in vivo through at least two independent mechanisms.

Animals↗
PubMed1990

The pattern of ovarian inhibin, estradiol, and androstenedione secretion during the estrous cycle of the ewe.

An experiment was conducted in order to determine the pattern of, and the relationships between, the secretion of inhibin, estradiol, and androstenedione by the ovary and the concentration of LH, FSH, and PRL during the estrous cycle of sheep. The estrous cycles of 6 Finn-Merino ewes in which the left ovary had been autotransplanted to the neck were synchronized by two injections of cloprostenol (100 micrograms im) a potent analog of prostaglandin F2 alpha (PG) given 14 days apart. The ewes had ovarian and jugular venous blood samples taken at four hourly intervals from 42 h before the second PG injection until day 6 of the following cycle. All animals responded to PG with the preovulatory LH surge occurring within 58 +/- 2 h (mean +/- SEM). The concentration of FSH in jugular venous plasma fell (P less than 0.001) after the induction of luteolysis and then exhibited 3 peaks, the first coincident with the LH surge, the second on day 1, and the third on day 6. After injection of PG the secretion rates of inhibin, estradiol, and androstenedione increased (P less than 0.05) within 4-8 h. After this increase in the early follicular phase the secretion rate of estradiol continued to rise until the time of the LH surge (P less than 0.001). Although the secretion of androstenedione and inhibin increased in the 36 h before the LH surge the magnitude of this rise was less marked than for estradiol and was not statistically significant. Within 4-8 h of the start of the LH surge the secretion of estradiol and androstenedione declined rapidly reaching barely detectable levels within 16 h (P less than 0.001). In contrast the secretion of inhibin increased after the LH surge reaching a broad peak (P less than 0.05) of approximately 16-h duration, coincident with the second peak of FSH. From days 2-6 mean secretion of inhibin remained relatively stable at 2-6 ng/min although considerable variation was observed in individual profiles. The rate of estradiol secretion increased steadily from its nadir on day 1 to a broad peak centered around day 3 (3-6 ng/min, P less than 0.001) followed by a decline until by day 6 the estradiol secretion rate was less than 1 ng/min (P less than 0.01). The secretory profile for PRL showed a close relationship with estradiol secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstenedione↗
PubMed1975

Content of nuclear estradiol receptor complex in rat corpora lutea during pregnancy: relationship to estrogen concentrations and cytosol receptor availability.

The content of estradiol receptor in cytosol and nuclear cell fractions of rat corpora lutea changed during pregnancy. The binding of (3-H)) estradiol to luteal cell cytosol was high early in pregnancy between days 3-11, decreased on days 12and15 and was low throughout of the remainder of pregnancy. In contrast, the binding of (3-H) estradiol to nuclear receptor, as measured by nuclear exchange assay, was low early in pregnancy, increased between days 10-15, remained high through day 18 and decreased on days 20 and 22. The administration in vivo of estradiol-17beta (40 mug) 1 hr prior to sacrifice stimulated an increase in nuclear receptor content early in pregnancy (days 3,6,8,10-12) but not later in pregnancy (15,18,20, and 22,). These results suggested that the estradiol binding component(s) present in rat luteal cell cytosol early in pregnancy represented available estradiol receptor capable of being translocated to the nucleus in the presence of sufficient estradiol. However, once available receptor has been saturated by endogenous hormone at midgestation, exogenous hormones hasno further effect on no nuclear receptor content. Importantly,loss of nuclear receptor content late in pregnancy appears to reflect decreased levels of total cellular receptor indicating that corpora lutea at the end of pregnancy have lost the primary mecchanism for responding to estrogens Thus, various stages of luteal cell differentiation are associated with changes in the intra-cellular distribution and total cellular content of estradiol receptor suggesting that luteal cell function may be regulated selectively and separately by hormone concentrations and hormone receptor availability.

Animals↗
PubMed1992

Progesterone blocks the estradiol-induced gonadotropin discharge in the ewe by inhibiting the surge of gonadotropin-releasing hormone.

Previous studies indicate an elevation of circulating progesterone blocks the positive feedback effect of a rise in circulating estradiol. This explains the absence of gonadotropin surges in the luteal phase of the menstrual or estrous cycle despite occasional rises in circulating estradiol to a concentration sufficient for surge induction. Recent studies demonstrate estradiol initiates the LH surge in sheep by inducing a large surge of GnRH secretion, measurable in the hypophyseal portal vasculature. We tested the hypothesis that progesterone blocks the estradiol-induced surge of LH and FSH in sheep by preventing this GnRH surge. Adult Suffolk ewes were ovariectomized, treated with Silastic implants to produce and maintain midluteal phase concentrations of circulating estradiol and progesterone, and an apparatus was surgically installed for sampling of pituitary portal blood. One week later the ewes were allocated to two groups: a surge-induction group (n = 5) in which the progesterone implants were removed to simulate luteolysis, and a surge-block group (n = 5) subjected to a sham implant removal such that the elevation in progesterone was maintained. Sixteen hours after progesterone-implant removal (or sham removal), all animals were treated with additional estradiol implants to produce a rise in circulating estradiol as seen in the follicular phase of the estrous cycle. Hourly samples of pituitary portal and jugular blood were obtained for 24 h, spanning the time of the expected hormone surges, after which an iv bolus of GnRH was injected to test for pituitary responsiveness to the releasing hormone. All animals in the surge-induction group exhibited vigorous surges of GnRH, LH, and FSH, but failed to show a rise in gonadotropin secretion in response to the GnRH challenge given within hours of termination of the gonadotropin surges. The surges of GnRH, LH, and FSH were blocked in all animals in which elevated levels of progesterone were maintained. These animals in the surge-block group, however, did secrete LH in response to the GnRH challenge. We conclude progesterone blocks the estradiol-induced gonadotropin discharge in the ewe by acting centrally to inhibit the surge of GnRH secreted into the hypophyseal portal vasculature.

Animals↗
PubMed1992

Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus.

Ovarian steroids modulate learning, memory, and epileptic seizure activity, functions that are mediated in part by the hippocampus. Normal function depends on precise interactions between the inhibitory gamma-aminobutyric acid (GABA)ergic and excitatory glutamatergic neurons of the hippocampus. To determine whether estradiol and progesterone interact with GABAergic neurons, the levels of mRNA for glutamic acid decarboxylase (GAD), the rate-limiting enzyme for GABA synthesis, were measured by in situ hybridization histochemistry with 35S-labeled riboprobes complimentary to the feline GAD cDNA. The levels of mRNA for GAD were analyzed in selected region of the dorsal hippocampus and medial basal hypothalamus in ovariectomized, ovariectomized estradiol-treated, and ovariectomized estradiol- and progesterone-treated rats. In estradiol-treated rats, GAD mRNA levels increased in GABAergic neurons associated with the CA1 pyramidal cell layer, but not in the stratum oriens of CA1 or any other region of the hippocampus. Estradiol plus progesterone treatment reversed the estradiol-induced increase in GAD mRNA in CA1 and induced a small decrease in the hilus. No effect of estradiol or progesterone was observed in the dorsomedial, ventromedial, or arcuate nuclei of the hypothalamus. Estradiol or progesterone may alter cognitive performance and seizure activity by increasing or decreasing, respectively, the activity of GABAergic neurons in the hippocampus.

Animals↗
PubMed2000

Antigen-presenting cells in the female reproductive tract: influence of estradiol on antigen presentation by vaginal cells.

The objective of the present study was to define the afferent arm of the mucosal immune system in the lower female reproductive tract. We report here that antigen presentation by vaginal cells is under hormonal control. When vaginal cells from ovariectomized rats treated with estradiol (0.01-10 microg) were incubated with ovalbumin-specific T cells and ovalbumin, a dose-dependent inhibition of antigen presentation was measured. In time course studies, estradiol given to ovariectomized rats inhibited vaginal cell antigen presentation within 24 h after a single injection, relative to that seen in saline controls. To determine whether changes in antigen presentation were attributable to the effect of estradiol on the number of antigen-presenting cells (APCs) in the vagina, tissues were analyzed by immunohistochemistry. Our findings indicate that estradiol inhibited antigen presentation without affecting the number of major histocompatibility complex class II positive cells and at a time when macrophage/dendritic cells/granulocytes in the vagina increase in response to estradiol treatment. Antibody neutralization studies indicated that antigen presentation by vaginal cells from ovariectomized rats is mediated through class II and involves the expression of transmembrane proteins B7.1 and B7.2. In other studies, vaginal APCs interact with thymus APCs to synergistically enhance antigen presentation under conditions in which vaginal antigen presentation is inhibited by estradiol. Analysis of conditioned media indicates that enhancement of thymus antigen presentation involves the release of a soluble factor(s) into the culture media of vaginal cells. When spleen cells were cocultured with vaginal cells from saline-treated rats, proliferation increased in the presence of concanavalin A and/or phytohemagglutinin and decreased with lipopolysaccharide, relative to spleen cells and mitogen alone. In contrast, when incubated with vaginal cells from estradiol-treated rats, spleen cell proliferation was not affected with concanavalin but was inhibited with phytohemagglutinin and lipopolysaccharide. These studies demonstrate that estradiol regulates antigen presentation by vaginal cells and that vaginal cells, in turn, influence antigen presentation, as well as B and T cell proliferation.

Animals↗
PubMed2002

Estradiol-sensitive afferents modulate long-term episodic firing patterns of GnRH neurons.

GnRH neurons comprise the final common pathway of an estrogen-sensitive pattern generator controlling fertility. To determine estradiol effects on GnRH neuron firing patterns, adult transgenic mice were ovariectomized (OVX), and half were treated with estradiol (OVX+E). One week later targeted single-unit extracellular recordings were made from GnRH neurons identified by green fluorescent protein expression. Estradiol markedly affected GnRH neuron firing patterns, increasing the percentage and duration of time these cells were quiescent (< or = 1 action current/min). Estradiol increased the interval between episodes of increased firing rate determined by Cluster analysis of recordings more than 45 min (OVX+E 38.8 +/- 7.2 min, OVX 16.7 +/- 2.1 min, n = 6 each). Possible mechanisms of estradiol modulation were examined by simultaneously blocking ionotropic secretion of gamma-aminobutyric acid and glutamatergic receptors. This treatment had no effect on cells from OVX mice (n = 10), indicating episodic firing of GnRH neurons is not driven by activation of these receptors. Receptor blockade eliminated estradiol effects on GnRH neurons in the midventral preoptic area (n = 7) but not elsewhere (n = 7). Individual GnRH neurons thus display episodic firing patterns at intervals previously reported for secretory pulses. Estradiol modulates episode frequency to exert feedback control; in a substantial subset of GnRH neurons, estradiol feedback is enforced via GABAergic and/or glutamatergic afferents.

Animals↗
PubMed2004

Differential regulation of estrogen receptor subtypes alpha and beta in human aortic smooth muscle cells by oligonucleotides and estradiol.

We investigated the mechanisms regulating estrogen receptor (ER) expression in human aortic smooth muscle cells (HASMCs) and the mechanisms by which estradiol inhibits HASMC growth. The autologous down-regulation pathway involves binding of liganded ER to the ER gene, thus suppressing transcription. Blockade of this pathway with sense and AS-OLIGOs to ERs up-regulated the expression of ERalpha but not ERbeta. Activation of the autologous down-regulation pathway with ER agonists down-regulated the expression of ERalpha but not ERbeta. The proteasomal degradation pathway entails ubiquination of liganded ER, followed by proteasome-mediated degradation. Blockade of the proteasomal degradation pathway increased the expression of ERbeta. Up-regulation of ERalpha by AS-OLIGOs did not increase the antimitogenic effects of estradiol on HASMCs; the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol were more potent inhibitors of HASMC growth, compared with estradiol; and blockade of metabolism of estradiol to hydroxyestradiols and methoxyestradiols abrogated the inhibitory effects of estradiol on HASMC growth. We conclude that, in HASMCs: 1) the expression of ERalpha is regulated by the autologous downregulation pathway; 2) the expression of ERbeta is governed by the proteasomal degradation pathway; and 3) the antigrowth effects of estradiol are not mediated by ERalpha, but rather by metabolism of estradiol to methoxyestradiols.

Aorta↗