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PubMed1995

Mechanoinhibitory effect of estradiol in guinea pig urinary bladder smooth muscles.

The mechanoinhibitory effect of estradiol on the myogenic activity of guinea pig urinary bladder detrusor muscles was studied. In detrusor muscles tonically contracted with 80 mmol/lKCl, 17 beta-estradiol and the nonestrogenic isomer 17 alpha-estradiol at 30 mumol/l reduced the contraction by 64 +/- 3 and 59 +/- 1%, respectively. In detrusor muscles maintained in Ca(2+)-free media and depolarized with 80 mmol/lKCl, the contractile response of muscles to the reintroduction of Ca2+ was inhibited in a dose-dependent manner by 17 beta-estradiol, suggesting that 17 beta-estradiol blocked entry of extracellular Ca2+ into bladder smooth muscle cells and reduced the rise of intracellular Ca2+ required for contraction. In detrusor muscles mildly depolarized with 15 mmol/lKCl, 17 beta-estradiol reduced the myogenic activity with an IC50 of 6.8 +/- 1.3 mumol/l. The higher activity of 17 beta-estradiol in this latter test indicated that estradiol could also possess some K+ channel opening activity. Glibenclamide at 1 mumol/l did not affect the relaxant activity of 17 beta-estradiol in detrusor muscles stimulated with 15 mmol/l; however, this activity was diminished in a dose-dependent manner by iberiotoxin. Collectively, these results have demonstrated that in addition to the Ca2+ antagonist activity, 17 beta-estradiol possesses K+ channel opening activity in guinea pig urinary bladder smooth muscles, activating probably not the adenosine triphosphate sensitive, but the Ca(2+)-dependent large-conductance K+ channels.

Adenosine Triphosphate↗
PubMed2000

17beta-estradiol decreases endothelin-1 levels in the coronary circulation of postmenopausal women with coronary artery disease.

BACKGROUND: Estrogen reverses acetylcholine-induced coronary vasoconstriction via the possible facilitation of endothelium-derived NO. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the effects of 17beta-estradiol on coronary vasomotor responses to substance P (SP), and coronary sinus endothelin-1 and NO metabolite levels in postmenopausal women with coronary heart disease. METHODS AND RESULTS: We studied 20 women; 14 received estrogen (mean age 65+/-2 years) and 6 served as ethanol control subjects (age 63+/-3 years). Intracoronary infusions of papaverine (8 mg) and SP were administered before and 20 minutes after 50 pg/min 17beta-estradiol or 0.2 microL/min control. Coronary blood flow was calculated from the diameter, as measured with quantitative coronary angiography, and flow velocity, as measured with intracoronary Doppler. Coronary sinus plasma endothelin-1 and nitrite/nitrate (NO(2)/NO(3)) were measured at baseline, at peak velocity response to each infusion, and every 5 minutes during the estradiol infusion. Endothelin-1 levels were decreased after 20 minutes of estradiol (1.12+/-0.18 versus 0.86+/-0.17 pmol/L baseline2 versus estradiol, P:=0.05). Endothelin-1 levels to SP decreased after 17beta-estradiol (1.29+/-0. 18 versus 1.04+/-0.15 and 1.3+/-0.16 versus 0.99+/-0.17 pmol/L for before versus after estradiol, 10 and 25 pmol/min SP; both P:<0.05). NO(2)/NO(3) levels did not change. There was no change in vasomotor responses to estradiol alone or to papaverine or SP before versus after estradiol. CONCLUSIONS: Short-term intracoronary 17beta-estradiol administration decreases coronary endothelin-1 levels. There was no enhancement of vasomotor responses to SP after the administration of estrogen, suggesting that the effects of estrogen on coronary acetylcholine responses may be a specific and not a generalized effect on coronary vasoreactivity.

Arteries↗
PubMed2000

Estradiol inhibits smooth muscle cell growth in part by activating the cAMP-adenosine pathway.

Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved remain unclear. Because estradiol stimulates cAMP synthesis and adenosine inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of estradiol on vascular smooth muscle cell growth. To test this hypothesis, we examined the effects of estradiol (0.001 to 1 micromol/L) on serum-induced DNA, collagen, and total protein synthesis and cell number in the absence and presence of 1, 3-dipropyl-8-p-sulfophenylxanthine (10 nmol/L; A(1)/A(2) adenosine receptor antagonist), KF17837 (10 nmol/L; selective A(2) adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A(1) adenosine receptor antagonist), and 2', 5'-dideoxyadenosine (10 micromol/L; adenylyl cyclase inhibitor). Estradiol inhibited all measures of cell growth, and the concentration-dependent inhibitory curves for estradiol were shifted to the right (P<0.05) by 1,3-dipropyl-8-p-sulfophenylxanthine, KF17837, and 2',5'-dideoxyadenosine but not by 8-cyclopentyl-1, 3-dipropylxanthine. Moreover, the inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase with forskolin and by inhibition of adenosine metabolism with erythro-9-(2-hydroxy-3-nonyl)adenine plus iodotubericidin (adenosine deaminase and kinase inhibitors, respectively). Estradiol also increased levels of cAMP and adenosine, and these effects were blocked by 2',5'-dideoxyadenosine (P<0.05). Our results support the hypothesis that estradiol stimulates cAMP synthesis and cAMP-derived adenosine regulates smooth muscle cell growth via A(2) adenosine receptors. Thus, the cAMP-adenosine pathway may contribute importantly to the antivasooclusive effects of estradiol.

Adenosine↗
PubMed2005

Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase.

BACKGROUND: Estradiol activates endothelial nitric oxide synthase (eNOS) by mechanisms that involve estrogen receptor-alpha (ERalpha), protein kinase B/Akt, mitogen-activated protein kinases, and heat shock protein 90 (HSP90). Recently, AMP-activated protein kinase (AMPK), an enzyme that plays a crucial role in cellular adaptation to metabolic stress, has been implicated in physiological eNOS activation by the hormones adiponectin and insulin. We therefore investigated whether AMPK is activated by estradiol in endothelial cells and plays a role in estradiol-induced eNOS activation. METHODS AND RESULTS: Porcine aortic endothelial cells exhibited time- and concentration-dependent AMPK activation as determined by phosphorylation of AMPK and its downstream target acetyl coenzyme A carboxylase in response to estradiol (1 nmol/L to 10 micromol/L, 1 to 30 minutes). AMPK activation by estradiol was independent of both AMP levels and ERalpha but required estradiol conversion to its catechol metabolites. Estradiol treatment increased eNOS catalytic activity, an effect that was largely reversed when endothelial cells were infected with an AMPK dominant-negative adenovirus. However, inhibition of AMPK did not alter estradiol-induced eNOS phosphorylation at serine 1177 or threonine 495 but decreased eNOS interaction with HSP90. Consistent with this observation, blood vessels from alpha1-AMPK-null mice exhibited defective eNOS-mediated NO production in response to estradiol. CONCLUSIONS: Taken together, these data indicate that AMPK activity is essential for estradiol-induced eNOS activation via the promotion of eNOS interaction with HSP90. These data point to a novel role for AMPK in modulating endothelial cell NO bioactivity and HSP90 function.

Adenylate Kinase↗
PubMed1975

Metabolism of estradiol in greyhounds and German shepherd dogs. An investigation with special reference to hip dysplasia.

Metabolism of estradiol was investigated in 5 dogs, 3 female Greyhounds with radiographically perfect hip joints and 2 female German Shepherd dogs with hip dysplasia (one pregnant and the other non-pregnant). One of the Greyhounds was studied both when pregnant and non-pregnant. The non-pregnant dogs were injected with C14-labelled estradiol-17beta i.v. and 5 mg estradiol-17beta benzoate i.m. The pregnant dogs were given only radiolabelled estradiol-17beta. Twenty-four-hour-specimens of urine were collected from the dogs for 6--8 days. Determination of urinary estrone, estradiol-17beta, and estriol was made. It was found that most of the injected estradiol was excreted unmetabolized in all dogs. A significant amount of the injected estradiol was converted to estrone and a small amount to estriol. There was no significant difference in the excretion patterns of estrone, estradiol, and estriol between the Greyhounds with perfect hip joints and the German Shepherds with hip dysplasia, regardless whether the dogs were pregnant or not. The conclusion was drawn that the capacity of dogs with hip dysplasia to metabolize estradiol and to eliminate estradiol and metabolites is not impaired.

Animals↗
PubMed1983

Longitudinal relationships among endogenous testosterone, estradiol, and Quetelet index with high and low density lipoprotein cholesterols in adolescent boys.

In a 1-year longitudinal study of 19 adolescent boys, our major aim was to assess whether, and to what degree, testosterone, estradiol, Quetelet index, and their interactions related to concentrations of high and low density lipoprotein cholesterol (HDLC, LDLC). During the 1-year followup, mean HDLC and estradiol levels fell and triglycerides, LDLC, Quetelet index, and testosterone levels rose. For large decreases in estradiol, increases in testosterone were associated with decreases in HDLC. These decreases in HDLC were moderated by small decreases in Quetelet index. For boys with small decreases in estradiol, as the changes in testosterone increased, the change in HDLC varied from an increase to a decrease, except in those boys who also had a small decrease in Quetelet index, for whom the change in HDLC was positive. The greatest increases in LDLC were observed in boys having the largest increase in Quetelet index and a small decrease in estradiol; however, as the decrease in estradiol became large, the positive association of Quetelet with LDLC was moderated or nullified. For boys having large decreases in estradiol, the LDLC/HDLC ratio changed from small increments to substantial decrements as testosterone increased. As the decreases in estradiol became smaller, increases in the change of testosterone moderated the decreases in the LDLC/HDLC ratio, and large increases in Quetelet index tended to diminish this moderation. As the change in testosterone increased, the change in triglyceride increased, unless the decrease in estradiol was small. The overall pattern of change of HDLC and LDLC during sexual maturation in boys can be associated with changes in testosterone, estradiol, and Quetelet index.

Adipose Tissue↗
PubMed2003

Folliculostellate cells determine the susceptibility of lactotropes to estradiol's mitogenic action.

Estradiol is known to increase lactotropic cell proliferation, but estradiol susceptibility varies among human populations and among various strains of rats. We had reported that folliculostellate (FS) cells regulate estradiol's mitogenic action on lactotropes; therefore, we studied their role in determining the susceptibility to estradiol in a high estradiol-responsive rat strain, Fischer 344 (F344), and in a low-responsive strain, Sprague Dawley (SD). Determination of total S-100-positive FS cells in the pituitary revealed that F344 rats have significantly more FS cells than do SD rats. Estradiol treatment did not change the number of FS cells in both F344 and SD rats. When cotransplanted with F344 pituitaries under the kidney capsule or cocultured with F344-derived lactotropes in vitro, FS cells derived from F344 rats increased estradiol's mitogenic action. They also increased estradiol's mitogenic action on SD-derived lactotropes in primary cultures. However, SD-derived FS cells failed to increase estrogen's action on F344- or SD-derived lactotropes. The levels of basic fibroblast growth factor production and secretion by TGF-beta 3 and estradiol were much higher in F344-derived FS cells than in SD-derived FS cells. However, the lactotropes' growth response to basic fibroblast growth factor was similar in both strains. These data suggest that cell-cell interaction between FS cells and lactotropes regulates estradiol's mitogenic action on lactotropes and also determines lactotrope susceptibility to the steroid.

Animals↗
PubMed2003

Involvement of protein kinase C-dependent mitogen-activated protein kinase p44/42 signaling pathway for cross-talk between estradiol and transforming growth factor-beta3 in increasing basic fibroblast growth factor in folliculostellate cells.

We have recently shown that TGF-beta3, in the presence of estradiol, increases the release of basic fibroblast growth factor (bFGF) from folliculostellate (FS) cells in the pituitary. We determined the interactive effects of TGF-beta3 and estradiol on bFGF production and release from FS cells, and the role of the MAPK pathway in TGF-beta3 and estradiol interaction. We found that TGF-beta3 and estradiol alone moderately increased cell content and release of bFGF from FS cells; but together, they markedly increased the peptide. Estradiol and TGF-beta3 alone moderately activated MAPK p44/42; together they produced marked activation of MAPK p44/42. Pretreatment of FS cells with an MAPK kinase 1/2 inhibitor or with protein kinase C inhibitors suppressed the activation of MAPK p44/42, bFGF release, and protein level increases, all of which were induced by TGF-beta3 and estradiol. Estradiol and TGF-beta3, either alone or in combination, increased the levels of active Ras. Furthermore, bFGF induction by TGF-beta3 and estradiol was blocked by overexpression of Ras N17, a dominant negative mutant of Ras p21. Estrogen receptor blocker ICI 182,780 failed to prevent estrogen's and TGF-beta3's effects on bFGF. These data suggest that an estradiol receptor-independent protein kinase C- activated Ras-dependent MAPK pathway is involved in the cross-talk between TGF-beta3 and estradiol to increase bFGF production and/or release from FS cells.

Animals↗
PubMed2003

Prostaglandin mediates premature delivery in pregnant sheep induced by estradiol at 121 days of gestational age.

The experiments reported here were designed for both in vivo and in vitro approaches in the same animals to obtain a better picture of the role of estrogen in the control of parturition. Chronically catheterized pregnant ewes were treated with vehicle (n = 5) or estradiol (n = 6), 5 mg twice a day, im for 2 d starting at d 119 of gestation. Maternal and fetal plasma estradiol, progesterone, and cortisol were measured by RIA and maternal plasma prostaglandin (PG) F2alpha was measured by enzyme immunoassay. Intrauterine PG H synthase 2 mRNA and protein and placental P450(c17)alpha hydroxylase mRNA were determined by Northern, in situ hybridization, Western blot analysis, and immunocytochemistry. Data were analyzed by ANOVA. Five of six estradiol-treated ewes delivered their fetuses within 48 h; however, the placenta was still retained 5-6 h after fetal delivery. Both maternal plasma estradiol and PGF2 alpha increased significantly in the estradiol-treated group. Maternal and fetal plasma progesterone and cortisol were not altered in either group. There were significant increases of PGH synthase 2 mRNA and protein in myometrium, endometrium, and maternal placenta but not in fetal placenta in estradiol-treated ewes. Placental P450(c17)alpha hydroxylase mRNA was not detectable in vehicle or estradiol-treated groups. Estradiol can, in the absence of increase in plasma cortisol, stimulate uterine PG production and induce labor, resulting in fetal delivery in the sheep. Failure of placental delivery after estradiol treatment suggests that estradiol alone is insufficient to stimulate some of the key changes required to complete delivery at the stage of gestation studied.

Animals↗
PubMed1981

Insulin and 17 beta-estradiol increase the intracellular prolactin content of GH4C1 cells.

We investigated the effects of insulin and 17 beta-estradiol in PRL-producing rat pituitary tumor cells (GH cells) in culture. Incubation with 1.8 X 10(-7) M insulin and 1 X 10(-9) M estradiol always increased intracellular PRL significantly to a mean of 290% of control levels. Insulin or estradiol alone caused smaller increases in intracellular PRL that were significant in five out of six experiments with insulin and three out of five experiments with estradiol, producing average increases of 150% and 160% of controls, respectively. Combined treatment with insulin and estradiol increased PRL secreted into the medium to 160% of controls, which was smaller than the effect on intracellular PRL. The effects of insulin and estradiol were detectable after 2-4 days of treatment and were maximal between 6-8 days. The effects were dose dependent; the half-maximal dose of insulin was about 2 X 10(-8) M and of estradiol was about 5 X 10(-11) M. Treatment with both insulin and estradiol increased cellular uptake of [3H]leucine by 45% compared to controls, incorporation of [3H]leucine into PRL by 65%, and total protein by 50%. The increased incorporation into PRL may represent an increase in PRL synthesis, but it is not enough to account for the increased intracellular hormone. Insulin and estradiol did not change the time required for most newly synthesized PRL to be processed and released from the cells, which was 60 min. Therefore, the amount of intracellular PRL was not increased as a result of an increased intracellular transit time. We conclude that insulin and estradiol increase the amount of intracellular PRL as a result of either decreasing the rate of degradation or increasing the cells' capacity to store PRL.

Animals↗
PubMed1981

The maturation of estradiol-negative feedback in female rats: evidence that the resetting of the hypothalamic "gonadostat" does not precede the first preovulatory surge of gonadotropins.

Several experiments were performed to study the changes in the negative feedback of estradiol on gonadotropin secretion around the time of puberty in the female rat. Ovariectomy of juvenile, first diestrus, or adult animals elevated FSH and LH levels 2 and/or 4 days later. Estradiol administered via Silastic capsules, at several dose levels, was much more effective in preventing the postcastration rise of gonadotropins in juvenile than in the older animals. A dose of estradiol that inhibited gonadotropin levels in juvenile rats, but not in adult animals, maintained preovariectomy serum estradiol levels more efficiently in the adult rats. Therefore, a more rapid removal of estradiol from the blood stream cannot explain its lower effectiveness in suppressing gonadotropin release in adult rats. Estradiol-negative feedback effectiveness remained maximal until the day of first proestrus and decreased markedly on the next day (first estrus), remaining low thereafter. "Resetting" of the gonadostat to estradiol negative feedback was advanced by inducing precocious puberty by means of hyperprolactinemia, but not by mimicking the periovulatory changes in serum estradiol and progesterone in the absence of an LH surge. Serum progesterone levels were much higher in postpubertal rats than in juvenile animals. Ovariectomy of juvenile rats slightly decreased the already low levels of serum progesterone, but it produced a striking progesterone decrease in postpubertal animals. Quantitative replacement of preovariectomy serum progesterone levels in adult rats, treated with an ineffective dose of estradiol, almost completely restored the prepubertal effectiveness of estradiol in inhibiting LH release and, to a lesser extent, release of FSH...

Animals↗
PubMed1983

A role for estradiol in enhancing luteinizing hormone pulse frequency during the follicular phase of the estrous cycle of sheep.

Experiments were conducted to test the hypothesis that the increased frequency of LH pulses during the follicular phase of the sheep estrous cycle can be explained by the withdrawal of progesterone. This steroid imposes a profound inhibition of LH pulse frequency in the luteal phase. Experimental ewes were ovariectomized in the late luteal phase of the estrous cycle and divided into three groups: 1) no estradiol provided; 2) basal estradiol maintained at 1-2 pg/ml by small sc Silastic estradiol implants; and 3) peak estradiol of 5-6 pg/ml provided by larger estradiol implants. Control ewes had intact ovaries; their follicular phases were synchronized by insertion and subsequent removal of progesterone implants. LH pulses were monitored beginning 24 h after ovariectomy of experimental ewes or progesterone implant removal from intact control ewes. In the follicular phase controls, LH pulse frequency increased 3- to 4-fold after progesterone withdrawal, reaching up to two pulses per h. When estradiol was not provided after ovariectomy of experimental ewes, LH pulse frequency also increased, but not to the extent seen in the follicular phase control. This high frequency was achieved, however, in experimental ewes treated with either basal or peak estradiol. Both estradiol treatments also reduced LH pulse amplitude. These results fail to support the hypothesis that the high frequency of LH pulses in the follicular phase is solely a consequence of progesterone withdrawal at luteolysis. Rather, they suggest that estradiol (but not necessarily rising estradiol) also contributes to the high frequency pulses of LH that occur in the ewe at this time.

Animals↗
PubMed1985

Bipotential actions of estrogen on progesterone biosynthesis by ovarian cells. I. Relation of estradiol's inhibitory actions to cholesterol and progestin metabolism in cultured swine granulosa cells.

In short term, serum-free cultures of granulosa cells, estradiol inhibited basal progesterone production by more than 84% in a time- and dose-dependent fashion. Half-maximal inhibition (ID50) was observed at a mean estradiol concentration of 70 ng/ml. The acute inhibitory effects of estradiol were independent of cell density or maturational status of the parent follicle (small, medium, or large follicles). Estrogen decreased total progesterone biosynthesis, rather than merely progesterone secretion by granulosa cells. In addition, the production of progesterone and its 20 alpha-reduced metabolite were suppressed in parallel over a 30-fold range of inhibitory effects. Moreover, estradiol inhibited progesterone production from both endogenous and exogenous (25-hydroxycholesterol) substrate. In contrast to its inhibition of progesterone production, estradiol acutely enhanced pregnenolone accumulation and led to a 14- to 20-fold increase in the ratio of pregnenolone to progesterone. Inhibition of 3 beta-hydroxysteroid dehydrogenase activity was confirmed by demonstrating estrogen's ability to antagonize the conversion of exogenously supplied pregnenolone to progesterone in intact granulosa cells (ID50, 74 ng/ml) and to directly inhibit enzymic activity in ovarian homogenates (ID50, 79 ng/ml). On the other hand, estradiol did not alter the incorporation of [14C]acetate into cholesterol and specific progestins or influence the time-dependent hydrolysis of prelabeled cholesteryl ester stores in granulosa cells. In summary, in short term cultures of swine granulosa cells, estradiol significantly inhibits basal progesterone biosynthesis in a time- and dose-dependent fashion, encompassing estradiol concentrations attainable in vivo. Estrogen's inhibition is accomplished by mechanisms that are independent of cytotoxicity, cell density, and maturational stage of the parent follicle. The predominant locus of estrogen action is blockade of pregnenolone's conversion to progesterone, rather than accelerated metabolism of progesterone to its 20 alpha-reduced metabolite. Moreover, estradiol simultaneously enhances functional cholesterol side-chain cleavage activity without suppressing de novo cholesterol biosynthesis or impairing the mobilization of cellular cholesteryl ester stores. Thus, we infer that increasing concentrations of estradiol attained in antral follicular fluid during the later stages of follicle maturation could effectively limit the premature secretion of large quantities of progesterone before ovulation without impairing the cell's capacity for de novo cholesterol biosynthesis or cholesteryl ester hydrolysis.

Animals↗
PubMed1986

Modulation of the estradiol-induced luteinizing hormone surge by progesterone or antiestrogens: effects on pituitary gonadotropin-releasing hormone receptors.

The present study examined the question of whether modulation of estradiol-induced LH surges by progesterone or antiestrogens in the immature rat might be related to changes in the concentration of pituitary GnRH receptors (GnRH-R). Rats (28 days old) that received estradiol implants at 0900 h had LH surges approximately 32 h later. Administration of progesterone or nafoxidine (U-11,100 A; 1-(2-[P-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]pyrrolidine hydrochloride) concomitantly with estradiol led to blockade of these LH surges (progesterone or nafoxidine inhibition), while progesterone treatment 24 h after estradiol brought about premature and enhanced LH release (progesterone facilitation). GnRH-R-binding capacity was determined by saturation analysis in homogenates of single pituitaries from immature rats treated with estradiol and progesterone or nafoxidine and controls treated only with estradiol using [125I]iodo-(D-Ala6,Des-Gly10)GnRh ethylamide. The affinity of GnRH-R for this analog ranged from 8.2-15.1 X 10(9) M-1 and was not affected by in vivo steroid or antiestrogen treatment. The number of GnRH-R in gonadotrophs from untreated 28-day-old rats (57.2 +/- 2.6 fmol/pituitary or 177 +/- 11 fmol/mg protein) was comparable to values previously reported for 30 day-old females. GnRH-R levels were first measured 1, 8, 24, 32, and 48 h after estradiol treatment. The pituitary content of GnRH-R paralleled changes in total pituitary protein (nadir at 24 h, rebound at 32 h, continued increase at 48 h), while their concentration (femtomoles per mg protein) was highest at 8 h. Next, GnRH-R levels were examined at 1200 h and at hourly intervals (1400-1800 h) on the afternoon of the LH surge. While GnRH-R concentrations were significantly lower at 1400 and 1700 h than at 1200 or 1800 h in animals treated with estradiol in the progesterone facilitation model, they did not change over time in the other two paradigms. There was no significant difference in pituitary content or concentration of GnRH-R at any time between immature rats treated with estradiol and progesterone or nafoxidine and their respective estradiol-treated controls. These results suggest that changes in GnRH-R levels in pituitary gonadotrophs do not play a major role in enhancement of LH surges by progesterone or in their suppression by progesterone or nafoxidine in the immature rat; therefore, these compounds may affect the pituitary at a site distal to the GnRH receptor.

Animals↗
PubMed1976

A cytoplasmic estradiol receptor in rat testicular tissue.

Testicular cytosol from Sprague-Dawley rats was shown to possess an estradiol binding component which exhibited the properties of a receptor. Specific binding of estradiol by the receptor was shown, at 4C in vitro, to reach equilibrium by 6 h. That level of binding was maintained at a plateau for 18 h. Estradiol binding was demonstrated to increase linearly as a function of testicular cytosol concentration ultilized. The Ka at equilibrium was determined as 4.07 .05 x 1010M-1, while the number of binding sites for whole testicular tissue from mature rats was 1.16 x 10-14 +/- 0.061 moles/mg cytosol protein. Sucrose gradient sedimentation analysis of the cytosol receptor revealed that the major peak of radioactivity migrated in the 8S region. Enzymatic treatment of the cytosol demonstrated that the binding component was protein in nature. Heat treatment, 70 C for 10 min, resulted in 83% loss of the receptor activity. Storage in liquid N2 (for as long as 60 days) was shown to maintain receptor activity. Steroid specificity studies revealed that other estrogens were competitive with 17beta-estradiol for binding sites, but progestins, testosterone, and dihydrotestosterone did not affect estradiol binding. Tissue specificity studies showed that the capacity of testicular cytosol to bind estradiol was much greater than that of several non-target organs. Ontogenically, the cytoplasmic estradiol-binding capacity/testis was low from 7 to 21 days of age, but rose dramatically between 3 and 7 weeks of age, and an apparent plateau was reached at 15 weeks. The injection of unlabeled 17beta-estradiolin vvio was shown to deplete the cytosol of estradiol binding sites as determined in vitro. Depletion was rapid, occurring within 30 min, and the cytoplasmic estradiol receptors remained low for a period of 4 h. At 6 h, replenishment has occurred and control levels of cytoplasmic receptors were restored by 12 h. These results suggest that an estradiol receptor is present in testicular tissue of the rat, and that binding capacity is maximum in the mature testis.

Animals↗
PubMed1976

The content of a specific cell product in the vaginal epithelium of normal and neonatally estrogenized mice: its dependence on an estradiol-prolactin interaction.

The amount of an immunological marker (CVA) in mucified cells of the mouse vaginal epithelium was quantified by a mixed hemagglutination technique for tissue sections. Immature mice, adult mice which had been estrogenized neonatally (5 mug diethylstilbestrol daily for the first five days after birth), and adult non-estrogenized mice were studied. All adult animals were castrated 7-10 days before starting the experiments. Injections of 5 mug estradiol-17beta (48 and 24 h before killing the animals) increased the amount of CVA in all three groups of animals, but most markedly in the neonatally estrogenized mice. The amount of CVA found following estradiol treatment was decreased in adult animals injected with the ergot alkaloid CB154 (0.5 mg twice daily for 6 days) in addition to the hormone. This partial block of the estradiol-induced CVA response by CB154 was relieved by exogenous rat prolactin. The CVA content in immature animals was not influenced by CB154, given alone or together with estradiol. Combined treatment with estradiol and rat prolactin (3 mug every 8 h for 6 days) increased more efficiently than estradiol alone the amount of CVA in immature and adult nonestrogenized animals. Prolactin injected alone had no effect on the CVA content. These data strongly suggest a synergistic action of estradiol and prolactin in augmenting the epithelial CVA content. Explants of the vaginal wall from normal and neonatally estrogenized mice were grafted into the thigh muscles of newborn mice, every host carrying one graft from both types of animals. The CVA content in the epithelium of the two grafts increased to the same level in response to estradiol. When the hosts were injected with estradiol and prolactin, the CVA content was higher in grafts from estrogenized donors than in those from nonestrogenized animals. Our results demonstrate that the mucified vaginal cells in adult, neonatally estrogenized mice have a content of CVA which is higher than in nonestrogenized animals. This difference may be ascribed to hormonal factors (estradiol-prolactin) as well as to persistent effects in the vaginal cells as a result of the neonatal estrogen treatment.

Age Factors↗
PubMed2004

Cytochromes 1A1/1B1- and catechol-O-methyltransferase-derived metabolites mediate estradiol-induced antimitogenesis in human cardiac fibroblast.

We investigated the role of specific cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT) in the growth inhibitory effects of estradiol in cardiac fibroblasts (CFs) expressing functional estrogen receptors. 3-Methylcholantherene, phenobarbital (broad-spectrum CYP450 inducers), and beta-naphthoflavone (CYP1A1/1A2 inducer) augmented, and 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor) blocked, the inhibitory effects of estradiol on serum-induced CF growth (DNA synthesis, cell number, and collagen synthesis). Neither ketoconazole (3A4 inhibitor) nor furafylline (selective 1A2 inhibitor) altered the antimitogenic effects of estradiol on CF growth. In contrast, ellipticine (selective 1A1 inhibitor), pyrene (selective 1B1 inhibitor), and alpha-naphthoflavone (1A1>1A2 inhibitor) abrogated the antimitogenic effects of estradiol on CF growth. OR486 (COMT inhibitor) also blocked the antimitogenic effects of estradiol in both the presence and absence of the CYP450 inducers. ICI182780 (estrogen receptor antagonist) attenuated the growth inhibitory effects of estradiol, but only at concentrations that inhibit the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). CFs expressed CYP1A1 and CYP1B1, isozymes that convert estradiol to hydroxyestradiols. Moreover, CFs metabolized estradiol to hydroxyestradiol, and 2-hydroxyestradiol to 2-methoxyestradiol. OR486 and quercetin (COMT inhibitor) blocked the conversion of 2-hydroxyestradiol to 2-methoxyestradiol in CFs. We conclude that the antimitogenic effects of estradiol on CF growth are mediated in part by conversion to hydroxyestradiols via CYP1A1 and CYP1B1, followed by metabolism of hydroxyestradiols to methoxyestradiols by COMT.

Aryl Hydrocarbon Hydroxylases↗
PubMed1990

Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome.

We have compared the time courses of serum inhibin and estradiol responses to ovarian hyperstimulation in patients undergoing in vitro fertilization and embryo transfer as well as their predictive value for outcome of intermediate variables and pregnancy in in vitro fertilization and embryo transfer. Blood samples (n = 749) were collected for up to 6 days before hCG administration in 100 consecutive treatment cycles, of which 44 resulted in pregnancy, as defined by elevated luteal phase serum hCG beta levels. Inhibin and estradiol levels increased markedly in parallel during hyperstimulation and were highly correlated (r = 0.89; P less than 0.001). Inhibin responses were significantly lower in women 35 yr of age or older (P less than 0.001), although estradiol responses were not influenced by age. Gravidity and tubal disease also had marginal effects on the time course of inhibin responses, but not on overall mean inhibin levels or estradiol responses. The time course of hormonal responses to hyperstimulation was not influenced by any other demographic or etiological factors. Peak values of both hormones correlated with the total number of follicles (inhibin, r = 0.70; estradiol, r = 0.65; P less than 0.001) and oocytes retrieved per cycle (inhibin, r = 0.49; estradiol, r = 0.39; P less than 0.001). The time course and peak values of inhibin and estradiol responses to hyperstimulation did not differ significantly between conception or nonconception cycles whether judged by biochemical (luteal hCG beta) or clinical (viable ongoing pregnancy) criteria. Luteal phase serum inhibin, estradiol, progesterone, and hCG levels were significantly higher in conception than in nonconception cycles (P less than 0.001). These data suggest that the rises in serum inhibin and estradiol levels during hyperstimulation have similar predictive properties for IVF-ET outcomes and could, therefore, be used interchangeably to monitor hyperstimulation regimens. The age-related reduction in inhibin, but not estradiol, responses suggests that these two hormones reflect different granulosa cell functions and that serum inhibin responses to maximal ovarian stimulation may be a sensitive and early index of declining ovarian function with advancing age.

Adult↗