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PubMed1996

Regulation of the estrogen receptor and its messenger ribonucleic acid in the ovariectomized sheep myometrium and endometrium: the role of estradiol and progesterone.

Estrogen receptor (ER) mRNA is dramatically increased in sheep myometrium and endometrium during glucocorticoid-induced premature labor and term spontaneous labor. However, the underlying mechanism for the up-regulation of uterine ER in labor is still unknown. We used ovariectomized (OVX) non-pregnant sheep to analyze the role of estradiol and progesterone in the regulation of myometrial and endometrial ER protein and ER mRNA in vivo. Twenty-one OVX ewes were treated with saline (n = 6), or with estradiol infused i.v. for 2 days (50 micrograms/day, n = 5), or with an intravaginal progesterone sponge for 10 days (containing 0.3 g progesterone, n = 5), or with an intravaginal progesterone sponge for 10 days with estradiol (50 micrograms/day) administered on Days 9 and 10 with the progesterone sponge still in place (n = 5). The ER protein concentration in both cytosolic and nuclear compartments, analyzed by Western blot, increased significantly (P < 0.05) in the myometrium after estradiol treatment, while progesterone alone had no detectable effect on ER level. Elevated ER protein was observed only in the nuclear fraction of endometrium. However, when estradiol was given together with progesterone treatment, progesterone antagonized the up-regulatory effect of estradiol on the ER level both at the endometrium and myometrium. The changes in cellular ER mRNA followed the pattern observed at the ER protein level. Estrogen receptor mRNA was elevated significantly (p < 0.01) only in estradiol-treated ewes. Expression of the ER gene in ewes receiving progesterone alone or progesterone combined with estradiol was similar to that of the control group. From these observations we conclude that ER gene expression and active ER synthesis in nonpregnant sheep myometrium and endometrium are estradiol-dependent. Progesterone antagonizes this estrogen action. Progesterone down-regulated the elevated ER mRNA when used together with estradiol. In situ hybridization showed that ER mRNA was evenly distributed in the smooth muscle cells and blood vessels of the myometrium and the epithelial cells of the glands in endometrium. In conclusion, we have observed estradiol-dependent activation of ER gene expression as well as active ER synthesis in the nonpregnant sheep myometrium and endometrium. Progesterone acted as an antagonist of estradiol on ER gene expression.

Animals↗
PubMed1997

Estradiol up-regulates estrogen receptor and progesterone receptor gene expression in specific ovine uterine cells.

The regulation of estrogen receptor (ER) and progesterone receptor (PR) genes is critical to estrogen and progesterone responsiveness of the uterus during the estrous cycle. A low dose of estradiol, given to ovariectomized ewes to mimic the preovulatory estrogen surge, acutely enhanced ER and PR gene expression in most uterine cells. Estradiol effects were measured at 12, 24, and 48 h post-injection (n = 6 ewes per time) with immunohistochemistry and in situ hybridization. Whereas vehicle-treated ovariectomized ewes demonstrated low to moderate ER and PR mRNA and protein expression, estradiol enhanced PR mRNA and protein expression (at 12 h and 24 h, respectively) more rapidly than ER mRNA and protein expression (at 24 h and 48 h, respectively) in most uterine cells. However, the timing and extent of the estradiol response depended partly upon cell type (epithelial, stromal, or myometrial), cell region (luminal, superficial, middle, or deep endometrial or myometrial), adjacent cells, and prior progesterone treatment. For example, PR mRNA up-regulation was prolonged in middle and deep endometrial stroma, but increases in PR protein expression were highest in superficial and middle endometrial compartments, including the luminal epithelium. The luminal epithelium and myometrium were unique in that estradiol failed to up-regulate ER gene expression within them. ER mRNA levels rose within these compartments only when estradiol followed steroid hormone treatment designed to induce an artificial estrous cycle (estradiol-progesterone-estradiol [EPE] treatment). The EPE treatment also augmented the rise in ER mRNA concentrations within stromal cells compared to estradiol treatment alone. Within uterine cell compartments, subpopulations of adjacent cells showed distinct estradiol responses, e.g., very high levels of ER and PR gene expression within stromal cells directly underlying glandular epithelial cells. Because the estradiol response did not always correlate with initial ER protein levels and was partly dependent upon cell compartment and adjacent cells, we must conclude that direct transcriptional and/or posttranscriptional actions of estradiol cooperate with other cellular and paracrine regulatory factors to regulate ER and PR gene expression and, thus, the steroid responsiveness of uterine cells.

Animals↗
PubMed2000

Selection of the dominant follicle in cattle: role of estradiol.

Involvement of estradiol in the deviation in growth rates between the two largest follicles of a wave was studied in 39 heifers. In experiment 1, the largest follicle remained intact in a control group and was ablated in five estradiol-treated groups when the largest follicle reached 8.5 mm or larger (expected beginning of deviation; Hour 0). The ablation groups were given a single injection of 0, 0.004, 0.02, 0.1, or 0.5 mg of estradiol. Blood samples were taken from a jugular vein every hour at Hours 0 to 16. By Hour 8, FSH concentrations were greater (P < 0.05) in the ablation group that received 0 mg of estradiol than in the controls. Among the estradiol groups, that receiving 0.02 mg had the lowest detectable increase in estradiol. In this group, FSH concentrations were not suppressed below the control concentrations, but the increase in FSH concentrations following ablation of the largest follicle was delayed for 2 or 3 h. This delay in the increase of FSH concentrations corresponded to the hours that estradiol was maximal. In experiment 2, blood samples were taken every 4 h from the caudal vena cava cranial to the junction with the ovarian veins in heifers with the largest follicle intact (controls) or ablated at 8.5 mm or larger (Hour 0). Averaged over Hours 4 to 48, estradiol concentrations were higher (P < 0.04) in the controls than in the ablation group. During Hours 0 to 12, estradiol concentrations increased (P < 0.05) in the controls, whereas FSH concentrations decreased (P < 0.05). In the ablation group, estradiol concentrations were lower than in the controls by Hour 4, and FSH concentrations increased (P < 0.05) between Hours 4 and 12. These results support the hypothesis that the largest follicle releases increased estradiol into the blood at the beginning of follicular deviation, and that the released estradiol is involved in the continuing depression of FSH concentrations to below the requirement of the smaller follicles.

Animals↗
PubMed2000

Estradiol facilitates kainic acid-induced, but not flurothyl-induced, behavioral seizure activity in adult female rats.

PURPOSE: This study was designed to determine whether previously demonstrated increases in hippocampal axospinous synapse density and NMDA receptor function induced by estradiol are paralleled by increased susceptibility to limbic (kainic acid induced) or generalized (flurothyl induced) behavioral seizures. METHODS: Kainic acid was injected systemically to ovariectomized adult female rats treated with either estradiol or oil vehicle. The latencies to each of five stages of seizure-related behaviors (staring, wet-dog shakes, head waving and chewing, forelimb clonus, rearing, and falling) were recorded for each animal. Flurothyl was administered by inhalation to ovariectomized adult female rats treated with estradiol alone, estradiol followed by short-term progesterone, or oil vehicle. The latencies to each of three stages of seizure-related behaviors (first myoclonic jerk, forelimb clonus, wild running and bouncing) were recorded for each animal. RESULTS: Estradiol treatment decreased the latency to seizure-related behaviors induced by kainic acid, but neither estradiol alone nor estradiol followed by progesterone had any effect on flurothyl-induced seizure-related behaviors. CONCLUSIONS: The same estradiol treatment paradigm known to induce structural and functional changes in the excitatory circuitry of the hippocampus facilitates the progression of kainic acid-induced seizures, which are known to involve the hippocampus, but has no effect on flurothyl-induced seizures. The lack of an effect of estradiol alone or estradiol followed by progesterone on flurothyl-induced seizures indicates that estradiol's effects on seizure susceptibility do not result from increased neuronal excitability throughout the brain, but rather involve action within the limbic system. The data suggest that structural and functional changes in hippocampal circuitry induced by estradiol may contribute to increased susceptibility to limbic seizure activity.

Animals↗
PubMed2002

Differential modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed estradiol-3-glucuronidation by the addition of UGT1A1 substrates and other compounds to human liver microsomes.

Previous results demonstrating homotropic activation of human UDP-glucuronosyltransferase (UGT) 1A1-catalyzed estradiol-3-glucuronidation led us to investigate the effects of 16 compounds on estradiol glucuronidation by human liver microsomes (HLM). In confirmation of previous work using alamethicin-treated HLM pooled from four livers, UGT1A1-catalyzed estradiol-3-glucuronidation demonstrated homotropic activation kinetics (S(50) = 22 microM, Hill coefficient, n = 1.9) whereas estradiol-17-glucuronidation (catalyzed by other UGT enzymes) followed Michaelis-Menten kinetics (K(m) = 7 microM). Modulatory effects of the following compounds were investigated: bilirubin, eight flavonoids, 17alpha-ethynylestradiol (17alpha-EE), estriol, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), anthraflavic acid, retinoic acid, morphine, and ibuprofen. Although the classic UGT1A1 substrate bilirubin was a weak competitive inhibitor of estradiol-3-glucuronidation, the estrogens and anthraflavic acid activated or inhibited estradiol-3-glucuronidation dependent on substrate and effector concentrations. For example, at substrate concentrations of 5 and 10 microM, estradiol-3-glucuronidation activity was stimulated by as much as 80% by low concentrations of 17alpha-EE but was unaltered by flavanone. However, at higher substrate concentrations (25-100 microM) estradiol-3-glucuronidation was inhibited by about 55% by both compounds. Anthraflavic acid and PhIP were also stimulators of estradiol 3-glucuronidation at low substrate concentrations. The most potent inhibitor of estradiol 3-glucuronidation was the flavonoid tangeretin. The UGT2B7 substrates morphine and ibuprofen had no effect on estradiol 3-glucuronidation, whereas retinoic acid was slightly inhibitory. Estradiol-17-glucuronidation was inhibited by 17alpha-EE, estriol, and naringenin but was not activated by any compound. This study demonstrates that the interactions of substrates and inhibitors at the active site of UGT1A1 are complex, yielding both activation and competitive inhibition kinetics.

Algorithms↗
PubMed2000

17-beta-estradiol modulation of area postrema potassium currents.

The purpose of this study was to determine the effects of 17-beta-estradiol on area postrema neuronal activity in vivo and on area postrema potassium currents (IK) in vitro. In anesthetized rats, intravenous injection of 17-beta-estradiol (10 ng/kg bw) -inhibited area postrema neuronal activity in 8/8 neurons tested. The averaged firing rate decreased from 2.9 +/- 1.1 to 1.1 +/- 0.3 Hz. The inhibitory effects of 17-beta-estradiol on area postrema neuronal activity were rapid in onset (within 1 min) and long-lasting (>8 min). To study the cellular mechanisms involved in this response, the effects of 17-beta-estradiol were examined in dissociated area postrema neurons. In these cells, 17-beta-estradiol (0.5 nM) increased the averaged peak IK 27 +/- 8%. The time course for the potentiation was observed within approximately 0.5-1 min after the application of 17-beta-estradiol. Full recovery from the potentiation usually occurred within approximately 3-4 min after the washout of 17-beta-estradiol. The biologically inactive 17-alpha-estradiol had no effect on area postrema IK and the 17-beta-estradiol antagonist, ICI 182,780 blocked the effects of 17-beta-estradiol on area postrema IK. Finally, big conductance calcium-activated potassium current (MaxiK(+)) was identified in area postrema neurons (n = 12/12). Blockade of MaxiK(+) with 100 nM iberiotoxin blocked the effects of 17-beta-estradiol on IK. These results suggested 17-beta-estradiol might modulate area postrema neuronal activity by increasing MaxiK(+) current.

Animals↗
PubMed1975

Interactions of 17beta-estradiol and L-norepinephrine on the rat uterus.

Norepinephrine increased the in vitro uptake of 3H-estradiol by the uterus of spayed rats. This effect was observed at 15 and 30 min but not at 90 min. Norepinephrine also increased the binding of 3H-estradiol by the nuclear (p less than 0.02) and the cytosol fractions (p less than 0.01) when incubated with uterine homogenates, suggesting that norepinephrine does not require the presence of the intact tissue to exert its effects. The in vivo uptake of 3H-estradiol and the determination of the number of binding sites were performed in the uterus of rats treated with estradiol and estradiol plus norepinephrine. Norepinephrine alone increased the uptake of 3H-estradiol and the number of binding sites. The highest increment in both parameters was observed in the uterus of rats treated with estradiol plus norepinephrine. The estradiol Ka of the rat uterus cytosol treated with estradiol alone or plus norepinephrine was higher than that observed in the group without estradiol, suggesting the presence of different proteins that bind estradiol. These results indicate that norepinephrine increases the entrance of estradiol into the rat uterus both in vitro and in vivo.

Animals↗
PubMed1997

Nitric oxide mediates LDL uptake in the artery wall in response to high concentrations of 17 beta-estradiol.

Female sex hormones are known to affect lipoprotein flux in the artery wall and atherosclerosis. However, the mechanisms of these artery wall effects are unclear. To examine the effect of 17 beta-estradiol (estradiol) on LDL uptake in the artery wall, we developed an isolated perfused rat carotid artery model from ovariectomized rats. LDL flux in the artery wall was measured by quantitative fluorescence microscopy before and after treatment with estradiol (0.001 to 10,000 nmol/L). Dose-response experiments showed no significant difference in the rate of LDL uptake when arteries were perfused with estradiol at physiological concentrations (0.001 to 1 nmol/L) compared with control perfusions. However, higher concentrations of estradiol (10 to 10,000 nmol/L) significantly increased the rate of LDL uptake in isolated arteries. Artery lumen volume significantly increased with perfusion of estradiol (1 to 100 nmol/L) but decreased after perfusions of higher concentrations of estradiol (1000 to 10,000 nmol/L). Additional studies were performed to examine mechanisms of estradiol-mediated increases in LDL uptake. The effect of estradiol (10 nmol/L) on the rate of LDL uptake was blocked by nitric oxide synthase inhibitors. However, the estrogen receptor antagonist tamoxifen did not block the effects of estradiol on the rate of LDL uptake. Our study indicates that modulation of LDL uptake in the artery wall by estradiol is concentration dependent. High concentrations of estradiol increase LDL uptake by production of endothelium-derived nitric oxide. These observations suggest that increased nitric oxide production compromises endothelial layer barrier function to increase LDL uptake in the artery wall.

Animals↗
PubMed1999

17 beta-estradiol reduces glycoxidative damage in the artery wall.

Glycoxidative damage in the vasculature has been linked to atherosclerotic cardiovascular disease. Estrogens protect against the development and progression of atherosclerosis. Because estrogens are potent antioxidants that also effect glucose metabolism, part of their protection against atherosclerosis could be through attenuation of glycoxidative damage in the vascular wall. In this study, we tested the hypothesis that chronic estradiol administration is associated with decreased levels of glycoxidative damage in arterial walls. We harvested and examined iliac arteries from ovariectomized, 8-month-old rats that had been implanted for 6 months with 1 of the following subcutaneous hormone pellets: low estradiol (2.5 mg estradiol), high estradiol (25 mg estradiol), P4 (200 mg progesterone), low estradiol and P4, placebo (no hormone), or control (no implant). Using pentosidine as a biomarker of glycoxidative damage, we found that all vessels from rats receiving estradiol (low estradiol, high estradiol, and low estradiol+P4) exhibited a 50% reduction in glycoxidative damage compared with P4, placebo, and control vessels (P<0.05). Consistent with this finding, we observed that estradiol-treated rats had a 30% decrease in tissue levels of hydroperoxides, a marker of oxidative stress. Finally, estradiol-treated rats had a small, but significant, decrease in plasma glucose levels (P<0.01). In summary, we report the novel finding that chronic estrogen administration is associated with significant decreases in glycoxidative damage and oxidative stress in the arterial wall. It seems likely that these actions may constitute a mechanism by which estrogen attenuates the progression of atherosclerosis.

Animals↗
PubMed2001

Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism.

Estradiol inhibits endothelin-1 synthesis, an effect that may contribute to the cardiovascular protective effects of estradiol. Recent findings that estradiol inhibits neointima formation in mice lacking estrogen receptors suggests that the cardiovascular protective effects of estradiol may be mediated by means of an estrogen receptor-independent mechanism. Because 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little/no affinity for estrogen receptors, are more potent than estradiol in inhibiting vascular smooth muscle cell growth, we investigated whether these metabolites also inhibit endothelin-1 synthesis by means of an receptor-independent mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 micromol/L of estradiol, 2-hydroxyestradiol, or 2-methoxyestradiol concentration-dependently inhibited basal as well as serum-induced (2.5%), TNFalpha-induced (10 ng/mL), angiotensin II-induced (100 nmol/L), and thrombin-induced (4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol also inhibited serum-induced mitogen-activated protein kinase activity. As compared with estradiol, its metabolites were more potent in inhibiting endothelin-1 secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyestradiol and 2-methoxyestradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 micromol/L), an estrogen receptor antagonist. Our findings indicate that the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol potently inhibit endothelin-1 synthesis by means of an estrogen receptor-independent mechanism. This effect of estradiol metabolites may be mediated by inhibition of mitogen activated protein kinase activity and may contribute to the cardioprotective effects of estradiol.

2-Methoxyestradiol↗
PubMed2006

Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix metalloproteinase-9.

BACKGROUND: Recent data have indicated that estradiol can modulate the kinetics of endothelial progenitor cells (EPCs) via endothelial nitric oxide synthase (eNOS)-dependent mechanisms. We hypothesized that estradiol could augment the incorporation of bone marrow (BM)-derived EPCs into sites of ischemia-induced neovascularization, resulting in protection from ischemic injury. METHODS AND RESULTS: Myocardial infarction (MI) was induced by ligation of the left coronary artery in ovariectomized mice receiving either 17beta-estradiol or placebo. Estradiol induced significant increases in circulating EPCs 2 and 3 weeks after MI in estradiol-treated animals, and capillary density was significantly greater in estradiol-treated animals. Greater numbers of BM-derived EPCs were observed at ischemic sites in estradiol-treated animals than in placebo-treated animals 1 and 4 weeks after MI. In eNOS-null mice, the effect of estradiol on mobilization of EPCs was lost, as was the functional improvement in recovery from acute myocardial ischemia. A decrease was found in matrix metalloproteinase-9 (MMP-9) expression in eNOS-null mice under basal and estradiol-stimulated conditions after MI, the mobilization of EPCs by estradiol was lost in MMP-9-null mice, and the functional benefit conferred by estradiol treatment after MI in wild-type mice was significantly attenuated. CONCLUSIONS: Estradiol preserves the integrity of ischemic tissue by augmenting the mobilization and incorporation of BM-derived EPCs into sites of neovascularization by eNOS-mediated augmentation of MMP-9 expression in the BM. Moreover, these data have broader implications with regard to our understanding of the role of EPCs in post-MI recovery and on the sex discrepancy in cardiac events.

Animals↗
PubMed1982

Facilitative interactions between estradiol and luteinizing hormone in the regulation of progesterone production by cultured swine granulosa cells: relation to cellular cholesterol metabolism.

Well differentiated swine granulosa cells in monolayer culture were employed to investigate the mechanisms by which estradiol amplifies the stimulatory actions of LH in the later stages of follicular maturation. The facilitative interaction between estradiol and LH could not be attributed to altered rates of catabolism of progesterone to 20 alpha-hydroxypregn-4-en-3-one. Moreover, estradiol, LH, and estradiol combined with LH clearly stimulated pregnenolone production, measured in the presence of trilostane, to inhibit 3 beta-hydroxysteroid dehydrogenase-delta-5-4-isomerase activity. Thus, at least one component of the synergism between estradiol and LH must reside at or proximal to the cholesterol side-chain cleavage system. In the absence of lipoproteins, the magnitude of the synergism between estradiol and LH was significantly reduced. However, the facilitative interaction between estradiol and LH could still be observed in lipoprotein-deficient and serum-free medium and after the administration of ML-236B to suppress the de novo biosynthesis of cholesterol. In contrast, estradiol alone and LH alone significantly augmented progesterone production in the presence of the oxygenated sterol 5-cholesten-3 beta,25-diol, which can serve as an effective substrate for cholesterol side-chain cleavage. In addition, in the presence of 5-cholesten-3 beta,25-diol, the magnitude of the synergism between estradiol and LH was increased markedly. Thus, the present studies demonstrate that estradiol and LH significantly stimulate progesterone production, at least in part, by augmenting pregnenolone biosynthesis, but not by inhibiting progesterone catabolism. Studies with 5-cholesten-3 beta-25-diol further suggest that estradiol and LH increase cholesterol side-chain cleavage activity. These observations delineate important mechanisms by which estradiol and LH prepare well differentiated granulosa cells for the high rates of steroidogenesis that are ultimately required in the corpus luteum.

20-alpha-Dihydroprogesterone↗
PubMed1983

Intraovarian localization of luteinizing hormone/human chorionic gonadotropin stimulation of testosterone and estradiol synthesis in the pregnant rat.

The objective of this investigation was to determine whether LH acts directly on luteal cells to stimulate testosterone and estradiol synthesis or whether it stimulates follicular and/or interstitial production of androgen and thus provides androgen substrate for luteal cell production of estradiol. Pregnant rats were injected with 1.5 IU human CG (hCG) twice daily sc between days 12 and 14. On day 14, blood was obtained from both the jugular and ovarian vein. Corpora lutea (CL), follicles, and interstitium were isolated and incubated at 37 C for 4 h. Estradiol, testosterone, and progesterone levels were measured in the peripheral circulation, ovarian vein plasma, tissues, and medium. After hCG treatment, no ovulation occurred, rats remained pregnant, and progesterone levels in the serum and in the ovarian vein plasma remained unchanged. In contrast, estradiol and testosterone levels in the ovarian vein increased from 0.7 +/- 0.1 and 0.6 +/- 3.4 ng/ml, respectively, in vehicle-treated rats to 12.5 +/- 3.5 and 4.8 +/- 1.4 ng/ml in hCG-treated animals. In vivo treatment with hCG dramatically increased the in vitro capacity of luteal cells to synthesize de novo both testosterone and estradiol but had no stimulatory effect on progesterone synthesis. Testosterone synthesis by CL increased from 21 +/- 4 to 255 +/- 114 pg/CL whereas estradiol synthesis rose from 30 +/- 7 to 4481 +/- 641 pg/CL. hCG also increased follicular synthesis of both estradiol and testosterone. The interstitium responded to the hCG challenge with a 50-fold increase in testosterone synthesis but with no change in estradiol production. To determine whether hCG rapidly stimulates ovarian production of testosterone, both in vivo and in vitro approaches were used. In the in vitro experiments, CL follicles, or interstitium obtained from day 14 pregnant rats were incubated with or without 3 IU hCG. In the in vivo experiments, day 14 pregnant rats were injected with 3 IU hCG iv and were bled from the jugular and ovarian veins 0.5 and 2 h later. No increase in testosterone and estradiol production was observed after a short challenge with hCG. In summary, this study demonstrates that in the pregnant rat a sustained increase in serum hCG activity stimulates ovarian secretion of both testosterone and estradiol. We conclude that LH can act to induce the synthesis and/or activation of enzyme(s) involved in the conversion of progesterone to androgen in luteal tissue. The results also demonstrate that LH stimulates the synthesis of androgens but not of estradiol in interstitial tissue and confirms the finding that LH stimulates follicular production of both testosterone and estradiol.

Animals↗
PubMed1984

Preovulatory gonadotropin surge system of prepubertal female sheep is exquisitely sensitive to the stimulatory feedback action of estradiol.

The sensitivity of the LH surge mechanism to estradiol-positive feedback was examined in immature lambs (19 weeks of age) several weeks before first ovulation (31 weeks of age). To minimize differences in basal estradiol concentrations, lambs were pretreated with a low level of estradiol (2 pg/ml; Silastic capsule) for 4 days and were ovariectomized before they were challenged with one of five levels of estradiol (n = 5 lambs/level). The estradiol increments produced after insertion of the second set of estradiol implants ranged from 2-11 pg/ml. All estradiol increments, even those as low as 2 pg/ml, produced LH surges; in the absence of an estradiol increment (second implant not inserted; n = 5 lambs), a LH surge did not occur. The similarity of the dose-response curve for estradiol-induced LH release in the lamb to that which we previously reported for the mature female indicates that the lamb is equally sensitive to estradiol stimulatory feedback action long before the age of first ovulation. This suggests that low estradiol secretion, rather than reduced sensitivity of the surge mechanism to estradiol-positive feedback, is responsible for the anovulatory condition of the immature female sheep.

Animals↗
PubMed1991

Estradiol regulation of the rabbit corpus luteum: in vivo and in vitro studies.

The objective of this study was to determine whether estradiol has a direct effect on progesterone secretion by the rabbit corpus luteum. Empty or estradiol-filled Silastic capsules were implanted sc into pseudopregnant rabbits (day 0). Ten days later (day 10), peripheral blood was obtained via the marginal ear vein, and Silastic capsules were removed. Twenty-four hours after capsule removal (day 11), blood samples were obtained and ovaries removed for in vitro perfusion. The artery and vein of each ovary were individually cannulated, and ovaries were perfused in vitro for 6 h. Mean progesterone secretion rates were determined from perfusate samples taken every 30 min. On day 10, serum progesterone concentrations were similar in control and estradiol-treated animals. On day 11, 24 h after withdrawal of Silastic capsules, serum progesterone concentration in the estradiol-treated rabbits decreased significantly compared to controls. The withdrawal of estradiol also significantly reduced the secretion of progesterone by in vitro perfused ovaries in estradiol-withdrawn rabbits compared to empty capsule controls. Addition of estradiol or 25-hydroxycholesterol (25-OH) to the perfusion medium significantly increased progesterone secretion by ovaries from estradiol-withdrawn rabbits but not to control values. In contrast, a combination of estradiol plus 25-OH restored progesterone secretion to control levels. Although estradiol together with 25-OH stimulated progesterone secretion 24 h after estradiol withdrawal, progesterone secretion in vitro was unaffected 48 h after capsule removal, whereas pregnenolone stimulated secretion 5-fold. These results demonstrate that estradiol has a direct and acute stimulatory effect on progesterone secretion by the rabbit corpus luteum.

Animals↗
PubMed2003

Quantitative determination of estradiol fatty acid esters in lipoprotein fractions in human blood.

According to experimental studies, 17 beta-estradiol associates with lipoproteins in blood in the form of fatty acid esters. However, concentrations of endogenous estradiol esters in human lipoprotein fractions have not been previously reported. We investigated the distribution of estradiol fatty acid esters between plasma lipoproteins in 10 healthy women during late pregnancy. Following extraction from serum and ultracentrifugally isolated, gel-filtered lipoproteins, estradiol esters were separated from nonesterified estradiol by column chromatography. After saponification and chromatographic purification of the estradiol ester fraction, the concentration of hydrolyzed esters was determined by estradiol time-resolved fluoroimmunoassay. Of total serum estradiol, a mean of 0.7% (549 pmol/liter, n = 10) was in the form of fatty acid esters. Estradiol fatty acid ester concentrations measured in serum and lipoprotein fraction correlated positively (n = 10; r = 0.98; P < 0.001). The majority of lipoprotein estradiol esters, 54%, was recovered in high-density lipoprotein, and 28% in low-density lipoprotein fraction. Most lipoprotein fractions contained undetectable amounts of nonesterified estradiol (< 36 pmol/liter). In conclusion, our results indicate that estradiol fatty acid esters are mostly bound by lipoproteins in blood in vivo.

Adult↗
PubMed2004

Catecholamines block the antimitogenic effect of estradiol on human coronary artery smooth muscle cells.

Sequential conversion of estradiol to catecholestradiols and methoxyestradiols by cytochrome-P(450) (CYP450) and catechol-O-methyltransferase (COMT), respectively, contributes to the antimitogenic effects of estradiol on vascular smooth muscle cell (SMC) growth via estrogen receptor-independent mechanisms. Because catecholamines are also substrates for COMT, we hypothesize that catecholamines may abrogate the vasoprotective effects of estradiol by competing for COMT and inhibiting methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic/inhibitory effects of estradiol on human coronary artery SMC growth (cell number, DNA synthesis, collagen synthesis, and SMC migration) and ERK1/2 phosphorylation in the presence and absence of catecholamines. Norepinephrine, epinephrine, isoproterenol, and OR486 (COMT inhibitor) abrogated the inhibitory effects of estradiol on SMC growth and ERK1/2 phosphorylation. The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, alpha- and beta-adrenoceptor antagonists, respectively. The antimitogenic effects of 2-hydroxy-estradiol, but not 2-methoxyestradiol, were abrogated by epinephrine, isoproterenol, and OR486. Catecholamines inhibited the conversion of both estradiol and 2-hydroxy-estradiol to 2-methoxyestradiol, and SMCs expressed CYP1A1 and CYP1B1. Our findings suggest that catecholamines within the coronary arteries may abrogate the antivasoocclusive effects of estradiol by blocking the conversion of catecholestradiols to methoxyestradiols. The interaction between catecholamines and estradiol metabolism may importantly define the cardiovascular effects of estradiol therapy in postmenopausal women.

2-Methoxyestradiol↗
PubMed2004

Endogenous levels of serum estradiol and sex hormone binding globulin determine bone mineral density, bone remodeling, the rate of bone loss, and response to treatment with estrogen in elderly women.

A total of 489 elderly women aged 65-75 yr who participated in a 3-yr, randomized, blinded osteoporosis trial underwent measurements of serum estradiol, bioavailable estradiol, and SHBG. At baseline, bone mineral density (BMD) was lower at the femoral sites (7-19%, P < 0.05), total body (6-8%, P < 0.05), and spine (5-9%, P = 0.2) in women in the lowest tertile for serum total estradiol [<9 pg/ml (33 pmol/liter)], serum bioavailable estradiol [<2.4 pg/ml (8.8 pmol/liter)], or highest tertile for serum SHBG (>165 nmol/liter), compared with women in the highest tertiles of total estradiol [>13.3 pg/ml (49 pmol/liter)] and bioavailable estradiol [>4 pg/ml (14 pmol/liter)] or lowest tertile for SHBG (<113 nmol/liter). Bone markers were increased in women in the lowest tertile for serum total estradiol (not significant) and bioavailable estradiol (P < 0.05) and highest tertile for SHBG (P < 0.05). In the longitudinal study, the rate of bone loss in the placebo group was significantly higher in total body (P < 0.05) and spine (P < 0.05) in women in the lowest tertile, compared with the highest tertile of serum bioavailable estradiol. After treatment with conjugated equine estrogens 0.625 mg/d, the increase in BMD was 4-6% higher at the femoral sites (P < 0.05), total body (P < 0.05), and spine (not significant), in the lowest tertile, compared with the highest tertile of serum bioavailable estradiol or highest tertile, compared with the lowest tertile of serum SHBG. In summary, small variations in endogenous serum estradiol and high serum SHBG determine differences in BMD and rate of bone loss in elderly women and also affect the response to treatment with estrogen. Women with a serum estradiol level of less than 9 pg/ml (33 pmol/liter) are optimal candidates for estrogen therapy for osteoporosis prevention.

Aged↗