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PubMed1998

Transdermal delivery of estradiol in postmenopausal women with a novel topical aerosol.

The objective of this study was to determine if a novel metered-dose topical aerosol (MDTA) formulation containing the new dermal penetration enhancer, padimate O, could enhance the transdermal delivery of estradiol to an extent that would result in clinically relevant plasma concentrations. The estradiol MDTA (with padimate O) was applied once daily at 0800 h to postmenopausal women for 9 days, and plasma estradiol and estrone was measured daily (24 h postapplication) by radioimmunoassay. The topical dose was administered as three 1 mg doses of estradiol, each applied as a single spray over 10 cm2 which were placed adjacent to each other on the subject's ventral forearm. None of the subjects tested showed any sign of skin irritation at the application site over the entire study period using the Draize irritation score. In four postmenopausal women (age 54-63 years, weight 67-93 kg) the mean estradiol level 24 h postapplication over the 9 day study period was 53 pg/mL. This result was significantly greater (p < 0.001) than the baseline value of 13 pg/mL. The mean estradiol/estrone ratio also rose significantly (p < 0.04) from a baseline value of 0.2 up to 0.8. We conclude that this novel MDTA formulation significantly enhances the transdermal delivery of estradiol to allow a clinically relevant dose of estradiol to be delivered in postmenopausal women with once daily dosing.

4-Aminobenzoic Acid↗
PubMed1998

Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes.

Of seven cDNA-expressed human cytochrome P450 (P450) enzymes (P450s 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) examined, P450 1A2 was the most active in catalyzing 2- and 4-hydroxylations of estradiol and estrone. P450 3A4 and P450 2C9 also catalyzed these reactions although to lesser extents than P450 1A2. P450 1A2 also efficiently oxidized estradiol at the 16alpha-position but was less active in estrone 16alpha-hydroxylation; the latter reaction and also estradiol 16alpha-hydroxylation were catalyzed by P450 3A4 at significant levels. Anti-P450 1A2 antibodies inhibited 2- and 4-hydroxylations of these two estrogens catalyzed by liver microsomes of some of the human samples examined. Estradiol 16alpha-hydroxylation was inhibited by both anti-P450 1A2 and anti-P450 3A4, while estrone 16alpha-hydroxylation was significantly suppressed by anti-P450 3A4 in human liver microsomes. Fluvoxamine efficiently inhibited the estrogen hydroxylations in human liver samples that contained high levels of P450 1A2, while ketoconazole affected these activities in human samples in which P450 3A4 levels were high. alpha-Naphthoflavone either stimulated or had no effect on estradiol hydroxylation catalyzed by liver microsomes; the intensity of this effect depended on the human samples and their P450s. Interestingly, in the presence of anti-P450 3A4 antibodies, alpha-naphthoflavone was found to be able to inhibit estradiol and estrone 2-hydroxylations catalyzed by human liver microsomes. The results suggest that both P450s 1A2 and 3A4 have major roles in oxidations of estradiol and estrone in human liver and that the contents of these two P450 forms in liver microsomes determine which P450 enzymes are most important in hepatic estrogen hydroxylation by individual humans. P450 3A4 may be expected to play a more important role for some of the estrogen hydroxylation reactions than P450 1A2. Knowledge of roles of individual P450s in these estrogen hydroxylations has relevance to current controversies in hormonal carcinogenesis [Service, R. F. (1998) Science 279, 1631-1633].

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

Postischemic cerebral blood flow recovery in the female: effect of 17 beta-estradiol.

Female reproductive hormones are considered to be protective agents in atherosclerotic vascular disease and stroke. The present study determined if there are unique cerebrovascular responses in female animals to global cerebral ischemia and if 17 beta-estradiol is important to postischemic outcome in brain. Three groups of anesthetized, sexually mature rabbits were treated with normotensive four-vessel occlusion (6 min) and 3 h of reperfusion: females chronically instrumented with 17 beta-estradiol implants (EFEM; n = 8, plasma estradiol level = 365 +/- 48 pg/ml), untreated females (FEM; n = 8, estradiol = 13 +/- 3 pg/ml), and untreated males (M; n = 8, estradiol < limit of radioimmunoassay). CBF (microspheres) and somatosensory evoked potential (SEP) amplitude were measured during ischemia/reperfusion. Baseline hemispheric blood flow and regional flow distribution were not altered by chronic estradiol treatment. Hemispheric blood flow was equivalently reduced during ischemia in FEM and M (6 +/- 1 and 9 +/- 2 ml min-1 100 g-1, respectively); however postischemic hyperemia was greater in FEM than M (CBF = 257 +/- 27 and 183 +/- 27 ml min-1 100 g-1. However, EFEM experienced higher CBF during ischemia (e.g., 13 +/- 2 ml min-1 100 g-1) and less hyperemia (134 +/- 4 ml min-1 100 g-1 in hemispheres) in numerous brain regions than FEM. CBF at 3 h reperfusion was not different among the groups. Recovery of SEPs was incomplete and similar in all groups. We conclude that chronic exogenous 17 beta-estradiol treatment increases CBF during global incomplete ischemia and ameliorates postischemic hyperemia in the female animal.

Animals↗
PubMed2006

Inhibitory effect of obesity on gonadotropin, estradiol, and inhibin B levels in fertile women.

OBJECTIVE: To examine whether obesity and insulin resistance have an independent effect on the gonadotropin, estradiol, and inhibin B serum levels and follicle count in the early follicular phase of fertile women with a wide range of BMI and without signs of hyperandrogenism. RESEARCH METHODS AND PROCEDURES: Twenty-two overweight and obese (BMI > or =25.0 kg/m(2)) women and 10 normal-weight (BMI <25.0 kg/m(2)) women, all having apparently normal fertility, were studied. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, inhibin B, and insulin, level of insulin resistance (estimated by homeostasis model assessment for insulin resistance), and follicle count were measured during the early follicular phase (Days 2 to 5 of the menstrual cycle). RESULTS: Overweight women showed lower FSH (p < 0.001), LH (p < 0.001), and inhibin B (p < 0.05) levels compared with normal-weight women, whereas estradiol concentrations and follicle count were not significantly different between the two groups. When normal-weight and overweight women were examined as a group and multiple regression analyses were performed, estradiol showed a negative association with BMI (or waist circumference) (p < 0.05) and a positive correlation with LH (p < 0.05) and FSH (p < 0.05); inhibin B maintained a positive association only with estradiol (p < 0.05); and FSH and LH showed a negative correlation with BMI (or waist circumference) (p < 0.001 and p < 0.01, respectively). DISCUSSION: Overweight and obese fertile women have lower FSH, LH, inhibin B, and estradiol levels in the early follicular phase, with a possible direct inhibitory effect of body mass on gonadotropin and estradiol production, independently of age, insulin (concentrations and sensitivity), and other hormones. By contrast, the number of ovary follicles does not seem to be influenced by insulin and body mass in these patients.

Adult↗
PubMed2000

Enhanced relaxation of porcine coronary arteries after acute exposure to a physiological level of 17beta-estradiol involves non-genomic mechanisms and the cyclic AMP cascade.

The present study extends our previous finding that the endothelium-independent relaxation in porcine coronary artery rings is enhanced after short-term (20 min) exposure to a physiological concentration (1 nM) of 17beta-estradiol and demonstrates that this effect may be attributable to activation of the cyclic AMP pathway. Isometric tension was recorded in isolated rings of porcine coronary arteries. Relaxation by levcromakalim and sodium nitroprusside, but not bradykinin and calcium ionophore A23187, were significantly potentiated following 20 min treatment with 1 nM 17beta-estradiol. This enhancing effect was insensitive to the transcriptional and translational inhibitors, actinomycin D and cycloheximide respectively and absent following repeated washing of the rings prior to construction of relaxation-response curves. The potentiating actions of 1 nM 17beta-estradiol on endothelium-independent relaxation were mimicked by the cyclic AMP analogue 8-Bromo-cyclic AMP and the protein kinase A activator Sp-cyclic AMPS but not by the cyclic GMP analogue 8-Bromo-cyclic GMP. The modulatory effect of 17beta-estradiol was increased in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. The cyclic AMP-dependent protein kinase A inhibitor Rp-cyclic AMPS, but not the cyclic GMP antagonist Rp-8-Bromo-cyclic GMPS, effectively inhibited the enhancing effects 1 M 17beta-estradiol had on the relaxation responses of levcromakalim and sodium nitroprusside. These data support our earlier findings that physiologically relevant concentrations of 17beta-estradiol can acutely modify vasorelaxation in vitro. Furthermore, we report that this short-term effect of 17beta-estradiol on vasorelaxation appears to be mediated via non-genomic pathways and involves the cyclic AMP cascade.

Animals↗
PubMed2005

Nongenomic responses to 17beta-estradiol in male rat mesenteric arteries abolish intrinsic gender differences in vascular responses.

The aim of the present study was to investigate the gender differences in the acute effects of 17beta-estradiol on the rat superior mesenteric artery. Isometric tension was measured in rings of mesenteric arteries from both male and female Sprague-Dawley rats. Relaxation to acetylcholine was not significantly different between arteries (with endothelium) from male and female rats in the absence or presence of 17beta-estradiol. After blockade of endothelium-dependent hyperpolarizations with apamin (0.3 microM) plus charybdotoxin (0.1 microM), acute exposure to 17beta-estradiol (1 nM) for 30 min resulted in enhancement of relaxation to acetylcholine in arteries from male but not female rats. After acute exposure to 17beta-estradiol, mesenteric arteries from male rats were more sensitive to sodium nitroprusside than arteries from female rats. Contractions of mesenteric arteries to phenylephrine and 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) were greater in arteries from male rats than female rats. This difference was not detected after acute exposure to 17beta-estradiol. In preparations without endothelium, the enhancement of relaxation and reduction in contraction in arteries from male rats were preserved. These results suggest that there exists a gender difference in the response to the acute nongenomic modulatory effect of 17beta-estradiol in rat mesenteric arteries. Arteries from male rats seem to be more sensitive to the modulatory effects of 17beta-estradiol than arteries from female rats. The effect appears to be mainly at the level of the vascular smooth muscles.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Greater antiarrhythmic activity of acute 17beta-estradiol in female than male anaesthetized rats: correlation with Ca2+ channel blockade.

BACKGROUND AND PURPOSE: Female sex hormones may protect pre-menopausal women from sudden cardiac death. We therefore investigated the effects of the main female sex hormone, 17beta-estradiol, on ischaemia-induced cardiac arrhythmias and on the L-type Ca2+ current (ICaL). EXPERIMENTAL APPROACH: In vivo experiments were performed in pentobarbital-anaesthetized rats subjected to acute coronary artery occlusion. ICaL was measured by the whole-cell patch-clamp technique, in rat isolated ventricular myocytes. KEY RESULTS: Acute intravenous administration of 17beta-estradiol as a bolus dose followed by a continuous infusion, commencing 10 min before coronary artery occlusion, had dose-dependent antiarrhythmic activity. In female rats 300 ng kg(-1) + 30 ng kg(-1) min(-1) 17beta-estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17beta-estradiol was required to cause similar effects in male rats. In vitro 17beta-estradiol reduced peak ICaL in a concentration-dependent manner. The EC50 was ten-fold higher in male myocytes (0.66 microM) than in females (0.06 microM). CONCLUSIONS AND IMPLICATIONS: These results indicate that 17beta-estradiol has marked dose-dependent antiarrhythmic activity that is greater in female rats than in males. A similar differential potency in blocking ICaL in myocytes from female and male rats can account for this effect. This provides an explanation for the antiarrhythmic activity of 17beta-estradiol and gender-selective protection against sudden cardiac death.

Anesthesia↗
PubMed2003

Pharmacokinetics of oral micronized beta-estradiol in postmenopausal women receiving maintenance hemodialysis.

BACKGROUND: Although 11% of postmenopausal women with end-stage renal disease (ESRD) are prescribed hormone replacement therapy (HRT), the appropriate use remains poorly explored. Although there remains controversy surrounding the benefits of HRT, it may be of particular interest in this population, which has a high risk of bone loss and a fourfold increase in fracture risk compared to the general population. However, the appropriate dose of estrogen for use in postmenopausal women with ESRD is not known. The objective of this study was to evaluate the steady-state pharmacokinetics of oral micronized beta-estradiol in postmenopausal women with ESRD compared with postmenopausal women with normal renal function in order to determine equivalent dosing. METHODS: Six postmenopausal women with ESRD receiving maintenance hemodialysis and 6 healthy postmenopausal controls received 14 days of micronized beta-estradiol (1.0 mg for control, 0.5 mg for ESRD). Blood, urine, and dialysate samples were obtained during a dosage interval on day 14. Estradiol, estrone, albumin, and sex-hormone binding globulin (SHBG) concentrations were determined. Free estradiol concentrations were calculated using a previously described method. RESULTS: Women with ESRD had significantly lower serum albumin (610 +/- 31 micromol/L vs. 684 +/- 83 micromol/L) and SHBG (78 +/- 17 vs. 118 +/- 13 nmol/L) than control subjects. Total clearance of estradiol was not significantly different. Due to difference in binding, free estradiol concentrations were significant higher in ESRD women (53.2 +/- 17.7 pg/mL) than control women (43.5 +/- 8.7 pg/mL), despite receiving 50% of the dose. There was no significant difference in estrone concentrations. Clearance of both estradiol and estrone in the dialysate was minimal. CONCLUSION: Women with ESRD should receive approximately 50% of the dose typically prescribed to women without ESRD.

Administration, Oral↗
PubMed2003

Inhibition of human polymorphonuclear cell oxidative burst by 17-beta-estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin.

PROBLEM: Polymorphonuclear cell (PMN) function may be directly influenced by 17-beta-estradiol and the endocrine disruptor, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). This may have significant consequences on PMN function within the female reproductive tract. This study evaluated the effects of 17-beta-estradiol and TCDD on PMN oxidative burst. METHOD OF STUDY: Peripheral blood PMN were isolated from normal male donors. Following treatment with 17-beta-estradiol, TCDD or both, PMN were stimulated with phorbol 12-myristate 13-acetate. Superoxide production was measured by lucigenin-enhanced chemiluminescence. RESULTS: Following 24-hr culture with either 17-beta-estradiol or TCDD, PMN superoxide production was significantly reduced, however, no such inhibition was observed when PMN were cultured with both estradiol and TCDD. Using antagonists, the estradiol and TCDD effects on PMN superoxide production was shown to be estrogen and aryl hydrocarbon receptor mediated. CONCLUSIONS: Estradiol and TCDD influence PMN oxidative burst through receptor mediated events. Such altered PMN function may have profound effects upon the normal endometrial cycle.

Cell Line, Tumor↗
PubMed2000

Effects of oral and transdermal 17beta-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women.

Few studies have examined the effects of 17beta-estradiol on parameters of insulin and glucose metabolism. We studied 42 healthy, untreated postmenopausal women seeking relief from menopausal symptoms. They were randomized to receive either oral 17beta-estradiol 2 mg daily combined with sequential oral norethindrone acetate (NETA) 1 mg daily from days 12 to 22, or transdermal 17beta-estradiol 0.05 mg daily combined with sequential oral NETA 1 mg daily from days 17 to 28. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and after 46 weeks (estrogen-alone phase) and 48 weeks (combined phase) of completed therapy. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. Both types of therapy were associated with a decrease in fasting insulin and glucose levels. Insulin sensitivity was increased by oral estradiol during the estrogen-alone phase but was reversed by the addition of NETA. Transdermal estradiol did not affect insulin sensitivity. Hepatic insulin uptake and insulin secretion were increased with both types of treatment. The oral regimen of estradiol therapy was favorable to both insulin elimination and sensitivity. Transdermal estradiol therapy had relatively few effects on insulin metabolism.

Administration, Cutaneous↗
PubMed2001

Rapid effects of calciotropic hormones on female rat enterocytes: combined actions of 1,25(OH)2-vitamin D3, PTH and 17beta-estradiol on intracellular Ca2+ regulation.

1,25(OH)(2)-Vitamin D(3) [1,25(OH)(2)D(3)], PTH and 17beta-estradiol increase intracellular Ca(2+) levels ([Ca(2+)](i)) in rat enterocytes by stimulating inner Ca(2+) store mobilization and voltage-dependent Ca(2+) channels through non-genomic activation of second-messenger cascades. The participation of store-operated Ca(2+) (SOC) channels in 17beta-estradiol regulation of enterocyte [Ca(2+)](i) has also been suggested. The aim of this work was to investigate whether PTH and/or 17beta-estradiol exert additive or synergistic effects acting in concert with the classic intestinal calciotropic hormone 1,25(OH)(2)D(3). Fura-2-loaded rat duodenal cells were stimulated using rPTH (10 nM), 17beta-estradiol (0.1 nM) or 1,25(OH)(2)D(3) (0.1 nM). The resulting Ca(2+) signal was characterized by an almost immediate rise in [Ca(2+)](i) (within 30 s) rapidly reaching peak levels, followed by a plateau phase that remained sustained as long as the cells were exposed to the stimulus. The addition of PTH at the sustained phase induced by 1,25(OH)(2)D(3) or, conversely, the addition of the secosteroid after the PTH-induced effect, did not induce additional increases in [Ca(2+)](i). Simultaneous treatment with both hormones resulted in an elevation of [Ca(2+)](i) equivalent to the maximal level caused by either agonist alone, suggesting common components for [Ca(2+)]i stimulation by PTH and 1,25(OH)(2)D(3). Treatment with 17beta-estradiol at the sustained phase induced by 1,25(OH)(2)D(3) or, conversely, treatment with the secosteroid after the 17beta-estradiol effect, induced additional increments in [Ca(2+)](i) (58 % and 63 %, respectively). Simultaneous treatment of enterocytes with both steroids potentiated their individual effects to the same extent as when added sequentially, also indicative of additive actions mediated by different sources of calcium signaling cascades. Moreover, 17beta-estradiol failed to further increase the 1,25(OH)(2)D(3)-induced initial Ca(2+) elevation in Ca(2+)-free medium, thus suggesting that extracellular influx mechanisms rather than intracellular Ca(2+) mobilization account for estrogen potentiation of 1,25(OH)(2)D(3) modulation of [Ca(2+)](i) in duodenal cells.

Animals↗
PubMed2004

Inhibition of human breast cancer cell proliferation with estradiol metabolites is as effective as with tamoxifen.

The anti-estrogenic substance tamoxifen is effective in the adjuvant therapy applied in human breast cancer. Since it partly exhibits estrogenic activity and has serious side-effects, however, pure anti-estrogenic compounds are being sought. In our experimental study, we compared the anti-proliferative effect of estradiol and 13 endogenous estradiol metabolites on human breast cancer cells with the effect of tamoxifen. We used MCF-7 and MDA-MB 231, the well-established estrogen receptor-positive and -negative cell lines. 4-hydroxytamoxifen, the active metabolite of tamoxifen, estradiol and 13 estradiol metabolites were tested in concentrations ranging from 3.1 to 100 microM. Incubation time was 4 days and cell proliferation was measured by means of the ATP chemosensitivity test. 4-hydroxytamoxifen showed an IC50 value of 27 microM and 18 microM in MCF-7 and MDA-MB 231 cells, respectively. Estradiol and its metabolites were anti-proliferative in both cell lines. A few A-ring metabolites were more effective in inhibiting cell proliferation than D-ring metabolites and the parent substance 17beta-estradiol. 4-OHE1, 2-MeOE1 and 2-MeOE2 were as effective in both cell lines as tamoxifen. For the first time it has been demonstrated that endogenous estradiol metabolites are equally anti-proliferative as tamoxifen in the context of human breast cancer cells. Since some of these metabolites exhibit no estrogenic activity, they are likely to be valuable in clinical studies of chemoprevention and adjuvant therapy of breast cancer.

Breast Neoplasms↗
PubMed1997

Influence of norethisterone acetate and estradiol on the serotonin metabolism of postmenopausal women.

Previous studies have shown that estradiol increases urinary excretion of the main stable metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), reflecting an increase in serotonin production. In the present study, the effect of the progestin norethisterone acetate (NETA) on serotonin metabolism was investigated, both alone and in addition to estradiol replacement in 20 postmenopausal women. Urinary excretion of 5-HIAA was measured after treatment with NETA orally for 8 days, estradiol valerate orally for 9 days and a combination of both hormones for 12 days. 5-HIAA values, expressed as percentages of the pretreatment values, were significantly increased only after the estrogen treatment phase. NETA alone did not significantly alter the serotonin metabolite excretion; in combination with estradiol, the estradiol effect on serotonin metabolism was abolished. This indicates that adding norethisterone acetate to estradiol replacement therapy may have a negative impact on the effect of estradiol on serotonin metabolism.

Estradiol↗
PubMed2002

Stimulatory effect of cigarette smoking on the 15 alpha-hydroxylation of estradiol by human term placenta.

OBJECTIVE: Our objective was to characterize the oxidative metabolism of estradiol by human term placenta and its modulation by cigarette smoking. METHODS: Placental microsomes were prepared from term placentas obtained from 13 cigarette smokers (20 to 30 cigarettes per day until the time of delivery) and 13 control subjects who were nonsmokers. Estrogen metabolism was studied by incubation of 250 nmol/L [(3)H]estradiol with placental microsomes and NADPH, and the estrogen metabolites were determined by HPLC and gas chromatography-mass spectrometry. RESULTS: 2-Hydroxyestradiol was the major hydroxyestrogen detected, followed by 6alpha-hydroxyestradiol. Small amounts of several other hydroxyestrogen metabolites (4-hydroxyestradiol, 6beta-hydroxyestradiol, 7alpha-hydroxyestradiol, and 16alpha-hydroxyestradiol) were also detected. Large amounts of estrone plus small amounts of 2-hydroxyestrone and unidentified nonpolar metabolites were formed. Cigarette smoking stimulated the placental hydroxylation of benzo[a ]pyrene by about 16-fold. Cigarette smoking had little or no effect on the overall rate of placental estradiol metabolism or on the formation of estrone, 2-hydroxyestradiol, 2-hydroxyestrone, or 16alpha-hydroxyestradiol. However, placental formation of 4-hydroxyestradiol and 7alpha-hydroxyestradiol was increased 38% (P =.08) and 150% (P =.05), respectively, in cigarette smokers. The formation of 6alpha-hydroxyestradiol was decreased 33% (P =.04). Metabolic formation of 15alpha-hydroxyestradiol was observed during incubations of estradiol with placental microsomes from 11 of the 13 cigarette smokers, but this metabolite was not detected during incubations with placental microsomes from any of the 13 nonsmokers. Analysis of data from all 26 placentas showed that the 15alpha-hydroxylation of estradiol was highly correlated with benzo[a ]pyrene hydroxylation (r = 0.93; P <.001). CONCLUSIONS: Many hydroxylated estradiol metabolites were formed by placental microsomes from cigarette smokers and nonsmokers. 15alpha-Hydroxylation of estradiol was markedly stimulated in the placentas of cigarette smokers.

Adult↗
PubMed2000

Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss.

OBJECTIVE: Our purpose was to study combinations of estradiol and gestodene for prevention of bone loss in early postmenopausal women. STUDY DESIGN: We randomly assigned 278 healthy, early postmenopausal women to receive either 2 mg 17beta-estradiol sequentially combined with 25 microg gestodene (group 2/25s), 2 mg estradiol sequentially combined with 50 microg gestodene (group 2/50s), 1 mg estradiol sequentially combined with 25 microg gestodene (group 1/25s), 1 mg estradiol continuously combined with 25 mg gestodene (group 1/25c), or placebo. RESULTS: After 3 years the changes in bone mineral density of the spine were as follows (mean +/- SEM): group 2/25s, 7. 41% +/- 0.72%; group 2/50s, 8.53% +/- 0.90%; group 1.25s, 6.67% +/- 0.88%; group 1/25c, 4.44% +/- 0.59%; and placebo group, -2.03% +/- 0. 64%. The changes in bone mineral density were mirrored in the biochemical bone markers. The average responses for the urinary C-terminal telopeptide fragments of type I collagen corrected for creatinine excretion were as follows (mean of baseline +/- SEM): group 2/25s, -68.8% +/- 0.03%; group 2/50s, -72.8% +/- 0.02%; group 1/25s, -60.7% +/- 0.03%; group 1/25c, -52.28% +/- 0.04%; and placebo group, 6.5% +/- 0.09%. Beneficial lipid effects were found in all active groups. The decreases in low-density lipoprotein were as follows (mean +/- SEM): group 2/25s, -13.7% +/- 3.0%; group 2/50s, -14.6% +/- 3.2%; group 1/25s, -9.28% +/- 2.2%; group 1/25c, -9.92% +/- 2.4%; and placebo group, 1.53% +/- 1.9%. CONCLUSION: These results demonstrate that estradiol therapy with 1 mg estradiol is fully protective against early postmenopausal bone loss.

Bone Density↗
PubMed1984

Estradiol feedback effects on the alpha-subunit mRNA in the sheep pituitary gland: correlation with serum and pituitary luteinizing hormone concentrations.

The effects of estradiol feedback on pituitary luteinizing hormone (LH) content, serum LH concentration, and in vitro-translated alpha subunit was examined in the ewe. Three animal models were used representing positive, negative, and no estradiol feedback. Two experiments were carried out: (i) anestrous ewes were treated acutely with five Silastic estradiol implants to induce a LH surge (positive feedback) and (ii) ovariectomized ewes were treated chronically with an estradiol implant (negative feedback) or were not treated (no feedback). Pituitary RNA was prepared and translated in a cell-free system; the alpha subunit was identified by immunoprecipitation and NaDodSO4/PAGE. cpm/microgram of RNA and immunoprecipitated growth hormone and prolactin were used to evaluate possible differences in RNA translational efficiencies among the treatment groups. In experiment 1, significantly higher amounts of the alpha subunit were observed in animals exhibiting an estradiol-induced LH surge than in normal anestrous ewes (P less than 0.001). Examination of values from individual animals suggested a correlation between the stage of the LH surge, pituitary LH, and translated alpha subunit. In experiment 2, the amount of alpha subunit observed in animals exposed to chronic estradiol negative feedback was significantly less (P less than 0.005) than that in the untreated ovariectomized animals (no feedback) and no different from that in intact anestrous ewes. These results suggest that both the negative and the positive feedback effects of estradiol include regulation of the amount of alpha-subunit mRNA.

Animals↗
PubMed1988

Enhanced osteoblast proliferation and collagen gene expression by estradiol.

Estrogens play a crucial role in the development of postmenopausal osteoporosis. However, the mechanism by which estrogens exert their effects on bone is unknown. To examine possible direct effects of 17 beta-estradiol on bone-forming cells, we used pure rat osteoblast-like cells in vitro as a model. Osteoblast-like cells prepared from calvaria of newborn rats were cultured serum-free in methylcellulose-containing medium for 21 days. Osteoblast-like cells proliferate selectively into clonally derived cell clusters of spherical morphology. 17 beta-Estradiol at concentrations of 0.1 nM and 1 nM enhanced osteoblast-like cell proliferation by 41% and 68% above vehicle-treated controls. The biologically inactive stereoisomer 17 alpha-estradiol (same concentrations) had no effect. Moreover, the antiestrogen tamoxifen abolished the stimulation of osteoblast-like cell proliferation by 17 beta-estradiol. After 21 days of culture, RNA was prepared and analyzed in a dot-hybridization assay for the abundance of pro alpha 1(I) collagen mRNA. Steady-state mRNA levels were increased in cultures treated with 17 beta-estradiol in a dose-dependent manner with maximal stimulation at 1 nM and 10 nM. At the same concentrations, the percentage of synthesized protein (labeled by [3H]proline pulse) that was digestible by collagenase was increased, indicating that 17 beta-estradiol acts at pretranslational levels to enhance synthesis of bone collagen. These data show that the osteoblast is a direct target for 17 beta-estradiol.

Animals↗
PubMed1996

Inhibition of catechol O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by quercetin. Possible role in estradiol-induced tumorigenesis.

Catecholestrogens have been postulated to mediate the induction of kidney tumors by estradiol in male Syrian hamsters. In this study, we examined the mechanism of inhibition by quercetin of the catechol O-methyltransferase-catalyzed O-methylation of catecholestrogens as a basis for the previously reported enhancement of estradiol-induced tumorigenesis by this flavonoid. In hamsters treated with 50 micrograms of [6,7-3H]estradiol, quercetin increased concentrations of 2- and 4-hydroxyestradiol in kidney by 80 and 59%, respectively. In animals treated with two 10-mg estradiol implants, quercetin also decreased by 63-65% the urinary excretion of 2- and 4-hydroxyestradiol monomethyl ethers. Taken together, these results demonstrate the in vivo inhibition of the O-methylation of catecholestrogens by quercetin. S-Adenosyl-L-homocysteine, produced by the methylation of catecholestrogens, noncompetitively inhibited the O-methylation of 2- and 4-hydroxyestradiol by hamster kidney cytosolic catechol O-methyltransferase (IC50 approximately 10-14 microM). Due to the rapid O-methylation of quercetin itself, quercetin decreased renal concentrations of S-adenosyl-L-methionine by approximately 25% in control or estradiol-treated hamsters and increased concentrations of S-adenosyl-L-homocysteine by 5-15 nmol/g of wet tissue, which was estimated to cause a 30-70% inhibition of the enzymatic O-methylation of catecholestrogens. Quercetin or fisetin (a structural analog) inhibited the O-methylation of 2- and 4-hydroxyestradiol by a competitive plus noncompetitive mechanism (IC50 approximately 2-5 microM). These results suggest that the in vivo O-methylation of catecholestrogens is inhibited more by S-adenosyl-L-homocysteine than by quercetin. The accumulation of 2- and 4-hydroxyestradiol during co-administration of estradiol and quercetin may enhance metabolic redox cycling of catecholestrogens and thus estradiol-induced kidney tumorigenesis.

Animals↗