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PubMed1986

Activation of estradiol-positive feedback at puberty: estradiol sensitizes the LHRH-releasing system at two different biochemical steps.

Experiments were performed to examine whether estradiol (E2) can influence some of the intraneuronal mechanisms involved in luteinizing hormone-releasing hormone (LHRH) release during the onset of puberty in the female rat. The capacity of median eminence (ME) nerve terminals to secrete LHRH, as determined by both their basal release of LHRH and by their response to prostaglandin E2 (PGE2) in vitro, increased significantly during the juvenile-early peripubertal periods of development (postnatal days 22-34). Ovariectomy (OVX) on day 22 led to a striking reduction in LHRH response to PGE2 on day 34. E2 administered via s.c. Silastic capsules, at a dose that reproduces juvenile serum E2 levels, restored the response. Simulation of first proestrous serum E2 levels in late juvenile (28-day-old) female rats enhanced both the sensitivity and the responsiveness of LHRH-containing terminals to PGE2. Furthermore, E2 enhanced the sensitivity and the responsiveness of LHRH terminals to norepinephrine (NE). This effect appeared to be related to both the increased LHRH response to PGE2 and an enhanced sensitivity of the PGE2-synthesizing pathway to NE. This is because MEs from E2-treated rats showed a marked increase in PGE2 release in response to a NE concentration which was barely effective in untreated controls. It is suggested that one of the mechanisms by which E2 activates the first preovulatory discharge of LHRH release in the female rat is by facilitating the occurrence of two different but sequentially related biochemical events: the stimulation of PGE2 formation by NE and the enhancement of LHRH release by PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Antioxidant protection of LDL by physiological concentrations of 17 beta-estradiol. Requirement for estradiol modification.

BACKGROUND: Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17 beta-estradiol (E2) inhibit oxidative modification of LDL. METHODS AND RESULTS: Plasma incubated with E2 (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu2+ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E2 at these concentrations in buffered saline produced no effect on Cu(2+)-mediated oxidation. Incubation of plasma with E2 had no effect on LDL alpha-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [3H]E2 was associated with dose-dependent association of 3H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [3H]E2 indicated that the majority of the associated species were not detectable as authentic E2 but as nonpolar forms of E2 that were susceptible to base hydrolysis consistent with fatty acid esterification of E2. Plasma-mediated association of E2 and subsequent antioxidant protection was inhibited by 5,5'-dithiobis(2-nitrobenzoic acid), an inhibitor of plasma acyltransferase activity. CONCLUSIONS: Exposure of LDL to physiological levels of E2 in a plasma milieu is associated with enhanced resistance to Cu(2+)-mediated oxidation and incorporation of E2 derivatives into LDL. This antioxidant capacity may be another means by which E2 limits coronary artery disease in women.

Amidines↗
PubMed1981

Effects of withdrawal of exogenous estradiol from pseudopregnant rabbits: transient nature of loss of luteal function and reversal of estradiol-induced suppression of luteinizing hormone-responsive adenylyl cyclase.

We have reported in recent studies that exogenous estradiol (E2) suppresses luteal LH-responsive adenylyl cyclase activity in pseudopregnant rabbits. The purpose of the present study was to determine whether this suppression is reversible. High or low level E2-filled Silastic capsules or empty capsules were sc implanted in day 5 pseudopregnant rabbits. On day 8 of pseudopregnancy, the high level E2 implants were either sham replaced, replaced with low level E2 implants, or replaced with empty capsules. The low level E2 implants and empty capsules were sham replaced. Animals from each of the five resulting groups were killed on days 9-12 of pseudopregnancy (1, 2, 3, and 4 days postimplant manipulation). As previously reported using an intermittent injection protocol, exogenous E2 had little effect upon serum progesterone concentrations. Both high and low level E2 implants suppressed the luteal LH-responsive adenylyl cyclase, but the suppression due to the low level E2 implants was not as great as that for the high level E2 implants. Within 24 h of switching from high to low level E2 implants, LH-responsive adenylyl cyclase activity increased from the level found for animals with high level E2 throughout to that found for animals with low level E2 throughout. Total withdrawal of exogenous E2 resulted in a precipitous fall in serum progesterone concentrations, as predicted by previous studies. However, within 4 days of withdrawal, both serum progesterone and luteal LH-responsive adenylyl cyclase activity had returned to control values. E2 implants also suppressed serum LH concentrations and follicular LH-responsive adenylyl cyclase activities. Both of these effects were reversed within 24-48 h after implant withdrawal. We conclude, therefore, that effects of exogenous E2 are reversible and that the previously reported E2-induced dependency upon exogenous E2 is related to the experimental protocol used.

Adenylyl Cyclases↗
PubMed1999

Differential effects of estradiol and estradiol-BSA conjugates.

The steroid 17beta-estradiol (E2) acts to modulate transcription through classical nuclear estrogen receptors (ER-alpha and ER-beta). However, E2 also induces a number of rapid responses (<10 min) within cells, including cells devoid of classical ERs, consistent with the presence of a membrane receptor for E2. Membrane impermeable steroids, typically bovine serum albumin (BSA) conjugates, are commonly used to characterize these non-genomic actions of E2 to exclude the involvement of nuclear ERs. Here we report that E2-BSA conjugate preparations, but not unconjugated E2, activate extracellular signal-regulated protein kinases (ERK1 and ERK2) in the SK-N-SH neuroblastoma cell line, raising concerns regarding the use of these reagents as E2 mimics. Freshly prepared solutions of E2-BSA were found to contain free immunoassayable E2 (iE2), which could be removed by filtration. E2-BSA solutions devoid of free iE2 failed to compete for binding of 125I16alpha-iodo-E2 to ER-alpha or ER-beta. Furthermore, in contrast to E2, E2-BSA conjugates did not bind to ER-alpha or ER-beta as assessed by electrophoretic mobility shift analyses. Protein analysis demonstrated that certain E2-BSA preparations were of very high molecular weight, suggesting extreme protein cross-linking. These findings suggest that E2-BSA does not mimic E2 and is not an appropriate ligand for investigating estrogen receptors. This underscores the need to design stable, cell impermeable analogs of estrogen for the characterization of membrane estrogen receptors.

Binding, Competitive↗
PubMed1975

Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17beta-estradiol in postmenopausal women.

Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.

Administration, Oral↗
PubMed1985

Changes in sex hormone-binding globulin binding capacity and percent free estradiol during development in the female rhesus monkey (Macaca mulatta): relation to the metabolic clearance rate of estradiol.

Circulating sex hormone-binding globulin (SHBG) binding capacity and percent free estradiol (% free E2) were measured in separate groups of female rhesus monkeys from 2 months of age through adulthood (greater than 4.5 yr old). The SHBG concentration alone was also measured in 11 adult and 6 sexually immature animals on the same day as the blood MCR of E2. Serum SHBG levels were the highest (range, 12-25 micrograms T/dl) and the % free E2 the lowest (0.88%) in animals 6 months old or less. After the age, serum SHBG binding capacity declined generally at an average rate of 0.11 SHBG U (microgram T/dl)/month toward a nadir in adulthood. There was no difference in the SHBG levels in the follicular or luteal phase of the menstrual cycle. The relative blood MCR E2 and circulating SHBG binding capacity were significantly greater (P less than 0.001) in the sexually immature animals [MCR E2, 48.4 +/- 5.2 (SEM) liters/day . kg body wt; SHBG, 9.8 +/- 1.0 microgram T/dl, n = 6] than in adult animals (MCR E2, 27.7 +/- 1.7 liters/day kg body wt; SHBG, 4.6 +/- 0.3 microgram T/dl, n = 11). There was no relation between the MCR E2 and circulating SHBG levels within each group of adult or immature animals. The mean % free E2 doubled (to 1.6%) between 1 and 54 months of age; there was no relation between total circulating E2 and % free E2. Although a high SHBG binding capacity and a low % free E2 in the circulation of the immature animal does not inhibit the metabolic clearance of E2; it remains possible that these factors (and others) may hinder the access of E2 to reproductive target tissues and thereby contribute to the slow acquisition of reproductive competence in this species.

Aging↗
PubMed2000

Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women.

Regularly menstruating women are relatively protected from cardiovascular disease. Epidemiological and endothelial function studies attribute this protection to estradiol (E(2)), but both progesterone (P) and E(2) are normally present. A range of vascular effects of added progestins have been described, from neutral to detrimental, but the effects of P per se on endothelial function in humans have not been reported. We therefore investigated the acute effects of E(2), P, and E(2) combined with P, on endothelium-dependent and -independent forearm blood flow responses. Using venous occlusion plethysmography, forearm blood flow (FBF) was measured during acute brachial artery infusions, achieving physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P in healthy menopausal women with no cardiovascular disease risk factors. Vehicle or hormones were infused, in random order, on 4 days, 1 week apart. Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Twenty-seven healthy menopausal women were studied, and all had normal baseline endothelial responses. Small ( approximately 15%), statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments. No impairment in response was seen with P alone or in combination with 17-beta-E(2). In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function, acute exposure to physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P produced equivalent endothelium-dependent responses. These data suggest that P does not have detrimental vascular effects in humans.

Cross-Over Studies↗
PubMed1992

Skeletal muscle protein metabolism and serum growth hormone, insulin, and cortisol concentrations in growing steers implanted with estradiol-17 beta, trenbolone acetate, or estradiol-17 beta plus trenbolone acetate.

Skeletal muscle protein degradation, measured by urinary N tau-methylhistidine excretion, and circulating concentrations of growth hormone (GH), insulin (INS), and cortisol (CT) were monitored in steers before and after implantation with estradiol-17 beta (E2; 24 mg) and trenbolone acetate (TBA; 300 mg). Yearling crossbred steers (n = 43) were randomly assigned to four treatment groups in a 2 x 2 factorial arrangement: nonimplanted controls (C); TBA; E2; and TBA plus E2 (TBA+E2). A subgroup (Block 1) of 16 steers was bled on d -12, 31, and 72 after implanting. Deposition of skeletal muscle protein was markedly increased (P less than .001) by E2 and TBA+E2 treatment. This response occurred mainly within the first 40 d after implantation and declined (P less than .001) in concert with decreasing (P less than .01) concentration of serum E2. Anabolic steroid treatment did not affect the rate of skeletal muscle protein breakdown. There was no apparent relationship between reduced serum CT concentration (linear effect; P less than .01) in TBA-treated steers and skeletal muscle protein degradation rate. Blood concentration and pulse activity of INS were not affected by anabolic steroid administration. Both TBA- and TBA+E2-implanted steers displayed a linear decrease (P less than .05) in serum GH concentration over time, which was similar to C. Lowered mean GH concentration resulted from a reduction (TBA main effect; P less than .05) in pulse amplitude of GH. Unlike TBA, TBA+E2, and C, only E2 maintained serum GH concentrations over time. Although increased muscle protein deposition was evident in TBA+E2-treated steers, an obvious causal relationship between this response and circulating GH, INS, and CT was not revealed. These results do not support the concept that combined androgenic agent and estrogen administration effectively reduce bovine muscle protein degradation by static modulation of circulating endogenous anabolic and antianabolic hormones.

Anabolic Agents↗
PubMed1997

Serum concentrations of trenbolone-17 beta and estradiol-17 beta and performance of heifers treated with trenbolone acetate, melengestrol acetate, or estradiol-17 beta.

The effects of the growth-promoting steroids estradiol-17 beta (E2), trenbolone acetate (TBA), and melengestrol acetate (MGA) in heifers on serum concentrations of E2 and trenbolone-17 beta (TBOH) were examined. Feed intake and growth performance were also measured. Serum concentrations of E2 and TBOH were measured on d 0, 1, 3, 5, 7, 13, 21, 28, 42, 56, 84, 112, and 140 in finishing heifers administered the following treatments: 1) control; 2) MGA, .5 mg per heifer daily; 3) Revalor-H (140 mg TBA + 14 mg E2); 4) Revalor-H + MGA; 5) Finaplix-H (200 mg TBA); and 6) Finaplix-H + MGA. Revalor-H implantation (Treatments 3 and 4) increased (P < .05) serum E2 concentrations; peak concentrations (67.5 pg/mL) occurred between d 21 and 56. Feeding MGA (Treatment 4) had no effect (P > .05) on this increase in serum E2 concentrations (63.3 pg/mL). From d 84 until d 140, serum E2 was greater (P < .05) for the Revalor-H treatment (average of 19 pg/mL) than for the control (7 pg/mL) or Finaplix-H treatments (6.5 pg/mL). Serum E2 concentrations increased numerically two- to threefold from d 56 to 140 in controls fed MGA, compared with controls not fed MGA. There was the expected increase in serum TBOH concentrations after TBA implantation in the Revalor-H and Finaplix-H treatments; concentrations were similar (P > .05) for Revalor-H (221 pg/mL) and Finaplix-H (280 pg/mL). After d 56, serum TBOH concentrations decreased in both treatments to 10 and 20% of these concentrations, respectively. Feeding MGA increased serum TBOH (P < .05). Dry matter intake by heifers did not differ among treatments. Feeding of MGA improved gains (P = .12) and efficiencies (P < .01) in nonimplanted heifers and had no effect (P > .4) on gains or efficiencies in Finaplix-implanted heifers.

Anabolic Agents↗
PubMedDate not supplied

Cycle control, tolerability, and satisfaction among women switching from 30-35 microg ethinyl estradiol-containing oral contraceptives to the triphasic norgestimate/25 microg ethinyl estradiol-containing oral contraceptive Ortho Tri-Cyclen LO.

OBJECTIVE: To determine cycle control, tolerability, and satisfaction among women (aged 18-45) switching from oral contraceptives (OCs) containing 30-35 microg ethinyl estradiol (EE) to Ortho Tri-Cyclen LO (norgestimate 180/215/250 microg/EE 25 microg) and Loestrin Fe 1/20 (norethindrone acetate 1 mg/EE 20 microg). DESIGN: A subset of patients from a study comparing Ortho Tri-Cyclen LO (N = 864) with Loestrin Fe 1/20 (N = 565) was analyzed. The subset was defined as those who had taken a 30-35 microg EE-containing OC within 60 days of study start. The total number of cycles of exposure for the subset was 6,054 for Ortho Tri-Cyclen LO and 3,814 for Loestrin Fe 1/20. Additional analyses evaluated switchovers from Ortho Tri-Cyclen to Ortho Tri-Cyclen LO (N = 111). MAIN OUTCOME MEASURES: Cycle control was assessed by daily diary cards reporting the frequency, severity, and duration of bleeding/spotting. Discontinuation rates due to adverse events (AEs) were considered to reflect tolerability. Satisfaction was evaluated by questionnaire. RESULTS: The proportion of cycles in which subjects experienced breakthrough bleeding and/or spotting was significantly lower with Ortho Tri-Cyclen LO than Loestrin Fe 1/20. Discontinuations due to AEs and serious AEs were comparable for Ortho Tri-Cyclen LO (3.4% and 0.6%, respectively) and Loestrin Fe 1/20 (3.2% and 0.7%, respectively). More women on Ortho Tri-Cyclen LO versus Loestrin Fe 1/20 were very or somewhat satisfied at Cycle 6 (86% vs. 81.1%; P < 0.05) and last visit (81.6% vs. 78.1%; P < 0.05). At Cycle 6, 89.3% of Ortho Tri-Cyclen to Ortho Tri-Cyclen LO switchovers were very or somewhat satisfied, and 72.6% desired to continue taking Ortho Tri-Cyclen LO after study conclusion. Conclusions-Switchovers from OCs containing 30-35 microg EE to Ortho Tri-Cyclen LO had excellent cycle control and tolerability, and were satisfied.

Adolescent↗
PubMed2004

Neither sildenafil nor vaginal estradiol improves endometrial thickness in women with thin endometria after taking oral estradiol in graduating dosages.

PURPOSE: To determine if sildenafil improves endometrial thickness better than vaginal estradiol (E2) in women with a history of thin endometria. METHODS: Women failing to attain an 8 mm endometrial thickness on either the oocyte retrieval cycle or their first frozen embryo transfer (ET) despite an oral graduated E2 regimen were treated again with graduated oral E2 and were also randomly assigned to vaginal sildenafil or vaginal E2 therapy. Endometrial thickness was compared between the groups. RESULTS: Neither vaginal E2 nor sildenafil significantly improved endometrial thickness or blood flow in the subsequent frozen ET-cycle. CONCLUSIONS: These data fail to corroborate previous claims that 25 mg sildenafil four times daily intravaginally can improve endometrial thickness.

Administration, Intravaginal↗
PubMed1991

Effects of vehicle supplementation on total estradiol absorption from a transdermal estradiol delivery system.

OBJECTIVE: To evaluate the effects of vehicle supplementation on serum estradiol (E2) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch. DESIGN: Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period. SETTING: Normal human volunteers were studied in an academic research environment. PATIENTS, PARTICIPANTS: The subject pool included eight healthy postmenopausal women between 32 and 60 years of age. INTERVENTIONS: In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, and identical patch was worn into which 0.6 mL of ethanol was injected on day 3 of use. MAIN OUTCOME MEASURES: Serum E2 levels were measured in both groups. RESULTS: Although E2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours. CONCLUSION: The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.

Absorption↗
PubMed1991

Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol.

The pharmacokinetics of three transdermal estradiol (E2) replacement regimens were studied following establishment of steady-state dynamics. Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm transdermal delivery system 4 mg (0.05 mg/day) were administered for 14 days each to 15 postmenopausal volunteers, with a 14-day washout period between each regimen. The percutaneous E2 pharmacokinetics were compared with an oral micronized E2 preparation. Venous samples were obtained at 0, 1, 2, 4, 8, 12, and 24 hours on 3 sequential days 11 days after initial application of the Oestrogel and the transdermal delivery system, and at the same times after oral E2 ingestion. All three percutaneous regimens provided nearly constant serum E2 and estrone (E1) levels throughout their use. The mean serum E2 levels were 102.9 +/- 39.9, 68.1 +/- 27.4, and 41.1 +/- 13.5 pg/mL for Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm, respectively. Oral E2 resulted in a mean serum E2 level of 114.0 +/- 65.2 pg/mL with marked peak and nadir values. The E1/E2 ratio was comparable with all three percutaneous regimens (1.08-1.33) and was significantly lower than that found with oral Estrace (5.05).

Administration, Cutaneous↗
PubMed1989

Comparison of two monophasic oral contraceptives: gestodene/ethinyl estradiol versus desogestrel/ethinyl estradiol.

The contraceptive efficacy, cycle control, safety, and subject acceptance of the new contraceptive (OC) preparations containing gestodene (GTD) plus ethinyl estradiol (EE) are being compared with the combination containing desogestrel (DSG) plus EE in a randomized, open-label outpatient study. Interim data from six cycles of this ongoing study were obtained for 378 women receiving 75 micrograms GTD + 30 micrograms EE per day and 384 women receiving 150 micrograms DSG + 30 micrograms EE per day. Each group received OCs for 21 days per cycle. There were no pregnancies in subjects receiving either OC during 1,658 cycles of GTD + EE or 1,707 cycles of DSG + EE use. The continuation rates were similar in the two groups, and no major differences in type or incidence of side effects were observed. There were also no clinically significant changes in blood pressure or body weight in either group. Slightly better cycle control was observed for subjects taking GTD + EE, since the incidence of spotting and breakthrough bleeding was slightly greater for women taking DSG + EE. The incidence of amenorrhea (missed periods) tended to be lower for the subjects taking the GTD-containing preparation: 7 (0.5%) cycles compared with 12 (0.9%) DSG + EE cycles. The GTD + EE-treated subjects also had a lighter menstrual flow. Fewer subjects taking GTD + EE withdrew because of side effects typically associated with OCs. The data from this study indicate that the new combination of GTD + EE provides safe and effective oral contraception, with good tolerance and cycle control.

Adult↗
PubMed1995

High-performance liquid chromatography separation of hydroxylated estradiol metabolites: formation of estradiol metabolites by liver microsomes from male and female rats.

A high-performance liquid chromatography method has been described for the separation of estradiol (E2), estrone (E1) and 27 hydroxylated and keto derivatives of these estrogens. Chromatography of a mixture of 29 estrogen standards resulted in 20 different peaks. Solvent extraction followed by the chromatographic separation and quantification of radioactive metabolites was used for studies on the metabolism of [4-14C]E2 by liver microsomes from adult male and female rats. Liver microsomes from male rats metabolized [4-14C]E2 more rapidly and to a larger number of metabolites than liver microsomes from female rats. Under conditions in which less than 10% of the substrate was metabolized, major metabolites from liver microsomes of male rats cochromatographed with E1, 2-OH E2, 15 alpha-OH E2 and 16 alpha-OH E2, and major metabolites from liver microsomes of female rats cochromatographed with E1, 2-OH E2 and 16 alpha-OH E2. The identity of the metabolites was confirmed by mass spectrometry. Using liver microsomes from male rats and conditions in which more extensive metabolism of the substrate occurred, more than 15 additional metabolites of [4-14C]E2 were observed. Liver microsomes from male rats were many-fold more active than liver microsomes from female rats at catalyzing the 2-, 15 alpha- and 16 alpha-hydroxylation of E2. Our studies on the metabolism of [4-14C]E2 by rat liver microsomes indicate that the profile of E2 metabolites is dependent on the time of incubation, microsomal protein concentration and substrate concentration.

Animals↗
PubMed1993

Pharmacokinetics of estradiol, free and total estrone, in young women following single intravenous and oral administration of 17 beta-estradiol.

The pharmacokinetic parameters of estradiol (E2, CAS 50-28-2), free and total estrone (E1, CAS 53-16-7) were determined in 14 young women following a single oral administration of 2, 4 and 8 mg E2 and a single intravenous administration of 0.3 mg E2 in an open, intraindividual comparison with 4 treatments. The purpose of the study was to determine the absolute bioavailability of orally administered E2 in a larger group of women and to assess the inter- and intraindividual variability of basic pharmacokinetic parameters of E2 and metabolically derived E1. In addition, the outcome of this study should provide a basis for the decision whether E2 could potentially be used in a combination oral contraceptive. There was a dose proportional increase in the AUC-values following the oral administration of 2 mg and 4 mg doses of E2. At the high dose of 8 mg, however, only about 76%, 78% and 70% of the expected values were found for E2, free and total E1, respectively. Especially the reduction in total E1 concentrations points to an incomplete absorption of E2 at the high dose level. The absolute bioavailability of orally administered E2 was calculated based on the 4 mg dose and was found to be 4.9 +/- 5.0%. The mean ratio of free E1 and E2 concentrations in the serum, following parenteral and oral administration of E2 was about 1.0 (i.v.) and between 8.8 to 19.8 (p.o.), respectively. Pharmacokinetic parameters, like AUC, derived from serum level-time curves of E2, free and total E1 showed a high intra- and interindividual variability.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1996

Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study.

After menopause the haemostatic balance shifts towards a latent hypercoagulable state. To evaluate the effects of two regimens of transdermal estradiol (E2) combined with progestin on the balance between procoagulant factors and inhibitors, 255 women in physiological menopause for 1-5 years were randomly allocated to 1 year of treatment with cyclic transdermal E2 (50 micrograms/day for 21 days) plus medroxyprogesterone acetate (MPA) (10 mg/day from days 10 to 21), continuous transdermal E2 (50 micrograms/day for 28 days) plus MPA (10 mg/day from days 14 to 25), or placebo. Fibrinogen, factor VII (FVII), factor VIII:C (FVIII:C), antithrombin III (ATIII), protein C, protein S, heparin cofactor II (HCII) and plasminogen activator inhibitor (PAI-1) levels were measured at baseline and after 6 and 12 cycles. 167 women who took the treatment for at least 6 cycles were evaluable. The continuous treatment group had significantly lower final values of fibrinogen, FVII, ATIII, protein S and HCII than the placebo group; the cyclic treatment reduced fibrinogen in comparison with placebo but the difference was not significant. In conclusion, both regimens produce a clinically relevant decrease of fibrinogen levels; the continuous regimen affects also the levels of FVII and inhibitors suggesting that the haemostatic balance is shifted to a more physiological state.

Administration, Cutaneous↗
PubMed1996

Pharmacokinetics of estradiol and of estrone during repeated transdermal or oral administration of estradiol.

The estradiol (CAS 50-28-2, E2) and estrone (CAS 53-16-7, E1) concentrations in blood were investigated during a 3-week twice weekly application of an E2 transdermal patch, or daily oral administration of E2 tablets. The transdermal patch (Dermestril 50, hereinafter called "Patch") contains 4 mg E2 and delivers daily 50 micrograms E2. The E2 tablets (hereinafter called "Tablet") contains 2 mg micronized E2. The study was performed on 32 healthy postmenopausal women randomly assigned to two parallel groups, each of 16 subjects, one treated with Patch and the other with Tablet. During the first transdermal Patch application, E2 reached effective concentrations of 30 pg/ml of more 12 h after application. During the following 5 applications the concentrations of E2 remained rather constant (fluctuation = 0.65). The study state was reached with the second Patch, with an average concentration (Cav) of 35 pg/ml. After removal of the last Patch, the E2 concentrations returned to the basal levels within 12 h. The E1 concentrations reached the maximum concentration (Cmax) of 48 pg/ml 41 h after the first Patch application and then remained rather constant (fluctuation = 0.28), with a Cav at steady state of 47 pg/ml. During the oral administration of the first Tablet, E2 reached the peak of 1084 pg/ml 49 min after administration and then decreased rapidly in the following 3 h. There was a progressive cumulation of E2 until steady state, which was reached after the 5th Tablets with a Cav of 418 pg/ml i.e. 12.0 times greater than during Patch, and very large pulses of E2 (fluctuation = 3.68). The E1 concentrations reached the peak of 334 pg/ml 4.28 h after the first administration. The steady was reached with the 14th daily administration. There were Large pulses of E1 (fluctuation = 1.15). The Cav was 441 pg/ml, i.e. 9.4 times greater than during Patch. In conclusion the twice weekly application of the transdermal Patch elicits rather constant and therapeutically effective blood concentrations of E2 and E1. In contrast, the daily oral administration of E2 Tablets elicits large pulses of E2 and E1, and exposes the subjects to high concentrations of E2 and of E1, which are 12.0 and 9.4 times greater, respectively, than those elicited by the Patch. Both treatments were fairly well tolerated, and no withdrawal of the medications during the study was necessary.

Administration, Cutaneous↗