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PubMed1976

[Changes in the concentration of estrone, estradiol and estradiol in the blood of pregnant ewes].

A chemical method was used for the study of the concentration of the three main groups of oestrogens in the blood of five ewes after mating in natural heat. The concentration values of all the three groups of oestrogens was found to increase in proportion with the length of gravidity. From the 30th to the 140th day of gravidity the average concentration values of oestrone increased from 309 to 1380 ng per 100 ml blood, those of oestradiol from 48 to 192 ng per 100 ml blood. Significant changes were recorded in oestrone between the 50th and 60th day and between the 130th and 140th day of gravidity; in oestradiol and oestriol such changes occurred on the 140th day of gravidity.

Animals↗
PubMed2005

Evidence that 17alpha-estradiol is biologically active in the uterine tissue: antiuterotonic and antiuterotrophic action.

BACKGROUND: 17alpha-Estradiol has been considered as the hormonally inactive isomer of 17beta-estradiol. Recently, nongenomic (smooth muscle relaxation) and genomic (light estrogenic activity) effects of 17alpha-estradiol have been reported, but no reports have yet determined its possible antiestrogenic activity. Therefore, this study investigated: the nongenomic action of 17alpha-estradiol on uterine contractile activity and its potential agonist-antagonist activity on uterine growth. METHODS: Uterine rings from rats were isometrically recorded. Different concentrations (0.2-200 microM) of 17alpha-estradiol were tested on spontaneous contraction and equimolarly compared with 17beta-estradiol. To examine the mechanism of 17alpha-estradiol action, its effect was studied in presence of beta2-antagonist (propranolol), antiestrogens (tamoxifen and ICI 182,780) or inhibitors of protein synthesis (cycloheximide) and transcription (actinomycin D). Moreover, contractions induced by high potassium (KCl) solution or calcium in depolarized tissues by KCl-calcium free solution were exposed to 17alpha-estradiol. Collaterally, we performed an uterotrophic assay in adult ovariectomized rats measuring the uterine wet weight. The administration for three days of 0.3 microM/day/Kg 17beta-estradiol was equimolarly compared with the response produced by 17alpha-estradiol. Antiuterotrophic activity was assayed by administration of 0.3 microM/day/Kg 17beta-estradiol and various doses ratios (1:1, 1:3, 1:5, and 1:100) of 17alpha-estradiol. RESULTS: The estradiol isomers elicited an immediate relaxation, concentration-dependent and reversible on spontaneous contraction. 17alpha-Estradiol presented lower potency than 17beta-estradiol although it did not antagonize 17beta-estradiol-induced relaxation. Relaxation to 17alpha-estradiol was not inhibited by propranolol, tamoxifen, ICI 182,780, cycloheximide or actinomycin D. The KCl contractions were also sensitive to 17alpha-estradiol-induced relaxation and calcium contractions in depolarized tissues were markedly prevented by 17alpha-estradiol, implying a reduction of extracellular calcium influx through voltage-operated calcium channels (VOCCs). Uterotrophic assay detected significant increase in uterine weight using 17alpha-estradiol, which was significantly minor as compared with 17beta-estradiol. 17alpha-Estradiol, at all doses ratios, significantly antagonized the hypertrophic response of 17beta-estradiol. CONCLUSION: 17alpha-Estradiol induces a relaxing effect, which may be independent of the classical estrogen receptor, nongenomic action, apparently mediated by inactivation of VOCCs. 17alpha-Estradiol is also a weak estrogen agonist (uterotrophic response); likewise, 17alpha-estradiol may act as an antiestrogen (antiuterotrophic response). The overall data document a nongenomic relaxing action and a novel antiestrogenic action of 17alpha-estradiol, which are relevant in estrogen-mediated uterine physiology.

Animals↗
PubMed1986

Selecting constant serum estradiol levels achieved by vaginal rings.

Prolonged, constant, systemic administration of estradiol-17 beta is useful for research and clinical purposes. Sustained systemic administration of estradiol-17 beta can be accomplished by means of estradiol-17 beta-containing polydimethylsiloxane vaginal rings. The ability to preselect a specific circulating serum level of estradiol-17 beta from several possible levels using estradiol-17 beta vaginal rings would be advantageous. In the present study, the author examined the effects of changes in the surface area and estradiol-17 beta content of estradiol-17 beta vaginal rings on the resulting serum levels of estradiol-17 beta. During three months of estradiol-17 beta vaginal ring exposure, the average serum levels of estradiol-17 beta produced were 53 +/- 10 pg/mL with a 100-mg estradiol-17 beta vaginal ring, 81 +/- 7 pg/mL with a 200-mg estradiol-17 beta vaginal ring, and 152 +/- 14 pg/mL with a 400-mg estradiol-17 beta vaginal ring. When compared with levels of estradiol-17 beta observed in normal menstrual cycles, the levels obtained with the 100-mg estradiol-17 beta vaginal ring, 200-mg estradiol-17 beta vaginal ring, and 400-mg estradiol-17 beta vaginal ring correspond to early follicular phase, midfollicular phase, and complete menstrual cycle, respectively. The author concludes that stable circulating levels of estradiol-17 beta resulting from estradiol-17 beta vaginal ring administration resemble estradiol-17 beta levels characteristic of specific phases of the normal menstrual cycle. Therefore, estradiol-17 beta administration by estradiol-17 beta vaginal ring may be helpful for research and clinical applications.

Adult↗
PubMed1988

Dynamic pattern of estradiol binding to uterine receptors of the rat. Inhibition and stimulation by unsaturated fatty acids.

The binding of estradiol to uterine cytosoluble receptors from 24-day-old rats was reduced or potentiated by unsaturated fatty acids (NEFAs), depending on the concentrations of estradiol and unsaturated NEFAs. At estradiol concentrations of up to 1.5 x 10(-8) M, unsaturated NEFAs inhibited estradiol binding to the 8 S cytosol receptor. This inhibition was dose-dependent (10-70%, p less than 0.001) and a function of NEFA unsaturation. Scatchard analysis indicated that unsaturated NEFAs caused a large decrease in receptor affinity for estradiol. Polyunsaturated NEFAs had no apparent effect on estradiol binding at estradiol concentrations of 2-4 x 10(-8) M. At high estradiol concentrations (above 4 x 10(-8) M), estradiol binding was increased 130-250% (p less than 0.01) by polyunsaturated NEFAs. This increased binding was particularly associated with proteins sedimenting at 12.5 S and the 8 S binding was, in fact, reduced. Metabolic studies showed that the reduced binding in the presence of unsaturated fatty acids was correlated with a decrease in reversibly bound estradiol at low estradiol concentrations. The increase in estradiol binding at high estradiol concentrations is the result of a reduction in reversibly bound estradiol and an increase in nonorganic solvent-extractable (water-soluble) estradiol. The amounts of these water-soluble estradiol derivatives depended on both estradiol and unsaturated NEFA concentrations. 70% of the water-soluble estradiol derivatives were trichloroacetic acid-precipitable, suggesting a covalent protein-steroid link. Thus, changes in the hydrophobic fatty acid environment of the uterine cytosol estrogen receptor could modify estrogen-receptor function by altering binding site conformation and/or by inducing changes in estradiol metabolism.

Animals↗
PubMed2001

Biological effects of hormone replacement therapy in relation to serum estradiol levels.

OBJECTIVE: Tissues in various parts of the body have different sensitivities to estradiol. However, it is very difficult to measure the serum estradiol levels precisely in women receiving oral conjugated equine estrogen, which is a mixture of estrogens. In the present study, we precisely measured the serum levels of estradiol in postmenopausal women undergoing hormone replacement therapy (HRT), and we clarified the relationships between serum estradiol levels and the effects of HRT on the Kupperman index, bone mineral density (BMD), serum gonadotropin, lipid metabolism and unscheduled bleeding as the clinical endpoints. METHODS: Sixty-eight postmenopausal or bilaterally ovariectomized women, aged 30-64 years, who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly assigned to two groups: one group of 34 patients who received oral administration of 0.625 mg conjugated equine estrogen (CEE, Premarin, Wyeth) and 2.5 mg medroxyprogesterone acetate (MPA, Provera, Upjohn) every other day, and another group of 34 patients who received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. All subjects were re-classified into three groups according to the serum estradiol level after 12 months of treatment: (1) low estradiol group (<15 pg/ml, n = 25); (2) middle estradiol group (> or =15 and <25 pg/ml, n = 27), and (3) high estradiol group (> or =25 pg/ml, n = 16). We examined the relationships between serum estradiol level and the effects of estradiol on the Kupperman index, BMD, serum gonadotropin levels, lipid profile and unscheduled bleeding in these three groups. RESULTS: RESULTS obtained by using our newly developed high-performance liquid chromatography (HPLC)-radioimmunoassay (RIA) system clearly showed that the effects on each tissue in postmenopausal women receiving oral CEE and MPA is closely related to estradiol level. The effects of HRT on BMD, serum gonadotropin levels and lipid profile were shown to be clearly dependent on the serum estradiol levels, while the effect of HRT on the Kupperman index was independent of the serum estradiol level. Furthermore, it was also found that a very low concentration of estradiol (<15 pg/ml) was sufficient to suppress the serum LH and FSH levels and to relieve vasomotor symptoms, and that the minimum concentration of estradiol required to increase BMD was 15 pg/ml. On the other hand, the level of estradiol required to reduce total cholesterol, low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (Apo B) was found to be more than 25 pg/ml, while the level required to increase high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A1) was at least 15 pg/ml. The incidence of unscheduled bleeding was also lower in the low estradiol group than in the other estradiol level groups. CONCLUSION: These results suggest that the different clinical endpoints have different response thresholds and thus reflect tissue sensitivity to estradiol levels achieved by HRT.

Adult↗
PubMed1975

Premature regression of corpora lutea in pseudopregnant rabbits following the removal of polydimethylsiloxane capsules containing 17 beta-estradiol.

17-beta-Estradiol, which is luteotropic in rabbits, was administered during pseudopregnancy via polydimethylsiloxane (Silastic) implants to determine the effects on serum progesterone concentrations. Implants which released estradiol at a rate of approximately 2 mug/day were place beneath the skin the day after sterile mating and ovulation (day 0). Blood (3 ml) was obtained from the marginal ear vein on days 3, 6, 9, 10, 11 and 12. Serum estradiol levels, determined by radioimmunoassay, were 2- to 3-fold higher in estradiol-treated rabbits (11.7 plus or minus 1.2 pg/ml) than in untreated pseudopregnant controls (5.9 plus or minus 1.4 pg/ml). Weights of corpora lutea in treated and control rabbits were not different at the conclusion of the experiment on day 12. Serum progesterone concentrations, also determined by radioimmunoassay, were not significantly different between treated and control animals. However, when estradiol implants were removed from other rabbits on day 10, a rapid decline in serum progesterone occurred, from 14.0 plus or minus 2.4 to 2.6 plus or minus 0.8 ng/ml 24 h later. By comparison, serum progesterone concentrations in rabbits with estradiol implants left in place and in untreated rabbits on day 12 were similar (similar to 12 ng/ml). The premature decline in serum progesterone was accompanied by a decrease in the wet weight of corpora lutea. Other experiments revealed: 1) a precipitous fall in serum estradiol to basal values within 2 h after estradiol implants were removed, preceding the decline in serum progesterone by approximately 6 to 10 h; 2) reduced levels of estradiol in ovarian venous blood, but elevated levels of estradiol in peripheral arterial blood of rabbits with estradiol impants. The inability to elevated estradiol to increase serum progesterone or weights of corpora litea suggests that the luteotropic effect is maximal when estradiol is present at physiological concentrations. Following the continuous administration of estradiol, ovarian secretion of estradiol appears diminished and the corpora lutea become dependent upon the exogenous estradiol for luteotropic support. Although the ovaries continue to release measureable quantities of estradiol, this is inmeasurable quantities of estradiol, this is insufficient to prevent regression of corpora lutea when exogenous estradiol is rapidly withdrawn from the circulation.

Animals↗
PubMed1998

Effects of estradiol and exogenous insulin-like growth factor I (IGF-I) on the IGF-I axis during growth hormone inhibition and antagonism.

In adult female monkeys, serum concentrations of insulin-like growth factor I (IGF-I) are decreased by estradiol replacement, whereas levels of IGF-binding protein-3 (IGFBP-3) are increased. Furthermore, chronic IGF-I supplementation elevates serum IGFBP-3 despite a suppression of GH. To better understand how estradiol and IGF-I affect the IGF-I axis, a series of three studies was conducted to examine how estradiol and GH interact to affect the IGF-I axis and how IGF-I regulates IGFBP-1 and -3 during GH inhibition or receptor antagonism in adult female rhesus monkeys. In Exp 1, adult ovariectomized females were studied during a 28-day baseline condition and a 28-day treatment condition in which females received a constant s.c. infusion of a somatostatin analogue (octreotide, Sandoz; SSa; 6 microg/kg x day) with a 14-day washout period separating the two conditions. Within each 28-day phase, females were studied for 14 days with no estradiol replacement and for 14 days with estradiol replacement (3 microg/kg x day, s.c.). Treatment with estradiol and SSa alone significantly lowered serum IGF-I compared with baseline. In contrast, estradiol and SSa given in combination resulted in a significant increase in serum IGF-I. Serum IGFBP-3 was significantly increased by estradiol and the combination of estradiol and SSa. The response of serum GH to the acute administration of the excitatory amino acid analogue, n-methyl-D,L-aspartic acid (5 microg/kg, i.v.) was not differentially affected by any of the treatments. In Exp 2, the effects of a GH receptor antagonist (Trovert, Sensus Corp.) was assessed in ovariectomized, young adult, treated females (GHa; 1.0 mg/kg, s.c., weekly) and compared with that in untreated cohorts (Con) during 3 weeks of no estradiol and 3 weeks of estradiol replacement (3 microg/kg x day, s.c.). Serum IGF-I and IGFBP-3 were significantly suppressed in GHa compared with Con females. In Con females, estradiol replacement significantly decreased serum IGF-I and increased serum IGFBP-3. In contrast, estradiol replacement significantly elevated both serum IGF-I and IGFBP-3 in GHa females. In Exp 3, the effects of acute IGF-I administration (110 microg/kg, s.c.) were assessed during baseline conditions and during treatment with either GHa (1.0 mg/kg, s.c., weekly) or SSa (16 microg/kg, s.c. infusion) in young adult females during no estradiol replacement and during estradiol replacement (3 microg/kg x day, s.c.). Acute IGF-I administration produced a similar net increase in serum IGF-I during baseline and GHa or SSa treatment. Although serum IGFBP-3 was significantly reduced by both GHa and SSa, acute treatment with IGF-I produced a significant elevation in IGFBP-3, peaking by 3 h after treatment before returning to baseline at 7 h. Estradiol replacement elevated serum IGFBP-1 under baseline conditions as well as during GHa and SSa treatments. However, changes in serum insulin in response to the feeding patterns during the acute treatment with IGF-I, predicted changes in serum IGFBP-1. As GH secretion was inhibited during SSa, acute IGF-I had little effect on serum GH. Although acute IGF-I significantly suppressed serum GH by 3 h after treatment during baseline, the hypersecretion of GH during GHa treatment was unaffected by acute IGF-I. In conclusion, the results of the present analysis indicate that the effects of estradiol in postadolescent females on serum IGF-I are dependent on GH status, whereas estradiol consistently elevates serum IGFBP-3. Furthermore, acute IGF-I increases serum IGFBP-3 in females even during GH inhibition or receptor antagonism. Although overall serum concentrations of IGFBP-1 are elevated by estradiol and may be differentially affected by IGF-I treatment, acute changes in IGFBP-1 are more a consequence of changes in serum insulin in response to food intake. Taken together, these data suggest that IGFBP-3 is regulated by factors in addition to GH and that IGF-I can affect its own bioavailabi

Analysis of Variance↗
PubMed2001

Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women.

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronised, oral 17beta-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 microg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate). According to data from randomised, comparative trials of 1 year's duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells. In a randomised, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 microg/day than in placebo-treated patients. Two randomised, double-blind studies indicated that the addition of norgestimate 90 microg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels. In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhoea, oedema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was associated with a favourable uterine bleeding profile that improved over time. In a randomised trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 microg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day. In conclusion, data from a limited number of randomised studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favourable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

Contraceptives, Oral, Synthetic↗
PubMed2002

Spotlight on estradiol and norgestimate as hormone replacement therapy in postmenopausal women.

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronized, oral 17beta-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronized, oral norgestimate 90 microg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate). According to data from randomized, comparative trials of 1 year's duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells. In a randomized, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 microg/day than in placebo-treated patients. Two randomized, double-blind studies indicated that the addition of norgestimate 90 microg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels. In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhea, edema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was associated with a favorable uterine bleeding profile that improved over time. In a randomized trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 microg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day. In conclusion, data from a limited number of randomized studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favorable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

Contraceptives, Oral, Synthetic↗
PubMed1985

The metabolism of estradiol; oral compared to intravenous administration.

We administered [6,7-3H]estradiol p.o. and [4-14C]estradiol i.v. simultaneously to 5 women 22-35 years of age. Fourteen blood samples were collected over 480 min, and all urine was collected for 96 h. The blood samples were analyzed for radioactivity as estradiol, estrone, estrone-sulfate and estradiol glucuronide. The urine samples were analyzed for radioactivity as the glucuronide and pH 1 hydrolyzable conjugates of estradiol, estrone, estriol, 16 alpha-hydroxy-estrone, 2-hydroxy-estrone, 2-hydroxy-estradiol, 2-methoxy-estradiol and 2-methoxy-estrone. The major circulating estrogen, after either estradiol, p.o. or i.v. administration, was estrone sulfate; approximately 50% of estradiol administered by either route being converted to and measured as estrone sulfate in the blood. Following oral administration about twice as much estradiol was converted to and measured as estradiol glucuronide in the blood as after i.v. administration. Of the estradiol administered p.o., only 10% was absorbed into the blood as estradiol the rest being metabolized prior to absorption. After estradiol, p.o., the major radioactive compounds in the urine were the glucuronides of estrone and estradiol, but after estradiol, i.v., the conjugates of estrone, estradiol and estriol were present to about the same extent as the conjugates of the 2-oxygenated compounds. Following p.o., considerable metabolism of estradiol administration occurs in the splanchnic tissue, much of it in the intestinal wall.

Administration, Oral↗
PubMed2001

Estradiol-intranasal: a review of its use in the management of menopause.

UNLABELLED: Estradiol-intranasal is a nasal spray formulation containing an aqueous solution of 17beta-estradiol that has a unique pulse-like pharmacokinetic profile. In a well designed, placebo-controlled trial estradiol-intranasal 200 to 400 microg/day significantly reduced the incidence and severity of climacteric symptoms in women with moderate to severe menopausal symptoms after 4 and 12 weeks' treatment. The efficacy of estradiol-intranasal 300 microg/day was similar to that of oral estradiol 2 mg/day in this and another double-blind placebo-controlled trial. This equivalent efficacy was maintained in a subgroup of women with initially severe symptoms, and in smokers. Reductions in the incidence of atrophic vaginal mucosa and genitourinary symptoms and increases in the karyopyknotic index achieved with estradiol-intranasal 300 microg/day were also similar to those observed with oral estradiol 2 mg/day. Assessments of the effects of estradiol-intranasal on the complications of menopause (increased risk of cardiovascular disease and osteoporosis) are ongoing; however, estradiol-intranasal (sequentially combined with a progestogen) produced significant beneficial effects on some lipid parameters and on markers of bone resorption and formation, and bone mineral density in postmenopausal women. Estradiol-intranasal had no significant effects on serum levels of most of the assessed haemostatic factors, or on angiotensinogen or insulin levels. Estradiol-intranasal 100 to 600 microg/day was generally well tolerated in clinical trials and most adverse events were mild to moderate. The most commonly reported events were nasal symptoms and mastalgia. There was no evidence of endometrial hyperplasia with up to 1 year's treatment with estradiol-intranasal 300 microg/day combined with a progestogen. The incidence of mastalgia and withdrawal or breakthrough bleeding was lower with estradiol-intranasal 300 microg/day than with oral estradiol 2 mg/day (both administered with a progestogen) in one trial. In another trial, the incidence of mastalgia was lower with estradiol-intranasal 300 microg/day than with estradiol transdermal 50 microg (both administered with a progestogen). However, the overall incidence of adverse events was similar between the two treatments in this trial. CONCLUSIONS: Estradiol-intranasal 200 to 400 microg/day (optimal initiating dose 300 microg/day) reduces the incidence and severity of menopausal climacteric symptoms and has a good tolerability profile. Thus, evidence to date suggests that estradiol-intranasal is a useful treatment option for menopausal symptoms.

Administration, Intranasal↗
PubMed2002

Spotlight on estradiol-intranasal in the management of menopause.

Estradiol-intranasal is a nasal spray formulation containing an aqueous solution of 17beta-estradiol that has a unique pulse-like pharmacokinetic profile. In a well designed, placebo-controlled trial estradiol-intranasal 200 to 400 microg/day significantly reduced the incidence and severity of climacteric symptoms in women with moderate to severe menopausal symptoms after 4 and 12 weeks' treatment. The efficacy of estradiol-intranasal 300 microg/day was similar to that of oral estradiol 2 mg/day in this and another double-blind placebo-controlled trial. This equivalent efficacy was maintained in a subgroup of women with initially severe symptoms, and in smokers. Reductions in the incidence of atrophic vaginal mucosa and genitourinary symptoms and increases in the karyopyknotic index achieved with estradiol-intranasal 300 microg/day were also similar to those observed with oral estradiol 2 mg/day. Assessments of the effects of estradiol-intranasal on the complications of menopause (increased risk of cardiovascular disease and osteoporosis) are ongoing; however, estradiol-intranasal (sequentially combined with a progestogen) produced significant beneficial effects on some lipid parameters and on markers of bone resorption and formation, and bone mineral density in postmenopausal women. Estradiol-intranasal had no significant effects on serum levels of most of the assessed hemostatic factors, or on angiotensinogen or insulin levels. Estradiol-intranasal 100 to 600 microg/day was generally well tolerated in clinical trials and most adverse events were mild to moderate. The most commonly reported events were nasal symptoms and mastalgia. There was no evidence of endometrial hyperplasia with up to 1 year's treatment with estradiol-intranasal 300 microg/day combined with a progestogen. The incidence of mastalgia and withdrawal or breakthrough bleeding was lower with estradiol-intranasal 300 microg/day than with oral estradiol 2 mg/day (both administered with a progestogen) in one trial. In another trial, the incidence of mastalgia was lower with estradiol-intranasal 300 microg/day than with estradiol transdermal 50microg (both administered with a progestogen). However, the overall incidence of adverse events was similar between the two treatments in this trial. In conclusion, estradiol-intranasal 200 to 400 microg/day (optimal initiating dose 300 microg/day) reduces the incidence and severity of menopausal climacteric symptoms and has a good tolerability profile. Thus, evidence to date suggests that estradiol-intranasal is a useful treatment option for menopausal symptoms.

Administration, Intranasal↗
PubMed1986

Ribosome-associated estradiol-binding components in the uterus and their relationship to the translational capacity of uterine ribosomes.

Estradiol transiently increases the rate of peptide elongation on uterine ribosomes from ovariectomized mature rats during the first 2 h after hormone injection, suggesting the existence of direct or indirect estradiol receptor interaction with ribosomes. Characterization of estradiol-binding components on isolated uterine ribosomes, microsomes, and cytosol under identical assay conditions indicated that microsomes and cytosol contain estradiol-binding components with similar affinities for estradiol (Kd = 0.5 nM) and sucrose gradient sedimentation characteristics (3.8S and 5.2S for preparations incubated at 0 and 30 C for 1 h, respectively). Those on ribosomes exhibited a higher affinity for estradiol (Kd = 0.14 nM) and had heterogeneous and more dense sedimentation characteristics (5.5-6.0S). The ribosome-associated estradiol binder was clearly different from transformed cytosol and nuclear estradiol receptors based on sedimentation characteristics under identical conditions. Like cytosol and nuclear receptors, microsomal and ribosomal estradiol binding underwent exchange reactions in vitro at 30 C, but not at 0 C. All in vitro bound, but not all in vivo bound, [3H] estradiol could be exchanged from microsomes or ribosomes by estradiol. [3H]Estradiol could be exchanged from ribosomes by a variety of estrogens, but not by progestins, glucocorticoids, or androgens. The amount of estradiol-binding activity on ribosomes decreased after estradiol administration in vivo and was inversely correlated with the rate of peptide elongation by the ribosomes in a cell-free protein synthesis system. These results suggest that accumulation of an estradiol-binding protein, perhaps a nascent estradiol receptor, on ribosomes in the absence of in vivo estradiol may directly or indirectly inhibit the peptide elongation reaction.

Animals↗
PubMed1985

The naturally occurring C-17 fatty acid esters of estradiol are long-acting estrogens.

C-17 fatty acid esters of estradiol are naturally occurring biosynthetic metabolites of estradiol. A representative component of this family of esters, estradiol-17-stearate, was studied in order to determine the estrogenic properties of these unusual hydrophobic steroids. Following the classical estrogen bioassay, a solution of this ester in oil was injected subcutaneously into immature rats once a day for 3 days. There was little effect on the uterus on the first day after the third injection. However, on subsequent days a large stimulation of uterine growth occurred. The course of this estrogenic effect was exactly opposite to that obtained with estradiol. In order to eliminate the possibility that this effect on the time course of estrogenic stimulation was caused by increased solubility of the hydrophobic esters in the carrier oil, the steroids were administered to adult ovariectomized animals in aqueous medium via a single intravenous injection. The uterotrophic response to estradiol was maximal at 12 h and was completely dissipated in 48-60 h. Estradiol-17-stearate produced a uterotrophic effect of twice the duration of estradiol. In the immature rat, aqueous intravenous injections of estradiol-17-stearate produced a greater uterotrophic effect than estradiol and this effect was still maximal 96 h later. In addition, this single injection of estradiol-17-stearate advanced the time of vaginal opening, a marker for puberty in the female rat. The mechanism of the prolonged estrogenic stimulation was investigated by studying the steroidal content of the uterus after injecting [3H]estradiol and [3H]estradiol-17 -stearate i.v. into immature rats. At 1 and 4 h there was significantly more radioactivity in the uteri of the [3H]estradiol treated animals. At later times (8 h and onwards) the total radioactivity in the uterus did not differ appreciably between the two groups. However at these later times, the amount of [3H]estradiol was far greater in the uteri of animals receiving [3H]estradiol-17-stearate. Consequently, the prolonged estrogenic effects of the endogenous C-17 fatty acid esters of estradiol are caused by the increased duration of the estrogenic signal. It is hypothesized that one of the roles of the fatty acid is to protect the steroid nucleus from metabolism and thereby prolong the life of the parent C18 steroid. Thus, the results of these experiments are consistent with the family of endogenous alkyl esters of estradiol having a physiological role as long-acting estrogens.

Animals↗
PubMed2000

Effect of dose on the absorption of estradiol from a transdermal gel.

OBJECTIVES: To study whether dose adjustments in transdermal estradiol gel treatment would result in proportional changes in estradiol bioavailability and concentrations. METHODS: In an open study, 23 healthy postmenopausal women were treated consecutively with 0.5, 1.0 and 1.5 mg estradiol daily as a transdermal gel. Each dose was given for 16 days. Venous blood samples for serum estradiol and estrone measurements with RIA were taken at steady state on the 16th study day. From these concentrations, pharmacokinetic parameters for estradiol were calculated and corrected to correspond to equal dose by dividing the values by the dose. RESULTS: Area under the estradiol time-concentration curve and peak estradiol level increased linearily and dose-proportionally with daily estradiol doses of 0.5-1.5 mg. This was shown by lack of significant differences in the dose-corrected parameters. However, the 90% confidence intervals between the doses were outside the commonly accepted levels for bioequivalence. Peak estradiol level was clearer and occurred earlier with the highest 1.5 mg estradiol dose, while more stable estradiol levels were seen with the lowest 0.5 mg estradiol dose. CONCLUSIONS: The amount of estradiol on a certain skin area seems to be the determining factor in absorption. With higher estradiol doses, the absorption will be accelerated with a clearer peak estradiol level. The linear and dose proportional absorption indicates that flexible dose adjustments within the dose range of 0.5-1.5 mg estradiol daily can be made with an anticipated effect in estradiol bioavailability and concentrations.

Administration, Cutaneous↗
PubMed2002

Impact of hormone replacement therapy on endogenous estradiol metabolism in postmenopausal women.

OBJECTIVES: Changes in estradiol metabolism may play a role in the pathophysiology of different diseases, of special interest being an increase in D-ring over A-ring metabolites for the risk of breast cancer. In the present work we investigated the effect of exogenous estradiol therapy on endogenous estradiol metabolism in postmenopausal women. METHODS: Three different studies were carried out in 126 women: in study A the women were treated for 4 weeks either with oral or with transdermal 17beta-estradiol, in study B for 4 weeks with oral or transdermal 17beta-estradiol sequentially combined with oral or transdermal norethisterone acetate, and in study C for 12 weeks either with oral 17beta-estradiol or with an oral continuous combination of 17beta-estradiol with the new progestin dienogest. As main representatives of the A- and D-ring metabolism, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16-OHE1), respectively, were measured in 8 h night urine using enzyme immunoassay technique. RESULTS: Oral estradiol treatment resulted in a significant higher excretion of estradiol metabolites compared to transdermal treatment. Neither oral nor transdermal estradiol induced a significant change in the ratio of 16-OHE1 to 2-OHE1. The addition of oral or transdermal norethisterone acetate to estradiol did not alter on average the endogenous estradiol metabolism, although in individual patients a significant increase in 16-OHE1 metabolism was observed only with oral norethisterone. The continuous oral addition of dienogest did not lead to any significant change in estradiol metabolism. CONCLUSIONS: These results indicate that oral estradiol replacement therapy enhances the quantity of circulating estradiol metabolites. This may have a more negative impact on estrogenic target cells as compared to transdermal application. Progestin addition to estradiol replacement therapy seems to have no major impact on endogenous estradiol metabolism. Further studies, however, are necessary to evaluate the progestin effect in possible pre-disposed patients.

Estradiol↗