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PubMed1992

Intranasal administration of estradiol in combination with progesterone to oophorectomized women: a pilot study.

A pilot study was done to investigate the pharmacokinetics and acceptability of an intranasal 17 beta-estradiol/progesterone formulation. This formulation contained dimethyl-beta-cyclodextrin as a solubilizer and absorption enhancer of the steroid hormones. The study was performed in four oophorectomized and hysterectomized patients. After nasal delivery of 0.34 mg estradiol and 0.85 mg progesterone, concentration-time curves of progesterone, estradiol and its metabolite estrone were established. Rapid absorption of progesterone and estradiol was demonstrated. Progesterone peak-levels (3.9-6.7 nmol/l) exceeded the levels which are found in the follicular phase of the menstrual cycle, but did not reach the levels of the luteal phase. Comparison with an earlier reported study in which only estradiol was administered shows that the addition of progesterone does not alter the absorption and pharmacokinetics of estradiol. The nasal formulation was well accepted by the four patients and no adverse effects were noted.

Administration, Intranasal↗
PubMed1985

Behavioral consequences of hormonal deprivation on the responsiveness of female rats to estradiol.

Female rats which had been ovariectomized either 7 days earlier (short-term deprivation, N = 11) or 35 days earlier (long-term deprivation, N = 11) were tested for their response to treatments of estradiol benzoate (6.0 micrograms/kg body weight) and progesterone (1.2 mg/kg). The long-term deprived females showed less sexual behavior than females deprived for only 7 days prior to treatment. In particular, lordosis quotients after treatment with estradiol alone were significantly lower in the long-term deprived females, t(20) = 3.194, p less than 0.01. Following a supplemental progesterone injection, the lordosis scores and the number of proceptive behaviors displayed by long-term deprived females were also significantly lower than these measures in short-term deprived females, t(20) = 3.481, p less than 0.01 and t(20) = 3.737, p less than 0.01, respectively. In contrast, the two groups did not differ in the degree to which estradiol treatment suppressed food intake, F(1,20) = 2.306, N.S. Likewise, the changes in water intake and body weight produced by estradiol treatment did not differ significantly between the two groups, F(1,20) = 0.118, N.S. and F(1,20) = 0.452, N.S., respectively. The results obtained from the sex behavior tests are generally consistent with the notion that hormonal deprivation alters the responsivity or sensitivity of female rats to estradiol. However, these changes do not appear to involve a general decline in receptor sensitivity or number, because the ability of estradiol to suppress ingestive behaviors was not diminished in the long-term deprived females.

Animals↗
PubMed1985

Preoptic implants of estradiol increase wheel running but not the open field activity of female rats.

In order to localize the neural substrate for estrogen induction of increases in activity, bilateral implants of dilute estradiol (in concentrations of 1:10, 1:100, and 1:250) were made into the medial preoptic area (n = 5), the anterior hypothalamus (n = 8), the ventromedial hypothalamus (n = 6), and the posterior hypothalamus (n = 4) of ovariectomized female rats housed in running wheels. The same animals were also tested for open field activity and lordosis. The preoptic area was the most effective site tested for estrogenic stimulation of running wheel activity, with 3/5 animals responding consistently to estradiol application. 3/8 animals with cannulae in the anterior hypothalamus (AHA) responded with increases in activity measured in the running wheel on at least two out of three estradiol treatments. No animals with cannula placements posterior to the AHA exhibited consistent running wheel responses to estradiol. No estrogen-induced increase in open field activity was found, regardless of cannula location or concentration of estradiol; however, there was a tendency for the number of squares entered during the later tests to decrease in the ventromedial hypothalamic nucleus group and in the subgroup of animals not showing estrogen-sensitive wheel running in the anterior hypothalamic area group. Only the ventromedial hypothalamic estradiol treatments stimulated lordosis behavior. These results support earlier reports suggesting that the medial preoptic area (and possibly the adjacent anterior hypothalamic area) is the critical brain site for estrogenic stimulation of running wheel activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Diverse effects of estradiol-17 beta: concurrent suppression of appetite, blood pressure and vascular reactivity in conscious, unrestrained animals.

Evidence from epidemiological and clinical investigations have suggested a relationship between estrogen-containing oral contraceptives and hypertension. The present series of studies, however, documents the ability of estradiol-17 beta, a natural ovarian estrogen, to lower resting blood pressure and pressor responses to norepinephrine in conscious, unrestrained guinea pigs. Arterial measurements were made of resting blood pressure and heart rate, plus pressor responses to intravenous infusions of 1.56 micrograms norepinephrine. Injection of 30 micrograms estradiol-17 beta reduced resting pressures up to 12% and pressor responses up to 20% in the interval from 12 to 48 hours postinjection. The estradiol treatment also significantly and reversibly lowered food intake, water intake, and body weight. These effects could be induced by either 3 or 30 micrograms of estradiol benzoate for up to 4 days if estradiol treatment was continued. Parallel studies indicated that NE-induced contractions of the isolated aorta were markedly reduced by pretreatment with estradiol. These studies indicate that natural ovarian estrogens may reduce blood pressure by reducing the contractility of the arterial smooth muscle.

Animals↗
PubMed1993

Stimulus characterization of estradiol applying a crossfamiliarization taste aversion procedure in female mice.

In female mice (n = 240), the estradiol stimulus was characterized by studying preexposure effects of sex steroids and sickness-inducing drugs on estradiol-induced (50 micrograms/kg SC) conditioned taste aversion (CTA). It was established that preexposure to estradiol itself (2-50 micrograms/kg SC) attenuates the development of CTA produced by the hormone. Only partial crossfamiliarization effects were found with progesterone (50-200 micrograms/kg SC) and testosterone (250-1000 micrograms/kg SC), steroids that induce CTA themselves. Preexposure to the sickness-inducing drugs lithium chloride (22 mg/kg SC) and apomorphine (0.1-0.2 mg/kg SC) prevented or substantially reduced the development of estradiol-induced CTA, respectively. It was concluded that only a low degree of stimulus resemblance exists between estradiol and the other principal sex steroids, progesterone and testosterone. In addition, it was concluded that the estradiol stimulus resembles the stimuli produced by sickness-inducing drugs.

Animals↗
PubMed1993

Modulation of the satiety effect of cholecystokinin by estradiol.

Data obtained from a wide variety of mammalian species indicate that feeding behavior can be influenced by changes in endogenous estrogens and by exogenous estrogenic treatments. The present experiment represents an initial investigation of the hypothesis that the suppression of food intake by estradiol is mediated by an enhancement of the satiety effect of cholecystokinin (CCK). Twenty-four female rats were ovariectomized and implanted either with a 5% estradiol silastic capsule or an empty capsule on the day of surgery. Three weeks later, animals received IP injections of CCK-octapeptide (5.0 or 10.0 micrograms/kg) or saline after 24-h food deprivation. Food and water intake were measured 60 min after treatment. Although CCK suppressed feeding in all subjects, the effects on food intake were greater in estradiol-treated females. CCK injections also reduced water intake, but there was no interaction between estradiol and CCK on drinking. These findings indicate that the inhibitory effect of CCK on food intake is enhanced in females treated with a physiological dose of estradiol, and suggest that the effects of estradiol on feeding behavior may be mediated by a potentiation of the satiety effect of CCK.

Afferent Pathways↗
PubMed1994

Cyclic estradiol replacement increases the satiety effect of CCK-8 in ovariectomized rats.

The influence of cyclic ovarian hormone replacement therapy on the satiety effect of exogenous CCK-8 was determined to investigate the mechanism mediating the preestrous decrease in meal size in female rats. Once weekly, food-deprived ovariectomized rats were IP injected with 0.5-4 micrograms/kg CCK-8 and offered 0.4-0.8 M sucrose 52 h after the second of two daily SC injections of 2.5 or 10 micrograms estradiol benzoate or vehicle and 4 h after 500 mg progesterone or vehicle. In each of three tests, estradiol significantly increased CCK-8's inhibitory effect on sucrose intake. In contrast, progesterone alone or in combination with estradiol did not consistently influence the satiating potency of CCK-8. The interaction of estradiol and CCK-8 was clearest for the dose of 4 micrograms/kg CCK-8. The interaction occurred during diurnal tests and during dark-onset tests in which estradiol did not decrease baseline sucrose intake. These results demonstrate that a cyclic regimen of estradiol replacement in ovariectomized rats is sufficient to enhance the satiating effect of exogenous CCK-8 and that simultaneous progesterone treatment does not influence this effect. Potentiation of the satiating effect of CCK released from the small intestine by ingested food may be one of the mechanisms by which food intake decreases during the period of high estrogen concentration in the estrus cycle.

Animals↗
PubMed1976

Metabolism of radioactive 17 beta-estradiol 3-methyl ether by humans.

A mixture of 2-3H and 4-14C-17beta-estradiol 3-methyl ether was administered orally to a man and to a woman. 34 and 35 percent of the 3H was liberated into the body water of the man and of the woman, respectively, reflecting reactions involving position 2. The metabolism of estradiol methyl ether was qualitatively similar to that observed previously for radioactive estradiol administered intravenously to the same subjects, as judged by the measurement of various urinary metabolites by reverse isotope dilution. Evidence was obtained for hydroxylation at position 2 without demethylation by the isolation of urinary 2-hydroxyestrone 3-methyl ether which retained 33% of the original 3H. This 3H was presumably at position 1, resulted from an NIH shift which does not occur during hydroxylation of estrone or estradiol. This was confirmed by subsequent administration of a mixture of 4-14C and 3H-(methoxyl)-estradiol 3-methyl ether to the man. There was no evidence (by reverse isotope dilution) for 1-hydroxyestrone, 1-hydroxyestrone 3-methyl ether, 4-hydroxyestrone 3-methyl ether or 4-hydroxyestradiol 3-methyl ether as urinary metabolites of estradiol 3-methyl ether.

Adult↗
PubMed1979

Some characteristics of 17 beta-estradiol dehydrogenase from bovine placenta.

The activity of 17 beta-estradiol dehydrogenase (E.C. 1.1.1.62) was measured, and its distribution in the subcellular fractions of bovine placenta was compared. Assay of activity was based on the formation of radioactive estrone from 17 beta[4(-14)C]-estradiol. Either NAD+ or NADP+ can serve as cofactor for the enzyme. The nuclear and microsomal fractions of the placental homogenate exhibited the highest specific enzymatic activities before and after treatment with Triton X-100. Electron micrographs of these two fractions prior to treatment with Triton X-100 showed satisfactory purity. 17 beta-estradiol dehydrogenase from bovine placenta exhibits a pH optimum of about 9.5-10.5, and is activated by 5 x 10(-6)M ZnCl2; comparable concentrations of CaCl2 and MgCl2 inactivate the enzyme. The apparent Michaelis constants, Km, for 17 beta-estradiol and NAD+ are 1.4 x 10(-6)M and 5.5 x 10(-5)M respectively. No 17 alpha-estradiol dehydrogenase activity was demonstrable when using 17 alpha-estradiol as substrate.

17-Hydroxysteroid Dehydrogenases↗
PubMed1982

Direct action of estradiol-17 beta on the atrial action potential.

The effect of the two C-17 isomers of estradiol on the shape of the action potential of rat atrial tissue was studied by means of classical glass electrodes for different concentrations of estradiol. Resting potential and upstroke were not affected by estradiol, but the duration of the action potential was reduced. Only estradiol-17 beta exhibits an effect in a concentration dependent way, while estradiol-17 alpha has no effect at all. The ionic mechanism was studied by adding specific ionic blockers to the perfusate. Since the effect was much less pronounced when a slow inward current blocker was added, it was concluded that estradiol-17 beta acts mainly via the slow inward current channel. Only a small part of the interaction takes place via the potassium outward channel.

Action Potentials↗
PubMed1992

Synthesis and evaluation for uterotrophic and antiimplantation activities of 2-substituted estradiol derivatives.

Two novel series of 2-substituted estradiol derivatives have been synthesized and evaluated for uterotrophic and antiimplantation activities. Among the compounds tested in the rat, 2-acetylestradiol 17 beta-acetate (1), 2-(3'-dimethylamino-1'-propionyl)estradiol 3,17 beta-diacetate (7), 2-(3'-diethylamino-1'-propionyl)estradiol 3,17 beta-diacetate (8), 2-(3'-piperidino-1'-propionyl)estradiol 3,17 beta-diacetate (9), 1'-(2-estradiol 3,17 beta-diacetate-3'-diethylaminopropionyl thiosemicarbazone (12), and 1'-(2-estradiol 3,17 beta-diacetate)-3'-morpholinopropionyl thiosemicarbazone (14) displayed estrogenic activity. At dosages of 4 microliters/rat/day, none of the tested compounds elicited antiimplantation activity. All compounds shared a similar characteristic: nuclear substitution at the C-2 position of the steroid nucleus, a property previously thought to be markedly inhibitory for estrogenic activity.

Animals↗
PubMed1994

Effect of estradiol and progesterone on cholesterol 7 alpha-hydroxylase activity in rats subjected to different feeding conditions.

The regulation of cholesterol 7 alpha-hydroxylase activity by estradiol and progesterone was investigated in liver microsomes isolated from rats fed standard diet, either ad libitum or fasted for 24 h, and diet containing the bile acid sequesterant cholestyramine. Differential effects were observed when the direct action of estradiol and progesterone on microsome preparations was examined. Cholesterol 7 alpha-hydroxylase activity was inhibited by progesterone in a dose-dependent way to almost complete abolition; similar patterns of declines were found in the three feeding groups under study. In contrast, the addition of 5 microM estradiol induced small and selective 7 alpha-hydroxylase increases in fasting and cholestryamine-fed animals, then activity declined to control values and consistent decreases were found from 20 microM. The administration of estradiol (50 micrograms) or progesterone (100 micrograms) for 21 days resulted in depressed cholesterol 7 alpha-hydroxylase activity in rats with high bile acid synthesis basal rate due to cholestyramine feeding. In rats receiving a standard diet, either ad libitum or after 24 h fasting, the hormonal effects did not reach significance. Declines in the content of free cholesterol were provoked by progesterone, not by estradiol, in liver microsomes prepared from all feeding groups. No changes in cholesterol 7 alpha-hydroxylase activity and microsomal free cholesterol were observed after administration of the sex hormones for 3 days. Rapid and transient inhibitions in 7 alpha-hydroxylase activity were found after the single injection of progesterone to fed animals. Estradiol, on the contrary, was unable to alter rapidly the hepatic 7 alpha-hydroxylase capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Reduced estradiol production by a substituted triazole results in delayed ovulation in rats.

Ovulation in the rat is delayed by a single administration of the substituted triazole R151885 (1,1-di(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-ethanol). This delay results from a 24-hr shift in the preovulatory luteinizing hormone (LH) surge since administration of chorionic gonadotrophin on proestrus restores ovulation. Plasma levels of estradiol are markedly reduced (42-45%) 6-12 hr after administration of R151885. The restoration of ovulation in R151885-pretreated rats, by administration of exogenous estradiol benzoate, indicates that the reduced estradiol levels play a pivotal role in the delay of ovulation. Granulosa cells isolated from rat ovaries produce estradiol and progesterone in vitro in the presence of both follicle-stimulating hormone and testosterone. The addition of R151885 to such cultures results in a dose-dependent inhibition of estradiol production (69% by 1 microM) without a significant effect on progesterone production. This inhibition occurs at concentrations of R151885 similar to those measured in vivo. R151885 is a competitive inhibitor of human placental aromatase (apparent Ki with androstenedione substrate of 410 nM) and produces a type II spectral perturbation of cytochrome P-450 from placental microsomes. Pituitaries isolated from R151885-treated rats have reduced LH output in response to gonadotrophin-releasing hormone stimulation compared with those of controls. It is proposed that R151885 competitively inhibits aromatase activity in developing ovarian follicles. The resultant temporary reduction of plasma estradiol levels at a critical time in the estrous cycle, and consequent inadequate pituitary sensitization, produces a 24-hr delay in the preovulatory LH surge and hence ovulation is delayed by 24 hr.

Animals↗
PubMed1986

Effect of dextran-coated charcoal treatment on 17 beta-estradiol receptor in human benign prostatic hyperplasia.

Using glycerol density gradient centrifugation technique, single saturation dose assay, and Scatchard plot, the effect of dextran-coated charcoal (DCC) treatment of homogenate or crude cytosol on estradiol binding protein in human benign prostatic hyperplasia was investigated. Receptor binding is increased after thirty minutes DCC treatment of homogenate or cytosol. Increase in estradiol binding is accompanied by loss in cytosolic protein. A 75 per cent increase in binding of estradiol to its receptor was observed after two hours incubation of DCC with homogenate. The concomitant increase in estradiol binding and decrease in protein concentration in both homogenate or cytosol after DCC treatment indicate the possible removal of some protein(s) which inactivate(s) the estradiol receptor. Removal of cofactors required for activation of proteases and removal of endogenous steroids which could be occupying the estradiol sites also are possible. This simple experimental procedure has improved significantly the methodology for the measurement and characterization of estrogen receptor in human BPH.

Charcoal↗
PubMed1976

Release of prostaglandin F, regression of corpora lutea and induction of premature parturition in goats treated with estradiol-17beta.

Premature parturition was induced in five pregnant goats infused intravenously with 4.65-8.4 mg estradiol-17beta but not in one treated with 5.85 mg estradiol-17alpha. A single intramuscular injection of 12 mg estradiol benzoate (8.8 mg estradiol-17beta equivalents) was also effective. These doses were estimated to provide plasma concentrations of estradiol-17beta in the physiological range for animals at sponteneous parturition. Circulating plasma concentrations of progesterone decreased and lactogenesis occurred before all instances of induced parturition but no such changes resulted from infusion of estradiol-17alpha. Placental delivery was normal in all animals but neonates of more than 10 days prematurity were non-viable.

Animals↗
PubMed1991

Estradiol effect on indomethacin and prostaglandin E2-modulation of adrenergic transmission in rabbit oviduct.

The effect of prostaglandin E2 /PGE2/ and indomethacin on 3H-noradrenaline (3H-NA) release- and on contractions-evoked by field electrical stimulation (FES) was studied in vitro in oviductal isthmus of mature rabbits (untreated and treated with estradiol). FES evoked guanethidine-sensitive contractions and calcium-dependent tritium overflow, which reflected 3H-NA overflow. Marked and concentration-dependent decrease of FES-evoked contractions by PGE2 (0.1-100 nM) was observed in both groups of animals. The inhibitory effect of PGE2 was more pronounced in estradiol treated animals (IC50 1.5 nM, n = 9) than in untreated animals (IC50 18 nM, n = 6). Indomethacin, 1 microM, induced a remarkably pronounced increase of FES-evoked contractions in estradiol treated (by 57.3 +/- 6.3%, n = 8) in comparison with untreated rabbits (21.4 +/- 3.8%, n = 7). The amount of FES-evoked release of tritium was significantly higher in untreated than in estradiol treated rabbits. PGE2 decreased and indomethacin increased tritium-evoked release. The effects of PGE2 and indomethacin on tritium-evoked release showed no estradiol dependence. The competitive results of PGE2 and indomethacin on both evoked contraction and 3H-NA release suggest that endogenous prostaglandin E2 takes part in modulation of adrenergic mediated contraction and that estradiol enhanced the prostaglandin effect.

Adrenergic Fibers↗
PubMed1992

Inhibitory effect of 17 beta -estradiol on prostaglandin E2-induced phosphoinositide hydrolysis in osteoblast-like cells.

We examined the effect of estradiol on PGE2-induced phosphoinositide hydrolysis and cAMP production in cloned osteoblast-like MC3T3-E1 cells. 17 beta -Estradiol pretreatment significantly inhibited the formation of inositol phosphates induced by 10 microM PGE2 in a dose-dependent manner between 1 pM and 10 nM. This effect of 17 beta -estradiol was dependent on the time of pretreatment and submaximum inhibition was observed at 4 h. However, 17 beta -estradiol had little effect on the formation of inositol phosphates induced by 20 mM NaF, a GTP-binding protein activator. The cAMP production induced by PGE2 was not influenced by 17 beta -estradiol. These results suggest that 17 beta -estradiol modulates the signal transduction by PGE2 and that the effect seems to be exerted between PGE2 receptor and the GTP-binding protein coupled to phospholipase C in osteoblast-like MC3T3-E1 cells.

Animals↗
PubMed1987

Evidence for the reestablishment of copulatory behavior in castrated male rats with a brain-enhanced estradiol-chemical delivery system.

We have developed a redox-chemical system for brain-enhanced drug delivery of estradiol based on an interconvertible dihydropyridine in equilibrium with pyridinium salt carrier. Estradiol, when combined with the carrier, readily crosses the blood-brain barrier and upon oxidation of the carrier is "locked" in the brain. The aim of this study was to evaluate the effects of an estradiol-chemical delivery system (E2-CDS) versus an equimolar dose of estradiol-17-valerate (E2-VAL) on copulatory behavior in orchidectomized rats. The data revealed that a single dose of E2-CDS was more efficacious than E2-VAL in stimulating mounting behavior (percent responding) and the effect was 100% through 5 weeks. E2-CDS increased intromission behavior more than E2-VAL through 28 days. Mount and intromission latencies were reduced by E2-CDS to a greater extent and for a longer time (28 days) than E2-VAL. Neither form of estradiol restored ejaculation parameters or penile reflexes. These data suggest that E2-CDS causes a potent and long-acting stimulation of proceptive and consummatory components of male sexual behavior, presumably acting through the local brain-release of estradiol.

Animals↗