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PubMed2003

Differences in the mechanisms for relaxation of aorta induced by 17beta-estradiol or progesterone between normotensive and hypertensive rats.

The tension in isolated ring preparations of the thoracic aorta from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) was measured isometrically to study if there are any differences in the mechanisms of 17beta-estradiol- or progesterone-induced relaxation between WKY and SHR aortic rings. 17beta-Estradiol and progesterone caused dose-dependent vascular relaxation of the thoracic aorta precontracted with norepinephrine in both WKY and SHR, and the relaxation induced by 17beta-estradiol was greater in SHR than WKY. However, no difference was observed in progesterone-induced relaxation between SHR and WKY. With the exception of tetraethylammonium, an inhibitor of Ca(2+)-activated K(+) channels, glibenclamide, a selective inhibitor of ATP-sensitive K(+) channels, or 4-aminopyridine, a selective inhibitor of voltage-dependent K(+) channels, significantly reduced 17beta-estradiol-induced relaxation only in SHR, but not in WKY. Both 17beta-estradiol and progesterone inhibited Ca(2+)-induced vasocontraction of the thoracic aorta in K(+) depolarization medium in WKY and SHR. These results suggest that the mechanisms of 17beta-estradiol-induced relaxation in SHR aorta are at least partially mediated via ATP-sensitive and voltage-sensitive K(+) channels in addition to the inhibition of Ca(2+) channels, although those of progesterone-induced relaxation in both WKY and SHR are mainly concerned with the inhibition of Ca(2+) channels rather than the operation of K(+) channels. Moreover, a difference in 17beta-estradiol-induced relaxation between WKY and SHR aorta suggests a possibility that vascular response in SHR is modified by hypertension.

Animals↗

PubMed1999

Estradiol inhibits Ca2+ and K+ channels in smooth muscle cells from pregnant rat myometrium.

The purpose of this study was to investigate the actions of 17beta-estradiol on the electrical activity of pregnant rat myometrium. The longitudinal layer of the myometrium was dissected from pregnant rats (17 to 19 days of gestation), and single cells were isolated by enzymatic digestion. Calcium currents and potassium currents were recorded by the whole-cell voltage-clamp method, and the single calcium-dependent potassium current was recorded by the outside-out patch-clamp method. The effects of 17beta-estradiol on these currents were investigated. When a myometrial cell was held at -50 mV, depolarization to a potential more positive than -30 mV produced an inward current followed by a slowly developing outward current. Application of tetraethylammonium inhibited the outward current while the inward current was completely abolished in a calcium-free solution. Estradiol at high concentrations (> 3 microM) inhibited both inward and outward currents in a voltage-dependent manner. Removal of estradiol restored the amplitude of the outward but not of the inward current. Estradiol (30 microM) also inhibited the activity of single calcium-dependent potassium channels without changing single channel conductance. In conclusion, estradiol at high concentrations inhibited: (1) voltage-dependent calcium, (2) calcium-dependent potassium and (3) voltage-dependent potassium currents. These actions of estradiol would prevent action potential generation and after-hyperpolarizations. Suppression of the after-hyperpolarization might further prevent spike generation due to slowing of the calcium channel's recovery from the inactivated state.

Animals↗

PubMed1998

Estradiol and progesterone regulate the proliferation of human breast epithelial cells.

OBJECTIVE: To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. DESIGN: Double-blind randomized study. SETTING: Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.

Aged↗

PubMed1998

Day 4 estradiol levels predict pregnancy success in women undergoing controlled ovarian hyperstimulation for IVF.

OBJECTIVE: To evaluate the usefulness of serum estradiol levels obtained on the fourth day of gonadotropin stimulation in predicting the likelihood of pregnancy during controlled ovarian hyperstimulation (COH) using luteal phase leuprolide acetate (LA). DESIGN: A 4-year retrospective analysis of day 4 estradiol levels and subsequent clinical pregnancy and delivery rates. SETTING: A university hospital tertiary referral center. PATIENT(S): Couples undergoing IVF treatment. MAIN OUTCOME MEASURE(S): Primary outcome measures included clinical pregnancy and delivery rates. Secondary outcome measures included the number of oocytes retrieved and the number of embryos available for transfer per COH cycle. RESULT(S): The clinical pregnancy and delivery rates for cycles with day 4 estradiol levels of >75 pg/mL were 42.3% (30/71) and 32.4% (23/71), respectively. These rates differed significantly from those for cycles with day 4 estradiol levels of < or = 75 pg/mL, which were only 9.1% (4/44) and 6.8% (3/44), respectively. The number of oocytes retrieved and the number of embryos available for transfer for cycles with day 4 estradiol levels of >75 pg/mL also differed significantly from those for cycles with day 4 estradiol levels of < or = 75 pg/mL (11.4 and 7.8 versus 6.8 and 4.3, respectively). CONCLUSION(S): Estradiol levels obtained on the fourth day of gonadotropin therapy are highly predictive of successful ovulation induction and pregnancy outcome in cycles using luteal phase LA.

Delivery, Obstetric↗

PubMed2001

17beta-estradiol, gender independently, reduces atheroma development but not neointimal proliferation after balloon injury in the rabbit aorta.

The aim of the present study was to investigate anti-proliferative and anti-atherogenic properties of 17beta-estradiol in balloon injured female and male rabbit aortae. Thirty-two female and 32 male New Zealand White rabbits where gonadectomised. Vascular injury was performed with a balloon catheter in the lower abdominal aorta. Male and female rabbits were randomised into four groups of eight animals each. Only two of four groups received a 0.5% cholesterol-enriched diet. One cholesterol-diet group and one normal-diet group received intramuscular injections of estradiol valerate (1 mg/kg body weight/week). After 28 days, the denuded part of the abdominal aorta was excised and analysed by morphometry and immunohistochemistry. Estrogen treatment did not show an inhibitory effect on neointimal proliferation in normo-cholesterolemic male or female rabbits. A gender independent inhibitory effect of 17beta-estradiol was seen on atheroma development in cholesterol-fed female and male rabbits, while plasma total cholesterol levels were significantly reduced in male rabbits only. The 17beta-estradiol treatment was associated with a significantly decreased number of luminal endothelial cells in normo and hyper-cholesterolemic female rabbits, as evaluated by immunohistochemical staining for 'von Willebrand factor'. Staining for Ki-67-positive proliferating cells after 28 days showed a statistically significant increased proliferative activity in the neointima of hyper-cholesterolemic female rabbits. The neointimal content of macrophages increased significantly in all hyper-cholesterolemic rabbits. Under 17beta-estradiol treatment, the number of macrophages was increased in female and decreased in male rabbits by tendency. Additionally, the 'classical' vascular estrogen receptor was present in both female and male rabbit aortae without statistically significant differences. In conclusion, 17beta-estradiol did not reduce post-injury neointima formation in normo-cholesterolemic rabbits. However, in hyper-cholesterolemic rabbits, 17beta-estradiol reduced atheroma development gender independently. This effect cannot be explained by lowering of plasma cholesterol levels or endothelium-mediated pathways, and requires further investigation on, for example, antioxidative, antiproliferative or estrogen receptor mediated effects.

Actins↗

PubMed1980

Estradiol affinity chromatography: application to purification of murine alpha-fetoprotein.

A one-step batch procedure is described for purification of murine alpha-fetoprotein (AFP) by estradiol affinity chromatography. Various ratios of carbodiimide (C), diaminononame (D) and estradiol hemisuccinate (E) were tested to determine optimal conditions for AFP purification. Although yields of AFP ranged from 15 to 44% depending on the reagent ratio employed, AFP isolates free of other protein contaminants were achieved at C:D:E ratios of 10:10:1 with a 29% yield. Both estrone and estradiol proved efficient as elution agents to free AFP bound to the estradiol-Sepharose beads, but higher yields were produced with estrone. After isolation the estrogen-eluted AFP preparations were analyzed by (1) estradiol-binding assays, (2) third-party radiocoprecipitation, (3) inhibition of radioimmunoassay for estrone and estradiol and (4) exchange of unlabeled for radiolabeled estradiol. These results indicated that the steroid remained attached to the eluted AFP molecule.

Animals↗

PubMed1996

Estradiol-17beta as an antioxidant: some distinct features when compared with common fat-soluble antioxidants.

Estrogens are potent antioxidants both in vitro and in vivo. In this study the antioxidant affect of estradiol-17beta (estradiol) was compared with those of fat-soluble antioxidants (alpha-tocopherol and beta-carotene) in terms of both fatty acid (thiobarbituric acid-reactive substances and diene conjugation) and cholesterol oxidation (oxysterols). The addition of alpha-tocopherol (54 micromol/L) inhibited low-density lipoprotein (LDL) oxidation by 92.6% and high-density lipoprotein (HDL) oxidation by 76.5%. In similar experiments, estradiol (54 micromol/L) inhibited LDL oxidation by 77.5% but inhibited HDL oxidation by only 55.4%. Beta-carotene had no antioxidant effect. Lag times (diene conjugation method) for alpha-tocopherol and beta-carotene increased by 175% and 125%, respectively. Estradiol markedly reduced the maximum formation of diene conjugates as compared with results with alpha-tocopherol and beta-carotene, and it exhibited a linear curve (no change in lag time). In terms of cholesterol oxidation, estradiol was far more effective than alpha-tocopherol or beta-carotene in inhibiting oxysterol formation (microg/ml plasma) (control = 24.56 +/- 2.31, beta-carotene = 20.59 +/- 3.32, alpha-tocopherol = 20.19 +/- 1.58, estradiol = 14.38 +/- 0.70). This study shows that estradiol is as effective an antioxidant as alpha-tocopherol in terms of fatty acid peroxidation but is far more effective than alpha-tocopherol in terms of cholesterol peroxidation.

Adipocytes↗

PubMed1992

The influence of ovariectomy and estradiol replacement on urinary bladder function in rats.

Female Fischer 344 rats were ovariectomized or sham operated and treated with oil or estradiol cypionate (100 mg./100 gm./month) for two or four months. Rats were then placed in metabolism cages for measurement of micturition characteristics, and bladders were removed for bladder strip studies. Ovariectomy had no effects on micturition characteristics. However, estradiol treatment of ovariectomized rats caused significant increases in water consumption and urine excretion, and in mean and maximal micturition volumes compared to both ovariectomized and sham-operated rats. These effects were more pronounced at four months. Estradiol treatment also caused significant increases in bladder body mass, while ovariectomy was without effect. Two months after ovariectomy and/or estradiol treatment, there were no differences in contractile responses of bladder body or base strips to contractile agents when compared to shams. However, after four months, ovariectomy caused significant decreases in contractile responsiveness to nerve stimulation. ATP, carbachol, and KCl compared to sham-operated rats. Estradiol treatment caused increased responsiveness to nerve stimulation, ATP, carbachol, and KCl compared to ovariectomized rats, and to carbachol compared to sham operated rats. Possible causes for the effects of ovariectomy on bladder contractility include decreases in calcium influx. Although estradiol reversed the effects of ovariectomy on bladder function, in addition we observed some indirect effects which were probably the result of estradiol-induced polyuria and increases in bladder mass.

Adenosine Triphosphate↗

PubMed2001

Influence of estradiol and progesterone on the sensitivity of rat thoracic aorta to noradrenaline.

The aim of this study was to investigate the effects of low and high doses of estradiol, and of progesterone on the response to noradrenaline in rat thoracic aorta. Two weeks after bilateral ovariectomy, female rats received a s.c. injection of vehicle (corn oil, 0.1 mL/day), estradiol (10 microg/kg/day or 4 mg/kg/day) and/or progesterone (20 mg/kg/day), for eight days. On the ninth day, the rats were sacrificed and aortic rings, with or without endothelium, were used to generate concentration-response curves to noradrenaline. Aortic rings with intact endothelium from the high-dose (4 mg/kg/day) estradiol group were supersensitive to noradrenaline compared to the vehicle or low-dose (10 microg/kg/day) estradiol groups (pD2 values = 7.86+/-0.09, 7.30+/-0.11 and 7.35+/-0.04, respectively). Endothelium-intact aortic rings from high-estradiol rats were supersensitive to noradrenaline when compared to vehicle-, progesterone- and progesterone + high-estradiol-treated rats (pD2 values = 7.77+/-0.12, 7.21+/-0.13, 6.93+/-0.04 and 7.22+/-0.18, respectively). There were no significant differences among the pD2 values for noradrenaline in aortic rings without endothelium. In conclusion, at high but not low doses, estradiol increased the sensitivity to noradrenaline and this was prevented by progesterone. Both of these effects were endothelium-dependent.

Acetylcholine↗

PubMed2002

The association between serum estradiol level and hearing sensitivity in postmenopausal women.

OBJECTIVE: To estimate whether hearing sensitivity in postmenopausal women is associated with serum estradiol level or bone mineral density. METHODS: Serum estradiol level, bone mineral densities of the lumbar vertebrae and femoral neck, and hearing sensitivity were measured in 1830 postmenopausal women. Serum estradiol level was measured by radioimmunoassay, and dual energy x-ray absorptiometry was used to measure bone mineral densities of the lumbar vertebrae and femoral neck. Hearing sensitivity was evaluated by pure tone audiometry. Age, serum estradiol level, bone mineral densities of the lumbar vertebrae and femoral neck, and the proportion of women on hormone replacement therapy were analyzed in women with and without hearing loss. RESULTS: On univariate analysis, significant differences were found in mean age, serum estradiol level, bone mineral densities of the lumbar vertebrae and femoral neck, and the proportion of women on hormone replacement therapy between the two groups (mean +/- standard deviation, 59.4 +/- 5.6 versus 56.9 +/- 4.7 years, P <.001; 8.4 +/- 3.8 versus. 9.9 +/- 8.7 pg/mL, P <.001; 0.85 +/- 0.14 versus 0.88 +/- 0.15 g/cm(2), P <.01; 0.65 +/- 0.10 versus 0.68 +/- 0.10 g/cm(2), P <.005; 0.006% versus 0.03%, P <.05, respectively). On multiple logistic regression analysis, significant association was found between age and hearing loss and between serum estradiol level and hearing loss (P <.001, P =.02, respectively). CONCLUSION: This study suggests that a lower level of serum estradiol possibly impedes hearing sensitivity in postmenopausal women.

Audiometry, Pure-Tone↗

PubMed2000

The impact of endogenous estradiol metabolites on carcinogenesis.

The available literature on estrogen metabolism and estrogen metabolites involved in carcinogenesis is reviewed. Endogenous estradiol metabolism leads to metabolic products that can have various, and, to some extent, contrary, biologic effects. Thus, there are numerous research findings on the stimulation and inhibition of cancer growth by estrogen metabolites. Furthermore, there are indications that, in certain types of cancer, the production of growth-stimulating estradiol metabolites is increased. There are also reports on substances that can influence estradiol metabolism. So far, only a few estradiol metabolites have been examined with respect to their influence on the development and growth of cancer. It is presumed that other metabolites can also intervene directly or indirectly in the cancer process, but there is a great lack of research in this area. An understanding of the actions of estradiol metabolites may open up new avenues for the therapy of malignant diseases. Although little is known about the biologic effects of most of the estradiol metabolites, the reported actions of certain estradiol metabolites already justify clinical investigations on their possible beneficial uses in tumor therapy.

Animals↗

PubMed2002

Acute relaxant effects of 17-beta-estradiol through non-genomic mechanisms in rabbit carotid artery.

Estrogens could play a cardiovascular protective role not only by means of systemic effects but also by means of direct effects on vascular structure and function. We have studied the acute effects and mechanisms of action of 17-beta-estradiol on vascular tone of rabbit isolated carotid artery. 17-Beta-estradiol (10, 30, and 100 microM) elicited concentration-dependent relaxation of 50 mM KCl-induced active tone in male and female rabbit carotid artery. The stereoisomer 17-alpha-estradiol showed lesser relaxant effects in male rabbits. Endothelium removal did not modify relaxation induced by 17-beta-estradiol. The NO synthase inhibitor L-NAME (100 microM) only reduced significantly relaxation produced by 30 microM 17-beta-estradiol. Relaxation was not modified by the estrogen receptor antagonist ICI 182,780 (1 microM), the protein synthesis inhibitor cycloheximide (1 microM), and the selective K(+) channel blockers charybdotoxin (0.1 microM) and glibenclamide (1 microM). CaCl(2) (30 microM -10 mM) induced concentration-dependent contraction in rabbit carotid artery depolarized by 50 mM KCl in Ca(2+) free medium. Preincubation with 17-beta-estradiol (3, 10, 30, or 100 microM) or the L-type Ca(2+) channel blocker nicardipine (0.01, 0.1, 1, or 10 nM) produced concentration-dependent inhibition of CaCl(2)-induced contraction. In conclusion, 17-beta-estradiol induces endothelium-independent relaxation of rabbit carotid artery, which is not mediated by classic estrogen receptor and protein synthesis activation. The relaxant effect is due to inhibition of extracellular Ca(2+) influx to vascular smooth muscle, but activation of K(+) efflux is not involved. Relatively high pharmacological concentrations of estrogen causing relaxation preclude acute vasoactive effects of plasma levels in the carotid circulation.

Animals↗

PubMed1981

Estradiol binding by intact cells isolated from DMBA-induced mammary tumors of the rat.

Study of hormone binding in intact cells enables one to examine binding under conditions which elicit a biological response. Cells from 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors of the rat were enzymatically dispersed. More than 80% of these cells excluded trypan blue and were used to study binding of [3H] estradiol-17 beta. Specific binding was determined by subtracting the amount of [3H]estradiol bound in the absence and presence of 200-fold excess unlabeled estradiol. Specific binding at 37 degrees was maximal after 15 min. Steroid competition studies indicated that [3H]estradiol binding sites were relatively specific for estrogens, although there was a 9-18% inhibition of binding by androgens and progestins when present at 150-fold molar excess. Scatchard analyses of [3H]estradiol (0.15-5.0 nM) binding by whole cells suggest a single, high-affinity binding site (Kd = 7.5 x 10-10M) of low capacity (6.1 fmol/10(6) cells). More [3H]estradiol was translocated to the nucleus after 1 hr at 37 degrees than at 0 degrees. Preliminary studies indicated that incubations at 37 degrees result in appreciable metabolism of [3H]estradiol to other steroids and/or conjugates when examined by silica gel thin layer chromatography.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Lack of effects of acute estradiol on mood in postmenopausal women.

Chronic treatment with estrogen is believed to improve mood in postmenopausal women, and recent preclinical evidence suggests that estradiol may also affect mood and behavior through acute neuronal membrane-mediated effects on the central nervous system. This study was designed to characterize potential mood effects of single doses of transdermal estradiol in healthy postmenopausal women who were not taking hormone replacement therapy (HRT). Twelve women participated in a five-session, within-subjects, double-blind study, in which they received placebo, transdermal estradiol (0.2, 0.4, and 0.8 mg), or D-amphetamine (15 mg, oral) in a randomized order. Amphetamine was included as a positive control. Dependent measures included self-report measures of mood, physiological measures, and plasma hormone levels. Despite dose-dependent increases in plasma estradiol levels, and despite the fact that D-amphetamine produced its prototypic stimulant-like effects in these postmenopausal women, estradiol did not produce effects on mood. The finding that acute administration of exogenous estradiol did not alter mood suggests that more chronic exposure to estradiol is needed to produce mood-enhancing effects.

Affect↗

PubMed2000

An estradiol matrix transdermal system for the prevention of postmenopausal bone loss.

OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of 2 years' application of an estradiol matrix transdermal system for the prevention of postmenopausal bone loss. METHODS: In this multicenter, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally postmenopausal women were randomized to apply the estradiol matrix transdermal system (0.025, 0.0375, 0.05, or 0.1 mg/d) or matching placebo twice a week for 2 years. The study was double blind with respect to treatment (active vs placebo) but not to the dose levels of active treatment (because of the differing sizes and shapes of the patches). In addition to receiving the assigned treatment, the 100 nonhysterectomized women received 2.5 mg medroxyprogesterone acetate daily throughout the study. RESULTS: The evaluable group (n = 259) had a mean age of 52 years and a mean duration of menopause of 32 months. Following 2 years of treatment, there were significant differences in favor of estradiol between all doses of the estradiol matrix transdermal system and placebo in terms of the percentage change from baseline in the bone mineral density (BMD) of the L1-L4 anteroposterior lumbar spine (0.1 and 0.05 mg/d, P < 0.001; 0.0375 mg/d, P = 0.024; 0.025 mg/d, P = 0.002). Percentage changes from baseline in the BMD of the femoral neck after 2 years of treatment also consistently demonstrated the efficacy of the estradiol matrix transdermal system compared with placebo (all, P < or = 0.044). The estradiol matrix transdermal system was well tolerated. CONCLUSION: The estradiol matrix transdermal system was effective in preventing postmenopausal bone loss at dosages of 0.025 to 0.1 mg/d, and had a safety profile consistent with the known effects of estrogen/progestin.

Administration, Cutaneous↗

PubMed2001

Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression.

The effect of hormone withdrawal following hormone-simulated "pregnancy" on "depressive-like behavior" in the Forced Swim Test (FST) was investigated in female Long-Evans rats. Females were randomly assigned to "pregnant", "pregnant"+estradiol benzoate (EB), and control groups. Both the "pregnant" and "pregnant"+EB groups received daily injections of the hormones estradiol and progesterone to simulate the 23-day gestational period in the rat. However, the "pregnant"+EB group continued to receive daily estradiol injections after "pregnancy". All groups were tested 48 h after the last injection of the pregnancy period in the FST and subsequently in the Open Field Test (OFT). Results revealed that the "pregnant" rats exhibited significantly increased immobility and decreased struggling and swimming behaviors as compared to the "pregnant"+EB and control groups. These findings could not be explained by an overall depression in general locomotor activity among "pregnant" rats, as the "pregnant" rats made more area crossings in the OFT. Thus "pregnant" rats exhibited behaviors consistent with "depressive-like" symptoms "post-partum" (after their hormone regime was discontinued). Continual treatment with high levels of estradiol in the "pregnant"+EB group, however, reversed the exhibition of these behaviors. These results imply that withdrawal from chronic high levels of pregnancy-associated hormones (estradiol and progesterone) can produce depressed symptomology in rodents, which can be prevented by prolonging exposure to high levels of estradiol through the post-partum period. These findings are the first demonstration of "depressive-like" symptoms in a rodent model of post-partum pregnancy and the ability of high levels of estradiol to attenuate these "depressive-like" symptoms.

Analysis of Variance↗

PubMed2001

High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory.

The present study investigated the effects of high levels of estradiol in female rats on four different radial arm maze tasks: the hippocampus-dependent spatial working-reference memory task; the prefrontal cortex-hippocampus dependent delayed win-shift task; the striatum-dependent cued win-stay task; and the amygdala-dependent conditioned place preference task. Ovariectomized female rats were injected daily with either 10 microg of estradiol benzoate or sesame oil vehicle approximately 4 h prior to testing. In Experiment 1, treatment with estradiol disrupted learning on the spatial working-reference memory task by increasing the number of reference memory errors to reach criterion. In Experiment 2, treatment with estradiol had no significant effect on the delayed win-shift task. In Experiment 3, treatment with estradiol resulted in impaired performance on a striatum-dependent cued win-stay task. In Experiment 4, treatment with estradiol impaired the acquisition of a conditioned place-preference task. Taken together these findings suggest that high levels of estradiol inhibit reference memory, stimulus response learning, and amygdala-dependent appetitive conditioning while having little effect on working memory.

Amygdala↗

PubMed1999

Cloning of the 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-2 gene in the baboon: effects of estradiol on promoter activity of 11beta-HSD-1 and -2 in placental JEG-3 cells.

In the baboon, estrogen regulated 11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalyzed metabolism of cortisol and cortisone by the placenta is an important component in the sequence of events regulating the fetal pituitary-adrenocortical axis. The present study was designed to isolate and sequence the promoter region of the baboon 11beta-HSD-2 gene and to produce constructs of this gene and the 1.7 kb fragment of 5'-flanking region of baboon 11beta-HSD-1 isolated previously in order to determine whether the promoters of these two genes were activated in human placental JEG-3 cells and whether expression could be modulated by estradiol. The 11beta-HSD-2 genomic DNA was isolated from a baboon kidney genomic library using a human 11beta-HSD-2 cDNA as a probe. The sequence of a 1.2 kb fragment of the 5'-flanking region showed extensive homology with that published by others for human 11beta-HSD-2, particularly in exon 1 (>95%) and in the proximal promoter (>90%). Primer extension confirmed that the baboon 11beta-HSD-2 gene has multiple transcriptional start sites which are preceded by a GC box. To determine promoter activity of 11beta-HSD-2 and -1, the 5'-flanking regions of these genes were subcloned into luciferase reporter pGL3 vectors, transiently transfected into human placental JEG-3 cells, and then incubated for 16-18 h in the presence or absence of 10-8 M 17beta-estradiol or 17alpha-estradiol. To augment the low level of estrogen receptor (ER) in JEG cells, promoter activity studies were also performed in JEG cells co-transfected with an expression vector containing the human ER cDNA. The promoters of both 11beta-HSD-1 and -2 were activated following transient transfection into JEG-3 cells although basal activity of 11beta-HSD-2 (87+/-21 RLU/microg protein) always exceeded (P<0.05) that of 11beta-HSD-1 (37+/-7). In the absence of co-transfected ER, basal promoter activities of both 11beta-HSD genes were not altered by 17beta-estradiol. In contrast, in cells co-transfected with ER, 17beta-estradiol but not 17alpha-estradiol increased (P<0.05) basal promoter activities of 11beta-HSD-1 and -2 by 8.1+/-1.5 and 8.3+/-2. 0 fold, respectively. Collectively, these findings indicate that the promoter region of the baboon 11beta-HSD-2 gene is comparable to that in the human and that the 5'-flanking region of both the baboon 11beta-HSD-1 and -2 genes were active when transiently transfected into JEG-3 cells and that activation could be enhanced by estradiol in the presence of an estrogen receptor.

11-beta-Hydroxysteroid Dehydrogenases↗