J Urol. 2003 Aug;170(2 Pt 1):634-7.
The effect of ovariectomy and estradiol on rabbit bladder smooth muscle contraction and morphology.
Aikawa K, Sugino T, Matsumoto S, Chichester P, Whitbeck C, Levin RM.
Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, and Stratton Veteran's Medical Center, New York, USA.
PURPOSE: The bladder can be considered a target organ for the actions of estrogen. Decreases in circulating estrogen after menopause have been associated with bladder dysfunctions, including incontinence and detrusor instability. We determined the effects of estrogen on rabbit bladder contractile function and morphology. MATERIALS AND METHODS: Female New Zealand White rabbits were ovariectomized or sham operated and treated with vehicle or estradiol (1 mg/kg weekly) for 5 weeks. Serum estradiol concentration was monitored every 2 weeks. After treatment each rabbit was anesthetized, the bladder was catheterized, cystometry was performed, and the bladder was removed for contractile and morphological studies. Apoptosis in paraffin embedded rabbit bladder tissue was detected using in situ end-labeling, specifically terminal deoxynucleotidyl-transferase nick end labeling or the TUNEL assay. RESULTS: Ovariectomy resulted in a 50% decrease in circulating estrogen and estradiol treatment resulted in a 5-fold increase. Ovariectomy had no significant effects on bladder capacity, micturition pressure or bladder weight; whereas estradiol treatment resulted in significant increases in bladder capacity and bladder weight. Ovariectomy resulted in a decreased rate of tension generation in response to field stimulation, carbachol and KCl. Estradiol resulted in increased contractile responses to FS and carbachol, and an increased rate of tension generation for carbachol and KCl. Histologically ovariectomy resulted in significant urothelial apoptosis, which was not present in the sham operated or estradiol treated groups. Estradiol treatment resulted in the appearance of larg
J Anim Sci. 2003 Jul;81(7):1830-6.
Oxytocin-induced secretion of prostaglandin F2alpha in postpartum beef cows: effects of progesterone and estradiol-17beta treatment.
Kieborz-Loos KR, Garverick HA, Keisler DH, Hamilton SA, Salfen BE, Youngquist RS, Smith MF.
Animal Sciences Department, University of Missouri, Columbia 65211, USA.
The purpose of the present study was to determine the effect of progesterone or progesterone + estradiol-17beta on oxytocin-induced prostaglandin F2alpha (PGF2alpha) secretion in postpartum beef cows. Thirty-four anestrous postpartum beef cows were ovariectomized (d 32 [Groups 1 to 3] or d 23 [Groups 4 to 6] postpartum [d 0 = parturition]) and allotted to six treatments (Group 1; negative control) to simulate short (Groups 2 through 5) or normal (Group 6) length estrous cycles. Steroid treatments for the respective groups were as follows: Group 1) no estradiol-17beta or progesterone treatment (n = 8; negative control); Group 2) progesterone (d 34 to 40; n = 6); Group 3) estradiol-17beta (d 32 to 33) and progesterone (d 34 to 40; n = 6); Group 4) progesterone (d 23 to 29), no estradiol-17beta (d 32 to 33), and progesterone (d 34 to 40; n = 5); Group 5) progesterone (d 23 to 29), estradiol-17beta (d 32 to 33), and progesterone (d 34 to 40; n = 5); and Group 6) progesterone (d 23 to 29), estradiol-17beta (d 32 to 33), and progesterone (d 34 to 50; n = 4; positive control). Oxytocin (100 IU) was injected (i.v.) at the end of each treatment to test the ability of the postpartum uterus to secrete PGF2alpha as measured by a stable metabolite of PGF2alpha, 15keto-13,14 dihydro-PGF2alpha (PGFM). Peak concentrations ofPGFM (P < 0.08) and total PGFM secreted (area under the curve; P < 0.05) were increased on d 6 following first (Group 2) or second (Group 4) exposure to progesterone and were similar to peak concentrations and total PGFM secreted 16 d following a simulated normal estrous cycle (Group 6). Administration of estradiol-17beta before first progesterone e
Biol Reprod. 2003 Nov;69(5):1642-50. Epub 2003 Jul 09.
Androgens inhibit estradiol-17beta synthesis in Atlantic croaker (Micropogonias undulatus) ovaries by a nongenomic mechanism initiated at the cell surface.
Braun AM, Thomas P.
Department of Biological Sciences, University of Nevada, Las Vegas, NV 89154, USA. alyssa.braucmail.nevada.edu
The presence of androgen receptors in the ovaries of several vertebrate species, including Atlantic croaker, suggests that androgens may have important roles in ovarian function. In the current study the effects of androgens on ovarian steroidogenesis in Atlantic croaker were investigated. Addition of 17beta-hydroxy-5alpha-androstan-3-one (DHT), 11-ketotestosterone (11-KT), or Mibolerone to ovarian incubations caused dose-dependent decreases in gonadotropin-stimulated in vitro estradiol production, which was not reversed by cotreatment with the antiandrogens, cyproterone acetate or 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene. Androgen treatment also caused significant decreases in estradiol production in the presence of 17-hydroxyprogesterone, which suggests that the site of androgen action is downstream of this steroid in the steroidogenic pathway. The mechanism of androgen action on ovarian steroidogenesis was also investigated. Coincubation with actinomycin D did not reverse the inhibitory effect of the androgens, which suggests that the mechanism of androgen action is nongenomic. An androgen conjugated to bovine serum albumin (DHT-BSA), which does not enter the cell, also caused inhibition of estradiol production in vitro, indicating that the androgen is acting at the cell surface. In addition, time course experiments revealed that the androgen action is rapid; 5-min exposure to DHT was sufficient to cause a significant reduction in estradiol production. Finally, preliminary evidence was obtained for the existence of a high-affinity, low-capacity androgen binding site in croaker ovarian plasma membranes. These studies suggest that androgens can down-regulate es
Clin Exp Pharmacol Physiol. 2003 May-Jun;30(5-6):329-35.
Purinoceptor-mediated contractility of the perfused uterine vasculature of the guinea-pig: influence of oestradiol and pregnancy.
Haynes JM, Pennefather JN, Sikorski B.
Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia. john.haynecp.monash.edu.au
1. The effects of ATP, the stable ATP analogues alpha,beta-methylene ATP (alpha,beta-mATP), 2-methylthioATP (2meSATP) and adenosine tetraphosphate (ATP4), the pyrimidine nucleotide uridine 5'-triphosphate (UTP) and the alpha1-adrenoceptor agonist phenylephrine were examined on the isolated perfused uterine vasculature of dioestrous, oestradiol-treated, dexamethasone-treated and late-pregnant guinea-pigs. 2. The alpha1-adrenoceptor agonist phenylephrine elicited concentration-dependent vasoconstriction from preparations of perfused uterine vasculature from dioestrous, estradiol-treated and late-pregnant guinea-pigs. The mean maximal response to phenylephrine was unaffected by treatment of dioestrus guinea-pigs with oestradiol or dexamethasone, but was reduced in preparations from late-pregnant animals. 3. In perfused uterine arteries from dioestrous animals, the pyrimidine UTP, but not ATP4 and ATP, elicited vasoconstrictor responses. In preparations from oestradiol-treated animals, all three agonists elicited vasoconstriction, with a rank order of potency of ATP4 = UTP >> ATP, whereas in preparations from late-pregnant animals this order of potency was ATP4 >> UTP = ATP. In preparations from dexamethasone-treated animals, the vasoconstriction was similar to that seen in dioestrous animals. Vasoconstrictor responses to ATP4 were significantly greater in preparations of uterine vasculature from oestradiol-treated and pregnant animals than in preparations from dioestrous animals or dexamethasone-treated animals. 4. In preparations from dioestrous, oestradiol-treated, pregnant and dexamethasone-treated animals, al
Eur J Pharmacol. 2003 Jul 4;472(1-2):119-26.
Differences in the mechanisms for relaxation of aorta induced by 17beta-estradiol or progesterone between normotensive and hypertensive rats.
Unemoto T, Honda H, Kogo H.
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1, Horinouchi, Hachioji, Tokyo 193-0392, Japan.
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.
Endocrinology. 2003 Aug;144(8):3382-98.
Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms.
Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT.
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, USA.
We systematically characterized the oxidative metabolites of 17beta-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17beta-estradiol 2-hydroxylation, followed by 15alpha-, 6alpha-, 4-, and 7alpha-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15alpha- or 6alpha-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17beta-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9-13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16alpha- and 16beta-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone with CYP3A4 was 0.22 or 0.51, respectively. CYP3A5 had similar catalytic activity for the formation of 2- and 4- hydroxyestrogens. Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone (0.53 or 1.26, respectively). CYP3A4 and 3A5 also catalyzed the formation of nonpolar estrogen metabolite peaks (chromatographically less polar than estrone). CYP3A7 had a distinct catalytic activity for the 16alpha-hydroxylatio
Br J Cancer. 2003 Jul 21;89(2):385-90.
Oestradiol enhances tumour regression induced by B7-1/IL-2 adenoviral gene transfer in a murine model of breast cancer.
Dabrosin C, Palmer K, Gauldie J.
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada L8N 3Z5. lotdmk.liu.se
The majority of breast cancers are oestrogen dependent and although current treatment strategies have improved, approximately 50% of the patients will develop metastasis. New treatments that result in long-term systemic immunity are therefore being developed. We have previously shown that adenoviral gene transfer of B7-1/IL-2 to murine breast cancer induces a high rate of complete tumour regression and systemic immunity. Since oestrogens not only affect breast cancer but also have been shown to modulate immune function and secretion of immune-regulatory cytokines, we explored whether administration of oestradiol altered the immune response induced by an adenoviral vector expressing B7-1/IL-2. An oestrogen-dependent murine breast cancer tumour was used in ovariectomised mice, supplemented either oestradiol or placebo. We report the somewhat unexpected finding that intratumoral injection of adenovirus expressing B7-1/IL-2 induces complete tumour regression in 76% of oestradiol-supplemented mice, while only 18% of the tumours regressed in the oestrogen-depleted group. Cured mice in both groups exhibited a similar CTL response against the tumour antigen. However, intratumoral IFN-gamma levels, 2 days after B7-1/IL-2 injection, were significantly higher in mice treated with oestradiol compared to placebo. This may be one mechanism explaining the higher response rate of tumours in oestradiol-replenished mice.
Hua Xi Yi Ke Da Xue Xue Bao. 2000 Jun;31(2):242-5.
[The change in placental estradiol-progesterone ratio and its relationship with the fetal membrane's response to IL-1 beta in labor]
[Article in Chinese]
Zeng W, Wang Y, Yan F.
Department of Obstetrics and Gynecology, Second Affiliated Hospital, WCUMS, Chengdu 610041.
This study was designed to investigate the local changes in the levels of placental estradiol and progesterone and their ratio during term labor and to determine whether the PGE2-generating ability of the fetal membrane in response to IL-1 beta at term labor is greater than that at term not-in-labor. Forty pregnant women were divided into two groups: term labor and term not-in-labor. Placental estradiol and progesterone were measured by radioimmunoassay. The levels of fetal membrane PGE2 were measured by enzymoimmunoassay. The results showed that the placental concentration of estradiol and progesterone remained unchanged at the onset of labor, but the ratio of estradiol to progesterone increased significantly (P < 0.05). IL-1 beta stimulated fetal membrane to produce more PGE2 at term labor, and at term not-in-labor, too. But the increment of PGE2 generated by fetal membrane at term labor was greater than that at term not-in-labor. It is concluded that the change in placental estradiol to progesterone ratio may play an important role in the initiation of labor by altering the PGE2-generating ability of fetal membrane in response to cytokines.
Neurochem Res. 2002 Dec;27(12):1677-83.
17beta-estradiol effect on the extracellular concentration of amino acids in the glutamate excitotoxicity model in the rat.
Ritz MF, Schmidt P, Mendelowitsch A.
Neurosurgery Laboratory, Pharmazentrum, Easel, Switzerland. Marie-Francoise.Ritnibas.ch
Estrogen has demonstrated a neuroprotective role in a rat model of glutamate excitotoxicity and other neurodegenerative disorders. We studied the effect of 17beta-estradiol on glutamate-induced increases in amino acids levels (aspartate, histidine, taurine and GABA) in the rat cortex. Local perfusion of glutamate produced a transient increase of aspartate, histidine, taurine and GABA in the extracellular fluid. Pretreatment with 17beta-estradiol significantly reduced the increases of taurine and moderately attenuated that of histidine, whereas aspartate and GABA releases were not modified. The effect of 17beta-estradiol on histidine release was reversed by the antiestrogen tamoxifen, suggesting a receptor-dependent mechanism. Good correlations between the volumes of the glutamate-induced lesions and the extracellular concentrations of taurine and aspartate were observed. These findings suggest that the attenuation of the glutamate-induced release of taurine by 17beta-estradiol may participate in the neuroprotective effects of 17beta-estradiol and that increased levels of aspartate and taurine are markers for the severity of the glutamate-induced cortical lesions.
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