APMIS. 2001 May;109(5):365-75.
Uterotrophic effect of a saturated fatty acid 17-ester of estradiol-17beta administered orally to juvenile rats.

Paris A, Goutal I, Richard J, Becret A, Gueraud F.

INRA, Lab. Xenobiotiques, Toulouse, France. aparioulouse.inra.fr

In comparison to estradiol-17beta, the naturally synthesized estradiol-17beta-17-fatty acid esters are potent estrogens when administered subcutaneously. A lipophilic character of estradiol-17-esters could partially protect them from metabolic inactivation. In order to compare their relative estrogenic potency when administered orally, the uterotrophic response to different dosages (0, 2.5, 25, 250 and 2500 nmol/kg BW/day) of estradiol-17beta and estradiol-17beta-17-stearate was assessed in juvenile Sprague-Dawley female rats. Estrogens were administered by oral gavage once a day for 6 days. On the 7th day uterus and vagina were dissected, weighed, and examined microscopically. At 2.5 and 25 nmol/kg BW/day, no difference was detected in the uterus weight compared to control animals which received the vehicle alone (corn oil). At 250 nmol/kg BW/day, the uterotrophic response was maximal in estradiol-17beta-17-stearate-treated animals (x2.40-2.70), whereas it was moderate in estradiol-17beta-treated rats (x1.86) at the same dosage. This differential weight gain effect of estradiol-17beta-17-stearate was correlated with typical microscopic changes in uterus and vagina. The results are in favour of a stronger estrogenic effect of orally given lipoidal estrogens compared to estradiol-17beta. This could be explained by a slower but sustained absorption of estradiol-17beta released from estradiol-17beta-17-stearate by esterases and/or by a facilitated transfer of esters in the lymphatic circulation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11478684&dopt=Abstract estradiol




Biochem Biophys Res Commun. 2001 Aug 3;285(5):1259-66.
2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer.

Qadan LR, Perez-Stable CM, Anderson C, D'Ippolito G, Herron A, Howard GA, Roos BA.

Geriatric Research, Education, and Clinical Center and Research Service, VA Medical Center, Miami, Florida 33125, USA.

Few therapeutic treatment options are available for patients suffering from metastatic androgen-independent prostate cancer. We investigated the ability of the estrogen metabolite 2-methoxyestradiol to inhibit the proliferation of a variety of human prostate cancer cell lines in vitro and to inhibit the growth of androgen-independent prostate cancer in a transgenic mouse model in vivo. Our results showed that 2-methoxyestradiol is a powerful growth inhibitor of LNCaP, DU 145, PC-3, and ALVA-31 prostate cancer cells. Cell flow cytometry of 2-methoxyestradiol-treated DU 145 cells showed a marked accumulation of cells in the G2/M phase of the cell cycle and an increase in the sub-G1 fraction (apoptotic). In addition, staining for annexin V, changes in nuclear morphology, and inhibition of caspase activity support a role for apoptosis. More importantly, we showed that 2-methoxyestradiol inhibits prostate tumor progression in the Ggamma/T-15 transgenic mouse model of androgen-independent prostate cancer without toxic side effects. These results in cell culture and an animal model support investigations into the clinical use of 2-methoxyestradiol in patients with androgen-independent prostate cancer. Copyright 2001 Academic Press.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11478793&dopt=Abstract estradiol




J Endocrinol. 2001 Aug;170(2):441-50.
Effect of estrogen on calcium and sodium transport by the nephron luminal membranes.

Brunette MG, Leclerc M.

Maisonneuve-Rosemont Hospital, Research Center and University of Montreal, Quebec, Canada. visionfrsmr.qc.ca

Estrogens are widely used for contraception and osteoporosis prevention. The aim of the present study was to investigate the effect of 17 beta-estradiol on calcium (Ca(2+)) transport by the nephron luminal membranes, independently of any other Ca(2+)-regulating hormones. Proximal and distal tubules of rabbit kidneys were incubated with 17 beta-estradiol or the carrier for various periods of time, and the luminal membranes of these tubules were purified and vesiculated. Ca(2+) uptake by membrane vesicles was measured using the Millipore filtration technique. Incubation of proximal tubules with the hormone did not influence Ca(2+) uptake by the luminal membranes. In contrast, incubation of distal tubules with 10(-8) M 17 beta-estradiol for 30 min decreased the initial uptake of 0.5 mM Ca(2+) from 0.34+/-0.04 (s.e.m. ) to 0.17+/-0.04 pmol/microg per 5 s (P<0.05). In the presence of 100 mM Na(+), 0.5 mM Ca(2+) uptake was strongly diminished and the effect of 17 beta-estradiol disappeared (0.17+/-0.01 and 0.21+/-0.07 pmol/microg per 5 s in vesicles from the control and treated tubules). Direct incubation of the membranes with 17 beta-estradiol, however, failed to show any influence of the hormone on Ca(2+) transport. The action of 17 beta-estradiol was dose-dependent, with a half-maximal effect at approximately 10(-9) M. Ca(2+) uptake by the distal tubule membranes presents dual kinetics. 17 beta-Estradiol decreased the V(max) value of the high-affinity component from 0.42+/-0.02 to 0.31+/-0.03 pmol/microg per 10 s (P<0.02). In contrast with the effect of the hormone on Ca(2+) transport, estradiol increased Na(+) uptake by both the proximal and distal tubule luminal membranes. In conclusion, incubation of proximal and distal tubules




Indian J Physiol Pharmacol. 2001 Apr;45(2):161-71.
Morphological and functional characteristics of rabbit uterine epithelial cells grown on free floating collagen gel.

Venkataraman L, Upadhyay S, Lalitkumar PG, Sengupta J, Ghosh D.

Department of Physiology, All India Institute of Medical Sciences, New Delhi-110 029.

In the present study isolated uterine epithelial cells from normal rabbits were maintained in culture on free floating rat-tail collagen matrix, and the morphological characteristics of these cells were examined. Additionally, the pattern of protein synthesis and secretion by rabbit uterine epithelial cells grown on free floating collagen gels following estradiol and/or progesterone treatment in vitro was examined. Isolated epithelial cells cultured on collagen gels in complete medium containing serum attached to form monlayers, and eventually the gels became free floating and contracted giving rise to luminal arrangements. These cells were cytokeratin positive epithelial cells and were ultrastructurally polarized. These cells also exhibited differential upregulation and down regulation in the synthesis and secretion of proteins in response to estradiol, progesterone, and estradiol plus progesterone. Additionally, a permissive action between progesterone and estradiol in the synthesis of two species of secretory proteins was observed. It however remains to be examined whether different species of proteins produced in vitro in response to estradiol and progesterone bear any association with physiological states in reproductive cycle in this species.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11480222&dopt=Abstract estradiol




Rev Esp Cardiol. 2001 Aug;54(8):990-6.
[Estradiol enhances endothelium-dependent vasodilation via a nitric oxide pathway]

[Article in Spanish]

Sitges M, Roque M, Solanes N, Rigol M, Heras M, Roig E, Luis Pomar J, Jimenez W, Sanz G.

Instituto de Enfermedades Cardiovasculares Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Facultad de Medicina, Universidad de Barcelona.

BACKGROUND AND AIM: The mechanisms by which estradiol dilates arterial vessels are still unclear. Our aim was to study if estradiol enhances endothelium-dependent vasodilation in an experimental model of human arteries in vitro, and if this effect is nitric oxide mediated. METHODS: Using organ bath chambers, we studied 18 arterial rings obtained from left internal mammary arteries during coronary artery bypass grafting surgery. Response to acetylcholine was evaluated at baseline and after the addition of estradiol 10-6 mol/l to the medium, both in the presence or absence of a nitric oxide synthase inhibitor (L-NNA 10-4 mol/l). RESULTS: Estradiol significantly enhanced the relaxation of the arterial rings in response to acetylcholine (52 +/- 20% after estradiol versus 42 +/- 22% at baseline; n = 10; p = 0.02). However, endothelium-dependent vasodilation relaxation after estradiol addition was not enhanced in the presence of L-NNA (47 +/- 25% after estradiol versus 38 +/- 22% at baseline; n = 8; p = NS). CONCLUSIONS: Estradiol in vitro enhances endothelium-dependent vasodilation of internal human mammary artery rings; this effect is blunted after the addition to the medium of a nitric oxide inhibitor. Therefore, the vasodilator properties of estradiol at the studied dosage depend on the nitric oxide pathway.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11481114&dopt=Abstract estradiol




Am J Obstet Gynecol. 2001 Jul;185(1):182-9.
Inhibition of cyclooxygenase but not nitric oxide synthase influences effects on the human omental artery of the thromboxane A2 mimetic U46619 and 17beta-estradiol.

Vedernikov YP, Belfort MA, Saade GR, Garfield RE.

Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA.

OBJECTIVE: These experiments were performed to study the influence of endothelial factors on the contractile effect of the thromboxane A(2) analog U46619 and on the relaxant action of 17beta-estradiol on isolated human omental arteries from nonpregnant women, women with normal pregnancies, and women with preeclampsia. STUDY DESIGN: Arterial rings (3 mm) with or without endothelium were suspended in organ chambers filled with Krebs buffer, 37 degrees C, aerated with 5% carbon dioxide in air, pH approximately 7.4, for isometric tension recording. Rings were incubated with indomethacin, N(omega)-nitro-L -arginine, or 17beta-estradiol, alone or in combination. The concentration that produced 50% of maximal effect, the area under the curve, and the maximal effect of U46619, normalized with respect to a reference contraction in response to potassium chloride, were compared. RESULTS: Neither indomethacin nor N(omega)-nitro-L -arginine changed the basal tone of omental artery rings. Neither N(omega)-nitro-L -arginine nor removal of the endothelium affected either the contractile action of U46619 or the relaxant action of 17beta-estradiol. In contrast, indomethacin potentiated the contractile effect of U46619 and abolished the inhibitory effect of 17beta-estradiol in rings from all three groups. The effects of U46619 and 17beta-estradiol were significantly less in rings from women with normal pregnancy than in those from women with preeclampsia. Tissues from women with preeclampsia demonstrated the highest contractile response to U46619. CONCLUSION: The inhibitory effect of 17beta-estradiol is not due to increased production o




Parasitol Res. 2001 Jul;87(7):513-20.
Modulation induced by estradiol in the acute phase of Trypanosoma cruzi infection in mice.

de Souza EM, Rivera MT, Araujo-Jorge TC, de Castro SL.

Departamento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.

We investigated the effect of 17beta-estradiol on mice resistant to infection by Trypanosoma cruzi. Infected Balb/C, C3H and C57BL/6 female mice had a longer survival time than males, C57BL/6 showing the highest difference (50% cumulative mortality in females versus 100% in males). This lineage was treated with estradiol (from 0.05 microg to 500 microg/mouse) 1 day before infection. Treatment with 50 microg or 500 microg estradiol/ mouse increased mortality and parasitaemia. Low doses had no effect or tended to reduce both parameters. Given that estradiol presented no in vitro effect on trypomastigotes or epimastigotes, the involvement of a direct hormonal effect on the parasite is improbable. Alterations in the humoral T. cruzi-specific response were also discarded, since the kinetics and concentration of anti-T. cruzi IgG were not affected by the treatment. Females infected during an estradiol-descending phase (meta-oestrus) survived longer than those infected during other phases of the oestrous cycle. We confirmed that estradiol interferes with T. cruzi infection.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11484845&dopt=Abstract estradiol




Life Sci. 2001 Jul 6;69(7):815-27.
Progesterone and 17 beta-estradiol acutely stimulate nitric oxide synthase activity in rat aorta and inhibit platelet aggregation.

Selles J, Polini N, Alvarez C, Massheimer V.

Departamento de Biologia, Bioquimica y Farmacia, Universidad Nacional del Sur, Bahia Blanca, Argentina.

The rapid non-genomic stimulatory action of progesterone (Pg) and estradiol (E2) on nitric oxide synthase (NOS) activity of endothelium intact aortic rings and its effect on platelet aggregation was investigated. First we measured the effect of the hormones on platelet aggregation when added to rat aortic strips (RAS) incubated in a PRP. RAS induced an antiaggregatory activity, which was enhanced by the presence of the hormones. The inhibitory action induced by the hormones was evoked in a dose dependent manner (10 pM-100 nM). These effects are specific for progesterone and 17-beta-estradiol, since either testosterone and 17-alpha-estradiol were devoid of activity. The hormones induced rapid responses, producing significant inhibition within 1 to 5 minutes of hormonal exposure. The addition of 10(-5) M L-NAME suppressed the antiaggregatory effect of 1 nM E2 or 10 nM Pg. Furthermore, we specifically quantified the NO generation by the 3H-citrulline technique. 10(-8) M E2 induced 2-fold increase of RAS citrulline production, while the increment induced by 10(-7) M Pg was 55% over control. Preincubation with 10(-5) M L-NAME completely suppressed the stimulatory action of 10(-9) M E2 or 10(-8) M Pg, confirming that the antiaggregatory factor released from the aortic tissue was NO. Preincubation with cycloheximide did not block the increment in NO induced by the hormones. In conclusion the present study provides for the first time evidence of acute, non-genomic effects of Pg on rat aorta NOS activity and platelet aggregation in coincidence with the results obtained with estradiol treatment.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11487093&dopt=Abstract estradiol




Regul Pept. 2001 Sep 15;101(1-3):87-91.
Progesterone and norethisterone have different effects on tachykinin-like immunoreactivity in rat cortex and striatum.

Rugarn O, Hammar M, Theodorsson E.

Faculty of Health Sciences, Division of Obstetrics and Gynecology, Linkoping University Hospital, S-581 85, Linkoping, Sweden. mats.hammakl.us.lio.se

OBJECTIVE: The purpose of this study was to investigate the effects of progesterone and the most commonly prescribed synthetic progestogen, norethisterone, on regional immune-like reactivity of neuropeptide Y (NPY), substance P (SP), neurokinin A (NKA) and neurotensin (NT) in brains of female ovariectomized estradiol-substituted rats. Results: Norethisterone+estradiol-treated rats had 44% lower SP levels compared with estradiol-only-treated in frontal cortex and 20% lower NKA levels in comparison with progesterone+estradiol-treated in frontal cortex. Progesterone+estradiol-treated rats had 66% lower SP levels in striatum in comparison with both estradiol-only-treated and norethisterone+estradiol-treated. No significant results were found for NPY and NT. CONCLUSION: Progesterone and the synthetic progestogen, norethisterone, have different effects on SP- and NKA-like immunoreactivity in rat cortex and striatum.The effects of NET on SP- and NKA-like immunoreactivity in frontal cortex may contribute to the mood effects ascribed to this progestogen in clinical usage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11495683&dopt=Abstract estradiol