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PubMed2002

Loss of luteinizing hormone surges induced by chronic estradiol is associated with decreased activation of gonadotropin-releasing hormone neurons.

Chronic exposure of young ovariectomized rats to elevated circulating estradiol causes loss of steroid-induced LH surges. Such LH surges are associated with cFos-induced activation of GnRH neurons; therefore, we hypothesized that chronic estradiol treatment abolishes LH surges by decreasing activation of GnRH neurons. Regularly cycling rats were ovariectomized and immediately received an estradiol implant or remained untreated. Three days or 2 or 4 wk later, the estradiol-treated rats received vehicle or progesterone at 1200 h, and 7 hourly blood samples were collected for RIA of LH. Thereafter, all rats were perfused, and the brains were examined for immunocytochemical localization of cFos and GnRH. The GnRH neurons from untreated ovariectomized rats rarely expressed cFos. As reported, LH surges induced by 3 days of estradiol treatment were associated with a 30% increase in cFos-containing GnRH neurons, and progesterone enhanced both the amplitude of LH surges and the proportion of cFos-immunopositive GnRH neurons. As hypothesized, the abolition of LH surges caused by 2 or more weeks of estradiol was paralleled by a reduction in the percentage of cFos-containing GnRH neurons, and this effect was delayed by progesterone. These results suggest that chronic estradiol abolishes steroid-induced LH surges in part by inactivating GnRH neurons.

Aging↗
PubMed1997

Roles of NO and Ca2+-activated K+ channels in coronary vasodilation induced by 17beta-estradiol in ischemic heart failure.

Estrogen induces the generation of nitric oxide (NO) and produces coronary vasodilation by opening the Ca2+-activated K+ (K[Ca]) channels. The hypothesis that 17beta-estradiol produces NO and activates K(Ca) channels during coronary hypoperfusion was investigated. In open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. 17beta-Estradiol was infused into the bypass tube for 20 min after coronary blood flow was reduced by partial occlusion of the bypass tube. 17beta-Estradiol increased the difference in NO concentrations between the coronary venous and arterial blood as well as coronary blood flow. The lactate extraction ratio and pH of coronary venous blood were both also increased by 17beta-estradiol, indicating a reduction in myocardial anaerobic metabolism. Whereas the increase in the coronary arteriovenous difference in NO concentration was completely attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase), the increase in coronary blood flow induced by 17beta-estradiol was only partially attenuated by L-NAME. The combination of L-NAME and iberiotoxin (a blocker of high-conductance K(Ca) channels) completely abolished the coronary vasodilatory effect of 17beta-estradiol. The data indicate that during coronary hypoperfusion in canine hearts, 17beta-estradiol increases coronary blood flow and improves metabolic dysfunction by increasing NO release and opening K(Ca) channels.

Animals↗
PubMed1998

Estradiol protects against ischemic injury.

Clinical studies demonstrate that estrogen replacement therapy in postmenopausal women may enhance cognitive function and reduce neurodegeneration associated with Alzheimer's disease and stroke. This study assesses whether physiologic levels of estradiol prevent brain injury in an in vivo model of permanent focal ischemia. Sprague-Dawley rats were ovariectomized; they then were implanted, immediately or at the onset of ischemia, with capsules that produced physiologically low or physiologically high 17beta-estradiol levels in serum (10 or 60 pg/mL, respectively). One week after ovariectomy, ischemia was induced. Estradiol pretreatment significantly reduced overall infarct volume compared with oil-pretreated controls (mean+/-SD: oil = 241+/-88; low = 139+/-91; high = 132+/-88 mm3); this protective effect was regionally specific to the cortex, since no protection was observed in the striatum. Baseline and ischemic regional CBF did not differ between oil and estradiol pretreated rats, as measured by laser Doppler flowmetry. Acute estradiol treatment did not protect against ischemic injury. Our finding that estradiol pretreatment reduces injury demonstrates that physiologic levels of estradiol can protect against neurodegeneration.

Animals↗
PubMed2002

17-beta-estradiol induces heat shock proteins in brain arteries and potentiates ischemic heat shock protein induction in glia and neurons.

Estradiol reduces brain injury from many diseases, including stroke and trauma. To investigate the molecular mechanisms of this protection, the effects of 17-beta-estradiol on heat shock protein (HSP) expression were studied in normal male and female rats and in male gerbils after global ischemia. 17-beta-estradiol was given intraperitoneally (46 or 460 ng/kg, or 4.6 microg/kg) and Western blots performed for HSPs. 17-beta-estradiol increased hemeoxygenase-1, HSP25/27, and HSP70 in the brain of male and female rats. Six hours after the administration of 17-beta-estradiol, hemeoxygenase-1 increased 3.9-fold (460 ng/kg) and 5.4-fold (4.6 microg/kg), HSP25/27 increased 2.1-fold (4.6 microg/kg), and Hsp70 increased 2.3-fold (460 ng/kg). Immunocytochemistry showed that hemeoxygenase-1, HSP25/27,and HSP70 induction was localized to cerebral arteries in male rats, possibly in vascular smooth muscle cells. 17-beta-estradiol was injected intraperitoneally 20 minutes before transient occlusion of both carotids in adult gerbils. Six hours after global cerebral ischemia, 17-beta-estradiol (460 ng/kg) increased levels of hemeoxygenase-1 protein 2.4-fold compared with ischemia alone, and HSP25/27 levels increased 1.8-fold compared with ischemia alone. Hemeoxygenase-1 was induced in striatal oligodendrocytes and hippocampal neurons, and HSP25/27 levels increased in striatal astrocytes and hippocampal neurons. Finally, Western blot analysis confirmed that estrogen induced heat shock factor-1, providing a possible mechanism by which estrogen induces HSPs in brain and other tissues. The induction of HSPs may be an important mechanism for estrogen protection against cerebral ischemia and other types of injury.

Animals↗
PubMed1997

Effect of 17-beta estradiol in the rabbit: endothelium-dependent and -independent mechanisms of vascular relaxation.

Short-term estrogen administration has been independently proposed to produce arterial vasodilation by both an indirect mechanism and a direct mechanism (inhibition of calcium entry though the L-type calcium channel). The proposed contributions of such diverse mechanisms to the vascular actions of 17beta-estradiol were examined in perfused hearts and in aortic ring sections isolated from female rabbits. In isolated rabbit hearts retrogradely perfused with Tyrode's solution, concentration-response curves to 17beta-estradiol (10(-9)-10(-5) M) were performed under control conditions and during perfusion with Bay K8644 (10(-7) M). 17beta-Estradiol produced a concentration-dependent decrease in coronary vascular resistance proportional to nitric oxide (NO) release in the presence and absence of Bay K8644. The addition of N(G)-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) to the perfusate (a) completely inhibited NO formation, (b) produced a 2.3-fold and 1.55-fold rightward shift in the concentration-response curve to 17beta-estradiol for Bay K8644 treated and control hearts, respectively, and (c) failed to prevent coronary artery vasodilation. In isolated aortic rings contracted with Bay K8644, 17beta-estradiol (10(-5) M) relaxed both intact (58%) and denuded (54%) aortic rings. L-NAME (10(-4) M) completely blocked NO release in intact rings but did not prevent relaxation in denuded aortic rings. The data demonstrate (a) an endothelium-dependent relaxation by 17beta-estradiol, coincident with NO formation and suppressed by L-NAME, and (b) a direct relaxation of aortic and coronary smooth muscle independent of NO formation at higher 17beta-estradiol concentrations.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Physiological concentrations of 17beta-estradiol inhibit the synthesis of nitric oxide synthase in macrophages via a receptor-mediated system.

We investigated the effect of estrogen on inducible nitric oxide synthase (iNOS), which is not well understood, in contrast to the known effect of estrogen on endothelial nitric oxide synthase (eNOS). When J774 cells, a murine macrophage cell line, were incubated with interferon-gamma and lipopolysaccharide, iNOS was induced, and a large amount of NO was released. Pre- or coincubation with 17beta-estradiol inhibited this induction of iNOS protein and NO release; however, 17beta-estradiol did not have a direct effect on enzyme activity of iNOS. The analog, 17alpha-estradiol, did not have such an effect. Tamoxifen, an antiestrogen, and ICI182780, an estrogen-receptor antagonist, inhibited the influence of 17beta-estradiol on iNOS. Thus 17beta-estradiol inhibited the induction of iNOS by a classic receptor-mediated pathway. The inhibition of the NO release from iNOS by 17beta-estradiol is in contrast to the reported augmentation of continuous NO release from eNOS. These harmonious effects of estrogen on iNOS and eNOS may have some role in the antiatherosclerotic effects of 17beta-estradiol.

Animals↗
PubMed1991

Inhibition of myointimal hyperplasia and macrophage infiltration by estradiol in aorta allografts.

A major cause of organ graft loss after heart transplantation is accelerated atherosclerosis. In this study we used aorta allografts and investigated the effect of estradiol-17 beta treatment on both the degree of myointimal hyperplasia and morphological changes evaluated by light and electron microscopy. Outbred New Zealand white male rabbits (2.7-3.5 kg) were fed cholesterol (0.5%) from one week prior to transplantation, and until sacrifice three weeks later. The donor abdominal aorta was transplanted end-to-end to the right carotid artery of the recipient animals. Immediately following surgery, cyclosporine (10 mg/kg/d s.c.) was administered to prevent graft rejection. The allograft recipients were randomly assigned to one of five groups and treated with cottonseed oil (placebo) or estradiol cypionate at 1, 10, 100, or 1000 micrograms/kg/d i.m. for 3 weeks. The aorta grafts were harvested and fixed for transmission electron microscopy and morphometry. The area of myointimal thickening was calculated as a percent of total vessel area (mean +/- SEM); the control group was 6.6 +/- 0.5% (n = 5). Estradiol treatment significantly inhibited (P less than 0.05) myointimal hyperplasia at all doses. The values were 3.9 +/- 0.6% (n = 6) for 1 microgram/kg/day; 4.4 +/- 0.7% (n = 5) for 10 micrograms/kg/day; 3.5 +/- 0.4% (n = 6) for 100 micrograms/kg/day; and 2.9 +/- 0.1% (n = 3) for 1000 micrograms/kg/day. Electron microscopic evaluation revealed that the four doses of estradiol protected the endothelium from the degenerative changes seen in all aorta allografts from the animals in the control group. Furthermore 10, 100, and 1000 micrograms/kg/day of estradiol prevented the appearance of vacuolized macrophages (foam cells) and also the vacuolization of smooth muscle cells that was observed in the aorta allografts from the control group and the group treated with 1 microgram/kg/day of estradiol. We conclude that the inhibitory effect of estradiol on the development of graft atherosclerosis may be due to inhibition of smooth muscle cell proliferation and preservation of ultrastructurally normal endothelial cells. The inhibitory effect on foam cell production and a concomitant vacuolization of smooth muscle cells may play a lesser role. We suggest that estrogen replacement therapy may be beneficial in postmenopausal women with organ allografts.

Animals↗
PubMed2005

17beta-estradiol exerts a beneficial effect on coronary vascular remodeling in the early stages of hypertension in spontaneously hypertensive rats.

OBJECTIVE: Estrogens may induce cardioprotective effects and prevent neointima formation in response to vascular injury in vivo. The present study evaluated the effect of 17beta-estradiol on myocardial arterial remodeling and on vascular mitogen-activated protein kinase expression in experimental hypertension. DESIGN: The experiments were performed in intact female spontaneously hypertensive rats (SHR), in SHR that were ovariectomized at 10 or 25 weeks of age, and in ovariectomized SHR that were supplemented with 17 beta-estradiol (OVX + E2, 1.5 mg every 8 weeks, subcutaneous pellets). RESULTS: At 18 weeks of age, in all myocardial arterioles and small arteries studied, we found significant increases in wall-to-lumen ratio in ovariectomized rats as compared with intact animals. 17beta-estradiol significantly reduced the wall-to-lumen ratio in OVX + E2 rats. Perivascular fibrosis of small coronary arteries was significantly increased by ovariectomy, and this effect was prevented by long-term treatment with 17beta-estradiol. Phosphorylated extracellular signal-regulated kinase 1/2 significantly increased in mesenteric arteries from ovariectomized animals and this effect was prevented by 17beta-estradiol. Wall-to lumen ratio and perivascular fibrosis were significantly higher in older intact animals at 33 weeks of age. However, neither ovariectomy nor estradiol replacement had any effect on long-term hypertension-induced vascular remodeling. CONCLUSIONS: These data suggest that estradiol may exert a beneficial effect by protecting the vasculature from hypertension-induced myocardial arterial remodeling in the early stages of hypertension, but not when chronic alterations are established after a long-term period of hypertension.

Animals↗
PubMedDate not supplied

Estradiol in micellar nanoparticles: the efficacy and safety of a novel transdermal drug-delivery technology in the management of moderate to severe vasomotor symptoms.

OBJECTIVE: To assess the efficacy and safety of topical micellar nanoparticle estradiol emulsion (MNPEE; Estrasorb; Novavax, Inc., Malvern, PA) in postmenopausal women with moderate to severe vasomotor symptoms. DESIGN: A multicenter, randomized, double-blind, placebo-controlled study was conducted in 200 postmenopausal women with seven or more moderate to severe hot flushes per day. The study consisted of a 3-week screening period followed by a 1-week placebo emulsion run-in period and a 12-week active or placebo treatment period. Women were randomized (1:1) to receive MNPEE (3.45 g daily dose of emulsion containing 8.6 mg estradiol) or matching placebo emulsion. The primary efficacy variable was the change from baseline in the frequency of moderate and severe hot flushes at weeks 4 and 12. Adverse events were monitored throughout the trial. RESULTS: Topical micellar nanoparticle estradiol emulsion was statistically significantly superior to placebo emulsion in reducing the mean frequency of moderate to severe vasomotor symptoms by week 3 (P = 0.003), with superiority to placebo maintained from weeks 4 to 12 (P < 0.001). At week 12 (peak benefit), MNPEE reduced mean daily frequency of hot flush count by 11.1 (P < 0.001 vs placebo). MNPEE significantly reduced mean symptom severity from weeks 4 to 12 (P < 0.001) compared with placebo. At endpoint, mean serum concentrations of estradiol and estrone were 63 and 89 pg/mL, respectively, in the MNPEE group. The mean endpoint ratio of estradiol to estrone in these patients was 0.774. MNPEE was safe and well tolerated. CONCLUSION: Once-daily application of 3.45 g of micellar nanoparticle estradiol emulsion containing 8.6 mg of estradiol was safe and effective in providing significant relief of vasomotor symptom frequency and severity in postmenopausal women.

Administration, Cutaneous↗
PubMed2005

Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial.

OBJECTIVE: The purpose of this multicenter, double-blind, randomized, parallel-group study was to determine the effect of thirteen 28-day cycles of drospirenone combined with estradiol, compared with estradiol alone, on the endometrium of postmenopausal women. DESIGN: Postmenopausal women not on hormone therapy but with an intact uterus were enrolled (N = 1,147); 1,142 were evaluated. Participants were randomly assigned to treatment with 1.0 mg of estradiol alone (E(2) monotherapy) or 1.0 mg of estradiol plus 0.5, 1.0, 2.0, or 3.0 mg of drospirenone (DRSP/E(2)). Endometrial biopsies were performed at baseline, at 7 months if indicated, and at study end in the 13th month. Safety was evaluated with peripheral blood samples for hematology, liver and renal function, and lipids, along with vital signs and interval medical evaluations. RESULTS: When compared with estradiol alone, combinations of drospirenone and estradiol were effective in protecting against endometrial hyperplasia. The probability of hyperplasia was 0.060 (95% CI, 0.043-0.078) for the E(2) monotherapy group, 0.007 for the 2-mg DRSP/E(2) group, and nonsignificant for the remaining drospirenone/estradiol groups. Endometrial bleeding decreased in all treatment groups over time. The combination of drospirenone and E(2) relieved menopausal symptoms and resulted in improvements in health-related quality-of-life measures. There were no significant adverse events, and effects on triglycerides, total cholesterol, and high-density lipoprotein cholesterol were positive. CONCLUSIONS: The use of drospirenone combined with estradiol provides protection against endometrial hyperplasia, reduces endometrial bleeding with time, and relieves menopausal symptoms. There were no safety issues and blood pressure was reduced in women with hypertension.

Adult↗
PubMedDate not supplied

Estradiol and phytoestrogens differently influence the rodent postmenopausal mammary gland.

OBJECTIVE: In the following study, we investigated treatment-related changes in mammary gland histomorphology and structure after the administration of soy to adult virgin ovariectomized (OVX) female rats. Additionally, mammary receptor regulation was extensively evaluated by immunohistochemical analysis, and tissue proliferative activity analyzed by cell nuclear proliferating antigen expression (Ki67). DESIGN: OVX rats were treated, for 6 weeks, with either the vehicle, the soy extract (SSE 100 mg/kg/d PO), or 17beta-estradiol (0.5 mg/kg/d PO); a sham control group (SHAM) was also included in the study. When killed, mammary glands were collected and subsequently processed for light microscopy or immunohistochemistry. Immunoreactivity was quantified by a scoring system that took into account both the percentage of positive cells and the intensity of the staining. RESULTS: The 17beta-estradiol--treated rats had stimulated mammary glands compared with OVX rats, with an average lobulo-alveolar development not different from the SHAM controls. Only a partial regression of the glandular atrophy was observed in OVX rats receiving 100 mg/kg/d SSE, with a histological appearance between that of the OVX and SHAM controls. No significant changes were observed among experimental groups in the median ERalpha scores of the epithelial compartment (score of 3 in all groups); in the stromal compartment, a tendency toward decreased expression was seen with 17beta-estradiol rats compared with OVX controls (scores of 2 and 5, respectively). A significant reduction in ERbeta immunostaining was observed in the mammary glands of SSE-treated rats, in both epithelium and stroma (scores of 4 and 3, respectively), compared with those of OVX controls (score of 8 in both compartments). The ERbeta receptor status was not significantly affected by 17beta-estradiol. Compared with OVX rats (score of 1), PR expression was up-regulated by 17beta-estradiol (score of 6), whereas an ovariectomy-like pattern was observed after the administration of SSE (score of 0). Ki67 immunoreactivity in the epithelium and stroma was increased by the administration of 17beta-estradiol (scores of 4 and 5, respectively) and was unchanged after SSE treatment (scores of 0 and 2, respectively), compared with OVX controls (scores of 1 and 2, respectively). CONCLUSIONS: The differences observed in the histological pattern, hormonal receptor status regulation, and Ki67 modulation suggest a different role for phytoestrogens and 17beta-estradiol in postmenopausal rodent mammary glands.

Animals↗
PubMed2003

Transdermal estradiol therapy for advanced prostate cancer--forward to the past?

PURPOSE: Current hormonal therapies for prostate cancer are associated with significant morbidities, including symptoms of andropause and osteoporosis. Oral estrogens prevented many of these problems but were abandoned due to cardiovascular toxicity attributed to hepatic effect. In contrast, parenteral estrogens prevent first pass hepatic metabolism and substantially reduce cardiovascular risk, and long-term transdermal estradiol therapy is believed to be cardioprotective. We report preliminary results of a pilot study using transdermal estradiol therapy to treat men with advanced prostate cancer. MATERIALS AND METHODS: A total of 20 patients with advanced prostate cancer were enrolled in a before and after study that examined the impact of estradiol patches on hormones, disease, thrombophilia, vascular flow, osteoporosis and quality of life. RESULTS: Median followup is 15 months. Estradiol levels greater than 1,000 pmol./l. were achieved using 2 patches and higher levels were obtained by increasing the number of patches. All patients achieved castrate levels of testosterone within 3 weeks and had biochemical evidence of disease regression. One patient died of disease at 14 months and 1 cardiovascular complication occurred. Thrombophilic activation was avoided and vascular flow improved. Bone mineral density was significantly increased. Mild or moderate gynecomastia occurred in 80% of patients but no patient had hot flushes. All other functional and symptomatic quality of life domains improved. CONCLUSIONS: Transdermal estradiol therapy produced an effective tumor response. Cardiovascular toxicity was substantially reduced compared with that expected of oral estrogen, and other morbidity (gynecomastia) was negligible. Transdermal estradiol therapy prevented andropause symptoms, improved quality of life scores and increased bone density. Transdermal estradiol costs a tenth of current therapy cost, with the potential for considerable economic savings over conventional hormone therapies.

Administration, Cutaneous↗
PubMed2003

The effect of ovariectomy and estradiol on rabbit bladder smooth muscle contraction and morphology.

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 large cytoplasmic vacuoles in the urothelium and significant smooth muscle hypertrophy. CONCLUSIONS: These findings demonstrate that bladder function and structure can be significantly affected by modulating the circulating estrogen level. In addition, estrogen given in pharmacological doses can have a significant hypertrophic effect on bladder smooth muscle, resulting in increased contractile function.

Animals↗
PubMed2004

Differential effects of 17beta-estradiol upon stroke damage in stroke prone and normotensive rats.

We previously reported that during pro-estrus (high endogenous estrogen levels), brain damage after middle cerebral artery occlusion (MCAO) was reduced in stroke-prone spontaneously hypertensive rats (SHRSP) but not in normotensive Wistar Kyoto rat (WKY). In the present study, we examined the effect of exogenous estrogen on brain damage after MCAO in SHRSP and WKY. A 17beta-estradiol (0.025 mg or 0.25 mg, 21 day release) or matching placebo pellet was implanted into ovariectomized WKY and SHRSP (3 to 4 months old) who then underwent distal diathermy-induced MCAO 2 weeks later. Plasma 17beta-estradiol levels for placebo and 17beta-estradiol groups were as follows: WKY 0.025 mg 16.4 +/- 8.5 (pg/mL, mean +/- SD) and 25.85 +/- 12.6; WKY 0.25 mg 18.2 +/- 9.0 and 69.8 +/- 27.4; SHRSP 0.25 mg 20.7 +/- 8.8 and 81.0 +/- 16.9. In SHRSP, infarct volumes at 24 hours after MCAO were similar in placebo and 17beta-estradiol groups: SHRSP 0.025 mg 126.7 +/- 15.3 mm (n = 6) and 114.0 +/- 14.1 mm (n = 8) (not significant); SHRSP 0.25 mg 113.5 +/- 22.3 mm (n = 8) and 129.7 +/- 26.2 mm (n = 7) (not significant), respectively. In WKY, 17beta-estradiol significantly increased infarct volume by 65% with 0.025 mg dose [36.1 +/- 20.7 mm (n = 8) and 59.7 +/- 19.3 mm (n = 8) (P = 0.033, unpaired t-test)] and by 96% with 0.25 mg dose [55.9 +/- 36.4 mm (n = 8) and 109.7 +/- 6.7 mm (n = 4) (P = 0.017)]. Thus, 17beta-estradiol increased stroke damage in normotensive rats with no significant effect in stroke-prone rats. Despite being contrary to our hypothesis, our findings add substance to the recently reported negative effects of 17beta-estradiol in clinical studies.

Animals↗
PubMed1989

Differential modulation of D1 and D2 dopamine-sensitive adenylate cyclases by 17 beta-estradiol in cultured striatal neurons and anterior pituitary cells.

Primary cultures of anterior pituitary cells from female rats and of mouse embryonic striatal neurons were used to study the effects of 17 beta-estradiol on D1- and D2-dopamine (DA)-sensitive adenylate cyclase. 17 beta-Estradiol pretreatment (10(-9) M, 72 h) suppressed the D2-DA-induced inhibition of adenylate cyclase activity in anterior pituitary cells. The steroid (10(-9) M, 24 h) also blocked the D2-DA-evoked response in striatal neurons whereas it enhanced by twofold the D1-DA-induced stimulation of the enzyme activity in these neurons. All these effects of the steroid were dose dependent and specific, as neither 17 alpha-estradiol, dexamethasone, nor progesterone used at the same concentration (10(-9) M) was effective. Furthermore, the modulation of DA-sensitive adenylate cyclases by the steroid required long-term exposure of living cells to 17 beta-estradiol since neither 17 beta-estradiol pretreatment for 4 h nor its addition to broken cells directly into the adenylate cyclase assay induced any alteration in the DA-sensitive adenylate cyclase activity. These results are in agreement with a genomic effect of the steroid. Using both anterior pituitary cells and striatal neurons in culture, 17 beta-estradiol affected neither the total number of DA (D1 and D2) receptors nor the estimated number of adenylate cyclase catalytic units. Therefore, it is suggested that the steroid modifies the coupling process by a mechanism that still has to be elucidated. These results demonstrate an effect of 17 beta-estradiol on DA target cells in both systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1986

In vitro effects of estradiol, testosterone, and progesterone on 5-methoxyindole content, cyclic adenosine 3',5'-monophosphate synthesis, and norepinephrine release in different parts of the female guinea pig pineal complex.

To examine the effects of estradiol, testosterone, or progesterone on cyclic adenosine 3',5'-monophosphate (AMP) accumulation, 5-methoxyindole levels, and norepinephrine (NE) release by the female guinea pig pineal complex, samples of the deep, intermediate, or superficial portions of the complex were incubated in vitro with varied concentrations of either hormone. Exposure for 10 minutes to physiological amounts of estradiol (10 nM) or to 100 microM NE increased significantly cyclic AMP levels to the same extent in the three pineal regions. A maximal effect on cyclic AMP accumulation was observed at 100-nM concentrations of estradiol, with a tendency to return to basal levels at 1-10 microM of estradiol. Only high concentrations of testosterone or progesterone (i.e., 1-10 microM) increased cyclic AMP accumulation in incubated guinea pig pineal fragments. At a 100-nM concentration estradiol did not affect NE-stimulated cyclic AMP accumulation in guinea pig pineal fragments. In samples of either pineal region incubated for 6 hours in TC 199 medium with 10(-7) M or greater concentrations of estradiol and analyzed for melatonin, 5-methoxyindoleacetic acid, and 5-methoxytryptophol by high-pressure liquid chromatography with electrochemical detection, a significant increase of melatonin levels was found. Neither testosterone nor progesterone modified 5-methoxyindole levels of incubated explants. K+-stimulated transmitter release from guinea pig pineal fragments previously incubated with 3H-NE was not affected by hormone exposure. These results suggest that physiological concentrations of estradiol may exert a postsynaptic stimulation of cyclic AMP and melatonin synthesis to the same extent in all three regions of the female guinea pig pineal complex.

Animals↗
PubMed1997

Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages.

PROBLEM: In vivo and in vitro studies have indicated that estradiol can affect cytokine production in different cell types. This study examines whether estradiol affects inflammatory cytokine production by murine splenic macrophages. METHODS: Mouse splenic macrophages were first treated with 17 beta-estradiol, followed by lipopolysaccharide (LPS) stimulation. The production of cytokines by macrophages with or without estradiol treatment was determined at both the protein and mRNA levels. The nuclear factor-kB (NFkB) activity of activated mouse splenic macrophages was also evaluated by electrophoretic mobility shift assay. RESULT: Our results show that 17 beta-estradiol decreases LPS-induced IL-1 alpha, IL-6, and TNF-alpha production but not IL-10, IL-12, and macrophage inflammatory protein (MIP) production by splenic macrophages. Furthermore, inhibition of cytokine production by 17 beta-estradiol was associated with a decreased LPS-induced NFkB-binding activity. CONCLUSION: Because cytokines are important mediators of immune function, the alteration of cytokine production by 17 beta-estradiol may thus have a profound effect on the outcome of immune response during inflammation.

Animals↗
PubMed2003

Cardiovascular pharmacology of estradiol metabolites.

A discussion of the role of endogenous estradiol metabolites in mediating important biological actions of estradiol is essentially nonexistent in standard textbooks of pharmacology and endocrinology. Indeed, the prevailing view is that all biological effects of estradiol are initiated by binding of estradiol per se to estrogen receptors and that estradiol metabolites are more or less irrelevant. This orthodox view, which is most likely incorrect, is the fundamental premise (an estrogen is an estrogen is an estrogen) underlying the design of important clinical trials such as the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Study. Accumulating data provide convincing evidence that some metabolites of estradiol, the major estrogen secreted by human ovaries, are biologically active and mediate multiple effects on the cardiovascular and renal systems that are largely independent of estrogen receptors. More specifically, metabolites of estradiol, particularly catecholestradiols and methoxyestradiols, induce multiple estrogen receptor-independent actions that protect the heart, blood vessels, and kidneys from disease. These protective effects are mediated in part by the inhibition of the ability of vascular smooth muscle cells, cardiac fibroblasts, and glomerular mesangial cells to migrate, proliferate, and secrete extracellular matrix proteins, as well as by an improvement in vascular endothelial cell function. The purpose of this review is to highlight the cardiovascular and renal pharmacology of catecholestradiols and methoxyestradiols. The take home message is simple: that when it comes to cardiovascular and renal protection, the concept that all estrogenic compounds are created equal may not be true.

Animals↗