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PubMed2005

17Beta-estradiol modulates hMT1 melatonin receptor function.

Estrogen modulates expression and function of G-protein-coupled receptors. The goal of this study was to assess the effect of 17beta-estradiol (10 nM) exposure for 1 (E1) or 6 (E6) days on density and function of hMT1 and hMT2 melatonin receptors expressed in Chinese hamster ovary (CHO) cells (CHO-MT1/CHO-MT2 cells). This strain of CHO cells expressed both estrogen receptor alpha and beta mRNAs, as determined by RT-PCR amplification. 17beta-Estradiol treatment did not modify the affinity of either receptor; however, it significantly increased the density of 2-[125I]iodomelatonin-binding sites in CHO-MT2 cells. 17beta-Estradiol treatment (1-6 days) did not affect the potency of melatonin to inhibit forskolin stimulation of cAMP formation through activation of either MT1 or MT2 receptors; however, it significantly attenuated the maximal inhibition of forskolin-stimulated cAMP formation induced by melatonin (0.01-1 microM) in CHO-MT1 cells. Melatonin stimulation of [35S]GTPgammaS binding to CHO-MT1 cell membranes was also attenuated following estradiol treatment. The inverse agonist luzindole reduced basal [35S]GTPgammaS binding in estradiol-treated cells but not in control CHO-MT1 cells, suggesting that estradiol promotes constitutive activity of MT1 melatonin receptors. We suggest that 17beta-estradiol differentially affects MT1 and MT2 melatonin receptor functions, attenuates melatonin responses through activation of MT1 receptors, and increases the MT2 receptors density.

Analysis of Variance↗
PubMed1975

Potentiation of luteinizing hormone release by estradiol at the level of the pituitary.

The objective of this study was to determine the influence of estradiol-17beta and/or progesterone on gonadotropon secretion at the level of the pituitary. Female rats in which the hypothalamo-hypophyseal connections had been permanently interrupted after castration served as the experimental model in which the effect of estradiol and/or progesterone on LH-RH-induced gonadotropin release was examined. In out experimental animals, LH secretion was readily activated by LH-RH administration. LH release was greatly augmented by the prior administration of estradiol benzoate (1 mug/kg b.w./day). Progesterone (5 mg/day) in the absence of estradiol did not modify the 10-min responese to LH-RH but reduced the enhancement of LH secretion caused by estradiol pretreatment. Our findings suggest that estradiol potentiated the releasing effect of LH-RH at the level of the gonadotroph, whereas progesterone interfered with the potentiation effect. Plasma levels of FSH were not significantly elevated above the basal value by the administration of LH-RH alone, or in combination with estradiol and/or progesterone.

Animals↗
PubMed1984

Long-term treatment with estradiol induces reversible alterations in tuberoinfundibular dopaminergic neurons: a decreased responsiveness to prolactin.

Previous studies have demonstrated that short-term (3-5 days) treatment with estradiol increases the rate of turnover and synthesis of dopamine (DA) in terminals of tuberoinfundibular (TI) neurons in the median eminence by virtue of the ability of this hormone to increase circulating concentrations of prolactin. The present studies were undertaken to examine the long-term effects of estradiol on serum prolactin concentrations and TIDA neuronal activity (estimated by the rate of DOPA accumulation in the median eminence after the administration of a decarboxylase inhibitor). Female rats, ovariectomized for 2 weeks, were implanted subcutaneously with silastic capsules containing estradiol benzoate and sacrificed 6, 12 and 18 days after capsule implantation. Serum prolactin concentrations were markedly increased at 6, 12 and 18 days whereas the rate of DOPA accumulation was increased at 6 days but not at 12 days, and was decreased at 18 days. The concentration of DA in the median eminence was reduced at 6 days and further reduced at 12 and 18 days. The low rate of DOPA accumulation in the median eminence despite the high circulating concentrations of prolactin suggests that long-term estradiol treatment reduces the ability of TIDA neurons to respond to prolactin. This was confirmed by the finding that direct intracerebroventricular (icv) injections of prolactin increased the rate of DOPA accumulation in the median eminence of sham-implanted rats but not in 18 day estradiol-treated rats. To determine if the effects of estradiol were reversible, ovariectomized rats were implanted with estradiol-containing capsules for 18 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

A subset of beta-endorphin- or dynorphin-containing neurons in the medial basal hypothalamus accumulates estradiol.

We used the combined steroid autoradiography-immunocytochemical method to determine whether estradiol- or dexamethasone-concentrating cells contain endogenous opioid peptides. Ovariectomized-adrenalectomized female rats were given highly radioactive doses of 3H-estradiol or 3H-dexamethasone, then sacrificed to demonstrate nuclear steroid binding. Autoradiograms were prepared, exposed for 2-12 months, photodeveloped, and fixed; immunocytochemistry was carried out on the same sections using antibodies to beta-endorphin or dynorphin A (1-17). In the medial basal hypothalamus, many estradiol- and some dexamethasone-concentrating neurons were found intermingled with beta-endorphin or dynorphin-immunoreactive neurons. Of the beta-endorphin-immunoreactive neurons in the medial basal hypothalamus, 4% concentrated estradiol in their nuclei. In addition, a subset of beta-endorphin-immunoreactive cells in the anterior pituitary concentrated estradiol in their nuclei. Although none of the beta-endorphin-immunoreactive neurons in the medial basal hypothalamus concentrated dexamethasone in their nuclei, many of the beta-endorphin-immunoreactive cells in the anterior pituitary did. Of the dynorphin-immunoreactive neurons in the medial basal hypothalamus, 10% concentrated estradiol in their nuclei. These data are consistent with the hypothesis of a genomic effect of estradiol on a particular subset of medial basal hypothalamic neurons that produce endogenous opioid peptides.

Adrenalectomy↗
PubMed1992

Trophic effects of estradiol on fetal rat hypothalamic neurons.

Sex steroids play an important role in the development and functioning of the central nervous system (CNS); however, the mechanisms by which such hormones exert these effects are not well understood. We addressed the question as to whether sex steroids affect the development of the hypothalamus, at least in part, by acting as a trophic factor to modulate the number of neurons in the hypothalamus. To this end, primary hypothalamic cultures were prepared from the brains of embryonic (day 15) fetuses. Cultures received either 17 beta-estradiol (10(-12) M) or vehicle 6-h after seeding and everyday throughout the study. As early as 24 h later, cultures receiving 17 beta-estradiol had significantly more neurons (44%, p < 0.001) than the control cultures. This effect not only continued throughout the duration of the study, but the difference between the two groups increased so that after 5 days, 17 beta-estradiol-treated cultures had 209% more neurons than control cultures (p < 0.001). Thus, addition of 17 beta-estradiol to fetal hypothalamic cultures produced a significant increase in the number of neurons surviving in vitro. The presence of glia was not required for this phenomenon, since the number of neurons surviving in glial-free cultures was also significantly increased by the addition of 17 beta-estradiol. The neuron survival promoting effect of 17 beta-estradiol was saturable and could be blocked by the estrogen antagonist tamoxifen (10(-7) M). Testosterone (10(-10) M), but not the nonaromatizable androgen dihydrotestosterone (10(-10) M), could mimic the neuron survival-promoting effects of estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Is the inhibitory action of estradiol on luteinizing hormone pulse frequency in anestrous ewes mediated by noradrenergic neurons in the preoptic area?

This study tested the hypothesis that estradiol inhibits luteinizing hormone (LH) pulse frequency in anestrous ewes by increasing the activity of an inhibitory noradrenergic (NE) system that acts in the ovine preoptic area (POA). The effects of estradiol on the release of NE and other neurotransmitters in the POA were determined using intracranial microdialysis. Microdialysis probes (5 mm membrane length) were inserted via chronic guide tubes into the POA. Ringer's solution was pumped through the probes at a rate of 2 microliters/min for 8 h, the alpha-adrenergic antagonist phenoxybenzamine (PBZ; 60 micrograms/ml of Ringer's solution) was then administered via the probe from hours 8 to 12, and Ringer's solution alone was given the last 4 h. The outflow from the dialysis probes was collected every 20 min from 2 to 16 h and concentrations of aminergic transmitters and gamma aminobutyric acid determined by high-performance liquid chromatography. Blood samples were collected every 10 min throughout the experiment and the LH pulse patterns determined. Dialysis was done in the same neural area twice in each ewe, without (ovariectomy only) and with estradiol treatment (ovariectomy and a 1.5-cm-long Silastic capsule filled with crystalline estradiol placed subcutaneously for 2 days); the order of dialysis was randomized. As expected, estradiol decreased the LH pulse frequency. This negative feedback action of estradiol was associated with a decrease in mean NE concentrations in dialysate samples and an increase in the intra-animal variability of NE. Estradiol had no effect on any other neurotransmitter measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Anestrus↗
PubMed1994

Diurnal variation in the acute effects of estradiol and progesterone on beta-endorphin and Met-enkephalin levels in specific brain regions of ovariectomized rats.

The present investigation was conducted to evaluate the effects of estradiol and progesterone on beta-endorphin and Met-enkephalin levels in specific brain regions of ovariectomized rats. Female Sprague-Dawley rats (100-120 g) adapted to a 12-hour light, 12-hour dark illumination cycle were used in these studies. Animals were ovariectomized under pentobarbital anesthesia. After a recovery period of 10-14 days, estradiol (50 micrograms/kg in 0.2 ml olive oil) was administered subcutaneously to rats at either 8.00, 14.00 or 16.00 h, progesterone (5 mg/kg in 0.1 ml olive oil) or estradiol plus progesterone was administered subcutaneously at 16.00 h. Control rats were injected with olive oil. Animals were sacrificed 2 h later. The cerebral cortex, hypothalamus, hippocampus and midbrain were dissected, and their beta-endorphin and Met-enkephalin levels were determined by radioimmunoassay. Estradiol administration at 8.00 h resulted in a significant decline in beta-endorphin levels of the hippocampus (66% decrease) and a significant rise in Met-enkephalin levels of the hypothalamus (37.8% increase) but had no effect on other brain regions studied. When estradiol was administered at 14.00 h, it produced a significant change in beta-endorphin levels in the cerebral cortex (34.7% increase) and in the midbrain (31.3% increase), but these levels were not altered in the other brain regions. At 16.00 h estradiol and progesterone alone caused a significant increase (29 and 43%, respectively) in beta-endorphin levels of the hippocampus. Similarly, the Met-enkephalin levels in the hippocampus significantly increased following administration of estradiol (57% increase) and progesterone (54% increase) alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Pharmacokinetics and biotransformation of estradiol valerate in ovariectomized women.

Estradiol valerate is well suited for treatment of the characteristic symptoms accompanying menopause in women. The pharmacokinetics and biotransformation of estradiol valerate were studied in women following intravenous, intramuscular and oral administration. Intravenously given, estradiol valerate is split by enzymatic hydrolysis into 17 beta-estradiol and the fatty acid. The estrogen arising in vivo from the steroid ester is subject to intermediate metabolism. The metabolites are eliminated at a nearly constant rate mainly in urine. The biotransformation of estradiol valerate was not different following intravenous or intramuscular injection. Orally given estradiol valerate is subject to an extensive first pass metabolism. Daily repeated oral administration does not result in accumulation of 17 beta-estradiol and its metabolites.

Administration, Oral↗
PubMed1998

Estradiol suppresses MCP-1 expression In vivo : implications for atherosclerosis.

The mechanisms by which 17beta-estradiol retards atherogenesis are not known. The adhesion of monocytes to endothelial cells followed by the migration of monocytes into the artery wall are key cellular events that occur throughout the entire atherogenic process and may be responsive to estradiol. Monocyte chemoattractant protein-1 (MCP-1), a chemokine that is expressed in atherosclerotic lesions, is thought to play a major role in stimulating the migration of blood monocytes into developing atherosclerotic lesions. We therefore assessed the effects of estradiol in vivo on MCP-1 protein and mRNA expression in the descending thoracic aorta of rabbits fed a cholesterol-enriched (0.5%) diet for 6 weeks and in animals fed normal chow. MCP-1 protein was quantified by Western blot analysis and monocyte chemotaxis bioassay, and reverse transcription-polymerase chain reaction was used to ascertain the level of MCP-1 mRNA expression. We observed that in both ovary-intact and ovariectomized (OVX) animals, MCP-1 protein and mRNA expression were significantly increased by 6 weeks in animals fed a high-cholesterol diet. The cholesterol-induced increase in MCP-1 protein and mRNA expression was significantly attenuated in OVX rabbits supplemented with estradiol pellets (1.5- and 10.0-mg 60-day-release pellets), which yielded a range of estradiol concentrations encompassing the physiological levels. MCP-1 protein and mRNA expression were increased in normocholesterolemic OVX rabbits compared with normocholesterolemic ovary-intact animals, and this increase was prevented in OVX animals supplemented with estradiol pellets. Our observations indicate that both basal and hypercholesterolemia-induced increases in MCP-1 protein are modulated by physiological concentrations of estradiol.

Animals↗
PubMed1998

Effect of 17beta-estradiol on inhibition of platelet aggregation in vitro is mediated by an increase in NO synthesis.

The low prevalence of coronary heart disease in premenopausal women and its increase after menopause are well established. Although estrogen is thought to play a role in protecting the vasculature, the mechanism has not been fully clarified. The contribution of platelets to atherosclerotic cardiovascular diseases is well recognized. The present study focused on the still-controversial effect of estrogen on platelet function. We investigated the in vitro effects of estrogen on human platelets, including their aggregation, Ca2+ metabolism, the synthesis of cyclic nucleotides, and NO (nitrite/nitrate) synthesis after stimulation with thrombin or ADP. Pretreatment of platelets with 17beta-estradiol reduced the platelet aggregation induced by thrombin or ADP, whereas 17alpha-estradiol had no effect. 17Beta-estradiol accelerated the recovery of [Ca2+]i after the agonist-induced peak and reduced the area under the curve of accumulated platelet [Ca2+]i but did not alter the baseline [Ca2+]i, Ca2+ influx induced by thrombin or ADP, the release of Ca2+ from internal stores, or the size of internal Ca2+ stores. Pretreatment of platelets with 17beta-estradiol had no effect on the intracellular concentration of cAMP but increased that of cGMP in agonist-stimulated platelets. Additionally, 17beta-estradiol increased the platelet concentration of nitrite/nitrate in a dose-dependent manner. These effects of 17beta-estradiol on platelet aggregation, Ca2+ metabolism, and NO synthesis were abolished by exposure to N(G)-monomethyl-L-arginine, an NO synthesis inhibitor. These results suggest that 17beta-estradiol plays an important role in inhibiting platelet aggregation by promoting Ca2+ extrusion or reuptake activity that is dependent on the production of cGMP by increasing NO synthesis.

Adult↗
PubMed1999

Modified LDL-mediated increases in endothelial layer permeability are attenuated with 17 beta-estradiol.

-Current research suggests that estrogen may have primary effects on the artery wall. To investigate the mechanisms of female sex hormone actions in the artery wall, we used an isolated, perfused, rat carotid artery model to examine the effects of estradiol on the rates of accumulation of normal (N-LDL) and minimally modified (MM-LDL) low density lipoprotein in ovariectomized rats. N-LDL, MM-LDL, and oxidized LDL (OX-LDL) were fluorescently labeled and perfused into individual arteries. The rate of LDL accumulation was measured by quantitative fluorescence microscopy before and after treatment with estradiol (1 nmol/L, 272 pg/mL). Estradiol had no effect on the rate of N-LDL accumulation (45+/-12 versus 48+/-15 ng cholesterol per cm2 per h). However, estradiol significantly decreased the rate of MM-LDL (240+/-48 versus 160+/-48 ng cholesterol per cm2 per h; P<0.05) and OX-LDL (191+/-53 versus 112+/-36 ng cholesterol per cm2 per h; P<0.05) accumulation. Further experiments showed that perfusion of unlabeled MM-LDL (100 microgram/mL) increased endothelial layer permeability when the rate of accumulation of a water-soluble, fluorescently labeled, reference molecule (64 000-molecular weight dextran) was determined before and after perfusion of MM-LDL (319+/-96 versus 510+/-191 ng per cm2 per h, n=6 arteries; P<0.05). Estradiol prevented the expected increase in the rate of dextran accumulation when perfused with MM-LDL (control, 415+/-49 ng per cm2 per h and MM-LDL+estradiol, 415+/-160 ng per cm2 per h). Our studies show that estradiol prevents compromise of the endothelial barrier mediated by MM-LDL and attenuates accumulation of MM-LDL in the artery wall.

Animals↗
PubMed1994

17 beta-Estradiol inhibits flow- and acute hypoxia-induced prostacyclin release from perfused endocardial endothelial cells.

BACKGROUND: Because of the marked difference in the incidence and severity of cardiovascular diseases between men and premenopausal women, several groups have studied the effect of sex steroids, particularly estrogen, on vascular endothelial prostacyclin (PGI2) release. No previous studies have addressed the effect of estrogen on endocardial endothelial cells (EECs), which are involved in the modulation of the myocardium and potentially in downstream pulmonary and systemic vascular tone. Furthermore, all previous studies of estrogen effects on cultured endothelial cell function have used cells grown under standard static cell culture conditions, thereby ignoring the contribution of flow, the ubiquitous environmental endothelial stimulus. METHODS AND RESULTS: The effect of 17 beta-estradiol pretreatment (100 ng/mL, 72 hours) on cultured sheep EEC PGI2 release in response to multiple physiologically relevant stimuli was studied. EECs were grown in six-well plates (static conditions) or on microcarrier beads and perfused at a constant flow with normoxic (PO2 = 150 mm Hg, PCO2 = 35 mm Hg) or hypoxic (PO2 = 35 mm Hg, PCO2 = 35 mm Hg) Krebs solution. The stable metabolite of PGI2, 6-keto-PGF1 alpha, was determined in samples from both static and perfusion experiments by direct radioimmunoassay. 17 beta-Estradiol pretreatment did not alter basal or stimulated (arachidonic acid, 1 mumol/L, 10 mumol/L; A23187, 10 mumol/L; and bradykinin, 1 mumol/L) PGI2 release in static conditions. Untreated and acutely treated (100 ng/mL added to perfusate) EECs responded to flow with a time-dependent increase in PGI2 release that plateaued between 60 and 100 minutes. In contrast, 17 beta-estradiol-pretreated, perfused EECs did not increase PGI2 release over time. During perfusion, acute hypoxia increased PGI2 release: 140 +/- 65 (normoxia) to 296 +/- 113 pg (hypoxia) 6-keto-PGF1 alpha/mg per minute. 17 beta-Estradiol inhibited hypoxia-induced PGI2 release: 296 +/- 113 pg (untreated EECs, hypoxia) versus 159 +/- 60 pg (17 beta-estradiol pretreated, hypoxia) 6-keto-PGF1 alpha/mg per minute. CONCLUSIONS: This study demonstrates for the first time an inhibitory effect of 17 beta-estradiol on flow- and acute hypoxia-induced increase in PGI2 release from perfused EECs in the absence of any effect on pharmacologically stimulated PGI2 release from static cultures. These effects of 17 beta-estradiol may explain in part the well-recognized gender and estrogen effects in cardiovascular diseases and highlight the importance of flow in studies of endothelial cell function.

6-Ketoprostaglandin F1 alpha↗
PubMed2006

Effects of a new hormone therapy, drospirenone and 17-beta-estradiol, in postmenopausal women with hypertension.

Drospirenone (DRSP), a progestin with antialdosterone activity, has been developed for hormone therapy in combination with 17-beta-estradiol (E2) in postmenopausal women. We evaluated the antihypertensive efficacy and safety of various doses of DRSP and E2 and estradiol alone in postmenopausal women with hypertension using ambulatory and clinic blood pressure (BP) monitoring. This was a randomized, double-blind clinical trial of 3 doses of DRSP combined with estradiol, estradiol alone, and placebo in 750 postmenopausal women with stage 1 to 2 hypertension between 45 to 75 years. Ambulatory and clinic BPs, potassium, aldosterone, and lipid measurements and adverse events were evaluated in postmenopausal women with stages 1 to 2 hypertension during 8 weeks of double-blind therapy. DRSP and E2 induced dose-related reductions in the ambulatory and clinic systolic BP with physiological increases in serum aldosterone. Significant decreases in 24-hour systolic pressure were observed at doses of 2 and 3 mg of DRSP combined with estradiol but not by estradiol alone or 1 mg of DRSP with estradiol. There were no significant changes from baseline in potassium in any treatment group. Small, significant reductions in total and low-density lipoprotein cholesterol occurred on all of the active treatments, and serum triglycerides did not change. Adverse event rates were low and similar across treatment groups. In conclusion, these data show that DRSP combined with E2 significantly reduces BP in postmenopausal women with hypertension and did not induce significant increases in serum potassium. These characteristics may lead to a new benefit for this novel hormone therapy in postmenopausal women with hypertension.

Aged↗
PubMed1999

Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis.

The mechanism by which estrogens protect against atherosclerosis is not known. We evaluated in vivo whether there is a gender difference in monocyte adhesion and subendothelial migration in hypercholesterolemic rabbits and whether any gender differences observed are due to estradiol. Monocyte adhesion and subendothelial migration were assessed in a blinded fashion by analyzing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adhesion molecule-1 (VCAM-1) protein using Western blot and flow cytometric analyses. We observed that male rabbits develop more monocyte adhesion and subendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes than do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized animals supplemented with placebo, and this increase was attenuated by estradiol. Finally, in cultured rabbit aortic endothelial cells stimulated with lysophosphatidylcholine, we observed an increase in VCAM-1 protein that was inhibited in a concentration-dependent fashion by estradiol. We have demonstrated in vivo that there is a gender difference in monocyte adhesion to endothelial cells and transendothelial migration after hypercholesterolemia and that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1.

Animals↗
PubMed1983

Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone.

Prepubertal girls and gonadotropin-releasing hormone (GnRH)-deficient females secrete follicle-stimulating hormone (FSH) preferentially in response to intravenous GnRH. With continued pulsatile GnRH stimulation, FSH secretion is reduced when plasma estradiol (E2) is increasing. To delineate the mechanisms involved in these changing gonadotropin responses, e studied the effect of low dose (0.025 micrograms/kg) pulsatile injections of GnRH in females with varying degrees and/or duration of endogenous GnRH deficiency (idiopathic panhypopituitarism, PHP; isolated growth hormone deficiency, IGHD; isolated gonadotropin deficiency, IGD; and anorexia nervosa, AN; both at low body weight and after weight regain). In patients presumed to have the most severe GnRH deficiency (PHP), responses of both FSH and luteinizing hormone (LH) were small and delayed, and no increase in plasma estradiol occurred during the 5 d of GnRH injections. In patients previously exposed to prepubertal or adult levels of endogenous GnRH secretion (IGHD, IGD, AN at low body weight), a rapid initial FSH response occurred that subsequently declined when plasma estradiol rose to concentrations greater than 40-50 pg/ml. Prior therapy with estrogen (micronized estradiol, Estrace) abolished FSH responses but LH responses were only slightly impaired. The degree of FSH response was dependent upon the time of initiation of estrogen relative to the onset of GnRH injections. Administration of estrogen after the first GnRH injection inhibited gonadotropin responses, whereas later estrogen therapy (after 1 d of GnRH pulses) blunted the GnRH induced FSH secretion without significantly impairing the LH response. In weight-regained anorexic patients who had spontaneous pulsatile LH secretion and a mean basal plasma estradiol concentration of 53 +/- 15 pg/ml, administration of GnRH pulses did not change plasma LH and a minimal FSH response was seen. The data indicate that the pattern of gonadotropin responses to low dose GnRH injections depends upon the degree of previous exposure of the pituitary to endogenous GnRH. Furthermore, estradiol selectively inhibits FSH secretion by a direct action on the pituitary gland. This action of estradiol provides an explanation for the selective reduction in FSH responses to GnRH seen during pubertal maturation in girls and during the mid-follicular stage of the menstrual cycle.

Adolescent↗
PubMed1994

Estradiol enhances leukocyte binding to tumor necrosis factor (TNF)-stimulated endothelial cells via an increase in TNF-induced adhesion molecules E-selectin, intercellular adhesion molecule type 1, and vascular cell adhesion molecule type 1.

Adhesion of leukocytes to endothelial cells is a critical step in the development of acute and chronic inflammatory lesions. We report here that estradiol treatment of cultured human umbilical vein endothelial cells stimulated up to a twofold increase in TNF-induced adhesion of both polymorphonuclear leukocytes and PMA-activated peripheral blood mononuclear cells. This effect was more evident (threefold increase) when endothelial cells were cultured on the basement membrane glycoprotein laminin. Progesterone, but not testosterone, had a similar stimulatory effect. Estradiol also promoted a slight increase in interferon gamma-stimulated endothelial cell adherence for peripheral blood mononuclear cells, but no effect of estradiol was observed when adhesion of leukocytes to endothelial cells was stimulated with IL-1 or IL-4. The estradiol-induced increase in leukocyte binding to human umbilical vein endothelial cells was partially blocked by antibodies to the adhesion molecules E-selectin, intercellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1). Indirect immunofluorescence techniques showed that estradiol produces an increase in TNF-induced cell surface expression of these molecules. Northern blot analysis demonstrated a transient increase in TNF-induced expression of mRNA for E-selectin, ICAM-1, and VCAM-1 in endothelial cells treated with estradiol. Our data demonstrate that estradiol has important regulatory functions in promoting leukocyte-endothelial cell interactions that might contribute to the observed predominance in females of some autoimmune inflammatory diseases.

Adipose Tissue↗
PubMedDate not supplied

Low serum estradiol and high serum progesterone concentrations characterize hypertensive pregnancies at high altitude.

OBJECTIVE: Intrauterine growth retardation and preeclampsia are more common at high than at low altitude. Because altered hormonal profiles have been linked with these disorders, we asked whether placental steroid hormone concentrations were altered during pregnancy at high altitude. METHODS: We measured progesterone, unconjugated estradiol, and estriol (by radioimmunoassay) at weeks 20, 30, and 36 of pregnancy in 18 women at low altitude (1600 m) and 40 women at high altitude (3100 m). RESULTS: Women at 3100 m compared with 1600 m had lower serum estradiol concentrations at week 36 of pregnancy, and lower estriol and higher progesterone concentrations throughout pregnancy. As a result, the progesterone/estradiol ratio was greater in the high- versus the low-altitude women. Estradiol fell between weeks 30 and 36 in women who developed transient hypertension or preeclampsia. The fall in estradiol was accompanied by a marked increase in progesterone concentrations among the preeclamptic women. At 3100 m, estradiol correlated negatively (r = -0.37, P < .05) and progesterone positively (r = 0.46, P < .05) with mean arterial pressure at week 36 of pregnancy. CONCLUSIONS: We speculate that reduced placental oxygen pressure (PO2) at high altitude may decrease placental aromatase activity and thereby lower estradiol and estriol concentrations. The factor(s) responsible for the rise in progesterone is unknown. Possibly, high progesterone relative to estradiol concentrations contributes to the development of preeclampsia at high altitude.

Adult↗
PubMed2006

Effects of testosterone, 17beta-estradiol, and downstream estrogens on cytokine secretion from human leukocytes in the presence and absence of cortisol.

Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol.

Adult↗