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PubMed2002

17-Beta-estradiol protects the liver against warm ischemia/reperfusion injury and is associated with increased serum nitric oxide and decreased tumor necrosis factor-alpha.

BACKGROUND: Ischemia/reperfusion injury (I/R injury) to the liver can occur in low-flow states associated with trauma and shock and surgical procedures such as liver transplantation. Recent studies have shown that the administration of the female sex hormone 17-beta-estradiol after trauma-hemorrhage in animals restores depressed cardiac, hepatocellular, and immune functions. In this study we evaluated the effects of 17-beta-estradiol on I/R injury to the liver. METHODS: The medial lobe of the liver in normal male C57BL/6 mice was clamped at its base for 90 minutes. 17-Beta-estradiol was given 1 hour before I/R injury at 40 and 4000 microg/kg intraperitoneally. Biochemical analysis was performed, and liver biopsy specimens were obtained at 24 hours. RESULTS: A dose-dependent reduction in aspartate aminotransferase level was observed in animals (n = 8) given estradiol (243 +/- 23 IU/L) compared with saline-treated animals (902 +/- 42 IU/L, P <.001). The majority (90%) of the cytoprotective effect of estradiol was reverted by ICI 182,780 (a potent estrogen receptor antagonist). A significant increase in serum nitric oxide (NO) level was observed in animals given estradiol compared with controls; the effect was reversed by ICI 182,780 and N-nitro-L-arginine-methyl ester (an inhibitor of NO synthesis). A reduction in serum tumor necrosis factor-alpha was observed after injury in animals given estradiol compared with controls (30.2 +/- 11.1 vs 75.8 +/- 17.2 pg/mL, P <.001). Estradiol treatment significantly reduced liver necrosis, disintegration of hepatic cords, and neutrophil infiltration in an estrogen receptor-dependent manner. CONCLUSIONS: Estradiol administration significantly reduced injury after I/R to the liver, an effect that is mainly receptor-mediated and is associated with increased serum NO, decreased TNF-alpha, and decreased number of neutrophils in liver biopsy specimens. Estrogen therapy may be important in clinical conditions associated with I/R injury to the liver.

Animals↗
PubMed2003

Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction.

BACKGROUND: The c-Jun N-terminal kinase (JNK) activation occurs after islet isolation, oxidative stress, and proinflammatory cytokine (PIC) exposure to beta-cells. Previous studies demonstrated that 17beta-estradiol modulates the activity of JNK; therefore we assessed the effects of 17beta-estradiol on JNK activation on islet survival and function after transplantation. METHODS: Isolated human pancreatic islets were incubated with PIC and 17beta-estradiol. Viability was analyzed by a colorimetric assay, islet mass by DNA content, JNK activity by Western blots, AP-1 nuclear activity with a promoter-Luciferase AP-1 responsive construct, and c-Fos, Jun-D, and ATF-2 nuclear activities by an enzyme-linked immunosorbent assay. Islet functionality was evaluated after transplantation in streptozotocin-induced diabetic NOD-SCID mice. RESULTS: The 17beta-estradiol enhanced islet viability and islet mass after exposure to PIC. A significant reduction in JNK activation occurred in islets treated with 17beta-estradiol, compared with controls, an effect partially dependent on estrogen receptors. The 17beta-estradiol induced a significant reduction in nuclear AP-1, c-fos, Jun-D, and ATF-2 activities. Animals that received 17beta-estradiol-treated islets had better islet functionality compared with saline solution-treated controls. CONCLUSIONS: The 17beta-estradiol improved isolated human pancreatic islets survival after PIC exposure by inhibition of JNK. These effects were associated with reduction in JNK targets, including the nuclear activities of transcription factors AP-1, c-Jun, c-Fos, Jun-D and ATF-2, involved in apoptosis in beta-cells. The 17beta-estradiol therapy may improve the results in clinical transplantation.

Activating Transcription Factor 2↗
PubMed1984

Identification of 17 beta-estradiol as the estrogenic substance in Saccharomyces cerevisiae.

Saccharomyces cerevisiae possesses a high-affinity estrogen binding protein and an endogenous ligand that displaces [3H]estradiol from both the yeast binding protein and mammalian estrogen receptors. Semipurified preparations of this ligand have been shown to exhibit estrogenic activity in mammalian systems. We now describe the purification procedure and ultimate identification of the estrogenic substance in extracts of S. cerevisiae as 17 beta-estradiol. Organic solvent extracts of commercially obtained dried yeast were sequentially chromatographed on silica gel columns and then subjected to a series of reversed phase HPLC fractionations. Active ligand was monitored by [3H]estradiol displacement in a rat uterine cytosol assay. After seven chromatography steps, the purified and highly active ligand exhibited a single peak with retention times identical to those of 17 beta-estradiol on both HPLC and GC. The yeast material was identified as 17 beta-estradiol by its UV absorbance and mass spectrometric fragmentation pattern. In addition, radioimmunoassay confirmed the presence of approximately the same mass of 17 beta-estradiol (approximately equal to 800 ng/1.5 kg of yeast) as estimated both by a competitive binding assay with estrogen receptor and by mass spectrometry. Extraneous contamination by estradiol was excluded by repeat experiments with different batches of starting material and demonstration of estradiol by RIA in conditioned medium and cell pellets of laboratory-grown S. cerevisiae whereas non-conditioned medium did not possess the steroid. We conclude that 17 beta-estradiol is a yeast product.

Estradiol↗
PubMed2002

17beta -Estradiol modulates mechanical strain-induced MAPK activation in mesangial cells.

Gender is an important determinant of clinical outcome across a broad spectrum of kidney diseases, but the mechanism(s) responsible for the protective effect of female gender have not been fully elucidated. Remnant kidney glomerular injury is limited in female rats compared with male rats despite similar elevations in glomerular capillary pressure. In vitro, mechanical strain leads to the activation of p44/42 mitogen-activated kinase (p44/42 MAPK) and Jun N-terminal kinase/stress-activated protein kinase (SAPK) in glomerular mesangial cells (MC). Accordingly, we studied the effect of 17beta-estradiol on mechanical strain-induced signal transduction in MC. Exposure of MC to mechanical strain increased p44/42 MAPK activation (3-fold) and SAPK activation (2.5-fold), and kinase activation was inhibited by pretreatment with 17beta-estradiol (10(minus sign8) to 10(minus sign11) m) for 24 h in a dose-dependent manner. Mechanical strain-induced nuclear translocation of p44/42 MAPK and SAPK and nuclear protein binding to AP-1 were also attenuated by 17beta-estradiol. The inhibitory effects of 17beta-estradiol were not reproduced by the cell-impermeable estrogen, BSA/17beta-estradiol, nor did preincubation with 17beta-estradiol lead to actin cytoskeleton disassembly or impaired stress fiber formation. However, 17beta-estradiol did increase base-line levels of the dual specificity phosphatase MKP-1. The inhibitory effects of 17beta-estradiol on p44/42 MAPK activation and SAPK activation, translocation, and AP-1 binding were all abrogated by the estrogen receptor antagonist, ICI-182,780. We conclude that attenuation of mechanical strain-induced MAPK activation by 17beta-estradiol is dependent on intracellular estrogen receptor. The attenuation of stretch-induced kinase activation may be due, at least in part, to an effect of 17beta-estradiol on MKP-1 expression. Together, these findings add insight into the protective effect of gender on renal disease progression.

Active Transport, Cell Nucleus↗
PubMed2003

Estradiol binding to maxi-K channels induces their down-regulation via proteasomal degradation.

Estrogens exert their biological action via both genomic and non-genomic mechanisms. Proteins different from classical estradiol receptors are believed to mediate the latter effects. Here we demonstrate that the maxi-K channel functions as an estrogen-binding protein in transfected HEK293 cells. Whole-cell maxi-K channel currents and protein expression were attenuated by exposure to either 17alpha- or 17beta-estradiol. This effect was dose-dependent for 17beta-estradiol at concentrations ranging from 10 nm to 1 microm, while 17alpha-estradiol inhibited channel expression only at 1 microm. These effects were mediated by direct low affinity binding of estradiol to the maxi-K channel but not to its accessory beta1-subunit, as revealed by cell membrane estradiol binding assays. However, specific binding of estradiol to the channel was facilitated by the presence of the beta1 subunit. Addition of MG-132, a blocker of proteasomal degradation, stabilized channel expression. These data suggest that channel down-regulation is mediated by estrogen-induced proteasomal degradation, similar to the pathway used for estrogen receptor degradation. Membrane expression of endogenous maxi-K channels in cultured vascular smooth muscle cells was also attenuated by prolonged exposure to 17alpha- and 17beta-estradiol. Thus our studies demonstrate that estrogen binds to maxi-K channels and may directly regulate channel expression and function. These results will have important implications in understanding estradiol-induced effects in multiple tissues including vascular smooth muscle.

Amino Acid Motifs↗
PubMed2005

Serum concentrations of 17beta-estradiol in ovariectomized rats during two times six weeks crossover treatment by daily injections in comparison with slow-release pellets.

Estrogens exert widespread biological functions that reach far beyond their well-known role in reproduction. Exogenous administration of 17beta-estradiol to ovariectomized experimental animals is of the utmost importance in elucidating its mechanisms of action. In the present study, we compared two different modes of exogenous administration of 17beta-estradiol to ovariectomized rats in relation to the serum 17beta-estradiol concentrations over prolonged periods of time. 17beta-estradiol was administered either by slow-release pellets (Innovative Research of America, Sarasota, Fl. 34236, USA, 90-day release, NHH-115, 1.5 mg) or by daily subcutaneous injections of 15 microg 17beta-estradiol dissolved in sesame oil. After 6 weeks, the mode of administration of estradiol was changed to the opposite method and continued for a further 6 weeks. Blood samples for measurement of serum 17beta-estradiol were taken every second week. After 2 weeks, the serum concentrations of 17beta-estradiol in group A initially receiving the pellets were 73 % higher (p<0.001) compared to those of group B receiving daily injections. The difference was even more prominent, 580 % (p<0.001), after 4 weeks. Steady state was reached at week 6 in group A, but already by week 4 in group B. Once steady state was reached, the concentrations were the same in both groups for the remainder of the experiment (12 weeks in total). Our study indicates that steady-state concentrations of 17beta-estradiol occur 5-6 weeks later than the 48 h the manufacturer of the slow-release pellets claims.

Animals↗
PubMed2003

Interactions of insulin-like growth factors and estradiol in rat pituitary gonadotrophs.

Insulin-like growth factors are involved in the regulation of gonadotropin secretion. Insulin-like growth factor I (IGF-I) has an augmenting effect on gonodotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release from female rat gonadotrophs that is facilitated by estradiol. To identify the underlying mechanisms, we investigated whether IGF-I influences total LH pool and the production of intracellular inositol phosphate. In another series of experiments we tested whether IGF-II and estradiol affect LH release of gonadotrophs. Pituitary cells were incubated with 100 pM IGF-I and/or 100 pM estradiol for 24 h. They were stimulated, partially in the presence of Wortmannin, an inhibitor of phosphoinositide 3-kinase, with 330 pM GnRH for 3 h. Subsequently, total LH pool (released and remaining hormone content in lysed cells) in cultures was measured. Intracellular inositol trisphosphate of alphaT3-1 cells, a gonadotrope cell line, treated with estradiol and IGF-I as described before and stimulated with 100 nM GnRH for 15 min was analyzed by ion exchange chromatography. To determine the interaction of IGF-II and estradiol on GnRH-stimulated LH secretion, cells were treated with increasing concentrations of IGF-II (0.05 pM-10 nM) and 100 pM estradiol. IGF-I significantly increased the accumulation of inositol trisphosphate in basal and GnRH-stimulated cells. IGF-I, estradiol, or their combinations did not change total LH pool, although they enhanced LH secretion. Wortmannin abolished the positive effects of IGF-I and estradiol on LH secretion. IGF-II alone increased basal, but not GnRH-induced LH secretion at low concentrations (0.05 pM). Additional estradiol treatment further increased basal, but not GnRH-induced LH secretion. In conclusion, our results suggest that increased LH secretion from female anterior pituitary cells after IGF treatment is due to the amplification of early signal transduction steps rather than changes in LH pool. The inositol trisphosphate signaling pathway is involved in the regulation of LH secretion from gonadotrophs treated with IGF-I. It is not likely that IGF-II plays an important role in the regulation of gonadotropin secretion.

Animals↗
PubMed2004

Low levels of endogenous estradiol protect bone mineral density in young postmenopausal women.

OBJECTIVE: Low levels of endogenous estrogens may play a role in the protection of bone mineral density (BMD) in healthy postmenopausal women. The aim of this study was to evaluate the effect of endogenous estradiol and testosterone on bone mass in young and older healthy postmenopausal women. METHODS: The study involved 99 postmenopausal women aged 55-75 years. The BMDs of the lumbar spine, proximal femur and total skeleton were determined. Measurements were taken of serum calcium, bone alkaline phosphatase, Crosslaps, estradiol, estrone, sex hormone binding globulin, testosterone, bioavailable testosterone and urine calcium. Estradiol was measured using a sensitive assay with a lower detection limit at 5 pg/ml. RESULTS: A multivariate analysis showed that the BMD of the lumbar spine was significantly predicted by estradiol (p < 0.05), and testosterone (p < 0.0001). Likewise, testosterone was found to be an independent predictor of the BMD of the total femur (p < 0.001) and the total skeleton (p < 0.001). The population was divided into two groups: < or = 65 (Group 1) and > 65 years (Group 2) of age and also stratified according to estradiol levels: > 10 and < or = 10 pg/ml. Significant differences in BMD were found in women in Group 1 in whom estradiol levels higher than 10 pg/ml were associated with a higher BMD of the lumbar spine (+ 14%, p < 0.01), proximal femur (+ 6%, p < 0.05) and total skeleton (+ 7%, p < 0.05) compared with women with estradiol levels below 10 pg/ml. Bone alkaline phosphatase levels (p < 0.05) and serum Crosslaps (not significant) were lower in women in Group 1 with a level of estradiol more than 10 pg/ ml. CONCLUSION: Endogenous estradiol levels higher than 10 pg/ml and testosterone protected bone mass in healthy postmenopausal women under 65 years of age. These results were not observed in the group of older women.

Age Factors↗
PubMed2002

Endometrial safety of a transdermal sequential estradiol-levonorgestrel combination.

OBJECTIVE: The aim of this 1-year, randomized, multinational, open-label study was to assess the effect on the endometrium of three dosages of estradiol and sequential levonorgestrel, each administered in a novel 7-day transdermal matrix patch. METHODS: A total of 468 postmenopausal women received patches of 15 cm2 (50 micrograms/day estradiol for 2 weeks followed by 50 micrograms/day estradiol-10 micrograms/day levonorgestrel for 2 weeks), 22.5 cm2 (75 micrograms/day estradiol for 2 weeks followed by 75 micrograms/day estradiol-15 micrograms/day levonorgestrel for 2 weeks) or 30 cm2 (100 micrograms/day estradiol for 2 weeks followed by 100 micrograms/day estradiol-20 micrograms/day levonorgestrel for 2 weeks). Each patch was applied for 7 days. RESULTS: Endometrial biopsies were taken before and after 1 year of treatment, with final valid biopsy results being obtained in 399 women. There were two cases of endometrial hyperplasia (one in the 22.5-cm2 and one in the 30-cm2 group). All three doses of this 7-day sequential combined estradiol-levonorgestrel transdermal hormone replacement therapy therefore had excellent endometrial safety. The lowest dose, however, was associated with less bleeding and a somewhat different histological pattern, compared with the two higher doses. All three doses provided a high level of patient satisfaction with the bleeding response. CONCLUSION: Estradiol and sequential levonorgestrel administered in a 7-day transdermal matrix patch for 1 year provide endometrial protection.

Administration, Cutaneous↗
PubMed2001

Effect of trimegestone alone or in combination with estradiol on bone mass and bone turnover in an adult rat model of osteopenia.

The effects of trimegestone (1 mg/kg/day orally), a novel norpregnane progestin, and 17 beta-estradiol (10 micrograms/kg/day subcutaneously), alone and in combination, on bone mass and turnover were investigated using an experimental model of osteoporosis involving ovariectomized rats. An equivalent dose (1 mg/kg/day orally) or norethisterone was used as a reference progestin. Six-month-old rats were ovariectomized and left untreated for 2 months to allow the development of osteopenia. Treatment with a progestin, alone or in combination with estradiol, was then started and continued for 2 months. Bone was assessed by a combination of static and dynamic histomorphometric measurements, by densitometry and by the use of biochemical markers of bone turnover. Ovariectomy induced a pronounced uterine atrophy, which was reversed by estradiol. Trimegestone effectively counteracted the uterotropic effect of estradiol, whilst norethisterone showed a less pronounced antagonistic effect. A severe osteopenia was established in the initial 2 months after ovariectomy, and further bone loss occurred during the 2-month treatment period in animals not receiving estradiol. This effect was associated with a marked increase in both biochemical and dynamic histomorphometric markers of bone turnover, reflecting in an imbalance between resorption and formation. 17 beta-estradiol given alone prevented further bone loss, but neither trimegestone nor norethisterone alone had a beneficial effect on bone mass and turnover. When given in combination with 17 beta-estradiol, however, trimegestone significantly improved its effect on bone mass and turnover. This effect was more potent than that induced by combined 17 beta-estradiol and norethisterone therapy. We conclude that trimegestone, when combined with 17 beta-estradiol, is a more effective progestin than norethisterone in preventing bone loss in adult ovariectomized rats.

Administration, Oral↗
PubMed2001

Effects of 17 beta-estradiol and trimegestone alone, and in combination, on the bone and uterus of ovariectomized rats.

Trimegestone is a novel norpregnane progestin, which is being developed, in combination with 17 beta-estradiol, for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. A model of osteoporosis in the ovariectomized rat has been used to evaluate the effects of 17 beta-estradiol and trimegestone, alone and in combination, on bone and uterus in these animals. Two treatment protocols were investigated, preventive with treatment starting immediately after ovariectomy and curative with treatment starting 1 or 6 months after ovariectomy. 17 beta-Estradiol was administered subcutaneously at a dose of 10 micrograms/kg/day with trimegestone or norethisterone being administered orally at a dose of 1 mg/kg/day; treatment was given 5 days per week. Treatment on both protocols was for 6 months. Given alone, 17 beta-estradiol maintained bone mass, either partially or completely, when given on the preventive protocol, or on the curative protocol with treatment starting 1 month after ovariectomy; it did not restore bone mass when given on the curative protocol with 6 months lapsing between ovariectomy and start of treatment. Trimegestone did not block the beneficial effects of 17 beta-estradiol on bone. 17 beta-Estradiol induced uterine hypertrophy on all these protocols and this was blocked completely by trimegestone. Trimegestone administered alone had no effect on bone or uterus but, when given in combination with 17 beta-estradiol, it did not inhibit the effect of 17 beta-estradiol in maintaining bone mass but completely blocked its uterotropic effect. Norethisterone at a similar dose did not inhibit the effects of 17 beta-estradiol on bone but also did not block its uterotropic effect.

Animals↗
PubMed2004

Systemic administration of 17beta-estradiol reduces apoptotic cell death and improves functional recovery following traumatic spinal cord injury in rats.

Recent evidence indicates that estrogen exerts neuroprotective effects in both brain injury and neurodegenerative diseases. We examined the protective effect of estrogen on functional recovery after spinal cord injury (SCI) in rats. 17beta-estradiol (3, 100, or 300 microg/kg) was administered intravenously 1-2 h prior to injury (pre-treatment), and animals were then subjected to a mild, weight-drop spinal cord contusion injury. Estradiol treatment significantly improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Fifteen to 30 days after SCI, BBB scores were significantly higher in estradiol-treated (100 microg/kg) rats when compared to vehicle-treated rats. Morphological analysis showed that lesion sizes increased progressively in either vehicle-treated or 17beta-estradiol-treated spinal cords. However, in response to treatment with 17beta-estradiol, the lesion size was significantly reduced 18-28 days after SCI when compared to vehicle-treated controls. Terminal deoxynucleotidyl transferase-mediated UTP nickend labeling (TUNEL) staining and DNA gel electrophoresis revealed that apoptotic cell death peaked 24-48 h after injury. Also, SCI induced a marked increase in activated caspase-3 in the spinal cord, evident by 4 h after injury. However, administration of 17beta-estradiol significantly reduced the SCI-induced increase in apoptotic cell death and caspase-3 activity after SCI. Furthermore, 17beta-estradiol significantly increased expression of the anti-apoptotic genes, bcl-2 and bcl-x, after SCI while expression of the pro-apoptotic genes, bad and bax, was not affected by drug treatment. Finally, intravenous administration of 17beta-estradiol (100 microg/kg) immediately after injury (post-treatment) also significantly improved hind limb motor function 19-30 days after SCI compared to vehicle-treated controls. These data suggest that after SCI, 17 beta-estradiol treatment improved functional recovery in the injured rat, in part, by reducing apoptotic cell death.

Animals↗
PubMed1980

Nuclear uptake of a 17 beta-estradiol-fluorescein derivative as a marker of estrogen dependence.

17-Fluorescein-labeled estradiol was prepared by linkage of fluorescein-isothiocyanate through a succinamide-ethyl-amine chain to the 17 position of 17 beta-estradiol. This compound, N-fluoresceino-N'[17 beta-(estradiol-hemisuccinamido)-ethyl]-thiourea, displaced tritiated estradiol from purified estrogen-receptor protein and readily crossed intact cellular membranes. In female rats, in-vivo injection was followed by nuclear labeling of endometrium, whereas nuclear labeling of non-target tissue was absent. Temperature-dependent nuclear transfer could be visualized directly by fluorescent microscopy when human estradiol target tissue (mammary and proliferative endometrium) was incubated in vitro with the compound. Temperature-dependent nuclear labeling was not present in human non-target tissue, including skeletal muscle, skin, stomach, colon, appendix, and lung, after in-vitro incubation. Temperature-dependent nuclear labeling with the compound was inhibited by estradiol and mixtures of natural and synthetic estrogens. A significant positive correlation of the presence of nuclear labeling in human mammary cancer was obtained with standard dextran-coated charcoal radioligand assay for estradiol receptor. Unlike radiologand assay and cytochemical assays, nuclear uptake of the fluorescein-labeled estradiol appears to require an intact estradiol-receptor mechanism.

Adult↗
PubMed1984

Enhancement of the mutagenicity of carcinogenic arylamines by ethinyl estradiol.

Ethinyl estradiol, the estrogenic component of oral contraceptives, has been shown to enhance the mutagenicity of 2-aminofluorene, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, and N-acetoxy-2-acetylaminofluorene with strain TA 98 of Salmonella typhimurium and various rat liver activating systems. The magnitude of the enhancement of mutation produced by ethinyl estradiol is dependent upon: the type of mixed-function oxidase inducer of the liver activating system; the structure and concentration of the arylamine; the concentration of ethinyl estradiol; and metabolism of ethinyl estradiol to its catechol, 2-hydroxyethinyl estradiol, by the activating system. Moxestrol, a biologically potent estrogenic derivative of ethinyl estradiol which is not metabolized effectively to its catechol by the mixed-function oxidases, does not enhance the mutagenicity of the above arylamines and related compounds. Both 2-hydroxyethinyl estradiol and 2-hydroxymoxestrol enhance the mutagenicity of 2-aminofluorene and 2-acetylaminofluorene. Neither the estrogens nor their catechols are mutagenic by themselves in this system. In the presence of ethinyl estradiol, a marked inhibition of ring hydroxylation of 2-acetylaminofluorene was demonstrated. Since ring hydroxylation is a well established detoxification pathway of arylamine and arylamide metabolism, the enhancement of mutagenicity by ethinyl estradiol may be the result of a net increase in N-hydroxylation of arylamines and arylamides.

2-Acetylaminofluorene↗
PubMed1994

Premenopausal estradiol levels and the risk of breast cancer: a new method of controlling for day of the menstrual cycle.

Levels of total estradiol in premenopausal women vary widely over the course of the menstrual cycle with a spike at the time of ovulation and dissimilar patterns pre- and post-ovulation. Evaluating the association between breast cancer and premenopausal measurements of total estradiol when the measurements cannot be taken on a uniform day of the cycle is therefore a difficult methodological challenge. In a matched case-control study of breast cancer nested within a prospective study, premenopausal serum samples obtained up to 7 years before breast cancer diagnosis were available for total estradiol assay. By fitting a three-piece spline model that regressed the logarithm of total estradiol (ln estradiol) on day of menstrual cycle, the authors were able to adjust the measurements for day of the cycle on which they were collected by expressing them in terms of the number of standard deviations above or below the fitted ln estradiol value for that day. Applying the adjusted measurements to the nested case-control study, they found evidence of a 1.5 to 2-fold risk for women in the upper two tertiles of ln estradiol relative to women in the lowest tertile. Conditional logistic regression analysis for day-of-cycle-adjusted ln estradiol treated as a continuous variable resulted in a relative risk estimate of 1.19 (95% confidence interval 0.91-1.55) per standard-deviation increase in adjusted ln estradiol.

Adult↗
PubMed2003

Somatostatin-14 neurons in the ovine hypothalamus: colocalization with estrogen receptor alpha and somatostatin-28(1-12) immunoreactivity, and activation in response to estradiol.

Pituitary gland growth hormone (GH) secretion is influenced by two hypothalamic neuropeptides: growth hormone-releasing hormone (GHRH) and somatostatin. Recent data also suggest that estrogen modulates GH release, particularly at the time of the preovulatory luteinizing hormone surge, when a coincident surge of GH is observed in sheep. The GHRH neurons do not possess estrogen receptor alpha (ERalpha), suggesting that estrogen does not act directly on GHRH neurons. Similarly, few somatotropes express ERalpha, suggesting a weak pituitary effect of estradiol on GH. It was hypothesized, therefore, that estradiol may affect somatostatin neurons to modulate GH release from the pituitary. Using immunocytochemical approaches, the present study revealed that although somatostatin neurons were located in several hypothalamic sites, only those in the arcuate nucleus (13% +/- 2%) and ventromedial nucleus (VMN; 29% +/- 1%) expressed ERalpha. In addition, we found that all neurons immunoreactive for somatostatin-14 were also immunoreactive for somatostatin-28(1-12). To determine whether increased GH secretion in response to estradiol is through modulation of GHRH and/or somatostatin neuronal activity, a final study investigated whether c-fos expression increased in somatostatin- and GHRH-immunoreactive cells at the time of the estradiol-induced LH surge in intact anestrous ewes. Estradiol significantly (P < 0.05) increased the percentage of GHRH (estradiol, 75% +/- 3%; no estradiol, 19% +/- 2%) neurons expressing c-fos in the hypothalamus. The percentage of somatostatin-immunoreactive neurons coexpressing c-fos in the estradiol-treated animals was significantly (P < 0.05) higher (periventricular, 44% +/- 3%; arcuate, 72% +/- 5%; VMN, 81% +/- 5%) than in the control animals (periventricular, 22% +/- 1%; arcuate, 29% +/- 3%; VMN, 31% +/- 3%). The present study suggests that estradiol modulates the activity of GHRH and somatostatin neurons but that this effect is most likely mediated through an indirect interneuronal pathway.

Animals↗
PubMed1983

Relationship between seasonal plasma estradiol-17 beta and testosterone levels and in vitro production by ovarian follicles of amago salmon (Oncorhynchus rhodurus).

Plasma estradiol-17 beta and testosterone levels were assessed by radioimmunoassay during the sexual maturation of female amago salmon (Oncorhynchus rhodurus). Estradiol-17 beta levels gradually increased during vitellogenesis (June to September), reached a peak in September (about 16 ng/ml) and rapidly decreased in mature and ovulated fish (about 3-4 ng/ml) in October. The seasonal pattern of plasma testosterone levels lagged behind and followed that of estradiol-17 beta during vitellogenesis, but levels remained high in mature and ovulated fish (90-110 ng/ml). Estradiol-17 beta levels and the gonadosomatic index (GSI) values correlated well during vitellogenesis: GSI values showed a linear increase, and reached a peak (29.9 +/- 1.4) in October. Values were extremely low in ovulated fish (1.2 +/- 0.2). In vitro production of estradiol-17 beta and testosterone by ovarian follicles in response to partially purified chinook salmon gonadotropin (SG-G100) was examined monthly using 18-h incubations. Throughout the vitellogenic period SG-G100 stimulated both estradiol-17 beta and testosterone production: the steroidogenic response of follicles increased from June (about 2 ng/ml estradiol-17 beta; 0.1 ng/ml testosterone) to September (about 10 and 14 ng/ml, respectively). In October full-grown immature follicles which could be induced to mature in vitro by hormone treatment produced large amounts of testosterone (about 130 ng/ml) but not estradiol-17 beta. Postovulatory follicles also produced testosterone but the values were low (10 ng/ml) compared with full-grown immature follicles. Very low levels of estradiol-17 beta were produced by postovulatory follicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Progesterone directly inhibits pituitary luteinizing hormone secretion in an estradiol-dependent manner.

We recently demonstrated that progesterone and estradiol inhibit pituitary LH secretion in a synergistic fashion. This study examines the direct feedback of progesterone on the estradiol-primed pituitary. Nine ovariectomized (OVX) ewes underwent hypothalamic-pituitary disconnection (HPD) and were infused with 400 ng GnRH every 2 h throughout the experiment. After 7 days of infusion, estradiol was implanted s.c. Four days later, estradiol implants were exchanged for blank implants in 4 ewes and for progesterone implants in 5 ewes. These implants remained in place for another 4 days. Blood samples were collected around exogenous GnRH pulses before and 0.5 to 96 h after implant insertion and exchange. Serum LH and progesterone concentrations were determined through RIA. One month later, 4 of the HPD-OVX ewes previously implanted with steroids were reinfused with GnRH and the implantation protocol was repeated using blank implants only. In estradiol-primed ewes, progesterone significantly lowered LH secretion after 12 h of implantation and LH secretion remained inhibited while progesterone implants were in place (p less than 0.05). Removing estradiol transiently lowered LH secretion, and this effect was significant only 24 h after estradiol withdrawal (p less than 0.05). These data suggest that progesterone has a direct, estradiol-dependent inhibitory effect on pituitary LH release and that estradiol may sustain pituitary gonadotrope response to GnRH.

Animals↗