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PubMed2004

Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels.

UNLABELLED: In healthy middle-aged men, raloxifene treatment was associated with increased serum estradiol and decreased biochemical markers of bone turnover in subjects with estradiol levels below a threshold of 101.8 pM. INTRODUCTION: We investigated the effects of the selective estrogen receptor modulator raloxifene on bone remodeling in healthy middle-aged men. MATERIALS AND METHODS: Forty-three healthy eugonadal men (mean age, 56 years; range, 49-70 years) were enrolled in a randomized placebo-controlled, double-blind, two-sequence crossover study. The subjects received either raloxifene 120 mg/day or placebo for 6 weeks, followed by a 2-month washout period, before crossing over. To predict changes of urinary total deoxypyridinoline/creatinine on raloxifene treatment, we used a logistic regression model to determine cut-off values of sex hormones for highest sensitivity and specificity. RESULTS: In the whole group, raloxifene treatment was associated with an increase in serum sex hormones, that is, total testosterone (+13%, p < 0.01), bioavailable testosterone (+11%, p = 0.02), total estradiol (+11%, p < 0.002), and bioavailable estradiol (+11%, p = 0.035), and with a decrease in serum osteocalcin (-13%, p < 0.05) and serum total alkaline phosphatase (-6%, p < 0.05). Other biochemical markers of bone turnover remained unchanged. Using a logistic regression model to predict changes in urinary deoxypyridoline, we calculated thresholds for total (101.8 pM) and bioavailable (4.79 pM) estradiol, as well as for total (19.4 nM) and bioavailable (0.35 nM) testosterone. Raloxifene treatment was associated with an increase in serum estradiol and decrease in biochemical markers of bone turnover in men with estradiol values below these estradiol thresholds, without any significant change in subjects with values above them. Similarly, raloxifene treatment was associated with an increase in serum testosterone and a decrease in biochemical markers of bone turnover in those with baseline testosterone values below the testosterone thresholds. The association between antiresorptive effects of raloxifene and low sex hormone levels was more pronounced for estradiol than for testosterone. CONCLUSIONS: The antiresorptive effect of raloxifene was only detectable in men with low baseline estradiol levels. Unlike in postmenopausal women, the increase of estradiol may contribute to the antiresorptive effect of raloxifene in men.

Aged↗
PubMed2001

Interactions of insulin-like growth factor-I, insulin and estradiol with GnRH-stimulated luteinizing hormone release from female rat gonadotrophs.

BACKGROUND: It is well established that ovarian steroids modulate gonadotropin secretion from anterior pituitary cells. It has been speculated that insulin and IGF-I might influence gonadotropin secretion. OBJECTIVE: To investigate the effects of IGF-I and estradiol alone, or combinations of IGF-I with insulin and estradiol on GnRH-stimulated LH release from female rat pituitary cells in serum-supplemented and serum-free culture conditions. METHODS: Pituitary cells were incubated for 24 h or 48 h with a series of increasing concentrations of IGF-I or estradiol and stimulated with 1 nmol/l GnRH for 3 h. To determine the interaction of IGF-I and estradiol on GnRH-stimulated LH secretion, cells were exposed to increasing concentrations of IGF-I and 100 pmol/l estradiol for 24 h. We also investigated the effects of combined treatment with IGF-I and insulin on GnRH-stimulated LH secretion. RESULTS: Our findings indicate that long-term IGF-I treatment (24 h) alone has a significant augmenting effect on GnRH-stimulated LH release in serum-free medium only, with a maximum at low concentrations (10 and 100 pmol/l). Estradiol significantly increased GnRH-induced LH release in a dose-dependent manner. The extent of GnRH-stimulated LH secretion by long-term estradiol treatment (24 h) was significantly greater in serum-supplemented (+42%) medium than in serum-free medium. Estradiol facilitated IGF-I-primed LH responses to GnRH in serum-free medium. In contrast, in serum-supplemented medium, the facilitating potential of estradiol was lower. We also found that, in GnRH-stimulated cells, LH release was augmented by insulin treatment, in contrast to quiescent cells that had been pretreated with 100 pmol/l IGF-I alone and 1 nmol/l insulin alone. CONCLUSIONS: IGF-I and to a lesser extent insulin stimulate GnRH-induced LH secretion from pituitary gonadotrophs. This action is enhanced by estradiol treatment of the cells. However, the well known stimulatory action of estradiol on LH secretion is dependent on the presence of growth factors.

Animals↗
PubMed2003

Estradiol in premenstrual asthma: a double-blind, randomized, placebo-controlled, crossover study.

STUDY OBJECTIVES: To characterize asthma symptoms and pulmonary function throughout two menstrual cycles, with and without exogenous estradiol administration, in women with premenstrual asthma, and to determine the effect of estradiol administration on asthma symptoms, pulmonary function, quality of life, and biomarkers of airway inflammation. DESIGN: Double-blind, randomized, placebo-controlled, crossover study. SETTING: Respiratory clinic and clinical research center. SUBJECTS: Twelve women with documented premenstrual asthma (> or = 20% premenstrual worsening of asthma symptoms and/or of peak expiratory flow [PEF] during a 1-month screening phase). INTERVENTION: Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 (i.e., premenstrually, or before the onset of menses) in the first cycle and then crossed over to the other arm in the second cycle. Throughout both cycles, the women recorded daily morning and evening PEF readings and asthma symptoms. MEASUREMENTS AND MAIN RESULTS: Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 (follicular phase), 22 (luteal phase), and 28 (premenstrually) of both the estradiol and placebo cycles. During the two premenstrual visits, the Asthma Quality of Life Questionnaire was administered. No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores. The area under the curve (AUC) for the composite asthma symptoms versus time profile was numerically, but not statistically, lower (denoting less severe symptoms) during the estradiol cycle than during the placebo cycle. Likewise, no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle. Despite differences (p<0.05) in day-28 estradiol concentrations for estradiol and placebo cycles, no significant differences were found in forced expiratory volume in 1 second, serum endothelin-1, serum and urine eosinophil protein X, urine leukotriene E4, or quality-of-life scores. CONCLUSION: Exogenously administered estradiol did not have a significant effect in women with premenstrual asthma whose asthma was classified predominantly as mild and under excellent control. As in the case of premenstrual syndrome, the placebo effect may be prominent in premenstrual asthma. Further trials, involving women with more severe asthma under poorer control, are warranted to discern underlying mechanisms for the worsening of asthma in relation to menstruation.

Adult↗
PubMed2000

Positive treatment effect of estradiol in postpartum psychosis: a pilot study.

BACKGROUND: Postpartum illnesses with psychiatric symptoms and serious adverse sequelae are highly prevalent during the childbearing years. Despite multiple medical contacts, these illnesses often remain unidentified and untreated. To study the association between estradiol and puerperal psychosis, we measured serum concentration of estradiol and performed an open-label trial of physiologic 17beta-estradiol in women with this disorder. METHOD: Ten women with ICD-10 psychosis with postpartum onset consecutively recruited from a psychiatric duty unit were studied. Serum estradiol concentration was measured at baseline and weekly during sublingual 17beta-estradiol treatment for 6 weeks. The treatment effect was evaluated by a clinician-rated psychiatric symptom scale (the Brief Psychiatric Rating Scale [BPRS]). RESULTS: The baseline serum estradiol levels (mean = 49.5 pmol/L; range, 13-90 pmol/L) were even lower than the threshold value of gonadal failure, and the patients exhibited high scores on the psychiatric symptom scale (mean BPRS total score = 78.3; range, 65-87). During the first week of 17beta-estradiol treatment, psychiatric symptoms diminished significantly (BPRS score decreased to a mean of 18.8, p < .001). Until the end of the second week of treatment, serum estradiol concentrations rose to near the values normally found during the follicular phase, and the patients became almost free of psychiatric symptoms. CONCLUSION: The reversal of psychiatric symptoms in all patients by treating documented estradiol deficiency suggests that estradiol plays a role in the pathophysiology and may have a role in the treatment of this condition. There was a rebound of psychotic symptoms in the 1 patient who discontinued estradiol treatment. Given the small number of patients, this area deserves further study.

Administration, Sublingual↗
PubMed2001

Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study.

BACKGROUND: The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol. METHOD: Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients. CONCLUSION: This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.

Administration, Sublingual↗
PubMed1999

Estradiol receptor and prognostic parameters of human breast cancer.

Estradiol receptors are regarded to predict a likely success of hormonal therapeutic efforts and the prognosis of breast cancer patients. But today its prognostic importance is controversial, discussed as either reflecting intrinsic property of the tumor tissue or better therapeutic accessibility of receptor positive tumors. Moreover, the most important clinical prognosticators--tumor size and axillary lymph node involvement do not seem to be related to the estradiol receptor status. In our investigation, the length of disease free interval is similar in estradiol receptor positive and negative patients and in all sites of distant metastases, but it is significantly reduced if more than 4 axillary lymph nodes are involved. Post recurrence survival is significantly longer in estradiol receptor positive than negative patients and also in patients treated by tamoxifen containing therapies. Its length is independent of the number of axillary lymph node metastases and the type of distant metastases, with a tendency to be longer in estradiol receptor positive than negative patients. In addition, the overall survival is longer for estradiol receptor positive than negative patients and becomes reduced with more than 4 axillary lymph node metastases. Frequency of deaths in estradiol receptor positive patients is half that of negative subjects. Furthermore, the length of overall survival is independent on the type of distant metastases, with tendency to be longer in estradiol receptor positive than negative patients. Longest overall survival could be observed for estradiol receptor positive patients who got therapy regimens containing tamoxifen. The weak prognostic advantages of estradiol receptor positive patients are interpreted by estradiol receptors as intrinsic parameters of breast cancer tissue characterizing more its biological behavior than therapeutic accessibility.

Adult↗
PubMed1999

Combination of automatic HPLC-RIA method for determination of estrone and estradiol in serum.

We developed a highly sensitive assay for estrone and 17 beta-estradiol in serum. Estrone and 17 beta-estradiol, obtained by solid-phase extraction using a Sep pak tC18 cartridge, were purified by high-performance liquid chromatography (HPLC). Quantitation of estrone and 17 beta-estradiol were carried out by radioimmunoassay. Not insignificantly, this automatic system of extraction and HPLC succeeded in analyzing 80 samples a week. Intra-assay coefficients of variation (CV) for estrone and 17 beta-estradiol ranged from 19.5 to 28.7%, and from 8.5 to 13.7%, respectively. The minimum detectable dose for estrone and 17 beta-estradiol were 1.04 pg/ml and 0.64 pg/ml, respectively. The serum levels of 17 beta-estradiol using our method strongly correlated with those by Gas chromatography mass spectrometry (GC-MS). The serum levels of estrone and 17 beta-estradiol in 154 peri- and postmenopausal women were estimated to be between 15 and 27 pg/ml and between 3.5 and 24.0 pg/ml, respectively, while the serum level of 17 beta-estradiol in postmenopausal women, in particular, was estimated to be from 3.5 to 6.3 pg/ml. For postmenopausal women who suffered from vasomotor symptoms, the mean levels of estrone and 17 beta-estradiol at 12 to 18 hours after treatment with daily 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) were 135.0 and 21.3 pg/ml at 12 months, respectively. On the other hand, levels of estrone and 17 beta-estradiol at 12 to 18 hours after treatment with CEE and MPA every other day, were 73.4 and 15.3 pg/ml, respectively. These highly sensitive assays for estrone and 17 beta-estradiol are useful in measuring low levels of estrogen in postmenopausal women, and monitoring estrogen levels in women receiving CEE as hormone replacement therapy.

Adult↗
PubMed1976

Effects of ethinyl estradiol and phenobarbital on bile acid synthesis and biliary bile acid and cholesterol excretion.

Bile acid synthesis calculated from respiratory (14)CO2 derived from the catabolism of [26 or 27-(14)C]cholesterol to bile acids in rats with intact enterohepatic circulations decreased 50% after 5 days of ethinyl estradiol treatment (5 mg per kg per day). Maximal derepressed bile acid synthesis, measured as biliary bile acid excretion after bile acid pool depletion, was also reduced 50% by ethinyl estradiol treatment. Because ethinyl estradiol did not alter biliary cholesterol excretion, bile contained less bile acid relative to cholesterol. Hepatic bile acid concentration was not increased by ethinyl estradiol treatment. Because the inhibitory effect of ethinyl estradiol on bile acid synthesis required 5 days of treatment it is concluded that bile acid synthesis probably was not reduced by negative feedback repression of 7alpha-hydroxylase, the rate-limiting enzyme in bile acid synthesis, which has a half-life of 2 to 3 hr. During the first 14 hr after bile duct cannulation, before bile acid pool depletion, ethinyl estradiol-treated rats excreted less than one-half as much bile acid and the same amount of cholesterol as controls. The bile acid to cholesterol ratio was therefore decreased. Rats treated simultaneously with phenobarbital and ethinyl estradiol excreted significantly more bile acid than rats treated with ethinyl estradiol alone, but biliary cholesterol excretion was not increased. The proportion of biliary bile acid relative to cholesterol was thereby restored to the control value. In contrast, after 14 hr of bile drainage and depletion of the bile acid pool, rats treated with ethinyl estradiol and those treated with phenobarbital-ethinyl estradiol excreted the same amount of bile acid. Thus, when phenobarbital is administered with ethinyl estradiol, it increases the bile acid pool size and biliary bile acid excretion, but it does not increase bile acid synthesis. The increase in pool size and biliary bile acid excretion might be due to the phenobarbital-induced increase in ileal absorption of bile acids.

Animals↗
PubMed2005

Effect of estradiol on expression of cytoskeletal proteins during spermatogenesis in testis of sexually mature rats.

Earlier studies had shown that long term treatment with estradiol arrests spermatogenesis in adult male rats, at a dose of 0.1 mg/kg/day. The present study was therefore undertaken to ascertain the causes underlying the reduction in sperm counts by administering estradiol for a short term, at the dose of 0.1 mg/kg/day. Estradiol valerate was injected at a dose of 0.1 mg/kg/day, for a period of 10 days to one group of adult male rats, which were administered saline for 12 days prior to estradiol injection, and sacrificed after 22 days. The control group was administered saline for 22 days. The sera were analyzed for testosterone and FSH levels. One testis of each male was immersion fixed for histology, and for immunohistochemistry of two testicular cytoskeletal proteins, vimentin and vinculin. The contralateral testes were used for analysis of vimentin and vinculin gene expression by reverse transcriptase polymerase chain reaction (RTPCR) and western blotting. Another group exposed to estradiol for 10 days was injected with bromodeoxyuridine (BrdU), at a dose of 100 mg/kg/day, to ascertain the effect on germ cell proliferation, and sacrificed 12 days later, while estradiol treatment was continued till sacrifice. BrdU, at a dose of 100 mg/kg/day was injected i.p. to a group of control rats treated with saline for 10 days, and sacrificed 12 days later. The testes from both groups were immersion fixed for immunohistochemical detection of BrdU. Histology of estradiol treated testis showed predominance of tubules with round spermatids with accumulation of lipid droplets in Sertoli cell cytoplasm and decreased cell height, whereas controls showed elongating spermatids. BrdU immunolocalization in the testis, irrespective of treatment, indicated its incorporation in deoxyribonucleic acid (DNA) suggesting that estradiol sustained germ cell proliferation. Both vimentin and vinculin could be immunolocalized to the testis. The testicular levels of vimentin and vinculin, quantified after western blotting, were unaffected. The testicular expression of vimentin and vinculin seen by RTPCR was also unaffected. The study suggested that estradiol induced reduction in sperm counts was not due to adverse effects on proliferation. The observed predominance of seminiferous tubules showing round spermatids, accumulation of lipid droplets as compared to controls suggested that reduction in elongated spermatids occurred through reduced spermiation and phagocytosis. The study also suggested that reduction in Sertoli cell height after short-term estradiol treatment was not due to reduced expression of vimentin and vinculin, which could be maintained by estradiol. However, reduction in Sertoli cell height could have been due to suppression of FSH and testosterone, implicated in the polymerization of vimentin and organization of vinculin, two cytoskeletal proteins involved in inter-Sertoli or Sertoli-germ cell junctions. The study suggested that disorganization of Sertoli cell cytoskeleton and reduction in the volume of Sertoli cells could be an important factor for reduced efficiency of spermatogenesis after exposure to estrogenic molecules.

Animals↗
PubMed1990

Growth control of human mammary cancer cells (MCF-7 cells) in culture: effect of estradiol and growth factors in serum-containing medium.

The growth control of estrogen-dependent mammary cancer is very complex and only partly understood. The present study was undertaken in order to establish conditions for growth control of MCF-7 cells in monolayer culture with focus on the effect of estradiol-17 beta, fetal calf serum, and growth factors. The effect of charcoal-stripped fetal calf serum (CSFCS) on cell growth was dependent upon the presence of hormones or growth factors in the medium. In the presence of insulin (or insulin-like growth factor 1) and in the absence of estradiol-17 beta, increasing concentrations of CSFCS, 0.625-20%, produced a bell-shaped growth response curve. Serum concentrations greater than 2.5% inhibited cell growth in the absence of estradiol-17 beta, whereas CSFCS in a dose-dependent way up to 10% stimulated growth in the presence of estradiol-17 beta (5 x 10(-10) mol/liter). The growth inhibitory effect of CSFCS could not be demonstrated in the absence of insulin (or insulin-like growth factor 1) and estradiol-17 beta. CSFCS stimulated growth in a dose-dependent way in the presence of estradiol-17 beta and also in the absence of insulin. Both the putative growth inhibitor and stimulator were found to be heat stable and not dialyzable. Epidermal growth factor stimulated growth but was unable to eliminate the growth inhibitory effect of 5-10% CSFCS. Interleukin-1 alpha inhibited MCF-7 cell growth in a dose-dependent way and produced a 75% reduction in cell number at a concentration of 5 x 10(-10) mol/liter. This inhibition was almost totally overcome by estradiol-17 beta. It is concluded that serum appears to contain factors with both stimulatory and inhibitory effects on the growth of MCF-7 cells. The inhibitory effect can be eliminated by estradiol (5 x 10(-10) mol/liter). In the presence of estradiol cell growth is stimulated by CSFCS in a dose-related way up to 5-10%. Taken together these data seem to indicate that estradiol stimulates cell growth in two principal ways: partly by eliminating the effect of an inhibitor, in support of a "negative hypothesis," and partly by an effect whereby estradiol permits a growth stimulator in CSFCS to be expressed, in support of the "indirect positive hypothesis."

Breast Neoplasms↗
PubMed1988

Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture.

Estradiol and triphenylethylene antiestrogen actions have been studied extensively in breast cancer cell lines. However, their effects are still poorly understood on normal human breast cells. We have developed a culture system of normal human breast epithelial (HBE) cells. It has been shown previously that cultured HBE cells were hormone dependent and well adapted for the study of hormone/antihormone actions. However, until now, no data were available on estradiol receptor (ER) in HBE cells. In this study, the presence of ER was demonstrated by (a) whole-cell biochemical assay on breast cells after enzymatic tissue dissociation and (b) an immunocytochemical method using an anti-ER monoclonal antibody both on enzymatically dissociated cells and on 8-day cultured cells. Immunostaining was nuclear and cell positivity was heterogeneous. However, the percentage of positive cells and staining intensity were far greater in the presence of estradiol in the culture, indicating estradiol stimulation of ER. Moreover, HBE cells were used to study the action on cell growth of estradiol versus trans-tamoxifen (TAM), trans-4-hydroxytamoxifen (trans-4OHTAM), and cis-4-hydroxytamoxifen (cis-4OHTAM) alone or added to estradiol. Cell growth was estimated daily by a histometric method and by DNA assay at the end of the 7-day study. When the medium was minimally supplemented with human serum (1%), estradiol stimulated cell growth in a dose-dependent manner at concentrations varying from 10(-9) to 10(-7) M. TAM and trans-4OHTAM clearly inhibited mammary cell division when estradiol was added to the medium and, to a lesser extent, in the absence of estradiol. This inhibitory effect was dose dependent. trans-4OHTAM was 100 times more active than trans-TAM. cis-4OHTAM also clearly inhibited breast cell division at 10(-7) and 10(-6) M concentrations but was 3-fold less efficient than trans-4OHTAM. In conclusion, (a) the presence and estradiol dependence of ER have been demonstrated in HBE cells, which constitute a fruitful model for the study of hormone/antihormone actions, and (b) in these normal cells, estradiol stimulates growth, whereas TAM and the 4OHTAM isomers are potent inhibitors of cell multiplication, as they are in breast cancer cell lines in culture.

Breast↗
PubMed1981

Effects of 17 beta-estradiol on progesterone receptors and the uptake of thymidine in human breast cancer cell line CAMA-1.

Two sublines, CAMA-1R and CAMA-1N, were derived from the original CAMA-1 cells after continuous passages in our laboratory. 1R cells were supplemented in culture with estradiol and retained the properties of the original cell line, whereas 1N cells, not supplemented with estradiol, had a partial loss of estrogenic responsiveness. The doubling times for 1R and 1N cells were 2 and 2.4, respectively. These two sublines showed different effects on thymidine uptake after estradiol stimulation. Cells of 1R had a 2-fold greater thymidine incorporation than did the control without estradiol. In contrast, no difference of thymidine uptake was demonstrated in cells of 1N in the presence or absence of estradiol. Both cell lines contained cytoplasmic progesterone receptors with a Kd of 0.56 nM and a sedimentation coefficient of 6 to 7S on a 5 to 20% sucrose gradient. The progesterone receptor level in 1N was about 8-fold higher than in 1R cells. Both sublines exhibited a dose-dependent increase in progesterone receptor levels in response to estradiol with the maximal stimulation (8-fold increase) reached by using 5 nmol of estradiol. The rate of increase for estradiol-induced progesterone receptor appears to be the same for both sublines; a liner increase was demonstrated between Days 3 and 7 following plating. Our results show that estrogen regulation of thymidine uptake and progesterone receptor induction may be mediated through two separate mechanisms. Thus, following a chronically deficient supply of estradiol to 1N cells, there is apparent loss of responsiveness to estradiol-induced thymidine uptake, but the ability of these cells to respond to estradiol induction of progesterone receptor was retained.

Biological Transport↗
PubMed1996

Estradiol increases cyclic adenosine monophosphate in rat pulmonary vascular smooth muscle cells by a nongenomic mechanism.

Estrogen, like other steroids, may induce rapid nongenomic cellular effects. We studied the effect on intracellular cAMP of short-term exposure (5 min) of cultured rat pulmonary vascular smooth muscle cells (VSMC) to estradiol 17 beta. At confluence, VSMC were incubated in phosphate buffer saline for 1 hr before exposure to different hormones. The reaction was stopped with 0.1 N HCl and cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The 5-min incubation with estradiol 17 beta (0.3-30 microM) significantly increased basal intracellular cAMP in a concentration-dependent manner. The stimulatory effect of estradiol on cAMP was time-dependent, increasing with prolonged exposure to the hormone, and was not affected by the protein synthesis inhibitor, actinomycin D (5 micrograms/ml), at 5 and 30 min. Comparable concentrations of testosterone or estradiol 17 alpha had no significant effect on cAMP. The estrogen receptor partial agonist, tamoxifen also significantly increased basal cAMP in a concentration-dependent manner, but inhibited the effect of estradiol. Furthermore, forskolin elicited a concentration-dependent increase in cAMP (396.6 +/- 53% at 10 microM concentration), which was significantly potentiated in presence of estradiol. The effect of estradiol is unlikely to be mediated by G-protein activation, because the G protein inhibitor, pertussis toxin (100 ng/ml), did not significantly affect estradiol-induced increase in cAMP. Removal of Ca++ from the incubation medium inhibited the stimulatory effect of estradiol 17 beta suggesting that estradiol may increase pulmonary VSMC cAMP via a Ca(++)-dependent pathway. We suggest that the effect of estradiol 17 beta in these experiments is nongenomic in nature, and is possibly mediated by direct interaction of the hormone with specific membrane binding sites.

Animals↗
PubMedDate not supplied

Estradiol regulates tumor growth by influencing p53 and bcl-2 expression in human endometrial adenocarcinomas grown in nude mice.

This study analyzes the effects of estradiol on p53 and bcl-2 expression, tumor growth and cell kinetic parameters in three human endometrial adenocarcinomas grown in nude mice. The tumors used were estradiol receptor (ER) positive but differed in receptor concentration and hormone sensitivity. All three tumors expressed wild-type p53 protein. Using a tumor with an estradiol independent but responsive (inhibited) growth phenotype, we found that an increase in the circulating estradiol concentration led to increases in p53 expression and a decrease in bcl-2 levels, resulting in increased cell loss (CL) measured as delayed tumor growth. In another tumor which demonstrated estradiol independent and resistant growth, we observed an estradiol dose-related increase in p53 expression but no changes in bcl-2 expression or cell kinetic parameters. The ER mechanism of these cells was at least partly intact, as evidenced by maintained PgR induction. The third tumor showed an estradiol independent and resistant growth phenotype and a non-functional ER mechanism, lacking PgR induction. After estradiol treatment of the tumor-bearing animals no changes were observed in p53 or bcl-2 expression or in cell kinetics. We conclude that estradiol may regulate tumor growth in some ER positive human endometrial adenocarcinomas through regulation of p53 expression, which in turn regulates the bcl-2 protein concentration. Furthermore, this regulation of p53 expression is estradiol dose dependent. These growth regulating functions appear to be strongly influenced by ER mechanisms and do not seem to operate synchronously in tumors with an estradiol resistant growth phenotype.

Animals↗
PubMed1979

Steroid levels after intramuscular injection of radioactive estradiol-17beta, estrone, progesterone and testosterone in the bovine.

Eight 2 year old Hereford cows from days 8 to 12 of the estrous cycle were injected intramuscularly with 5 ml of corn oil containing 5 mg of estradiol-17beta (two cows), estrone (two cows), progesterone (two cows) or testosterone (two cows). Each cow treated with estradiol received 494 microc of estradiol-17beta-6, 7 H3 and each cow treated with estrone received 492 microc of estrone-6, 7 H3. Each cow treated with progesterone or testosterone received 400 muc of H3 compound labeled in the 7 position. Total urine was collected by urethral catheterization of the cows treated with estrogens. Blood samples for plasma and serum were collected via jugular cannulae. Blood and urine samples from estrogen-treated cows were collected hourly for the first 24 hr, at 2 hr intervals for the next 26 hr, at 4 hr intervals for the next 12 hr and at 12 hr intervals until background was reached. Blood samples were collected hourly from 1 to 8 hr after injection from progesterone or testosterone-treated cows. Plasma and serum levels of radioactive estradiol-17beta, estrone, progesterone and testosterone were similar. Blood levels of radioactivity peaked at 2 hr post-injection in cows receiving estradiol-17beta and at 3 hr in cows receiving estrone. Blood levels of labeled estradiol-17beta and estrone were nondetectable by 54 hr and 83 hr, respectively. Peak urinary excretion of radioactivity was reached at 7 hr for estradiol-17beta and at 14 hr for estrone and nondetectable levels were reached by 95 hr for estradiol-17beta and 14 hr for estrone. At these times, 15.5% of the total dose of radioactive estradiol-17beta and 17.5% of the injected estrone had been excreted in the urine. Peak blood and urinary excretion levels were reached earlier for radioactive estradiol-17beta than for estrone, and excretion of estradiol-17beta was completed more rapidly. No difference was found in plasma and serum levels for any steroid studies; thus, endogenous steroid titers in blood plasma and serum are not different in the cow.

Journal Article↗
PubMed1985

Serum estradiol-17beta concentrations during spontaneous silent estrus and after prostaglandin treatment in the mare.

Serum estradiol-17beta concentrations were determined during silent estrus in the mare. Relationships between serum estradiol-17beta concentration, corpus luteum regression, follicular development, ovulation, prostaglandin treatment and behavioral estrus were investigated. The expression of behavioral estrus was found to be related to the patterns of progesterone and estradiol-17beta secretion during the periovulatory period. When compared to normal estrous cycles, silent estrus was accompanied by a significantly lower maximum serum estradiol-17beta concentration (47.8 vs 34.6 pg/ml), a significantly longer interval from maximum estradiol-17beta concentration to ovulation (1.7 vs 4.0 days), and a significantly shorter interval from corpus luteum regression to ovulation (5.3 vs 2.8 days). Silent estrus following prostaglandin treatment was related to a significantly shorter interval from prostaglandin treatment to ovulation (3.6 +/- 0.4 days) than from normal corpus luteum regression to ovulation (5.3 +/- 0.3 days). Silent estrus appeared to be related to changes in follicular estradiol-17beta secretion and to the pattern of its secretion as related to regression of the corpus luteum. There appeared to be not only less estradiol-17beta present, but also less time available after luteal regression for it to interact with the central nervous system to elicit the changes necessary to cause behavioral estrus. There fore, unusual relationships between luteal function and folliculogenesis can result in one type of silent estrus. Significant correlations (P<0.05) were found between follicle size and serum estradiol-17beta concentration whenever behavioral estrus occurred [follicle diameter in mm = 0.96 (serum estradiol-17beta in pg/ml) + 6.08 and 0.73 (serum estradiol-17beta + 13.32 for control and normal estrus following prostaglandin treatment groups, respectively]. During silent estrus, however, no significant correlations between follicle size and serum estradiol-17beta concentration were observed.

Journal Article↗
PubMed2003

Regulation of biliary cholesterol secretion is associated with abcg5 and abcg8 expressions in the rats: effects of diosgenin and ethinyl estradiol.

In this study, we evaluate the effect of diosgenin, ethinyl estradiol and these co-administration on changes of lipoprotein metabolism and expression of hepatic genes those are important for cholesterol metabolism including the recently identified abcg5 and abcg8 in male Wistar rats. Rats were subjected to four experimental groups: (1) control group, (2) diosgenin group, which was fed the diet containing 1% diosgenin for 7 days, (3) ethinyl estradiol group, which received ethinyl estradiol in a dose of 5 mg/kg daily for 5 days, (4) diosgenin-ethinyl estradiol group, which received ethinyl estradiol treatment and was fed the diet containing 1% diosgenin. Diosgenin-feeding induced the hepatic abcg5/abcg8 expressions and biliary cholesterol secretion. Ethinyl estradiol administration reduced hepatic abcg5/abcg8 expressions and biliary cholesterol secretion. There was a positive correlation between hepatic expressions of abcg5/abcg8 and biliary cholesterol secretion. These findings strongly suggest that abcg5 and abcg8 are key proteins for biliary cholesterol excretion. Diosgenin-feeding did not affect the hepatic abcg5/abcg8 expressions and biliary cholesterol excretion in ethinyl estradiol-treated rat. Serum bile acid and bilirubin were higher and biliary bile acid and bilirubin secretions were lower in diosgenin-ethinyl estradiol group than those in ethinyl estradiol group. This finding suggests that diosgenin enhances the cholestatic effect of ethinyl estradiol in the rat. In conclusion, alteration of biliary cholesterol secretion is related to the expressions of hepatic abcg5 and abcg8 in diosgenin- or ethinyl estradiol-treated rat.

Journal Article↗
PubMed1990

[Basic characteristics of rat brain microsomal estradiol 2-hydroxylase].

The basic properties of estradiol 2-hydroxylase in rat brain microsomes were studied and compared to the known characteristics of rat liver microsomal estradiol 2-hydroxylase. Rat liver microsomal estradiol 2-hydroxylase, which has been considered to be a cytochrome P450-like enzyme, was largely inhibited by carbon monoxide. On the other hand, the effect of carbon monoxide on the activity of rat brain microsomal estradiol 2-hydroxylase was rather weak. A known inhibitor of cytochrome P450, SKF-525A inhibited rat liver microsomal estradiol 2-hydroxylase in a concentration-dependent manner. The concentration of SKF-525A causing 50% inhibition of liver microsomal estradiol 2-hydroxylase was 33 microM where the substrate concentration was 1 microM. Conversely, the inhibitory effect of SKF-525A on the activity of brain microsomal estradiol 2-hydroxylase was much less. Moreover, norepinephrine inhibited brain microsomal estradiol 2-hydroxylase in a competitive manner, however, the effect of physiological concentrations of norepinephrine on liver microsomal estradiol 2-hydroxylase was negligible. These results suggest that the nature of microsomal estradiol 2-hydroxylase in rat brain is quite different from that of liver microsomal estradiol 2-hydroxylase.

Animals↗