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PubMed1993

Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives.

OBJECTIVE: We determined the independent effects of various doses of ethinyl estradiol used in oral contraceptives or norethindrone acetate, as well as their combination, on insulin sensitivity in normal women. STUDY DESIGN: Thirty-three normal ovulatory female volunteers were recruited for this study. Insulin tolerance tests were performed after carbohydrate loading to determine the kinetic disappearance of glucose and insulin. After initial testing the women were randomized into four groups: ethinyl estradiol 20 micrograms, 35 micrograms, and 50 micrograms and norethindrone 1 mg. Insulin tolerance tests were repeated after 1 month of treatment and again after a second month, when all ethinyl estradiol groups received the addition of norethindrone 1 mg to their doses of ethinyl estradiol. Plasma glucose and insulin were measured, and insulin sensitivity (K(itt) glucose) and the disappearance of insulin (K(itt) insulin) were calculated. RESULTS: All groups were comparable at baseline, and no significant changes in fasting glucose and insulin were evident with treatment. After ingestion of 50 micrograms ethinyl estradiol the K(itt) glucose value decreased significantly (p < 0.03) and ingestion of 20 micrograms and 35 micrograms showed individual changes, but as groups the changes were not statistically significant. All ethinyl estradiol groups combined had a significant decrease in K(itt) glucose (p < 0.01). Norethindrone 1 mg alone did not change K(itt) glucose values, and after the addition of norethindrone to ethinyl estradiol, K(itt) glucose values normalized. K(itt) insulin values were also lower with treatment but were lower with ethinyl estradiol plus norethindrone compared with ethinyl estradiol alone (p < 0.04), suggesting an attenuation of insulin clearance with the progestin. CONCLUSION: Ethinyl estradiol alone decreases insulin sensitivity, and this may occur at lower doses, but norethindrone 1 mg does not appear to do so. However, progestins may alter insulin clearance.

Adult↗
PubMed2001

Metabolism of estradiol, ethynylestradiol, and moxestrol in rat uterus, vagina, and aorta: influence of sex steroid treatment.

Estrogen replacement therapy for postmenopausal women consists of an estrogenic and a progestagenic compound. The treatment has a positive estrogenic effect on bone, the cardiovascular system, and vagina but is dependent of the estrogen-progestagen balance in uterus to prevent unwanted proliferation. We were interested in the influence of estrogens and progestagens on estrogen metabolism in target tissues of estrogen replacement therapy. Therefore, we studied the metabolism of estradiol, 17alpha-ethynylestradiol, and moxestrol (11beta-methoxy-17alpha-ethynylestradiol) in rat uterus, vagina, and aorta. In uterus and vagina, estradiol was converted to estrone, estradiol-3-glucuronide, and estrone-3-glucuronide. These metabolites demonstrate the presence of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and UDP-glucuronosyl transferase (UDP-GT) in uterus and vagina. We found that the conversion of estradiol by 17beta-HSD in uterus was increased in animals treated with estradiol or with a combination of estradiol and progesterone. The conversion of estradiol in uterus by UDP-GT was estradiol-induced and in contrast, progesterone-suppressed. In the vagina, steroid hormone treatment had no effect on estradiol conversion by 17beta-HSD or UDP-GT. Ethynylestradiol was glucuronidated only, and this was not affected by steroid treatment. Moxestrol was not converted in any of the three organs that were studied, indicating that the 11beta-methoxy substituent renders it a poor substrate for glucuronidation. Overall, the estrogen metabolism, and its regulation by sex steroids, in rat uterus is different compared with human uterus. Therefore, the rat may not be the best-suited model to investigate uterine effects of estradiol-progestagen combined treatment.

Animals↗
PubMed1996

Estradiol activation of human colon carcinoma-derived Caco-2 cell growth.

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis.

Caco-2 Cells↗
PubMed2000

Estradiol causes a dose-dependent stimulation of prostate growth in castrated beagle dogs.

BACKGROUND: Previous studies have shown that chronic treatment of castrate dogs with androgen and estrogen results in significant prostate growth. Estrogen treatment of castrate dogs in the absence of androgen has resulted in conflicting data as reported by several authors. The purpose of this experiment was to evaluate the effect of a physiological dose of estradiol on prostate growth in dogs, using ultrasound to study size changes over time. METHODS: Dogs (n = 25) were randomly divided into groups (n = 5) and treated as follows: castration alone (CC), castration plus low dose estradiol (E(2) low), castration plus high estradiol (E(2) high), castration plus estradiol and androstanediol (E(2)A), or no treatment (normal controls, NC). Silastic implants containing 5alpha-androstan-3alpha-17beta-diol (3alphadiol), and/or 17beta-estradiol were used for continous delivery of steroids. Prostate volume was measured by transrectal ultrasonography, and blood was drawn for hormone and sex hormone binding globulin (SHBG) determinations. RESULTS: Results show that serum estradiol and SHBG levels were fairly constant over 12 weeks in all groups. Estradiol-treated groups had mean serum estradiol values of approximately 40 and 60 pg/ml, respectively. Initially, all groups had similar prostate volumes. Over 12 weeks the castrate dogs had a decline in prostate volume, whereas the intact dogs and those treated with E(2) and 3alpha-diol maintained a constant prostate volume. Estradiol treatment caused a large, late onset (week 7), dose-dependent increase in prostate volume relative to the intact group (P < 0.01). At 12 weeks, animals were euthanized and prostates weighed. The mean prostate weights in each group were: NC 14.8 +/- 2. 9, CC 2.4 +/- 0.5, E(2)A 9.7 +/- 2.0, E(2) low 21.7 +/- 4.3, and E(2) high 63.6 +/- 12.6 g (geometric mean +/- SEM). Histologically, prostates of estrogen-treated dogs showed metaplastic squamous epithelium. CONCLUSIONS: These results demonstrate that estradiol causes marked dose-dependent stimulation of prostate growth in the castrate dog.

Anabolic Agents↗
PubMed1991

Counteraction of estradiol-induced activation of tissue-type plasminogen activator in a human breast cancer cell line by an anti-estrogen, LY117018.

LY117018 is a non-steroid anti-estrogen which exhibits about 100 times higher affinity for estrogen receptor than tamoxifen, another anti-estrogen. The cell line ES-1, which was isolated from human breast cancer MCF-7 cells, was highly sensitive to the cytocidal action of estradiol. Growth of ES-1 cells was inhibited by 10(-8)M 17 beta-estradiol, a concentration that stimulated the growth of parental MCF-7 cells. The estradiol-induced growth inhibition of ES-1 cells was almost completely reversed by treatment with LY117018, but not by treatment with tamoxifen. The relative binding affinity of LY117018 for estradiol receptor was equal to that of estradiol in both MCF-7 and ES-1 cells. Treatment of ES-1 cells with estradiol specifically induced tissue-type plasminogen activator (t-PA), whereas such estradiol-induced activation was not observed in parental MCF-7 cells. Quantitative immunoreactive assays and Northern blot analysis showed that estradiol-induced expression of t-PA was blocked by LY117018 in ES-1 cells. The inhibitory effect of tamoxifen was about 100 times lower than that of LY117018. The inhibition of t-PA gene expression by LY117018 might be due to competitive inhibition with estradiol in estradiol receptor binding.

Breast Neoplasms↗
PubMed1992

Estradiol pulses induce progestin receptors selectively in substance P-immunoreactive neurons in the ventrolateral hypothalamus of female guinea pigs.

Low doses of estradiol, administered as pulses, are as effective as higher doses for priming ovariectomized (OVX) guinea pigs to display progesterone-facilitated lordosis. High doses of estradiol, administered by constant-release implants, induce progestin receptors in many substance P-immunoreactive (SP-IR) neurons in the ventrolateral hypothalamus (VLH), a site at which estradiol primes OVX guinea pigs to respond behaviorally to progesterone. To test the hypothesis that behaviorally effective estradiol pulses induce progestin receptors selectively in substance P-containing neurons in the VLH, OVX females received estradiol implants 1 week prior to perfusion, or two pulses of estradiol-17 beta, injected 39 and 11 h before perfusion. Colchicine was administered intracerebroventricularly prior to perfusion. No significant differences were observed in the total number of progestin receptor-immunoreactive (PR-IR) or substance P-immunoreactive cells in the VLH and VLH/ventromedial hypothalamus (VMH), respectively, of females receiving the two estradiol treatments. However, the percentage of PR-IR cells in the VLH also immunoreactive for SP was significantly higher in the estradiol pulse-treated (53%), than in the estradiol capsule-implanted animals (36%). These data suggest that behaviorally effective estradiol pulses induce progestin receptors selectively in substance P-containing neurons in the VLH and are consistent with the hypothesis that substance P is involved in progesterone-facilitated lordosis in guinea pigs.

Animals↗
PubMed1996

Early administration of 17beta-estradiol partially masculinizes song control regions and alpha2-adrenergic receptor distribution in European starlings (Sturnus vulgaris).

The vocal control system in many songbird species is a sexually dimorphic neural circuit that mediates learning and production of song. The mechanism by which this system is sexually differentiated has been investigated in only one species, the zebra finch (Taeniopygia guttata). Estradiol may be involved in the sexual differentiation of this system, as female zebra finches treated with estradiol as nestlings develop a male-like song system; however, blocking estradiol action in embryonic and nestling male zebra finches does not demasculinize the song system. Therefore, the role of estradiol in song system development is unclear. The role of estradiol in song system sexual differentiation was assessed in European starlings (Sturnus vulgaris). This species is of potential interest because it is less extreme in the degree of sexual dimorphism of the song system and song behavior than zebra finches. While in the field, starling nestlings were implanted with 500 microg of estradiol at 3 days of age. These birds were brought into the laboratory at Day 11 and hand-reared. In females, estradiol produces significant increases in the volumes of song control regions defined by Nissl stain, as well as by autoradiography for alpha2-adrenergic receptors; however, these estradiol-treated females have song systems that more closely resemble those of control females than control males. Estradiol-treated males exhibit significant hypermasculinization at 210 days of age, but this effect is transient and hypermasculinization is no longer evident at Day 345. The role of estradiol in sexual differentiation of the neural circuit mediating song behavior remains enigmatic.

Animals↗
PubMed2002

Cyclic estradiol treatment normalizes body weight and restores physiological patterns of spontaneous feeding and sexual receptivity in ovariectomized rats.

Hypothalamic-pituitary-gonadal axis function strongly influences feeding and body weight in cycling females in many species. To test the sufficiency of cyclic variations in plasma estradiol to reproduce normal patterns of spontaneous feeding, food intake, and body weight, ovariectomized Long-Evans rats were subcutaneously injected every fourth day with 2 microg estradiol benzoate or with the oil vehicle alone. Cyclic estradiol treatment completely normalized the trajectory of body weight gain and total food intake through seven treatment cycles. The hyperphagia of ovariectomized rats was expressed as an increase in spontaneous meal size. Meal frequency decreased, but not enough to compensate for the increase in meal size. Estradiol treatment normalized both parameters. In addition, cyclic estradiol treatment produced a further phasic decrease in meal size (and increase in meal frequency) and a decrease in food intake during the second night after injection. This phasic change is similar to the feeding changes occurring during estrus in intact rats. Sexual receptivity was measured during the eighth estradiol treatment cycle, 4 h after injection of 0.5 mg progesterone. Lordosis scores at the time of the treatment cycle modeling estrus were maximal, and scores at the time modeling diestrus were slightly increased over those of rats that did not receive estradiol. Finally, plasma estradiol levels, measured during the ninth treatment cycle, revealed a near-normal cyclic pattern of plasma estradiol levels. These results provide the first demonstration that the induction of a cyclic, near-physiological pattern of plasma estradiol is sufficient to maintain normal levels of body weight, spontaneous feeding patterns, total food intake, and (together with progesterone) sexual receptivity in ovariectomized rats.

Animals↗
PubMed1996

Possible mechanism of induction of benign prostatic hyperplasia by estradiol and dihydrotestosterone in dogs.

A mechanism of induction of canine benign prostatic hyperplasia (BPH) by androgen-stimulated growth of prostatic cells exposed to estrogen-induced toxicity. Estrogen is thought to be activated by redox cycling of catechol metabolites, a mechanism of generation of active radicals. Mongrel dogs, 4 animals/group, were sham-operated (controls) or were treated for 60 days with implants of 5 alpha-dihydrotestosterone and/or estradiol-17 beta. The activities of drug and hormone metabolizing enzymes (aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase, and estradiol-17 beta-2- and -4-hydroxylase) in prostate were significantly elevated by chronic treatment with either estradiol-17 beta or 5 alpha-dihydrotestosterone plus estradiol-17 beta, but not in kidney or liver which are not targets of hormone-induced hyperplasia. Activities of the detoxifying enzymes catalase and glutathione peroxidase I in prostate were increased by estradiol-17 beta treatment, whereas in kidney or liver they were not affected or changed to a lesser degree than observed in prostate. Free radial-induced damage (carbonyl content) of proteins was observed in prostate of dogs treated with either estradiol-17 beta or 5 alpha-dihydrotestosterone plus estradiol-17 beta and in liver protein by treatment with either 5 alpha-dihydrotestosterone or 5 alpha-dihydrotestosterone plus estradiol-17 beta. It was concluded that the patterns of estradiol-17 beta- or 5 alpha-dihydrotestosterone plus estradiol-17 beta-induced increases in activities of catechol estrogen synthase and of other drug metabolizing enzymes were consistent with the postulated free radical generation by redox cycling of catechol estrogen specifically in the prostate. The increases in activities of detoxifying enzymes may represent an (albeit insufficient) response to prostatic free radical damage to protein in prostate is consistent with a postulated induction of BPH via injury by estrogen metabolites followed by 5 alpha-dihydrotestosterone-stimulated growth of altered prostatic cells.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1998

Effects of dietary 17 beta-estradiol exposure on serum hormone concentrations and testicular parameters in male Crl:CD BR rats.

A 90-day/one-generation reproduction study was conducted in male and female Crl:CD BR rats using dietary levels of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol. The goals of this study were to set dose levels and evaluate several mechanistic endpoints for inclusion in multigeneration reproduction and combined chronic toxicity/oncogenicity studies with 17 beta-estradiol. In this report we discuss the effects of dietary 17 beta-estradiol exposure on serum hormonal levels and sperm parameters from P1 and F1 male rats. Sperm parameters were also evaluated in recovery P1 and F1 male rats that were fed control diets for 105 and 103 days, respectively, following 97 and 86-94 days of estradiol exposure, respectively. Measurement of Sertoli cell number from F1 male rats was performed to test the hypothesis that in utero exposure to estrogens will decrease Sertoli cell number and sperm production. Other findings from this 90-day/one-generation reproduction study are summarized elsewhere. 17 beta-Estradiol produced a dose-dependent decrease in body weight in P1 male rats at > or = 2.5 ppm and in the F1 male rats at 2.5 ppm. This decrease in body weight was due to a combination or reduced food consumption and food efficiency. In the recovery P1 males, body weight increased in the affected groups, albiet not to control levels, due to food consumption returning to control levels accompanied by an increase in food efficiency. However, in F1 males there was no corresponding rebound in body weight. In the P1 rats, exposure to 17 beta-estradiol decreased testis and epididymis weights in the 10 and 50 ppm groups, while no effects were seen in the P1 2.5 ppm group. In contrast, epididymis weights in the F1 and F1 recovery 2.5 ppm groups were statistically decreased; however, there were no histopathological effects observed. The decreases in testis weights in the P1 generation correlated with histopathologic evidence of interstitial cell atrophy and seminiferous tubule degeneration and reduced sperm production. Correlative changes in the epididymides of P1 rats were characterized by oligospermia or aspermia, the presence of germ cell debris in the lumen of tubules, and atrophy of epididymal tubules. 17 beta-Estradiol decreased testicular spermatid numbers, epididymal sperm numbers, and sperm motility in the P1 males in the 10 and 50 ppm groups, but not in the 2.5 ppm group. Following a 105-day recovery period in the P1 males, all sperm parameters and reproductive organ weights returned to control values except for the epididymal sperm count. Overall, the decline in testicular spermatid and epididymal sperm numbers in the P1 rats correlated with the reduced organ weights and the observed histopathological changes and appeared primarily related to the decrease in serum testosterone levels. In the F1 rats, no significant decreases were noted in the testicular spermatid number but a slight decrease in epididymal sperm number was seen in the 2.5 ppm group, which showed no evidence of recovery. Using morphometric analysis, no change was seen in the number of Sertoli cell nuclei per testis in F1 males. The pattern of hormonal responses seen in this study was characteristic of an estrogen receptor agonist such as 17 beta-estradiol: increased serum prolactin and decreased testosterone, luteinizing hormone, and follicle stimulating hormone levels. The data demonstrate that in utero and postnatal dietary administration of 17 beta-estradiol at levels which increased serum estradiol levels to approximately 400% of control and decreased testosterone levels to 33% of control did not reduce the number of Sertoli cell nuclei per testis.

Animals↗
PubMed1998

Sensitivity of a Tier I screening battery compared to an in utero exposure for detecting the estrogen receptor agonist 17 beta-estradiol.

A Tier I screening battery for detecting endocrine active compounds (EACs) has been evaluated for its ability to identify 17 beta-estradiol, a pure estrogen receptor agonist. In addition, the responses obtained with the Tier I battery were compared to the responses obtained from F1 generation rats from a 90-day/one-generation reproduction study with 17 beta-estradiol in order to characterize the sensitivity of the Tier I battery against the sensitivity of an in utero exposure for detecting EACs. The Tier I battery incorporates two short-term in vivo tests (5-day ovariectomized female battery; 15-day intact male battery) and an in vitro yeast transactivation system (YTS) for identifying compounds that alter endocrine homeostasis. The Tier I female battery consists of traditional uterotrophic endpoints coupled with biochemical and hormonal endpoints. It is designed to identify compounds that are estrogenic/antiestrogenic or modulate dopamine levels. The Tier I male battery consists of organ weights coupled with microscopic evaluations and a comprehensive hormonal assessment. It is designed to identify compounds that have the potential to act as agonists or antagonists to the estrogen, androgen, progesterone, or dopamine receptor; steroid biosynthesis inhibitors (aromatase, 5 alpha-reductase, and testosterone biosynthesis); or compounds that alter thyroid function. The YTS is designed to identify compounds that bind to steroid hormone receptors (estrogen, androgen, and progesterone) and activate gene transcription. The profile generated for 17 beta-estradiol was characteristic of the responses expected with a pure estrogen receptor agonist. In the female battery, responses to 17 beta-estradiol included increases in uterine fluid imbibition, uterine weight, estrus conversion, uterine stromal cell proliferation, uterine epithelial cell height, uterine progesterone receptor content, serum prolactin and estradiol levels, and decreases in uterine estrogen receptor content and follicle stimulating hormone and luteinizing hormone levels. In the male battery, responses to 17 beta-estradiol included decreases in absolute testis and epididymides weights, decreases in relative weights for androgen-dependent tissues (prostate, seminal vesicles, and accessory sex gland unit), hormonal alterations (decreased serum testosterone, dihydrotestosterone, and LH and increased serum prolactin levels), and microscopic alterations of the testis and epididymides. In the YTS for the estrogen receptor, 17 beta-estradiol had an EC50 value of 7.2 x 10(-9) M, while DHT and progesterone had little cross-activation. The androgen and progesterone receptor systems were less selective in that 17 beta-estradiol activated these systems within 3 orders of magnitude of the primary ligand. In the 90-day/one-generation reproduction study, responses to dietary administration of 17 beta-estradiol included alterations in organ weights, developmental landmarks, and hormonal levels. Comparison of the responses obtained with our Tier I battery and an in utero exposure demonstrates that the Tier I screening battery is as sensitive as an in utero exposure for detecting 17 beta-estradiol-induced alterations in hormonal homeostasis.

Animals↗
PubMed2005

Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER(+) breast cancer cells.

Postmenopausal women with estrogen receptor positive (ER(+)) breast cancer frequently respond paradoxically to estrogen administration with tumor regression. Using both LTED and E8CASS cells derived from MCF-7 breast cancer cells by long-term estrogen-deprivation, we previously reported that 17beta -estradiol (estradiol) is a powerful, pro-apoptotic hormone which kills the cancer cells through activation of the Fas/FasL death receptor pathway. We postulated that the mitochondrial interactive protein Bcl-2 might play a role in the regulation of estradiol-induced apoptosis in both LTED and E8CASS cells. In this study, we assessed estradiol effects on cell growth, proliferation and apoptosis. Additionally we investigated the effect of estradiol on caspase activation, NF-KB and Bcl-2 expression. The functional role of Bcl-2 in estradiol-induced apoptosis was further studied by knockdown or decrease of Bcl-2 with siRNA. Our results show that estradiol significantly inhibited cell growth primarily through a pro-apoptotic action involving caspase-7 and 9 activations (p < 0.01). Basal Bcl-2 and NF-KB levels were greatly elevated and estradiol decreased NF-KB, but not Bcl-2 expression. Knockdown of Bcl-2 expression with siRNA decreased the levels of this protein by 9 fold (p < 0.01). This reduction markedly sensitized both LTED and E8CASS cells to the pro-apoptotic action of estradiol, leading to a synergistic induction of apoptosis and a concomitant reduction in cell number (p < 0.01). Therefore, down-regulation of Bcl-2 synergistically enhanced estradiol-induced apoptosis in ER(+) postmenopausal breast cancer cells.

Apoptosis↗
PubMed1988

Influence of preovulatory estradiol concentration on diurnal and pulsatile prolactin secretion patterns.

We evaluated the effect of preovulatory concentrations of estradiol on the 24-hour profile of prolactin secretion in women with regular menstrual cycles. An estradiol preparation was chosen to allow comparison with physiologic events. Estradiol benzoate, 1 mg intramuscularly, was administered for 7 days to achieve estradiol concentrations just above preovulatory levels (424 +/- 54 pg/ml); 24-hour mean prolactin concentrations increased threefold (14.0 +/- 2.1 to 40.6 +/- 7.1 ng/ml). Prolactin pulse frequency increased significantly (p less than 0.001) during waking hours after estradiol benzoate administration. The diurnal pattern of prolactin secretion was maintained with estradiol benzoate, although the sleep acrophase often reached high concentrations (86 +/- 11 ng/ml). These results suggest in women with regular menstrual cycles: (1) that estrogen administration that achieves slightly greater than preovulatory estradiol concentrations can stimulate prolactin release, (2) that estradiol may elevate prolactin by increasing its pulsatile secretion, (3) that estradiol does not alter the diurnal pattern of prolactin secretion, (4) that estradiol concentrations just above preovulatory levels can be associated with markedly elevated prolactin concentrations.

Adult↗
PubMed1987

Induction of zinc-thionein by estradiol and protective effects on inorganic mercury-induced renal toxicity.

The castrated or unoperated male rats received an intravenous injection of HgCl2 at a dose of 0.7 mg/kg of body weight (b.w.) after pretreatment with 30% ethanol or estradiol dissolved in 30% ethanol at a dose of 0.5 mg/kg b.w. subcutaneously twice a day for six consecutive days. Renal total protein, gamma-GTP and K excretion in the rats treated with Hg and estradiol were significantly lower than the corresponding values in the rats treated with Hg alone, suggesting that pretreatment with estradiol ameliorates the renal toxicity of Hg in male rats. Pretreatment with estradiol significantly increased Hg and Hg-thionein(Hg-MT) concentrations in the renal cortex of the animals treated with Hg, though in the liver this agent did increase the Hg-MT without elevation of Hg concentration. Treatment with estradiol alone (0.5 mg/kg, s.c., twice a day, for six consecutive days) significantly increased the zinc-thionein (Zn-MT) concentration in the kidney and liver. Simultaneous treatment with 10(-5) M estradiol and Hg in human amniotic-fluid cells caused a significant increase in the uptake of Hg and the synthesis of Hg-MT, suggesting that estradiol may directly stimulate an accumulation of Hg into the cells and the synthesis of Hg-MT. Together, all of the above findings suggest that pretreatment with estradiol may increase the uptake of Hg, which in turn leads to the increase in the Hg-MT concentration. The induction of Zn-MT by pretreatment with estradiol may account for the protective effect of estradiol on Hg-induced renal toxicity.

Animals↗
PubMed1994

Studies on a vaginal ring releasing levonorgestrel at an initial rate of 27 micrograms/24 h when used alone or in combination with transdermal systems releasing estradiol.

Vaginal rings releasing levonorgestrel (L-NOG) at an initial rate of 27 micrograms/24h were studied in a group of 24 normally menstruating women during three months (i.e., during three four-week segments). Each segment consisted of three weeks with the vaginal rings in situ followed by a treatment-free period of one week. The women were divided into three groups (8 subjects each). The first group received vaginal rings only, the second and third groups were treated, in addition, with transdermal systems (patches) releasing estradiol at a rate of 50 and 100 micrograms/24h, respectively. Peripheral blood samples were withdrawn three times weekly (Monday, Wednesday and Friday) during a pretreatment cycle and during the following three months of treatment. The levels of L-NOG, estradiol and progesterone were analyzed by radioimmunoassay techniques. In all subjects, endometrial biopsies were taken in a control cycle and during the last days with vaginal rings in situ in segments II and III. The treatment with estradiol did not significantly influence L-NOG levels. Considerable differences in the L-NOG levels between the subjects of the same group were observed. Fluctuation in ovarian reaction within groups was also large. Nevertheless, estradiol noticeably increased the proportion of anovulatory cycles; the total number of anovulatory segments was 5, 9 and 19 (out of 24) in the groups "No estradiol", "50 micrograms/24h estradiol" and "100 micrograms/24h estradiol", respectively. A morphometric study of the endometrium indicated a significant decrease in the diameter of glands. This change was due to L-NOG alone, but it seemed to be accentuated by the exogenous estradiol. The occurrence of glandular mitoses increased in both groups receiving estradiol in a dose-dependent manner, indicating an increased endometrial proliferation. The treatment with estradiol did not significantly alter the bleeding pattern.

Administration, Cutaneous↗
PubMed1991

Effects of ethinyl estradiol on isoproterenol-induced death in ventricular fibrillation in DOCA-salt pretreated male and female rats.

To assess the effects of ethinyl estradiol on the incidence of death in ventricular fibrillation induced by isoproterenol in DOCA-salt pretreated rats we implanted male and female rats simultaneously with a 20 mg DOCA pellet and pellets containing either ethinyl estradiol or vehicle (wax). Rats drank saline after implantation. After 6 days rats were challenged with a single, sc dose of 150 micrograms of isoproterenol. The average daily dose of estradiol per rat was estimated on the basis of the quantity of pellet lost during 6 days. In male rats the average daily dose of 61.2 +/- 20.2 micrograms/rat of ethinyl estradiol decreased the incidence of mortality by 80%, from 73.3% (11/15) in vehicle treated to 13.3% (2/15) in estradiol treated rats. Death occurred within 19.2 +/- 8.0 minutes from the injection of isoproterenol and was due to ventricular fibrillation. Serum levels of magnesium and potassium were comparable in the two groups both before and after isoproterenol. Isoproterenol induced death in 9 of 11 DOCA-salt pretreated, ovariectomized rats within 22.3 +/- 9.8 minutes. Only 3 of 11 DOCA-salt ovariectomized rats receiving the average daily dose of 28.4 +/- 12.1 micrograms/rat of ethinyl estradiol died. None of 10 ovariectomized untreated rats died from isoproterenol challenge. Serum levels of magnesium and potassium were comparable in the estradiol and vehicle treated groups. The average daily dose of 2.8 +/- 0.42 micrograms/rat of ethinyl estradiol elicited uterine growth but did not influence the incidence of mortality, since 9 out of 16 and 10 out of 16 rats died following isoproterenol in vehicle and estradiol treated DOCA-salt ovariectomized rats. We conclude that only pharmacological doses of estradiol exert protective effects against DOCA-salt induced myocardial sensitization to isoproterenol and that this protection is not associated with relevant changes in serum potassium or magnesium.

Animals↗
PubMed1995

Interaction of male sensory cues and estradiol in the induction of estrus in the prairie vole.

In the prairie vole, estrus and ovulation are induced by stimulation from a male, which also increases the female's gonadal weight and serum estradiol level. It is not known whether the induction of receptivity is dependent solely on an endogenous increase in circulating estradiol or an interaction of increased estradiol and male sensory stimulation. Using a dose response paradigm, we examined if a dose of estradiol within physiological range was sufficient to induce receptivity. We also examined if extended male contact could induce receptivity in ovariectomized females tested either without estradiol replacement or with a subthreshold dose of estradiol. We found that elevating blood levels of estradiol to those found during estrus was sufficient to induce sexual receptivity; male contact was not necessary. Extended male cohabitation did induce estrus in ovariectomized females treated with a subthreshold dose of estradiol, a dose which without male contact did not support sexual receptivity. In these same females, the extended male contact elevated circulating estradiol levels; the source of the estradiol is unknown.

Animals↗
PubMed1976

The effect of a synthetic steroid (trienbolone) on the rate of release and excretion of subcutaneously administered estradiol in calves (18).

With the objective of obtaining values for the rate of release and excretion of subcutaneously implanted estradiol and to relate them to the metabolic effect of the hormone, a study was carried out with young Jersey bull calves. After subcutaneous administration of lactose tablets (implants) containing tritiated estradiol (4 mCi in 20 mg estradiol) the activity was followed in plasma, urine and feces for 107 days. Three calves received implants containing 140 mg trienbolone in addition to the 20 mg estradiol. In the first group maximum plasma concentration of estradiol-17 beta was 3 nmol/1. In the other group it was only 0.33 nmol/1. In calves receiving estradiol as the only steroid, 95% of the activity was excreted within 20 days after implantation. In the other group collection of urine and feces had to be carried out for 107 days in order to account for all the implanted activity. No 3H could be detected in urine and feces samples collected from the estradiol group more than 31 days ater implantation. The feces and urine samples collected from calves in the estradiol-trienbolone group 107 days after implantation contained from 1.4 - 3 nCi per gram. The remarkably decreasing effect of trienbolone on the release of estradiol and its possible importance for the effect of subcutaneously administered estradiol are discussed.

Anabolic Agents↗