Administration Of Ethinyl Estradiol Research Articles

INKT17 cells play a pathogenic role in ethinylestradiol-induced cholestatic hepatotoxicity.

IL-17 is closely associated with inflammation in intrahepatic cholestasis (IHC). Targeting IL-17 ameliorates IHC in mice. Invariant natural killer T (iNKT) cells are predominantly enriched in the liver and they mediate drug-induced liver injury through their secreted cytokines. However, whether iNKT17 cells are involved in ethinylestradiol (EE)-induced IHC remains unclear. In the present study, the administration of EE (10mg/kg in vivo and 6.25μM in vitro) promoted the activation and expansion of iNKT17 cells, which contributed to a novel hepatic iNKT17/Treg imbalance. iNKT cell-deficient Jα18-/- mice and the RORγt inhibitor digoxin (20μg) alleviated EE-induced cholestatic hepatotoxicity and downregulated the IL-17 signalling pathway. In contrast, the co-administration of EE with recombinant IL-17 (1μg) to Jα18-/- mice induced cholestatic hepatotoxicity and increased the infiltration of hepatic neutrophils and monocytes. Importantly, the administration of IL-17-/- iNKT cells (3.5 × 105) to Jα18-/- mice resulted in the attenuation of hepatotoxicity and the recruitment of fewer hepatic neutrophils and monocytes than the adoptive transfer of wild-type iNKT cells. These results indicated that iNKT17 cells couldexert pathogenic effects. The recruitment and activation of iNKT17 cells could be attributed to the high level of CXCR3 expression on their surface. CXCL10 deficiency ameliorated EE-induced cholestatic liver damage, reduced hepatic CXCR3+ iNKT cells and inhibited RORγt expression. These findings suggest that iNKT17 cells play a key role in EE-induced cholestatic liver injury via CXCR3-mediated recruitment and activation. Our study provides new insights and therapeutic targets for cholestatic diseases.

Activation of natural killer T cells contributes to Th1 bias in the murine liver after 14 d of ethinylestradiol exposure

BACKGROUNDAs the main component of oral contraceptives (OCs), ethinylestradiol (EE) has been widely applied as a model drug to induce murine intrahepatic cholestasis. The clinical counterpart of EE-induced cholestasis includes women who are taking OCs, sex hormone replacement therapy, and susceptible pregnant women. Taking intrahepatic cholestasis of pregnancy (ICP) as an example, ICP consumes the medical system due to its high-risk fetal burden and the impotency of ursodeoxycholic acid in reducing adverse perinatal outcomes.AIMTo explore the mechanisms and therapeutic strategies of EE-induced cholestasis based on the liver immune microenvironment. METHODSMale C57BL/6J mice or invariant natural killer T (iNKT) cell deficiency (Jα18-/- mice) were administered with EE (10 mg/kg, subcutaneous) for 14 d.RESULTSBoth Th1 and Th2 cytokines produced by NKT cells increased in the liver skewing toward a Th1 bias. The expression of the chemokine/chemokine receptor Cxcr6/Cxcl16, toll-like receptors, Ras/Rad, and PI3K/Bad signaling was upregulated after EE administration. EE also influenced bile acid synthase Cyp7a1, Cyp8b1, and tight junctions ZO-1 and Occludin, which might be associated with EE-induced cholestasis. iNKT cell deficiency (Jα18-/- mice) robustly alleviated cholestatic liver damage and lowered the expression of the abovementioned signaling pathways.CONCLUSIONHepatic NKT cells play a pathogenic role in EE-induced intrahepatic cholestasis. Our research improves the understanding of intrahepatic cholestasis by revealing the hepatic immune microenvironment and also provides a potential clinical treatment by regulating iNKT cells.

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats.

Multidrug resistance-associated protein 2 (Mrp2) mediates biliary secretion of anionic endobiotics and xenobiotics. Genetic alteration of Mrp2 leads to conjugated hyperbilirubinemia and predisposes to the development of intrahepatic cholestasis of pregnancy (ICP), characterized by increased plasma bile acids (BAs) due to mechanisms that are incompletely understood. Therefore, this study aimed to characterize BA metabolomics during experimental Mrp2 deficiency and ICP. ICP was modeled by ethinylestradiol (EE) administration to Mrp2-deficient (TR) rats and their wild-type (WT) controls. Spectra of BAs were analyzed in plasma, bile, and stool using an advanced liquid chromatography–mass spectrometry (LC–MS) method. Changes in BA-related genes and proteins were analyzed in the liver and intestine. Vehicle-administered TR rats demonstrated higher plasma BA concentrations consistent with reduced BA biliary secretion and increased BA efflux from hepatocytes to blood via upregulated multidrug resistance-associated protein 3 (Mrp3) and multidrug resistance-associated protein 4 (Mrp4) transporters. TR rats also showed a decrease in intestinal BA reabsorption due to reduced ileal sodium/bile acid cotransporter (Asbt) expression. Analysis of regulatory mechanisms indicated that activation of the hepatic constitutive androstane receptor (CAR)-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by accumulating bilirubin may be responsible for changes in BA metabolomics in TR rats. Ethinylestradiol administration to TR rats further increased plasma BA concentrations as a result of reduced BA uptake and increased efflux via reduced Slco1a1 and upregulated Mrp4 transporters. These results demonstrate that Mrp2-deficient organism is more sensitive to estrogen-induced cholestasis. Inherited deficiency in Mrp2 is associated with activation of Mrp3 and Mrp4 proteins, which is further accentuated by increased estrogen. Bile acid monitoring is therefore highly desirable in pregnant women with conjugated hyperbilirubinemia for early detection of intrahepatic cholestasis.

Pubertal induction in girls with Turner Syndrome.

Turner Syndrome (TS) is the most common female sex chromosome aneuploidy in females, and patients may present with hypergonadotropic hypogonadism due to gonadal dysgenesis. Timing and modalities of pubertal induction in these patients is still a matter of debate. Aim of this review was to focus on the latest update on pubertal induction in TS. Based on literature data, the following practical approach to this issue is recommended. Pubertal induction should begin between 11 and 12 years of age, starting with low doses of estradiol to preserve height potential. Transdermal 17β-Estradiol (17β-E2) could represent the first-choice induction regimen as it is more physiologic compared to an oral regimen and avoids the first-pass mechanism in the liver. In the case of poor compliance, administration of oral 17β-E2 or ethinyl estradiol could be offered. Incremental dose increases, approximately every 6 months, can contribute to mimic normal pubertal progression until adult dosing is reached over a 2- to 3-year period. Progestin should be added once breakthrough bleeding occurs or after 2 to 3 years of estrogen therapy or if ultrasound shows a mature uterus with thick endometrium. Treatment needs to be individualized and monitored by clinical assessment in relation to patient compliance and satisfaction. Well-designed prospective randomized clinical trials aimed to identify the best estrogen regimen for pubertal induction in TS girls are needed.

Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice

Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.

Pubertal induction in girls with Turner syndrome

Turner Syndrome (TS) is the most common female sex chromosome aneuploidy in females, and patients may present with hypergonadotropic hypogonadism due to gonadal dysgenesis. Timing and modalities of pubertal induction in these patients is still a matter of debate. Aim of this review was to focus on the latest update on pubertal induction in TS. Based on literature data, the following practical approach to this issue is recommended. Pubertal induction should begin between 11 and 12 years of age, starting with low doses of estradiol to preserve height potential. Transdermal 17β-Estradiol (17β-E2) could represent the first-choice induction regimen as it is more physiologic compared to an oral regimen and avoids the first-pass mechanism in the liver. In the case of poor compliance, administration of oral 17β-E2 or ethinyl estradiol could be offered. Incremental dose increases, approximately every 6 months, can contribute to mimic normal pubertal progression until adult dosing is reached over a 2- to 3-year period. Progestin should be added once breakthrough bleeding occurs or after 2 to 3 years of estrogen therapy or if ultrasound shows a mature uterus with thick endometrium. Treatment needs to be individualized and monitored by clinical assessment in relation to patient compliance and satisfaction. Well-designed prospective randomized clinical trials aimed to identify the best estrogen regimen for pubertal induction in TS girls are needed.

Comparative pharmacokinetic estimates of drospirenone alone and in combination with ethinyl estradiol after single and repeated oral administration in healthy females

ObjectiveTo determine the pharmacokinetics (PK) of drospirenone (DRSP), alone versus in combination with ethinyl estradiol (EE), after single and repeated administration. Study designWe conducted a single-centre, open-label, crossover, 2-treatment, 2-period, 2-sequence study in which non-micronized DRSP 4 mg or a combination of DRSP 3 mg and EE 0.02 mg were administered to healthy female subjects on day 1 to obtain a single-dose kinetic profile, and from day 4 to day 15 to obtain a repeated-dose kinetic profile. The maximum observed concentration (Cmax) and area under the concentration/time curve (AUC) were determined in a model-independent way using non dose corrected data. Statistical analysis was based on a parametric method (ANOVA-log). ResultsA total of 24 healthy female subjects were randomized 1:1 into the study. The mean relative, non-dose-corrected PK estimates after single-dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 543.5 ng*h/mL, 296.1 ng*h/mL and 27.3 ng/mL for DRSP alone, and 442.0 ng*h/mL, 264.7 ng*h/mL and 37.5 ng/mL for the DRSP/EE combination; p < 0.001. The mean relative, non-dose-corrected PK estimates after repeated dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 1066.8 ng*h/ml, 570.2 ng*h/mL and 41.0 ng/mL for DRSP alone, and 1394.5 ng*h/mL, 732.8 ng*h/mL and 61.4 ng/mL for the DRSP/EE combination; p < 0.001. ConclusionsDRSP alone exhibits a lower accumulation ratio than together with EE. The extent of systemic exposure at steady-state is about 32% less with the new formulation (AUC(0-24h), steady-state geometric mean ratio: 77.8%; 90% confidence interval: 74.6%–81.1%). This PK profile may be caused by EE. ImplicationsOur results suggest that metabolic pathways of DRSP can be inhibited by EE resulting in higher DRSP plasma concentrations in DRSP/EE formulations than in a DRSP-alone formulation. The enzymes CYP3A4 and SULT1A1 may play a role. Additional drug-drug-interaction studies are needed to better understand these metabolic pathways and their future clinical implications.

Evaluation of folic acid supplementation by concomitant administration of ethinyl estradiol + levonorgestrel in healthy female subjects .

Folic acid supplementation prevents 50-75% of cases of neural tube defects. This study evaluated the folic acid supplementation after oral administration of the ethinyl estradiol 0.02 mg + levonorgestrel 0.10 mg + folic acid 0.4 mg coated tablet as well as its safety and tolerability in healthy female subjects. 36 healthy female subjects received 1 coated tablet of the test product - ethinyl estradiol 0.02mg + levonorgestrel 0.10mg + folic acid 0.4mg for 21days and a placebo coated tablet containing folic acid 0.4mg only on the last 7days of the cycle, in 3 cycles. Blood samples were collected to quantify folate by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The safety was assessed by recording adverse events, monitoring of vital signs, and the evaluation of laboratory tests and ECG. The mean whole blood level of folic acid at baseline (1st day of 1st cycle) was 42.7±22.2ng/mL, while on the 28th day of the 3rd cycle it was 47.6±20.1ng/mL, with a variation of 11.32%. The subjects tolerated the clinical protocol well and reported no clinically significant adverse effects. Oral contraceptives may be a good vehicle for folate supplementation in women of reproductive age.

Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance

Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 μg EE and 60 μg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperinsulinemia and lower plasma C-peptide/insulin ratio, indicating reduced insulin clearance. Furthermore, COC mice displayed reduced protein content of the β subunit of the insulin receptor (IRβ) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperinsulinemia, due to enhancement of insulin secretion and the reduction of insulin degradation, which possibly lead to the down-regulation of hepatic IRβ. These findings suggest that the continuous administration of COC could cause insulin resistance with the prolongation of treatment.

Comparison of Endometrial Thickness with Concomitant Administration of Sildenafil Citrate and Ethinyl Estradiol vs Ethinyl Estradiol Alone for Frozen Embryo Transfer

Introduction: Infertility is one of the common medical issues in today's world. One of the common causes of infertility is the lack of implantation of the embryo. Aim: To compare the effect of Ethinyl Estradiol (E2) alone on Endometrial Thickness (ET) with that of sildenafil citrate and E2 combination. Materials and Methods: In this clinical trial, 70 infertile women undergoing treatment with Assisted Reproductive Techniques (ARTs) were randomly divided into two groups of 35 each. One group received E2 and vaginal sildenafil and the other E2 alone. On the seventh day of the cycle and, if necessary, until ET reached 8 mm, ET in both groups was measured by transvaginal ultrasound. After the embryo transfer, Beta-Human Chorionic Gonadotropin (BHCG) was performed in both groups. The measured thickness of uterus and BHCG were recorded in the checklist for both groups. Data were analysed by SPSS and p<0.05 was considered significant. Results: The mean duration (in days) to reach an 8 mm ET in infertile women in the E2+sildenafil group (13.59 +/- 3.07) was lower than that in the E2 group (14.88 +/- 4.78), yet insignificant (p=0.21). Although the mean dose (mg) of E2 and duration (day) to reach an 8 mm ET in the E2+ sildenafil group was lower than those in the E2 group, significance (p) levels were 0.02 and 0.21, respectively. Conclusion: In infertile women undergoing ARTs, co-administration of sildenafil citrate and E2 increased ET relatively and reduced the dose of E2 and the duration of its administration.

The Modulatory Effects of Pentoxifylline in Biochemical Changes Induced By 17α-Ethinyl Estradiol in the Rat Model

Background: Ethinylestradiol (EE) has induced cholestasis and hepatotoxicity in animal studies through reducing bile acid uptake by hepatocytes and induce of oxidative stress. Pentoxifylline (PTX) is a drug that by inhibition of release or transcription of proinflammatory cytokine cause prevents oxidative stress of liver cell and reduction of damage. We aimed to evaluate the effects of pentoxifylline on liver injury induced by Ethinylestradiol in rats. Methods: Twenty-four female Wistar rats (300±20 gr) were divided into four groups, equally. Duration of treatment was 5 consecutive days for each group. The control group Simultaneously received orally and subcutaneously normal saline. PTX group Simultaneously received Pentoxifylline orally and normal saline subcutaneously, EE Group Simultaneously received EE subcutaneously and normal saline orally. In the EE+PTX group, rats Simultaneously received EE subcutaneously and PTX orally. Rats were anesthetized and blood and tissue samples were collected for measurement of hematological and biochemical parameters. Results: The EE administration increased the serum levels of ALP and MDA significantly. The EE administration also decreased albumin and GPX levels were significant. These aberrations were improved by PTX treatment in EE + PTX group. Most of hematological parameters were not significant by the EE. The plasma level of TNF- in the PTX+ES treated group showed a significant decrease in comparison to that in the ethinyl estradiol group. Conclusion: PTX has partial capacity to protect against liver changes induced by Ethinyl Estradiol.

Blood pressure predicts endothelial function and the effects of ethinyl estradiol exposure in young women.

Hypertension, obesity, and endothelial function predict cardiovascular disease in women, and these factors are interrelated. We hypothesized that hypertension and obesity are associated with endothelial dysfunction in young women and that short-term ethinyl estradiol exposure mitigates this dysfunction. We examined flow-mediated dilation (FMD) responses before and during 7 days of oral ethinyl estradiol (30 µg/day) in 19 women (25 ± 5, 18-35 yr). We divided our sample into two groups based on two criteria: blood pressure and obesity. Women were divided into normal blood pressure (NBP; mean arterial pressure range: 78-91 mmHg, n = 7) and high blood pressure (HBP; mean arterial pressure range: 95-113 mmHg, n = 9) groups. We also stratified our subjects by body composition (lean: 18-31%, n = 8; obese: 38-59%, n = 9). We evaluated brachial FMD after two distinct shear stress stimuli: occlusion alone and occlusion with ischemic handgrip exercise. Obesity was unrelated to both FMD responses. Before ethinyl estradiol administration, the HBP group had blunted ischemic exercise responses relative to the NBP group (8.0 ± 3.5 vs. 12.3 ± 3.2%, respectively, P = 0.05). However, during ethinyl estradiol administration, ischemic exercise responses increased in the HBP group (12.8 ± 6.1%, P = 0.04) but decreased in the NBP group (5.6 ± 2.4%, P = 0.01). Standard FMD did not reveal differences between groups. In summary, 1) moderate HBP predicted endothelial impairment, 2) ethinyl estradiol administration had divergent effects on FMD in women with NBP versus HBP, and 3) enhanced FMD (ischemic handgrip exercise) revealed differences in endothelial function, whereas standard FMD (occlusion alone) did not. NEW & NOTEWORTHY We are the first to show that mild hypertension is a stronger predictor of endothelial dysfunction than obesity in healthy women without overt cardiovascular dysfunction. Importantly, the standard 5-min flow-mediated vasodilation stimulus did not detect endothelial dysfunction in our healthy population; only an enhanced ischemic handgrip exercise shear stress stimulus detected endothelial impairment. Estradiol administration increased flow-mediated dilation in women with high blood pressure, so it may be a therapeutic intervention to improve endothelial function.

POTENTIAL OF ACEH ARABICA COFFEE EXTRACT (Coffea arabica L.) IN REJUVENATION OF AGING SKIN IN RAT

This study aimed to u determine the potency of Aceh Arabica coffee In rejuvenation of aging skin in rat. This study was conducted in vivousing completely randomized design (RAL), which consisted of 4 treatment groups as follows: premenopausal rats as negative control (KON),premenopausal rats with administration of distilled water as placebo (PLS), premenopausal rats with administration of ethinylestradiol 9x10-3mg/day/200 g BW (EST), and premenopausal rats with coffee extract administration of 300 mg/day/200 g BW (KOP). Each treatment groupconsisted of 5 rats. The parameters observed were skin collagen, water content/skin hydration, and skin ribonucleic acid (RNA) level. The datawere analyzed using analysis of variance (ANOVA) and Duncan test using SAS 9.13 software. The result showed the average skin collagen andRNA levels were higher in premenopausal rats with administration of coffee extract and ethinylestradiol (P&lt;0.05) than control rats. On the otherhand, average of water level in premenopausal rats with coffee extract and ethinylestradiol administration were the same as control rats. It can beconcluded that administration of Aceh Arabica coffee extract can repair skin quality, which is indicated by the increase of collagen and RNAlevel on aging skin in rat.

A Single Neonatal Injection of Ethinyl Estradiol Impairs Passive Avoidance Learning and Reduces Expression of Estrogen Receptor α in the Hippocampus and Cortex of Adult Female Rats.

Although perinatal exposure of female rats to estrogenic compounds produces irreversible changes in brain function, it is still unclear how the amount and timing of exposure to those substances affect learning function, or if exposure alters estrogen receptor α (ERα) expression in the hippocampus and cortex. In adult female rats, we investigated the effects of neonatal exposure to a model estrogenic compound, ethinyl estradiol (EE), on passive avoidance learning and ERα expression. Female Wistar-Imamichi rats were subcutaneously injected with oil, 0.02 mg/kg EE, 2 mg/kg EE, or 20 mg/kg 17β-estradiol within 24 h after birth. All females were tested for passive avoidance learning at the age of 6 weeks. Neonatal 0.02 mg/kg EE administration significantly disrupted passive avoidance compared with oil treatment in gonadally intact females. In a second experiment, another set of experimental females, treated as described above, was ovariectomized under pentobarbital anesthesia at 10 weeks of age. At 15–17 weeks of age, half of each group received a subcutaneous injection of 5 μg estradiol benzoate a day before the passive avoidance learning test. Passive avoidance learning behavior was impaired by the 0.02 mg/kg EE dose, but notably only in the estradiol benzoate-injected group. At 17–19 weeks of age, hippocampal and cortical samples were collected from rats with or without the 5 μg estradiol benzoate injection, and western blots used to determine ERα expression. A significant decrease in ERα expression was observed in the hippocampus of the estradiol-injected, neonatal EE-treated females. The results demonstrated that exposure to EE immediately after birth decreased learning ability in adult female rats, and that this may be at least partly mediated by the decreased expression of ERα in the hippocampus.

Mechanism of Action of the Aqueous Leaves Extract of Sarcocephalus latifolius (Smith) on the Reproductive System of Female Rat

Prized for its many therapeutic virtues, Sarcocephalus latifolius (Smith) is a rubiaceae whose roots alone or in combination with the leaves are used in the treatment of infertility and genital diseases. In the search for mechanisms of action of natural substances, uterotrophic bioassay is essential and frequently used. Thus, ovariectomized impubere female rats received during 7 days, 250; 500 and 1000 mg/kg body weight of aqueous leaves extract of Sarcocephalus latifolius and 0, 02 mg/kg body weight (BW) ethinyl estradiol. Variation in animal body weight, vaginal opening, uterine horns, cervix and adrenal glands weights, as well as serum levels of proteins, cholesterol and glucose were assessed. Treatment of the animals at the different doses of extract produced no significant (p> 0.05) change in the parameters studied. Only the dose of 1000 mg / kg body weight extract induced a significant (p <0.001) vaginal opening. Administration of ethinyl estradiol to ovariectomized female rats resulted in a significant (p <0.001) reduction in body weight variation, serum protein and cholesterol levels, as well as a significant increase (p <0.001) in the vaginal opening, the uterine horns and cervix weights, and serum glucose. Similarly, the combination of ethinyl estradiol with the different doses of Sarcocephalus latifolius extract produced the same significant effects (p <0.001) as previously mentioned in the treated female rats compared to the controls. However, only the variation in body weight, vaginal opening and serum cholesterol levels in these animals decreased significantly (p <0.05, p <0.01 and p <0.001) with regard to those treated with ethinyl estradiol. These results would assume that the aqueous extract of leaves of Sarcocephalus latifolius would possess estrogen-like properties or would act on the hypothalamic-pituitary-gonadal axis.

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&lt;p&gt;FEATURES OF FREE RADICAL OXIDATION AND ANTIOXIDANT SYSTEM PARAMETRS OF ANIMALS AT ACUTE TOXIC AND SUBCHRONIC POISONING BY ACETAMINOPHEN WITH PROLONGED USAGE OF ESTROGEN AND PROGESTIN AT THE CORRECTION BY THIOTRIAZOLINE AND HEPADIF&lt;/p&gt;&lt;p align="center"&gt;I.B. Ivanusa&lt;/p&gt;&lt;p align="center"&gt;TernopilStateMedicalUniversity&lt;/p&gt;&lt;p&gt; &lt;/p&gt;&lt;p&gt;Activation of lipid peroxidation of animals at poisoning by acetaminophen with prolonged usage of estrogen and progestin are investigated. This is evidenced by increased concentration of reactive oxygen species by mononuclear leukocytes, the content of lipid peroxidation products: malondialdehyde, diene and triene conjugates. The ability of the corrective factors inhibits the formation of these products in the plasma and homogenate can indirectly evidenced about the antioxidant properties of the drug. So it is interested to investigate the influence of thiotriazoline and hepadif on activity of these processes in rats, which are poisoned by acetaminophen with prolonged usage of estrogen and progestin.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;&lt;p&gt;KEY WORDS: acetaminophen, thiotriazoline, hepadif, free radical oxidation of lipids and proteins, antioxidant system.&lt;/p&gt;&lt;p&gt;INTRODUCTION. Acetaminophen is present in more than 200 drugs at various brand names. Almost all of them are used as analgesic and antipyretics. Poisoning may be at usages a big single dose of pure drug or combined drugs containing acetaminophen. Hepatoprotectors are one of the most widely using drugs for the treatment of liver diseases. These drugs are used for metabolism normalization, increase resistance to pathogenic factors, normalization of functional activity and stimulation of reparative - regenerative processes in the liver.&lt;/p&gt;&lt;p&gt;Therefore, we set a goal to investigate the effect of acetaminophen on parameters of free radical oxidation and antioxidant system of animals at poisoning by acetaminophen with prolonged usage of estrogen and progestin at the correction by Thiotriazoline and Hepadif.&lt;/p&gt;&lt;p&gt;INVESTIGATION METHODS. The experiments were performed on white female rats weighing 200 ±20 g, are kept on a standard diet of vivarium and free access to water.&lt;/p&gt;&lt;p&gt;We did three series of experiments. In the first experiment: toxic damage of rats caused by a single intragastric administration of acetaminophen suspension in 2% starch solution at a dose of 1250 mg/kg body weight (1/2 LD&lt;sub&gt;50&lt;/sub&gt;), the second - a suspension of acetaminophen in 2% starch solution at a dose of 55 mg/kg (highest therapeutic dose) is administered within 7 days. Levonorgestrel in 2% solution of starch is administered both series intragastric at a dose of 1.17 mg/kg, and ethinylestradiol - a dose of 0.23 mg/kg within 40 days. Thiotriazoline was injected intraperitoneally at a dose of 100 mg/kg; Hepadyf - intraperitoneally at a dose of 8.6 mg/kg.&lt;/p&gt;&lt;p&gt;In 1 series of experiments, the experimental rats were divided into 3 groups: 1st - intact (control); 2nd – poisoning by acetaminophen after 40-day administration of levonorgestrel and ethinylestradiol, 3rd - poisoning by acetaminophen after 40-days administration of levonorgestrel, ethinylestradiol and once Thiotriazoline administration.&lt;/p&gt;&lt;p&gt;In 2 series of experiments, the experimental rats were divided into 3 groups: 1st - intact (control); 2nd - rats with acetaminophen administration within 7 days after 40-day administration of levonorgestrel and ethinylestradiol, 3rd - poisoning by acetaminophen after 40-days administration of levonorgestrel, ethinylestradiol and 7-days Thiotriazoline administration.&lt;/p&gt;&lt;p&gt;In 3 series of experiments, the experimental rats were divided into 3 groups: 1st - intact (control); 2nd - rats with acetaminophen administration within 7 days after 40-day administration of levonorgestrel and ethinylestradiol, 3rd - poisoning by acetaminophen after 40-days administration of levonorgestrel, ethinylestradiol and 7-days Hepadif administration.&lt;/p&gt;&lt;p&gt;RESULTS AND DISCUSSION. Concentration of diene conjugates decreased in blood plasma of rats with single and 7-days administration of acetaminophen after 40-days administration of estrogen and progestin and Thiotriazoline administration. Decrease intensity generation of reactive oxygen by blood mononuclear leukocytes is observed at Hepadif action, and Hepadif almost neutralized its toxic effect at seven-times administration of acetaminophen at therapeutic doses. Concentration diene (respectively 2.8 and 2.6 times), and triene conjugates (3.7 and 3.2 times) decreased in plasma of affected animals. Similarly effect was in liver homogenate.&lt;/p&gt;&lt;p&gt;Amount of oxidized modified proteins in blood plasma and liver of affected animals decreased at correction of lesion by Thiotriazoline and Hepadif. The administration of corrective drugs is caused decrease of malonic aldehyde concentration in plasma and liver of affected rats. Peroxidase activity in blood at correction by Thiotriazoline decreased respectively on 159 and 162% compared with affected animals. Greater effect is observed at action of Hepadif, administration of which normalizated of the peroxidase activity of blood and concentration of ceruloplasmin. Administration of Thiotriazoline and Hepadif has protective effects on glutathione system.&lt;/p&gt;&lt;p&gt;CONCLUSIONS. Usage Thiotriazoline and Hepadif in rats with acetaminophen toxic damage against prolonged administration of estrogens and progestins inhibit reactive oxygen species formation by mononuclear leukocytes, decreas intensity of lipid peroxidation and protein, and normalization of enzyme and nonenzyme links of antioxidant system.&lt;/p&gt;

Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: Tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity

Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high injection doses of EE reduced the number of ChAt-immunoreactive cells in the basal forebrain, and cell population estimates in the vertical/diagonal bands negatively correlated with working memory errors.

Estrogenic Activity of Bauhinia racemosa Extract in Female Albino Rats: An Investigational Study

Bauhinia racemosa in female albino rats. Materials and Methods: Plant extracts were tested for their estrogenic activity using ovariectomized method at two dose level: 200 mg/kg and 400 mg/kg, respectively. Further, plant extracts and standard drug ethinyl estradiol (1 µg/kg) combination were tested for synergistic estrogenic activity. Results: In‑vivo investigation revealed that ethanol extract at dose of 200 mg/kg and 400 mg/kg shows significance increase 325.23 ± 5.23, 328.84 ± 4.56 and 3.252 ± 0.47, 3.288 ± 0.27 in uterine wet weight and uterine weight ratio, respectively, in female albino rat as compared to control and petroleum ether and water extracts. Simultaneous administration of standard drug ethinyl estradiol (1 µg/kg) with ethanol extract at dose of 200 mg/kg and 400 mg/kg potentiates (327.36 ± 5.78, 330.95 ± 6.21 and 3.273 ± 0.64, 3.309 ± 0.49 uterine wet weight and uterine weight ratio respectively in female albino rat) the estrogenic activity as compared to individual administration of ethanol extract as a synergistic effect. Conclusion: It was observed that ethanol extract of B. racemosa produced significance estrogenic activity.

The efficacy of ethinylestradiol for castration-resistant prostate cancer

We analyzed the efficacy of ethinylestradiol as estrogen therapy on Castration-resistant Prostate Cancer (CRPC). The study was conducted on 14 patients who were diagnosed as having CRPC and who were being prescribed ethinylestradiol (1.5-2.0 mg/day) with aspirin (100 mg/day) and an LH-RH agonist in our hospital from August 2011. All patients had already been treated with a combined androgen blockade (CAB), 8 patients had been treated with docetaxel, 9 patients with tegafur-uracil, 4 patients with estramustine phosphate sodium. Age and prostate-specific antigen (PSA) at prescription of ethinylestradiol was 55-85 (median 75.5) and 0.784-508.7 ng/ml (median 4.842 ng/ml). Thirteen patients (92.9%) achieved a decline in PSA, 8 patients (57.1%) achieved a decline in PSA > 50%. Time to progression was 0-18 months (median 7 months), and there were no severe adverse events including venous thromboembolic diseases. Oral ethinylestradiol administration may have efficacy for CRPC without severe adverse events. Ethinylestradiol may be one of the selective drugs for CRPC patients who do not wish to undergo intravenous chemotherapy or become resistant to docetaxel.

Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women

Objective To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women.Method Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3).Results In Studies 1 and 2, there was a linear dose-dependent increase in DRSP Cmax and systemic exposure across the range of doses used in both ethnic groups. The co- administration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation. There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC0–24h were 1.05 (90% CI: 0.95–1.17) and 1.02 (90% CI: 0.76–1.38), respectively.Conclusion Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE.