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At least 865 records · Page 48Linked to original sources
PubMed1984

Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins.

The pharmacokinetics of progesterone after oral administration were investigated. After a single dose of 100 mg, serum concentrations of progesterone around 50-60 nM and of 20 alpha-hydroxy-4-pregnene-3-one around 5-6 nM were recorded within 1-4 hours and elevated levels persisted for 8-12 hours. There were only minor changes in 17 alpha-hydroxyprogesterone concentrations and serum levels of androstenedione and cortisol were unaffected. A significant conversion of circulating progesterone into deoxy-corticosterone was demonstrated. During clinical treatment with oral progesterone the individual serum concentrations of this potent mineralocorticoid were closely correlated to the progesterone concentrations. This observation could be important as regards the etiology of certain clinical disorders characterized by fluid retention. According to competitive binding analyses there was no evidence that progesterone or medroxyprogesterone acetate could cause significant displacement of cortisol from corticosteroid-binding globulin during clinical treatment. The effects of natural and synthetic hormones upon subfractions of high density lipoprotein (HDL) cholesterol and liver proteins were followed in postmenopausal women during replacement therapy with various estrogen-progestogen combinations. The total serum cholesterol level was significantly reduced during treatment with all estrogen regimens. The concentrations of HDL cholesterol, HDL2 cholesterol, apolipoprotein A I and A II were increased in a dose-dependent pattern during unopposed estrogen therapy. The potency of 10 micrograms of ethinyl estradiol was estimated to be equivalent to 3-4 mg of estradiol valerate. Estrogen effects were significantly reversed by levonorgestrel 250 micrograms and also by medroxyprogesterone acetate 10 mg. During treatment with natural progesterone, no changes were recorded in HDL cholesterol or its subfractions. As compared with the lipoproteins, pregnancy zone protein and sex hormone binding globulin (SHBG) were found to be more sensitive to the alkylated than to the non-alkylated estrogen. Both levonorgestrel and medroxyprogesterone acetate clearly reduced SHBG levels after 3 months, whereas micronized progesterone had no such effect. While tamoxifen counteracted the therapeutic and metabolic effects of estrogen the sequential addition of estriol had no apparent influence. Unopposed estrogen treatment enhanced liver lecithin synthesis along pathway I, i.e. reduced the amount of stearic acid and increased the amount of palmitic acid. The effects were dose-dependent and no qualitative differences between ethinyl estradiol and estradiol valerate were recorded.

Administration, Oral↗
PubMed1998

Short-term results of transdermal estrogen replacement therapy in cardiovascular disease-free postmenopausal females with and without hypertension.

BACKGROUND: Many studies have shown that estrogen replacement with oral micronized 17 beta-estradiol reduces the risk of cardiovascular disease. The aim of the present study was to evaluate the efficacy of transdermal estrogen replacement therapy in improving the risk profile of cardiovascular disease in postmenopausal women. METHODS: Two hundred and fifty postmenopausal women were enrolled from the "Bene Essere Donna" Center and grouped according to the absence (Group I, n = 175; mean age 54.6 +/- 3.5) or presence of mild to moderate hypertension (Group II, n = 75; mean age 54.1 +/- 4.5). Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose and fibrinogen levels were tested in all women. The total study population was treated with estrogen replacement therapy for 12 months: hysterectomized women received 17 beta-estradiol (0.05 mg/die), while non-hysterectomized women received 17 beta-estradiol 0.05 mg/die plus 5 mg/die of medroxyprogesterone acetate for 12 days during every 28-day cycle. After 12 months, blood pressure and blood chemistry were measured as baseline. RESULTS: Total cholesterol, LDL cholesterol and glucose levels decreased in both groups. HDL cholesterol levels increased significantly only in the sub-group of Group II treated with estrogen plus progesterone. Triglycerides glucose and fibrinogen blood levels decreased in both groups. No cardiovascular events were recorded during the first year of follow-up. CONCLUSION: Transdermal estrogen replacement therapy should be considered as a therapeutic support in order to contrast the elevated cardiovascular risk in postmenopausal women.

Antihypertensive Agents↗
PubMed2005

Estrogens and glucocorticoids have opposing effects on the amount and latent activity of complement proteins in the rat uterus.

The mammalian uterus faces unique immunological challenges. It must nurture and protect the semiallogenic fetus from attack by the maternal immune system while guarding against infection by pathogens that compromise fetal and maternal health. Complement has recently been implicated in the etiology of pregnancy loss, but its regulation by steroid hormones and its role in host defense in the uterus are not clearly defined. Here we use biochemical, functional, and physiological assays to elucidate the regulation of complement proteins in the rat uterus. We demonstrate that estrogens (17 beta-estradiol) and glucocorticoids (dexamethasone) have major, but opposing, effects on the amount and latent activity of complement effectors in the uterus. Treatment with 17 beta-estradiol induced vasodilation and an increase in vascular permeability, which resulted in extravasation of plasma and complement into the uterus, rather than de novo complement biosynthesis. In vitro assays revealed that 17 beta-estradiol induced a potent bactericidal activity in uterine luminal fluid and that the antibacterial component was complement. These proinflammatory and immunomodulatory effects were evident within 4 h of treatment and were blocked by coadministration of dexamethasone. We also found that estrogen effects on the vasculature were mediated in part by activation of the contact system and bradykinin B1 receptors. These results indicate that complement plays a central role in innate immunity in the female reproductive tract and suggest that estrogens or glucocorticoids might be used therapeutically to enhance or inhibit complement-dependent processes in the uterus.

Animals↗
PubMed2005

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands.

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERalpha and ERbeta. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17beta-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERalpha-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERbeta-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERbeta agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERalpha-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

Adoptive Transfer↗
PubMedDate not supplied

Tetrahydrobiopterin improves vascular endothelial function in ovariectomized rats.

The goal of the present study is to investigate the role of tetrahydrobiopterin (BH4) in the vascular response in ovariectomized rats. Rats were randomly assigned to two groups: (1) sham group: sham-operated female rats, and (2) Ovx group: rats were ovariectomized. Our results have shown that the plasma 17 beta-estradiol levels in the Ovx group at the end of the experiment were significantly lower than in the sham group. Vasoreactivity assessed with intact aortic rings indicated that the phenylephrine-induced vasocontractile response to aortic rings from the Ovx group was greater than that of the sham group. In contrast, the vasodilator responses to acetylcholine and L-arginine (L-Arg) in the sham group were significantly greater than in the Ovx group. Differences in vasoreactivity in denuded aorta between the two groups were not noted. Moreover, exogenous BH4 significantly restored L-Arg-induced vasodilator responses in the Ovx group. However, this improvement effect was not found in the sham group. In addition, there were significant increases in superoxide anion production in aortic tissue and significant decreases in plasma nitric oxide levels in the Ovx group. Furthermore, BH4 contents in the aorta in the Ovx group were significantly decreased compared with the sham group. In conclusion, the present study demonstrates that the impairment of vascular reactivity was found in the ovariectomized rats. The possible mechanism of this defect may have resulted from the deficiency of available BH4. Thus, this study may provide a novel therapeutic strategy for the treatment of postmenopausal cardiovascular disorders.

Animals↗
PubMed2002

In vivo imaging of transcriptionally active estrogen receptors.

Through intracellular receptors, estrogens control growth, differentiation and function of not only reproductive tissues, but also other systems. Estrogen receptors are ligand-dependent transcription factors whose activity is modulated either by estrogens, or by alternative intracellular signaling pathways downstream of growth factors and neurotransmitters. To determine the dynamics of estrogen receptor activity and the dependence of estrogen receptor on 17beta-estradiol in vivo, we generated a transgenic mouse that expresses a luciferase reporter gene under the control of activated estrogen receptors. As expected, luciferase activity, monitored with a cooled charged coupled device camera, paralleled circulating estrogen levels in reproductive tissues and in liver, indicating that the peak transcriptional activity of the estrogen receptor occurred at proestrus. In contrast, in tissues such as bone and brain, the peak activity of estrogen receptors was observed at diestrus. These tissue-specific responses are masked when mice undergo conventional hormone treatment. We also demonstrate that estrogen receptors are active in immature mice before gonadal production of sex hormones as well as in ovariectomized adult mice. These findings emphasize the importance of hormone-independent activation of the estrogen receptor, and have implications for the therapeutic use of estrogens, such as hormone replacement therapy.

Animals↗
PubMedDate not supplied

Effects of raloxifene, one of the selective estrogen receptor modulators, on pituitary-ovary axis and prolactin in postmenopausal women.

To investigate the clinical effects of raloxifene, one of the selective estrogen receptor modulators (SERMs), on the pituitary-ovary axis and prolactin, a prospective, randomized, double-blinded study on 59 healthy postmenopausal women was performed. Forty-eight women received raloxifene 60 mg daily. The other 11 received combined conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 5 mg daily (CCEP) as active controls. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and pro-lactin were measured at baseline and 1 yr after treatment. The mean levels of FSH and LH were significantly decreased in the raloxifene group (FSH: -10.7%; p < 0.01, LH: -10.3%; p < 0.05) and CCEP group (FSH: -53.7%, p < 0.001; LH: -46.8%, p < 0.001). The prolactin level decreased in the raloxifene group but not in the CCEP group (-17.0%; p < 0.001 vs +13.3%, p = no significance; NS). Consequently, long-term administration of raloxifene up to 1 yr decreases serum prolactin level significantly and may be a therapeutic alternative for postmenopausal osteoporotic women with hyperprolactinemia.

Administration, Oral↗
PubMed1999

Regulation of vascular endothelial growth factor secretion in human meningioma cells.

Previously, we induced vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) secretion in glioma cell lines by using physiologic concentrations of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or platelet-derived growth factor-BB (PDGF-BB). We hypothesized that VEGF/VPF might enhance the blood supply required for the unregulated growth of tumors, and that it acts as the central mediator of tumor angiogenesis. The objective of this study was to determine whether the expression of VEGF/VPF by meningiomas is regulated by growth factors or sex hormones. By means of an enzyme-linked immunosorbent assay of CH-157MN meningioma cell supernatants, we demonstrated that EGF and bFGF similarly induce VEGF secretion by CH-157MN meningioma cells. At the maximum concentrations of EGF (50 ng/mL) and bFGF (50 ng/mL) used in this study, VEGF secretion was induced to 140% to 160% above baseline constitutive secretion. PDGF-BB homodimer did not enhance VEGF secretion significantly. Estradiol (up to 10(-7) mol/L), progesterone (up to 10(-5) mol/L), or testosterone (up to 10(-5) mol/L) did not stimulate or inhibit VEGF secretion in CH-157MN meningioma cells (p > 0.05). Furthermore, we demonstrated that dexamethasone decreased VEGF secretion to 32% of baseline constitutive secretion. This might explain the effect of corticosteroids in alleviating peritumoral brain edema in meningiomas. These results suggest that VEGF secretion in CH-157MN meningioma cells is mainly regulated by growth factors and corticosteroids, but not by sex hormones. Understanding the regulation of VEGF/VPF secretion in meningiomas might contribute to the development of a new therapeutic strategy.

Dexamethasone↗
PubMed1990

The use of the antiprogestin RU486 (mifepristone) as an abortifacient in early pregnancy--clinical and pathological findings; predictive factors for efficacy.

RU486, a potent antiprogesterone steroid was administered to 124 women requesting therapeutic abortion. All were less than 49 days from their last menstrual period. Ten of these subjects (Group I) received high doses of RU486 in a decremental dose regimen (400, 300, 200 and 100 mg/day) over 4 successive days and 14 received 50 mg/day for 7 days (Group II). A further 50 subjects (Group III) received 100 mg/day for seven days and the remaining 50 subjects (Group IV) received 450 mg in a single dose. In the first three groups, half the daily dose was given in the morning and the remainder in the evening. Blood was collected before, and on Days 4 and 7 and then once a week after commencing therapy until disappearance of circulating beta HCG. In addition to beta HCG, estradiol-17 beta (E2), progesterone (P), cortisol, and various metabolic and hematological parameters were measured. Plasma RU486 concentrations were also assayed in Group II, III and IV subjects on Day 7 of therapy and in some cases on Days 14 and 21. Ultrasonography was performed in all cases on Day 1 and on Day 14. All the patients bled within five days following RU486 administration, for 1 to 21 days. A complete abortion occurred in 60% in Group I, 50% in Group II, 86% in Group III, and 80% in Group IV. The difference between the last two groups and the first two was significant at p less than 0.01. The non-responders were submitted to a uterine vacuum aspiration. A stepwise discriminant analysis was performed and indicated that the best predictors of the outcome of therapy were beta HCG values and the gestational sac diameter. With these criteria, the prediction was accurate in 86.4% of the cases. The best results were obtained in the cases where the ultrasonic measurement of gestational sac was under 10 mm in diameter and the initial beta HCG values under 15,000 mIU/ml. Among the observed side effects were moderate pelvic cramps (20.9%), nausea (27%), fainting (4.8%); 61.3% of the women complained of fatigue. Heavy bleeding occurred in 15.3% of the women but only one of them required blood transfusion. In the patients with complete abortion, beta HCG values decreased to below 500 mIU/ml by Day 14 (but in 11 cases values fell below 2,000 mIU/ml only by Day 21). Plasma estradiol and progesterone also fell. Cortisol levels increased during therapy especially in subjects of Group I, but returned to basal values after termination of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Abortifacient Agents↗
PubMed1975

The chemotherapy of urologic cancer.

A review of the status of evaluation of chemotherapeutic agents in the urologic malignancies reveals a largely neglected area of investigation. Except for testicular carcinomas, which are highly responsive to drug therapy, active agents have not been clearly established for the other urogenital tumor sites. Published information and data on file in the Cancer Therapy Evaluation Program of the National Cancer Institute are reviewed, and studies currently in progress are outlined. Adequate clinical testing of the standard antitumor agents that are active against other human malignancies should receive high priority in future therapeutic trials in urologic cancer.

Adenocarcinoma↗
PubMed1994

Estrogen receptors: new perspectives in breast cancer management.

The imbalance between proliferative and differentiative estrogenic effect, caused by quantitative and qualitative alteration of the estrogen receptor (ER) expression, may play a determinant role in mammary neoplastic transformation. Our studies demonstrate that ER levels are significantly higher in human mammary neoplastic tissues when compared to perineoplastic tissues and that increased ER expression is associated with ER gene hypomethylation. During progressive multifactorial carcinogenesis, ER overexpression may represent an early step in neoplastic transformation. In fact, high levels of ER represent good markers of differentiation and can predict the likelihood of benefiting from anti-estrogen therapy. Nevertheless, about 35% of ER-positive breast cancers are resistant to endocrine therapy and 10% of ER-negative tumors behave as hormone-sensitive tumors. Recent studies on ER mRNA variants, which naturally occur in human breast tumors, demonstrated mutations, deletions and alternative splicings, yielding deletions of exons 3, 4, 5 and 7. ER variants exhibited altered functions or changed the responsiveness to hormonal therapy. Analysis of these variants could be a useful parameter to better predict tumor responsiveness to anti-estrogen therapy. Recently, a regain of hormonal responsiveness by ER-negative breast cancer cells has been reported following ER gene transfection. However, estradiol treatment inhibits rather than stimulates cell growth as well as the metastatic and invasive potential of the ER gene transduced cells. Transfer of the ER gene may be considered as a new therapeutic approach in the management of hormone-independent breast cancer.

Breast Neoplasms↗
PubMed1983

Sustained gonadal suppression in fertile women with the LHRH agonist buserelin.

Nine fertile women were treated with the luteinizing- hormone-releasing hormone agonist buserelin (seven women received 800 micrograms, two women 1200 micrograms intranasally for up to 24 weeks). Both doses produced sustained suppression of ovarian function, accompanied by hot flushes. In five women chemical castration was established within 1 to 5 weeks, whereas in the other four volunteers transient peaks of serum oestradiol occurred between the 6th and 19th weeks. Thereafter low postmenopausal oestradiol levels persisted. Chemical castration was confirmed by hormonal parameters and endometrial biopsies (inactive endometrium). After cessation of treatment normal cyclical function occurred immediately. This reversible chemical castration may be useful for new therapeutical approaches in sexual hormone dependent diseases (endometriosis, precocious puberty, metastatic breast cancer).

Buserelin↗