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PubMed2001

Therapeutic value and long-term safety of pulsed estrogen therapy.

OBJECTIVES: To demonstrate equivalent efficacy for menopausal symptoms between Aerodiol nasal spray and reference oral estradiol therapy, and to investigate the endometrial safety and tolerability of Aerodiol in the long term. METHODS: The efficacy of Aerodiol 300 microg, once daily, was compared with oral estradiol 2 mg/day in a randomized, double-blind trial. A statistical test of noninferiority was performed on the mean absolute Kupperman index (KI) obtained after 14 and 23 weeks of the two treatments. Long-term safety was assessed in a 1-year open-label study. The initial Aerodiol dose was 300 microg/day, and was adjusted if required. Endometrial biopsies were obtained at inclusion and at the end of the trial and examined independently by two pathologists. RESULTS: In the equivalence trial, the KI improved similarly in the Aerodiol group (n=317) and the oral estradiol group (n=342). Aerodiol was shown statistically to be at least as effective as oral therapy (P<0.001), but the incidences of mastalgia and withdrawal bleeding were significantly lower in the Aerodiol group (P<0.01 and P<0.001, respectively). In the long-term safety trial (n=408), the rate of Aerodiol treatment continuation at 12 months was 85%, and there was no incidence of endometrial hyperplasia or cancer. Aerodiol dose adaptation was performed by 29% of women. CONCLUSIONS: Aerodiol was shown to have equivalent efficacy to reference oral estradiol therapy, but with better gynaecological acceptability. The endometrial safety of Aerodiol was confirmed in the long term, and the ability to adjust the dosage easily was of benefit to a substantial proportion of women.

Administration, Intranasal↗
PubMed2000

[Determination of acceptability of 2 cutaneous estradiol gels, in a dose of 1.5 mg daily].

OBJECTIVE: The aim was to compare acceptability of a percutaneous 0. 1% estradiol gel (Gel A, Estreva(R) Gel, Laboratoire Théramex, Monaco) to that of an 0.06% estradiol gel (Gel B, Oestrodose(R), Laboratoires Besins-Iscovesco) in its new formulation and packaging. MATERIAL AND METHODS: This randomized, crossed, simple-blind study was carried out in 48 volunteer healthy postmenopausal women. The volunteers applied on one forearm 1.5 mg/day of cutaneous estradiol in the form of either gel, according to randomized allocation, for four days without free period between the two therapeutic periods. The application and drying times of the two gels were measured during the first application; gel subjective women assessment was collected at the beginning and at the end of the study. RESULTS: Mean application and drying times with Gel A are significantly reduced, compared to Gel B (p=0.0259 and p=0.0001, respectively) with drying time 61% shorter; these data are confirmed by subjective women evaluation. The two gels are not significantly different regarding several criteria as consistency, ease of application and sensation of lasting stickiness. However, a significant difference is found in favour of Gel A on the following items: practicality of application (p=0.007), ease of penetration (p<0.001), quantity of gel to apply (p<0.001) after the first application. After four days of administration, a same significant difference is observed concerning practicality of the gel (p=0.0078), duration of use (p<0. 001), packaging, women opinion on the gel (p=0.022) and the product, gel and packaging (p<0.001). At the end of the study, gel A utilization is considered by women more practical (p=0.001) with an easier application (p<0.001) and less restricting while applying (p=0.001), compared to Gel B; 72.9% of women prefer the Gel A and 12. 5% of women prefer the Gel B. CONCLUSION: A better acceptability of the 0.1% estradiol gel and of its packaging compared to that of the 0.06% estradiol gel in this new formulation and packaging is observed in this study.

Administration, Cutaneous↗
PubMed2000

Do female sex steroids adversely or beneficially affect the depressed immune responses in males after trauma-hemorrhage?

HYPOTHESIS: Administration of female sex steroids in males after trauma-hemorrhage has salutary effects on the depressed immune responses. DESIGN: Randomized laboratory experiment. INTERVENTIONS: Male C3H/HeN mice were subjected to midline laparotomy and hemorrhagic shock (35+/-5 mm Hg for 90 minutes, then resuscitation) or sham operation and received subcutaneous 17beta-estradiol (40 microg/kg body weight) or corn oil vehicle at the beginning of resuscitation. MAIN OUTCOME MEASURES: At 24 hours after hemorrhage, the animals were killed and plasma 17beta-estradiol and IL-6, splenocyte interleukin (IL) 2, IL-3, and IL-10 production as well as splenic and peritoneal macrophage IL-1beta, IL-10, and IL-6 release were measured. RESULTS: Splenocyte IL-2 and IL-3 release were significantly depressed after hemorrhage in vehicle-treated mice (P<.05, analysis of variance). Treatment with 17beta-estradiol after hemorrhage led to the restoration of splenocyte IL-2 and IL-3 release. The depressed proinflammatory cytokine (IL-1 and IL-6) release seen in splenic and peritoneal macrophages was restored in the 17beta-estradiol-treated hemorrhage group. In contrast, the sustained release of the anti-inflammatory cytokine IL-10 by splenocytes and splenic and peritoneal macrophages in vehicle-treated mice after hemorrhage was decreased in 17beta-estradiol-treated mice. The increase in circulating IL-6 levels after hemorrhage was significantly attenuated in 17beta-estradiol-treated mice. Although administration of 17beta-estradiol increased plasma 17beta-estradiol levels by approximately 100% in sham as well as hemorrhage groups, improved immune responses were seen only in posthemorrhage 17beta-estradiol-treated mice. There was no adverse effect of 17beta-estradiol treatment in the sham or posthemorrhage groups. CONCLUSION: Since administration of a single dose of 17beta-estradiol in males after trauma-hemorrhage restores the immune functions and decreases circulating levels of IL-6, hormones with estrogenic properties should be considered as safe and novel therapeutic agents for restoring the immune responsiveness in male trauma victims.

Adjuvants, Immunologic↗
PubMed2000

Effects of norethisterone acetate addition to estradiol in long term HRT.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of hormone replacement therapy (HRT) among postmenopausal women living in the Lund area of Southern Sweden and to analyze treatment effects in different types or routes of HRT administration, as well as to compare with unopposed estrogen therapy. METHOD: in an ongoing, large population-based, prospective cohort study, this interim analysis included 3900 women. Of them, 693 postmenopausal women were eligible in the present analyses as they continued to use one of the four commercial HRT products for at least 2-3 years, i.e. continuous oral estradiol (E(2)) 2 mg+norethisterone acetate (NETA) 1 mg (CON-O), sequential oral estradiol 2 mg + norethisterone acetate 1 mg (CYC-O), sequential transdermal estradiol 50 microg + norethisterone acetate 250 microg (CYC-TRANS) and estradiol monotherapy. These women completed one generic questionnaire and one specific 'hormonal' questionnaire, as well as a personal interview pertaining to socio-demographics, detailed status of HRT use, and therapeutic efficacy and untoward side-effects by HRT. RESULTS: comparing the three combined E(2)+NETA groups with E(2) monotherapy, the beneficial effects on sexual desire and emotional well-being were significantly less in the combined groups than in E(2) monotherapy group. There was no significant difference regarding the negative side-effects between the groups. No significant difference was found between CON-O and CYC-O groups either in positive effects or in negative side-effects. A higher prevalence of positive effects was found in CYC-TRANS group than that in CYC-O group, especially in amelioration of sleep and urinary symptoms. Higher odd ratios of negative effects by HRT, such as irregular bleeds, weight gain, food craving and skin disorders were also found in CYC-TRANS group. CONCLUSION: in long-term HRT administration, the addition of a progestogen in HRT could compromise the beneficial effects of estradiol, particularly, the effects on women's emotional well being and psychosexual functioning. Administration of NETA continuously and sequentially had similar therapeutic efficacy and tolerability. More marked positive effects, such as improving of sleep and urinary symptoms, as well as nuisance side-effects, i.e. irregular bleeds, weight gain, food craving and skin disorders were encountered by the women using sequential transdermal regimen

Administration, Cutaneous↗
PubMed2004

Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression.

OBJECTIVE: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression. METHOD: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND). RESULTS: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35). CONCLUSION: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.

Depression↗
PubMed1995

Estrogen acutely increases peripheral blood flow in postmenopausal women.

PURPOSE: To test the acute effect of estrogen on peripheral blood flow and vascular resistance in postmenopausal women. PATIENTS AND METHODS: Eleven normotensive, post-menopausal female volunteers (mean age 53 +/- 6 years) were studied. Six women were in natural menopause and 5 had had a hysterectomy (mean age of the menopause 49 +/- 3 years). We used a double-blind, randomized protocol to assess the acute response to sublingual estradiol-17 beta (1 mg) on the forearm resistance vessels, compared with sublingual placebo. Blood flow was measured by strain-gauge plethysmography, and mean peripheral vascular resistance was then calculated. Mean blood pressure was also measured. RESULTS: The mean blood flow induced by estradiol-17 beta after 40 minutes was significantly greater than that induced by placebo (3.9 +/- 0.5 mL/100 mL per minute versus 2.4 +/- 0.4 mL/100 mL per minute, respectively, P < 0.05). The forearm resistance was significantly reduced at 40 minutes after estradiol-17 beta compared with placebo (25.7 +/- 4.4 resistance units (RU) to 44.4 +/- 6.4 RU, respectively, P < 0.05). Mean blood pressure 40 minutes after the administration of estradiol-17 beta was no different when compared with placebo (91 +/- 1.5 mm Hg versus 90 +/- 2.5 mm Hg, respectively, P = NS). CONCLUSIONS: These results indicate that the acute administration of estradiol-17 beta affects blood flow in the peripheral vasculature in human subjects. The mechanism of this effect has not been determined, but it may explain some of the beneficial effects of estrogen on the vascular system and have future therapeutic potential in postmenopausal women.

Administration, Sublingual↗
PubMed1996

Expression of beta 1 integrins in human endometrial stromal and decidual cells.

The present study was undertaken to investigate the expression of beta1 integrins in human endometrium and decidua using flow cytometry, immunohistochemistry, and immunoprecipitation. Fluorescence-activated flow cytometry demonstrated the greater expression of the beta 1, alpha 1, alpha 2, and alpha 5 subunits of the beta1 integrin family in cultured stromal cells from the midsecretory phase, than in those of the early proliferative phase. The addition of estradiol (E2) and progesterone (P) to cultured stromal cells in the early proliferative phase increased the expression of beta1 integrins in vitro. The immunohistochemical distribution of beta1 integrins demonstrated predominantly glandular epithelial staining in the proliferative phase, and mesenchymal and glandular staining in the midsecretory phase. Flow cytometry also demonstrated the expression of the beta 1, alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 subunits of beta 1 integrin family in cultured decidual cells, and the enriched-fraction of prolactin (PRL)-producing decidual cells isolated by Percoll gradients showed high levels of beta 1, integrins expression. Immunohistochemistry confirmed the beta 1 integrin cell surface phenotypes in cultured decidual cells observed by flow cytometry. Autoradiography of immunoprecipitate subjects to SDS-PAGE revealed three major polypeptides with molecular weights of 130 kDa (beta 1 subunit), 165 kDa (alpha 2 subunit), and 210 kDa (alpha 1 subunit) under reducing conditions. In summary, the present study demonstrated that endometrial stromal and decidual cells expressed beta1 integrin subunits at their surfaces. The expression exhibited a variability throughout the menstrual cycles, being predominantly detected in the secretory phase, and was maintained highly in the decidua. Thus, beta 1 integrins in human endometrium and decidua may be important in mediating the organization of extracellular matrix proteins derived from embryos during the early stage of implantation.

Abortion, Therapeutic↗
PubMed2000

Drug concentration effect relationship of estradiol from two matrix transdermal delivery systems: Menorest and Climara.

OBJECTIVES: To relate the pharmacokinetics of estradiol to pharmacological effects. METHODS: Drug concentration effect relationship of estradiol from two matrix transdermal delivery systems, Menorest and Climara, was studied in a single centre, open, randomised, comparative crossover study. The trial consisted of two treatment periods, 14 days for each patch separated by a 4-week washout period. Blood hormone levels were followed during the second week of each treatment. Estradiol levels during treatments were related to three concentration levels previously proposed as efficacy or safety limits. The effect of treatment on FSH-levels was examined and the relationship between the levels of estradiol and FSH was described using an inhibitory sigmoidal I(max) model. Estrone levels and estradiol/estrone before and during treatment were followed. RESULTS: The C(average) of FSH during treatment was 38% lower than baseline plasma levels. Estradiol had an inhibitory effect on FSH with an I(max) of 0.68 and an IC(50) of 19 pg/ml. The fraction of time above the minimum concentration for therapeutic effect and the tolerability limit did not differ between the two treatments, whereas the fraction of time above the suggested threshold for osteoporosis prophylaxis was significantly larger for Menorest than for Climara (P<0.05). The low baseline estradiol/estrone ratios increased towards pre-menopausal levels during treatment. CONCLUSIONS: The drug concentration effect relationship of estradiol may be of use in evaluation of the effects of prophylactic estrogen therapy and to facilitate comparisons between different forms of estrogen treatments.

Administration, Cutaneous↗
PubMed1986

Pharmacokinetic studies of estradiol enantate in menopausic women.

Healthy menopausic women received 10 mg i.m. of estradiol enantate (estra-1,3,5(10)-triene-3-ol-17 beta-heptanoate, one of the components of Perlutal or Topasel). Their estradiol serum levels were determined by radioimmunoassay (RIA) on days 1, 2, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29 and 31 after the injection. Based on these data, the elimination rate constant (K = 0.12445 d-1), the elimination half-life (t1/2 = 5.57 d), the absorption rate constant (Kabs. = 1.5050 d-1), the absorption half-life (t1/2 abs. = 0.46 d) and the volume of distribution (Vd = 5087 l) were calculated. These results are compared with others not obtained by RIA and discussed from a therapeutic-clinical point of view.

Estradiol↗
PubMed1995

Alternative cyclosporine metabolic pathways and toxicity.

There are some indications from clinical studies (41,43) for aberrant cyclosporine metabolism resulting in formation of potentially toxic metabolites. When the activity of cytochrome P450 3A enzymes is low, more substrate is available for hypothetical alternative pathways of cyclosporine. There are several reasons for low P450 3A activity in a liver graft such as inter-individual genetic variability (43,49,84), cold ischemia and reperfusion damage, changes of the P450 activity during cholestasis (85) or other liver diseases (86), the influence of cytokines (87) and drug interactions such as inhibition or enzyme induction (88). Furthermore, low concentrations of cytochrome P450 3A influence the cyclosporine blood trough concentrations. The P450 3A concentration as estimated by the erythromycin breath test can be used to calculate the initial cyclosporine dose required to obtain cyclosporine blood trough concentrations in the therapeutic window (89). In vitro such alternative pathways comprising 3-methylcholanthrene-inducible (44,46,47) and/or ethinyl estradiol-inducible cytochrome P450 enzymes (48) could be identified and resulted in production of cyclized cyclosporine metabolites. The exact identification of the P450 enzymes involved requires metabolism of cyclosporine using reconstituted purified enzymes or single P450 enzymes expressed in cell lines. In addition, it remains to be clarified whether cyclosporine itself or its metabolite AM1 is the substrate for cyclization. Because cyclized metabolites have a low affinity to cyclophilin (58,59) they are mainly found in plasma. When more cyclized metabolites are formed primarily the concentration of cyclosporine metabolites in plasma increases. The free fraction of cyclosporine at 37 degrees C was found to be 1%-1.5% (90,91) of the cyclosporine concentration in blood. To date, nothing is known about the free fraction of cyclosporine metabolites. Because distribution characteristics of the cyclized metabolites in blood and urine are different from those of cyclosporine, it can be speculated that the free fraction of the cyclized metabolites is higher than that of cyclosporine. This might be reflected by a higher renal clearance resulting in relatively higher concentrations in urine compared with blood (61; Figure 3). If this is the case, a shift in the metabolite pattern with increased concentrations of cyclized metabolites will lead to an overproportional increase of the free fraction of cyclosporine metabolites. Although it is tempting to assume that cyclization is the alternative pathway explaining cyclosporine toxicity in patients with low concentrations of P450 3A enzymes in the liver (Figure 6), this has not yet been proven and will require not only quantification of P450 3A but of the complete P450 enzyme pattern in the liver in combination with characterization of the cyclosporine metabolite pattern by HPLC with special respect to the cyclized metabolites AM1c and AM1c9. Also, it is still unclear whether or not the cyclized metabolites contribute to cyclosporine toxicity. At least, it is unlikely that they are involved in covalent binding to macromolecules in the liver and kidney (44,71). In a clinical study using an HPLC method which allowed the specific quantification of 16 cyclosporine metabolites it was shown that the blood trough concentrations of the cyclized metabolite AM1c9 is elevated during early nephrotoxicity in liver graft recipients (82) and it was shown in an in vitro model that AM1c9 increases endothelin production and therefore might have a negative effect on renal hemodynamics.(ABSTRACT TRUNCATED)

Animals↗
PubMed1991

Synthesis and biological activity of new halo-steroidal antiestrogens.

Antiestrogen therapy is the most widely used endocrine manipulation for the treatment of breast cancer, especially in postmenopausal women. Unfortunately, the compounds presently available possess mixed agonistic/antagonistic activity, thus potentially limiting their therapeutic efficacy. Following the observations that an aliphatic chain at the 7 alpha-position of 17 beta-estradiol does not prevent binding to the estrogen receptor while halogenation of estradiol can increase the affinity of its binding (expressed as RBA) to the estrogen receptor, we have synthesized a series of new steroidal antiestrogens (6-10) which possess both an 7 alpha-undecanamide group and an halogen atom (Cl, Br, or I) at the 16 alpha-position. The stereochemistry of these compounds was unambiguously established by high-field (400-MHz) nuclear magnetic resonance. Some of the compounds obtained possess potent in vivo antiestrogenic activity. At the low twice daily 3-micrograms dose, 16 alpha-chloro 3,17 beta-diol amide, 16 alpha-iodo 3,17 beta-diol amide, 16 alpha-bromo 3,17 beta-diol amide, 16 alpha-chloro 3,17 alpha-diol amide, and 16 alpha-bromo 3,17 alpha-diol amide inhibit by 74, 63, 52, 35, and 60%, respectively, the estradiol-induced stimulation of uterine weight in ovariectomized Balb/c mice while 78-99% blockade of estradiol action is achieved at the 20-micrograms dose. These new antiestrogens show no estrogenic activity on uterine weight at the doses used while tamoxifen (2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N- dimethylethanamine) shows full estrogenic activity and is only a weak partial antiestrogen in the same assay.

Animals↗
PubMed1997

Antiestrogens: future prospects.

Tamoxifen is currently the endocrine therapy of choice for early and advanced breast cancer. Attempts to improve the therapeutic efficacy have included altering the triphenylethylene ring structure of tamoxifen, forming new nonsteroidal ring structures or creating steroidal estradiol analogs with greater antiestrogenic activity. There are now six nonsteroidal compounds either on the market or in clinical development and one steroidal "pure" antiestrogen has entered clinical trials. A number of these agents show improved estrogen-receptor binding affinity, antiestrogenic activity, and/or antitumor activity compared with tamoxifen. Preclinical and clinical data on these compounds are discussed and compared with tamoxifen when possible.

Estrogen Antagonists↗
PubMed2000

Estrogen receptors alpha and beta: two receptors of a kind?

Ever since the discovery of estradiol and the elucidation of its chemical structure, there has been a great deal of interest in its mechanism of action and its potential therapeutic value. It is now well established that estrogens have many different functions in many different cell-types. With respect to the potential use of estrogens as therapeutics, there is an interest in controlling reproductive function, bone metabolism, cardiovascular disease, as well as in the prevention of hot flushes, mood changes and Alzheimer s disease. For over a decade, it was believed that estrogens signal through a a single estrogen receptor, now referred to as ERalpha, which belongs to a family of ligand-activated transcription factors. More recently, however, a second estrogen receptor ERbeta was identified. The current review describes similarities as well as differences between these two distinct estrogen receptors. Both ERalpha and ERbeta bind 17beta-estradiol with high affinity and they bind to classical estrogen response elements in a similar if not identical fashion. However, there are also major differences between ERalpha and ERbeta for instance with respect to their tissue distribution, the phenotype of the corresponding knock-out mice and their transcriptional activities. It is anticipated that a better understanding of these two receptors will eventually lead to more selective ways of modulating physiological processes which are influenced by estrogens. For this purpose, the development of ERalpha and ERbeta specific ligands, both agonists as well as antagonists, will be of great importance.

Animals↗
PubMed2005

High-dose estrogen and clinical selective estrogen receptor modulators induce growth arrest, p21, and p53 in primate ovarian surface epithelial cells.

Ovarian cancer is the most lethal gynecological cancer affecting women. Hormone-based therapies are variably successful in treating ovarian cancer, but the reasoning behind these therapies is paradoxical. Clinical reagents such as tamoxifen are considered to inhibit or reverse tumor growth by competitive inhibition of the estrogen receptor (ER); however, high-dose estrogen is as clinically effective as tamoxifen, and it is unlikely that estrogen is acting by blocking ER activity; however, it may be activating a unique function of the ER that is nonmitogenic. For poorly defined reasons, 90% of ovarian cancers derive from the ovarian surface epithelium (OSE). In vivo the ER-positive OSE is exposed to high estrogen levels, reaching micromolar concentrations in dominant ovarian follicles. Using cultured rhesus OSE cells in vitro, we show that these levels of estradiol (1 mug/ml; approximately 3 mum) block the actions of serum growth factors, activate the G(1) phase retinoblastoma checkpoint, and induce p21, an inhibitor of kinases that normally inactivate the retinoblastoma checkpoint. We also show that estradiol increases p53 levels, which may contribute to p21 induction. Supporting the hypothesis that clinical selective ER modulators activate this novel ER function, we find that micromolar doses of tamoxifen and the "pure antiestrogen" ICI 182,780 elicit the same effects as estradiol. We propose that, in the context of proliferation, these data clarify some paradoxical aspects of hormone-based therapy and suggest that a fuller understanding of normal ER function is necessary to improve therapeutic strategies that target the ER.

Animals↗
PubMed1996

17-beta-Estradiol therapy lessens angina in postmenopausal women with syndrome X.

OBJECTIVES: We sought to investigate the hypothesis that estrogen replacement therapy ameliorates symptoms in postmenopausal women with syndrome X. BACKGROUND: Syndrome X (angina pectoris, positive findings on exercise electrocardiography and normal results on coronary angiography) frequently occurs in menopausal women. This observation, in conjunction with the known vasoactive properties of estrogens, suggests that estrogen depletion may contribute to the pathogenesis of syndrome X in some women. METHODS: Twenty-five postmenopausal patients with syndrome X completed a double-blind, placebo-controlled study of the effect of 17-beta-estradiol cutaneous patches (100 micrograms/24 h) on the frequency of chest pain and on exercise tolerance. Patients were randomly assigned to receive either placebo or 17-beta-estradiol patches for 8 weeks and were then crossed over to the other treatment. RESULTS: During the placebo phase, patients had a mean of 7.3 episodes of chest pain/10 days. A reduction to 3.7 episodes/10 days was observed during the 17-beta-estradiol phase (p < 0.05). No significant differences were observed between the effects of 17-beta-estradiol and placebo on exercise duration or the results of other cardiologic investigations. CONCLUSIONS: Estrogen replacement reduces the frequency of chest pain and may be a useful new therapeutic option for treating postmenopausal women with syndrome X.

Cross-Over Studies↗
PubMed2006

MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells.

Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

Breast Neoplasms↗