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PubMed2001

Estrogenic activity and metabolism of n-butyl benzyl phthalate in vitro: identification of the active molecule(s).

Some phthalates are suspected to disrupt the endocrine system, especially by mimicking estrogens. N-butyl benzyl phthalate (BBP) has estrogenic effects in vitro but not in vivo. The aim of this study was to identify the active molecule(s) (parent compound and/or metabolite(s)) involved in the estrogenic activities of BBP. The estrogenic effects of BBP and its in vivo metabolites were assessed using the following tests: E-Screen, ER binding, and PR induction tests on the human breast cancer cell line MCF-7 (ER(+)). BBP, the parent compound, was a partial agonist. It stimulated MCF-7 proliferation in the E-Screen assay and increased cytosolic progesterone receptors (PR) levels in a concentration-dependent manner. No BBP metabolites were active except hippuric acid (HA), which had a weak effect at very high concentrations. BBP and HA stimulatory effects on MCF-7 proliferation were antagonized by tamoxifen. However, no competition was observed between BBP or HA and 17beta-estradiol for binding to the estrogen receptor (ER). BBP metabolism by MCF-7 cells was also investigated. After a 48-h incubation, only 10% of the initial BBP remained in the culture medium, demonstrating that BBP was extensively metabolized by the MCF-7 cells. The radioactivity recovered in the medium was represented by: mono-n-butyl phthalate (MBuP, 25%) and mono-n-benzyl phthalate (MBeP, 48%), phthalic acid (6%), and benzoic acid (3%). Since none of these metabolites had estrogenic activities, this study demonstrates that the parent compound was the active molecule involved in the in vitro estrogenic effects of BBP.

Binding, Competitive↗
PubMed2005

Basis of melengestrol acetate action as a progestin.

To provide insight into potential mechanisms contributing to the various biological responses of cattle to treatment with progesterone, norgestomet, and melengestrol acetate (MGA), MCF-7 cells were utilized to determine the relative binding affinity of the progesterone receptor for MGA, norgestomet, progesterone, and a progesterone agonist (R5020), and to determine if progesterone, MGA, or norgestomet have estrogenic and/or anti-estrogenic activities. The progesterone receptor had greater affinity (P<0.05) for MGA, R5020, and norgestomet than for progesterone; and the affinity for norgestomet exceeded (P<0.05) that of MGA and R5020. Estrogen stimulates proliferation of MCF-7 cells; therefore these cells have been utilized as a bioassay to detect estrogenic and anti-estrogenic activity. Progesterone (10(-11) to 10(-5)M) did not promote cellular proliferation. However, MGA (10(-8), 10(-7), and 10(-6)M) increased (P<0.05) cell proliferation compared to the control group (10(-11) to 10(-9) and 10(-5)M MGA did not stimulate cell proliferation), and MGA-induced cell proliferation (10(-8)M) was reduced (P=0.095) by an estradiol antagonist (ICI 182,780; ICI). Cellular proliferation increased (P<0.05) with norgestomet (10(-5)M) compared to the control group (10(-11) to 10(-6)M norgestomet did not stimulate cell proliferation) and the increased proliferation was decreased (P<0.05) by ICI. Neither progesterone nor MGA demonstrated anti-estrogenic activity. Norgestomet (10(-10) to 10(-6)M) did reduce (P<0.05) maximal estrogen-stimulated cell proliferation, but not to basal levels. In summary, the affinities of the progesterone receptor for norgestomet, MGA, and progesterone are consistent with their effective dose to inhibit ovulation in vivo, but their progestin and their estrogenic/anti-estrogenic activities cannot fully explain why progesterone and norgestomet are more capable of reprogramming the reproductive axis in anestrous postpartum cows compared to MGA.

Animals↗
PubMed2002

An estrogen-responsive element-targeted histone deacetylase enzyme has an antiestrogen activity that differs from that of hydroxytamoxifen.

We showed previously that prolonged treatment of a MCF-7-derived cell line with hydroxytamoxifen (OHT) induces the irreversible silencing of some estrogen-responsive genes, whereas OHT-resistant cell growth appears simultaneously (E. Badia et al., Cancer Res., 60: 4130-4138, 2000). Based on the hypothesis that particular gene silencings could be involved in triggering the resistance phenomenon, we focused our study on the mechanism of OHT-induced silencing. More precisely, we wished to determine to what extent the recruited histone deacetylase (HDAC) activity, which is known to be involved in the repressive effect induced by antagonist ligands of nuclear receptors, could participate in various aspects of OHT effects, particularly in gene silencing. A fusion protein (HDAC-EG) of human HDAC1 fused with the estrogen receptor DNA-binding domain and the glucocorticoid receptor ligand-binding domain allowed targeting of chimeric HDAC1 activity on estrogen-responsive elements (EREs) in the presence of glucocorticoid ligands. When HDAC-EG was transiently expressed in HeLa cells together with estrogen receptor, an antiestrogen-like effect was obtained on an ERE-controlled luciferase reporter gene in the presence of agonist or antagonist glucocorticoids. In MCF-7-derived cells stably expressing HDAC-EG and an estrogen-regulated luciferase, liganded HDAC-EG again produced an antiestrogenic effect on expression of natural estrogen-regulated genes such as pS2, progesterone receptor, and cathepsin D and cell growth together with chimeric luciferase gene expression. However, a prolonged HDAC-EG-mediated antiestrogen effect did not lead to irreversible luciferase gene silencing, as OHT does. It nevertheless accelerated the OHT-driven phenomenon. The antiestrogen effect of OHT thus differs from that of an ERE-targeted HDAC1 activity that might participate in irreversible silencing but is not sufficient to trigger it.

Animals↗
PubMed1999

Synthesis and biological activity of trans-2,3-dihydroraloxifene.

The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. Evaluation in vitro shows the compound to be a potent selective estrogen receptor modulator (SERM).

Binding, Competitive↗
PubMed2004

Estrogen and regulation of heat shock protein expression in female cardiomyocytes: cross-talk with NF kappa B signaling.

UNLABELLED: Estrogen is associated with increased heat shock protein (HSP)72 and protection during hypoxia-reoxygenation in cardiomyocytes from adult male rats, as previously reported. We have also reported that female rats have more cardiac HSP72 than males. We hypothesized that, despite higher endogenous estrogen levels and higher baseline HSP72, 17 beta-estradiol treatment would still result in increased HSP72 and protection during hypoxia-reoxygenation in cardiomyocytes from females. METHODS/RESULTS: Cardiac cells isolated from adult female rats were treated for 12 hr with 17 beta-estradiol (0.1, 10, or 50 microM), tamoxifen, (10 or 25 microM; estrogen receptor agonist/antagonist), geldanamycin (2, 5, or 10 microg/ml; inactivates HSP90, preventing interaction with HSF1), or vehicle. Western blot analyses revealed that treatment with 17 beta-estradiol (10 or 50 microM), tamoxifen (25 microM), and geldanamycin (all doses) resulted in significant increases in HSP72. Electromobility shift assays revealed activation of HSF1 by 2 to 3 hr, and NF kappa B activation by 15 min. HSP72 induction via HSF1 activation was confirmed using transcription factor decoys containing the heat shock element, which prevented the estrogen-related HSP72 induction. Estrogen pretreatment resulted in decreased LDH release during 24 hr hypoxia. This protective effect persisted despite decoy-mediated blockade of nuclear HSF1 binding. However, transfection with an NF?B decoy not only prevented an estrogen-associated increase in HSP72, but also abolished the estrogen-related protection during hypoxia. CONCLUSIONS: Despite higher endogenous estrogen, 17 beta-estradiol and the selective estrogen receptor modulator, tamoxifen, upregulate HSP72 in cardiomyocytes from adult females, and provide cytoprotection during hypoxia, independent of HSP induction. NF kappa B activation is necessary for the increase in HSP72, suggesting that estrogen treatment activates NF kappa B, with subsequent HSF1 activation. NF kappa B activation is critical for estrogen-associated HSP induction, and protection during hypoxia in female cardiocytes. Treatment with 17 beta-estradiol and tamoxifen may provide a novel means of protecting both male and female cardiac myocytes against hypoxia-induced damage. Further studies are needed to define the cross-talk between HSF1 and NF kappa B signaling pathways.

Animals↗
PubMed1992

Melatonin decreases estrogen receptor expression in the medial preoptic area of inbred (LSH/SsLak) golden hamsters.

Daily late afternoon injections of melatonin (25 micrograms/day s.c.) were found to reduce the number of cells expressing estrogen receptor immunoreactivity in the medial preoptic area of ovariectomized inbred (LSH/SsLak) golden hamsters. Employing immunocytochemical analysis with the H222 monoclonal antibody to the human estrogen receptor, we examined the effects of melatonin on estrogen receptor expression in the hypothalamus, particularly the medial preoptic area, of ovariectomized virgin female hamsters. Analysis of the results showed that melatonin administration induced a 50-70% decrease in numbers of estrogen receptor-immunoreactive neurons in the medial preoptic area of ovariectomized female hamsters. Furthermore, an overall qualitative decrease in the intensity of estrogen receptor immunoreactivity was observed. In intact regularly cycling female hamsters used to monitor the efficacy of melatonin treatment, there were significant reductions in the serum levels of FSH, LH, and prolactin as measured by radioimmunoassay and in uterine and pituitary weights after 8 wk of melatonin treatment. These results suggest that melatonin may exert its anti-reproductive effects in hamsters by modulating estrogen receptor levels in medial preoptic area neurons, thus influencing steroid feedback mechanisms.

Animals↗
PubMed2002

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women.

OBJECTIVE: To evaluate the effects of a 6 month administration of raloxifene hydrochloride, a selective estrogen receptor modulator which was recently approved for the prevention of osteoporosis, on serum gonadotropin and prolactin (PRL) levels and on TRH-stimulated PRL responsiveness in postmenopausal women who have not undergone estrogen replacement therapy. DESIGN AND METHODS: Sixteen healthy postmenopausal women were divided into two groups on the basis of their bone status, evaluated by dual energy X-ray absorptiometry at the lumbar level. Eight women (chronological age 52.4+/-4.1 (s.d.) years, menopausal age 42.4+/-3.9 years), in whom T-score L2-L4 was less than -2.5 s.d., were treated with raloxifene (60 mg p.o.) administered daily for 6 months (group 1), while the other eight women (chronological age 52.6+/-2.5 years, menopausal age 42.1+/-3.6 years), in whom the T-score L2-L4 ranged between -1 and -2.5 s.d., were used as a control group (group 2). Serum PRL, FSH, LH and 17beta-estradiol (E2) levels were evaluated at baseline and after 3 and 6 months of treatment. In all subjects, PRL responsiveness to TRH (200 microg i.v.) administration was evaluated at baseline and at the end of the study. RESULTS: At baseline, mean PRL, LH and FSH levels were not significantly different in the two groups (PRL 133.6+/-21.7 vs 136.7+/-28.1 mIU/l (NS), LH 25.1+/-6.8 vs 24.4+/-6.7 mIU/ml (NS), FSH 74.4+/-25.0 vs 71.1+/-24.1 mIU/ml (NS), in group 1 and group 2 respectively). No significant variations in serum FSH and LH values, in either group, or in serum PRL levels in group 2, were observed at the 3 and 6 month examinations. On the contrary, serum PRL values decreased significantly in group 1 after 3 months (100.1+/-47.7 mIU/l, P<0.05) and 6 months (81.5+/-30.2 mIU/l, P<0.001). At baseline, no significant differences were observed in the TRH-stimulated serum PRL peak between the groups (1015.4+/-30.5 vs 1030.2+/-25.7 mIU/l in group 1 and in group 2 respectively), while it decreased significantly at the 6 month examination in group 1 (770.5+/-47.4 mIU/l, P<0.001) and it was significantly lower than in group 2 (1068.1+/-301.8 mIU/l, P=0.02). Serum E2 was not detected at baseline and at each examination, in all patients. CONCLUSIONS: The decrease of PRL values induced by long-term raloxifene administration in postmenopausal women could be explained by a direct antiestrogenic effect of raloxifene on lactotrope cells or by the recently suggested increase of opiatergic tone on the hypothalamic-pituitary region.

Adult↗
PubMed2002

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells.

Estrogen receptor-mediated transcription is enhanced by overexpression of G1/S cyclins D1, E or A in the presence as well in the absence of estradiol. Excess of G1/S cyclins also prevents the inhibition of transactivation of estrogen receptor (ER) by the pure antiestrogen ICI 182780. Cyclin D1 mediates this transactivation independent of complex formation to its CDK4/6 partner. This raises the possibility that overexpression of G1/S cyclins renders growth of ER-positive breast cancer hormone-independent and resistant to treatment with antiestrogens. Transient transfection of ER-positive breast cancer cell lines T47D and MCF7 with G1/S cyclins could overcome the growth arrest induced by ICI 182780 treatment. The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A- and E2F- promoter based reporter activities in the presence of ICI 182780. Transfection of a mutant cyclin D1 (cyclin D1-KE) that was unable to bind CDK4 and was reported to transactivate ER in the presence of ICI 182780, could not stimulate proliferation in ICI 182780 treated cells. On the other hand, cyclin D1-LALA, which is unable to stimulate ERE transactivation, could overcome the ICI 182780 cell cycle arrest. Furthermore, transient transfection of T47D cells using cyclin D1 together with a catalytic inactive mutant of CDK4 (CDK4-DN) indicated that the observed effect is due to binding to CDK inhibitors. However, a moderate, sixfold overexpression of cyclin D1 in stably transfected MCF7 cells did not overcome the ICI 182780 mediated growth arrest. These results indicate that CDK-independent transactivation of the estrogen receptor by cyclin D1 is by itself, not sufficient to result in estradiol-independent growth of breast cancer cells, whereas a vast overexpression of G1/S cyclins is able to do so, most likely by capturing of CDK inhibitors.

Adenocarcinoma↗
PubMedDate not supplied

The protection against trimetrexate cytotoxicity in human bone marrow by sequence-dependent administration of raloxifene, 5-fluorouracil/trimetrexate.

BACKGROUND: Currently, one of the most effective strategies for the treatment and prevention of breast cancer is the use of drugs that block estrogen action in the breast. The success of the first clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, provided the foundation for further testing of this drug to reduce breast cancer incidence in high-risk women. However, the negative effects associated with the long-term use of tanrhoxifen have initiated the search for compounds that are more effective but less toxic. The discovery of raloxifene (RAL), which functions as a potent antiestrogen in the breast but an estrogen receptor (ER) agonist in the bone and cardiovascular system with very little uterotropic activity, provided an alternative strategy to the targeted use of tamoxifen. The aim of this study was to evaluate RAL in combination with 5-fluorouracil (5-FU)/trimetrexate (TMX) to determine the most effective regimes and cellular mechanism of action to mitigate trimetrexate cytotoxicity in human bone marrow cells. MATERIALS AND METHODS: The cell viability was performed using the Quick Cell Proliferation Assay by exposing the cells to TMX, 5-FU and RAL alone; RAL 24 h prior to 5-FU followed 2 h by TMX, and 5-FU 2 h prior to TMX followed 24 h by RAL determined the sequence-dependent interaction between TMX, 5-FU and RAL on the proliferation. RESULTS: The growth rate in MCF-7 in late RAL was 34.75 +/- 4.79% of the control, whereas in bone marrow the same drug combination exhibits a significant protection against TMX cytotoxicity with late RAL yielding 51.25 +/- 4.43% of the control. The findings were also supported by Cell flow cytometry and Western blot analysis. CONCLUSION: Sequence-dependent administration of RAL in combination with 5-FU/TMX can act against TMX toxicity in human bone marrow, while not affecting the maximum inhibitory effect of TMX in breast cancer.

Antineoplastic Agents↗
PubMed1999

SERM Drugs for the Prevention of Osteoporosis.

Although estrogens have proved useful in the prevention and treatment of osteoporosis, their side effects (for example, those on breast and endometrial cancer) are worrying to patients and physicians alike. Therefore, selective estrogen receptor modulator (SERM) drugs have been developed for use in their stead. The triphenylethylene drug tamoxifen proved to be protective against bone loss, but had side effects on uterus similar to those of natural estrogens. The tamoxifen derivative toremifene has less effect on bone. Further derivatives of tamoxifen (droloxifene, idoxifene) can be expected to act like tamoxifen when approved for clinical testing. The non-steroidal benzothiophene derivative, raloxifene, is the best SERM available thus far. It does not increase the incidence of endo-metrial cancer; in addition, like tamoxifen, it has the potential to prevent breast cancer, but has a better profile in its actions on bone (for example, it reduces the vertebral fracture rate more effectively than tamoxifen). Unlike estrogen, it decreases blood triglicerides as well as cholesterol.

Journal Article↗
PubMed2003

Alternatives for optimal hormone replacement therapy.

To satisfy the needs of women with a wide variety of different medical histories and preferences, a wide choice of various forms of hormone replacement therapy (HRT) is desirable. The potential long-term benefits of HRT, in terms of osteoporosis, cardiovascular disease and dementia, require good compliance, which in turn requires an HRT formulation that is highly acceptable. An absence of weight gain and lack of androgenic effects are of great importance, as are predictable bleeding and positive effects on postmenopausal symptoms and quality of life. HRT should be tailored to each woman's needs by the choice of appropriate estrogens and particularly a progestogen with a suitable pharmacological profile. An ideal progestogen should be targeted at preventing endometrial hyperplasia without opposing the effects of estrogen on the vessels. Several new progestogens have been synthesized in recent years. Dienogest, the progestogenic component of a new hormone replacement therapy with estradiol valerate, has many desirable features, including antiandrogenic properties; in this respect, it is unique amongst progestogens derived from testosterone. Tailored HRT should treat symptoms, minimize risk factors, meet personal preferences and lifestyle needs, and not be contraindicated for concomitant diseases. During the next decade, optimal HRT must match a number of trends, including an aging population, and is likely to be influenced by the outcome of major trials such as the Women's Health Initiative trial whose negative results will impact the prescriptions, the advent of new compounds--particularly the selective estrogen receptor modulators and progestogen receptor modulators--and the introduction of new methods of delivery, including vaginal rings and medicated intrauterine systems.

Chemistry, Pharmaceutical↗
PubMed2003

Sphingosine kinase transmits estrogen signaling in human breast cancer cells.

Current understanding of cytoplasmic signaling pathways that mediate estrogen action in human breast cancer is incomplete. Here we report that treatment with 17beta-estradiol (E2) activates a novel signaling pathway via activation of sphingosine kinase (SphK) in MCF-7 breast cancer cells. We found that E2 has dual actions to stimulate SphK activity, i.e. a rapid and transient activation mediated by putative membrane G protein-coupled estrogen receptors (ER) and a delayed but prolonged activation relying on the transcriptional activity of ER. The E2-induced SphK activity consequently activates downstream signal cascades including intracellular Ca2+ mobilization and Erk1/2 activation. Enforced expression of human SphK type 1 gene in MCF-7 cells resulted in increases in SphK activity and cell growth. Moreover, the E2-dependent mitogenesis were highly promoted by SphK overexpression as determined by colony growth in soft agar and solid focus formation. In contrast, expression of SphKG82D, a dominant-negative mutant SphK, profoundly inhibited the E2-mediated Ca2+ mobilization, Erk1/2 activity and neoplastic cell growth. Thus, our data suggest that SphK activation is an important cytoplasmic signaling to transduce estrogen-dependent mitogenic and carcinogenic action in human breast cancer cells.

Antineoplastic Agents, Hormonal↗
PubMed2000

Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells.

There is an increasing demand for natural compounds that improve women's health by mimicking the critical benefits of estrogen to the bones and the cardiovascular system but avoiding its deleterious effects on the breast and uterus. The estrogenic properties of glabridin, the major isoflavan in licorice root, were tested in view of the resemblance of its structure and lipophilicity to those of estradiol. The results indicate that glabridin is a phytoestrogen, binding to the human estrogen receptor and stimulating creatine kinase activity in rat uterus, epiphyseal cartilage, diaphyseal bone, aorta, and left ventricle of the heart. The stimulatory effects of 2.5-25 microg/animal glabridin were similar to those of 5 microg/animal estradiol. Chemical modification of glabridin showed that the position of the hydroxyl groups has a significant role in binding to the human estrogen receptor and in proliferation-inducing activity. Glabridin was found to be three to four times more active than 2'-O-methylglabridin and 4'-O-methylglabridin, and both derivatives were more active than 2',4'-O-methylglabridin. The effect of increasing concentrations of glabridin on the growth of breast tumor cells was biphasic. Glabridin showed an estrogen receptor-dependent, growth-promoting effect at low concentrations (10 nM-10 microM) and estrogen receptor-independent antiproliferative activity at concentrations of > 15 microM. This is the first study to indicate that isoflavans have estrogen-like activities. Glabridin and its derivatives exhibited varying degrees of estrogen receptor agonism in different tests and demonstrated growth-inhibitory actions on breast cancer cells.

Animals↗
PubMed2000

Chemoprevention of breast cancer by tamoxifen: risks and opportunities.

The antiestrogen tamoxifen is widely used in the adjuvant therapy of breast cancers in women and helps to prevent the occurrence of breast tumors in healthy women. However, epidemiological studies have shown tamoxifen treatment to be associated with a 2- to 5-fold increased risk of endometrial cancer. In rats but not in mice, long-term administration of tamoxifen results in an increase in hepatocellular carcinomas. Mechanistically, this occurs through metabolic activation of the drug, mainly by the CYP3A family, to an electrophilic species, that causes DNA damage in target tissues, and subsequently leads to gene mutations. It is controversial whether low levels of DNA damage occur in human uterine tissues, and there is no evidence that this can be causally related to the mechanisms of carcinogenesis. In healthy women, the risk:benefits for the use of tamoxifen is in part related to the risk of developing breast cancer. The results from the carcinogenicity studies in rats do not predict the likelihood that women will develop liver cancer or indeed cancers in other organs. The mechanism of endometrial cancer in women remains unresolved, but the experience with tamoxifen has highlighted the potential problems that need to be addressed in the assessment of future generations of selective estrogen receptor modulators.

Animals↗
PubMedDate not supplied

Oestrogenic activity of benzylparaben.

Previous work has demonstrated that the alkyl esters of p-hydroxybenzoic acid (parabens) possess oestrogenic activity, which increases with length of alkyl chain from methylparaben to n-butylparaben and with branching in the alkyl chain from n-butylparaben to isobutylparaben. This study reports on the oestrogenic activity of benzylparaben in a variety of assays in vitro and in vivo. Benzylparaben was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor (ER) of MCF7 human breast cancer cells by 22% at 1000-fold molar excess, by 40% at 10,000-fold molar excess, by 57% at 100 000-fold molar excess and by 100% at 1,000,000-fold molar excess. It was able to increase expression of a stably transfected oestrogen responsive reporter gene (ERE-CAT) in MCF7 cells after 24 h at 10(-5)M/10(-4)M and after 7 days at 10(-6)M/10(-5)M/10(-4)M. Proliferation of MCF7 cells could be increased by 10(-6)M/10(-5)M benzylparaben and this could be inhibited by 10(-7)M pure anti-oestrogen ICI 182,780, indicating that growth effects were ER mediated. Further evidence for ER-mediation was provided from the ability of benzylparaben to increase the growth of a second oestrogen-dependent human breast cancer cell line ZR-75-1, but not the oestrogen-insensitive MDA-MB-231 cell line. When tested in the presence of 10(-10)M 17beta-oestradiol, benzylparaben gave no antagonist response on the growth of either MCF7 or ZR-75-1 cells. Finally, benzylparaben could increase uterine weight in the immature mouse following topical application of three daily doses of 33 mg to dorsal skin. These results demonstrate that the oestrogenicity of methylparaben can be increased by the addition of an aryl group as well as by lengthening or branching the alkyl grouping.

Administration, Topical↗
PubMed2005

Extended adjuvant endocrine therapy of early breast cancer.

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen. This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.

Aromatase Inhibitors↗
PubMed2003

Significance of oestrogens in male (patho)physiology.

Traditionally conceptualized as 'female hormones', oestrogens appear to have significant effects in the male biological system. Favorable effects have been noted on bone, brain and cardiovascular physiology while a potential role in the prostate pathology of the aging male has been seriously suspected. Oestrogens in male are predominantly the products of peripheral aromatization of testicular and adrenal androgens. While the testicular and adrenal production of androgens declines with aging, levels of total plasma oestradiol do not decline. This is to be ascribed to the common increase in fat mass with aging (the substrate of peripheral aromatization) and an increased aromatase activity with aging. But free or bioavailable oestrogens may decline due to an increase in sex hormone binding globulin. Oestrogens produce significant beneficial effects on skeletal growth and bone maturation. In old age oestrogens are better predictors of bone fractures than androgens. Oestrogens exert effects on the brain: on cognitive function, co-ordination of movement, pain and affective state, and are maybe protective of Alzheimer's disease. Oestrogen effects on the cardiovascular system include those on lipid profiles, fat distribution, endocrine/paracrine factors produced by the vascular wall (such as endothelins, nitric oxide), blood platelets, inflammatory factors and coagulation. The potentially adverse effects of oestrogens on the prostate may be due to a shift in the oestrogen / androgen ratio with aging. Sources of estrogens in men are endogenous androgens, or in case of androgen deficiency, exogenous androgens. Dietary phytoestrogens or selective estrogen receptor modulators, as drugs, may be significant as well.

Aging↗