equilin and Breast-Neoplasms

The data concerning post-menopausal hormone replacement therapy (HRT) were recently completely modified. The aim of this review is to present the last studies about post-menopausal HRT and to describe new alternatives to this treatment.. In May 2002, the women's health initiative (WHI) trial of post-menopausal HRT was interrupted earlier than expected. The studied hormonal formulation in this arm of the WHI trial was the association of conjugated equine estrogens and medroxyprogesterone. The reason for termination was an increased risk of breast cancer and myocardial infarction in the hormone-therapy group. Later, reports confirmed that this type of HRT could not be used any more for the primary prevention of coronary heart disease even if the absolute risk remained low. There is an increased risk for venous thromboembolism with post-menopausal estroprogestative replacement. This risk does not seem to exist with transdermal estrogens. The other WHI findings concerned the lack of protection against dementia and cognitive decline. On the contrary, osteoporotic hip fractures and colorectal cancers were reduced in the treated group. In April 2004, the estrogen only arm of the same WHI study was also prematurely interrupted because of an increase in the incidence of stroke. The risk of breast cancer was on the contrary not increased after 6.8 years, raising the question of the eventual role of progestins.. The impact of the WHI trial on clinical practice was very important since then. The "Agence Francaise de sécurité sanitaire des produits de santé" (AFSSAPS) edited in May 2004 a public recommendation limiting indication for HRT to patients with severe climacteric symptoms. The treatment must now be prescribed for the shortest time and at the minimal dose. The patient has to be precisely informed about the risks with HRT and the practitioner has to re-evaluate his prescription annually. Hormonal or non-hormonal alternatives have also to be considered as phytoestrogens and tibolone for hot flashes, and raloxifene and diphosphonates for osteoporosis prevention. In any case, a healthy diet, exercise and smoking cessation should be encouraged.

Topics: Breast Neoplasms; Clinical Trials as Topic; Equilin; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Life Style; Medroxyprogesterone; Menopause; Myocardial Infarction; Phytoestrogens; Risk Assessment; Thromboembolism; Treatment Outcome

A combination of E and progestogens significantly increased matrix metalloproteinase (MMP)-2 in both T47D cells (E(2)-medroxyprogesteroneacetate [MPA] and E(2)-P) and MCF-7 cells (E(2)-MPA, E(2)-P, and equilin-MPA). All combinations resulted in higher MMP-9 levels in MCF-7 cells, but higher MMP-9 levels resulted only with equilin-norethinderone in T47D cells.

Topics: Breast Neoplasms; Cell Line, Tumor; Equilin; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Medroxyprogesterone Acetate; Norethindrone; Norethindrone Acetate; Progesterone

So far, most epidemiological studies investigating breast cancer risk and hormone replacement therapy have been conducted with conjugated equine estrogens (CEE). Recent trials indicate that the addition of progestogens may increase breast cancer risk. In the present study, we compared the effects of the human estrogen 17beta-estradiol (E(2)) with those of the main equine components of CEE, i.e. equilin (Eq) and 17alpha-dihydroequilin (Dheq) on the proliferation of human breast cancer cells. The proliferative effect of progestogen addition was also investigated.. The well-established human breast cancer cell line MCF-7 was used as an in vitro model. The proliferative effect of E(2), Eq and Dheq was tested in the concentration range 0.01-10 nmol/l. The progestogens progesterone, medroxyprogesterone acetate (MPA) and norethisterone (NET) were continuously combined with 0.1 nmol/l estrogen at concentrations of 0.01 nmol/l, 1 nmol/l, 0.1 mumol/l and 10 mumol/l. Proliferation was measured after 7 days by the adenosine triphosphate (ATP) chemosensitivity test.. All three estrogens increased the proliferation of MCF-7 cells by between 40 and 180%. The most proliferatively potent estrogen was E(2), followed by Eq and Dheq, which showed a slightly lower proliferative activity than E(2). The addition of progesterone inhibited E(2)-induced proliferation by about 30%, but only at the high non-physiological concentration of 10 mumol/l. All three progestogens inhibited Eq-induced proliferation, although their effect tended to be low, with values between 5 and 40%. No progestogen reduced Dheq-induced proliferation by more than 20%. In contrast, MPA slightly increased the proliferation rate by about 5% at the high physiological concentration of 0.1 mumol/l when combined with Dheq. The same held true when MPA and NET were added at the high pharmacological concentration of 10 mumol/l, causing increases of about 10%.. Our results indicate that equine estrogens have a proliferative action similar to that of 17beta-estradiol. Continuous addition of progestogens does not result in any major reduction of proliferative potency. Some progestogens may even enhance the estrogen-induced proliferation of pre-existing breast cancer cells, particularly when combined with certain equine estrogens. However, in none of the tested circumstances do progestogens increase the proliferative effect of estradiol, and progesterone has no deleterious effect even at pharmacological levels, in contrast to progestogens.

Topics: Breast Neoplasms; Cell Division; Dose-Response Relationship, Drug; Equilin; Estradiol; Estrogens, Conjugated (USP); Female; Humans; Medroxyprogesterone Acetate; Norethindrone; Progesterone; Progestins; Tumor Cells, Cultured

The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with a slight increased cancer risk. Previously, we showed that equilenin, a minor component of Premarin (Wyeth-Ayerst), was metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. In this study, we have compared the chemistry of the major catechol metabolite of equilin (4-hydroxyequilin), which is found in several estrogen replacement formulations, to the equilenin catechol (4-hydroxyequilenin). Unlike endogenous catechol estrogens, both equilin and equilenin were primarily converted by rat liver microsomes to 4-hydroxylated rather than 2-hydroxylated o-quinone GSH conjugates. With equilin, a small amount of 2-hydroxyequilin GSH quinoids were detected (4-hydroxyequilin:2-hydroxyequilin ratio of 6:1); however, no peaks corresponding to 2-hydroxyequilenin were observed in incubations with equilenin. These data suggest that unsaturation in the B ring alters the regiochemistry of P450-catalyzed hydroxylation from primarily 2-hydroxylation for endogenous estrogens to 4-hydroxylation for equine estrogens. 4-Hydroxyequilenin-o-quinone reacts with GSH to give two mono-GSH conjugates and one di-adduct. The behavior of 4-hydroxyequilin was found to be more complex than 4-hydroxyequilenin as conjugates resulting from 4-hydroxyequilenin were detected in addition to the 4-hydroxyequilin-GSH adducts. The mechanism of decomposition of 4-hydroxyequilin likely involves isomerization to a quinone methide which readily aromatizes to 4-hydroxyequilenin followed by autoxidation to 4-hydroxyequilenin-o-quinone. Similar results were obtained with 2-hydroxyequilin, although, in contrast to 4-hydroxyequilenin, 2-hydroxyequilenin does not autoxidize and the reaction stops at the catechol. Since 4-hydroxyequilin is converted to 4-hydroxyequilenin and 4-hydroxyequilenin-o-quinone, similar effects were observed for this equine catechol, including consumption of NAD(P)H likely by the 4-hydroxyequilenin-o-quinone, depletion of molecular oxygen by 4-hydroxyequilenin or its semiquinone radical, and alkylation of deoxynucleosides and DNA by 4-hydroxyequilenin quinoids. Finally, preliminary studies conducted with the human breast tumor cell line MCF-7 demonstrated th

Topics: Animals; Breast Neoplasms; Cytochrome P-450 Enzyme System; Equilenin; Equilin; Estradiol Congeners; Estrone; Female; Humans; Microsomes, Liver; Oxidation-Reduction; Quinones; Rats; Rats, Sprague-Dawley; Stereoisomerism; Tumor Cells, Cultured

Topics: Animals; Breast Neoplasms; Equilenin; Equilin; Estradiol; Estrogens; Estrogens, Catechol; Ethinyl Estradiol; Female; Humans; Hydroxyestrones; Hydroxylation; Microsomes, Liver; Papio