Modern approaches to the treatment of mastopathy and correction of hyperestrogenic conditions in women of fertile age

Among the diseases that can lead to miscarriage and premature termination of a planned pregnancy, hyperestrogenic conditions play an important role. The state of impaired synthesis of estradiol metabolites significantly affects the development of mastopathy, endometrial hyperplasia, impaired implantation of fertilized eggs, metabolic disorders in women and is a risk factor for cancer of the reproductive system.To date, the urgency of the problem of hormonal diseases of the female reproductive system, including the mammary glands, is beyond doubt. In this case, dyshormonal diseases of the breast are a reflection of hormonal disorders of the entire female body and serve as a basis for the development of breast cancer. The main method of treatment for dyshormonal processes is hormone replacement therapy, but currently there is an alternative to hormonal drugs, which include non-hormonal phytotherapeutic complexes based on the biologically active substances indole-3-carbinol, barberry extract and polyphenols that normalize estrogen antiproliferative activity, have an antioxidant effect, implement antitumor action.

Nordihydroguaiaretic Acid as a Novel Substrate and Inhibitor of Catechol O-Methyltransferase Modulates 4-Hydroxyestradiol-Induced Cyto- and Genotoxicity in MCF-7 Cells

Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in Larrea spp., which are widely used in South America to treat various diseases. In breast tissue, estradiol is metabolized to the catechol estrogens such as 4-hydroxyestradiol (4-OHE2), which have been proposed to be cancer initiators potentially involved in mammary carcinogenesis. Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens to their less toxic methoxy derivatives, such as 4-O-methylestradiol (4-MeOE2). The present study investigated the novel biological activities of NDGA in relation to COMT and the effects of COMT inhibition by NDGA on 4-OHE2-induced cyto- and genotoxicity in MCF-7 human breast cancer cells. Two methoxylated metabolites of NDGA, 3-O-methylNDGA (3-MNDGA) and 4-O-methyl NDGA (4-MNDGA), were identified in the reaction mixture containing human recombinant COMT, NDGA, and cofactors. Km values for the COMT-catalyzed metabolism of NDGA were 2.6 µM and 2.2 µM for 3-MNDGA and 4-MNDGA, respectively. The COMT-catalyzed methylation of 4-OHE2 was inhibited by NDGA at an IC50 of 22.4 µM in a mixed-type mode of inhibition by double reciprocal plot analysis. Molecular docking studies predicted that NDGA would adopt a stable conformation at the COMT active site, mainly owing to the hydrogen bond network. NDGA is likely both a substrate for and an inhibitor of COMT. Comet and apurinic/apyrimidinic site quantitation assays, cell death, and apoptosis in MCF-7 cells showed that NDGA decreased COMT-mediated formation of 4-MeOE2 and increased 4-OHE2-induced DNA damage and cytotoxicity. Thus, NDGA has the potential to reduce COMT activity in mammary tissues and prevent the inactivation of mutagenic estradiol metabolites, thereby increasing catechol estrogen-induced genotoxicities.

In Vitro Maturation of Fully Grown Mouse Antral Follicles in the Presence of 1 nM 2-Hydroxyestradiol Improves Oocytes’ Developmental Competence

Cathecolestrogens are estradiol metabolites produced during folliculogenesis in the mammalian ovary. 2-Hydroxyestradiol (2-OHE2) is one of the most abundant although its role remains unknown. The aim of this study is to investigate whether the presence of 2-OHE2 during the germinal vesicle-to-metaphase II transition affects oocyte meiotic and preimplantation developmental competence. Mouse cumulus-oocyte complexes (COCs), isolated from fully grown antral follicles, were in vitro–matured (IVM) in the presence of 2-OHE2 (0.1, 1, 10 or 100 nM) for 6 or 15 h; then, their meiotic and developmental competence was evaluated using a number of cytological quality markers. With the exception of the highest dose (100 nM), the addition of 2-OHE2 to the IVM medium, did not alter, compared with untreated control, the frequency of oocytes that reached the MII stage. Instead, IVM in the presence of 1 nM 2-OHE2 highly increased the rate of preimplantation development and blastocyst quality. To understand whether this positive effect could be attributed to the events occurring during meiosis resumption, we analysed a number of specific cytological quality markers of the asymmetric division, such as PB-I volume and position, presence and extension of the cortical F-actin cap, meiotic spindle shape and area, and microtubule organisation centre localisation. The results highlighted how the presence of 1 nM 2-OHE2 significantly improved the overall cytological organisation required for a correct asymmetric division. Our results contribute a first step to acknowledge a potential role of this estradiol metabolite during the GV-to-MII transition, contributing to the acquisition of oocytes developmental competence.

Effect of estrogens and their metabolites genotoxicity on the pathogenesis and progression of estrogen-dependent breast cancer

Oncological diseases, due to the still increasing morbidity and mortality, are one of the main problems of modern medicine. Cancer of the mammary gland is the most common cancer among women around the world, and is the second cause of cancer deaths in this group, immediately after lung cancer. This kind of cancer belongs to an estrogen-dependent cancer, with proven associations with hormonal disorders in the body, occurring especially in the perimenopausal period and among women using hormone replacement therapy, as well as a result of the action of various xenobiotics that may interact with the estrogen receptor. Hormone steroids are widely used in medicine and their side effects are constantly discussed. The role of these compounds and their metabolites in maintaining hormonal balance is well understood, while many studies indicate the possible contribution of these steroids in the progression of the cancer process, especially in mammary gland tissue. Therefore, the genotoxic action of this group of compounds is still studied. Due to the limited number of scientific reports, the aim of this paper was to review and critically analyze data from the literature regarding the participation of estrogens (17β-estradiol) and their metabolites (2-methoxy estradiol, 4-hydroxy estradiol, 16α-hydroxyestrone) in the induction of carcinogenesis in mammary gland, in particular concerning the genotoxic activity of 17β-estradiol metabolites.