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Transdermal estrogen therapy and the risk of breast cancer: a clinical appraisal
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
The 2- and 4-hydroxy metabolites are methoxylated via catechol-o-methyltransferase (COMT) activity into anticarcinogenic metabolites (Figure 1). Genetically determined abnormal COMT activity may result in decreased formation of the estrogen-inhibiting 2-methoxyestrone estrogens and a diminished inactivation of the biologically potent 4-OHE1 estrogens. The net result is an increase in active breast tissue estrogen. Postmenopausal women with a variant COMT allele are at increased risk of breast cancer11.
Hydroxylated C18 and C19 Steroids; Their Significance and Factors Related to Their Biosynthesis
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
The pioneering work of Twombly and Levitz155 demonstrated considerable metabolism of ingested 14C-estrone sulfate by the human. Since only one label was used in that study, it was impossible to decide to what degree direct metabolism of the intact conjugate had occurred as compared with that following hydrolysis of the sulfate. More recent work156 in the same laboratory involved intravenous injection of 3H/35S-estrone sulfate into a woman who had a biliary fistula. Careful analysis of biliary and urinary metabolites revealed a considerable number of 2-, 16-, and 15-hydroxy metabolites. Due to the difficulty involved in separating the various monosulfates from each other in an intact form, it was difficult to state with confidence that hydroxylation of the estrone sulfate had occurred. However, the estriol-3-sulfate formed did contain some 35S, indicating probably some direct conversion. Stronger evidence for direct 2-hydroxylation of estrone sulfate has been obtained157 in the adult human by administering the 3H/35S form and subsequently recovering estrone sulfate, the 3-sulfate of 2-methoxyestrone [2-methyl-2,3-dihydroxyestra-1,3,5(10)-trien-17-one], and 2-hydroxyestrone-2-sulfate from the urine. The first two conjugates contained 23 and 21%, respectively, of the original 35S while the 2-sulfate of 2-hydroxyestrone contained 7%. This was attributed to direct hydroxylation of the substrate followed by partial O-methylation, on the one hand, and partial conversion of the 2-hydroxyestrone-3-sulfate to the 2-sulfate, with some loss of isotope, on the other. The absence of sulfatase activity in the human fetus158 has enabled investigators to demonstrate159 that estrone sulfate is, in these circumstances, the main substrate for 15α- and 16α-hydroxylase activities. Evidence that 2-hydroxysteroid formation may occur via estrone sulfate has been presented for rat160,161 and monkey162 liver systems.
Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial
Published in Nutrition and Cancer, 2019
Vicky C. Chang, Michelle Cotterchio, Beatrice A. Boucher, David J. A. Jenkins, Lucia Mirea, Susan E. McCann, Lilian U. Thompson
Serum sex hormone assays were performed by the Mount Sinai Services laboratory. Concentrations of total [conjugated (glucuronidated and sulfated) plus unconjugated] estradiol, estrone, estriol, and 2-methoxyestrone were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) as previously described (40,41). Briefly, standards for each estrogen and estrogen metabolite (Steraloids Inc., Newport, RI) and deuterated internal standards (Cambridge Isotope Laboratories, Andover, MA) were added to serum samples, followed by enzymatic hydrolysis with β-glucuronidase/arylsulfatase from Helix pomatia (Sigma Aldrich Canada Co., Oakville, ON). After incubation at 37 °C for 18 h, samples were extracted with methyl tert-butyl ether, evaporated under nitrogen gas, reconstituted in 70:30 water:methanol, and analyzed using the AB SCIEX Triple Quad™ 6500 LC-MS/MS System (AB Sciex, Concord, ON). Levels of 2-hydroxyestrone and 16α-hydroxyestrone were measured using Estramet™ enzyme immunoassay (EIA) kits (Immuna Care Corporation, Tampa, FL) (42) (because the laboratory was unable to detect levels of 2-hydroxyestrone using LC-MS/MS). The ratio of 2-hydroxyestrone to 16α-hydroxyestrone was also calculated. Estrone sulfate and androstenedione were analyzed using enzyme-linked immunosorbent assay kits (MyBioSource, Inc., San Diego, CA). DHEAS was measured by a competitive binding immunoenzymatic assay on the Unicel DxI 600 Access Immunoassay System (Beckman Coulter Canada, Mississauga, ON). Testosterone, prolactin, and SHBG were quantified using electrochemiluminescence immunoassays on the Roche Modular Analytics immunoassay analyzer (Roche Diagnostics Canada, Laval, QC). Free (non-albumin- and non-SHBG-bound) estradiol concentration was calculated from measured estradiol and SHBG concentrations and an assumed constant for albumin (4 g/dl), according to a validated algorithm based on the law of mass action (43). Calculated free estradiol concentrations have been shown to correlate strongly with directly measured values (43).
Synthesis, characterization and in vivo evaluation of cadmium telluride quantum dots toxicity in mice by toxicometabolomics approach
Published in Toxicology Mechanisms and Methods, 2018
Maryam Khoshkam, Yasamin Baghdadchi, Roghaye Arezumand, Ali Ramazani
Treatment of mice with different doses of QDs and CdCl2 resulted in alterations in the following pathways: steroid hormone biosynthesis, lysine biosynthesis, steroid biosynthesis, taurine and hypotaurine metabolism, starch, and sucrose metabolism and primary bile acid biosynthesis. Since only the first two of these pathways were considered statistically significant (p < 0.05 and FDR < 1), we will restrict our discussion to them. Our data in Table 2 exhibited that among altered pathways; steroid hormone biosynthesis shows the most significant perturbation in treated groups. Information on Table 2 shows that 72 metabolites are involved in the biosynthesis of steroid hormones, which 22 of them are altered due to treatment with QDs or CdCl2. One study consistent with our data reports that different nanoparticles can alter the endocrine system in different levels including biosynthesis of hormones (Iavicoli et al. 2013). Aldosterone, cortisone, estrogens, and progesterone are main altered metabolites. Also, cholesterol and cholesterol sulfate as the main precursors of steroid hormones are changed. Since the studied mice were female here and metalloestrogenic effects of cadmium have been demonstrated before, the alteration of estrogenic metabolites is more notable. Cadmium activates MAPK/ERK, and Ref-1 and is known as a potent activator/modulator of the mitogenic effects associated with estrogen receptor stimulation (Wallace 2015). In vivo studies have shown that cadmium mimics the effects of estrogen in target organs and induce hormone-regulated genes in ovariectomized animals (Johnson et al. 2003). Specific hormonal conditions and disturbed hormonal homeostasis was reported due to cadmium exposure (Silva et al. 2012). Although there are persuasive in vitro and in vivo studies regarding the metalloestrogenic effect of cadmium, the data are conflicting and not concentrated. Thus, we face a knowledge gap in this area (Nasiadek et al. 2011). Our data exhibited altered levels of several estrogenic metabolites including 16a-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestrone, 2-methoxyestradiol, 2-methoxyestrone, estradiol, and 2-methoxyestradiol. Nevertheless, the mechanism of induced alteration by cadmium remains to be elucidated.