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PubMed1998

Estrogen metabolism and the malignant potential of human papillomavirus immortalized keratinocytes.

Increased 16alpha-hydroxylation of estradiol has been shown to be associated with heightened cancer risk in estrogen responsive tissue. Certain types of human papillomavirus (HPV) are cofactors for cancer in the cervix, an estrogen sensitive tissue. We have demonstrated that estradiol and 16alpha-hydroxyestrone increased the number of cells positive for proliferating cell nuclear antigen in HPV immortalized keratinocytes, the in vitro correlate of the premalignant keratinocyte. These estrogens caused the abnormal proliferation and anchorage independent growth, which correlates with malignant conversion. Indole-3-carbinol, a phytochemical in cruciferous vegetables known to preferentially induce 2-hydroxylation with minimal effect on 16alpha-hydroxylation, markedly blocked the ability of estradiol to increase anchorage independent growth. The results indicate that 16alpha-hydroxyestrone increases the malignant phenotype of HPV immortalized keratinocytes. However, indole-3-carbinol will block this response.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Urinary estrogen metabolites and mammographic parenchymal patterns in postmenopausal women.

It has been hypothesized that women who metabolize their endogenous estrogens predominantly via 16(alpha)-hydroxylation rather than via 2-hydroxylation and, as a result, have a low ratio of 2-hydroxyestrone (2-OHE1):16(alpha)-hydroxyestrone (16(alpha)-OHE1) are at an increased risk of breast cancer. Epidemiological evidence in support of this hypothesis is scarce and mostly based on measurements made after the onset of the disease. To gain insight into the role of these metabolites in the etiology of breast cancer, we assessed their relationship with high-density Wolfe mammographic parenchymal patterns (P2/DY), a recognized indicator of risk of this tumor. The study was nested within a large cross-sectional survey on determinants of mammographic patterns carried out in a population-based breast screening program in Northern Greece. Urinary levels of 2-OHE1 and 16(alpha)-OHE1 were measured in a random sample of 70 postmenopausal women with P2/DY mammographic patterns and in a random sample of 70 women with N1 mammographic patterns, individually matched to the P2/DY women on year of birth, years since menopause and date of urine collection. Women with a P2/DY pattern had, on average, 58% higher levels of 2-OHE1 (P = 0.002) and 15% higher levels of 16(alpha)-OHE1 (P = 0.37) than those with an N1 pattern. The ratio of 2-OHE1:16(alpha)-OHE1 was 35% higher (P = 0.005) in women with a P2/DY pattern. Women in the highest one-third of this ratio were six times more likely to have a P2/DY pattern than those in the lowest one-third after adjusting for potential confounders (prevalence odds ratio, 6.2; 95% CI, 1.7-22.9; test for linear trend, P = 0.002). These findings seem to suggest that a high, rather than a low, 2-OHE1:16(alpha)-OHE1 ratio may be associated with an increase in breast cancer risk at postmenopausal ages, unless the pathway through which estrogen metabolites may affect breast cancer risk is unrelated to mammographic parenchymal patterns.

Adult↗
PubMed1979

Effect of catechol estrogens on rat mammary tumors.

The effect of 1,3,5(10)-estratriene-3, 16 alpha, 17 beta-triol (estriol), 1, 3, 5(10)-estratriene-2,3-diol-17-one (2-hydroxyestrone), and 1,3,5(10)-estratriene-2,3,17 beta-triol (2-hydroxyestradiol) on the growth of dimethylbenz(a)anthracene-induced mammary tumor and of R3230AC-transplantable mammary tumor was compared with that produced by estradiol benzoate treatment. Estriol showed minimal inhibition of tumor growth in dimethylbenz(a)anthracene-induced tumor and no effect on R3230AC tumor while 2-hydroxyestrone showed no effect of tumor inhibition. On the other hand, 2-hydroxyestradiol showed appreciable inhibition of tumor growth in both tumors studied. That 2-hydroxyestradiol has been found to bind to estrogen receptors in mammary tumors and is uterotropic suggests that the inhibition of tumor growth by 2-hydroxyestradiol may be similar to the mechanism of inhibition of mammary tumors by high concentrations of estradiol.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

The relationship of exercise to anovulatory cycles in female athletes: hormonal and physical characteristics.

The objective of this study was to examine the mechanisms by which physical activity affects the menstrual cycle. Women with high, medium, and low levels of physical activity were compared for menstrual function, physical characteristics, and urinary and serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol-17 beta, and 2-hydroxyestrone. None of the physical characteristics other than age and muscle area were significantly different in the three groups. The percentage of body fat did not appear to be a factor in the amenorrhea induced by strenuous exercise, as the percent of body fat in all three groups was less than 22%. The group of athletes under strenuous exercise which correlated with oligomenorrhea had decreased serum levels of luteinizing hormone, prolactin, and estradiol-17 beta but elevated levels of 2-hydroxyestrone. These data suggest that anovulatory cycles are correlated with the amount of exercise and increased levels of catechol estrogens. Catecholamines and beta-endorphin elevated by exercise may interact to suppress luteinizing hormone release at the hypothalamic pituitary axis.

Adolescent↗
PubMedDate not supplied

Estrogen metabolism and human papillomavirus-induced tumors of the larynx: chemo-prophylaxis with indole-3-carbinol.

A relationship was established between estradiol 16 alpha-hydroxylation, papillomavirus and its malignant sequelae. In this study, we determined that 16 alpha-hydroxylation was substantial in normal larynx and further increased in laryngeal papillomas. Estradiol or 16 alpha-hydroxyestrone stimulated proliferation in both kinds of cells while 2-hydroxyestrone was antiproliferative. Indole-3-carbinol, which induces 2-hydroxylation, abrogated the proliferative effects of estradiol. In immunocompromised mice, papilloma cysts formed in HPV-11 infected laryngeal tissue implanted under the renal capsules in 100% of control mice but only in 25% of mice fed indole-3-carbinol.

Animals↗
PubMed1996

Measurement of urinary estrogen metabolites using a monoclonal enzyme-linked immunoassay kit: assay performance and feasibility for epidemiological studies.

We evaluated an enzyme-linked immunoassay kit (Estramet 2/16) for the measurement of 2-hydroxyestrone (2-OH E1) and 16-alpha hydroxyestrone (16 alpha-OH E1), major metabolites of estradiol. Urine samples from 14 healthy premenopausal women on days 1, 8, 15, and 22 of their menstrual cycle were assayed along with standards, kit controls, and in-house controls. The intra-assay percentage CVs of 2-OH E1, 16 alpha-OH E1, and the 2-OH E1: 16 alpha-OH E1 ratio were 6.8, 7.4, and 1.8, respectively; the interassay percentage CVs were 15.3, 30.7, and 23.3, respectively. The assay linearity was between 0 and 40 ng/ml. The mean 2-OH E1:16 alpha-OH E1 ratio was relatively constant throughout the day, but it increased by around 50% between the follicular and luteal portions of the menstrual cycle. Individual reagent kits within each lot for 16 alpha-OH E1 were stable for 2 weeks. There was considerable lot-to-lot variation over a 5-month period. In lots used during the last 2 months of the study, values of 2-OH E1 from in-house controls increased by 30-50%, and those of 16 alpha-OH E1 by 50-100%, relative to values obtained initially on the same samples. Depending on the lot, the ratio of the two metabolites ranged from 2 to 5.5. These data suggest that the assay is useful for studies where samples can be assayed with the same kit lot over a period of not more than 2 weeks, but that it is not now suitable for studies that extend over a long enough period of time so that multiple kit lots are required.

Adolescent↗
PubMed1997

Dose-ranging study of indole-3-carbinol for breast cancer prevention.

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.

Adult↗
PubMed1999

In Vitro and In Vivo Modulation of Growth Regulation in the Human Breast Cancer Cell Line MCF-7 by Estradiol Metabolites.

BACKGROUND: The natural estrogen 17 beta-estradiol (E2) functions as a potent tumor promoter during tumorigenic transformation of the mammary gland. From amongst the various pathways of E2 metabolism upregulation of C16 alpha-hydroxylation of E2 has been associated with carcinogenesis. In the present study in vitro and in vivo experiments were performed on estrogen receptor positive human breast cancer MCF-7 cells to examine whether the natural estrogen E2 and its metabolites 16 alpha-hydroxyestrone (16 alpha-OHE1) and 2-hydroxyestrone (2-OHE1)function as modulators of tumor cell growth. METHODS: An anchorage-independent growth assay was used for in vitro study bycounting the number of tri-dimensional colonies formed by MCF-7 cells suspendedin 0.33% agar. In vivo experiments examined the effect of implanting metabolitematerial pellets into female nude mice. RESULTS: In the anchorage-independent growth assay (AIG), continuous 14-day exposure to E2 and to 16 alpha-OHE1 at 200 ng/ml induced a 59.4% and a 105.9% increase (P= 0.001)respectively in the number of colonies of MCF-7 cells. Identical treatment with 2-OHE1, however, failed to increase AIG relative to that seen in the solvent treated control cultures. In the in vivo tumorigenicity assay, treatment of nude mice with 1.5 mg E2 or 16 alpha-OHE1 resulted in a 335.4% and a 384.1% increase (P< 0.0002) in tumor growth, while identical treatment with 2-OHE1 failed to exhibit any increase relative to the control group. CONCLUSION: These results suggest that the 16 alpha- and 2-hydroxylated metabolites of E2 may directly affect in vitro growth of MCF-7 cells via an autocrine mechanism and in vivo growth via paracrine mechanisms. Thus, E2-mediated growth regulation in MCF-7 cells may in part be due to distinct effects of specific E2 metabolites on the breast cancer cells.

Journal Article↗
PubMed1986

Urinary estrogen profile determination in young Finnish vegetarian and omnivorous women.

For a long time it has been postulated that diet may influence estrogen metabolism and in this way affect breast cancer risk. In order to investigate possible effects of variations of dietary fiber intake on estrogen metabolism, the urinary estrogen profile (13 estrogens), including the catecholestrogens, was determined in one 72-h summer and one winter sample collected in the midfollicular phase of the menstrual cycle by 11 lactovegetarian and 12 omnivorous young Finnish women. Urinary estrogens were purified by ion-exchange chromatography and the quantitative determination was carried out by capillary gas chromatography-mass spectrometry. Detailed records of the subjects' diet during one 5-day period in summer and one in winter were obtained and dietary fiber intake calculated. The mean difference with regard to intake of total fiber in the two dietary groups was 3 g/day in the summer (not significant) and 5 g/day in the winter (P less than 0.05), the mean (geometric) consumption being 23 and 19 g/day by the vegetarian and omnivorous women, respectively. Within the groups we found seasonal variation in fiber intake only for the omnivorous women. During winter, compared to summer, the omnivorous women consumed significantly less grain (P less than 0.001), vegetable (P less than 0.02) and total fiber (P less than 0.02). The excretion of 13 estrogens was remarkably constant in the omnivoric group but a significant seasonal variation of total and individual catecholestrogens and of estrone was observed in the vegetarians (P less than 0.05-0.005). The quantitatively most important estrogen was 2-hydroxyestrone, followed by estrone, estriol, 2-hydroxyestradiol, 4-hydroxyestrone and estradiol, the three latter being excreted in similar amounts. Between the dietary groups there were no significant differences in excretion of total or individual urinary estrogens in any season or between the mean values for both seasons. However, numerous significant (P less than 0.05-0.01) negative correlations between dietary intake of total or grain fiber/kg body weight and the excretion of individual estrogens were found. These correlations disappeared if the fiber intake was not related to body weight. We conclude that dietary fiber intake significantly affects estrogen metabolism by reducing estrogen excretion in urine and that grain fiber seems to be most important in that respect. One of the mechanisms involved is a partial interruption of the enterohepatic circulation of the estrogens, due to alterations of the intestinal metabolism and reabsorption of these steroids, caused by the fiber.

Adult↗
PubMed1987

Metabolism of exogenous 4- and 2-hydroxyestradiol in the human male.

The metabolic fate of the isomeric catecholestrogens 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2) was studied to elucidate possible differences in their metabolism as an explanation for their different bioactivities. Healthy young men (n = 3 each) were infused (90 min) with 4-OHE2 (60 micrograms/h) or 2-OHE2 (100 micrograms/h). The main metabolites were determined in plasma and urine before, during and after infusion. Unconjugated and conjugated steroids, the latter after hot acid hydrolysis, were subjected to chromatography on LH-20 columns and measured by specific RIAs. During the infusion 4-OHE2 reached significant plasma concentrations whereas 2-OHE2 was so rapidly metabolised that its plasma levels remained virtually undetectable in spite of a higher infusion rate. The metabolism of 4-OHE2 was dominated by direct conjugation, that of 2-OHE2 by methyl ether formation. These findings were corroborated by the urinary excretion rates: during the infusion and the first hours afterwards, 4-OHE2 was mainly excreted as 4-OHE2 and 4-hydroxyestrone, while 2-OHE2 was predominantly excreted as 2-hydroxyestradiol 2-methyl ether and 2-hydroxyestrone 2-methyl ether.

Adult↗
PubMedDate not supplied

Increased urinary catechol estrogen excretion in female smokers.

Premenopausal female smokers show significantly increased estrogen 2-hydroxylation, which may account in part for the anti-estrogenic effects of cigarette smoking. We have measured five major urinary estrogens, including estradiol (E2), estrone (E1), 16 alpha-hydroxyestrone (16 alpha OHE1), estriol (E3), and 2-hydroxyestrone (2OHE1), in premenopausal female smokers and non-smokers, to determine whether increased C-2 hydroxylation affected the urinary excretory patterns in these subjects. While total measured estrogen excretion in the follicular phase did not differ significantly between the two groups, urinary 2OHE1 among the smokers constituted a significantly greater proportion of the total (31.1 vs 18.2%, P less than 0.02). This difference was largely caused by significantly increased urinary 2OHE1 and decreased E3 observed in smokers. A urinary catechol estrogen index, defined by [2OHE1]/[E3], was significantly elevated in smokers compared with non-smokers (1.67 +/- 0.21 vs 0.56 +/- 0.08, P less than 0.001), and this urinary index correlated strongly with radiometrically determined estrogen 2-hydroxylation (r = 0.84, P less than 0.01). Ratios of the various estrogen metabolites did not vary substantially throughout the menstrual cycle. Urinary estrogen indices as described here may therefore be useful in demonstrating differences in estrogen metabolism, specifically 2-hydroxylation vs 16 alpha-hydroxylation, in selected populations.

Adult↗
PubMed1992

Gas chromatography/mass spectrometry of catechol estrogens.

Catecholestrogens (CCEs), namely 2- or 4-hydroxyestradiol and hydroxyestrone, are highly polar, reactive, and extremely labile estrogen metabolites in many experimental conditions. For these reasons, indirect assay methods mainly have been used. Some experimental evidence suggests that CCEs are synthesized and biologically active mostly in target cells. At this level, unfortunately, the indirect assays cannot be used. We present a method of gas chromatographic/mass spectral (GC/MS) analysis for the identification of individual CCEs; the major fragmentation ions of authentic estrogen standards as trimethylsilylether derivatives, and the MS patterns of the major CCEs, namely, 2-hydroxyestradiol and hydroxyestrone, are included. Few examples of CCEs detected in human breast cancer tissues and in breast cyst fluids are reported. Sample extracts were submitted to reversed-phase, high-performance liquid chromatography (RP-HPLC) and were quantified by "on line" electrochemical (EC) detection; thereafter, either crude extracts or single eluted peaks were submitted to GC/MS, by which detection limits of less than 5 pmol were attained. As expected, the molecular ion was the most relevant molecule in all but one case. On the contrary, the other relative intensities of major fragmentation ions M -15, M -30, M -90, and M -15 + (-90) were unevenly distributed, although represented in the majority of cases. In all cases, the GC/MS of peak fractions, purified by RP-HPLC and UV detection, confirmed the results of liquid chromatographic analysis combined with EC detection. In contrast, GC/MS of crude extracts was not equally satisfactory. Comparison of a liquid chromatography system with EC detection and the GC/MS approach revealed some inconsistency in quantitation of individual CCEs.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1996

Modulation of hypertensive heart disease by estrogen.

UNLABELLED: Left ventricular hypertrophy is an independent risk factor for morbidity and mortality in patients with hypertensive heart disease. Cardiac hypertrophy, associated with increased cardiac fibrosis and myocardial relaxation impairment, shows gender-based differences with significantly higher mortality in men. The role of estrogen in the pathogenesis of this process is poorly understood. After our previous demonstration that cardiac myocytes and fibroblasts contain functional estrogen receptors, we therefore investigated: 1) the influence of different estrogen metabolites on cardiac fibroblast growth; 2) the influence of different estrogen metabolites on the expression of the immediate early gene c-Fos; 3) the influence of estrogen on the L-type calcium channel in cardiomyocytes. METHODS: 1) Neonatal rat cardiac fibroblasts were incubated with 17 beta-estradiol, estrone, 2-hydroxyestrone, and 2-methoxyestradiol (all 10(-9) M). Bromodeoxyuridine incorporation was measured after 24 h. 2) c-Fos expression was demonstrated by immunoblotting. 3) L-type (Ca2+) current with and without 17 beta-estradiol was assessed in adult guinea pig cardiomyocytes by whole cell patch clamp. RESULTS: Cardiac fibroblast growth was stimulated by estrogen metabolites with 2-hydroxyestrone as the most potent activator; in addition, 10(-5) M 17 beta-estradiol reduced the L-type Ca2+ current by about 20% in cardiomyocytes. CONCLUSIONS: Estrogen induces both short term effects (non-genomic) and long term effects (genomic) on the heart and may therefore account for gender- and age-based differences in hypertensive heart disease.

Animals↗
PubMedDate not supplied

P450 enzymes of estrogen metabolism.

Endogenous and exogenous estrogens undergo extensive oxidative metabolism by specific cytochrome P450 enzymes. Certain drugs and xenobiotics have been found to be potent inducers of estrogen hydroxylating enzymes with C-2 hydroxylase induction being greater than that of C-16 hydroxylase. Oxygenated estrogen metabolites have different biological activities, with C-2 metabolites having limited or no activity and C-4 and C-16 metabolites having similar potency to estradiol. Pathophysiological roles for some of the oxygenated estrogen metabolites have been proposed, e.g. 16 alpha-hydroxyestrone and 4-hydroxyestrone. These reactive estrogens are capable of damaging cellular proteins and DNA and may be carcinogenic in specific cells.

Animals↗
PubMed2004

Identification of UGT2B9*2 and UGT2B33 isolated from female rhesus monkey liver.

Two UDP-glucuronosyltransferases (UGT2B9(*)2 and UGT2B33) have been isolated from female rhesus monkey liver. Microsomal preparations of the cell lines expressing the UGTs catalyzed the glucuronidation of the general substrate 7-hydroxy-4-(trifluoromethyl)coumarin in addition to selected estrogens (beta-estradiol and estriol) and opioids (morphine, naloxone, and naltrexone). UGT2B9(*)2 displayed highest efficiency for beta-estradiol-17-glucuronide production and did not catalyze the glucuronidation of naltrexone. UGT2B33 displayed highest efficiency for estriol and did not catalyze the glucuronidation of beta-estradiol. UGT2B9(*)2 was found also to catalyze the glucuronidation of 4-hydroxyestrone, 16-epiestriol, and hyodeoxycholic acid, while UGT2B33 was capable of conjugating 4-hydroxyestrone, androsterone, diclofenac, and hyodeoxycholic acid. Three glucocorticoids (cortisone, cortisol, and corticosterone) were not substrates for glucuronidation by liver or kidney microsomes or any expressed UGTs. Our current data suggest the use of beta-estradiol-3-glucuronidation, beta-estradiol-17-glucuronidation, and estriol-17-glucuronidation to assay UGT1A01, UGT2B9(*)2, and UGT2B33 activity in rhesus liver microsomes, respectively.

Amino Acid Sequence↗
PubMed2006

CYP1A1 and CYP1B1 polymorphisms and their association with estradiol and estrogen metabolites in women who are premenopausal and perimenopausal.

The purpose of this study was to relate measured concentrations of estradiol (E2) and the urinary estrogen metabolites 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1) to single nucleotide polymorphisms (SNPs) from CYP1A1 and CYP1B1, the primary genes involved in estrogen catabolism. We investigated the association of 4 CYP1A1 SNPs (CYP1A1 rs4646903, CYP1A1 rs1531163, CYP1A1 rs2606345, and CYP1A1 rs1048943) and 2 CYP1B1 SNPs (CYP1B1 rs162555 and CYP1B1 rs1056836) to circulating serum E2 concentrations and the urinary estrogen metabolites 2-OHE1 and 16alpha-OHE1. The associations were evaluated in 1,340 participants of 4 racial/ethnic groups from the Study of Women's Health Across the Nation (SWAN) who were premenopausal and perimenopausal. There was substantial variation in the allele frequencies of the SNPs for African American and Caucasian women. There was, however, remarkable comparability between Chinese and Japanese women; their CYP1A1 and CYP1B1 allele frequencies differed by only < or =11%. There was significant variation in E2 concentrations by genotype within racial/ethnic group for CYP1A1 rs2606345. In particular, Japanese women with the CC genotype had lower E2 concentrations than did Japanese women with the AC genotype. Chinese women with the CC genotype had higher 2-OHE1 concentrations than did Chinese women with the AC genotype. Further, African American women with the CC genotype had higher 16alpha-OHE1 concentrations than did those with other genotypes. CYP1A1 rs2606345 may play an important role in estrogen metabolism in women who are premenopausal and perimenopausal.

Aryl Hydrocarbon Hydroxylases↗
PubMed2004

The oxidative metabolism of estrogen modulates response to ERT/HRT in postmenopausal women.

We have previously demonstrated that estrogen metabolism is one of the determinants of bone density after menopause. Increased hydroxylation to relatively nonestrogenic metabolites 2-hydroxyestrone (2OHE1) and 2-methoxyestrone (2MeOE1) was associated with low bone mineral density (BMD), while increased hydroxylation to the potent 16alpha-hydroxyestrone (16alphaOHE1) and weakly estrogenic estriol (E3) was associated with higher BMD. In this study, we tested the hypothesis that response to estrogen-hormone replacement therapy (ERT/HRT) is also related to individual differences in estrogen metabolism. Urinary estrogen metabolites were measured in 310 postmenopausal women using ESTRAMET enzyme immunoassay kit. Of these, 163 were on HRT with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA, Premarin and Provera) or ERT with conjugated equine estrogen alone (Premarin), and 147 women not on ERT/HRT acted as comparison. Annual rates of BMD changes were calculated on a subset of 81 women on ERT/HRT who had more than one previous BMD measured by dual-energy X-ray absorptiometry (DEXA). Controlling for age, years since menopause (YSM), body mass index (BMI), waist to hip ratio, and smoking, we found that urinary estrogen metabolite levels were significantly higher in ERT/HRT-treated women compared to those not on ERT/HRT. Furthermore, women in the higher 2 tertiles of 2OHE1 and 2OHE1/16áOHE1 ratio had positive increments in BMD compared to those in the lowest tertile who lost bone while on ERT/HRT. Thus, women with estrogen metabolism favoring the 2-hydroxylation pathway respond favorably to ERT/HRT.

Analysis of Variance↗
PubMed2004

Effects of estrogens and metabolites on endometrial carcinogenesis in young adult mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine.

The present study assessed effects of estrogens and their steroid metabolites on the endometrial carcinogenesis in young adult mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). A total of 272 female CD-1 (ICR) mice were used and equally divided into 17 groups. Mice were implanted cholesterol pellets to the back subcutis at 9 weeks of age. Pellets contained nothing (control) or one of the experimental agents, three different estrogens and their 13 different steroid metabolites, at a concentration of 0.5% (w/w). At 10 weeks of age, mice were given a single intra-uterine administration of ENNG at a dose of 25 mg/kg body weight. When reaching the 30 weeks of age (20 weeks after the ENNG treatment), mice were sacrificed to assess the development of endometrial proliferative lesions. While endometrial proliferative lesions, including hyperplasias and adenocarcinomas, were observed in all groups, the incidences of hyperplasias in the groups treated with 2-hydroxyestriol, 2-methoxyestradiol, 2-methoxyestriol and 16-epiestriol were significantly higher than that in the control group. On the other hand, adenocarcinomas were significantly developed in the groups treated with estrone, estradiol, estriol, 16beta-hydroxyestrone, 16alpha-hydroxyestrone and 17-epiestriol. These results indicate that, on the endometrial carcinogenesis in mice initiated with ENNG, estrogens and their metabolites belonging to the 16alpha-hydroxylation pathway and the upstream of the 16beta-hydroxylation pathway exert both promoting and progressing effects, whereas, the estrogen metabolites belonging to the 2- and 4-hydroxylation pathways (catechol estrogens) and the downstream of the 16beta-hydroxylation pathway exert only promoting or no effects. It is thus suggested that a metabolic profile of estrogens may be crucial for the endometrial carcinogenesis and that the rate of the 16alpha-hydroxylation may be associated with the increased carcinogenic risks of estrogens on the endometrium.

Adenocarcinoma↗