RESUMEN
BACKGROUND: Studies have shown associations of diabetes and endogenous hormones with exposure to a wide variety of organochlorines. We have previously reported positive associations of polychlorinated biphenyls (PCBs) and inverse associations of selected steroid hormones with diabetes in postmenopausal women previously employed in a capacitor manufacturing plant. METHODS: This paper examines associations of PCBs with diabetes and endogenous hormones in 63 men previously employed at the same plant who in 1996 underwent surveys of their exposure and medical history and collection of bloods and urine for measurements of PCBs, lipids, liver function, hematologic markers and endogenous hormones. RESULTS: PCB exposure was positively associated with diabetes and age and inversely associated with thyroid stimulating hormone and triiodothyronine-uptake. History of diabetes was significantly related to total PCBs and all PCB functional groupings, but not to quarters worked and job score, after control for potential confounders. None of the exposures were related to insulin resistance (HOMA-IR) in non-diabetic men. CONCLUSIONS: Associations of PCBs with specific endogenous hormones differ in some respects from previous findings in postmenopausal women employed at the capacitor plant. Results from this study, however, do confirm previous reports relating PCB exposure to diabetes and suggest that these associations are not mediated by measured endogenous hormones.
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Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/epidemiología , Exposición a Riesgos Ambientales , Contaminantes Ambientales/toxicidad , Hormonas/sangre , Bifenilos Policlorados/toxicidad , Factores de Edad , Estudios Transversales , Monitoreo del Ambiente , Contaminantes Ambientales/sangre , Estudios de Seguimiento , Humanos , Illinois/epidemiología , Masculino , Persona de Mediana Edad , Exposición Profesional , Bifenilos Policlorados/sangre , Tirotropina/sangre , Triyodotironina/sangreRESUMEN
Seaweed and soy foods are consumed daily in Japan, where breast cancer rates for postmenopausal women are significantly lower than in the West. Likely mechanisms include differences in diet, especially soy consumption, and estrogen metabolism. Fifteen healthy postmenopausal women participated in this double-blind trial of seaweed supplementation with soy challenge. Participants were randomized to 7 wk of either 5 g/d seaweed (Alaria) or placebo (maltodextrin). During wk 7, participants also consumed a daily soy protein isolate (2 mg isoflavones/kg body weight). After a 3-wk washout period, participants were crossed over to the alternate supplement schedule. There was an inverse correlation between seaweed dose (mg/kg body weight) and serum estradiol (E2) (seaweed-placebo = y = -2.29 x dose + 172.3; r = -0.70; P = 0.003), [corrected] which was linear across the range of weights. Soy supplementation increased urinary daidzein, glycitein, genistein, and O-desmethylangolensin (P = 0.0001) and decreased matairesinol and enterolactone (P < 0.05). Soy and seaweed plus soy (SeaSoy) increased urinary excretion of 2-hydroxyestrogen (2-OHE) (P = 0.0001) and the ratio of 2-OHE:16alpha-hydroxyestrone (16alphaOHE(1)) (P = 0.01). For the 5 equol excretors, soy increased urinary equol excretion (P = 0.0001); the combination of SeaSoy further increased equol excretion by 58% (P = 0.0001). Equol producers also had a 315% increase in 2:16 ratio (P = 0.001) with SeaSoy. Seaweed favorably alters estrogen and phytoestrogen metabolism and these changes likely include modulation of colonic bacteria.
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Dieta , Estrógenos/metabolismo , Fitoestrógenos/metabolismo , Posmenopausia/metabolismo , Algas Marinas , Anciano , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Equol , Estradiol/sangre , Estrógenos/sangre , Estrógenos/orina , Femenino , Genisteína/orina , Humanos , Isoflavonas/orina , Persona de Mediana Edad , Fitoestrógenos/orina , Placebos , Globulina de Unión a Hormona Sexual/análisis , Proteínas de Soja/administración & dosificaciónRESUMEN
Selective estrogen receptor modulators represent accepted therapy for estrogen receptor positive (ER+) breast cancer, exhibit adverse side effects, and reduce patient compliance. The use of phytoestrogen containing herbal medicines is limited because of efficacy and safety concerns. The ER+ MCF-7 model examined growth inhibitory effects of the medicinal herb Lycium barbarum (LB) and identified mechanistic leads for its efficacy. The MCF-7 cells maintained in 0.7% serum (17beta-estradiol, E2 < 1 nM) exhibited 11%-87% increased growth after treatment with 1nM to 20 nM E2. Growth promotion with 20 nM E2 exhibited 5.2-fold increased estrone (E1), 35.7% increased 2-hydroxyestrone (2-OHE1), 15.4% increased 16alpha-hydroxyestrone (16alpha-OHE1), and eightfold increased estriol (E3) formation. Treatment of E2 stimulated cells with LB exhibited a dose-dependent growth inhibition of 9.5%-42.8% at Day 3 and 33.9%-83.9% at Day 7. The 3-day inhibitory response to 1% LB (maximum cytostatic concentration) exhibited 84.8% increased E1, 3.6-fold increased 2-OHE1, 33.3% decreased 16alpha-OHE1, and 9.2-fold increased E3 formation. Thus, MCF-7 cells retain their mitogenic and metabolic response to E2 and LB downregulates E2-stimulated growth via the formation of antiproliferative 2-OHE1 and accelerated conversion of mitogenic 16alpha-OHE1 to antimitogenic E3.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Estradiol/metabolismo , Lycium , Fitoterapia , Extractos Vegetales/farmacología , Receptores de Estrógenos/análisis , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Femenino , HumanosRESUMEN
The Luminal A subtype of breast cancer expresses the estrogen receptor (ER)-α and progesterone receptor (PR), but not the human epidermal growth factor receptor (HER)-2 oncogene. This subtype of breast cancer responds to endocrine therapy involving the use of selective estrogen receptor modulators and/or inhibitors of estrogen biosynthesis. However, these therapeutic agents are frequently associated with long-term systemic toxicity and acquired tumor resistance, emphasizing the need to identify non-toxic alternative treatments for chemo-endocrine therapy responsive breast cancer. The present study utilized the human mammary carcinoma-derived, ER+/PR+/HER-2- MCF-7 cell line as a model of the Luminal A subtype of breast cancer to examine the growth inhibitory effect of the Chinese nutritional herb Epimedium grandiflorum (EG) and determine the mechanisms underlying this effect. MCF-7 cells maintained in a serum-depleted culture medium retained their ability to grow in response to 17ß-estradiol (E2). Treatment of the MCF-7 cells with EG resulted in dose-dependent inhibition of E2-promoted growth. Mechanistically, EG inhibited E2-promoted cell cycle progression through G1 stage arrest and modulated the cellular metabolism of E2, increasing the formation of the anti-proliferative metabolites 2-hydroxyestrone and estriol. Long-term treatment of MCF-7 cells with EG inhibited E2-promoted anchorage independent growth, a surrogate in vitro biomarker of tumorigenesis. In conclusion, the results of the present study demonstrate the growth inhibitory effects of EG on MCF-7 cells and identified clinically relevant mechanistic leads for its anti-tumorigenic efficacy.
RESUMEN
OBJECTIVE: To illustrate a relationship between proliferative thyroid disease and estrogen metabolism through the analysis of urinary estrogen metabolites. STUDY DESIGN AND SETTING: Case-control study of 49 subjects with proliferative thyroid disorders and matching them to 49 controls. Urinary estrogen metabolite ratios were obtained, measuring 2-hydroxyestrone, an anti-proliferative metabolite, to 16alpha-hydroxyestrone, a proliferative metabolite. The patients were stratified into low (0 to 1.00), medium (1.01 to 2.00), or high (>2.00) groups according to their estrogen metabolite ratio. RESULTS: Fifty-one percent (25 of 49) of the cases had a low 2/16 ratio compared to 31% (15 of 49) in the control group while 20% (10 of 49) of the control group had a high 2/16 ratio as compared to 8% (4 of 49) in the case group (P value < 0.05). CONCLUSIONS: Increased 16alpha-hydroxyestrone activity compared to 2-hydroxyestrone activity appears to be associated with proliferative thyroid disease. SIGNIFICANCE: Further study of estrogen metabolites in relation to proliferative thyroid disease is warranted and may lead to implications for new treatment modalities for proliferative thyroid disease. EBM RATING: B-3b.
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Carcinoma Papilar/metabolismo , Estrógenos/metabolismo , Bocio/metabolismo , Hidroxiestronas/orina , Neoplasias de la Tiroides/metabolismo , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/orina , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Bocio/diagnóstico , Bocio/orina , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/orinaRESUMEN
Controversy persists regarding the role of a low ratio of 2-hydroxyestone (2-OHE(1))/16alpha-hydroxyestrone (16alpha-OHE(1)) as a potential estrogen metabolism marker of increased risk for breast cancer. Most of the evidence has been provided by case-control studies, where tumor effects on hormone metabolism are not known. Studies in populations at various risk of breast cancer are not consistent, with some suggesting that levels of the ratio may be altered by changes in diet and exercise. We studied Asian American women participating as controls in a case-control study of breast cancer in which migration history--a composite of the subject's place of birth, type of residence in Asia (urban or rural), length of time living in the West, and grandparents' place of birth--was associated with a 6-fold risk gradient that paralleled the historical differences in incidence rates between the United States and Asian countries. This population offered the possibility to address whether the ratio of 2-OHE(1):16alpha-OHE(1) differs according to recognized breast cancer risk factors, including migration history. Overnight 12-hour urines were obtained from 368 premenopausal and 143 naturally postmenopausal women of Chinese, Japanese, or Filipino descent who donated urines between 1985 and 1988. The estrogen metabolites 2-OHE(1) and 16alpha-OHE(1) were measured with an ELISA kit and adjusted for creatinine levels. In each ethnic group, the ratio of 2-OHE(1):16alpha-OHE(1) was consistently lower in women born in the West than in those who had migrated from Asia. For premenopausal women, the ratio declined 20% due to lower levels of 2-OHE(1). Among postmenopausal women, the ratio was 23% lower in those born in the West, but no consistent patterns based on place of birth were observed for either 2-OHE(1) or 16alpha-OHE(1). The ratio did not vary with most recognized breast cancer risk factors, except for lower metabolite ratios in women with a younger age at first birth and more children, which runs contrary to the hypothesis, because both characteristics reduce breast cancer risk. Our study suggests that the ratio of 2-OHE(1):16alpha-OHE(1) may be a marker for lifestyle influences on estrogen metabolism associated with westernization.
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Asiático/estadística & datos numéricos , Neoplasias de la Mama/orina , Estrógenos/orina , Adulto , Análisis de Varianza , Neoplasias de la Mama/epidemiología , California/epidemiología , Estudios de Casos y Controles , China/etnología , Femenino , Humanos , Entrevistas como Asunto , Japón/etnología , Persona de Mediana Edad , Filipinas/etnología , Factores de RiesgoRESUMEN
BACKGROUND: The long-term clinical effects of soy protein containing various concentrations of isoflavones on endogenous hormones are unknown. OBJECTIVE: We examined the effects of ingestion of soy protein containing various concentrations of isoflavones on hormone values in postmenopausal women. DESIGN: Seventy-three hypercholesterolemic, free-living, postmenopausal women participated in a 6-mo double-blind trial in which 40 g protein as part of a National Cholesterol Education Program Step I diet was provided as casein from nonfat dry milk (control), isolated soy protein (ISP) containing 56 mg isoflavones (ISP56), or ISP containing 90 mg isoflavones (ISP90). Endogenous hormone concentrations were measured at baseline and at 3 and 6 mo. RESULTS: The concentration of thyroxine and the free thyroxine index were higher in the ISP56 group, and the concentration of thyroid-stimulating hormone was higher in the ISP90 group than in the control group at 3 and 6 mo (P < 0.05). Triiodothyronine was significantly higher in the ISP90 group only at 6 mo. Thyroxine, free thyroxine index, and thyroid-stimulating hormone at 6 mo were inversely associated with measures of baseline estrogenicity. No significant differences were found for endogenous estrogens, cortisol, dehydroepiandrosterone sulfate, insulin, glucagon, or follicle-stimulating hormone after baseline hormone values were controlled for. CONCLUSIONS: This study does not provide evidence that long-term ingestion of soy protein alters steroid hormone values, but it suggests that soy protein may have small effects on thyroid hormone values that are unlikely to be clinically important. The thyroid effects are, however, consistent with previous findings in animals and highlight the need for future research investigating possible mechanisms of action.
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Dieta , Flavonoides/farmacología , Hormonas/sangre , Posmenopausia/metabolismo , Proteínas de Soja/farmacología , Densidad Ósea , Método Doble Ciego , Ingestión de Energía , Femenino , Flavonoides/administración & dosificación , Flavonoides/sangre , Humanos , Persona de Mediana EdadRESUMEN
Although hormones produced in the body are normally considered to be beneficial in such matters as life, male and female development, fertility, and blood pressure regulation, these same compounds can act in some circumstances as carcinogens or carcinogen facilitators, In some such cases increased amounts of the hormone or changes in the formation of its metabolites might be responsible. In other cases the timing of hormone release plays a critical role. In some cases the hormone acts independently, while in others two or more compounds act in concert to promote cancer. The various compounds will be discussed separately, since they usually cause different kinds of cancer. Of the various hormones produced in the body, only aldosterone does not cause any cancers, although excess aldosterone can cause Conn's syndrome, which may be detected by the resultant hypertension.
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Carcinógenos , Neoplasias/metabolismo , Neoplasias de la Próstata/inducido químicamente , Esteroides/efectos adversos , Andrógenos/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Citocromo P-450 CYP1A1/química , Citocromo P-450 CYP1A2/metabolismo , Deshidroepiandrosterona/química , Estrógenos/química , Estrógenos/metabolismo , Femenino , Humanos , Hidrocortisona/química , Masculino , Modelos Químicos , Neoplasias/etiología , Polimorfismo Genético , Progesterona/metabolismo , Neoplasias de la Próstata/patología , Receptores de Progesterona/metabolismo , Esteroides/metabolismo , Testosterona/metabolismo , Factores de Tiempo , Transcripción Genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
The preponderance of evidence suggests a role for fat and alcohol as risk factors for breast cancer. The role of milk is more controversial with some studies suggesting that milk is a risk factor and others that consumption of milk is protective against breast cancer. No other major nutrient appears to play a significant role in increasing breast cancer risk. On the other hand, there is increasing evidence that a variety of micronutrients and hormones appear to have significant anticancer activity. These range from steroids such as dehydroepiandrosterone (DHEA) and its analysis to indoles, isothiocyanates, and isoflavone derivatives. These compounds act directly by interfering with cyclins and promoting apoptosis as well as indirectly by altering estrogen metabolism in a favorable direction. These effects are not merely theoretical actions in cell culture and tissue explants; they have been demonstrated in human patients as a range of studies have demonstrated.
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Neoplasias de la Mama/dietoterapia , Dieta , Animales , Neoplasias de la Mama/etiología , Neoplasias de la Mama/prevención & control , Catequina/análogos & derivados , Catequina/uso terapéutico , Bovinos , Ácidos Cumáricos/uso terapéutico , Ciclohexenos , Deshidroepiandrosterona/uso terapéutico , Femenino , Genisteína/uso terapéutico , Humanos , Indoles/uso terapéutico , Isotiocianatos/uso terapéutico , Limoneno , Leche/metabolismo , Terpenos/uso terapéuticoRESUMEN
BACKGROUND: The effects of 3,3'-diindolylmethane (DIM) together with the Gardasil vaccine on cervical histology were evaluated using the K14-HPV16-transgenic mouse model. The possibility that DIM could enhance the efficacy of this preventive vaccine in this model was explored. MATERIALS AND METHODS: Transgenic mice were given 1000 mg/kg of DIM in the diet for 28 weeks. The mice were injected with Gardasil Quadrivalent HPV vaccine. Some mice were sacrificed at 28 weeks. Other groups were removed from the DIM diet after 28 weeks to a diet with no DIM for either 4 or 8 weeks. RESULTS: Cervical histology indicated that a high percentage of transgenic mice fed DIM and vaccinated with Gardasil manifested normal cervical epitheliums at 4 weeks after DIM discontinuation. CONCLUSION: Vaccination pre-supplemented with DIM may provide with a window of protection of at least four weeks in this transgenic model. However, extrapolation to the effect in humans is beyond the limited scope of the histological data presented here.
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Cuello del Útero/efectos de los fármacos , Cuello del Útero/patología , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/inmunología , Indoles/farmacología , Vacunas contra Papillomavirus/inmunología , Animales , Anticarcinógenos/administración & dosificación , Anticarcinógenos/farmacología , Cuello del Útero/metabolismo , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Humanos , Indoles/administración & dosificación , Ratones , Ratones Transgénicos , Vacunas contra Papillomavirus/administración & dosificación , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/prevención & control , Displasia del Cuello del Útero/tratamiento farmacológico , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/prevención & controlRESUMEN
UNLABELLED: While cervical cancer incidence and mortality rates have declined in the United States, this cancer represents a worldwide threat. Human papilloma viral infection causes cervical neoplasia (CIN). 3,3'-Diindolylmethane (DIM) prevents or inhibits the progression from cervical dysplasia to cancer. The aim of this study is to determine the most effective dose of DIM given continuously in food, that significantly increases serum interferon gamma levels (IFN-γ) in the K14-HPV16 transgenic mouse model for cervical cancer. MATERIALS AND METHODS: Five doses of DIM in food were administered to the mouse model for 20 weeks. Serum Interferon gamma (IFN-γ) levels and estrogen metabolite levels were quantified. RESULTS: At 1000 ppm DIM, serum IFN-γ concentrations were significantly increased (p<0.0396). The estrogen metabolites were unchanged. IFN-γ concentrations in CIN free mice and the percentage of CIN free transgenic mice were well correlated (r=0.88). DISCUSSION: Significant increases in IFN-γ serum concentrations that correlate with the percentage of CIN free mice in each group indicate that 1000 ppm of DIM in food may be the most effective dose for future studies. These results may eventually lead to new and effective vaccination strategies in women already infected with the human papilloma virus.
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Anticarcinógenos/uso terapéutico , Carcinoma de Células Escamosas/prevención & control , Papillomavirus Humano 16/genética , Indoles/uso terapéutico , Interferón gamma/sangre , Queratina-14/genética , Neoplasias Hormono-Dependientes/prevención & control , Proteínas Oncogénicas Virales/fisiología , Proteínas E7 de Papillomavirus/fisiología , Proteínas Represoras/fisiología , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Administración Oral , Animales , Anticarcinógenos/administración & dosificación , Anticarcinógenos/farmacología , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Estradiol/análogos & derivados , Estradiol/sangre , Estradiol/farmacocinética , Estradiol/toxicidad , Femenino , Indoles/administración & dosificación , Indoles/farmacología , Ratones , Ratones Transgénicos , Neoplasias Hormono-Dependientes/sangre , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/patología , Proteínas Oncogénicas Virales/biosíntesis , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/biosíntesis , Proteínas E7 de Papillomavirus/genética , Regiones Promotoras Genéticas , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/fisiología , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Transgenes , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/sangre , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/patologíaRESUMEN
The role of body fat as a risk factor for breast cancer has been well established. A decrease in the urinary 2/16α-hydroxyestrone ratio has also been shown to be a risk marker for breast cancer. These two observations are connected by the fact that obese women have decreased levels of 2-hydroxyestrone. To test the hypothesis that fat depots secrete factors that inhibit 2-hydroxylation, the effect of substances released into the media from adipocytes incubated in Krebs-Ringer buffer, on estrogen metabolism by MCF-7 cells in minimum essential medium eagle (MEM) plus adipocyte-conditioned media (ACM) was studied. The 1:1 ACM-MEM culture system resulted in a substantial and highly significant decrease in 2-hydroxylation of estradiol. This inhibition was partially reversed by the addition of indole-3-carbinol, a potent inducer of 2-hydroxylation of estradiol. Centrifugal sizing showed that the active 2-hydroxylation inhibitor in the medium had a molecular weight of about 30 kDa. These results suggest a mechanism for the decrease in 2-hydroxylation of estradiol that is observed in obese women and the increase in 2-hydroxylation observed in women with depleted fat depots.
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Adipocitos/metabolismo , Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Obesidad/metabolismo , Línea Celular Tumoral , Medios de Cultivo Condicionados/análisis , Estradiol/metabolismo , Femenino , Humanos , Hidroxiestronas/metabolismo , Hidroxilación/fisiología , Oxidación-ReducciónRESUMEN
The human papilloma virus is the major cause of cervical cancer. Viral infection initiates cervical intraepithelial neoplasia, which progresses through several stages to cervical cancer. The objective of this study is to identify the minimum effective dose of diindolylmethane that prevents the progression from cervical dysplasia to carcinoma in situ. We document cervical histology in K14-HPV16 mice receiving different doses of diindolylmethane. Urinary diindolylmethane concentrations are reported. Diindolylmethane could enhance the efficacy of human papilloma virus vaccines, creating a new therapeutic use for these vaccines in women already infected with the virus. Five doses (0-2,500 ppm) of diindolylmethane were incorporated into each mouse diet. The reproductive tract was serially sectioned and urine was obtained for analysis of urinary diindolylmethane. The results indicate that 62% of mice receiving 1,000 ppm diindolylmethane remained dysplasia-free after 20 weeks compared with 16% of mice receiving no diindolylmethane and 18% receiving 500 ppm; 1,000 ppm of 3,3'-diindolylmethane in the diet completely suppressed the development of cervical cancer. Urinary diindolylmethane levels increased significantly as diindolylmethane in food increased. These findings imply usefulness for diindolylmethane in the search to prevent cervical cancer when used in combination with prophylactic or therapeutic vaccines.
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Anticarcinógenos/administración & dosificación , Indoles/administración & dosificación , Infecciones por Papillomavirus/prevención & control , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Animales , Anticarcinógenos/orina , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Indoles/orina , Ratones , Ratones Transgénicos , Papillomaviridae/clasificación , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/administración & dosificación , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virologíaRESUMEN
BACKGROUND: The incidence of thyroid cancer is four to five times higher in women than in men, suggesting a role for estrogen (E2) in the pathogenesis of thyroid proliferative disease (TPD) that comprises cancer and goiter. The objective of this study was to investigate the antiestrogenic activity of 3,3'-diindolylmethane (DIM), a bioactive compound derived from cruciferous vegetables, in patients with TPD. METHODS: In this limited phase I clinical trial study, patients found to have TPD were administered 300 mg of DIM per day for 14 days. Patients subsequently underwent a total or partial thyroidectomy, and tissue, urine, and serum samples were collected. Pre- and post-DIM serum and urine samples were analyzed for DIM levels as well as estrogen metabolites. DIM levels were also determined in thyroid tissue samples. RESULTS: DIM was detectable in thyroid tissue, serum, and urine of patients after 14 days of supplementation. Urine analyses revealed that DIM modulated estrogen metabolism in patients with TPD. There was an increase in the ratio of 2-hydroxyestrones (C-2) to 16α-hydroxyestrone (C-16), consistent with antiestrogenic activity that results in more of C-2 product compared with C-16. CONCLUSION: Our data suggest that DIM enhances estrogen metabolism in TPD patients and can potentially serve as an antiestrogenic dietary supplement to help reduce the risk of developing TPD. The fact that DIM is detected in thyroid tissue implicates that it can manifest its antiestrogenic activity in situ to modulate TPD.
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Estrógenos/metabolismo , Indoles/farmacología , Neoplasias de la Tiroides/metabolismo , Estrógenos/orina , Femenino , Humanos , Indoles/metabolismo , Indoles/orina , Proyectos Piloto , Glándula Tiroides/metabolismo , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
INTRODUCTION: Both indole-3-carbinol and dietary lignans have beneficial effects on estrogen metabolism and breast cancer risk. There is no published literature on the effects of a combination product. This study was designed to investigate the impact of a combination product on estrogen metabolism. The major trial objective was to determine whether a breast health supplement containing indole-3-carbinol and hydroxymatairesinol lignan would alter estrogen metabolism to favour C-2 hydroxylation and reduce C-16 hydroxylation. Higher concentrations of C-2 metabolites and lower concentrations of C-16 metabolites may reduce breast cancer risk and risk for other hormonally-related cancers. METHODS: Forty-seven pre-menopausal and forty-nine post-menopausal women were recruited for this study, and were divided by random allocation into treatment and placebo group. The treatment supplement contained HMR lignan, indole-3-carbinol, calcium glucarate, milk thistle, Schisandra chinesis and stinging nettle, and each woman consumed either treatment or placebo for 28 days. At day 0 and day 28, blood samples were analysed for serum enterolactone concentrations, and first morning random urine samples were assessed for estrogen metabolites. Repeated measures ANOVA statistical testing was performed. RESULTS: In pre-menopausal women, treatment supplementation resulted in a significant increase (P < 0.05) in urinary 2-OHE concentrations and in the 2:16α-OHE ratio. In post-menopausal women, treatment supplementation resulted in a significant increase in urinary 2-OHE concentrations. In pre- and post-menopausal women combined, treatment supplementation produced a significant increase in urinary 2-OHE concentration and a trend (P = 0.074) toward an increased 2:16α-OHE ratio. There were no significant increases in serum enterolactone concentrations in the treatment or placebo groups. CONCLUSIONS: Supplementation with a mixture of indole-3-carbinol and HMR lignan in women significantly increased estrogen C-2 hydroxylation. This may constitute a mechanism for the reduction of breast cancer risk as well as risk for other estrogen-related cancers. Further studies with higher numbers of subjects are indicated.
RESUMEN
Although estradiol itself is primarily responsible for female development, the metabolites are responsible for many of the other positive and negative properties of estrogens. Phase I metabolism of estradiol is exclusively oxidative unlike the other steroid hormones and involves a series of hydroxylations. The specific hydroxylations can be induced or suppressed by endogenous or exogenous compounds that influence the cytochrome enzymes that act on specific sites on the molecule. Modulation of estrogen hydroxylation is essential since some of the other metabolites increase the risk of breast and other hormone-related cancers. The various hydroxylation pathways are discussed as well as the effects of the products of estrogen hydroxylation. The interaction between the human papilloma virus (HPV) and 16alpha-hydroxyestrone is discussed with reference to recurrent respiratory papillomatosis, cervical dysplasia, and cervical cancer. The role of estrogen metabolites in predicting the relative risk for breast cancer is evaluated using prospective and case-control studies. In one pilot study a factor that is a component of body fat is identified to be an inhibitor of estrogen C-2 hydroxylation. The role of environmental toxins like the phthalate esters and how these compounds increase risk for hormonal cancers is examined in a second pilot study.
Asunto(s)
Estrógenos/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/fisiopatología , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Hidroxilación , Papillomaviridae/fisiología , Proyectos Piloto , Estudios Prospectivos , RiesgoRESUMEN
This study was designed to establish whether 3,3'-diindolylmethane (DIM) can inhibit cervical lesions, alter estrogen metabolism in favor of C-2 hydroxylation, and enhance immune function in the K14-HPV16 transgenic mouse model. Mice were bred, genotyped, implanted with E(2) pellets (0.25 mg/90-day release) under anesthesia, and divided into groups. Wild-type and transgenic mice were given either AIN76A diet alone or with 2,000 ppm DIM for 12 weeks. Blood and reproductive tracts were obtained. Blood was analyzed for estrogen metabolites and IFN-gamma. The cervical transformation zone was sectioned and stained for histology. Estradiol C-2 hydroxylation and serum IFN-gamma levels were significantly increased over controls in wild-type and transgenic mice receiving DIM. In wild-type mice without DIM, hyperplasia of the squamous epithelium was observed. Wild-type mice fed DIM displayed a normal thin epithelium. In transgenic mice without DIM, epithelial cell projections into the stroma (papillae) were present. An additional degree of nuclear anaplasia in the stratum espinosum was observed. Dysplastic cells were present. Transgenic mice fed DIM displayed some mild hyperplasia of the squamous epithelium. DIM increases estrogen C-2 hydroxylation in this model. Serum INF-gamma was increased, indicating increased immune response in the DIM-fed animals. Histopathology showed a marked decrease in cervical dsyplasia in both wild-type and transgenic mice, indicating that DIM delays or inhibits the progression from cervical dysplasia to cervical cancer. Using the K14-HPV16 transgenic mouse model, we have shown that DIM inhibits the development of E6/E7 oncogene-induced cervical lesions.
Asunto(s)
Anticarcinógenos/farmacología , Estrógenos/metabolismo , Indoles/farmacología , Papillomaviridae/genética , Infecciones por Papillomavirus/prevención & control , Displasia del Cuello del Útero/prevención & control , Animales , Anticarcinógenos/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunidad/efectos de los fármacos , Indoles/sangre , Interferón gamma/sangre , Ratones , Ratones Transgénicos , Proteínas Oncogénicas Virales/fisiología , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/metabolismo , Displasia del Cuello del Útero/inmunología , Displasia del Cuello del Útero/metabolismoRESUMEN
Long-chain 3-hydroxydicarboxylic acids (3-OHDCAs) are thought to arise via beta-oxidation of the corresponding dicarboxylic acids (DCAs), although long-chain DCAs are neither readily transported into nor beta-oxidized in mitochondria. We thus examined whether omega-hydroxylation of 3-hydroxy fatty acids (3-OHFAs), formed via incomplete mitochondrial oxidation, is a more likely pathway for 3-OHDCA production. NADPH-fortified human liver microsomes converted 3-hydroxystearate and 3-hydroxypalmitate to their omega-hydroxylated metabolites, 3,18-dihydroxystearate and 3,16-dihydroxypalmitate, respectively, as identified by GC-MS. Rates of 3,18-dihydroxystearate and 3,16-dihydroxypalmitate formation were 1.23 +/- 0.5 and 1.46 +/- 0.30 nmol product formed/min/mg protein, respectively (mean +/- SD; n = 13). Polyspecific CYP4F antibodies markedly inhibited microsomal omega-hydroxylation of 3-hydroxystearate (68%) and 3-hydroxypalmitate (99%), whereas CYP4A11 and CYP2E1 antibodies had little effect. Upon reconstitution, CYP4F11 and, to a lesser extent, CYP4F2 catalyzed omega-hydroxylation of 3-hydroxystearate, whereas CYP4F3b, CYP4F12, and CYP4A11 exhibited negligible activity. CYP4F11 was the lone CYP4F/A enzyme that effectively oxidized 3-hydroxypalmitate. Kinetic parameters of microsomal 3-hydroxystearate metabolism were K(m) = 55 microM and V(max) = 8.33 min(-1), whereas those for 3-hydroxypalmitate were K(m) = 56.4 microM and V(max) = 14.2 min(-1). CYP4F11 kinetic values resembled those of native microsomes, with K(m) = 53.5 microM and V(max) = 13.9 min(-1) for 3-hydroxystearate and K(m) = 105.8 microM and V(max) = 70.6 min(-1) for 3-hydroxypalmitate. Our data show that 3-hydroxystearate and 3-hydroxypalmitate are converted to omega-hydroxylated 3-OHDCA precursors in human liver and that CYP4F11 is the predominant catalyst of this reaction. CYP4F11-promoted omega-hydroxylation of 3-OHFAs may modulate the disposition of these compounds in pathological states in which enhanced fatty acid mobilization or impairment of mitochondrial fatty acid beta-oxidation increases circulating 3-OHFA levels.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Ácidos Grasos/metabolismo , Hidrocarburo de Aril Hidroxilasas/metabolismo , Familia 4 del Citocromo P450 , Humanos , Hidroxilación , Cinética , Microsomas Hepáticos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxidación-ReducciónRESUMEN
We examined associations between polymorphisms in genes related to estrogen metabolism (CYP1B1 codon 432G --> C rs#1056836, CYP1B1 codon 453A --> G rs#1800440, COMT codon 158G --> A rs#4680) and biosynthesis (CYP17 T --> C promoter rs#743572, CYP19 exon 4 TTTA repeat) and urinary estrogen metabolites (2-hydroxyestrogens (2-OHE), 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio) in a pilot study of 64 pre- and post-menopausal women with a family history of breast cancer. Women were participants in the Metropolitan New York Registry of Breast Cancer Families, one of six international sites of the National Cancer Institute's Breast Cancer Family Registry. We used linear regression to examine the effects of genetic variants on log-transformed urinary estrogen metabolites. After adjusting for menopausal status, BMI, and age, carriers of the CYP1B1 codon 453G variant allele had 31.0% lower levels of 2-OHE (P-value = 0.05) and 40.2% lower levels of 16alpha-OHE1 (P = 0.01). Results were similar after restricting the analyses to pre-menopausal women (n = 41). Consistent with other studies, among pre-menopausal women, carriers of the COMT codon 158A variant allele had increased 2-OHE levels (P = 0.03) and an increased 2-OHE/16alpha-OHE1 ratio (P = 0.04); carriers of the CYP17 C promoter variant allele had increased 2-OHE levels (P = 0.08). To our knowledge this is the first report showing associations between the CYP1B1 codon 453G variant allele and urinary 2-OHE and 16alpha-OHE1 metabolites. Further larger studies should be conducted to confirm these results. Future identification of individuals with genetic polymorphisms that affect estrogen metabolism and biosynthesis may help characterize women at higher breast cancer risk and could guide breast cancer prevention strategies for those individuals.
Asunto(s)
Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Polimorfismo Genético , Adulto , Anciano , Hidrocarburo de Aril Hidroxilasas/genética , Catecol O-Metiltransferasa/genética , Codón , Citocromo P-450 CYP1B1 , Estradiol/análogos & derivados , Estradiol/orina , Femenino , Humanos , Hidroxiestronas/orina , Persona de Mediana Edad , Esteroide 17-alfa-Hidroxilasa/genéticaRESUMEN
A modified ELISA assay for measurement of the two estrogen metabolites 2-hydroxyestrone (2OHE1) and 16alpha-hydroxyestrone (16alphaOHE1) in plasma and serum has been developed. Previously, these have only been measured in urine. It is not known how well the measurements of these metabolites in urine and plasma are correlated. The goal of this study was to compare urinary and plasma levels of 2OHE1 and 16alphaOHE1 and their ratios and to explore how they were affected by ethnicity, dietary and genetic factors, and medication use. Blood and urine samples were obtained from 511 nulliparous women, aged 17-35, from four ethnic groups during the same visit at the study center, on a random day of the menstrual cycle. The overall correlation between the 2OHE1/16alphaOHE1 ratio in plasma and urine was fair (rs = 0.52; p < 0.0001). In general, the correlation between the 2OHE1/16alphaOHE1 ratio in urine and plasma was higher among women not using oral contraceptives (OCs) (rs = 0.58; p < 0.0001) than among women currently using OCs (rs = 0.34; p < 0.0001). The correlation was highest for samples obtained during the mid-cycle in among non-OC users (rs = 0.83; p < 0.0001). Among non-OC users, the urinary 2OHE1/16alphaOHE1 ratio was stable over the menstrual cycle while there was an increase in the plasma 2OHE1/16alphaOHE1 ratio. The strongest factors predicting discordance between the urinary and plasma 2OHE1/16alphaOHE1 ratios among non-OC users were a baseline urinary 2OHE1/16alphaOHE1 ratio in the three upper quartiles (p < 0.001), the menstrual cycle phase (p = 0.001), and the number of cups of coffee consumed per day (p = 0.006). Among current OC users, the strongest predictors of discordance between the urinary and plasma 2OHE1/16alphaOHE1 ratios were a baseline urinary 2OHE1/16alphaOHE1 ratio in the three lower quartiles (p < 0.001), being black (p = 0.001), and being Asian (p = 0.014). In conclusion, we found that the correlation between the two methods was fair and varied according to the baseline urinary 2OHE1/16alphaOHE1 ratio, ethnic group, OC status, coffee consumption, and time of menstrual cycle when the samples were obtained.