ArticleLiterature Review

Can alcohol promote aromatization of androgens to estrogens? A review

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Abstract

Increased aromatization may be a mechanism for feminization of some male alcoholics, as well as for the reported increases in plasma estrogen levels in postmenopausal women subjected to moderate alcohol consumption. Alcohol consumption-related increases in estrogen levels may in turn be partially responsible for the associated decreased risk for coronary artery disease and osteoporosis, as well as for increased risk for breast cancer. The purpose of this review is to evaluate the literature to determine whether alcohol can promote aromatization of androgens to estrogens. In male rats, chronic heavy alcohol administration (36% of total calories=12-18 g/kg/day) led to increased aromatization of androgen in the liver, but the results were equivocal for the hypothalamus. In female rats, chronic heavy alcohol administration did not promote aromatization in the hypothalamus exposed to alcohol in utero. In human placental tissue, although ex vivo alcohol administration (less or more than 72 g/day) did not affect the rate of aromatization, in vitro incubation of choriocarcinoma cells with 5-50 mM of alcohol increased estradiol secretion, which could be due to increased aromatization. In in vitro human ovarian granulosa cell studies, alcohol increased, had no effect on, or decreased estradiol secretion, and in one study, 20 mM of alcohol significantly increased aromatization of androstenedione to estrogens. These results may not be fully relevant to normal human ovary because in both studies cells were heavily luteinized by gonadotropins. A study of ovariectomized rats shows that only heavy chronic alcohol intake (4.4 g/kg/day) for 10 weeks can increase plasma estradiol levels and uterine weight, which could be due to increased aromatization or delayed clearance of estradiol. In conclusion, chronic heavy alcohol administration can result in aromatization of androgens in male rat liver. It is not clear whether moderate alcohol intake can produce a similar effect in the liver nor whether alcohol can potentiate aromatization of androgens in other tissue or organs of male rats. In females, the available information is not adequate to evaluate the effect of alcohol on aromatization. Further studies are required in both genders to evaluate the ability of alcohol (moderate vs. heavy dose) to promote aromatization of androgens to estrogens.

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... mone therapy, including effects on the metabolism of estrogens and xenobiotics via activation of the P450 cytochrome family enzymes [10][11][12]. Activation of aromatase can lead to an increase in estrogen levels which may interfere with the effectiveness of the treatment, while activation of other P450 cytochrome family enzymes participating in xenobiotic metabolism may result in more rapid conversion of tamoxifen into biologically active metabolites [10][11][12][13][14]. ...
... mone therapy, including effects on the metabolism of estrogens and xenobiotics via activation of the P450 cytochrome family enzymes [10][11][12]. Activation of aromatase can lead to an increase in estrogen levels which may interfere with the effectiveness of the treatment, while activation of other P450 cytochrome family enzymes participating in xenobiotic metabolism may result in more rapid conversion of tamoxifen into biologically active metabolites [10][11][12][13][14]. ...
... The mechanism underlying the potential effect of alcohol consumption on survival after breast cancer diagnosis from previous studies is unclear but alcohol has been suggested to decrease breast cancer survival through its effects on estrogen metabolism [27]. Alcohol can induce CYP19 activity causing an increase in estrogen levels [10]. An increase in estrogen levels can result in a change of the hormone environment thus potentially affecting the effectiveness of adjuvant hormone therapy and negatively impacting breast cancer-free survival. ...
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Purpose: Alcohol consumption is associated with an increase in breast cancer risk, but findings on the association of alcohol with survival after breast cancer diagnosis have been inconsistent. Further, whether these associations could differ by adjuvant hormone therapy status is unknown. We examined interactions between alcohol consumption and adjuvant hormone therapy in relation to breast cancer-free survival among women with a primary breast cancer diagnosis. Methods: Participants in this study included 1,399 women diagnosed with primary breast cancer between 2007 and 2012 at the Moffitt Cancer Center. Alcohol consumption during the year preceding diagnosis was assessed in a patient survey. Information on tumor characteristics, breast cancer treatment and outcomes was available from the Moffitt Cancer Registry. Associations were examined using Cox proportional hazards models in stratified analyses by adjuvant hormone therapy status, after adjustment for potential confounders. Results: Overall, alcohol consumption was associated with significantly improved breast cancer-free survival (any vs. none: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65-0.92). Among women without adjuvant hormone therapy, alcohol consumption was associated with better survival in heavy drinkers (HR, 0.63; 95% CI, 0.43-0.93). Among women with adjuvant hormone therapy, survival was better in women consuming alcohol as compared to nondrinkers (moderate: HR, 0.69, 95% CI, 0.51-0.93; heavy: HR, 0.74, 95% CI, 0.57-0.96; any: HR, 0.71, 95% CI, 0.57-0.87). There was no significant interaction between alcohol and adjuvant hormone therapy (p-interaction=0.54 for alcohol modeled as none or any and p=0.34 for alcohol modeled as none, moderate, and heavy). Conclusion: Associations of alcohol consumption with breast cancer-free survival are similar in women with and without adjuvant hormone therapy. Future studies are warranted to elucidate potential mechanisms underlying the observed inverse associations.
... 13Z,16Zdocosadienoyl-CoA, a component of docosadienoyl-CoA, was downregulated in ALD patients with ascites, which implies that triacylglycerol biosynthesis pathway disorder might be a critical contributor to ascites. In contrast, alcohol metabolism triggers intracellular oxidative stress (13,24,25). As an antioxidant, the reduction of CoQ and the related metabolites in ALD patients may enhance oxidative stress and worsen the liver injury, which might further contribute to ascites production and accumulation in ALD patients. ...
... The hormones, 19-oxotestosterone and etiocholanedione, are also downregulated in ALD patients with ascites, which is in accordance with previous reports (25). In addition, etiocholanedione is an androgen catabolism 5-β metabolite, and its production has been reported to consume NAD + and transfer NAD + into NADH. ...
Article
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Ascites is one of the most common complications of cirrhosis, and there is a dearth of knowledge about ascites-related pathologic metabolism. In this study, 122 alcoholic liver disease (ALD) patients, including 49 cases without ascites, 18 cases with mild-ascites, and 55 cases with large-ascites (1) were established according to the International Ascites Club (2), and untargeted metabolomics coupled with pattern recognition approaches were performed to profile and extract metabolite signatures. A total of 553 metabolites were uniquely discovered in patients with ascites, of which 136 metabolites had been annotated in the human metabolome database. Principal component analysis (PCA) analysis was used to further identify 21 ascites-related fingerprints. The eigenmetabolite calculated by reducing the dimensions of the 21 metabolites could be used to effectively identify those ALD patients with or without ascites. The eigenmetabolite showed a decreasing trend during ascites production and accumulation and was negatively related to the disease progress. These metabolic fingerprints mainly belong to the metabolites in lipid metabolism and the amino acid pathway. The results imply that lipid and amino acid metabolism disturbance may play a critical role in the development of ascites in ALD patients and could be a potent prognosis marker.
... Importantly, E2 is also present in pubertal boys, since the enzyme aromatase converts T into E2 in boys and girls (Lenz et al., 2011). Interestingly, higher levels of aromatase have been linked to addictive behaviors, including alcohol use (Lenz et al., 2011;Purohit, 2000). Moreover, higher E2 levels are correlated with greater sensation-seeking tendencies in adolescent boys (Vermeersch et al., 2009). ...
... sensation-seeking behaviors (Vermeersch et al., 2009). Alternatively, the enzyme aromatase converts T into E2 and this enzyme has been implicated in addictive behaviors (Lenz et al., 2011;Purohit, 2000). Therefore, the heightened E2-levels in boys who report higher alcohol use might (indirectly) reflect increased activity of the enzyme aromatase. ...
Article
Adolescents often show risk-taking behavior, including experimentation with alcohol. Previous studies have shown that advanced pubertal maturation is related to increased alcohol use in adolescents, even when controlling for age. Little is known about the underlying mechanisms of this relation between pubertal maturation and alcohol use. The goal of the present study was twofold. In experiment 1, we investigated whether advanced pubertal maturation is associated with higher levels of alcohol use, when controlling for age. To this end, questionnaires on pubertal development and alcohol use were administered to a large sample of 797 Dutch adolescents (405 boys) aged 11-16 years. In experiment 2, we explored whether sex steroids contribute to this relation between pubertal maturation and alcohol use by examining the association between salivary sex steroid levels and alcohol use in 168 adolescents (86 boys). It was found that, when controlling for age, advanced pubertal maturation is related to increased alcohol use in adolescent boys and girls. Controlling for age, higher testosterone and estradiol levels correlated with the onset of alcohol use in boys. In addition, higher estradiol levels were associated with a larger quantity of alcohol use in boys. Correlations between sex steroids and alcohol use were not significant in girls. These findings show that advanced pubertal maturation is related to advanced alcohol use, and that higher sex steroid levels could be one of the underlying mechanisms of this relation in boys. Sex steroids might promote alcohol use by stimulating brain regions implicated in reward processing.
... Alcohol is one such factor. Alcohol may increase circulating estrogen and reduce oxidative stress in ovarian tissue, thus delaying menopause (8)(9)(10)(11)(12). Research on alcohol intake to date has focused primarily on menopausal timing (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). ...
... ethanol may modulate aromatase conversion of androgens to estrogen (9). Health benefits of wine and particularly red wine may be attributable to antioxidants in grapes, such as resveratrol (34). ...
Article
Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45. Therefore, we aimed to evaluate risk of early natural menopause among n=107,817 Nurses' Health Study II members followed from 1989-2011. Alcohol consumption overall, and by subtypes including beer, red wine, white wine, and liquor was assessed throughout follow-up. We estimated hazard ratios (HR) in multivariable models adjusting for age, body mass index, parity, smoking and other potential confounders. Women reporting moderate, current alcohol consumption had lower risks of early menopause than non-drinkers. Those reporting 10-14.9 g/day had lower risk of early menopause compared to non-drinkers (HR = 0.81, 95% confidence interval (CI): 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to white wine, and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine, and liquor. High consumption was not related to lower early menopause risk.
... Additionally, alcohol is more strongly associated to hormone-sensitive BCs than hormone-insensitive subtypes [26]. Increased aromatization [27,28], impairment of estrogen metabolism in the liver [27] or stimulation of adrenal steroidogenesis [17] are possible mechanisms by which alcohol increases sex-hormone concentrations in women. ...
... Additionally, alcohol is more strongly associated to hormone-sensitive BCs than hormone-insensitive subtypes [26]. Increased aromatization [27,28], impairment of estrogen metabolism in the liver [27] or stimulation of adrenal steroidogenesis [17] are possible mechanisms by which alcohol increases sex-hormone concentrations in women. ...
Article
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Background Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-hormone levels by modifying PPARγ activity. Methods In the present study we assessed whether genetic variation in CYP19A1 is associated with risk of BC in a case-control study group nested within the Danish “Diet, Cancer and Health” cohort (ncases = 687 and ncontrols = 687) and searched for gene-gene interaction between CYP19A1 and PPARGC1A, and CYP19A1 and PPARG, and gene-alcohol and gene-NSAID interactions. Association between the CYP19A1 polymorphisms and hormone levels was also examined among 339 non-HRT users. Incidence rate ratios were calculated based on Cox’ proportional hazards model. Furthermore, we performed a pilot randomised controlled trial to determine the effect of the PPARG Pro12Ala polymorphism and the PPARγ stimulator Ibuprofen on sex-hormone levels following alcohol intake in postmenopausal women (n = 25) using linear regression. ResultsGenetic variations in CYP19A1 were associated with hormone levels (estrone: Prs11070844 = 0.009, estrone sulphate: Prs11070844 = 0.01, Prs749292 = 0.004, Prs1062033 = 0.007 and Prs10519297 = 0.03, and sex hormone-binding globulin (SHBG): Prs3751591 = 0.03) and interacted with alcohol intake in relation to hormone levels (estrone sulphate: Pinteraction/rs2008691 = 0.02 and Pinteraction/rs1062033= 0.03, and SHBG: Pinteraction/rs11070844 = 0.03). CYP19A1/rs3751591 was both associated with SHBG levels (P = 0.03) and with risk of BC (Incidence Rate Ratio = 2.12; 95 % Confidence Interval: 1.02–4.43) such that homozygous variant allele carriers had increased levels of serum SHBG and were at increased risk of BC. Acute intake of alcohol decreased blood estrone (P = <0.0001), estrone sulphate (P = <0.0001), and SHBG (P = 0.009) levels, whereas Ibuprofen intake and PPARG Pro12Ala genotype had no effect on hormone levels. Conclusions Our results suggest that genetically determined variation in CYP19A1 is associated with differences in sex hormone levels. However, the genetically determined differences in sex hormone levels were not convincingly associated with BC risk. The results therefore indicate that the genetically determined variation in CYP19A1 contributes little to BC risk and to alcohol-mediated BC risk. Trial registrationNCT02463383, June 3, 2015.
... Auch ist die Lutealphase mit einer gesteigerten Empfindlichkeit gegenüber Stress vergesellschaftet (Lustyk et al., 2014). Die erhöhte Alkoholaufnahme könnte somit als "Eigenmedikation" zur Bewältigung der PMS bedingten Symptome und des ansteigenden Stresslevels betrachtet werden (Carroll et al., 2015;Sinha, 2008 Sexualhormonkonzentrationen zugunsten der Östrogene (Devaud et al., 2006;Erol and Karpyak, 2015;Hasselblatt et al., 2003;Maneesh et al., 2006;Purohit, 2000;Rivier, 1999). Entscheidend scheinen hierbei die Menge an aufgenommenem Alkohol und das ...
... Es zeigte sich eine signifikante negative Korrelation zwischen dem Alter und der MRT- Entscheidungsgeschwindigkeit zurückgeführt werden kann (Hertzog and Rypma, 1991;Peters et al., 2007;Techentin et al., 2014;Willis and Schaie, 1988 . Zum anderen ist bei den männlichen Patienten an eine mögliche alkoholbedingt gesteigerte Umwandlung von Testosteron zu Östrogen zu denken, welche mit einer negativen Leistung im MRT in Verbindung gebracht wird (Devaud et al., 2006;Erol and Karpyak, 2015;Hampson et al., 2014;Hasselblatt et al., 2003;Hausmann et al., 2000;Maneesh et al., 2006;Purohit, 2000;Rivier, 1999;Yonker et al., 2005). Des Weiteren sind vor allem die neurodegenerativen Effekte, die durch den Konsum von Alkohol entstehen, nicht zu vernachlässigen. ...
Thesis
Hintergrund und Ziele: Der Konsum von Alkohol und alkoholassoziierte Erkrankungen gehören weltweit neben Bluthochdruck und Rauchen zu den häufigsten Todesursachen. Die gesundheitlichen, sozialen und finanziellen Konsequenzen für die Betroffenen, deren Angehörige und die Gesellschaft insgesamt sind potenziell vermeidbar, weswegen die Suche nach Risikofaktoren und die rechtzeitige Einleitung wirkungsvoller Präventionsmaßnahmen entscheidend sind. Aus den zahlreichen möglichen Einflussfaktoren wurden im Rahmen dieser Studie die Wirkung von pränatalen und von aktuell zirkulierenden Sexualhormonkonzentrationen auf die Alkoholabhängigkeit ausgewählt und die geschlechtsspezifischen Unterschieden im Trinkverhalten näher beleuchtet. Aufgrund deutlicher Parallelen zwischen der Auswirkung dieser Parameter sowohl auf die Alkoholabhängigkeit als auch auf das räumliche Vorstellungsvermögen, wurde schließlich die Frage gestellt, ob Leistungen auf dem Gebiet der mentalen Rotation als Risikomarker für die Entstehung einer Alkoholabhängigkeit genutzt werden können. Methoden: Bei 235 Kontrollen (n(♀)=102; n(♂)=133) und 153 Patienten (n(♀)=66; n(♂)=87), welche die Kriterien einer Alkoholabhängigkeit nach ICD-10-, DSM-IV- und DSM-5 erfüllten, wurde die Leistung auf dem Gebiet der mentalen Rotation anhand der revidierten Version des Mental Rotation Test (MRT) basierend auf dem Original von Vandenberg und Kuse ermittelt. Pränatale Sexualhormonkonzentrationen wurden indirekt mittels der Längenverhältnisse der Zeige- und Ringfinger (kurz 2D:4D-Fingerlängenverhältnis) und der Händigkeit bestimmt. Aktuell zirkulierende Sexualhormonkonzentrationen wurden aus Blutproben gewonnen. Das Ausmaß des Alkoholkonsums der Patienten wurde mit dem Lifetime Drinking History-Erhebungsbogen erfasst. Darüber hinaus wurde die Gruppe der gesunden Kontrollen weiter in eine Gruppe der Binge Drinker und der Non-Binge Drinker unterteilt und deren Leistung im MRT mit denen von Patienten verglichen. Ergebnisse und Beobachtungen: Die Patienten- und Kontrollgruppe unterschieden sich nicht hinsichtlich der Geschlechterverteilung und des Alters. Die Gruppe der Kontrollen verfügte über signifikant mehr Bildungsjahre als die Gruppe der Patienten (p<0,001). Die höhere Anzahl an Bildungsjahren hatte in der Kontrollgruppe einen signifikant positiven Einfluss auf den MRT (p=0,022). Das Alter beeinflusste sowohl in der männlichen (p<0,001) und in der weiblichen (p<0,001) Kontrollgruppe als auch bei Frauen der Patientengruppe (p=0,009) die Leistung im MRT negativ. Innerhalb der Patientengruppe tranken die Frauen seit Beginn der Abhängigkeit signifikant weniger Alkohol pro Tag als die Männer (p<0,001). Auch lag die Gesamtmenge an konsumiertem Alkohol bei Patientinnen signifikant unter dem der männlichen Patienten (p<0,001). Männer erreichten nicht nur in der Kontrollgruppe (p<0,001), sondern auch in der Patientengruppe (p=0,001) signifikant höhere Ergebnisse im MRT als weibliche Studienteilnehmer der entsprechenden Gruppen. Die weibliche (p=0,026) und männliche (p<0,001) Kontrollgruppe schnitt im MRT signifikant besser ab als die entsprechenden Teilnehmer der Patientengruppe. Binge Drinker erzielten im Vergleich zu Patienten und Non-Binge Drinkern im Durchschnitt die besten Ergebnisse. Das 2D:4D-Fingerlängenverhältnis und die Händigkeit zeigten in keiner der Gruppen einen signifikanten Zusammenhang mit der erreichten Punktzahl im MRT. Aktuelle bioverfügbare Testosteron- (p=0,012), Dihydrotestosteron- (p<0,001) und Progesteronkonzentrationen (p=0,010) korrelierten bei Männern der Kontrollgruppe, die Dihydrotestosteron -Konzentration (p=0,012) korrelierte bei Frauen der Kontrollgruppe signifikant positiv mit dem Ergebnis des MRT. Die Anzahl an stationären Entwöhnungen korrelierte in der Patientengruppe signifikant positiv mit der Leistung im MRT (p=0,004). Praktische Schlussfolgerungen: Entgegen der Hypothese erzielten die Patienten und Patientinnen deutlich schlechtere Ergebnisse im Mental Rotation Test als die gesunden Kontrollgruppen, was hauptsächlich auf die alkoholbedingte Neurodegeneration zurückgeführt werden kann. Aufgrund des fehlenden Zusammenhangs zwischen der mentalen Rotation und den Markern für pränatale Androgene, dem 2D:4D-Fingerlängenverhältnis und der Händigkeit, kann geschlussfolgert werden, dass letztendlich eher eine schwächere Wechselbeziehung zwischen dem 2D:4D-Fingerlängenverhältnis, der Händigkeit und dem MRT besteht als zwischen dem 2D:4D-Fingerlängenverhältnis, der Händigkeit und dem Risiko einer Alkoholabhängigkeit. Die Subgruppe der Binge Drinker erreichte im Durchschnitt die besten Ergebnisse im MRT, was den Grundgedanken dieser Forschungsarbeit stützt, da Binge Drinker tendenziell ein kleineres 2D:4D-Fingerlängenverhältnis aufweisen als gesunde Kontrollen und gleichzeitig gesunde Kontrollen auf dem Gebiet der mentalen Rotation übertreffen. Hypothesenkonform konnte ein positiver Einfluss aktuell zirkulierender Androgenkonzentrationen, hier vor allem des Dihydrotestosterons, auf die mentale Rotation in der Kontrollgruppe beobachtet werden kann. Der Mental Rotation Test ist folglich bei bereits bestehender Alkoholabhängigkeit nicht als Risikomarker geeignet, da die potentielle kognitive Leistung der Probanden aufgrund der Substanzmissbrauchsstörung nicht sicher erfasst werden kann. Zur Beantwortung der zugrunde liegenden Studienfrage wären prospektive Längsschnittstudien notwendig, bei der die kognitive Leistungsfähigkeit vor Entwicklung einer Abhängigkeit erfasst wird, um eine Verzerrung der Ergebnisse durch alkoholbedingte neurodegenerative Effekte zu vermeiden.
... Evidence indicates that alcohol may alter sex hormone levels by affecting both the hypothalamus and gonads (Devaud et al., 2006), and may also increase estrogen to androgen ratio by promoting aromatization of androgens to estrogens (Purohit, 2000). ...
Article
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Aims: To review the contemporary evidence reflecting male/female differences in alcohol use and its consequences along with the biological (sex-related) and psycho-socio-cultural (gender-related) factors associated with those differences. Methods: MEDLINE, PubMed, Web of Science, SCOPUS, PsycINFO, and CINAHL databases were searched for relevant publications, which were subsequently screened for the presence/absence of pre-specified criteria for high quality evidence. Results: Compared to men, more women are lifetime abstainers, drink less, and are less likely to engage in problem drinking, develop alcohol-related disorders or alcohol withdrawal symptoms. However, women drinking excessively develop more medical problems. Biological (sex-related) factors, including differences in alcohol pharmacokinetics as well as its effect on brain function and the levels of sex hormones may contribute to some of those differences. In addition, differences in alcohol effects on behavior may also be driven by psycho-socio-cultural (gender-related) factors. This is evident by variation in the magnitude of differences in alcohol use between countries, decreasing difference in the rates of alcohol consumption in recent generations and other findings. Evidence indicates that both sex and gender-related factors are interacting with alcohol use in complex manner, which differentially impacts the risk for development of the behavioral or medical problems and alcohol use disorders in men and women. Conclusions: Discovery of the mechanisms underlying biological (sex-related) as well as psycho-socio-cultural (gender-related) differences in alcohol use and related disorders is needed for development of personalized recommendations for prevention and treatment of alcohol use disorders and related problems in men and women.
... G allele carriers showed only a negative association on Day 7. We suppose that these differences are mainly due to the genotypedependent changes in methylation levels and may hint toward a complex interplay between sex hormones and the specific methylation of ALDH2. Alcohol has been shown to convert testosterone to estrogen via the enzyme aromatase (Purohit, 2000). The negative association of cluster 1 methylation with testosterone indicates the involvement of estrogen. ...
Article
Aims: Aldehyde dehydrogenase 2 (ALDH2) protects cells from ethanol toxicity by metabolizing acetaldehyde. We studied the single nucleotide polymorphism (SNP) rs886205s located between a negative and a positive regulating promoter element in the ALDH2 gene. The negative regulatory region was already associated with differential DNA methylation in the two allele variations of rs886205 SNP. Another CpG island, in the positive regulatory region of the ALDH2 promoter, extends through the SNP rs886205 and a nuclear receptor response element. Methods: We assessed rs886305 genotype and DNA methylation using bisulfite sequencing in a cohort of 83 male alcohol-dependent patients undergoing detoxification treatment (Days 1, 7 and 14) and in 33 male age-matched controls. Luciferase reporter assays were performed to address the functional significance of genotype and methylation. Results: We observed a higher methylation in alcohol-dependent patients compared to controls. Patients with AA (n = 52) or GG/GA (n = 31) genotype differed significantly in baseline methylation levels as well as in methylation kinetics during withdrawal. AA carriers display an increase in methylation from low baseline levels while GG/GA showed the inverse pattern. The reporter gene assays corroborate these data by showing a significant effect of genotype on ALDH2 expression as well as an interaction between genotype and methylation. Conclusion: Our results describe a new regulatory role of rs886205 in the methylation of ALDH2 promoter region and provide additional insight into the complex regulation of ALDH2 under the condition of alcohol dependence. Short summary: Genetic variations have been described to influence DNA promoter methylation of various genes. We investigated the association between the polymorphism rs886205, located on ALDH2 promoter and methylation kinetics of the neighboring CpG island in alcohol-dependent patients. Luciferase reporter assays showed functional significance of genotype, methylation and a genotype-epigenotype interaction in vitro.
... 98 Alcohol can also alter hormone levels by increasing circulating estrogen metabolites through suppression of hepatic estrogen metabolism and by enhancing the conversion of androgens to estrogens. 99 Alcohol can also suppress immune function, increase cell proliferation, inhibit DNA repair, and promote cell invasion and migration. 91,100 Smoking In the past, conclusive evidence linking smoking to breast cancer has been difficult to demonstrate. ...
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Between the years 2010 and 2012, the lifetime probability of developing female breast cancer was 12.3%, or approximately 1 in 8. Worldwide, breast cancer is the most common cancer in women. Survival is increasing. Between 2005 and 2011, the 5-year relative survival was found to be 89%. This is thought to be due to both the increase in utilization of population-wide screening, as well as advances in treatment. Less than 10% of breast cancers can be attributed to an inherited genetic mutation. Breast cancer is more commonly associated with environmental, reproductive, and lifestyle factors, some of which are potentially modifiable.
... Chronic heavy alcohol ingestion impairs sex hormone balance, displaying elevated serum estrogen and lower testosterone levels [25,41,42]. We observed both increased serum estradiol and decreased free testosterone levels with increasing alcohol intake, and a poorer profile of liver laboratory findings in those drinking ≥2 drinks/day. ...
... In addition, alterations in the metabolism of sex steroids have been associated with alcohol consumption (Purohit, 2000). For example, metabolism of T to E2 is catalyzed by aromatase (CYP19A1). ...
Thesis
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Alcohol (ethanol) consumption is one of the leading risk factors for many serious diseases. The pharmacology of ethanol is extremely complex, affecting many of the signaling systems not only in the brain but widely throughout the body. Alcoholics are a heterogeneous group of subjects suffering a wide spectrum of problems. Cloninger’s typology divides the spectrum of alcoholics into two subgroups: anxiety-prone late onset type 1 alcoholics and early onset, impulsive and antisocial type 2 alcoholics. Here the post-mortem brain samples of Cloninger type 1 (N=9) and type 2 (N=8) alcoholics have been studied and compared to non-alcoholic controls (N=10). The first sub-study evaluated [3H]AMPA binding to AMPA receptors. Increased binding was observed in the anterior cingulate cortex of type 2 alcoholics in comparison with controls. This elevated [3H]AMPA binding could be associated with increased impulsivity in these individuals. The second study investigated the endocannabinoid levels in the post-mortem samples of hippocampus and amygdala. Increased docosahexaenoylethanolamide levels were observed in late-onset type 1 alcoholics in the amygdala. Furthermore, a negative correlation was observed between anandamide levels and previously published metabotropic glutamate receptor 1/5 levels in the hippocampus in type 1 alcoholics, but not in controls or type 2 alcoholics. These observations could be associated with the transient receptor potential vanilloid type 1 mediated synaptic plasticity which is dependent on metabotropic glutamate receptor 5 and anandamide function. In the third study, [3H]citalopram binding to serotonin transporters was measured in brain regions associated with social cognition. Decreased [3H]citalopram binding was observed in the posterior cingulate cortex and posterior insula in all alcoholics when compared to non-alcoholic controls. Furthermore, decreased [3H]citalopram binding in the parahippocampal gyrus was seen only in the antisocial type 2 alcoholics. The decreased serotonin transporter binding in alcoholics could be associated with altered social cognitive processes. The fourth study examined levels of neuroactive steroids in the post-mortem brain samples. Increased dehydroepiandrosterone levels were seen in all alcoholics compared to controls. There were also negative correlations detected between pregnenolone levels and the previously published [3H]naloxone binding to µ-opioid receptors and similarly, increased pregnenolone levels were observed only in a sub-group of alcoholics with decreased [3H]naloxone binding in comparison with the controls. Overall, the findings of the present thesis improve our understanding of the differences between the brains of alcoholics and controls. Furthermore, they highlight the need to recognize the spectrum of alcoholics in research which hopefully will be translated into improvements in the treatment of alcoholism.
... The consumption of alcoholic beverages may initiate cancer development by enhancing the level of estrogen in the body and affecting estrogen metabolism. Alcohol could increase plasma estrogen levels either by promoting the induction of aromatases, which can convert androgens to estrogens, or by impairing the metabolism of estrogens in liver, resulting in an accumulation of circulating estrogen [51]. Human uterus contains ADH of class I, III and IV isoenzymes. ...
Article
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According to International Agency for Research on Cancer, ethanol and acetaldehyde belong to group 1 of human carcinogens. The accurate mechanism by which alcohol consumption enhances carcinogenesis is still unexplained. Alcohol is oxidized primarily by alcohol dehydrogenase (ADH) to acetaldehyde, a substance capable of initiating carcinogenesis by forming adducts with proteins and DNA and causing mutations. Next, acetaldehyde is metabolized by aldehyde dehydrogenase (ALDH) to acetate. In tissues of many cancers, we can observe significantly higher activity of total alcohol dehydrogenase with any change in aldehyde dehydrogenase activity in comparison with healthy cells. Moreover, in malignant diseases of digestive system, significantly increased activity of ADH isoenzymes class I, III and IV was found. The gynecological, brain and renal cancers exhibit increased activity of class I ADH. ADH and ALDH can play also a crucial regulatory role in initiation and progression of malignant diseases by participation in retinoic acid synthesis and elimination of toxic acetaldehyde. Besides, changes of enzymes activities in tumor cells are reflected in serum of cancer patients, which create the possibilities of application ADH isoenzymes as cancer markers.
... testostérone, et ce même à faibles doses(Eriksson et al. 2003;Sarkola et al. 2000). L'alcool agirait également directement sur les métabolites des stéroïdes (estradiol et 5-dihydrotestostérone (DHT)), en induisant les réactions d'aromatisation(Purohit 2000) ou en diminuant le catabolisme hépatique(Sarkola et al. 2000), ce qui pourrait expliquer l'augmentation des taux d'estradiol chezles hommes (Eriksson et al. 2003) et les femmes (Purohit 2000) souffrant d'alcoolisme chronique. Enfin, malgré sa forte affinité pour les récepteurs androgéniques et des corrélations positives entre les taux plasmatiques et un comportement agressif, peu d'effets de l'alcool sur la DHT sont décrits dans la littérature (Sarkola et al. 1999; von der Pahlen 2005). ...
Article
Interindividual variability in ethanol-induced behavioural disorders, such as blackouts and violent impulsive behaviours (BOVIB) following binge drinking could partly be explained by polymorphisms in genes encoding enzymes and transporters of the tryptophan (Trp) catabolic pathway. Indeed, Trp is the precursor of serotonin, a neurotransmitter that modulates mood, cognition and impulsivity, and is also transformed into various kynurenine metabolites, most of them displaying neuroactive properties and being involved in cognitive and memory dysfunctions. The aims of our work were (1) to test the BOVIB hypothesis in relation with a dysregulation of Trp metabolism in alcohol-dependent (AD) patients with or without BOVIB history, (2) to analyse the genetic variability of the kynurenine pathway (KP) leading to variations in expression and/or activity of key enzymes, (3) to explore interactions between the KP and the main biological neuroendocrine systems involved in ethanol addiction, using a rodent model of prenatal stress. The main results of our study showed (1) a significant difference in the rate-limiting enzyme tryptophan 2,3-dioxygenase (TDO) activity between AD patients with or without BOVIB history, (2) the existence of polymorphisms in the promoter region of two key genes of the KP, TDO2 and IDO1, (3) the presence of functional Glucocorticoid Responsive Elements (GRE) in the promoter of TDO2 which might be affected by some of the polymorphisms identified, and (4) the identification of LEF-1 response elements in the IDO1 promoter. These findings support the genetic variability of the Trp metabolism, as well as its potential role in individual vulnerability to ethanol-induced behavioural disorders.
... Evidence indicates that alcohol may alter sex hormone levels by affecting both the hypothalamus and gonads (Devaud et al., 2006), and may also increase estrogen to androgen ratio by promoting aromatization of androgens to estrogens (Purohit, 2000). ...
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Introduction. We have previously demonstrated an association of PDYN rs2281285 and haplotypes including this variant with alcohol dependence, negative craving and propensity to drink to avoid alcohol withdrawal (Karpyak et al. 2013; Preuss et al. 2013). We re-analyzed our data to examine sex-related associations of PDYN variation with alcohol dependence and related phenotypes. Methods. 13 PDYN …
... Aromatase and 17beta-hydroxysteroid dehydrogenase enzymes are aberrantly expressed in fibroids. Some of the known factors that increase aromatase activity are age, insulin, obesity, gonadotropins, and alcohol [40]. Aromatase and 17beta-hydroxysteroid dehydrogenase convert circulating androstenedione (a pro-hormone released by the adrenal cortex & ovaries) into estradiol. ...
... Alcohol has been shown to influence circulating sex hormones in both premenopausal and postmenopausal women (Reichman et al, 1993;Dorgan et al, 2001), possibly through increased aromatase activity (Purohit, 2000) and expression (Monteiro et al, 2009), prolonged hepatic clearance of oestrogens (Ginsburg et al, 1995), and/or increased oestrogen receptor expression and signalling (Fan et al, 2000). Sex hormone levels have been shown to affect mammographic density (Boyd et al, 2011;Cuzick et al, 2011) and a dose-response relationship between alcohol consumption and breast cancer risk has repeatedly been described (Smith-Warner et al, 1998;Singletary and Gapstur, 2001;Chen et al, 2011). ...
Article
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Alcohol consumption has been suggested to increase risk of breast cancer through a mechanism that also increases mammographic density. Whether the association between alcohol consumption and mammographic density is modified by background breast cancer risk has, however, not been studied. We conducted a population-based cross-sectional study of 53 060 Swedish women aged 40-74 years. Alcohol consumption was assessed using a web-based self-administered questionnaire. Mammographic density was measured using the fully-automated volumetric Volpara method. The Tyrer-Cuzick prediction model was used to estimate risk of developing breast cancer in the next 10 years. Linear regression models were used to evaluate the association between alcohol consumption and volumetric mammographic density and the potential influence of Tyrer-Cuzick breast cancer risk. Overall, increasing alcohol consumption was associated with higher absolute dense volume (cm(3)) and per cent dense volume (%). The association between alcohol consumption and absolute dense volume was most pronounced among women with the highest (⩾5%) Tyrer-Cuzick 10-year risk. Among high-risk women, women consuming 5.0-9.9, 10.0-19.9, 20.0-29.9, and 30.0-40.0 g of alcohol per day had 2.6 cm(3) (95% confidence interval (CI), 0.2-4.9), 2.9 cm(3) (95% CI, -0.6 to 6.3), 4.6 cm(3) (95% CI, 1.5-7.7), and 10.8 cm(3) (95% CI, 4.8-17.0) higher absolute dense volume, respectively, as compared with women abstaining from alcohol. A trend of increasing alcohol consumption and higher absolute dense volume was seen in women at low (⩽3%) risk, but not in women at moderate (3.0-4.9%) risk. Alcohol consumption may increase breast cancer risk through increasing mammographic density, particularly in women at high background risk of breast cancer.British Journal of Cancer advance online publication, 2 June 2015; doi:10.1038/bjc.2015.185 www.bjcancer.com.
... These mechanisms lead to subsequent decrease in semen volume and sperm density. Another factor appears to be an elevation in serum estrogen caused by peripheral conversion of testosterone to estrogen through increased activity of the enzyme aromatase, which is present both in the liver and in peripheral fat cells (9). ...
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The hypothalamic pituitary gonadal axis (HPG), which plays a critical role in development of body systems including immune and reproductive systems all of which need to be in balance for optimum functioning of the body, mind, and spirit. Modern mechanisms of herbal remedy focus on adjusting immune dysfunction, regulating abnormal activity in the hypothalamic-pituitary-adrenal (HPA) axis and serving as an antioxidant. Some herbs nourish the HPA axis and promotes adrenal, thyroid and reproductive function. (HPG) axis is activated, leading to increases in luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex steroids (testosterone and estradiol) levels. The HPG axis, which regulates gonadal steroid production, is a multiple level hormonal system involving brain and pituitary with feed forward and feedback elements.
... Several studies have shown a positive association between alcohol intake and estrogen levels in women (3,4). Alcohol could increase plasma estrogen levels either by promoting the induction of aromatases, which can convert androgens to estrogens, or by impairing of the metabolism of estrogens in the liver (5). Moreover, it has been suggested that an increased risk for cancer is attributed to acetaldehyde, the first metabolite of ethanol (6). ...
Article
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Background/Aim: The aim of this study was to investigate the potential role of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as tumor markers for endometrial cancer. Serum samples were obtained from 40 women with endometrial cancer, 52 with myoma uteri and 52 healthy individuals. Class III, IV of ADH and total ADH activity was measured by a photometric method and class I, II ADH and ALDH activity, by a fluorometric method. The total activity of ADH and ADH class I was significantly higher in the serum of patients with endometrial cancer than in healthy individuals and patients with myoma. The diagnostic sensitivity for ADH I was 69%, specificity 77%, positive predictive value and negative predictive value were 75% and 71% respectively. The area under curve for ADH I was 0.682 and for total ADH was 0.623. The results suggest a potential role of ADH I as a marker for endometrial cancer.
... 69 Ethanol increases aromatase activity, an enzyme that converts androgens to estrogens, especially in the liver. 70 A decrease in IGF1 bioavailability as a result of liver disease, contributes at least in part to the development of hypogonadism associated with cirrhosis 71 because IGF1 is known to stimulate testosterone synthesis and spermatogenesis. 72 Both acute and chronic exposure of pubertal young male rats to alcohol induced a profound decrease in testosterone concentration, which was associated with lower or normal LH and FSH levels, which is abnormal given that low testosterone in normal conditions signals to the hypothalamus to produce LHRH, which in turn stimulates LH and FSH secretion and therefore stimulation of the testis to produce testosterone. ...
Article
Chronic consumption of a large amount of alcohol disrupts the communication between nervous, endocrine, and immune system and causes hormonal disturbances that lead to profound and serious consequences at physiologic and behavioral levels. These alcohol-induced hormonal dysregulations affect the entire body and can result in various disorders such as stress abnormalities, reproductive deficits, body growth defect, thyroid problems, immune dysfunction, cancers, bone disease, and psychological and behavioral disorders. This review summarizes the findings from human and animal studies that provide consistent evidence on the various effects of alcohol abuse on the endocrine system.
... Since alcohol consumption and smoking often co-exist, it is seen that alcohol consumption can substantially confound the effect of smoking on breast cancer (Hamajima et al., 2002). Alcohol is known to affect the metabolism of steroid hormones and thus increase breast cancer risk (Purohit, 2000;Singletary & Gapstur, 2001;Pierucci-Lagha et al., 2006). ...
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Breast cancer is the most frequently diagnosed cancer among women around the world. The hormone 17-estradiol (E2) is strongly implicated as a causative agent in this cancer. Since estrogen acts as a complete carcinogen, agents that interfere with the carcinogenic actions of E2 are required. Most agents effective against experimental mammary carcinogenesis have been employed as pure compounds disregarding the synergy that exists between several phytonutrients in a whole food. In these studies we have taken a unified approach, by employing a pure phytonutrient ellagic acid and whole foods that contain the phytonutrient at various levels berries, in the prevention of E2- induced mammary cancer in ACI rats. We have also used a tiered approach by screening several phytochemicals in vitro and implementing these results in both short- and long-term studies. Initially, several phytochemicals were tested as pure compounds against oxidative DNA damage induced by 4-hydroxy estradiol and CuCl2. Ellagic acid, was the most effective agent (andgt;98% reduction). In a short-term in vivo study, both dietary blueberry and strawberry (5% w/w), were ineffective in reducing the baseline oxidative DNA damage in the livers of CD-1 mice. However, red raspberry (5% w/w) was highly effective (50% reduction) and ellagic acid (400 ppm) was moderately effective (25% reduction). Further both diets up-regulated hepatic DNA repair genes in a similar fashion. In a long-term estradiol-induced mammary carcinogenicity study in ACI rats, dietary berries (2.5% w/w) and ellagic acid (400 ppm) reduced both tumor volume and tumors per animal to different extents (50-75%). One mechanism by which these dietary interventions inhibit mammary tumorigenesis may be via modulation of E2 metabolism, especially at the early stages of carcinogenesis. At 6 weeks after E2 treatment both berries and ellagic acid or berries alone significantly offset E2- induced changes in CYP1B1 and CYP1A1 expressions respectively. In addition, no toxicity or adverse effects are observed when rodents were fed either berries (1 - 5%) or ellagic acid (400 ppm). These data taken collectively support the possibility of using natural foods such as berries as an adjuvant to current pharmacological therapies in the prevention and treatment of breast cancer.
... Expression of AR was increased with melatonin treatment and returned to normal levels after the combination with ethanol. It seems plausible to consider that ethanol stimulates E2 by activating aromatase[46], while reducing androgen levels and, subsequently, AR levels. Furthermore, a direct inhibitory effect of the ER-/AR heterodimer on both AR and ER-may adversely affect the transactivation properties[47]. ...
Article
Chronic ethanol intake is associated with sex hormone disturbances, and it is well known that melatonin plays a key role in regulating several reproductive processes. We report the effects of ethanol intake and melatonin treatment (at doses of 100μg/100g b.w/day) on sex hormones and steroid receptors in the ovaries, oviducts and uteri of ethanol-preferring rats. After 150 days of treatment, animals were euthanized, and tissue samples were harvested to evaluate androgen, estrogen, progesterone and melatonin receptor subunits (AR,ER-α, and-β,PRA,PRB and MT1R, respectively). Melatonin decreased estradiol (E2) and increased progesterone (P4) and 6-sulfatoxymelatonin (6-STM), while an ethanol-melatonin combination reduced both P4 and E2. Ovarian AR was not influenced by either treatment, and oviduct AR was reduced after ethanol-melatonin combination. Oviduct ER-α, ER-β and uterine ER-β were downregulated by either ethanol or melatonin. Conversely, ovarian PRA and PRB were positively regulated by ethanol and ethanol-melatonin combination, whereas PRA was downregulated in the uterus and oviduct after ethanol consumption. MT1R was increased in ovaries and uteri of melatonin-treated rats. Ethanol and melatonin exert opposite effects on E2 and P4, and they differentially regulate the expression of sex steroid receptors in female reproductive tissues.
... En effet, des carcinogènes tels que l'acétaldéhyde ou le benzène sont retrouvés dans les boissons alcoolisées ou peuvent être générés par le métabolisme de l'alcool (Lachenmeier et al., 2012). L'alcool peut perturber les niveaux d'oestrogènes en impactant sur le métabolisme hépatique des oestrogènes mais également en augmentant la conversion d'androgènes en oestrogènes (Purohit, 2000). ...
Thesis
Le laboratoire INSERM U908 a montré le rôle déterminant du facteur de croissance NGF dans l’agressivité du cancer du sein. De précédentes études ont montré que l’inhibition de l’activité de TrkA, le récepteur du NGF, aboutissait à une diminution de la taille des tumeurs in vitro mais aussi dans des modèles pré-cliniques. Néanmoins, ces inhibiteurs ont donné lieu à des essais cliniques décevants. La résistance à ces inhibiteurs est en partie due à l’association de récepteurs membranaires. Plus précisément, mon travail de thèse a permis de démontrer qu’une forme particulière du récepteur CD44 interagit avec TrkA ce qui conduit à une résistance aux traitements. De plus, j’ai également montré l’existence d’une interaction entre TrkA et deux autres récepteurs. Ainsi, j’ai pu déterminer précisément comment ces récepteurs coopèrent afin de développer des inhibiteurs ciblant leur interaction. Ces inhibiteurs pourraient donc s’avérer efficaces pour le traitement de certains cancers du sein. Ma thèse souligne l’importance des complexes de récepteurs dans la plasticité des cellules cancéreuses et leur capacité à s’adapter pour résister aux thérapies ciblées.
... • The activity of the enzyme aromatase, which converts androgens to estrogens, especially in the liver, is increased by ethanol (Purohit 2000). This mechanism may explain why alcohol abuse results in hypo-gonadism even in the absence of liver disease. ...
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Alcohol can permeate virtually every organ and tissue in the body, resulting in tissue injury and organ dysfunction. Considerable evidence indicates that alcohol abuse results in clinical abnormalities of one of the body’s most important systems, the endocrine system. This system ensures proper communication between various organs, also interfacing with the immune and nervous systems, and is essential for maintaining a constant internal environment. The endocrine system includes the hypothalamic–pituitary–adrenal axis, the hypothalamic–pituitary–gonadal axis, the hypothalamic–pituitary–thyroid axis, the hypothalamic–pituitary–growth hormone/insulin-like growth factor-1 axis, and the hypothalamic–posterior pituitary axis, as well as other sources of hormones, such as the endocrine pancreas and endocrine adipose tissue. Alcohol abuse disrupts all of these systems and causes hormonal disturbances that may result in various disorders, such as stress intolerance, reproductive dysfunction, thyroid problems, immune abnormalities, and psychological and behavioral disorders. Studies in both humans and animal models have helped shed light on alcohol’s effects on various components of the endocrine system and their consequences.
... Aromatase and 17beta-hydroxysteroid dehydrogenase enzymes are aberrantly expressed in fibroids. Some of the known factors that increase aromatase activity are age, insulin, obesity, gonadotropins, and alcohol [67]. Aromatase and 17betahydroxysteroid dehydrogenase convert circulating androstenedione (a prohormone released by the adrenal cortex & ovaries) into estradiol [68]. ...
... Moreover, the destruction of liver function in alcoholics leads to an alteration in the metabolism of estrogens. Several studies have shown that alcohol can interfere with the balance of sex hormones by promoting the aromatization of androgens into estrogens and thereby impairing the ratio of androgens to estrogen [163][164][165][166]. ...
Article
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Otolaryngology (also known as ear, nose, and throat (ENT)) diseases can be significantly affected by the level of sex hormones, which indicates that sex differences affect the manifestation, pathophysiology, and outcomes of these diseases. Recently, increasing evidence has suggested that proinflammatory responses in ENT diseases are linked to the level of sex hormones. The sex hormone receptors are present on a wide variety of immune cells; therefore, it is evident that they play crucial roles in regulating the immune system and hence affect the disease progression of ENT diseases. In this review, we focus on how sex hormones, particularly estrogens, regulate ENT diseases, such as chronic rhinosinusitis, vocal fold polyps, thyroid cancer, Sjögren’s syndrome, and head and neck cancers, from the perspectives of inflammatory responses and specialized proresolving mediator-driven resolution. This paper aims to clarify why considering sex differences in the field of basic and medical research on otolaryngology is a key component to successful therapy for both males and females in the future.
... Alcohol interferes with sex hormone activity by promoting the aromatization of androgens during estrogen biosynthesis [8]. It therefore influences the androgen/estrogen ratio. ...
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Locally brewed alcoholic beverages have become part of the socioeconomic life of the Nigerian and West African communities. The negative effect of the use of the beverages on both health, economic and social life is worth exploring amidst the increasing challenges of poverty, inadequate health facilities, lack of basic social amenities amongst many others. This study aimed at evaluating the effect of some selected locally brewed Nigerian alcoholic beverage on the hormonal profile of male and female albino rats. A total of 60 screened rats (spaque Dawley strain) of body weight 180-200g and comprising 30 males and females each were randomly divided into five groups of six animals of same sex per cage and administered with various doses of local alcoholic beverages-goskolo, burukutu, pito and ogogoro per oral for a period of 21 days. Serum hormonal assays were carried out with the use of the respective EIA Kit, ELISA microwells and microplate immunoassay. Results revealed significant decrease (p < 0.05) in the sex hormones (estrogen, progesterone, and testosterone) in all the male treated with these alcoholic beverages, while LH and FSH were not significantly affected. The toxicological evaluation of traditional alcoholic beverages pito, burukutu, ogogorogo and goskolo revealed significant decrease in the sex hormonal profile of male and female albino rats. This buttressed the toxicological effect by way of decrease in the activity of the sex hormones necessary for fertility and reproduction the rats.
... Thus, sex differences in binge alcohol-induced neurodegeneration may be attributable, at least in part, to the differential activational effects of sex hormones on HPA reactivity via their direct actions at the level of the brain such as the hypothalamus and/or the periphery [10,180,212,213]. Moreover, repeated alcohol exposure is reported to downregulate circulating testosterone and upregulate estradiol levels puportedly by aromatization of androgens to estrogen although these changes in gonadal hormone milieu appear to be alcohol dose and duration-dependent as well as sex-and age-dependent [214][215][216]. It is also possible that sex hormones distinctly modulate neurobehavioral effects of binge alcohol via their organizational and/or activational effects (like CORT discussed above) on alcohol-vulnerable brain regions such as the hippocampus [10,217,218]. ...
Article
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Historically, most alcohol neurotoxicity studies were conducted in young adult males and focused on chronic intake. There has been a shift towards studying the effects of alcohol on the adolescent brain, due to alcohol consumption during this formative period disrupting the brain’s developmental trajectory. Because the most typical pattern of adolescent alcohol intake is heavy episodic (binge) drinking, there has also been a shift towards the study of binge alcohol-induced neurobehavioral toxicity. It has thus become apparent that binge alcohol damages the adolescent brain and there is increasing attention to sex-dependent effects. Significant knowledge gaps remain in our understanding of the effects of binge alcohol on the female brain, however. Moreover, it is unsettling that population-level studies indicate that the prevalence of binge drinking is increasing among American women, particularly those in older age groups. Therefore, although study of adolescents has made it apparent that binge alcohol disrupts ongoing brain maturational processes, we know almost nothing about how it impacts the aging brain, as studies of its effects on the aged brain are relatively scarce, and the study of sex-dependent effects is just beginning. Given the rapidly increasing population of older Americans, it is crucial that studies address age-dependent effects of binge alcohol, and given the increase in binge drinking in older women who are at higher risk for cognitive decline relative to men, studies must encompass both sexes. Because adolescence and older age are both characterized by age-typical brain changes, and because binge drinking is the most common pattern of alcohol intake in both age groups, the knowledge that we have amassed on binge alcohol effects on the adolescent brain can inform our study of its effects on the aging brain. In this review, we therefore cover the current state of knowledge of sex and age-dependent effects of binge alcohol, as well as statistical and methodological considerations for studies aimed at addressing them.
... Regarding the direct biologic effects of alcohol on breast cancer risk, one widely discussed hypothesis is that alcohol may have some effects on circulating estrogen levels. Although we could not define biological mechanisms explaining the difference in alcohol-related risk between discordant and concordant subtype, it is likely that such an alcohol dependent-mechanism would affect the growth of ER+/PgR+ cancer (Purohit 2000;Dorgan et al. 2001). Acetaldehyde, a metabolite of ethanol, may have direct carcinogenic effects (Scoccianti et al. 2014). ...
Article
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Alcohol consumption is a risk factor for breast cancer in Western countries, but few studies have evaluated the risk for Japanese women, who have a relatively low alcohol intake. This case-control study investigated the association of alcohol consumption with breast cancer risk according to estrogen-receptor and progesterone-receptor (ER/PgR) status in Japanese women. From female patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2011, 1,256 breast cancer cases (669 ER+/PgR+, 162 ER+/PgR-, 21 ER-/PgR+, 305 ER-/PgR-, and 99 missing) and 2,933 controls were selected. Alcohol-related measures were assessed using a self-administered questionnaire. Unconditional logistic regression analysis was performed. Alcohol-related measures were not associated with breast cancer risk among the women overall. Moreover, no association was observed between ever drinking and the risk of a concordant receptor subtype (ER+/PgR+ or ER-/PgR-). Conversely, ever drinking was inversely associated with the risk of discordant subtype (ER+/PgR-, odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.41-0.95; ER-/PgR+, OR = 0.44, 95% CI: 0.14-1.42). For ER+/PgR-, an inverse association with the amount of alcohol consumed per day was observed (P for trend = 0.04), and this inverse association was limited to premenopausal women. Alcohol consumption may have differential effects on concordant and discordant receptor subtypes of breast cancer. In view of the low frequency of discordant subtype in Japanese women and their relatively low alcohol intake, our findings may provide a clue for elucidating the etiology of breast cancer rather than for preventing discordant subtype.
... Moreover, alcohol oxidation competes with the production of testicular and testosterone. These mechanisms leading to reduce in sperm density and the volume of semen (6). There are still no unified results in this area. ...
... Furthermore, alcohol consumers and alcohol-dependent individuals can develop liver diseases that will impact the catabolism of steroids including testosterone. In fact, ethanol elevates the activity of aromatase, an enzyme that converts androgens to estrogens, especially in the liver (Purohit, 2000). In addition, ethanol reduces the metabolism of vitamin A, such as retinol, which impacts the retinoid homeostasis throughout the body (Clugston and Blaner, 2012). ...
... Accordingly, we detected positive correlations of the estradiol-to-testosterone ratios with liver 330 enzyme and CK activities in male alcohol-dependent patients. The literature on the effects of alcohol 331 on aromatization of testosterone in females is controversial (Purohit, 2000). As far as we know, our 332 study is the first to show significantly lower estradiol-to-testosterone and bioavailable estradiol-to-333 bioavailable testosterone ratios in alcohol-dependent females compared to controls. ...
... The susceptibility of certain genes combining with environmental factors plays an important role in developing breast cancer (Lichtenstein et al., 2000). Studies have shown that consumption of alcohol increases the level of estrogen that may subsequently stimulate the proliferation of breast cancer cells (Purohit, 2000) or the production of reactive oxygen species during alcoholic metabolism that results in breast cancer through the damage of DNA (Wright et al., 1999). ...
Article
Breast cancer remains a challenging disease globally due to its heterogeneity and complexity, with an annual increase rate of 3.1%. Cytochrome P450 2E1 (CYP2E1) rs2031920 and rs3813867 polymorphisms that reside in the 5’-flanking promoter region of the gene are in a complete linkage disequilibrium and have been associated with breast cancer risk, but the findings are inconsistent and inconclusive. Therefore, we investigated the association of the CYP2E1 rs2031920 and rs3813867 polymorphisms with the risk of breast cancer through a meta-analysis. After literature search, eight eligible studies were included in this meta-analysis with a total of 3650 breast cancer cases and 3607 controls. Our meta-analysis revealed no significant association of the CYP2E1 rs2031920 and rs3813867 polymorphisms with breast cancer risk in all comparison models including the allelic (OR = 0.968, 95% CI = 0.855-1.097; p = 0.612), heterozygous (OR = 1.003, 95% CI = 0.869-1.159; p = 0.963), homozygous (OR = 0.792, 95% CI = 0.519-1.207; p = 0.278), dominant (OR = 0.987, 95% CI = 0.858-1.134; p = 0.851), and recessive (OR = 1.265, 95% CI = 0.831-1.924; p = 0.273). In conclusion, this meta-analysis suggests that the CYP2E1 rs2031920 and rs3813867 polymorphisms are not associated with the risk of breast cancer.
... The susceptibility of certain genes combining with environmental factors plays an important role in developing breast cancer ( Lichtenstein et al., 2000). Studies have shown that consumption of alcohol increases the level of estrogen that may subsequently stimulate the proliferation of breast cancer cells (Purohit, 2000) or the production of reactive oxygen species during alcoholic metabolism that results in breast cancer through the damage of DNA (Wright et al., 1999). ...
Article
Breast cancer remains a challenging disease globally due to its heterogeneity and complexity, with an annual increase rate of 3.1%. Cytochrome P450 2E1 (CYP2E1) rs2031920 and rs3813867 polymorphisms that reside in the 5'-flanking promoter region of the gene are in a complete linkage disequilibrium and have been associated with breast cancer risk, but the findings are inconsistent and inconclusive. Therefore, we investigated the association of the CYP2E1 rs2031920 and rs3813867 polymorphisms with the risk of breast cancer through a meta-analysis. After literature search, eight eligible studies were included in this meta-analysis with a total of 3650 breast cancer cases and 3607 controls. Our meta-analysis revealed no significant association of the CYP2E1 rs2031920 and rs3813867 polymorphisms with breast cancer risk in all comparison models including the allelic (OR = 0.968, 95% CI = 0.855-1.097; p = 0.612), heterozygous (OR = 1.003, 95% CI = 0.869-1.159; p = 0.963), homozygous (OR = 0.792, 95% CI = 0.519-1.207; p = 0.278), dominant (OR = 0.987, 95% CI = 0.858-1.134; p = 0.851), and recessive (OR = 1.265, 95% CI = 0.831-1.924; p = 0.273). In conclusion, this meta-analysis suggests that the CYP2E1 rs2031920 and rs3813867 polymorphisms are not associated with the risk of breast cancer.
... Alcohol may influence oestradiol concentration by altering its metabolism and clearance [44,45,47], or by affecting aromatisation of androgens to oestrogens [48]. The overall null finding in our analysis may be due to certain limitations in the data for oestradiol. ...
Article
Background: Alcohol intake may influence breast cancer risk in women through hormonal changes, but the evidence to date is inconclusive. We investigated cross-sectional associations between habitual alcohol intake and serum concentrations of testosterone, SHBG (sex hormone binding globulin), IGF-1 (insulin-like growth factor-1) and oestradiol (pre-menopausal women only) in UK Biobank. Methods: We included 30,557 pre-menopausal and 134,029 post-menopausal women aged between 40-69 years when recruited between 2006 and 2010. At their initial assessment visit, habitual alcohol intake was assessed using a touchscreen questionnaire, and serum hormone concentrations were assayed. Multivariable linear regression analysis was performed. Results: Per 10 g/day increment in alcohol intake, testosterone concentration was 3.9% (95% CI: 3.3%, 4.5%) higher in pre-menopausal women and 2.3% (1.8%, 2.7%) higher in post-menopausal women (pheterogeneity<0.0001); SHBG concentration was 0.7% (0.2%, 1.1%) higher in pre-menopausal women and 2.4% (2.2%, 2.6%) lower in post-menopausal women (pheterogeneity<0.0001); and IGF-1 concentration was 1.9% (1.7%, 2.1%) lower in pre-menopausal women and 0.8% (0.6%, 0.9%) lower in post-menopausal women (pheterogeneity<0.0001). In pre-menopausal women, there was no significant overall association of alcohol with oestradiol but a positive association was observed in the early and mid-luteal phases: 1.9% (95% CI: 0.2%, 3.6%) and 2.4% (95% CI: 0.7%, 4.2%) higher respectively. Conclusions: This study confirms significant but modest associations between alcohol intake and hormones, with evidence of heterogeneity by menopausal status. Impact: The findings facilitate better understanding of whether alcohol intake influences hormone concentrations, but further work is necessary to fully understand the mechanisms linking alcohol with cancer risk.
... The decrease in serum testosterone concentration can stimulate the activity of the aromatase enzyme, present in peripheral fat cells, which is responsible for conversion of testosterone to estrogen. This substance can promote a decrease in sperm volume and density, thus influencing fertilization (Purohit, 2000). ...
Article
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Alcohol is the most commonly consumed substance in the world. The objective of this study was to evaluate the influence of alcoholic beverages on male reproduction and possible alterations in their offspring. The mice were divided into 4 groups: beer, wine, cachaça (a type of sugarcane rum), with ethanol concentrations of 1.9 g/kg, and control group treated with PBS. The treatment period was 35 days. The animals which received cachaça, demonstrated significant weight loss in the testes and epididymis. The alcoholic beverages promoted significant testosterone level and fertilization index diminution, and morphological alterations in the spermatozoa. The beer group presented decreased implantation sites and a high frequency of dominant lethal. The number of reabsorptions in the wine group was increased. The fermented beverages presented higher potential to induce visceral malformations, while the cachaça caused fetal skeletal malformations. The cachaça treated group presented a negative impact on semen quality and fertilization potential. The treatment with different alcoholic beverages, during spermatogenesis, demonstrated contrasting degrees of induction of toxic effects, interfering in a general aspect in male reproductive performance, fetal viability during intrauterine life, and birth defects. From the data, it is possible to infer that the distillated beverage caused more harmful effects to reproduction in this study.
... Plusieurs mécanismes ont été évoqués, parmi lesquels l'augmentation de la concentration d'oestrogènes liés à la consommation d'alcool (Lachenmeier et al. 2012), la diminution de l'efficacité de la réparation de l'ADN (Purohit 2000), la stimulation du métabolisme de substances cancérogènes comme l'acétaldéhyde induisant des dommages à l'ADN (Singletary et al. 2001). ...
Thesis
Les gènes du métabolisme des xénobiotiques (MX) impliqués dans l’activation et l’élimination des cancérogènes environnementaux pourraient moduler le risque de cancer du sein, mais leurs effets dans ce cancer ont été peu étudiés et sont mal connus. Les objectifs de la thèse étaient d’étudier le rôle des gènes MX dans le cancer du sein d’une part, et dans les niveaux biologiques de cancérogènes mammaires suspectés, d’autre part. Les analyses ont porté sur les données d’une étude cas-témoins en population sur les cancers du sein (étude CECILE). L’association avec le cancer du sein a été étudiée (1) avec les variants du gène NAT2 qui déterminent le type d’acétyleur lent ou rapide de chaque individu ; (2) les polymorphismes des gènes MX étudiés conjointement au niveau de chacun des gènes et au niveau de l’ensemble du pathway à l’aide d’une méthode exploratoire de type « gene-set ». Dans chacune de ces approches, les interactions avec la consommation de tabac ont été étudiées. Dans une dernière partie, nous avons cherché à identifier les polymorphismes des gènes MX prédictifs des concentrations sanguines de polluants organochlorés persistants (p,p’-DDE et PCB153) chez les témoins de l’étude CECILE. Le risque de cancer du sein était augmenté chez les femmes ayant un profil génétique NAT2 d’acétyleuses rapides par rapport aux femmes ayant un profil d’acétyleuses lentes. Parmi les acétyleuses lentes, les femmes fumeuses avaient un risque de cancer du sein augmenté par rapport aux non fumeuses indiquant l’existence d’une interaction tabac-NAT2. L’approche « gene-set » montrait que les polymorphismes au niveau de plusieurs gènes MX et au niveau de l’ensemble du pathway étaient associés collectivement au cancer du sein. L’association entre le cancer du sein et l’ensemble des polymorphismes du pathway XM était observée chez les fumeuses, indiquant le rôle de la consommation de tabac dans cette association. Enfin, nous avons montré l’effet du gène CYP2B6 en tant que déterminant des niveaux sanguins de p,p’-DDE et PCB153. Nos résultats mettent en évidence un rôle des gènes XM dans le cancer du sein qui peut être expliqué par leur fonction dans le métabolisme et l’élimination des cancérogènes environnementaux.
Article
Background & aims Determining dietary patterns in China is challenging due to lack of external validation and objective measurements. We aimed to characterize dietary patterns in a community-based population and to validate these patterns using external validation cohort and metabolomic profiles. Design We studied 5145 participants, aged 18–80 years, from two districts of Hangzhou, China. We used one district as the discovery cohort (N = 2521) and the other as the external validation cohort (N = 2624). We identified dietary patterns using a k-means clustering. Associations between dietary patterns and metabolic conditions were analyzed using adjusted logistic models. We assessed relationships between metabolomic profile and dietary patterns in 214 participants with metabolomics data. Results We identified three dietary patterns: the traditional (rice-based), the mixed (rich in dairy products, eggs, nuts, etc.), and the high-alcohol diets. Relative to the traditional diet, the mixed (ORadj = 1.7, CI 1.3–2.4) and the high-alcohol diets (ORadj = 1.9, CI 1.3–2.7) were associated with type 2 diabetes and hypertension, respectively. Similar results were confirmed in the external validation cohort. In addition, we also identified 18 and 22 metabolites that could distinguish the mixed (error rate = 12%; AUC = 96%) and traditional diets (error rate = 19%; AUC = 88%) from the high-alcohol diet. Conclusions Despite the complexity of Chinese diet, identifying dietary patterns helps distinguish groups of individuals with high risk of metabolic diseases, which can also be validated by external population and metabolomic profiles.
Article
Multiple symmetric lipomatosis (MSL, OMIM 151800), is a rare disease characterised by the growth of uncapsulated masses of abnormal adipose tissue around the neck, shoulders or other parts of the trunk and typically associated with high ethanol intake. We describe the case of a 33 year-old woman with MSL and secondary amenorrhea. Despite the presence of an ovarian failure confirmed by undetectable serum levels of inhibin B and anti-Müllerian hormone, the patient had normal serum levels of estrone and gonadotropins coexisting with a biological adrenal hyperandrogenism. We suggest that the adrenal hyperandrogenism observed in our patient could be attributed to an impairment of the cytochrome p450 function, inducing a relative 21-hydroxylase deficiency/insufficiency, related to alcohol abuse and that the increased peripheral aromatization of androgens in estrogens lead to normal circulating levels of estrone. The result is the absence of gonadotropin elevation despite primary ovarian failure. The peculiar functional pattern of brown adipocytes in patients with MSL may contribute to this biological phenomenon with an additive effect related to alcohol consumption. Altogether, these data could help to better define the peculiar pituitary-gonadal profile observed in this rare syndrome and in some cases of women with heavy alcohol consumption.
Article
1. For decades, it has been well documented that alcohol intake increases risk for cancers of the upper aerodigestive tract (oral cavity, pharynx, larynx, and esophagus), especially at high levels of intake, as well as for breast, colon, and liver cancers. 2. Many types of cancer associations were observed for all types of alcoholic beverages, suggesting that ethanol is the main carcinogenic constituent of alcohol drinks. 3. Alcohol has multiple actions in modifying carcinogenesis, not only directly, such as disordering cell membranes, but also indirectly, such as a consequence of ethanol oxidation to acetaldehyde and other reactive intermediates. 4. The magnitude, specificity, and variability of ethanol’s actions can depend on the dose and duration of exposure and on specific biochemical and molecular characteristics of the tissues to which ethanol comes in contact. 5. The possible mechanisms underlying alcohol’s carcinogenicity include the causation of DNA damage by alcohol’s metabolic product acetaldehyde, alcohol’s effect in increasing estrogen levels, alcohol being a solvent for carcinogens, alcohol-induced generation of reactive oxygen species, alcohol-associated alterations in nutritional status, and deleterious effects of alcohol on the host immune system.
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The rising incidence of T2DM is well recognised and associated with trends in obesity and ageing. It is estimated that 2.8% of the world population had a diagnosis of diabetes mellitus in 2000, which is projected to rise to 4.3% by 2030. Diabetes, obesity and ageing are also associated with an increased risk of isolated male hypogonadotropic hypogonadism, often labelled 'late onset hypogonadism' (LOH) to distinguish it from hypogonadism secondary to distinct hypothalamopituitary pathology. Whether the incidence of hypogonadism is increasing is open to question; the past decade, however, has witnessed a marked increase in the prescription of testosterone replacement therapy. Testosterone deficiency appears to be particularly common in type 2 diabetes with a prevalence of 33% observed in one cohort of 103 men (mean age 54.7). However, the diagnosis of androgen deficiency states is not necessarily straightforward, depending amongst other factors, upon whether a biochemical threshold or a syndromic approach (mandating the presence of certain key clinical features) is employed. The pathogenic mechanisms underlying obesity and diabetes related hypogonadism remain unclear with several competing theories, most of which are not mutually exclusive. Whilst a large body of epidemiological evidence associates testosterone deficiency with increased risk of cardiovascular disease and mortality, little evidence exists to support a protective effect of testosterone replacement. The benefits of androgen replacement in younger men with pituitary disease are well established, however, the potential benefits and safety of androgen replacement in older men is much less well developed. At present, replacement therapy in older men is advocated principally for the amelioration of sexual symptoms. This review will seek to explore issues around the pathogenesis, diagnosis, clinical consequences and management of male hypogonadism as it relates to T2DM.
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The article discusses relationships between concentrations of reproductive hormones (estradiol and progesterone) and the intake of energy, several nutrients (alcohol among others) and overall dietary patterns in women in reproductive age. Moreover, probable biological mechanisms responsible for the associations were indicated. There is no evidence for the relationship between dietary patterns and the levels of ovarian steroid hormones in women in reproductive age. In studies based on traditional diet analysis, in which the effects of single nutrients on a specific health problem are evaluated, also no convincing proof could be found that any dietary component can either increase or decrease the levels of reproductive hormones. Only alcohol intake seems to contribute to higher estrogen levels, which accounts for alcohol being the only dietary breast cancer risk factor.
Article
Hepatic encephalopathy (HE) is a neuropsychiatric state potentially complicating cirrhosis following the accumulation of toxic compounds that cross the blood–brain barrier and affect brain function; the compounds may undergo alveolar gas exchange and be partially excreted by exhalation. Thus breath analysis as a non-invasive means of diagnosing HE, cirrhosis and harmful drinking was investigated in a pilot study. One litre samples of breath were collected from patients with alcohol-related cirrhosis (n = 34) with HE (n = 11) and without HE (n = 23), non-alcoholic cirrhosis without HE (n = 13), harmful drinkers without cirrhosis (n = 7), and healthy controls (n = 15) in a hospital setting. Breath compounds trapped on adsorbent tubes were released via thermal desorption and analysed by gas chromatography mass spectrometry for separation and detection. Multivariate discriminant analysis was used to identify volatile organic compounds to differentiate patients according to disease status and build models for disease classification. HE was correctly identified in 90.9 % of alcoholic cirrhotic patients and liver cirrhosis in 100 % of alcoholic patients. In patients without clinical HE, alcohol was correctly predicted as the cause of cirrhosis in 78.3 % of patients and non-alcoholic causes of cirrhosis were correctly determined in 69.2 %. Non-alcoholic cirrhosis, alcoholic cirrhosis, and harmful drinking could be discriminated from healthy controls with a sensitivity of 92.3, 97.1 and 100 %, respectively. Breath volatile analysis has the potential to aid the diagnosis of HE and a range of liver disorders.
Chapter
Infertility affects roughly 15% of couples attempting to conceive. Male factor infertility affects approximately 7% of men and is the underlying cause in at least half of infertility cases. Recent large population studies evaluating semen parameters have highlighted alarming evidence of decreasing sperm concentration among modern societies. Increased interest in determining what lifestyle factors play a role in male infertility development has focused on modifiable risk factors. Recreational drugs such as cigarette smoke, alcohol, marijuana, methamphetamine/ecstasy, and cocaine have varying effects on male reproductive health. This chapter will review such modifiable risk factors and aid in appropriate counseling of reproductive aged males.
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Epidemiological and animal studies indicate that carcinogenesis may start as early as the prenatal period. Modifying the prenatal environment may alter genes through the epigenetic route, and, these alterations may be inherited by the offspring. Epigenetic factors like nutritional factors, endocrine disruptors, infection and lifestyle may affect tumour development, or, target cell differentiation to increase susceptibility to cancer. In this chapter, we discuss the evidence related to embryo-fetal origins of tumours. © Springer Science+Business Media Dordrecht 2014. All rights are reserved.
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When the outcome of a choice is less favourable than expected, humans and animals typically shift to an alternate choice option. Several lines of evidence indicate that this "lose-shift" responding is an innate sensorimotor response strategy that is normally suppressed by executive function. Therefore, the lose-shift response provides a covert gauge of cognitive control over choice mechanisms. We report here that the spatial position, rather than visual features, of choice targets drives the lose-shift effect. Furthermore, the ability to inhibit lose-shift responding to gain reward is different among male and female habitual cannabis users. Increased self-reported cannabis use was concordant with suppressed response flexibility and an increased tendency to lose-shift in women, which reduced performance in a choice task in which random responding is the optimal strategy. On the other hand, increased cannabis use in men was concordant with reduced reliance on spatial cues during decision-making, and had no impact on the number of correct responses. These data (63,600 trials from 106 participants) provide strong evidence that spatial-motor processing is an important component of economic decision-making, and that its governance by executive systems is different in men and women who use cannabis frequently.
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Background: Estrogen signaling is essential for the sexual dimorphism of the skeleton, is required for normal bone remodeling balance in adults, and may influence the skeletal response to alcohol. High levels of alcohol consumption lower bone mass in ovary-intact but not ovariectomized (ovx) rats. However, the extremely rapid rate of bone loss immediately following ovx may obscure the effects of alcohol. We therefore determined (1) whether heavy alcohol consumption (35% caloric intake) influences bone in sexually mature ovx rats with established cancellous osteopenia, and (2) whether ICI 182,780 (ICI), a potent estrogen receptor-signaling antagonist, alters the skeletal response to alcohol. Methods: Three weeks following ovx, rats were randomized into five groups: (1) baseline, (2) control+vehicle, (3) control+ICI, (4) ethanol+vehicle, or (5) ethanol+ICI and treated accordingly for four weeks. Dual energy X-ray absorptiometry, micro-computed tomography, blood measurements of markers of bone turnover, and gene expression in femur and uterus were used to evaluate response to alcohol and ICI. Results: Rats consuming alcohol had lower bone mass and increased fat mass. Bone microarchitecture of the tibia and gene expression in femur were altered; specifically, there was reduced accrual of cortical bone, net loss of cancellous bone, and differential expression of 19/84 genes related to bone turnover. Furthermore, osteocalcin, a marker of bone turnover, was lower in alcohol-fed rats. ICI had no effect on weight gain, body composition, or cortical bone. ICI reduced cancellous bone loss and serum CTX-1, a biochemical marker of bone resorption; alcohol antagonized the latter two responses. Neither alcohol nor ICI affected uterine weight or gene expression. Conclusion: Alcohol exaggerated bone loss in ovx rats in the presence or absence of estrogen receptor blockade with ICI. The negligible effect of alcohol on uterus and limited effects of ICI on bone in alcohol-fed ovx rats suggests that estrogen receptor signaling plays a limited role in the action of alcohol on bone in a rat model for chronic alcohol abuse. This article is protected by copyright. All rights reserved.
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Plusieurs études épidémiologiques ont montré qu'une consommation régulière d'alcool augmentait significativement la probabilité de développer un cancer mammaire. Les études réalisées in vitro et in vivo pour confirmer ces données indiquent que l'éthanol peut non seulement induire la cancérogenèse mammaire, mais également stimuler la tumorogenèse et l'invasion des cellules tumorales. Dans la mesure où ces effets semblent liés à l'hormono-dépendance des cellules cancéreuses, notre objectif visait à étudier les mécanismes moléculaires impliqués en utilisant la lignée MCF-7. Nous avons confirmé l'effet stimulateur de l'éthanol sur la prolifération de ces cellules. Celui-ci s'accompagne d'une augmentation du taux d'ERa, de COX-2 et de l'aromatase, enzyme responsable de la biosynthèse des oestrogènes. D'autres alcools tels que le méthanol ou le butanol-1 entraînent quant à eux une diminution significative de la prolifération cellulaire et n'induisent jamais d'augmentation du taux d'aromatase. Dans le contexte de la migration cellulaire, nous avons montré que l'éthanol stimulait la sécrétion des MMP-2 et -9 par les cellules MCF-7. La sécrétion de MMP-9 induite par l'éthanol est dépendante de l'activation de l'ERa. L'alcool pourrait agir non seulement par une production accrue d'oestrogènes liée à la surexpression d'aromatase mais aussi par une activation ligand-indépendante de l'ERa dont nous montrons qu elle est liée à la voie AMPc/PKA et au récepteur A2a à l'adénosine. Ce dernier pourrait constituer une nouvelle cible thérapeutique.
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Background. Circadian and circannual rhythms of sex steroids in men have been well described, but infradian dynamics of estradiol and progesterone in men are unknown. These hormones play a role in the physiology as well as in the pathophysiology of various clinical entities, and their chronobiology might be of importance.Aim. Infradian dynamics of salivary estradiol, testosterone, and progesterone were analysed for the presence of cyclic patterns.Subjects and methods. Five young healthy men collected saliva samples for 30 consecutive days. Salivary estradiol, testosterone, and progesterone were measured using radioimmunoassay. Analysis of Rhythmic Variance (ANORVA) was used and potential period lengths of 3–15 days were evaluated.Results. No infradian rhythms were found in testosterone and progesterone, but a significant (p
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Studies in men suggest that light-to-moderate alcohol intake is associated with a reduction in overall mortality, due primarily to a reduced risk of coronary heart disease. Among women with similar levels of alcohol consumption, an increased risk of breast cancer has been noted that complicates the balance of risks and benefits. We conducted a prospective study among 85,709 women, 34 to 59 years of age and without a history of myocardial infarction, angina, stroke, or cancer, who completed a dietary questionnaire in 1980. During the 12-year follow-up period, 2658 deaths were documented. The relative risks of death in drinkers as compared with nondrinkers were 0.83 (95 percent confidence interval, 0.74 to 0.93) for women who consumed 1.5 to 4.9 g of alcohol per day (one to three drinks per week), 0.88 (95 percent confidence interval, 0.80 to 0.98) for those who consumed 5.0 to 29.9 g per day, and 1.19 (95 percent confidence interval, 1.02 to 1.38) for those who consumed 30 g or more per day, after adjustment for other predictors of mortality. Light-to-moderate drinking (1.5 to 29.9 g per day) was associated with a decreased risk of death from cardiovascular disease; heavier drinking was associated with an increased risk of death from other causes, particularly breast cancer and cirrhosis. The benefit associated with light-to-moderate drinking was most apparent among women with risk factors for coronary heart disease and those 50 years of age or older. Among women, light-to-moderate alcohol consumption is associated with a reduced mortality rate, but this apparent survival benefit appears largely confined to women at greater risk for coronary heart disease.
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To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate-adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.
Article
Objective.— To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. Data Sources.— We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. Data Extraction.— Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. Data Synthesis.— For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate-adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. Conclusions.— Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.
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Chronic alcohol ingestion in the rat resulted in increased hepatic aromatase activity, elevation of plasma estradiol, and a decrease in plasma testosterone levels. Testicular incubation studies indicated that the source of the estrogen was not of gonadal origin but was, most likely, due to increased peripheral conversion. The failure of HCG in vitro to restore testicular secretion of testosterone to normal levels suggested a direct action of alcohol, or a metabolic product, on gonadal secretory processes, as distinct from trophic hormone effects. This study demonstrates that many of the hormonal alterations seen in cirrhosis of the liver in man may be produced directly by alcohol feeding without cirrhotic changes in the rat.
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After incubation of tritiated androstenedione with human adult liver homogenate, estrone and estradiol were identified in the unconjugated radioactive material, with conversion rates of .09 and .13% (uncorrected for losses). That finding indicates that the aromatizing capacity present in the human fetal liver has been preserved in the adult. Therefore, it is suggested that, in the adult, peripheral aromatization of C-19 steroids takes place, at least partially, in the liver. The presence of estradiol should be related to a 17β-hydroxysteroid dehydrogenase activity in the human liver. Neither estrone nor estradiol could be detected in the conjugated radioactive material, although almost 50% of it behaved like phenolic steroids.
Article
To determine whether ethanol per se affects testosterone metabolism, alcohol was administered to normal male volunteers for periods up to four weeks, resulting in an initial dampening of the episodic bursts of testosterone secretion followed by decreases in both the mean plasma concentration and the production rate of testosterone. The volunteers received adequate nutrition and none lost weight during the study, which tended to exclude a nutritional disturbance as the cause of the decreased testosterone levels. The changes in plasma luteinizing hormone suggested both a central (hypothalamus-pituitary) and gonadal effect of alcohol. In addition, alcohol consumption increased the metabolic clearance rate of testosterone in most subjects studied, probably owing to the combined effects of a decreased plasma binding capacity for the androgen and increased hepatic testosterone A-ring reductase activity. These results indicate that alcohol markedly affects testosterone metabolism independently of cirrhosis or nutritional factors.
Article
The contribution, by peripheral conversion, of androstenedione and testosterone to the circulating estrogens was determined in men with cirrhosis of the liver. The conversion ratio of androstenedione to estrone, estradiol and testosterone and the conversion ratio of testosterone to estrone (but not estradiol) and androstenedione were significantly increased. The plasma concentrations of androstenedione and testosterone were increased and decreased respectively; the mean plasma concentration of androstenedione being similar to that found in normal women. The metabolic clearance rate of androstenedione was not altered in cirrhosis although the metabolic clearance rate of testosterone was decreased. The production rate of androstenedione was elevated while that of testosterone was reduced. The instantaneous contribution of plasma androstenedione to estrone and estradiol was increased in cirrhosis as was the contribution of testosterone to estrone (but not to estradiol). Thus the increased estradiol levels in cirrhosis result, in large part, from increased peripheral conversion from the androgens. The percent contribution of plasma testosterone to plasma androstenedione was decreased although the absolute amount derived by conversion was normal. The percent contribution of plasma androstenedione to plasma testosterone was increased sevenfold in cirrhosis. The fraction of the daily androstenedione production derived from the plasma testosterone pool was not significantly altered. However, a significant fraction of the daily production rate of testosterone was derived from androstenedione. Thus, 15% of the circulating testosterone is not secreted but is derived by peripheral conversion from androstenedione. Normal levels of gonadotropins were found in cirrhosis.
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The purpose of this study was to evaluate the detectability of an effect of moderate alcoholic beverage consumption on the biologic correlate of postmenopausal estradiol levels. Total weekly consumption and beverage-specific intake were assessed using both self-reported usual consumption information and prospective food record data. In terms of total weekly drinks, discrepancies were observed in 35 of the 101 women who reported alcohol use; no consistent pattern of overreporting/underreporting was seen. Although the two alcohol estimates were highly correlated, the relationship between estradiol levels and total weekly alcohol intake was found to be detectable when alcohol consumption based on the food record data was analyzed, but not when the self-report data were examined in a two-tailed hypothesis-testing situation. Evaluating the association between postmenopausal estradiol levels and the two estimates of alcohol intake in random samples of varying sample sizes generated from the mother population of 128 normal postmenopausal women confirmed the finding that the prospectively obtained alcohol data better predict the relationship. Based on the results of this study, it must be concluded that self-reported usual alcohol consumption data must be used with caution when examining an association between alcohol intake and a biologic effect.
Article
A cross-sectional study of 351 healthy Finnish women aged 20-76 years was done to establish reference values of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DEXA). The effects of age and of several physical and lifestyle factors on BMD of the lumbar spine and proximal femur (femoral neck, trochanter, and Ward's triangle area) were investigated. Altogether 58 women were excluded from the final analysis due to significant spinal osteoarthritis or other diseases or drugs known to influence calcium or bone metabolism. The precision of the method was 0.9, 1.2, 2.7, and 2.4% in the lumbar, femoral neck, Ward's triangle and trochanter area, respectively. Lumbar BMD was increased by 30% (P less than 0.001) in 15 patients with osteoarthritis (21% of women 50 years or older), but it was apparently unaffected in 5 cases with aortic calcification. Except for the trochanter area, BMD diminished along with age, and this was significant after the menopause. The peak of mean BMD was observed at the age of 31-35 years in the spine and at the age of 20-25 years in the femoral neck and Ward's triangle. BMD was in a positive relationship to weight both in premenopausal and postmenopausal women and to the use of oral contraceptives in premenopausal women and to that of estrogen replacement therapy in postmenopausal women. Labors and pregnancies had a weak positive effect on BMD in premenopausal women. As compared with nonusers premenopausal women who had used alcohol showed a slightly decreased BMD of Ward's triangle. In postmenopausal women there was a positive correlation between alcohol intake and BMD.
Article
We have evaluated the direct effects of ethanol (EtOH) on the production of progesterone (P) and estradiol-17 beta (E2) by cultured human granulosa cells obtained during in vitro fertilization procedures. On day 3 of culture, cells were divided into control and ethanol (20 mM) groups and stimulated by hFSH (50 ng/ml), hLH (0-50 ng/ml), FSH+LH, 8 Br-cAMP (0.25 mM) and androstenedione (10(-7) M). Experiments were terminated on days 7 and 9 and DNA, P, and E2 were measured. Ethanol inhibited P and E2 secretion stimulated by LH; however, there was no significant effect of ethanol on P and E2 production in the control group or when the cells were stimulated by FSH or cAMP. EtOH also had no effect on androstenedione stimulated E2 production. There was no significant difference in the DNA contents of the human granulosa cells in the ethanol group as compared with the control group. These results are the first demonstration of a direct effect of ethanol on cultured granulosa-lutein cells and suggest that ethanol may inhibit action of LH on the corpus luteum. A direct selective toxic effect of EtOH on the ovary may be responsible for some of the reproductive abnormalities observed in alcoholic women.
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The local formation of the testosterone metabolites 5 alpha-dihydrotestosterone and 17 beta-estradiol within the hypothalamic-preoptic area (HPOA) is essential for the normal sexual differentiation of the male central nervous system (CNS) during a perinatal critical period in the rat. Testosterone, the substrate for these reactions, is derived primarily from synthesis within the fetal testis. Fetal alcohol exposure (FAE) during this critical period profoundly affects fetal testicular steroidogenesis as well as the sexual differentiation of the CNS. The present study was conducted to determine whether FAE directly affects the local metabolism of androgens within the developing CNS or whether reduced androgen substrate, via a testicular lesion, is a more likely explanation for the known effects of FAE on the CNS. The enzymatic activities of 5 alpha-reductase and aromatase were simultaneously quantitated in the newborn rat HPOA following FAE. Neither the enzymatic activity of 5 alpha-reductase, aromatase nor their ratio were significantly influenced (P greater than 0.05) by FAE with respect to controls. FAE apparently does not alter the disposition of the androgens within the newborn rat HPOA. These results support the hypothesis that FAE alters the sexual differentiation of the CNS through inhibition of androgen biosynthesis at the level of the perinatal rat testis.
Article
The present study was carried out to investigate if ethanol alters aromatization of androgens and concentrations of hepatic estrogen and androgen receptors. Hepatic aromatization of androgen to estrogen was significantly increased by ethanol administration. There was a significant increase in serum estrogen level but a decreased circulating testosterone level in alcohol-fed rats. Furthermore, the concentration of estrogen receptors in liver cytosol was significantly higher in alcohol-fed rats (37 +/- 5.3 fmol/mg protein), as compared to the intact control value (21 +/- 4.8 fmol/mg protein). However, hepatic androgen receptor levels were much lower (4.4 +/- 0.5) in alcohol-fed rats than those (10.2 +/- 1.4 fmol/mg protein) in control animals. Similarly, castration increased hepatic aromatization of androgens and concentrations of serum estrogen and hepatic estrogen receptors, but it decreased contents of circulating androgen and hepatic androgen receptors. These findings indicate that alcohol administration is considered a chemical form of castration, altering the hepatic steroid metabolism and sex hormone receptor contents and contributing to the pathogenesis of feminization. A combination of alcohol-feeding and castration has no synergistic effect on the hepatic steroid receptors and aromatization, but this combination does have a more profound effect in lowering the concentration of circulating androgen.
Article
A technique of feeding alcohol as part of a liquid diet is reviewed that achieves an alcohol consumption of clinical relevance, while maintaining dietary control and providing adequate nutrition. With this procedure, blood alcohol levels are obtained which mimic clinical conditions and allow experimental duplications of many pathological complications caused by alcohol. In the rat, the liquid diet technique provides a model for the alcoholic fatty liver, various alcohol-induced metabolic, endocrine and central nervous system abnormalities (including tolerance and dependence) and the interaction of ethanol with industrial solvents, many commonly used drugs, analgesics, carcinogens and nutrients. This technique also resulted in the discovery of a new pathway of ethanol metabolism in the microsomes involving an ethanol-specific cytochrome P-450 (P450IIE1), which has now been confirmed in man. P450IIE1 contributes not only to the metabolic tolerance to ethanol, but also explains the enhanced susceptibility of the alcoholic to many ubiquitous xenobiotic agents. The liquid diet technique provides the flexibility to adjust to special experimental or physiological needs by allowing for various substitutions including changes in lipids, proteins or other dietary constituents. This procedure is thereby ideally suited for the study of the interactions of alcohol with deficiency or excess of various nutrients. The technique also facilitates the comparison with controls by simplifying pair feeding procedures. Although the flexibility of the liquid diet technique is one of its key advantages, a standard 'all purpose' liquid diet is described which is appropriate for most experimental applications. In addition, two other general formulae are given, namely a low fat diet (that allows the study of the effects of ethanol in the presence of minimal hepatic lipid accumulation) and a high protein diet (to meet increased needs, e.g. during pregnancy and lactation). The optimal amount of ethanol for the rat liquid diet was found to be 5 g/dl or 36% of total energy. With lesser amounts of alcohol, intake falls below a critical threshold; blood levels of alcohol then become negligible and the model becomes irrelevant to clinical conditions. In the rat, amounts of ethanol above 5 g/dl were not found to be associated with any further gain in alcohol ingestion. By contrast, in the baboon, the ethanol content could be raised profitably to 7 g/dl or 50% of total energy and resulted in the development of cirrhosis. This higher alcohol intake, together with species difference, may explain the greater severity of liver lesions produced by alcohol in the baboon.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Fetal alcohol exposure has been shown to produce long-term feminizing and demasculinizing effects on male rat behaviors which are organizationally dependent upon perinatal androgen levels. Such exposure has previously been shown to suppress the normal surge of testosterone during the critical prenatal period. Since defeminization of male rat behavior is dependent upon estrogen derived from the aromatization of testosterone in brain, brain aromatase activity was measured during the perinatal period in males and females exposed to alcohol beginning on Day 14 of gestation. Aromatase activity was measured in whole hypothalamus of fetuses from Day 16 through 20 of gestation and in the hypothalamic preoptic area and amygdala of animals 6-12 hr postparturition. Hypothalamic aromatase activity was elevated in fetal alcohol exposed males compared to controls on Days 18 and 19 of gestation and on postnatal Day 1. No effect of prenatal alcohol exposure was found in females. A sex effect in aromatase activity in the amygdala was evident on Day 1 when activity was found to be greater in males than females. Overall, these findings indicate that fetal alcohol exposure will elevate regional brain aromatase activity in males, but not females during the perinatal period of neurobehavioral sexual differentiation.
Article
In 1980, 87,526 female nurses 34 to 59 years of age completed a dietary questionnaire that assessed their consumption of beer, wine, and liquor. By 1984, during 334,382 person-years of follow-up, we had documented 200 incident cases of severe coronary heart disease (164 nonfatal myocardial infarctions and 36 deaths due to coronary disease), 66 ischemic strokes, and 28 subarachnoid hemorrhages. Follow-up was 98 percent complete. As compared with nondrinkers, women who consumed 5 to 14 g of alcohol per day (three to nine drinks per week) had a relative risk of coronary disease of 0.6 (95 percent confidence interval, 0.4 to 0.9); for 15 to 24 g per day the relative risk was 0.6 (0.3 to 1.1), and for 25 g or more per day it was 0.4 (0.2 to 0.8), after adjustment for risk factors for coronary disease. Alcohol intake was also associated with a decreased risk of ischemic stroke. For 5 to 14 g of alcohol per day the relative risk was 0.3 (0.1 to 0.7), and for 15 g per day or more it was 0.5 (0.2 to 1.1). In contrast, although the number of cases of subarachnoid hemorrhage was small, alcohol intake tended to be associated with an increased risk of this disorder; for 5 to 14 g per day the relative risk was 3.7 (1.0 to 13.8). These prospective data suggest that among middle-aged women, moderate alcohol consumption decreases the risks of coronary heart disease and ischemic stroke but may increase the risk of subarachnoid hemorrhage.
Article
Factors that may affect the estrogenization of postmenopausal women are important because estrogen levels may modulate the risk of osteoporosis and cardiovascular disease in postmenopausal women. Ethanol, a potential estrogenization factor, has received scant attention, particularly in postmenopausal women who are moderate users of alcoholic beverages. Because as many as 22.6% of postmenopausal women are reported to have had a bilateral oophorectomy, mature oophorectomized rats were used as a model. Low to moderate ethanol consumption was approximated by administering graded doses of ethanol in drinking water (0, 1.8, 3.7 or 5.5% ethanol, v/v) to 90 oophorectomized rats for 4 or 10 weeks. In rats exposed for 4 weeks, neither estradiol levels nor uterus weight differed among the four groups. In contrast, among rats exposed for 10 weeks, there was a significant positive correlation between ethanol dose and both uterus weight and estradiol; analysis of variance demonstrated that inclusion of the data obtained from rats receiving the 5.5% ethanol dose accounted for the significance of these associations. Based on these findings, it is suggested that, at least in oophorectomized rats, prolonged exposure to moderate ethanol doses is required to induce sufficient aromatization of androgens to produce detectable changes in plasma estradiol or in uterus weight. Further studies will be required to determine whether low or moderate alcoholic beverage use by postmenopausal women may result in biologically relevant increases in serum estradiol.
Article
A hepatic microsomal ethanol-oxidizing system is described both in men and rats. It is distinguished from alcohol dehydrogenase by its subcellular localization (cytosol for alcohol dehydrogenase, microsomes for this system), its pH optimum (physiological pH versus pH 10 to 11 for alcohol dehydrogenase), and its cofactor requirements (NADPH versus NAD+ for alcohol dehydrogenase). It also requires oxygen and is inhibited by CO, properties commonly found among microsomal drug-detoxifying enzymes. That catalase is probably not involved was revealed by the partial or complete failure of cyanide, pyrazole, azide, or 3-amino-1,2,4-triazole to inhibit the NADPH-dependent microsomal ethanol-oxidizing system under conditions which diminished catalase activity. Moreover, a combination of administration in vivo of pyrazole and addition in vitro of azide virtually blocked catalase activity and abolished 95% of a H2O2-dependent microsomal ethanol oxidation, whereas two-thirds of the activity of the NADPH-dependent ethanol oxidation persisted. Ethanol feeding resulted in a striking rise of hepatic NADPH-dependent microsomal ethanol-oxidizing activity, whereas under the same conditions, activities of alcohol dehydrogenase in the cytosol and of microsomal as well as of total hepatic catalase did not increase. Furthermore, blood ethanol clearance was accelerated, which suggests that microsomal ethanol oxidation may play a role in vivo. Pyrazole, which inhibits alcohol dehydrogenase strongly (affecting also other hepatic functions, including microsomal enzymes) markedly reduced but did not block ethanol metabolism in vivo or in liver slices. Even after pyrazole, ethanol clearance rates remained significantly higher in ethanol-pretreated rats. The existence of a microsomal ethanol-oxidizing system, especially its capacity to increase in activity adaptively after ethanol feeding, may explain various effects of ethanol, including proliferation of hepatic smooth endoplasmic reticulum, induction of other hepatic microsomal drug-detoxifying enzymes, and the metabolic tolerance to ethanol which develops in alcoholics.
Article
To study the effect of chronic ethanol administration on the hepatic endoplasmic reticulum, rough and smooth microsomal membranes were separated from the liver of female rats pair-fed a nutritionally adequate diet with 36% of total calories either as ethanol or carbohydrate (controls). 6 weeks of ethanol feeding increased protein and phospholipid contents in smooth but not in rough microsomes. Cytochrome P-450 also increased mainly in smooth microsomes. In controls, the activity of the microsomal ethanol-oxidizing system was distributed about equally among the subfractions, whereas after ethanol feeding, it increased mainly in smooth microsomes. Catalase activity after ethanol feeding did not increase; when expressed per mg of microsomal protein, it decreased in smooth microsomes. A reduction of dietary fat content from 35 to 10% of total calories did not influence the effect of ethanol on the hepatic endoplasmic reticulum.
Article
Human placental microsomes were used to evaluate rates of andre stenedione aromatiration from patients selected for gestational alcohol consumption. After term delivery, kinetic comparisons of specific activity and Michaelis constants of reduced pyridine nucleotide cotactors were determined. The data failed to indicate a significant alcohol effect on these enzymatic parameters.
Article
To determine whether acute alcohol ingestion affects the pattern of decline of circulating E2 levels after removal of transdermal E2 patches. A randomized, placebo-controlled, crossover study. The study was performed in the Clinical Research Center of the Brigham and Women's Hospital. Twelve healthy postmenopausal women were enrolled. Transdermal E2 patches, 0.15 mg, were applied 13 hours before subjects ingested alcohol (1 mL/kg 95% ethanol) or carbohydrate placebo punch. The patches were removed immediately after drink ingestion. Estradiol, estrone (E1), and ethanol levels were measured. Serum samples were obtained for 40 minutes before drink ingestion and 5 hours after drink ingestion and E2 patch removal. At the time of patch removal, E2 levels rose acutely over 10 minutes and then decreased rapidly, suggesting a bolus effect that was more marked after ethanol ingestion. After ethanol ingestion and patch removal the half-life of E2 was calculated to be 378 minutes, and after carbohydrate punch and patch removal 245 minutes. There were no significant changes in E1 concentrations over the time course of the study between groups. Ethanol ingestion may decrease E2 clearance after removal of transdermal E2 patches.
Article
Clinical observations indicate that ethanol (EtOH) consumption has significant detrimental effects on pregnancy. However, there is a paucity of information on effects of EtOH on human placental function. We have used JEG choriocarcinoma cells that have many of the functional capabilities of syncytiotrophoblasts, as a model to study direct effects of EtOH on placental function. Between 20-100 mM EtOH decreased rate of cell growth by 25%, but no decrease in [35S]methionine incorporation into protein was noted. EtOH decreased in a dose-dependent manner the secretion of progesterone (P4) in response to cAMP when added with cAMP or when cells were pretreated with EtOH for 2 days. But after 4 or 6 days of pretreatment with EtOH, the P4 response to cAMP was increased by EtOH. Furthermore, EtOH increased the stimulation of P4 secretion by Forskolin. The development of this response was dependent on the period of exposure to EtOH. EtOH also increased estradiol (E2) secretion by unstimulated JEG cells in a dose- and time-dependent manner and increased cAMP stimulated E2 secretion > 2-fold following 4 days of pretreatment with EtOH. These results suggest that EtOH may directly alter hormone secretion by placental cells and such perturbations of endocrine function of the placenta may be responsible for some of the effects of EtOH on pregnancy.
Article
To extend further our previous observations on the inhibition of luteinizing hormone (LH)-induced increases in steroid secretion by ethanol (EtOH) (Alcohol. Clin. Exp. Res. 14:522-527, 1990), cultured human granulosa cells were pretreated with several EtOH concentrations (0-100 mM), and cells were stimulated with human LH (25 ng/ml) or human follicle stimulating hormone (FSH) (100 ng/ml) and the secretion of 17-beta-estradiol (E2) and progesterone (P) was measured. EtOH significantly increased basal E2 secretion in a dose-related manner (0-20 mM); however, in the same concentration range EtOH did not produce consistent changes in FSH-stimulated E2 secretion. In contrast, EtOH decreased LH-stimulated E2 secretion between 0-20 mM such that at 20 mM EtOH, the positive effect of LH was abolished. EtOH increased P secretion by 40% at 20 mM and at 100 mM, there was a 100% increase. The FSH-stimulated P secretion was not consistently changed by EtOH, whereas LH-stimulated P secretion was decreased in a dose-dependent manner. LH/human chorionic gonadotropin (hCG) receptors in cells exposed to EtOH showed a 15% (p < 0.01) and a 47% decrease at 20 mM and 50 mM EtOH, respectively. At 50 mM EtOH, there was a decrease in LH/hCG receptor number from 2900/cell to 1670/cell, without a change in receptor affinity for hCG and 50 mM EtOH decreased LH/hCG receptors in intact granulosa cells in a time-dependent manner. These results indicate that the selective effects of EtOH on LH action in human granulosa cells may be mediated in part by an action on LH/hCG receptors.
Article
To study the effects of alcohol consumption on bone mineral density in a defined population. Prospective study of bone mineral density, measured during 1988-91, in a cohort who had given baseline data on alcohol intake in the previous week and in the previous 24 hours and other factors affecting bone mineral density during 1973-5. Rancho Bernardo, California. 182 men and 267 women aged 45 and over at baseline, half having been randomly selected and half having been chosen for hyperlipidaemia, who gave baseline information on alcohol intake in one week. Of these subjects, 142 men and 220 women gave information on alcohol intake in 24 hours. Bone mineral density of the radial shaft, ultradistal wrist, femoral neck, and lumbar spine. Men and women were considered separately, and the tertiles of alcohol consumption were used to delineate low, medium, and high values of alcohol intake. With increasing alcohol intake in one week, bone mineral density (adjusted for age, body mass index, smoking, taking exercise, and oestrogen replacement therapy in women) increased significantly in the femoral neck of men (p < 0.01) and the spine of women (p < 0.01). With increasing alcohol intake in 24 hours, adjusted bone mineral density increased significantly in the radial shaft (p < 0.05) and spine (p < 0.001) of women. Similar, but not significant, patterns were seen at the other bone sites. Social drinking is associated with higher bone mineral density in men and women.
Article
To determine if moderate alcohol drinking increases circulating estradiol levels in postmenopausal women who are taking estrogen replacement. Randomized, double-blind, placebo-controlled crossover study of the effects of alcohol ingestion on plasma estradiol and estrone. Inpatient Clinical Research Center. Twelve healthy postmenopausal women receiving oral estrogen (estradiol, 1 mg/day) and progestin (medroxyprogesterone acetate) replacement therapy were compared with 12 postmenopausal women who were not using estrogen replacement therapy (ERT). Each group drank alcohol (0.7 g/kg) and an isoenergetic (isocaloric) placebo (randomized sequence) on consecutive days. Women who were taking ERT were studied during the estrogen-only portion of their replacement cycle, and estrogen was administered each evening at 2100 hours. The impact of alcohol ingestion on plasma estradiol and estrone levels. Alcohol ingestion lead to a 3-fold increase in circulating estradiol in women on ERT; however, alcohol did not change estradiol significantly in control women who were not on ERT. In women using ERT, estradiol levels increased from 297 to 973 pmol/L (81 to 265 pg/mL) within 50 minutes (P<.001) during the ascending limb of the blood alcohol curve and remained significantly above baseline for 5 hours (P<.001). No significant increase in circulating estrone was detected in either group. However, estrone levels decreased after alcohol and placebo in women on ERT (P<.05). Blood alcohol levels did not differ significantly in women who used ERT and those who did not. Peak blood alcohol levels of 21 mmol/L were attained in each of the 2 groups within 50 to 60 minutes after drinking began. Changes in estradiol were significantly correlated with changes in blood alcohol levels on both the ascending (P<.001) and descending (P<.001) limb of the blood alcohol curve. Acute alcohol ingestion may lead to significant and sustained elevations in circulating estradiol to levels 300% higher than those targeted in clinical use of ERT. Potential health risks and benefits of the interactions between acute alcohol ingestion and ERT should be further evaluated.
Article
We measured serum levels of estradiol (E2), sex hormone-binding globulin SHBG), progesterone, and dehydroepiandrosterone sulfate (DHEAS) in 61 postmenopausal women drawn from female residents in a community in Japan to evaluate the relationships between these hormone levels and potential breast cancer risk factors. The information on reproductive history, body size, alcohol use, and physical activity was obtained by means of a self-administered questionnaire. There was a significant trend in increasing E2 level with increasing height after taking account of age and body mass index (BMI) (p for trend = 0.04). BMI was inversely associated with SHBG level after controlling age (p for trend = 0.01). Decreasing progesterone with increasing BMI was observed after controlling age and history of hysterectomy (P = 0.05). Alcohol consumption was positively associated with E2 level and there was a strong linear trend after controlling for age, height, and BMI (p for trend = 0.001). Trend for increasing DHEAS with alcohol consumption was also statistically significant after controlling for age and history of hysterectomy (p for trend = 0.01). Reproductive factors as well as physical activity were not related to any of the hormone levels.
Article
To determine whether acute alcohol ingestion raises estradiol (E2) and estrone (E1) levels in a randomized, controlled, crossover study on postmenopausal women using transdermal E2. Healthy, non-smoking postmenopausal women (n = 7) using no medications were enrolled. Transdermal E2, 0.15 mg, was applied 13 hours before the subjects ingested alcohol (1 mL/kg 95% ethanol) or isocaloric carbohydrate punch. Serum samples were obtained for 40 minutes before drink ingestion and 6 hours after drink ingestion and were assayed for E2 and E1. Ethanol levels peaked 60 minutes after the start of ethanol-drink ingestion, at 25.4 mmol/L (117 mg/dL). Estradiol levels rose significantly above the mean baseline of 657 pmol/L (179 pg/mL) after ethanol-drink ingestion (P < or = .01), with a mean peak of 804 pmol/L (219 pg/mL) 35 minutes after the start of drink ingestion, and were significantly greater than the E2 levels that followed the carbohydrate drink (P < or = .0001). There were no significant changes in E2 or E1 levels after carbohydrate-drink ingestion. We conclude that ethanol ingestion may acutely raise circulating E2 concentrations in women using transdermal E2.
Article
This report reviews the literature to evaluate association between moderate alcohol consumption and estrogen levels in healthy postmenopausal women. Of the eight studies available in literature on postmenopausal women who were not on estrogen therapy, two analyzed urine samples and six analyzed blood samples for estrogen levels. Of the two urine sample studies, only one reported positive association (p < 0.05) between alcohol consumption and estrogen (estrone and estradiol) levels that increased by 16 to 20%. Of the six blood sample studies, only two--one in American women and one in European women--reported significant increases (p < 0.05) in estradiol levels in response to alcohol consumption. In the American women study, estradiol levels increased only with wine and not with beer or whiskey. In the European women study, estradiol levels increased in Danish and Portuguese women, but not in Spanish women. Thus, further studies are required to establish correlation between moderate alcohol consumption and estrogen levels in postmenopausal women. Of the two studies on postmenopausal women who were on estrogen replacement therapy, one administered estradiol through transdermal patch (0.15 mg) and one orally (1 mg/day). In both studies, blood estradiol levels were measured after administering a single dose of ethanol orally (0.7-0.75 g/kg of body weight). Estradiol levels were increased by 22 and 300% in the transdermal patch and oral studies, respectively. These results suggest that alcohol consumption may increase blood estradiol levels in postmenopausal women who are on estrogen replacement therapy, and this may increase the risk of breast cancer.
Chronic alcohol abuse is associated with low bone density and high risk of fracture. However, moderate alcohol consumption may help to maintain bone density in postmenopausal women by increasing endogenous estrogens or by promoting secretion of calcitonin. We conducted a prospective study among a sample of 188 white postmenopausal women (ages 50-74) from the Nurses' Health Study who participated in a health examination between 1993 and 1995 that included bone density assessments of the lumbar spine and proximal femur. Long-term alcohol intake was calculated as the average of the 1980 and 1990 measures from a food frequency questionnaire. Women who consumed 75 g or more of alcohol per week had significantly higher bone densities at the lumbar spine compared with non-drinking women (0.951 vs. 0.849 g/cm2, p = 0.002) after adjusting for age, body mass index (kg/m2), age at menopause, use of postmenopausal estrogens, and smoking status. Further adjustment for physical activity and daily intakes of calcium, vitamin D, protein, and caffeine did not alter the results. We also observed a linear increase in spinal bone density over increasing categories of alcohol intake (p = 0.002), suggesting that alcohol intakes of less than 75 g/week may also be of benefit. This positive association was observed among both current users and never users of postmenopausal estrogens. In contrast to the lumbar spine, femoral bone density was not higher among drinkers compared with nondrinkers, although density did increase among drinkers with increasing level of alcohol consumption. Further research is needed to determine whether moderate alcohol consumption can help to protect against spinal fractures in postmenopausal women. This finding must also be evaluated within a larger scope of the risks and benefits of alcohol on heart disease, breast cancer, and hip fractures.
Aromatization of androstenedione by microsomes from the human placenta after gestational alcohol consumption Alcohol and breast cancer in women: a pooled analysis of cohort studies
  • L A Sheean
  • S A Smith-Warner
  • D Spiegelman
  • S S Yaun
  • Van
  • P A Brandt
  • A R Folsom
  • R A Goldbohm
  • S Graham
  • L Holmberg
  • G R Howe
  • J R Marshall
  • A B Miller
  • J D Potter
  • F E Speizer
  • W C Willett
  • A Wolk
  • D J Hunter
Sheean, L. A. (1983). Aromatization of androstenedione by microsomes from the human placenta after gestational alcohol consumption. Alcohol Clin Exp Res 7, 93 ± 94. Smith-Warner, S. A., Spiegelman, D., Yaun, S. S., van den Brandt, P. A., Folsom, A. R., Goldbohm, R. A., Graham, S., Holmberg, L., Howe, G. R., Marshall, J. R., Miller, A. B., Potter, J. D., Speizer, F. E., Willett, W. C., Wolk, A., & Hunter, D. J. (1998). Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 279, 535 ± 540.
Alcohol, hormones, and health in postmenopausal women
  • Tivis