1 Department of Epidemiology and Preventive Medicine, Program in Toxicology, University of Maryland School of Medicine, 660 West Redwood Street, Howard Hall Room 133, Baltimore, MD 21201, USA, 2 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA and 3 Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
* Author to whom correspondence should be addressed at: Tel.: +1 410 706 3606; Fax: +1 410 706 1503; Email: jflaws{at}epi.umaryland.edu
(Received 15 June 2005; first review notified 1 July 2005; accepted in final revised form 12 July 2005)
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ABSTRACT |
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INTRODUCTION |
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Despite the importance of hot flashes as a public health concern, little is known about their risk factors or precipitating events. One potential risk factor for hot flashes may be consumption of alcohol, but the results from the few studies examining the association between alcohol use and hot flashes are equivocal. For example, in a study by Hyde Riley et al. (2004), consumption of 15 alcoholic drinks per week was associated with a reduced risk of hot flashes in perimenopausal women. Conversely, Schwingl et al. (1994)
showed that ever having consumed alcohol was associated with an increased risk of hot flashes in a study of postmenopausal women, though the association was not significant in the final multivariate model. These differences in study results are probably due to differences in the sample sizes, the populations studied, and the menopausal status of the subjects. Therefore, one purpose of this study was to examine the relation between alcohol use and hot flashes in more detail using a large sample size of midlife women who provided detailed menopausal status information.
Although no previous studies have examined the mechanism by which alcohol use is associated with risk of hot flashes, it is possible that the mechanism involves an ability of alcohol to alter endogenous sex steroid hormone levels. Alcohol consumption has been associated with increased levels of estradiol (Gavaler and Van Thiel, 1992; Gill, 2000
; Onland-Moret et al., 2005
), estrone (Gill, 2000
; Onland-Moret et al., 2005
), and testosterone (Garcia-Closas et al., 2002
) in women. Similarly, altered levels of these sex steroids have been associated with the risk of hot flashes (Erlik et al., 1982
). Therefore, the second purpose of this study was to test the hypothesis that alcohol use is associated with hot flashes through a mechanism that includes altered sex steroid hormone levels.
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MATERIALS AND METHODS |
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Names and addresses of women in the selected age range residing in Maryland were obtained from AccuData America (Fort Meyers, FL). The company compiles names and addresses using public sources, namely the Department of Motor Vehicles and voter registration lists. Recruitment letters requesting participants for a research study on the health of women aged 4554 years were mailed to all names on this list. Mailings were initially sent to zip codes located nearest to the clinic and then in concentric circles out from the site until the target number of enrollees was reached. Women who received the mailing and were interested in participating in the study were invited to call the clinic to obtain more information.
During the initial call, the clinic staff determined whether the potential participant met the eligibility criteria. Women were eligible for study participation if they were between 45 and 54 years of age and had intact ovaries and uterus. To ensure that women enrolled in the study were not postmenopausal, women were eligible only if they reported having at least three menstrual periods in the last 12 months. Women were excluded if they were pregnant, were taking hormone replacement therapy (HRT) or hormonal contraception, or had a history of cancer of the reproductive organs. If the clinic staff determined that the potential participant met the eligibility criteria, a clinic visit was scheduled.
Data collection
Clinic visits were scheduled in the morning (8:3010:00 a.m.) and the women were instructed to fast overnight prior to the visit. At the clinic visit, the participant was seated in a private comfortable room and asked to complete the study survey. The 26-page, single-sided survey took 4560 min to complete and included a detailed hot flash history. Specifically, information was collected on the following: whether the woman had ever experienced hot flashes, whether the woman had a hot flash in the last 30 days, the number of hot flashes experienced within the past 30 days, the severity and frequency of hot flashes, and the length of time each woman had experienced hot flashes. In terms of severity, each woman was asked to describe her hot flashes as: mild (sensation of heat without sweating), moderate (sensation of heat with sweating), or severe (sensation of heat with sweating that disrupts usual activity). In terms of frequency of hot flashes, each woman was asked to describe her hot flashes as occurring: every hour, every 25 h, every 611 h, every 1223 h, 12 days per week, 34 days per week, 56 days per week, 23 days per month, 1 day per month, <1 day per month, or never. Each woman was also asked to describe the duration of her hot flashes as occurring for: <1 month, 15 months, 611 months, 12 years, 34 years, or 5 years or longer.
In terms of alcohol use, each woman was asked if she had at least 12 alcoholic beverages in her entire life, at least 12 alcoholic beverages in any 1 year, and at least 12 alcoholic beverages in the previous 12 months. The women were also asked to think about a typical month during the previous 12 months and indicate on how many days they drank alcoholic beverages and the average number of drinks consumed on those days. The use of this set of standard quantity-frequency questions allows comparison of this study to other studies by investigators and also to national surveys (Dawson, 2003; Graham et al., 2004
). Based on responses to the questions, never drinkers were defined as those women who had not consumed at least 12 alcoholic beverages in their entire life. Former drinkers were defined as those women who had at least 12 alcoholic beverages in any 1 year, but not in the past 12 months. Current drinkers were defined as those women who had consumed at least 12 alcoholic beverages in the previous 12 months. Only 19 cases and 13 controls were categorized as never drinkers; therefore in some analyses, the never drinkers were combined with the former drinkers.
Participants were also asked questions regarding demographic information, reproductive history, menstrual cycle characteristics, hormonal contraceptive use, menopausal symptoms, HRT use, medical and family history, and health behaviours (smoking, vitamin use, and eating habits). Women were considered premenopausal if they reported experiencing their last menstrual period in the previous 3 months and 11 or more periods within the previous year. Women were considered perimenopausal if they reported their last menstrual period was within the previous year, but not within the previous 3 months, or their last menstrual period was within the previous 3 months, but they experienced 10 or fewer periods in the previous year. After each woman completed the survey, the clinic staff reviewed the survey for completeness. Casecontrol status was assigned using the participant's answer to the question Have you ever had hot flashes? Participants who answered yes to this question were classified as cases and those who answered no were classified as controls.
Hormone assays
In addition to the participant completing the questionnaire at the clinic visit, a blood sample was taken and stored at 20°C until assays were conducted to measure serum hormone levels. Blood samples were obtained from women in all phases of the menstrual cycle. Information from the questionnaire regarding date of last menstrual period was used in the statistical analyses to adjust for the cycle phase among the premenopausal women and time since last menstrual period among the perimenopausal women. Serum concentrations of estradiol, estrone, and testosterone were measured using enzyme-linked immunosorbent assays (ELISA). The ELISA kits for the estradiol and testosterone assays were obtained from Diagnostic Systems Laboratories, Inc. (Webster, TX). The ELISA kits for the estrone assay were obtained from American Laboratory Products Company (Windham, NH). The assays were run using the manufacturers' instructions and published methods (Gallicchio et al., 2005a, b
). All assays were conducted in the same laboratory by a single technician. All samples were run in duplicate and mean values for each participant were used in the analysis. The laboratory personnel were blind with respect to any information concerning study subjects. For quality control purposes, samples from both cases and controls were run within the same laboratory batches. In addition, two positive controls containing known amounts of estradiol, estrone, or testosterone were included in each batch. Further, some samples were run in multiple assays to ensure that the assay values did not dramatically shift over time.
The minimum detection limits for the estradiol, estrone, and testosterone assays were 7 pg/ml, 10 pg/ml, and 0.4 ng/ml respectively. No samples were below the limit of detection. For the assays, the average intra-assay co-efficient of variation was 3.3 ± 0.17% for estradiol, 4.8 ± 0.25% for estrone, and 2.2 ± 0.56% for testosterone. The average inter-assay co-efficient of variation for all assays was <5%.
At the completion of the study, 372 cases and 267 controls were enrolled. For this analysis, 10 cases (1 missing estradiol levels, 9 missing time since last menstrual period) and 3 controls (1 missing time since last menstrual period, 2 missing alcohol data) were excluded, leaving 362 cases and 264 controls for the analyses.
Statistical analyses
Characteristics of cases and controls were compared using chi-square analyses. Risk ratios (RR) and 95% confidence intervals (CI) were calculated using methods described by Greenland (2004) to assess the association between alcohol intake and the occurrence, severity, and frequency of hot flashes, controlling for confounders. Factors were considered potential confounders if they were associated (P < 0.1) with alcohol and/or hot flash status. To determine whether each potential confounder would remain in the final models, the unadjusted RR for current alcohol intake and experiencing any hot flashes was compared to the RR for current alcohol intake and experiencing any hot flashes adjusted for the potential confounder. If the RR for current alcohol use and experiencing of any hot flashes changed by >5% with the inclusion of the potential confounder, the potential confounder was retained in the final models. Variables tested as potential confounders were: race, body mass index (BMI), prior HRT use, and smoking status. Only the smoking status variable remained in the final confounder-adjusted models. All regression analyses were also adjusted for participant age.
The associations between current alcohol use and plasma hormone levels adjusted for age, race, smoking status, BMI, and menstrual cycle phase (for premenopausal women only) were assessed using generalized linear models (PROC GLM in SAS). For these and all of the analyses, the estradiol, estrone, and testosterone variables were log-transformed because none were normally distributed.
All analyses were stratified by menopausal status; however, the regression results for women categorized as pre- and peri-menopausal did not materially differ when compared to each other and to the results for the entire sample. Therefore, only the analyses for the entire sample are shown. All analyses were performed using SAS Version 8.2 (Cary, NC). A P-value of <0.05 was considered to be statistically significant.
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RESULTS |
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DISCUSSION |
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Results from our study also indicate that current alcohol use is not associated with sex hormone levels or their ratios. This finding is consistent with a few studies showing no association between alcohol intake and estradiol levels, testosterone levels (Gill, 2000; Onland-Moret et al., 2005
), or the ratio of estradiol to testosterone in postmenopausal women (Onland-Moret et al., 2005
). Our findings, however, differ from a few studies indicating that alcohol use is associated with altered levels of sex steroid hormones. In one study by Onland-Moret et al. (2005)
, consumption of >25 g (2.5 drinks) of alcohol per day by postmenopausal women was associated with an increase in estradiol and estrone levels, and in the ratio of estradiol to estrone. The difference with our findings and those of Onland-Moret et al. (2005)
may be due to their study being much larger and therefore having a greater statistical power to detect small differences in hormone levels. In other studies, alcohol use was associated with an increase in estradiol levels, as well as an increase in the ratio of estradiol to testosterone in postmenopausal women (Gavaler and Van Thiel, 1992
; Gill, 2000
). Gavaler and Van Thiel (1992)
collected alcohol intake by two methods, self-reported quantity/frequency information and a 3-day food record. If the results on alcohol intake differed by method, the 3-day food record was used for the calculation of alcohol consumption. Our findings may differ from those of Gavaler and Van Thiel (1992)
due to differences in collection of the alcohol intake data.
Sex hormone results from this study are not consistent with studies in premenopausal women that have shown an increase in estradiol and testosterone levels (Garcia-Closas et al., 2002), and estradiol and estrone levels (Gill, 2000
), with alcohol use. These studies had small sample sizes, the women were younger than those in our study, and the women were regularly cycling. These points may account for the difference with our findings.
Collectively, the data from this study suggest that current alcohol use is associated with a reduced risk of hot flashes in midlife women and that this association is not mediated by sex steroid hormones. This raises the possibility that current alcohol use may be associated with hot flashes through another pathway. It is possible that alcohol use may be associated with hot flashes by directly affecting the neurons that control the thermoregulatory centre located within the hypothalamuspituitaryadrenal axis (Onland-Moret et al., 2005). Alcohol inhibits the neurons that control core body temperature, stimulating the hypothalamus and causing fluctuations in body temperature. Therefore, an increase in body heat while consuming alcohol may lead a woman to associate the transient rise in body temperature with alcohol use, causing underreporting of hot flashes.
Although this study shows current alcohol use may be associated with a decreased risk of hot flashes, these findings must be considered with respect to their limitations. One of the limitations of this study is that alcohol use was obtained by self-report, and previous studies have shown that alcohol use tends to be underreported by women (Onland-Moret et al., 2005). Underreport of alcohol use would drive the results towards the null hypothesis. Our study, however, still showed a significant association between current alcohol use and hot flashes, suggesting that the observed reduction in risk may be even greater if alcohol use was reported accurately. Another limitation is that women were not asked questions about the type of alcohol (beer, wine, spirits) they consumed. Therefore, analyses could not be performed to determine which types of alcohol were associated with hot flashes or hormone levels. The design of this study does not enable us to determine the temporality of the association between alcohol use, sex hormone levels, and the occurrence of hot flashes, or the prevalence of hot flashes in the population. Although we had adequate sample size to examine the main effects, a larger sample size would have allowed us to explore all interactions.
Despite these limitations, this study had several strengths. A major strength is that the study was designed to examine hot flashes in midlife women. By presenting the study as research into factors related to midlife and not specifically as a study on hot flashes, women who participated in the study may have been less likely to over report hot flashes. Another strength is that, to our knowledge, this is the first study to examine the association between alcohol use, sex hormone levels, and hot flashes in the same study. An additional strength involves the minimization of misclassification of casecontrol status by assigning casecontrol status after the clinic visit based on the questionnaire information provided by each participant.
In conclusion, the results of this study suggest that limited alcohol intake may have some benefits to midlife women experiencing any, moderate or severe, or daily hot flashes. Future studies should be conducted to confirm our findings and to examine the mechanism by which current alcohol use decreases the risk of hot flashes in midlife women.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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