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Body mass, estrogen levels, and hot flashes in midlife women
American Journal of Obstetrics and Gynecology (2005) 193, 1353–60
www.ajog.org
Body mass, estrogen levels, and hot flashes in midlife women Lisa Gallicchio, PhD,a Kala Visvanathan, MBBS, MHS,a Susan R. Miller, ScD,b Janice Babus, BS,c Lynn M. Lewis, MA,c Howard Zacur, MD, PhD,b Jodi A. Flaws, PhDc,* Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Healtha; Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicineb; Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine,c Baltimore, MD Received for publication January 10, 2005; revised March 28, 2005; accepted April 1, 2005
KEY WORDS Hot flashes Menopausal transition Estrogen Obesity Body mass index
Objective: This study was undertaken to determine whether body mass index (BMI) is associated with hot flashes and whether the mechanism by which BMI increases the risk of hot flashes is by lowering estrogen levels. Study design: A case-control study was conducted among midlife women to examine risk factors for hot flashes. Cases were women who reported experiencing hot flashes (n = 353). Controls were women who reported never experiencing hot flashes (n = 258). Each participant completed a questionnaire and provided a blood sample for estrogen measurement. Results: Compared with normal weight women, very obese women had significantly higher odds of hot flashes. The odds ratios remained elevated although attenuated when the hormone variables were added to the model. Conclusion: These results indicate that very obese women are at increased risk for hot flashes compared with normal weight women. Estrogen levels may partly explain this relationship; however, other mechanisms appear to be involved as well. Ó 2005 Mosby, Inc. All rights reserved.
Hot flashes are described as transient periods of intense heat in the upper body, arms, and face, which are often followed by flushing of the skin and profuse sweating.1 Hot flashes are the most common vasomotor symptom reported by women undergoing the menopau-
This study was supported by NIH grant AG18400. * Reprint requests: Jodi A. Flaws, PhD, University of Maryland School of Medicine, Department of Epidemiology and Preventive Medicine, 660 W Redwood St, Howard Hall Room 133, Baltimore, MD 21201. E-mail: jfl[email protected] 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.04.001
sal transition1; however, few risk factors for hot flash occurrence have been identified. One of the potential risk factors for hot flashes is body mass index (BMI). As reviewed by Whiteman et al,2 the results of studies, most cross-sectional in nature, examining the relationship between BMI and hot flashes have been conflicting. However, in studies or analyses limited to women identified as being either perimenopausal or approaching the age of menopause (40-55 years), the evidence is more consistent in suggesting that BMI is positively associated with the risk of hot flashes among women undergoing the menopausal transition.3-7
1354 The reasons for this observed positive association between BMI and the experiencing of hot flashes among perimenopausal women are unclear. In studies of postmenopausal women, researchers have shown that women with a high BMI have higher estrogen levels than women with a low BMI because of greater peripheral conversion of androgens to estrogens by adipose tissue.4,8,9 As estrogen levels have been observed to be negatively associated with the risk for hot flashes, it has been hypothesized, based on these findings among postmenopausal women, that women with a high BMI would be at decreased risk of hot flashes.9-12 In contrast, published findings on the association of BMI and the risk of hot flashes among perimenopausal women, as previously reported, directly refute this hypothesis and suggest that the associations between BMI, hot flashes, and estrogen levels may differ among perimenopausal women compared with postmenopausal women. To our knowledge, no study has examined the association of BMI, estrogen levels, and hot flashes in a sample of midlife, perimenopausal women. Therefore, we conducted a large, population-based, case-control study of hot flashes among midlife women aged 45 to 54 years who were perimenopausal to investigate the associations between BMI and the occurrence of any, more severe, and more frequent hot flashes and to examine whether the mechanism by which BMI increases the risk of hot flashes is by lowering estradiol and estrone levels.
Materials and methods A case-control study of hot flashes among midlife women (45-54 years) was conducted during 2000 through 2004 among residents of the Baltimore metropolitan region who reported their history of hot flashes and other information through a survey and donated a blood sample for measurement of hormone levels. All women gave written informed consent according to procedures approved by the University of Maryland School of Medicine and Johns Hopkins University Institutional Review Boards. Names and addresses of women in the selected age range residing in Maryland were obtained from AccuData America (Fort Myers, FL). AccuData provides names and addresses of women in the target age range and geographic region on a fee for service basis. The company compiles the names and addresses using public sources, namely, the Department of Motor Vehicles. Recruitment letters requesting participants for a research study on the health of women ages 45 to 54 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 mailings and who were interested in participating in this study, which was
Gallicchio et al presented as a general ‘‘Midlife Health Study’’ to avoid reporting bias, were invited to call the clinic to obtain more information. During this 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 and had an intact uterus and ovaries. In addition, to ensure that women enrolled in the study were not postmenopausal, women were eligible only if they reported having at least 3 menstrual periods in the last 12 months. Women were excluded if they were pregnant, were taking hormone replacement therapy 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. Clinic visits were scheduled in the morning (8:3010:00 AM) to minimize daily fluctuations in hormone levels within participants. In addition, women scheduled for a clinic visit were instructed to fast overnight before the visit to avoid the influence of diet on hormone levels. 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 45 to 60 minutes to complete and asked questions regarding demographic information, reproductive history and menstrual cycle characteristics, hormonal contraceptive use, menopausal symptoms, hormone replacement therapy use, medical and family history, and health behaviors (smoking, alcohol use, vitamin use, eating habits). After each woman completed the survey, the clinic staff reviewed the survey for completeness. In addition, case-control 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. In addition to the participant completing the questionnaire at the clinic visit, the staff recorded any medications that the participant was taking on a regular basis and took the participant’s blood pressure. Waist circumference was measured at the narrowest part of the waist. Hip circumference was measured at the fullest part of the hips. The participant was weighed without shoes in street clothing to the nearest 0.05 lb, rounding down, on a calibrated scale. Her height was measured without shoes to the nearest 0.5 in, rounding down, with a standard stadiometer. BMI was calculated using the National Institutes of Health on-line BMI calculator.13 Finally, the participant donated blood for the hormone assays described later. In total, 363 cases and 259 controls scheduled and completed the required clinic visit that included the questionnaire administration and the blood draw for hormone analyses. However, because of the exclusion of 10 cases and 1 control from the statistical analysis for reasons described later, the results are based on a total of 353 cases and 258 controls.
Gallicchio et al
Variable definitions A detailed hot flash history was obtained through a series of questions on the enrollment questionnaire that asked for information on the following: whether the woman had experienced hot flashes within the last 30 days; the number of hot flashes experienced within the last 30 days; the age when hot flashes first occurred; and the severity and frequency of the hot flashes. Outcomes examined were the experiencing of any hot flashes, moderate to severe hot flashes, and daily hot flashes. Severity of hot flashes was determined using the question ‘‘How would you describe the majority of your hot flashes?’’ In response to this question, participants were asked to select 1 of the following possible responses: mild (sensation of heat without sweating), moderate (sensation of heat with sweating), and severe (sensation of heat with sweating that disrupts your usual activity). Menopausal status was categorized as pre- or perimenopausal. Premenopausal women were those who reported experiencing their last menstrual period within the past 3 months and experiencing 11 or more periods within the past year. Perimenopausal women were those who reported experiencing (1) their last menstrual period within the past year but not within the past 3 months, or (2) their last menstrual period within the past 3 months and experiencing 10 or fewer periods within the past year. For premenopausal women, phase of the menstrual cycle was determined by using the self-reported number of days since the last menstrual period. BMI was categorized as 24.9 kg/m2 or less, 25.0 to 29.9 kg/m2, 30.0 to 34.9 kg/m2, and 35.0 kg/m2 or greater. Smoking status was categorized as current/former/never. Current alcohol use was examined as a yes/no variable.
Measurement of hormone levels Samples were stored at 20(C until the hormone assays were conducted. Plasma concentrations of estradiol and estrone were measured using enzyme-linked immunosorbent assays (ELISA). ELISA kits and reagents for the estradiol assay were obtained from Diagnostic Systems Laboratories, Inc (Webster, TX). ELISA kits and reagents for the estrone assay were obtained from American Laboratory Products Company (Windham, NH). The assays were run according to the manufacturers’ instructions and published methods.14 All assays were conducted by a single technician in the same laboratory using kits from the same manufacturer lots. All samples were run in duplicate, and mean values for each participant were used in the analysis. The laboratory was blind with respect to any information concerning study subjects. Samples from both cases and controls were run within the same laboratory batches. For quality control purposes, 2 positive controls containing known amounts of estradiol or estrone were included in each batch, and,
1355 for all batches, values were within 5% of the known amount. In addition, 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 and estrone assays were 7 pg/mL and 10 pg/mL, respectively. No samples were below the limit of detection. For the estradiol assays, the average intra-assay coefficient of variation was 3.3% G 0.17% and the average interassay coefficient of variation was less than 5%. For the estrone assays, the average intra-assay coefficient of variation was 4.8% G 0.25% and the average interassay coefficient of variation was less than 5%.
Statistical analyses For this analysis, women were excluded if they did not have data on BMI (n [case] = 1) or days since last menstrual period (n [case] = 9; n [control] = 1). Characteristics of cases and controls were compared by using c2 analyses. Unadjusted associations between BMI and the experiencing of any hot flashes, severe/moderate hot flashes, and daily hot flashes were examined by using logistic regression. Multivariable logistic regression models were created to examine the association between BMI and the experiencing of any, severe, and daily hot flashes, controlling for potential confounders. Factors were considered to be confounders if they were associated (P ! .1) with BMI and case-control status or if they had been considered to be important confounders of the BMI and hot flashes association in the published literature.3 Variables tested as potential confounders were as follows: age, race, marital status, education, household income, parity, prior hormone replacement therapy or oral contraception use, current alcohol use, smoking status, and physical activity. Age, race, smoking status, and current alcohol use remained in the final confounder-adjusted model (model 1). The associations between BMI and plasma hormone levels adjusted for age and menstrual cycle phase (for premenopausal women only) were assessed by using generalized linear models (PROC GLM in SAS). For these and all of the analyses, the estradiol and estrone variables were log transformed because neither was normally distributed. To examine whether any observed association between BMI and hot flashes was due in part to hormone levels, the estimated odds ratio (OR) was calculated by adding either the estradiol or estrone variable to the confounder-adjusted model (model 2). It was expected that if estradiol and/or estrone levels were the mechanism by which BMI increases a woman’s risk of hot flashes, the OR for BMI would be attenuated. Results for the estradiol-adjusted and estrone-adjusted models were similar; thus, only the results for the estradioladjusted model are presented.
1356 Table I
Gallicchio et al Characteristics of cases and controls
Variable
Cases
Controls
Sample size (n)
353
258
Age (y) (%) 45-49 50-54 Race (%) White Black Other Marital status (%) Single Married Widowed Divorced/Separated Education (%) !College Some college College graduate Graduate school
Table II P-value*
58.9 41.1
72.9 27.1
.0004
81.6 17.6 0.9
86.9 10.9 1.9
.04
12.2 66.5 2.3 19.0
12.8 69.8 0.8 16.7
.43
17.6 28.9 23.2 30.3
13.6 24.8 26.7 34.9
.2
26.4 43.4 30.2
.7
56.2 43.8
!.0001
22.1 77.9
.9
Annual household income ($) (%) !50,000 28.9 50,000 to 99,999 41.4 R100,000 28.3 Menopausal status (%) Pre-menopausal 24.6 Peri-menopausal 74.8 Parity (%) Nulliparous 21.5 Multiparous 78.5
Prior hormone replacement therapy (%) Yes 7.4 2.3 No 92.6 97.3 Smoking Status (%) Current 11.3 5.8 Former 40.2 35.7 Never 48.2 58.5 Current alcohol use (%) Yes 62.0 71.7 No 38.0 28.3
Description of hot flashes among the cases
Variable Hot flashes in last 30 days Yes No Severity of hot flashes Mild Moderate Severe Frequency of hot flashes Daily Weekly Monthly Length of time experiencing hot flashes !1 y 1-4 y 5 y or longer
n
%
237 108
67.1 30.6
128 193 31
36.3 54.7 8.9
78 100 157
22.1 28.3 44.5
116 180 47
32.9 51.0 13.3
Because of missing information, some column percentages do not add up to 100.
differ when compared with each other and to the results for the entire sample. Therefore, only the regression analyses for the entire sample are shown. All analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). A P-value of less than .05 was considered to be statistically significant.
Results .01
.01
.01
119.7 !.001 Estradiol levels (pg/mL) 83.1 (1.2, 536.4) (13.0, 686.9) (geometric mean, range) Estrone levels (pg/mL) 114.4 154.1 !.001 (geometric mean, (7.6, 453.2) (15.2, 1177.0) range) Because of missing information, some column percentages do not add up to 100. * P-values reflect c2 comparisons for categorical variables and Student t test comparisons for continuous variables.
All analyses were stratified by menopausal status; however, the regression results for women categorized as premenopausal and perimenopausal did not materially
Characteristics of the cases and controls are presented in Table I. Cases were significantly older than controls and were significantly more likely to be perimenopausal, to smoke at the time of enrollment, and to report prior use of hormone replacement therapy. In addition, cases were less likely to be of white race and to report current alcohol use than the controls. The mean plasma concentrations of both estradiol and estrone were significantly lower among the cases compared with the controls. A description of the hot flashes experienced by the case group is presented in Table II. More than two thirds of the cases reported experiencing hot flashes within the last 30 days, and 63.6% reported that the majority of their hot flashes were either moderate or severe. Approximately 22% of the cases reported experiencing daily hot flashes, and 83.9% reported experiencing hot flashes for less than 5 years. BMI was negatively associated with estradiol among both pre- and perimenopausal women, independent of age and phase of menstrual cycle (for perimenopausal women only; Figure; P for trend !.0001). In addition, BMI was significantly and negatively associated with estrone among perimenopausal women. For both preand perimenopausal women, individuals with a BMI greater than or equal to 35.0 kg/m2 had significantly
Gallicchio et al
1357
Figure Geometric means and 95% CIs of estradiol and estrone concentrations adjusted for participant age and days since last menstrual period (for premenopausal women only) by BMI category. *P ! .05 for comparison of mean estradiol or estrone concentration for specific BMI group and BMI ! 25.0 kg/m2 group.
1358 Table III
Gallicchio et al Association between BMI and the reporting of any, severe, and daily hot flashes Cases*
Controls
Unadjusted
Model 1y
%
%
OR
OR
Any hot flashes BMI (kg/m ) %24.9 25.0-29.9 30.0-34.9 R35.0
39.4 26.1 16.7 17.9
48.1 30.2 13.6 8.1
1.00 Reference 1.05 (0.71-1.55) 1.50 (0.93-2.44) 2.68 (1.54-4.64) P-for-trend = .0004
1.00 Reference 1.00 (0.67-1.49) 1.34 (0.80-2.23) 2.24 (1.26-3.97) P-for-trend = .008
1.00 Reference 0.97 (0.64-1.45) 1.24 (0.74-2.08) 1.89 (1.06-3.40) P-for-trend = .04
Severe hot flashes BMI (kg/m2) %24.9 25.0-29.9 30.0-34.9 R35.0
38.4 29.5 14.7 17.4
48.1 30.2 13.6 8.1
1.00 Reference 1.22 (0.80-1.87) 1.36 (0.79-2.36) 2.69 (1.47-4.87) P-for-trend = .002
1.00 Reference 1.14 (0.73-1.78) 1.22 (0.68-2.17) 2.18 (1.17-4.07) P-for-trend = .02
1.00 Reference 1.12 (0.71-1.75) 1.15 (0.64-2.08) 1.92 (1.01-3.62) P-for-trend = .07
Daily hot flashes BMI (kg/m2) %24.9 25.0-29.9 30.0-34.9 R35.0
39.7 33.3 15.4 11.5
48.1 30.2 13.6 8.1
1.00 Reference 1.33 (0.74-2.41) 1.37 (0.64-2.95) 1.72 (0.72-4.11) P-for-trend = .2
1.00 Reference 1.30 (0.69-2.45) 1.05 (0.45-2.46) 1.51 (0.59-3.86) P-for-trend = .5
1.00 Reference 1.38 (0.70-2.71) 1.02 (0.42-2.52) 1.16 (0.41-3.28) P-for-trend = .8
95% CI
Model 2z 95% CI
OR
95% CI
2
* For severity analysis, includes cases reporting moderate or severe hot flashes; for frequency analysis, includes cases reporting daily hot flashes. y Confounder-adjusted model; adjusted for age, race, smoking, and current drinking status. z Confounder- and estradiol-adjusted model; adjusted for age, race, smoking, current drinking status, and estradiol concentration.
lower levels of estradiol compared to those with a BMI less than 25.0 kg/m2. Estrone levels were significantly lower among perimenopausal women with a BMI greater than or equal to 35.0 kg/m2 compared to perimenopausal women with a BMI less than 25.0 kg/m2. The results of the unadjusted, confounder-adjusted (model 1), and estradiol-adjusted (model 2) analyses of BMI and any, more severe, and daily hot flashes are shown in Table III. In the unadjusted analyses, women with a BMI greater than or equal to 35.0 kg/m2 had significantly greater odds of experiencing any and more severe hot flashes than women with a BMI less than 25.0 kg/m2. After adjustment for important confounders (model 1), the odds of experiencing any and more severe hot flashes among women with a BMI greater than or equal to 35 kg/m2 compared with women with a BMI less than 25.0 kg/m2 remained significant, although attenuated. Significant trends of increasing odds of experiencing hot flashes with higher BMI were observed for both any and more severe hot flashes in both the unadjusted and confounder-adjusted analyses. BMI was not associated with daily hot flashes. To explore the mechanistic involvement of hormone levels in the relation of BMI to the experiencing of hot flashes, the estradiol variable was added to each confounder-adjusted model (model 2). After adjustment for estradiol, the ORs of experiencing any and more severe hot flashes among women with a BMI greater than or equal to 35.0 kg/m2 compared with women with a BMI less than 25.0 kg/m2 remained significant and were further attenuated. In addition, significant or marginally
significant trends of increasing odds of experiencing any and more severe hot flashes with higher BMI were observed after adjustment for estradiol.
Comment The results of this case-control study confirm previous cross-sectional reports that high BMI increases a woman’s likelihood of experiencing any and more severe hot flashes during the menopausal transition.3-5,7,15-17 Importantly, we found that the significant increase in risk of any or more severe hot flashes was present among women who were very obese (R35.0 kg/m2), a group not examined in the previous literature. Similar to previous reports, we observed an elevated risk of any and more severe hot flashes, although not significant, among women with a BMI ranging from 30.0 to 34.9 kg/m2. However, we did not find that moderately high BMI (25.0-29.9 kg/m2) increases the risk of hot flashes among midlife women or that BMI is associated with daily hot flashes, as was reported by Whiteman et al.3 The difference in findings between our study and Whiteman et al3 may be due to differences in sample characteristics, data collection, or confounder adjustments. For example, Whiteman et al3 used self-reported height and weight data, and studies have shown that women frequently underreport their weight and overreport their height.18,19 Therefore, in the Whiteman et al3 study, there may have been a downward shift in the distribution of women in the BMI categories resulting in the observed elevated estimates of hot flashes risk among these lower BMI categories.
Gallicchio et al In analyses of BMI and estrogen levels, BMI was negatively associated with estradiol levels and, to a lesser extent, estrone levels in both pre- and perimenopausal women. This finding is consistent with the results of Klinga et al,20 which observed that, among a sample of midlife women, obese women had a significantly lower mean estradiol level than women of normal weight from the age of 45 to 52 years. To examine whether this decrease in estrogen levels might be due to ovarian insufficiency, as suggested by Klinga et al,20 we compared the mean number of days since last menstrual period as reported by the very obese women (R35 kg/ m2) with the mean number of days since last menstrual period as reported by the normal weight women (%24.9 kg/m2) and found that the very obese women had a significantly longer self-reported mean time since their last menstrual period compared with that of normal weight woman (data not shown). This finding supports the observations by Klinga et al,20 which suggest that the decrease in estrogen levels during the menopausal transition among women with a high BMI compared with women with a low BMI is due to early onset of ovarian insufficiency. Similar to Klinga et al,20 our results also suggest that the decrease in estrogen levels during the menopausal transition among obese women appears not be counterbalanced by peripheral conversion of estrogen by adipose tissue during midlife. To determine whether the associations between high BMI and the experiencing of any or more severe hot flashes were due to changes in estradiol levels, we added the estradiol variable to the confounder-adjusted models. In both models containing the estradiol variable, the ORs for experiencing any hot flashes and more severe hot flashes among women with a high BMI were attenuated compared with the confounder-adjusted models. These observations indicate that the association between BMI and the experiencing of any or more severe hot flashes is due, in part, to lower estradiol levels among women with a high BMI. Similar to our study, Gold et al21 found in an analysis of pre- and perimenopausal women a reduction in the strength of the association between BMI and the experiencing of any hot flashes when comparing an unadjusted OR estimate to an OR estimate controlling for other risk factors and estradiol levels. However, a confounder-adjusted model excluding the estradiol variable was not reported in the Gold et al21 study; thus, it is unclear whether the attenuation in the BMI OR was due to the addition of the estradiol variable or to the addition of the other potential risk factors into the model. Although our results indicate that one mechanism by which high BMI increases the risk for any and more severe hot flashes in midlife women is through the lowering of estradiol levels, the ORs for any and more severe hot flashes remained significantly elevated among women with a high BMI even after adjustment for estradiol levels. This finding suggests that other mechanisms may also be
1359 involved in explaining the associations between BMI and any and more severe hot flashes. One mechanism that has been discussed in the literature is that women with a high BMI are at increased risk of hot flashes because they have more body fat, and thus, more insulation, which may cause increases in the core body temperature and therefore hot flashes.4,22 A similar, yet distinctly different hypothesis is that heavy women have a narrowed thermoneutral zone, ie, the zone between sweating and shivering, which has been shown to increase a woman’s risk for hot flashes.23 It has also been suggested that other hormones produced by adipose tissue such as tumor necrosis factor-a may influence thermoregulation.6,24 These other mechanisms by which BMI is associated with the experiencing of any and more severe hot flashes should be the focus of future studies. Although this study provides novel information into the relationship between BMI, hot flashes, and estrogen levels in midlife women, one challenge that was present in this study and is present in the majority of research on the menopausal transition was the categorizing of the menopausal stages. Enrollment into this study was limited to women aged 45 to 54 years of age because this 10-year interval is the age period when the vast majority of women are perimenopausal. It was surprising that the regression results for women categorized as pre- and perimenopausal did not substantially differ from each other or from the findings for the entire sample reported in this manuscript. It is possible that the women in this study who were categorized as premenopausal were actually early perimenopausal and experiencing irregular periods. In fact, among those categorized as premenopausal, we observed estrone levels to be higher than estradiol levels, which is more consistent with perimenopausal (and post menopausal) hormone patterns.9,21 In addition, we also observed that a high percentage of women categorized as premenopausal reported experiencing symptoms associated with the menopausal transition, including irritability (50.0%), vaginal discharge (28.4%), insomnia (43.8%), and headache (40.2%). On the other hand, it is also possible the some of the women with a higher BMI were misclassified as perimenopausal when they were actually premenopausal. Our menopausal definition was based, in part, on the frequency of menses and many truly premenopausal obese patients have fewer menses per year than premenopausal women of normal weight.25 This possible misclassification may also have masked a true difference in the investigated associations by menopausal status. It must also be noted that hormone levels were determined by using a single sample of blood drawn at the clinic visit. Hormone levels can vary within individual women, depending on time of day, the day of her menstrual cycle, menopausal status, and other personal characteristics.26 Although the single measurement is noted as a limitation, we minimized the variation in hormone levels because of these variables by (1) collecting samples from fasting
1360 women, (2) collecting samples at the same time of day, (3) examining hormone levels stratified by menopausal status, and (4) controlling for days since last menstrual period at the time of questionnaire completion among premenopausal women. In addition, we minimized the variation in hormone levels because of individual assays by performing the assays using the same protocol and using quality control measures, such as the monitoring of inter- and intra-assay variation. The findings from this population-based case-control study further strengthen the evidence of a positive association between BMI and hot flashes among midlife women. In addition, our ability to examine whether hormone levels are involved in the mechanism by which BMI increases a women’s risk sheds light on the controversial topic of the relation between BMI, hot flashes, and hormone levels. Although estradiol levels appeared, in part, to explain the relationship between BMI and the experiencing of hot flashes, other mechanisms appear to be involved and may, in fact, be more important. Further research into other possible mechanisms is needed so that therapies to relieve hot flashes among women with a high BMI can be created and, in addition, the cause of hot flashes can be better understood. Such studies may also elucidate other factors that predispose women to hot flashes so that preventive measures can be used to maintain women’s quality of life as they go through the menopausal transition.
References 1. Kronenberg F, Downey JA. Thermoregulatory physiology of menopausal hot flashes: a review. Can J Physiol Pharmacol 1987;65:1312-24. 2. Whiteman MK, Staropoli CA, Benedict JC, Borgeest C, Flaws JA. Risk factors for hot flashes in midlife women. J Womens Health 2003;12:459-72. 3. Whiteman MK, Staropoli CA, Langenberg P, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol 2003;101:264-72. 4. Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol 2000;152:463-73. 5. Hyde Riley E, Inui TS, Kleinman K, Connelly MT. Differential association of modifiable health behaviors with hot flashes in perimenopausal and postmenopausal women. J Gen Intern Med 2004;19:740-6. 6. Freeman EW, Sammel MD, Grisso JA, Battistini M, GarciaEspagna B, Hollander L. Hot flashes in the late reproductive years: risk factors for African American and Caucasian women. J Womens Health Gend Based Med 2001;10:67-76. 7. den Tonkelaar I, Seidell JC, van Noord PA. Obesity and fat distribution in relation to hot flashes in Dutch women from the DOM-project. Maturitas 1996;23:301-5.
Gallicchio et al 8. Avis NE, Crawford SL, McKinlay SM. Psychosocial, behavioral, and health factors related to menopause symptomatology. Womens Health 1997;3:103-20. 9. Erlik Y, Meldrum DR, Judd HL. Estrogen levels in postmenopausal women with hot flashes. Obstet Gynecol 1982;59:403-7. 10. Overlie I, Moen MH, Holte A, Finset A. Androgens and estrogens in relation to hot flushes during the menopausal transition. Maturitas 2002;41:69-77. 11. Hutton JD, Jacobs HS, Murray MA, James VH. Relation between plasma oestrone and oestradiol and climacteric symptoms. Lancet 1978;1:678-81. 12. Wilbur J, Miller AM, Montgomery A, Chandler P. Sociodemographic characteristics, biological factors, and symptom reporting in midlife women. Menopause 1998;5:43-51. 13. National Institutes of Health. National Institutes of Health on-line BMI calculator. Bethesda (MD): National Institutes of Health National Heart, Lung, and Blood Institute; 2004. 14. Gallicchio L, Miller SR, Visvanathan K, Lewis LM, Babus J, Zacur H, et al. Cigarette smoking, estrogen levels, and hot flashes in midlife women. Maturitas 2005; in press. 15. Li C, Samsioe G, Borgfeldt C, Lidfeldt J, Agardh CD, Nerbrand C. Menopause-related symptoms: what are the background factors? A prospective population-based cohort study of Swedish women (The Women’s Health in Lund Area study). Am J Obstet Gynecol 2003;189:1646-53. 16. Kuh DL, Wadsworth M, Hardy R. Women’s health in midlife: the influence of the menopause, social factors and health in earlier life. BJOG 1997;104:923-33. 17. Staropoli CA, Flaws JA, Bush TL, Moulton AW. Predictors of menopausal hot flashes. J Womens Health 1998;7:1149-55. 18. Niedhammer I, Bugel I, Bonenfant S, Goldberg M, Leclerc A. Validity of self-reported weight and height in the French GAZEL cohort. Int J Obes Relat Metab Disord 2000;24:1111-8. 19. Roberts RJ. Can self-reported data accurately describe the prevalence of overweight? Public Health 1995;109:275-84. 20. Klinga K, von Holst T, Runnebaum B. Influence of severe obesity on peripheral hormone concentrations in pre- and postmenopausal women. Eur J Obstet Gynecol Reprod Biol 1983;15: 103-12. 21. Gold EB, Block G, Crawford S, Lachance L, Fitzgerald G, Miracle-McMahill HL, et al. Lifestyle and demographic factors in relation to vasomotor symptoms: baseline results from the Study of Women’s Health Across the Nation. Am J Epidemiol 2004;159: 1189-99. 22. Glickman-Weiss EL, Nelson AG, Hearon CM, Prisby R, Caine N. Thermal and metabolic responses of women with high fat versus low fat body composition during exposure to 5 and 27 degrees C for 120 min. Aviat Space Environ Med 1999;70:284-8. 23. Freedman RR. Hot flash trends and mechanisms. Menopause 2002;9:151-2. 24. Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 1998;275:R269-77. 25. Rowland AS, Baird DD, Long S, Wegienka G, Harlow SD, Alavanja M, et al. Influence of medical conditions and lifestyle factors on the menstrual cycle. Epidemiology 2002;13:668-74. 26. Garcia-Closas M, Herbstman J, Schiffman M, Glass A, Dorgan JF. Relationship between serum hormone concentrations, reproductive history, alcohol consumption and genetic polymorphisms in pre-menopausal women. Int J Cancer 2002; 102:172-8.
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Body mass, estrogen levels, and hot flashes in midlife women Lisa Gallicchio, PhD,a Kala Visvanathan, MBBS, MHS,a Susan R. Miller, ScD,b Janice Babus, BS,c Lynn M. Lewis, MA,c Howard Zacur, MD, PhD,b Jodi A. Flaws, PhDc,* Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Healtha; Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicineb; Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine,c Baltimore, MD Received for publication January 10, 2005; revised March 28, 2005; accepted April 1, 2005
KEY WORDS Hot flashes Menopausal transition Estrogen Obesity Body mass index
Objective: This study was undertaken to determine whether body mass index (BMI) is associated with hot flashes and whether the mechanism by which BMI increases the risk of hot flashes is by lowering estrogen levels. Study design: A case-control study was conducted among midlife women to examine risk factors for hot flashes. Cases were women who reported experiencing hot flashes (n = 353). Controls were women who reported never experiencing hot flashes (n = 258). Each participant completed a questionnaire and provided a blood sample for estrogen measurement. Results: Compared with normal weight women, very obese women had significantly higher odds of hot flashes. The odds ratios remained elevated although attenuated when the hormone variables were added to the model. Conclusion: These results indicate that very obese women are at increased risk for hot flashes compared with normal weight women. Estrogen levels may partly explain this relationship; however, other mechanisms appear to be involved as well. Ó 2005 Mosby, Inc. All rights reserved.
Hot flashes are described as transient periods of intense heat in the upper body, arms, and face, which are often followed by flushing of the skin and profuse sweating.1 Hot flashes are the most common vasomotor symptom reported by women undergoing the menopau-
This study was supported by NIH grant AG18400. * Reprint requests: Jodi A. Flaws, PhD, University of Maryland School of Medicine, Department of Epidemiology and Preventive Medicine, 660 W Redwood St, Howard Hall Room 133, Baltimore, MD 21201. E-mail: jfl[email protected] 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.04.001
sal transition1; however, few risk factors for hot flash occurrence have been identified. One of the potential risk factors for hot flashes is body mass index (BMI). As reviewed by Whiteman et al,2 the results of studies, most cross-sectional in nature, examining the relationship between BMI and hot flashes have been conflicting. However, in studies or analyses limited to women identified as being either perimenopausal or approaching the age of menopause (40-55 years), the evidence is more consistent in suggesting that BMI is positively associated with the risk of hot flashes among women undergoing the menopausal transition.3-7
1354 The reasons for this observed positive association between BMI and the experiencing of hot flashes among perimenopausal women are unclear. In studies of postmenopausal women, researchers have shown that women with a high BMI have higher estrogen levels than women with a low BMI because of greater peripheral conversion of androgens to estrogens by adipose tissue.4,8,9 As estrogen levels have been observed to be negatively associated with the risk for hot flashes, it has been hypothesized, based on these findings among postmenopausal women, that women with a high BMI would be at decreased risk of hot flashes.9-12 In contrast, published findings on the association of BMI and the risk of hot flashes among perimenopausal women, as previously reported, directly refute this hypothesis and suggest that the associations between BMI, hot flashes, and estrogen levels may differ among perimenopausal women compared with postmenopausal women. To our knowledge, no study has examined the association of BMI, estrogen levels, and hot flashes in a sample of midlife, perimenopausal women. Therefore, we conducted a large, population-based, case-control study of hot flashes among midlife women aged 45 to 54 years who were perimenopausal to investigate the associations between BMI and the occurrence of any, more severe, and more frequent hot flashes and to examine whether the mechanism by which BMI increases the risk of hot flashes is by lowering estradiol and estrone levels.
Materials and methods A case-control study of hot flashes among midlife women (45-54 years) was conducted during 2000 through 2004 among residents of the Baltimore metropolitan region who reported their history of hot flashes and other information through a survey and donated a blood sample for measurement of hormone levels. All women gave written informed consent according to procedures approved by the University of Maryland School of Medicine and Johns Hopkins University Institutional Review Boards. Names and addresses of women in the selected age range residing in Maryland were obtained from AccuData America (Fort Myers, FL). AccuData provides names and addresses of women in the target age range and geographic region on a fee for service basis. The company compiles the names and addresses using public sources, namely, the Department of Motor Vehicles. Recruitment letters requesting participants for a research study on the health of women ages 45 to 54 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 mailings and who were interested in participating in this study, which was
Gallicchio et al presented as a general ‘‘Midlife Health Study’’ to avoid reporting bias, were invited to call the clinic to obtain more information. During this 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 and had an intact uterus and ovaries. In addition, to ensure that women enrolled in the study were not postmenopausal, women were eligible only if they reported having at least 3 menstrual periods in the last 12 months. Women were excluded if they were pregnant, were taking hormone replacement therapy 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. Clinic visits were scheduled in the morning (8:3010:00 AM) to minimize daily fluctuations in hormone levels within participants. In addition, women scheduled for a clinic visit were instructed to fast overnight before the visit to avoid the influence of diet on hormone levels. 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 45 to 60 minutes to complete and asked questions regarding demographic information, reproductive history and menstrual cycle characteristics, hormonal contraceptive use, menopausal symptoms, hormone replacement therapy use, medical and family history, and health behaviors (smoking, alcohol use, vitamin use, eating habits). After each woman completed the survey, the clinic staff reviewed the survey for completeness. In addition, case-control 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. In addition to the participant completing the questionnaire at the clinic visit, the staff recorded any medications that the participant was taking on a regular basis and took the participant’s blood pressure. Waist circumference was measured at the narrowest part of the waist. Hip circumference was measured at the fullest part of the hips. The participant was weighed without shoes in street clothing to the nearest 0.05 lb, rounding down, on a calibrated scale. Her height was measured without shoes to the nearest 0.5 in, rounding down, with a standard stadiometer. BMI was calculated using the National Institutes of Health on-line BMI calculator.13 Finally, the participant donated blood for the hormone assays described later. In total, 363 cases and 259 controls scheduled and completed the required clinic visit that included the questionnaire administration and the blood draw for hormone analyses. However, because of the exclusion of 10 cases and 1 control from the statistical analysis for reasons described later, the results are based on a total of 353 cases and 258 controls.
Gallicchio et al
Variable definitions A detailed hot flash history was obtained through a series of questions on the enrollment questionnaire that asked for information on the following: whether the woman had experienced hot flashes within the last 30 days; the number of hot flashes experienced within the last 30 days; the age when hot flashes first occurred; and the severity and frequency of the hot flashes. Outcomes examined were the experiencing of any hot flashes, moderate to severe hot flashes, and daily hot flashes. Severity of hot flashes was determined using the question ‘‘How would you describe the majority of your hot flashes?’’ In response to this question, participants were asked to select 1 of the following possible responses: mild (sensation of heat without sweating), moderate (sensation of heat with sweating), and severe (sensation of heat with sweating that disrupts your usual activity). Menopausal status was categorized as pre- or perimenopausal. Premenopausal women were those who reported experiencing their last menstrual period within the past 3 months and experiencing 11 or more periods within the past year. Perimenopausal women were those who reported experiencing (1) their last menstrual period within the past year but not within the past 3 months, or (2) their last menstrual period within the past 3 months and experiencing 10 or fewer periods within the past year. For premenopausal women, phase of the menstrual cycle was determined by using the self-reported number of days since the last menstrual period. BMI was categorized as 24.9 kg/m2 or less, 25.0 to 29.9 kg/m2, 30.0 to 34.9 kg/m2, and 35.0 kg/m2 or greater. Smoking status was categorized as current/former/never. Current alcohol use was examined as a yes/no variable.
Measurement of hormone levels Samples were stored at 20(C until the hormone assays were conducted. Plasma concentrations of estradiol and estrone were measured using enzyme-linked immunosorbent assays (ELISA). ELISA kits and reagents for the estradiol assay were obtained from Diagnostic Systems Laboratories, Inc (Webster, TX). ELISA kits and reagents for the estrone assay were obtained from American Laboratory Products Company (Windham, NH). The assays were run according to the manufacturers’ instructions and published methods.14 All assays were conducted by a single technician in the same laboratory using kits from the same manufacturer lots. All samples were run in duplicate, and mean values for each participant were used in the analysis. The laboratory was blind with respect to any information concerning study subjects. Samples from both cases and controls were run within the same laboratory batches. For quality control purposes, 2 positive controls containing known amounts of estradiol or estrone were included in each batch, and,
1355 for all batches, values were within 5% of the known amount. In addition, 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 and estrone assays were 7 pg/mL and 10 pg/mL, respectively. No samples were below the limit of detection. For the estradiol assays, the average intra-assay coefficient of variation was 3.3% G 0.17% and the average interassay coefficient of variation was less than 5%. For the estrone assays, the average intra-assay coefficient of variation was 4.8% G 0.25% and the average interassay coefficient of variation was less than 5%.
Statistical analyses For this analysis, women were excluded if they did not have data on BMI (n [case] = 1) or days since last menstrual period (n [case] = 9; n [control] = 1). Characteristics of cases and controls were compared by using c2 analyses. Unadjusted associations between BMI and the experiencing of any hot flashes, severe/moderate hot flashes, and daily hot flashes were examined by using logistic regression. Multivariable logistic regression models were created to examine the association between BMI and the experiencing of any, severe, and daily hot flashes, controlling for potential confounders. Factors were considered to be confounders if they were associated (P ! .1) with BMI and case-control status or if they had been considered to be important confounders of the BMI and hot flashes association in the published literature.3 Variables tested as potential confounders were as follows: age, race, marital status, education, household income, parity, prior hormone replacement therapy or oral contraception use, current alcohol use, smoking status, and physical activity. Age, race, smoking status, and current alcohol use remained in the final confounder-adjusted model (model 1). The associations between BMI and plasma hormone levels adjusted for age and menstrual cycle phase (for premenopausal women only) were assessed by using generalized linear models (PROC GLM in SAS). For these and all of the analyses, the estradiol and estrone variables were log transformed because neither was normally distributed. To examine whether any observed association between BMI and hot flashes was due in part to hormone levels, the estimated odds ratio (OR) was calculated by adding either the estradiol or estrone variable to the confounder-adjusted model (model 2). It was expected that if estradiol and/or estrone levels were the mechanism by which BMI increases a woman’s risk of hot flashes, the OR for BMI would be attenuated. Results for the estradiol-adjusted and estrone-adjusted models were similar; thus, only the results for the estradioladjusted model are presented.
1356 Table I
Gallicchio et al Characteristics of cases and controls
Variable
Cases
Controls
Sample size (n)
353
258
Age (y) (%) 45-49 50-54 Race (%) White Black Other Marital status (%) Single Married Widowed Divorced/Separated Education (%) !College Some college College graduate Graduate school
Table II P-value*
58.9 41.1
72.9 27.1
.0004
81.6 17.6 0.9
86.9 10.9 1.9
.04
12.2 66.5 2.3 19.0
12.8 69.8 0.8 16.7
.43
17.6 28.9 23.2 30.3
13.6 24.8 26.7 34.9
.2
26.4 43.4 30.2
.7
56.2 43.8
!.0001
22.1 77.9
.9
Annual household income ($) (%) !50,000 28.9 50,000 to 99,999 41.4 R100,000 28.3 Menopausal status (%) Pre-menopausal 24.6 Peri-menopausal 74.8 Parity (%) Nulliparous 21.5 Multiparous 78.5
Prior hormone replacement therapy (%) Yes 7.4 2.3 No 92.6 97.3 Smoking Status (%) Current 11.3 5.8 Former 40.2 35.7 Never 48.2 58.5 Current alcohol use (%) Yes 62.0 71.7 No 38.0 28.3
Description of hot flashes among the cases
Variable Hot flashes in last 30 days Yes No Severity of hot flashes Mild Moderate Severe Frequency of hot flashes Daily Weekly Monthly Length of time experiencing hot flashes !1 y 1-4 y 5 y or longer
n
%
237 108
67.1 30.6
128 193 31
36.3 54.7 8.9
78 100 157
22.1 28.3 44.5
116 180 47
32.9 51.0 13.3
Because of missing information, some column percentages do not add up to 100.
differ when compared with each other and to the results for the entire sample. Therefore, only the regression analyses for the entire sample are shown. All analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). A P-value of less than .05 was considered to be statistically significant.
Results .01
.01
.01
119.7 !.001 Estradiol levels (pg/mL) 83.1 (1.2, 536.4) (13.0, 686.9) (geometric mean, range) Estrone levels (pg/mL) 114.4 154.1 !.001 (geometric mean, (7.6, 453.2) (15.2, 1177.0) range) Because of missing information, some column percentages do not add up to 100. * P-values reflect c2 comparisons for categorical variables and Student t test comparisons for continuous variables.
All analyses were stratified by menopausal status; however, the regression results for women categorized as premenopausal and perimenopausal did not materially
Characteristics of the cases and controls are presented in Table I. Cases were significantly older than controls and were significantly more likely to be perimenopausal, to smoke at the time of enrollment, and to report prior use of hormone replacement therapy. In addition, cases were less likely to be of white race and to report current alcohol use than the controls. The mean plasma concentrations of both estradiol and estrone were significantly lower among the cases compared with the controls. A description of the hot flashes experienced by the case group is presented in Table II. More than two thirds of the cases reported experiencing hot flashes within the last 30 days, and 63.6% reported that the majority of their hot flashes were either moderate or severe. Approximately 22% of the cases reported experiencing daily hot flashes, and 83.9% reported experiencing hot flashes for less than 5 years. BMI was negatively associated with estradiol among both pre- and perimenopausal women, independent of age and phase of menstrual cycle (for perimenopausal women only; Figure; P for trend !.0001). In addition, BMI was significantly and negatively associated with estrone among perimenopausal women. For both preand perimenopausal women, individuals with a BMI greater than or equal to 35.0 kg/m2 had significantly
Gallicchio et al
1357
Figure Geometric means and 95% CIs of estradiol and estrone concentrations adjusted for participant age and days since last menstrual period (for premenopausal women only) by BMI category. *P ! .05 for comparison of mean estradiol or estrone concentration for specific BMI group and BMI ! 25.0 kg/m2 group.
1358 Table III
Gallicchio et al Association between BMI and the reporting of any, severe, and daily hot flashes Cases*
Controls
Unadjusted
Model 1y
%
%
OR
OR
Any hot flashes BMI (kg/m ) %24.9 25.0-29.9 30.0-34.9 R35.0
39.4 26.1 16.7 17.9
48.1 30.2 13.6 8.1
1.00 Reference 1.05 (0.71-1.55) 1.50 (0.93-2.44) 2.68 (1.54-4.64) P-for-trend = .0004
1.00 Reference 1.00 (0.67-1.49) 1.34 (0.80-2.23) 2.24 (1.26-3.97) P-for-trend = .008
1.00 Reference 0.97 (0.64-1.45) 1.24 (0.74-2.08) 1.89 (1.06-3.40) P-for-trend = .04
Severe hot flashes BMI (kg/m2) %24.9 25.0-29.9 30.0-34.9 R35.0
38.4 29.5 14.7 17.4
48.1 30.2 13.6 8.1
1.00 Reference 1.22 (0.80-1.87) 1.36 (0.79-2.36) 2.69 (1.47-4.87) P-for-trend = .002
1.00 Reference 1.14 (0.73-1.78) 1.22 (0.68-2.17) 2.18 (1.17-4.07) P-for-trend = .02
1.00 Reference 1.12 (0.71-1.75) 1.15 (0.64-2.08) 1.92 (1.01-3.62) P-for-trend = .07
Daily hot flashes BMI (kg/m2) %24.9 25.0-29.9 30.0-34.9 R35.0
39.7 33.3 15.4 11.5
48.1 30.2 13.6 8.1
1.00 Reference 1.33 (0.74-2.41) 1.37 (0.64-2.95) 1.72 (0.72-4.11) P-for-trend = .2
1.00 Reference 1.30 (0.69-2.45) 1.05 (0.45-2.46) 1.51 (0.59-3.86) P-for-trend = .5
1.00 Reference 1.38 (0.70-2.71) 1.02 (0.42-2.52) 1.16 (0.41-3.28) P-for-trend = .8
95% CI
Model 2z 95% CI
OR
95% CI
2
* For severity analysis, includes cases reporting moderate or severe hot flashes; for frequency analysis, includes cases reporting daily hot flashes. y Confounder-adjusted model; adjusted for age, race, smoking, and current drinking status. z Confounder- and estradiol-adjusted model; adjusted for age, race, smoking, current drinking status, and estradiol concentration.
lower levels of estradiol compared to those with a BMI less than 25.0 kg/m2. Estrone levels were significantly lower among perimenopausal women with a BMI greater than or equal to 35.0 kg/m2 compared to perimenopausal women with a BMI less than 25.0 kg/m2. The results of the unadjusted, confounder-adjusted (model 1), and estradiol-adjusted (model 2) analyses of BMI and any, more severe, and daily hot flashes are shown in Table III. In the unadjusted analyses, women with a BMI greater than or equal to 35.0 kg/m2 had significantly greater odds of experiencing any and more severe hot flashes than women with a BMI less than 25.0 kg/m2. After adjustment for important confounders (model 1), the odds of experiencing any and more severe hot flashes among women with a BMI greater than or equal to 35 kg/m2 compared with women with a BMI less than 25.0 kg/m2 remained significant, although attenuated. Significant trends of increasing odds of experiencing hot flashes with higher BMI were observed for both any and more severe hot flashes in both the unadjusted and confounder-adjusted analyses. BMI was not associated with daily hot flashes. To explore the mechanistic involvement of hormone levels in the relation of BMI to the experiencing of hot flashes, the estradiol variable was added to each confounder-adjusted model (model 2). After adjustment for estradiol, the ORs of experiencing any and more severe hot flashes among women with a BMI greater than or equal to 35.0 kg/m2 compared with women with a BMI less than 25.0 kg/m2 remained significant and were further attenuated. In addition, significant or marginally
significant trends of increasing odds of experiencing any and more severe hot flashes with higher BMI were observed after adjustment for estradiol.
Comment The results of this case-control study confirm previous cross-sectional reports that high BMI increases a woman’s likelihood of experiencing any and more severe hot flashes during the menopausal transition.3-5,7,15-17 Importantly, we found that the significant increase in risk of any or more severe hot flashes was present among women who were very obese (R35.0 kg/m2), a group not examined in the previous literature. Similar to previous reports, we observed an elevated risk of any and more severe hot flashes, although not significant, among women with a BMI ranging from 30.0 to 34.9 kg/m2. However, we did not find that moderately high BMI (25.0-29.9 kg/m2) increases the risk of hot flashes among midlife women or that BMI is associated with daily hot flashes, as was reported by Whiteman et al.3 The difference in findings between our study and Whiteman et al3 may be due to differences in sample characteristics, data collection, or confounder adjustments. For example, Whiteman et al3 used self-reported height and weight data, and studies have shown that women frequently underreport their weight and overreport their height.18,19 Therefore, in the Whiteman et al3 study, there may have been a downward shift in the distribution of women in the BMI categories resulting in the observed elevated estimates of hot flashes risk among these lower BMI categories.
Gallicchio et al In analyses of BMI and estrogen levels, BMI was negatively associated with estradiol levels and, to a lesser extent, estrone levels in both pre- and perimenopausal women. This finding is consistent with the results of Klinga et al,20 which observed that, among a sample of midlife women, obese women had a significantly lower mean estradiol level than women of normal weight from the age of 45 to 52 years. To examine whether this decrease in estrogen levels might be due to ovarian insufficiency, as suggested by Klinga et al,20 we compared the mean number of days since last menstrual period as reported by the very obese women (R35 kg/ m2) with the mean number of days since last menstrual period as reported by the normal weight women (%24.9 kg/m2) and found that the very obese women had a significantly longer self-reported mean time since their last menstrual period compared with that of normal weight woman (data not shown). This finding supports the observations by Klinga et al,20 which suggest that the decrease in estrogen levels during the menopausal transition among women with a high BMI compared with women with a low BMI is due to early onset of ovarian insufficiency. Similar to Klinga et al,20 our results also suggest that the decrease in estrogen levels during the menopausal transition among obese women appears not be counterbalanced by peripheral conversion of estrogen by adipose tissue during midlife. To determine whether the associations between high BMI and the experiencing of any or more severe hot flashes were due to changes in estradiol levels, we added the estradiol variable to the confounder-adjusted models. In both models containing the estradiol variable, the ORs for experiencing any hot flashes and more severe hot flashes among women with a high BMI were attenuated compared with the confounder-adjusted models. These observations indicate that the association between BMI and the experiencing of any or more severe hot flashes is due, in part, to lower estradiol levels among women with a high BMI. Similar to our study, Gold et al21 found in an analysis of pre- and perimenopausal women a reduction in the strength of the association between BMI and the experiencing of any hot flashes when comparing an unadjusted OR estimate to an OR estimate controlling for other risk factors and estradiol levels. However, a confounder-adjusted model excluding the estradiol variable was not reported in the Gold et al21 study; thus, it is unclear whether the attenuation in the BMI OR was due to the addition of the estradiol variable or to the addition of the other potential risk factors into the model. Although our results indicate that one mechanism by which high BMI increases the risk for any and more severe hot flashes in midlife women is through the lowering of estradiol levels, the ORs for any and more severe hot flashes remained significantly elevated among women with a high BMI even after adjustment for estradiol levels. This finding suggests that other mechanisms may also be
1359 involved in explaining the associations between BMI and any and more severe hot flashes. One mechanism that has been discussed in the literature is that women with a high BMI are at increased risk of hot flashes because they have more body fat, and thus, more insulation, which may cause increases in the core body temperature and therefore hot flashes.4,22 A similar, yet distinctly different hypothesis is that heavy women have a narrowed thermoneutral zone, ie, the zone between sweating and shivering, which has been shown to increase a woman’s risk for hot flashes.23 It has also been suggested that other hormones produced by adipose tissue such as tumor necrosis factor-a may influence thermoregulation.6,24 These other mechanisms by which BMI is associated with the experiencing of any and more severe hot flashes should be the focus of future studies. Although this study provides novel information into the relationship between BMI, hot flashes, and estrogen levels in midlife women, one challenge that was present in this study and is present in the majority of research on the menopausal transition was the categorizing of the menopausal stages. Enrollment into this study was limited to women aged 45 to 54 years of age because this 10-year interval is the age period when the vast majority of women are perimenopausal. It was surprising that the regression results for women categorized as pre- and perimenopausal did not substantially differ from each other or from the findings for the entire sample reported in this manuscript. It is possible that the women in this study who were categorized as premenopausal were actually early perimenopausal and experiencing irregular periods. In fact, among those categorized as premenopausal, we observed estrone levels to be higher than estradiol levels, which is more consistent with perimenopausal (and post menopausal) hormone patterns.9,21 In addition, we also observed that a high percentage of women categorized as premenopausal reported experiencing symptoms associated with the menopausal transition, including irritability (50.0%), vaginal discharge (28.4%), insomnia (43.8%), and headache (40.2%). On the other hand, it is also possible the some of the women with a higher BMI were misclassified as perimenopausal when they were actually premenopausal. Our menopausal definition was based, in part, on the frequency of menses and many truly premenopausal obese patients have fewer menses per year than premenopausal women of normal weight.25 This possible misclassification may also have masked a true difference in the investigated associations by menopausal status. It must also be noted that hormone levels were determined by using a single sample of blood drawn at the clinic visit. Hormone levels can vary within individual women, depending on time of day, the day of her menstrual cycle, menopausal status, and other personal characteristics.26 Although the single measurement is noted as a limitation, we minimized the variation in hormone levels because of these variables by (1) collecting samples from fasting
1360 women, (2) collecting samples at the same time of day, (3) examining hormone levels stratified by menopausal status, and (4) controlling for days since last menstrual period at the time of questionnaire completion among premenopausal women. In addition, we minimized the variation in hormone levels because of individual assays by performing the assays using the same protocol and using quality control measures, such as the monitoring of inter- and intra-assay variation. The findings from this population-based case-control study further strengthen the evidence of a positive association between BMI and hot flashes among midlife women. In addition, our ability to examine whether hormone levels are involved in the mechanism by which BMI increases a women’s risk sheds light on the controversial topic of the relation between BMI, hot flashes, and hormone levels. Although estradiol levels appeared, in part, to explain the relationship between BMI and the experiencing of hot flashes, other mechanisms appear to be involved and may, in fact, be more important. Further research into other possible mechanisms is needed so that therapies to relieve hot flashes among women with a high BMI can be created and, in addition, the cause of hot flashes can be better understood. Such studies may also elucidate other factors that predispose women to hot flashes so that preventive measures can be used to maintain women’s quality of life as they go through the menopausal transition.
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