Abstract
Objective
The aim of this study was to examine the associations between demographic characteristics, health behaviors, hormone concentrations, and the experiencing of any, current, more severe, and more frequent midlife hot flashes.
Methods
Baseline data were analyzed from 732 women aged 45 to 54 years enrolled in the Midlife Women's Health Study. A clinic visit was conducted to collect blood samples for hormone assays and to measure ovarian volume using transvaginal ultrasound. A self-administered questionnaire ascertained information on demographic factors, health habits, and hot flashes history. Multivariable logistic regression was conducted to examine the associations between potential risk factors and the hot flashes outcomes.
Results
Approximately 45% of participants reported experiencing midlife hot flashes. In the covariate-adjusted models, older age, peri-menopausal status, current and former cigarette smoking, and depressive symptoms were significantly associated with increased odds of all of the hot flashes outcomes. In addition, history of oral contraceptive use was associated with increased odds of any hot flashes. In contrast, higher current alcohol intake was significantly associated with decreased odds of any, current, and more severe hot flashes. Higher estradiol and progesterone concentrations were significantly associated with decreased odds of all hot flashes outcomes.
Conclusions
Although the temporalities of such associations are not known due to the cross-sectional nature of the data, these observed relationships can help to identify women at risk for hot flashes.
Keywords: hot flashes, estrogen, progesterone, ovarian volume
INTRODUCTION
Hot flashes are the most prevalent and bothersome symptom reported by women during the menopausal transition. Recent estimates suggest up that up to 80% of women experience hot flashes during midlife1 and, that on average, symptoms last for approximately 10 years from symptom onset through the menopausal transition.2 Hot flashes consistently have been shown to be associated with discomfort, sleep disturbances, fatigue, and decreased quality of life.3 In addition, a recent study showed that, because of the negative effects of hot flashes on women's lives, women with hot flashes have lower work productivity and greater healthcare resource use than women without hot flashes.4 There is also some indication that hot flashes are associated with an increased risk of more serious adverse health outcomes, including cardiovascular disease5 and depression.6
Despite the impact that hot flashes can have on a woman's life, little remains known, to date, about risk factors for hot flashes or the events that precipitate them. Several characteristics and health behaviors have more often than not been reported to be significantly associated with an increased risk of hot flashes during midlife, including cigarette smoking7-9, obesity7, 10-12, and lower levels of education9, 12-14; however, these associations have not been observed in all studies examining these relationships.15 Other factors such as physical activity, alcohol intake, and reproductive history have also been examined in association with hot flashes; however, results pertaining to these risk factors have been less consistent than those reported for smoking, body mass index (BMI), and education (reviewed in: Ziv-Gal & Flaws16). There are a number of possible reasons why the results of studies examining the associations between risk factors and hot flashes have been inconsistent, including that the populations under study were composed of women of different race and ethnic backgrounds and that the measurement of hot flashes varied from a single question to a more detailed hot flashes history.
Starting in 2006, the longitudinal Midlife Women's Health Study has been conducted with the purpose of examining risk factors for hot flashes in a large population-based cohort study of women undergoing the midlife transition. In the Midlife Women's Health Study, detailed information on the experiencing of hot flashes is collected annually by self-report and a clinic visits are conducted to measure height and weight, to collect blood samples for hormone measurements, and a obtain ovarian volume measurement using a transvaginal ultrasound. The objective of this analysis was to describe the baseline characteristics of the cohort and to report, using the data collected at baseline, the associations between demographic characteristics, health behaviors, hormone concentrations, and the experiencing of any, more severe, and more frequent hot flashes.
METHODS
Study participants
The Midlife Women's Health Study is a cohort study of hot flashes among midlife women (45 to 54 years of age) that began in 2006, enrolling residents of the Baltimore metropolitan region, which includes Baltimore city and its surrounding counties. Detailed methods of this study are described in Gallicchio et al.15 All participants gave written informed consent according to procedures approved by the University of Illinois and Johns Hopkins University Institutional Review Boards.
Briefly, women in the selected age range were recruited through mass mailings in the targeted region. Women who were interested in participating in this study, which was presented as a general “Midlife Health Study” to avoid reporting bias, were invited to call the clinic to obtain more information. During this call, the clinic staff determined whether the woman met the eligibility criteria. Women were eligible if they were between 45 and 54 years of age, had intact ovaries and uteri, and were either pre- or peri-menopausal. Women were excluded if they were pregnant, had a history of cancer, or were postmenopausal. Women were also excluded if they were taking exogenous female hormones or herbal/plant substances so that we could study risk factors for hot flashes without the confounding effects of known treatments for hot flashes. Menopausal status was defined as follows: pre-menopausal women were those who experienced their last menstrual period within the past 3 months and reported 11 or more periods within the past year. Peri-menopausal women were those who experienced 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 experienced 10 or fewer periods within the past year. Post-menopausal women were those women who had not experienced a menstrual period within the past year.
If a woman was eligible and interested in participating in the study, she was asked to make a clinic visit (the baseline visit) to a Johns Hopkins clinical site. During this baseline clinic visit, the participant completed the detailed 26-page baseline study survey, donated blood and urine samples, was weighed and measured (height), had her blood pressure measured, and received a transvaginal ultrasound to measure ovarian volume. Each participant was then asked to visit the clinic once per week for the three weeks following the baseline visit so that the study staff could obtain additional blood and urine samples. Women also completed a brief questionnaire at the last of the three weekly visits following the baseline visit. These four consecutive weekly clinic visits were then repeated on a yearly basis throughout the woman's participation in the study. Only data from the baseline clinic visit were analyzed in this study.
Through April 2014, 736 women were enrolled in the study of which 734 completed the baseline clinic visit and questionnaire. Two of these women were determined to be post-menopausal, and, thus, ineligible, at baseline after enrolling into the study and completing the clinic visit. Therefore, the final analytic dataset was comprised of 732 pre- and peri-menopausal women.
Study variables
On the study questionnaires, hot flashes were defined for participants as “a sudden feeling of heat in the face, neck, or upper part of the chest. Hot flashes are often accompanied by reddening or flushing of the skin followed by sweating and chills.” At baseline, a detailed hot flash history was obtained through a series of questions on the survey that asked for information on the following: whether the woman had ever experienced hot flashes, whether she had a hot flash in the past 30 days, the usual severity of hot flashes, the frequency of hot flashes, and the length of time that the woman experienced hot flashes. Women who responded no to ever experiencing hot flashes were prompted to skip the more detailed hot flash questions. The hot flashes questions chosen for inclusion on the questionnaires have been used to collect data on hot flashes in the Midlife Health Studies for over 10 years.
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 2-5 hours, every 6-11 hours, every 12-23 hours, 1-2 days per week, 5-6 days per week, 2-3 days per month, 1 day per month, less than 1 day per month, or never. For analysis of the data, the following hot flash variables were examined as dependent variables (outcomes): ever experienced hot flashes (yes versus no); experienced any hot flashes in the past 30 days (yes versus no); moderate or severe hot flashes (yes versus no); and weekly or daily hot flashes (yes versus no).
Height and weight measured at the clinic visit were used to calculate BMI, which was categorized as less than 25 kg/m2, 25 to 29.9 kg/m2, and 30 kg/m2 or greater. Smoking was categorized as current, former, and never using the questions: “Have you ever smoked cigarettes?” and “Do you still smoke cigarettes?” Similarly, alcohol use data were collected using the following questions: “During your entire life, have you had a least 12 drinks of any kind of alcoholic beverage?” and “In the last 12 months have you had at least 12 drinks of any kind of alcoholic beverage?” Further queries for those responding that they had had at least 12 drinks in the last 12 months were made regarding the number of days per month, on average, that the woman drank and the number of drinks that the woman drank on those days. Physical activity was assessed by the participant's response to the question: “In comparison with others my own age, I think my physical activity leisure time is: [choices: much more, more, as much, less, and much less].” Employment status was categorized as employed (either full-time or part-time) and not employed. Medication use information was provided by the participant. The presence of depressive symptoms was assessed using the Centers for Epidemiologic Studies – Depression Scale (CES-D).17 Individuals with a score > 16 were identified as having depressive symptoms. Data on race, education, and reproductive history were also collected on the questionnaire.
Ovarian volume
The transvaginal ultrasound examinations to collect data on ovarian volume were performed using the 7.5 MHz transvaginal probe on a GE transvaginal ultrasound machine. Examination of the ovary was established by scanning from the outer to the inner margin. All of the transvaginal ultrasounds were conducted by highly trained physicians in the Department of Gynecology and Obstetrics at Johns Hopkins University. The physicians used a highly standardized protocol for the measurements on calibrated equipment. In pilot studies, the ultrasound measurements were determined to be highly repeatable. For example, when two different physicians performed ovarian size measurements on the same participant, the values were very close to each other (e.g., physician 1: right ovary, 2.98 × 2.05 × 2.04 cm and physician 2: right ovary, 2.75 × 1.95 × 1.71 cm) . Given the extensive training and experience of the physicians performing the transvaginal ultrasounds, the use of calibrated equipment, and the repeatability of the results, solid quality controls were in place for transvaginal ultrasound measurements in the study.
Hormone assays
Serum concentrations of estradiol, testosterone, and progesterone were measured in blood samples collected at each clinic visit. Women were asked to donate blood at four clinic visits over four weeks during year 1 (baseline) and each subsequent year of participation in the study; however, not all women were able to attend all four clinic visits in year 1 or in follow-up years. In year 1, 82.0% of participants completed all four visits; 12.2% completed three visits, 2.3% completed two visits, and 3.5% completed only one visit. A single concentration value for year 1 and for each subsequent follow-up year was calculated using the average value of the hormone concentrations that were measured in each year.
Estradiol, testosterone, and progesterone concentrations were measured using enzyme-linked immunosorbent assays (ELISA). ELISA kits were obtained from Diagnostic Systems Laboratories, Inc. (Webster, TX) and the assays were run using the manufacturers’ instructions.18 All assays were conducted in the same laboratory. 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 women with hot flashes and women without hot flashes were run within the same laboratory batches. In addition, positive controls containing known amounts of estradiol, testosterone, and progesterone 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 and intra-assay coefficients of variation were as follows: estradiol 7pg/ml, 3.3 ± 0.17%; testosterone 0.04ng/ml, 2.2 ± 0.56%; and progesterone 0.1ng/ml, 2.1 ± 0.65. The average inter-assay coefficient of variation for all assays was less than 5%.
Statistical analysis
Hormone concentration data were log-transformed because the values were not normally distributed. Normality was assessed by examining the distribution of hormone concentrations among women with and without hot flashes. Univariate analyses were done by calculating frequencies for categorical variables and geometric means for the continuous log-transformed hormone variables. Differences in demographic, reproductive, and health habit characteristics by hot flash status (ever versus never) were examined using chi-square tests for categorical variables; differences in hormone concentrations by hot flash status were examined using generalized linear models.
To examine the age- and covariate-adjusted associations between participant characteristics, hormone concentrations, and each hot flash outcome, odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression models. Variables included in all covariate-adjusted models were those that have been reported consistently in the published literature to be associated with hot flashes as well as those shown in the bivariate analyses to be significantly associated with a history of hot flashes at p<0.05. Hormone concentrations were not included as covariates in the covariate-adjusted models, as hormone concentrations may represent the mechanism by which certain risk factors are associated with hot flashes. Further, models examining the association between a hormone and a hot flash outcome were not adjusted for other hormone concentrations.
All analyses were conducted among the total sample and also by race (white and black); however, race was not determined to be an effect modifier of the associations and the race-stratified results are not presented. Analyses were performed with SAS, version 9.2 (SAS Institute, Inc., Cary, North Carolina). A two-sided p-value of less than 0.05 was considered statistically significant.
RESULTS
At baseline, 45.4% of the study participants reported experiencing midlife hot flashes. Characteristics of women with and without a history of hot flashes are presented in Table 1. Women with a history of hot flashes were more likely to be older, to have graduated college, to be current or former smokers, to be of peri-menopausal status, to have depressive symptoms, and to be taking an anti-hypertensive medication compared to women without hot flashes. Mean estradiol and progesterone concentrations were significantly lower among women reporting hot flashes compared to those not reporting hot flashes. Similarly, mean ovarian volume was lower among women with hot flashes compared to women without hot flashes.
Table 1.
Baseline characteristics by self-reported history of hot flashes
| Yes (n = 332) |
No (n = 400) |
||||
|---|---|---|---|---|---|
| Demographic characteristics and health habits | n | % | n | % | p-valuea |
| Age, years | <0.0001 | ||||
| 45 to 49 | 177 | 53.3 | 303 | 75.7 | |
| 50 to 54 | 155 | 46.7 | 97 | 24.3 | |
| Education | 0.001 | ||||
| Some college or tech school or less | 143 | 43.1 | 125 | 31.3 | |
| Graduated college or more | 188 | 56.6 | 272 | 68.0 | |
| Race | 0.18 | ||||
| White | 209 | 63.0 | 275 | 68.8 | |
| Black | 110 | 33.1 | 107 | 26.8 | |
| Other | 13 | 3.9 | 16 | 4.0 | |
| Employed | 0.51 | ||||
| Yes | 259 | 78.0 | 320 | 80.0 | |
| No | 72 | 21.7 | 79 | 19.8 | |
| Body mass index (kg/m2) | 0.4 | ||||
| <25 | 128 | 38.6 | 163 | 40.7 | |
| 25 to <30 | 87 | 26.2 | 114 | 28.5 | |
| ≥30 | 117 | 35.2 | 123 | 30.8 | |
| Cigarette smoking | 0.0002 | ||||
| Current | 45 | 13.6 | 29 | 7.2 | |
| Former | 133 | 40.1 | 129 | 32.3 | |
| Never | 153 | 46.1 | 242 | 60.5 | |
| Alcohol use in past year | 0.07 | ||||
| Yes, more than 1 drink per day | 118 | 35.5 | 153 | 38.3 | |
| Yes, 1 drink or less per day | 85 | 25.6 | 118 | 29.5 | |
| No | 127 | 38.3 | 127 | 31.8 | |
| Leisure time activity compared to others of own age | 0.07 | ||||
| More | 112 | 33.7 | 144 | 36.0 | |
| As much | 102 | 30.7 | 121 | 30.3 | |
| Less | 116 | 34.9 | 128 | 32.0 | |
| Reproductive characteristics | |||||
| Age at menarche | 0.5 | ||||
| <10 years | 26 | 7.8 | 22 | 5.5 | |
| 11 or 12 years | 126 | 38.0 | 160 | 40.0 | |
| 13 or 14 years | 140 | 42.2 | 159 | 39.8 | |
| ≥15 | 39 | 11.7 | 53 | 13.3 | |
| Menopausal status | <0.0001 | ||||
| Pre-menopausal | 146 | 44.0 | 334 | 83.5 | |
| Peri-menopausal | 186 | 56.0 | 66 | 16.5 | |
| History of oral contraceptive use | 0.07 | ||||
| Yes | 290 | 87.3 | 331 | 82.7 | |
| No | 41 | 12.3 | 69 | 17.3 | |
| Ever been pregnant | 0.1 | ||||
| Yes | 302 | 91.0 | 350 | 87.5 | |
| No | 29 | 8.7 | 50 | 12.5 | |
| Number of pregnancies | 0.4 | ||||
| Never been pregnant | 29 | 8.7 | 50 | 12.5 | |
| 1 or 2 | 104 | 31.3 | 131 | 32.7 | |
| 3 or 4 | 136 | 41.0 | 150 | 37.5 | |
| ≥5 | 62 | 18.7 | 69 | 17.3 | |
| Age at first birth | 0.5 | ||||
| No live births | 61 | 18.4 | 91 | 22.8 | |
| ≤20 years | 44 | 13.3 | 42 | 10.5 | |
| 21 to 25 years | 71 | 21.4 | 79 | 19.8 | |
| 26 to 30 years | 75 | 22.6 | 83 | 20.8 | |
| ≥30 years | 79 | 23.8 | 103 | 25.8 | |
| Health and medication use | |||||
| Depressive symptoms | 0.0002 | ||||
| Yes | 85 | 25.6 | 59 | 14.8 | |
| No | 236 | 71.1 | 329 | 82.3 | |
| Diabetes medication | 0.1 | ||||
| Yes | 18 | 5.4 | 12 | 3.0 | |
| No | 313 | 94.3 | 387 | 96.8 | |
| Hypertension medication | 0.04 | ||||
| Yes | 59 | 17.8 | 49 | 12.3 | |
| No | 272 | 81.9 | 350 | 87.5 | |
| Depression medication | 0.3 | ||||
| Yes | 43 | 13.0 | 41 | 10.3 | |
| No | 288 | 86.7 | 358 | 89.5 | |
| Hormones and ovarian volume | GM | 95% CL | GM | 95% CL | p-valuea |
| Estradiol, pg/mL (n = 726) | 43.2 | (40.2, 46.3) | 62.7 | (58.9, 66.8) | <0.0001 |
| Testosterone, ng/mL (n = 727) | 0.28 | (0.26, 0.30) | 0.29 | (0.27, 0.31) | 0.3 |
| Progesterone, ng/mL (n = 668) | 0.54 | (0.47, 0.64) | 1.53 | (1.33, 1.76) | <0.0001 |
| Ovarian volume, cm3 (n = 628) | 3.56 | (3.29, 3.97) | 4.49 | (4.09, 3.70) | 0.0001 |
GM = Geometric mean; 95% CL = 95% confidence limits
Chi-square p-values for categorical variables; t-test p-values for continuous variables
Among the women who had a history of midlife hot flashes, the majority reported experiencing hot flashes in the previous 30 days (72.3%) (Table 2). Approximately 9% reported their hot flashes as usually being severe, with 55.7% reporting them as being moderate in severity. About a quarter of those with hot flashes reported experiencing them daily and 26.2% reported experiencing hot flashes weekly. The majority of women with hot flashes in the study had experienced them for one to four years (44.9%).
Table 2.
Hot flash experience at baseline among women reporting a history of hot flashes (n = 332)
| n | % | |
|---|---|---|
| Experienced hot flashes in last 30 days | ||
| Yes | 240 | 72.3 |
| No | 86 | 25.9 |
| I don't know | 3 | 0.9 |
| Severity of hot flashes | ||
| Mild | 108 | 32.5 |
| Moderate | 185 | 55.7 |
| Severe | 31 | 9.3 |
| Hot flash frequency | ||
| Daily | 77 | 23.2 |
| Weekly | 87 | 26.2 |
| Monthly | 140 | 42.2 |
| I don't know | 22 | 6.6 |
| Length of time experiencing hot flashes | ||
| < 1 year | 97 | 29.2 |
| 1 to 4 years | 149 | 44.9 |
| ≥ 5 years | 60 | 18.1 |
| I don't know | 19 | 5.7 |
The age- and covariate-adjusted associations between the participant characteristics, hormone concentrations, and the hot flashes outcomes (history of hot flashes, current hot flashes, moderate to severe hot flashes, and weekly or daily hot flashes) are shown on Tables 3 and 4. In the covariate-adjusted models, older age, peri-menopausal status, current and former cigarette smoking, and depressive symptoms were significantly associated with increased odds of all of the hot flashes outcomes. Peri-menopausal status was the factor that was most strongly related to the hot flashes outcomes, with ORs ranging from 5.34 (history of hot flashes) to 12.42 (weekly or daily hot flashes) comparing peri-menopausal to pre-menopausal women. In addition, after adjustment for covariates, history of oral contraceptive use was associated with increased odds of ever experiencing hot flashes (OR 1.89; 95% CI 1.16, 3.08). In contrast, higher current alcohol intake (more than one drink per day) was significantly associated with decreased odds of ever experiencing hot flashes, currently experiencing hot flashes, and moderate to severe hot flashes.
Table 3.
Age- and covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the associations between demographic characteristics, health habits, reproductive factors, and hormones, with a history of hot flashes and hot flashes experienced in the last 30 days
| History of hot flashes |
Current hot flashes (Hot flashes in last 30 days) |
|||
|---|---|---|---|---|
| Age-adjusted OR (95% CI) | Covariate-adjusteda OR (95% CI) | Age-adjusted OR (95% CI) | Covariate-adjusteda OR (95% CI) | |
| Age, years | ||||
| 45 to 49 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 50 to 54 | 2.74 (2.00, 3.75) | 1.75 (1.22, 2.52) | 3.28 (2.33, 4.62) | 1.95 (1.30, 2.94) |
| Education | ||||
| Some college or tech school or less | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Graduated college or more | 0.61 (0.45, 0.83) | 0.77 (0.54, 1.12) | 0.56 (0.40, 0.79) | 0.83 (0.54, 1.25) |
| Race | ||||
| White | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Black | 1.37 (0.98, 1.91) | 1.15 (0.76, 1.74) | 1.58 (1.10, 2.27) | 1.02 (0.64, 1.64) |
| Other | 1.03 (0.47, 2.24) | 1.10 (0.47, 2.58) | 1.23 (0.54, 2.82) | 1.44 (0.57, 3.62) |
| Employed | ||||
| Yes | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| No | 0.89 (0.62, 1.29) | 1.18 (0.77, 1.81) | 0.75 (0.50, 1.11) | 1.02 (0.64, 1.63) |
| Body mass index (kg/m2) | ||||
| <25 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 25 to <30 | 0.89 (0.61, 1.29) | 0.64 (0.42, 0.98) | 1.16 (0.77, 1.76) | 0.76 (0.48, 1.27) |
| ≥30 | 1.16 (0.82, 1.66) | 0.75 (0.49, 1.14) | 1.47 (0.99, 2.19) | 0.96 (0.59, 1.56) |
| Cigarette smoking | ||||
| Never | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Former | 1.58 (1.14, 2.19) | 1.77 (1.23, 2.53) | 1.76 (1.22, 2.53) | 2.03 (1.35, 3.07) |
| Current | 2.61 (1.55, 4.40) | 2.68 (1.49, 4.84) | 3.42 (1.96, 5.98) | 3.80 (1.99, 7.26) |
| Alcohol use in past year | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes, 1 drink or less per day | 0.73 (0.50, 1.08) | 0.79 (0.51, 1.22) | 0.55 (0.36, 0.85) | 0.58 (0.35, 0.96) |
| Yes, more than 1 drink per day | 0.75 (0.53, 1.07) | 0.65 (0.43, 0.98) | 0.70 (0.48, 1.03) | 0.58 (0.37, 0.92) |
| Leisure time activity compared to others of own age | ||||
| As much | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| More | 0.91 (0.63, 1.33) | 0.97 (0.64, 1.48) | 0.89 (0.59, 1.35) | 0.98 (0.61, 1.59) |
| Less | 1.13 (0.78, 1.64) | 1.02 (0.68, 1.55) | 1.11 (0.73, 1.68) | 1.02 (0.64, 1.64) |
| Age at menarche | ||||
| <10 years | 1.64 (0.87, 3.09) | 1.22 (0.59, 2.51) | 1.86 (0.94, 3.66) | 1.28 (0.58, 2.82) |
| 11 or 12 years | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 13 or 14 years | 1.16 (0.83, 1.62) | 1.07 (0.74, 1.56) | 1.10 (0.75, 1.59) | 0.95 (0.61, 1.47) |
| ≥15 | 0.89 (0.54, 1.45) | 0.83 (0.48, 1.43) | 0.93 (0.55, 1.60) | 0.90 (0.48, 1.70) |
| Menopausal status | ||||
| Premenopausal | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Perimenopausal | 5.52 (3.86, 7.88) | 5.34 (3.69, 7.73) | 6.96 (4.72, 10.28) | 6.69 (4.44, 10.08) |
| History of oral contraceptive use | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.55 (1.01, 2.38) | 1.89 (1.16, 3.08) | 1.31 (0.82, 2.09) | 1.62 (0.95, 2.79) |
| Ever been pregnant | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.30 (0.79, 2.14) | 1.25 (0.72, 2.17) | 1.25 (0.72, 2.18) | 1.14 (0.61, 2.13) |
| Number of pregnancies | ||||
| Never been pregnant | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 1 or 2 | 1.19 (0.69, 2.03) | 1.22 (0.67, 2.22) | 1.13 (0.62, 2.07) | 1.10 (0.56, 2.18) |
| 3 or 4 | 1.38 (0.82, 2.34) | 1.35 (0.75, 2.43) | 1.30 (0.72, 2.34) | 1.24 (0.64, 2.42) |
| ≥5 | 1.35 (0.75, 2.43) | 1.07 (0.55, 2.07) | 1.39 (0.72, 2.66) | 0.97 (0.46, 2.07) |
| Age at first birth | ||||
| No live births | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| ≤20 years | 1.56 (0.91, 2.70) | 1.14 (0.60, 2.19) | 1.71 (0.94, 3.12) | 1.04 (0.50, 2.19) |
| 21 to 25 years | 1.20 (0.75, 1.91) | 1.26 (0.74, 2.13) | 1.27 (0.75, 2.14) | 1.22 (0.67, 2.22) |
| 26 to 30 years | 1.24 (0.78, 1.97) | 1.33 (0.80, 2.22) | 1.23 (0.73, 2.06) | 1.35 (0.75, 2.43) |
| ≥30 years | 1.03 (0.66, 1.62) | 1.23 (0.74, 2.02) | 0.99 (0.59, 1.64) | 1.20 (0.68, 2.13) |
| Depressive symptoms | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 2.03 (1.38, 2.97) | 1.62 (1.06, 2.48) | 2.34 (1.55, 3.53) | 1.84 (1.15, 2.95) |
| Diabetes medication | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 2.08 (0.97, 4.46) | 1.62 (0.69, 3.81) | 2.68 (1.20, 5.99) | 1.85 (0.74, 4.60) |
| Anti-hypertensive medication | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.52 (1.00, 2.32) | 1.39 (0.85, 2.27) | 1.80 (1.14, 2.84) | 1.55 (0.90, 2.67) |
| Depression medication | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.27 (0.79, 2.02) | 1.10 (0.65, 1.87) | 1.24 (0.74, 2.09) | 1.03 (0.57, 1.89) |
| Estradiol, pg/mL (continuous) | 0.44 (0.34, 0.57) | 0.63 (0.48, 0.83) | 0.39 (0.29, 0.51) | 0.59 (0.43, 0.81) |
| Testosterone, ng/mL (continuous) | 0.88 (0.70, 1.11) | 0.89 (0.69, 1.15) | 0.92 (0.71, 1.18) | 1.00 (0.75, 1.33) |
| Progesterone, ng/mL (continuous) | 0.64 (0.56, 0.72) | 0.79 (0.68, 0.92) | 0.59 (0.52, 0.68) | 0.77 (0.65, 0.91) |
| Ovarian volume, cm3 (continuous) | 0.72 (0.56, 0.93) | 0.92 (0.70, 1.22) | 0.69 (0.52, 0.91) | 0.88 (0.64, 1.20) |
95% CI = 95% confidence interval; OR = odds ratio
covariates included in all multivariable models are: participant age, race, education, body mass index, smoking, alcohol consumption, and menopausal status
Higher estradiol and progesterone concentrations were significantly associated with decreased odds of all of the hot flashes outcomes after adjustment for age, race, education, BMI, smoking, alcohol consumption and menopausal status. Testosterone concentration was not significantly associated with any of the hot flashes outcomes. Ovarian volume was significantly associated with all outcomes in the age-adjusted but not the covariate-adjusted analyses.
DISCUSSION
This study examined risk factors for experiencing any, current, more severe, and more frequent hot flashes among women aged 45 to 54 years participating in the Midlife Women's Health Study. Results of this study showed that older age, peri-menopausal status, cigarette smoking, and depressive symptoms were associated with a statistically significant increased risk of all of the hot flash outcomes. Conversely, greater alcohol intake and higher estradiol and progesterone concentrations were associated with a decreased risk of hot flashes. In general, the strength of the associations associated with each risk factor were similar across all outcomes except for menopausal status, where the OR for more frequent hot flashes was twice that of the other hot flashes outcomes. The consistency of the ORs suggests that the hot flashes the women report in the study that are associated with certain risk factors are likely be consistent in nature themselves – primarily moderate to severe in nature and experienced on a weekly or daily basis. Further, the stronger association between menopausal status and frequency of hot flashes confirms both clinical and research findings that the frequency of hot flashes increases during peri-menopause. In total, the results of this study add to previously published findings in that more detailed data on hot flashes were collected than in previous studies, allowing for a more thorough understanding of the role of certain factors in the development of midlife hot flashes.
Cigarette smoking has been the factor that has been most consistently reported to be associated with midlife hot flashes in previously published studies.7-9, 13, 19 Results from the present study confirm these previous findings. Specifically, current smoking was associated with a 2.6 fold increase in odds of ever experiencing hot flashes and, further, 3.4 to 3.8 increased odds of experiencing current, more severe, and more frequent hot flashes. Former smokers were also at significantly increased risk of all hot flashes outcomes, although the increase in odds was not as great as current smokers when compared to never smokers. A number of mechanisms for the increased risk of hot flashes associated with cigarette smoking have been postulated, including the anti-estrogenic effect of smoking.20 However, in this study, consistent with what has been reported in several other previously published studies8, 21, addition of estradiol as a covariate in the multivariable adjusted models for cigarette smoking did not attenuate the OR estimates (data not shown), indicating that other mechanisms may be involved. Such mechanisms could include alterations in neurotransmitter metabolism within the dopaminergic system, as hypothesized by Butts et al.22
In the present study, alcohol intake was significantly associated with decreased odds of experiencing any, current, and more severe hot flashes after adjustment for other risk factors and covariates, although there was little evidence of a dose-response relationship observed in terms of drinks per day in the analyses. Alcohol intake is a factor that has been shown in published studies to be associated with both increased19, 23, 24 and decreased risk25, 26 of midlife hot flashes. There is some evidence that alcohol consumption increases estrogen concentrations27, 28, which would support our finding of a decreased risk of hot flashes with more alcohol intake, as hot flashes are thought to be associated with low estradiol levels. However, similar to cigarette smoking, the OR estimates for the hot flashes outcomes associated with alcohol intake did not change after the addition of estradiol, or progesterone, to the multivariable model (data not shown). An alternative mechanism is that perhaps most of the alcohol consumed by participants of this study was in the form of wine, and that a major component of wine, resveratrol, exerts health benefits such as lowering oxidative stress29, leading to a decreased risk of hot flashes. We did not collect data on type of alcohol consumed (e.g., beer, wine, spirits, etc); thus, wine as the most common type of alcoholic beverage consumed is speculative based on the demographic characteristics of this study sample. Further, it unknown if there is a relationship between oxidative stress and hot flashes, although there are some data that suggest such an association.30 The relationship between alcohol intake and hot flashes could also be bi-directional, with women having hot flashes increasing the amount of alcohol consumed.
Depressive symptoms were also significantly associated with the occurrence of hot flashes in this study. As this analysis was cross-sectional in nature, the temporality of the association between depressive symptoms and hot flashes is not clear. A recently published systematic review by Worsley et al.31 on the association between vasomotor symptoms and depression during the menopausal transition concluded that there is a positive, bidirectional association between vasomotor symptoms and depression during peri-menopause, with women with depressive symptoms more likely to develop vasomotor symptoms and women with vasomotor symptoms more likely to develop depressive symptoms. The systematic review was based on 17 cross-sectional studies and 12 cohort studies, although three large longitudinal studies accounted for a large percentage of the reviewed publications [The Study of Women's Health Across the Nation (SWAN), the Seattle Midlife Women's Health Study (SMWH), and the Penn Ovarian Aging Study (POA)]. A positive association between depressive symptoms and hot flashes could indicate a common etiology or that a depressed mood, or stress, might lower the threshold for reporting vasomotor symptoms.32, 33 Adjustment for hormone concentrations in the covariate-adjusted model did not attenuate the OR estimates between hot flashes and depressive symptoms (data not shown), suggesting that hormones do not mediate the association.
It should be noted that BMI was not associated with any of the hot flashes outcomes in this study. This finding, and a more in-depth discussion of the BMI results, was reported in a previous publication from the same cohort.15 In brief, it is unclear why the findings for this study are different than those reported in similar types of studies. One possibility is that the perimenopausal women in our cohort study were later in peri-menopause than women in other similar studies of midlife women. Data collected in the study allowed for the determination of whether a woman was pre-menopausal, peri-menopausal, or post-menopausal; however, it is not possible to know from our data how early the participants were in each stage and how this compares to different studies. Thus, we can only speculate that reported differences in the association between BMI and hot flashes among studies are due to differences in where participants are in each stage of the menopausal transition.
Similarly, physical activity and reproductive factors such as having ever been pregnant, number of pregnancies, age at menarche, and age at first birth, were also not significantly associated with midlife hot flashes in this study. Findings in the published literature in regards to hot flashes and both physical activity and reproductive history have been inconsistent13, 16, 34-42 and, therefore, have not contributed to the identification of risk factors that could help provide clues to the etiology of hot flashes or measures to prevent the onset of hot flashes.
There has been much controversy about the etiology of midlife hot flashes. Numerous studies have examined the role of sex steroid hormones in hot flash etiology, with much of the focus being on estradiol. As shown in this study, and other longitudinal investigations9, 43, 44, the risk of hot flashes increases over the menopausal transition, a time period when estradiol concentrations decline dramatically. The finding of a statistically significant increase in the odds of hot flashes associated with a decrease in estradiol concentration in this study is consistent with previous cross-sectional and longitudinal studies45-49, and it is thought that estrogen is involved in the thermoregulatory homeostasis in the hypothalamus.50 In contrast to the numerous studies reporting on estradiol and hot flashes, the association observed in the present study between lower progesterone concentrations and an increased risk of hot flashes has only been reported in one previous study, conducted by our research group47, although many studies have shown that progestin therapies are effective in reducing or preventing hot flashes in perimenopausal women (examples: Prior et al.51, Hitchcock et al.52, Ruiz et al.53). There is some evidence that progestins, similar to estrogens, interact with several neurotransmitter pathways in the hypothalamus responsible for thermoregulation.54 There is a paucity of information on progesterone and the etiology of menopausal symptoms; thus, future work should be conducted in this area.
There are several limitations of this study that should be considered. First, this analysis was cross-sectional in nature; thus, we are unable to determine the temporality of the associations observed with hot flashes. Second, the study sample, although relatively large, was well-educated and included mostly African-American and white women. Therefore, there may be selection bias in this study, and the results may not be generalizable to all midlife women. Finally, most of the data collected in this study, including the data on hot flashes, were based on self-report and not on objective measurements. We elected to use self-reported occurrence of hot flashes rather than a physiologic assessment of their occurrence primarily because physiological measurement of hot flashes is technically difficult and has not been validated in large populations. Most population-based studies have used self-report as a valid measure of hot flashes,2, 8 and the National Institutes of Health accept self-report as a valid indicator of hot flashes.55
A major strength of this study was the collection of detailed data on hot flashes, pertaining to both the present and past experiencing of any, more severe, and more frequent, hot flashes. Few studies examining risk factors of hot flashes have collected such detailed data; most have relied on a single hot flash question or have focused on the hot flash experience within a brief time period (i.e. the previous four weeks). A second strength was the collection of multiple blood samples over a four week period for each participant. The hormone concentrations for these samples were averaged for each participant and analyzed, reducing variability due to the time in menstrual cycle of the clinic visit.
CONCLUSIONS
This study shows that older age, peri-menopausal status, cigarette smoking, and depressive symptoms are factors associated with a statistically significant increased risk of the experiencing of any, current, more severe, and more frequent hot flashes among midlife women. Conversely, greater alcohol intake and higher estradiol and progesterone concentrations are associated with a decreased risk of hot flashes. Although the temporality of such associations are not known due to the cross-sectional nature of the data, these observed relationships can help to identify women at risk for menopausal hot flashes and can provide intervention strategies (e.g. quitting cigarette smoking) to reduce risk. As the Midlife Women's Health Study cohort continues to be followed, future analyses from this study will examine the factors investigated in this study, including hormone concentrations, and their relation to hot flashes over the menopausal transition.
Table 4.
Age- and covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the associations between demographic characteristics, health habits, reproductive factors, and hormones, with more severe hot flashes or more frequent hot flashes
| Moderate or severe hot flashes |
Weekly or daily hot flashes |
|||
|---|---|---|---|---|
| Age-adjusted OR (95% CI) | Covariate-adjusteda OR (95% CI) | Age-adjusted OR (95% CI) | Covariate-adjusteda OR (95% CI) | |
| Age, years | ||||
| 45 to 49 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 50 to 54 | 3.07 (2.16, 4.36) | 1.81 (1.19, 2.76) | 3.62 (2.47, 5.30) | 1.61 (0.99, 2.62) |
| Education | ||||
| Some college or tech school or less | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Graduated college or more | 0.55 (0.38, 0.78) | 0.73 (0.48, 1.12) | 0.54 (0.37, 0.81) | 0.75 (0.46, 1.24) |
| Race | ||||
| White | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Black | 1.41 (0.97, 2.06) | 0.94 (0.58, 1.53) | 1.49 (0.99, 2.26) | 0.90 (0.51, 1.61) |
| Other | 1.28 (0.55, 2.99) | 1.39 (0.55, 3.55) | 1.10 (0.42, 2.88) | 1.58 (0.52, 4.82) |
| Employed | ||||
| Yes | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| No | 0.83 (0.55, 1.25) | 1.27 (0.78, 2.09) | 0.79 (0.51, 1.25) | 1.30 (0.74, 2.30) |
| Body mass index (kg/m2) | ||||
| <25 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 25 to <30 | 1.07 (0.69, 1.64) | 0.77 (0.47, 1.27) | 1.24 (0.78, 1.98) | 0.89 (0.50, 1.59) |
| ≥30 | 1.39 (0.93, 2.09) | 0.95 (0.58, 1.55) | 1.20 (0.76, 1.90) | 0.84 (0.47, 1.52) |
| Cigarette smoking | ||||
| Never | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Former | 1.91 (1.32, 2.78) | 2.12 (1.39, 3.22) | 1.51 (1.00, 2.29) | 1.78 (1.08, 2.92) |
| Current | 3.59 (2.03, 6.34) | 3.51 (1.82, 6.76) | 3.19 (1.72, 5.93) | 3.44 (1.60, 7.43) |
| Alcohol use in past year | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes, 1 drink or less per day | 0.67 (0.43, 1.05) | 0.73 (0.44, 1.21) | 0.72 (0.44, 1.17) | 0.75 (0.41, 1.37) |
| Yes, more than 1 drink per day | 0.71 (0.47, 1.06) | 0.58 (0.37, 0.94) | 0.80 (0.51, 1.24) | 0.66 (0.38, 1.15) |
| Leisure time activity compared to others of own age | ||||
| As much | 0.95 (0.62, 1.45) | 0.98 (0.60, 1.60) | 0.68 (0.43, 1.09) | 0.67 (0.37, 1.19) |
| More | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Less | 1.24 (0.81, 1.90) | 1.10 (0.69, 1.78) | 0.92 (0.58, 1.46) | 0.83 (0.48, 1.43) |
| Age at menarche | ||||
| <10 years | 1.69 (0.83, 3.44) | 1.08 (0.47, 2.51) | 1.60 (0.71, 3.61) | 0.92 (0.34, 2.49) |
| 11 or 12 years | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 13 or 14 years | 1.12 (0.76, 1.64) | 1.01 (0.66, 1.57) | 1.04 (0.68, 1.60) | 0.89 (0.53, 1.50) |
| ≥15 | 0.82 (0.47, 1.46) | 0.91 (0.48, 1.74) | 1.07 (0.59, 1.92) | 1.03 (0.60, 2.14) |
| Menopausal status | ||||
| Premenopausal | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Perimenopausal | 6.27 (4.21, 9.35) | 5.78 (3.80, 8.78) | 12.54 (7.90, 19.93) | 12.42 (7.64, 20.19) |
| History of oral contraceptive use | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.47 (0.90, 2.41) | 1.74 (0.99, 3.07) | 1.32 (0.77, 2.27) | 1.73 (0.90, 3.29) |
| Ever been pregnant | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.16 (0.66, 2.02) | 1.01 (0.54, 1.88) | 1.32 (0.69, 2.51) | 1.19 (0.56, 2.55) |
| Number of pregnancies | ||||
| Never been pregnant | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 1 or 2 | 0.95 (0.52, 1.76) | 0.89 (0.45, 1.77) | 1.08 (0.54, 2.20) | 1.15 (0.50, 2.63) |
| 3 or 4 | 1.41 (0.77, 2.54) | 1.27 (0.66, 2.46) | 1.40 (0.71, 2.77) | 1.31 (0.59, 2.95) |
| ≥5 | 0.99 (0.50, 1.95) | 0.62 (0.28, 1.37) | 1.59 (0.76, 3.34) | 1.03 (0.42, 2.51) |
| Age at first birth | ||||
| No live births | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| ≤20 years | 1.86 (1.01, 3.41) | 1.25 (0.60, 2.63) | 2.03 (1.04, 3.99) | 1.25 (0.51, 3.06) |
| 21 to 25 years | 1.29 (0.76, 2.20) | 1.27 (0.70, 2.32) | 1.27 (0.69, 2.32) | 1.35 (0.65, 2.81) |
| 26 to 30 years | 1.18 (0.69, 2.01) | 1.23 (0.68, 2.24) | 1.37 (0.75, 2.47) | 1.46 (0.72, 2.93) |
| ≥30 years | 0.85 (0.50, 1.45) | 1.06 (0.59, 1.92) | 1.01 (0.56, 1.83) | 1.25 (0.63, 2.50) |
| Depressive symptoms | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 2.39 (1.57, 3.64) | 1.78 (1.11, 2.86) | 2.34 (1.41, 3.54) | 1.82 (1.04, 3.17) |
| Diabetes medication | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 2.56 (1.13, 5.79) | 1.69 (0.66, 4.36) | 1.78 (0.66, 4.78) | 0.91 (0.28, 3.00) |
| Anti-hypertensive medication | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.75 (1.10, 2.79) | 1.47 (0.84, 2.55) | 1.49 (0.88, 2.52) | 1.36 (0.70, 2.67) |
| Depression medication | ||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| Yes | 1.44 (0.86, 2.40) | 1.19 (0.66, 2.17) | 1.28 (0.72, 2.29) | 1.06 (0.52, 2.15) |
| Estradiol, pg/mL (continuous) | 0.41 (0.31, 0.55) | 0.63 (0.46, 0.87) | 0.35 (0.25, 0.78) | 0.62 (0.43, 0.89) |
| Testosterone, ng/mL (continuous) | 0.93 (0.72, 1.20) | 0.98 (0.73, 1.32) | 0.87 (0.66, 1.16) | 0.93 (0.66, 1.32) |
| Progesterone, ng/mL (continuous) | 0.61 (0.53, 0.70) | 0.78 (0.66, 0.92) | 0.51 (0.43, 0.60) | 0.69 (0.57, 0.84) |
| Ovarian volume, cm3 (continuous) | 0.73 (0.55, 0.97) | 0.98 (0.72, 1.35) | 0.66 (0.47, 0.90) | 0.95 (0.66, 1.37) |
95% CI = 95% confidence interval; OR = odds ratio
covariates included in all multivariable models are: participant age, race, education, body mass index, smoking, alcohol consumption, and menopausal status
Acknowledgments
Source of funding: Supported by the National Institute on Aging (RO1 AG18400).
Footnotes
The authors report no conflict of interest.
REFERENCES
- 1.Freeman EW, Sherif K. Prevalence of hot flushes and night sweats around the world: a systematic review. Climacteric. 2007;10:197–214. doi: 10.1080/13697130601181486. [DOI] [PubMed] [Google Scholar]
- 2.Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2011;117:1095–1104. doi: 10.1097/AOG.0b013e318214f0de. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ayers B, Hunter MS. Health-related quality of life of women with menopausal hot flushes and night sweats. Climacteric. 2013;16:235–239. doi: 10.3109/13697137.2012.688078. [DOI] [PubMed] [Google Scholar]
- 4.Whiteley J, DiBonaventura M, Wagner JS, Alvir J, Shah S. The impact of menopausal symptoms on quality of life, productivity, and economic outcomes. J Womens Health (Larchmt) 2013;22:983–990. doi: 10.1089/jwh.2012.3719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA. Hot flashes and subclinical cardiovascular disease: findings from the Study of Women's Health Across the Nation Heart Study. Circulation. 2008;118:1234–1240. doi: 10.1161/CIRCULATIONAHA.108.776823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Seritan AL, Iosif AM, Park JH, DeatherageHand D, Sweet RL, Gold EB. Self-reported anxiety, depressive, and vasomotor symptoms: a study of perimenopausal women presenting to a specialized midlife assessment center. Menopause. 2010;17:410–415. doi: 10.1097/gme.0b013e3181bf5a62. [DOI] [PubMed] [Google Scholar]
- 7.Whiteman MK, Staropoli CA, Langenberg P, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol. 2003;101:264–272. doi: 10.1016/s0029-7844(02)02593-0. [DOI] [PubMed] [Google Scholar]
- 8.Gallicchio L, Miller SR, Visvanathan K, et al. Cigarette smoking, estrogen levels, and hot flashes in midlife women. Maturitas. 2006;53:133–143. doi: 10.1016/j.maturitas.2005.03.007. [DOI] [PubMed] [Google Scholar]
- 9.Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation. Am J Public Health. 2006;96:1226–1235. doi: 10.2105/AJPH.2005.066936. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Gallicchio L, Visvanathan K, Miller SR, et al. Body mass, estrogen levels, and hot flashes in midlife women. Am J Obstet Gynecol. 2005;193:1353–1360. doi: 10.1016/j.ajog.2005.04.001. [DOI] [PubMed] [Google Scholar]
- 11.Thurston RC, Sowers MR, Sutton-Tyrrell K, et al. Abdominal adiposity and hot flashes among midlife women. Menopause. 2008;15:429–434. doi: 10.1097/gme.0b013e31815879cf. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Duffy OK, Iversen L, Hannaford PC. Factors associated with reporting classic menopausal symptoms differ. Climacteric. 2013;16:240–251. doi: 10.3109/13697137.2012.697227. [DOI] [PubMed] [Google Scholar]
- 13.Herber-Gast GC, Mishra GD, van der Schouw YT, Brown WJ, Dobson AJ. Risk factors for night sweats and hot flushes in midlife: results from a prospective cohort study. Menopause. 2013;20:953–959. doi: 10.1097/GME.0b013e3182844a7c. [DOI] [PubMed] [Google Scholar]
- 14.Moilanen J, Aalto AM, Hemminki E, Aro AR, Raitanen J, Luoto R. Prevalence of menopause symptoms and their association with lifestyle among Finnish middle-aged women. Maturitas. 2010;67:368–374. doi: 10.1016/j.maturitas.2010.08.007. [DOI] [PubMed] [Google Scholar]
- 15.Gallicchio L, Miller SR, Kiefer J, Greene T, Zacur HA, Flaws JA. Change in body mass index, weight, and hot flashes: a longitudinal analysis from the midlife women's health study. J Womens Health (Larchmt) 2014;23:231–237. doi: 10.1089/jwh.2013.4526. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ziv-Gal A, Flaws JA. Factors that may influence the experience of hot flushes by healthy middle-aged women. J Womens Health (Larchmt) 2010;19:1905–1914. doi: 10.1089/jwh.2009.1852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;3:385–401. [Google Scholar]
- 18.Schilling C, Gallicchio L, Miller SR, Langenberg P, Zacur H, Flaws JA. Relation of body mass and sex steroid hormone levels to hot flashes in a sample of midlife women. Climacteric. 2007;10:27–37. doi: 10.1080/13697130601164755. [DOI] [PubMed] [Google Scholar]
- 19.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;189:1646–1653. doi: 10.1016/s0002-9378(03)00872-x. [DOI] [PubMed] [Google Scholar]
- 20.MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary estrogens. N Engl J Med. 1982;307:1062–1065. doi: 10.1056/NEJM198210213071707. [DOI] [PubMed] [Google Scholar]
- 21.Cochran CJ, Gallicchio L, Miller SR, Zacur H, Flaws JA. Cigarette smoking, androgen levels, and hot flushes in midlife women. Obstet Gynecol. 2008;112:1037–1044. doi: 10.1097/AOG.0b013e318189a8e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Butts SF, Freeman EW, Sammel MD, Queen K, Lin H, Rebbeck TR. Joint effects of smoking and gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women. J Clin Endocrinol Metab. 2012;97:E1032–E1042. doi: 10.1210/jc.2011-2216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Sievert LL, Obermeyer CM, Price K. Determinants of hot flashes and night sweats. Ann Hum Biol. 2006;33:4–16. doi: 10.1080/03014460500421338. [DOI] [PubMed] [Google Scholar]
- 24.Duche L, Ringa V, Melchior M, et al. Hot flushes, common symptoms, and social relations among middle-aged nonmenopausal French women in the GAZEL cohort. Menopause. 2006;13:592–599. doi: 10.1097/01.gme.0000227329.41458.86. [DOI] [PubMed] [Google Scholar]
- 25.Schilling C, Gallicchio L, Miller SR, Langenberg P, Zacur H, Flaws JA. Current alcohol use, hormone levels, and hot flashes in midlife women. Fertil Steril. 2007;87:1486–1486. doi: 10.1016/j.fertnstert.2006.11.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hyde RE, 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;19:740–746. doi: 10.1007/s11606-004-0002-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Gill J. The effects of moderate alcohol consumption on female hormone levels and reproductive function. Alcohol Alcohol. 2000;35:417–423. doi: 10.1093/alcalc/35.5.417. [DOI] [PubMed] [Google Scholar]
- 28.Onland-Moret NC, Peeters PH, van der Schouw YT, Grobbee DE, van Gils CH. Alcohol and endogenous sex steroid levels in postmenopausal women: a cross-sectional study. J Clin Endocrinol Metab. 2005;90:1414–1419. doi: 10.1210/jc.2004-0614. [DOI] [PubMed] [Google Scholar]
- 29.Bhavnani BR, Cecutti A, Gerulath A, Woolever AC, Berco M. Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women. Menopause. 2001;8:408–419. doi: 10.1097/00042192-200111000-00005. [DOI] [PubMed] [Google Scholar]
- 30.Leal M, Diaz J, Serrano E, Abellan J, Carbonell LF. Hormone replacement therapy for oxidative stress in postmenopausal women with hot flushes. Obstet Gynecol. 2000;95:804–809. doi: 10.1016/s0029-7844(00)00822-x. [DOI] [PubMed] [Google Scholar]
- 31.Worsley R, Bell R, Kulkarni J, Davis SR. The association between vasomotor symptoms and depression during perimenopause: a systematic review. Maturitas. 2014;77:111–117. doi: 10.1016/j.maturitas.2013.11.007. [DOI] [PubMed] [Google Scholar]
- 32.Swartzman LC, Edelberg R, Kemmann E. Impact of stress on objectively recorded menopausal hot flushes and on flush report bias. Health Psychol. 1990;9:529–545. doi: 10.1037//0278-6133.9.5.529. [DOI] [PubMed] [Google Scholar]
- 33.Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. J Clin Oncol. 1999;16:495–500. doi: 10.1016/s0002-9378(99)70437-0. [DOI] [PubMed] [Google Scholar]
- 34.Nakano K, Pinnow E, Flaws JA, Sorkin JD, Gallicchio L. Reproductive history and hot flashes in perimenopausal women. J Womens Health (Larchmt) 2012;21:433–439. doi: 10.1089/jwh.2011.2999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Sabia S, Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. Risk factors for onset of menopausal symptoms: results from a large cohort study. Maturitas. 2008;60:108–121. doi: 10.1016/j.maturitas.2008.04.004. [DOI] [PubMed] [Google Scholar]
- 36.Freeman EE, Munoz B, Schein OD, West SK. Hormone replacement therapy and lens opacities: the Salisbury Eye Evaluation project. Arch Ophthalmol. 2001;119:1687–1692. doi: 10.1001/archopht.119.11.1687. [DOI] [PubMed] [Google Scholar]
- 37.Ford K, Sowers M, Crutchfield M, Wilson A, Jannausch M. A longitudinal study of the predictors of prevalence and severity of symptoms commonly associated with menopause. Menopause. 2005;12:308–317. doi: 10.1097/01.gme.0000163869.89878.d9. [DOI] [PubMed] [Google Scholar]
- 38.Schwingl PJ, Hulka BS, Harlow SD. Risk factors for menopausal hot flashes. Obstet Gynecol. 1994;84:29–34. [PubMed] [Google Scholar]
- 39.Sherman BM, Wallace RB, Bean JA, Chang Y, Schlabaugh L. The relationship of menopausal hot flushes to medical and reproductive experience. J Gerontol. 1981;36:306–309. doi: 10.1093/geronj/36.3.306. [DOI] [PubMed] [Google Scholar]
- 40.Staropoli CA, Flaws JA, Bush TL, Moulton AW. Predictors of menopausal hot flashes. J Womens Health. 1998;7:1149–1155. doi: 10.1089/jwh.1998.7.1149. [DOI] [PubMed] [Google Scholar]
- 41.Nagata C, Takatsuka N, Kawakami N, Shimizu H. Soy product intake and hot flashes in Japanese women: results from a community-based prospective study. Am J Epidemiol. 2001;153:790–793. doi: 10.1093/aje/153.8.790. [DOI] [PubMed] [Google Scholar]
- 42.Gold EB, Sternfeld B, Kelsey JL, et al. Relation to demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol. 2000;152:463–473. doi: 10.1093/aje/152.5.463. [DOI] [PubMed] [Google Scholar]
- 43.Freeman EW, Sammel MD, Lin H, et al. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol. 2007;110:230–240. doi: 10.1097/01.AOG.0000270153.59102.40. [DOI] [PubMed] [Google Scholar]
- 44.Dennerstein L, Lehert P, Guthrie JR, Burger HG. Modeling women's health during the menopausal transition: a longitudinal analysis. Menopause. 2007;14:53–62. doi: 10.1097/01.gme.0000229574.67376.ba. [DOI] [PubMed] [Google Scholar]
- 45.Sturdee DW. The menopausal hot flush--anything new? Maturitas. 2008;60:42–49. doi: 10.1016/j.maturitas.2008.02.006. [DOI] [PubMed] [Google Scholar]
- 46.Dennerstein L, Lehert P, Burger HG, Guthrie JR. New findings from non-linear longitudinal modelling of menopausal hormone changes. Hum Reprod Update. 2007;13:551–557. doi: 10.1093/humupd/dmm022. [DOI] [PubMed] [Google Scholar]
- 47.Schilling C, Gallicchio L, Miller SR, Langenberg P, Zacur H, Flaws JA. Genetic polymorphisms, hormone levels, and hot flashes in midlife women. Maturitas. 2007;57:120–131. doi: 10.1016/j.maturitas.2006.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Fentiman IS, Allen D, Wheeler M, Rymer J. The influence of premenopausal hormones on severity of climacteric symptoms and use of HRT. Climacteric. 2006;9:135–145. doi: 10.1080/13697130600674184. [DOI] [PubMed] [Google Scholar]
- 49.Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause. 2014;21:924–932. doi: 10.1097/GME.0000000000000196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47. doi: 10.1186/1477-7525-3-47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Prior JC, Hitchcock CL. Progesterone for hot flush and night sweat treatment--effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. Gynecol Endocrinol. 2012;28:7–11. doi: 10.3109/09513590.2012.705390. [DOI] [PubMed] [Google Scholar]
- 52.Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms--a placebo-controlled randomized trial in healthy postmenopausal women. Menopause. 2012;19:886–893. doi: 10.1097/gme.0b013e318247f07a. [DOI] [PubMed] [Google Scholar]
- 53.Ruiz AD, Daniels KR. The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: an observational cohort study. Int J Pharm Compd. 2014;18:70–77. [PubMed] [Google Scholar]
- 54.Berendsen HH. The role of serotonin in hot flushes. Maturitas. 2000;36:155–164. doi: 10.1016/s0378-5122(00)00151-1. [DOI] [PubMed] [Google Scholar]
- 55.National Institutes of Health Assessing and improving methods for hot flashes. Summary of an NIH Workshop. 2004 Jan 20;:2–54. [Google Scholar]