Jennifer H. Madans

Smoking Cessation and Severity of Weight Gain in a National Cohort

BACKGROUND Many believe that the prospect of weight gain discourages smokers from quitting. Accurate estimates of the weight gain related to the cessation of smoking in the general population are not available, however. METHODS We related changes in body weight to changes in smoking status in adults 25 to 74 years of age who were weighed in the First National Health and Nutrition Examination Survey (NHANES I, 1971 to 1975) and then weighed a second time in the NHANES I Epidemiologic Follow-up Study (1982 to 1984). The cohort included continuing smokers (748 men and 1137 women) and those who had quit smoking for a year or more (409 men and 359 women). RESULTS The mean weight gain attributable to the cessation of smoking, as adjusted for age, race, level of education, alcohol use, illnesses related to change in weight, base-line weight, and physical activity, was 2.8 kg in men and 3.8 kg in women. Major weight gain (greater than 13 kg) occurred in 9.8 percent of the men and 13.4 percent of the women who quit smoking. The relative risk of major weight gain in those who quit smoking (as compared with those who continued to smoke) was 8.1 (95 percent confidence interval, 4.4 to 14.9) in men and 5.8 (95 percent confidence interval, 3.7 to 9.1) in women, and it remained high regardless of the duration of cessation. For both sexes, blacks, people under the age of 55, and people who smoked 15 cigarettes or more per day were at higher risk of major weight gain after quitting smoking. Although at base line the smokers weighed less than those who had never smoked, they weighed nearly the same at follow-up. CONCLUSIONS Major weight gain is strongly related to smoking cessation, but it occurs in only a minority of those who stop smoking. Weight gain is not likely to negate the health benefits of smoking cessation, but its cosmetic effects may interfere with attempts to quit. Effective methods of weight control are therefore needed for smokers trying to quit.

Anthropometric indicators and hip fracture. The NHANES I epidemiologic follow-up study.

A cohort of 3,595 white women aged 40–77 years was followed for an average of 10 years during which 84 new cases of hip fracture were identified. Triceps skinfold thickness and arm muscle area measured at baseline were examined as possible risk factors for hip fracture controlling for physical activity, height, menopausal status, calcium consumption, and smoking. Of these variables only arm muscle area, triceps skinfold thickness, and activity in recreation were independent predictors of hip fracture incidence using the Cox proportional hazards model. After adjustment, the estimated relative risk of hip fracture was approximately two for an increment of each anthropometric indicator (adjusted for the other) equivalent to comparing those at the 25th percentile to those at the 75th percentile (maximum width of 95% confidence intervals, 1.2–2.9). Risk of hip fracture was approximately two‐fold for persons who reported little recreational exercise compared to persons who reported much recreational exercise (95% confidence interval, 1.2–3.2).

Reduction of cardiovascular disease—related mortality among postmenopausal women who use hormones: Evidence from a national cohort

A national sample of 1944 white menopausal women greater than or equal to 55 years old from the epidemiologic follow-up of participants in the National Health and Nutrition Examination Survey was reviewed to investigate the role of hormone therapy in altering the risk of death from cardiovascular disease. Women in the study were observed for up to 16 years after the baseline survey in 1971 to 1975. By 1987 631 women had died; 347 of these deaths were due to cardiovascular disease. History of diabetes (relative risk, 2.38; 95% confidence interval 1.73 to 3.26), previous myocardial infarction (relative risk, 2.12; 95% confidence interval 1.56 to 2.86), smoking (relative risk, 2.18; 95% confidence interval, 1.69 to 2.81), and elevated blood pressure (relative risk, 1.49; 95% confidence interval, 1.14 to 1.94) were strong predictors of cardiovascular disease-related death in this cohort. After adjusting for known cardiovascular disease risk factors (smoking, cholesterol, body mass index, blood pressure, previous myocardial infarction, history of diabetes, age) and education, the use of postmenopausal hormones was associated with a reduced risk of death from cardiovascular disease (relative risk, 0.66; 95% confidence interval, 0.48 to 0.90). The same protective effect provided by postmenopausal hormone therapy was seen in women who experienced natural menopause (relative risk, 0.69; 95% confidence interval, 0.45 to 1.06).

Measuring disability and monitoring the UN Convention on the Rights of Persons with Disabilities: the work of the Washington Group on Disability Statistics.

The Washington Group on Disability Statistics is a voluntary working group made up of representatives of over 100 National Statistical Offices and international, non-governmental and disability organizations that was organized under the aegis of the United Nations Statistical Division. The purpose of the Washington Group is to deal with the challenge of disability definition and measurement in a way that is culturally neutral and reasonably standardized among the UN member states. The work, which began in 2001, took on added importance with the passage and ratification of the UN Convention on the Rights of Persons with Disabilities since the Convention includes a provision for monitoring whether those with and without disabilities have equal opportunities to participate in society and this will require the identification of persons with disabilities in each nation. The International Classification of Functioning, Disability and Health (ICF) developed by the World Health Organization provided a framework for conceptualizing disability. Operationalizing an ICF-based approach to disability has required the development of new measurement tools for use in both censuses and surveys. To date, a short set of six disability-related questions suitable for use in national censuses has been developed and adopted by the Washington Group and incorporated by the United Nations in their Principles and Recommendations for Population and Housing Censuses. A series of extended sets of questions is currently under development and some of the sets have been tested in several countries. The assistance of many National and International organizations has allowed for cognitive and field testing of the disability questionnaires in multiple languages and locations. This paper will describe the work of the Washington Group and explicate the applicability of its approach and the questions developed for monitoring the UN Convention on the Rights of Persons with Disabilities.

Cohort study of effect of being overweight and change in weight on risk of coronary heart disease in old age.

Abstract Objective: To evaluate risk of late life coronary heart disease associated with being overweight in late middle or old age and to assess whether weight change modifies this risk. Design: Longitudinal study of subjects in the epidemiological follow up study of the national health and nutrition examination survey I. Setting: United States. Subjects: 621 men and 960 women free of coronary heart disease in 1982-84 (mean age 77 years). Main outcome measure: Incidence of coronary heart disease. Results: Body mass index of 27 or more in late middle age was associated with increased risk of coronary heart disease in late life (relative risk=1.7 (95% confidence interval 1.3 to 2.1)) while body mass index of 27 or more in old age was not (1.1 (0.8 to 1.5)). This difference in risk was due largely to weight loss between middle and old age. Exclusion of those with weight loss of 10% or more increased risk associated with heavier weight in old age (1.4 (1.0 to 1.9)). Thinner older people who lost weight and heavier people who had gained weight showed increased risk of coronary heart disease compared with thinner people with stable weight. Conclusions: Heavier weight in late middle age was a risk factor for coronary heart disease in late life. Heavier weight in old age was associated with an increased risk once those with substantial weight loss were excluded. The contribution of weight to risk of coronary heart disease in older people may be underestimated if weight history is neglected. Key messages Little is known about the effects of being overweight (defined as a body mass index of ≥27) in old age on risk of heart disease In this study older people who were overweight had an increased risk of coronary heart disease once weight history was accounted for Weight history, particularly in late middle age, is important in assessing risk of coronary disease in older people Older heavier people who gained more than 10% of midlife body weight or thinner older people who had lost 10% or more of body weight show high risk compared with thinner people with stable weight

Coronary Heart Disease Incidence and Survival in African-American Women and Men: The NHANES I Epidemiologic Follow-up Study

Since a series of reviews and symposia in the early 1980s stimulated interest in and funding for studies of the clinical epidemiology of coronary heart disease in African-American persons [1-3], a considerable amount of new knowledge about the subject has accumulated. Many erroneous or outdated clinical concepts (for example, that coronary heart disease is rare or uncommon in African-American persons) have been put to rest [4-8]. In contrast to the many reports on white populations from the Framingham Study and other studies, the number of reports on the incidence of coronary heart disease from prospective, longitudinal studies of population-based cohorts of African-American women and men remains small [9]. Compared with white persons, African-American persons have higher rates of death from coronary heart disease at younger ages and lower rates after middle age; this makes examination of incidence data within age groups very important [1-5]. Such data are almost completely lacking, however, and several questions of vital importance to clinicians therefore remain incompletely answered. We analyzed data from a national cohort that was followed for 22 years to test the following hypotheses: 1) The incidence of first myocardial infarction or coronary heart disease or the rate of death from coronary heart disease in African-American persons differs from that in white persons, 2) these differences cannot be completely explained by standard risk factors for coronary heart disease and socioeconomic status, 3) survival after the first hospitalization for coronary heart disease among African-American persons differs from that among white persons, and 4) the incidence of coronary procedures done during or after hospitalization for coronary heart disease among African-American persons differs from that among white persons. Methods The first National Health and Nutrition Examination Survey (NHANES I) collected data from 1971 to 1975 on a nationwide probability sample of the civilian noninstitutionalized population of the United States (excluding Alaska, Hawaii, and reservation lands of American Indians) aged 1 to 74 years [10, 11]. Details of the plan, sample design, response rates, and the manner in which the study was conducted are published elsewhere, as are the procedures used to obtain informed consent and maintain confidentiality [10, 11]. Elderly persons, women of childbearing age, and persons residing in poverty areas were oversampled. The NHANES I Epidemiologic Follow-up Study is a longitudinal study of participants in NHANES I who were 25 to 74 years of age when the survey was conducted [12-17]. The personal interviews and physical and laboratory examinations of NHANES I provided the baseline data for the Follow-up Study. This analysis is based on four waves of follow-up data collection done in 1982 to 1984, 1986, 1987, and 1992. Information was obtained from an interview, medical records from health care facilities for the period between baseline and last follow-up interview, and death certificates for all decedents. A study that used both Medicare data and data from the follow-up study found that the follow-up study detected 80% of the hospital stays for coronary heart disease that were detected by either source [17]. This analysis included African-American and white persons who were 25 to 74 years of age at baseline for NHANES I. Of the 14 183 persons who were in this age group at baseline, 775 (5.5%) were lost to follow-up because they or their proxy was not interviewed during any follow-up wave or because no death certificate was available. Excluded from all analyses were 983 persons with unknown baseline history of heart disease, systolic blood pressure, serum cholesterol level, smoking status, family income, or level of education. Also excluded from analyses of coronary heart disease were 1019 persons who had a history of heart disease at baseline; these patients were defined as those who had ever been told by a physician that they had had a heart attack or heart failure or who had used any medicine, drugs, or pills for a weak heart during the 6 months before the baseline interview. After all exclusions, 11 406 persons examined at NHANES I survey locations 1 through 99 remained for analyses of coronary heart disease. The length of follow-up in the NHANES I Epidemiologic Follow-up Study for survivors who were free of coronary heart disease ranged from 8.0 to 22.1 years (median, 19.2 years). Incident cases of coronary heart disease met at least one of the following criteria: 1) the death certificate on which the underlying or primary cause of death was coded with ICD-9 [International Classification of Diseases, Ninth Revision] codes 410 through 414 or 2) there were one or more hospital stays during the follow-up period for which any discharge diagnosis was coded with ICD-9-CM (ICD-9, Clinical Modification) codes 410 to 414. An ICD-9-CM code of 410 served to identify incident cases of acute myocardial infarction that required hospitalization among the discharge diagnoses from the first recorded hospitalization in which coronary heart disease was the discharge diagnosis. Persons who were hospitalized for coronary heart disease that was not related to acute myocardial infarction were not considered to be at risk for subsequent incident cases of acute myocardial infarction requiring hospitalization. The date of occurrence was estimated as the date of first hospital admission with a diagnosis of coronary heart disease or the date of death for persons who died of coronary heart disease and whose hospital records did not list a diagnosis of coronary heart disease. For mortality analyses, cause of death was defined by the underlying cause of death: coronary heart disease with ICD-9 codes 410 to 414. Baseline Variables Blood samples were obtained, and frozen serum was sent to the Centers for Disease Control and Prevention for measurement of serum total cholesterol levels [10, 18]. The baseline questionnaire on medical history included questions about selected conditions and about medications used for these conditions during the preceding 6 months [10]. Ethnic group (race, designated black, white, and other) was determined by interviewer observation. A revised race variable was created during the 1982-1984 follow-up period to resolve discrepancies between the race observed by the NHANES I interviewer and the race reported by the respondent during the 1982-1984 follow-up period. Revised race codes were based on a case-by-case adjudication. At the beginning of the baseline physical examination, the physician measured the blood pressure with the examinee seated [10]. Information on smoking status was obtained at baseline for the subsample (approximately 50% of the whole) that underwent a more detailed baseline examination, as described elsewhere [10, 11]. For the remaining persons, information on smoking status at baseline was derived from responses to follow-up questions on lifetime smoking history or was imputed [19, 20]. The validity of this approach has been documented [19, 20]. Other baseline variables were measured as described elsewhere [10]. Statistical Analysis For the 25- to 54-, 55- to 64-, and 65- to 74-year-old age groups, approximate plots of cumulative probabilities of survival without coronary heart disease were based on Kaplan-Meier statistics calculated using the LIFETEST procedure in SAS software [21, 22]. Age-adjusted and risk-adjusted estimates of the risk for coronary heart disease in African-American persons relative to white persons were derived from Cox proportional-hazards regression models that were computed by using the PHREG procedure in SAS software [23, 24]. Separate analyses were done for groups categorized by age at baseline and sex. Results are shown for models that included age at baseline in single years and age plus other confounders, entered as continuous variables (systolic blood pressure, serum cholesterol level) or as indicator variables (history of current smoking, level of education < 12 years, family income <

Weight Loss and Subsequent Death in a Cohort of U.S. Adults

5000). Modification of the effect of ethnic group according to age or education was assessed in regression models and is reported only if the modification was significant. In the incidence analyses, duration of follow-up was calculated as the time from the date of examination to the date of coronary event or, for participants who did not have a coronary event, the date of last follow-up interview or death. For analyses of coronary disease-related mortality, participants whose underlying cause of death was a condition other than coronary heart disease were censored on their date of death; survivors were censored on the date of the last follow-up interview with the participant or proxy [24]. For analysis of survival after first diagnosis of coronary heart disease, 1858 persons who were hospitalized at least once and had a discharge diagnosis of coronary heart disease (ICD-9-CM codes 410 to 414) were followed from the date of the first recorded hospitalization for which the discharge diagnosis was coronary heart disease until death or the last follow-up contact. Duration of follow-up ranged from 0 days to 20.4 years (median, 4.2 years). Kaplan-Meier curves were examined and Cox proportional-hazards regression models were computed to obtain estimates of risk for death from all causes for African-American persons relative to white persons; these models controlled for age at first hospitalization for coronary heart disease and a discharge diagnosis of acute myocardial infarction at the first hospitalization for coronary heart disease. Separate models were run for men and women, for admission ages 25 to 64 years and 65 years and older, and for all admission ages combined. Survivors were censored on the date of the last follow-up interview with the participant or proxy. For analysis of coronary procedures, incidence rates per 1000 person-years were computed among persons who we

Weight loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: the NHANES I epidemiologic follow-up study.

To date, observational studies have provided conflicting evidence about the relation between weight loss and death [114]. Much of the difficulty in interpreting these findings results from the inability to distinguish directly voluntary weight loss from that produced by illness. The authors of these studies have tried to control for the effect of illness-associated weight loss by some combination of statistical techniques to adjust for preexisting illness within the study population; exclusion of persons with known illnesses; or exclusion of early deaththose occurring within the first 2 to 5 years after the assessment of weight change. Reservations remain, however, regarding the adequacy of these approaches. Persons with some types of illness may lose weight voluntarily and may be advised by their physician to do so. Also, exclusion of deaths occurring within a few years of baseline may not account for all weight loss due to occult illness. An additional problem is that most studies have not been able to control for the potentially confounding effect of cigarette smoking [15]. Previous Analysis of Weight Loss and Death In a recently published study [16], we examined the relation between weight loss and subsequent death among 2140 men and 2550 women between 45 to 74 years old who participated in the first National Health and Nutrition Examination Survey (NHANES I, 1971 to 1975). Weight loss was assessed as the difference between self-reported maximum lifetime weight and weight measured at baseline. Vital status was determined through 1987. Risk for death associated with relative weight loss (< 5%, 5% to 14%, 15% or more) was estimated for three strata of maximum body mass index (BMI; weight[kg]/height[m]2)less than 26, between 26 and 29, and 29 or more. We used Cox proportional-hazards models to adjust for age, race, parity (for women), cigarette smoking (never, former, or current), and maximum BMI as well as preexisting illnesses associated with weight loss (cancer, chronic bronchitis, or emphysema), preexisting illnesses associated with excess weight (heart attack, heart failure, stroke, hypertension, and diabetes), and diagnosis of both types of conditions. In addition, the analysis excluded persons who died in the first 5 years after the baseline examination. We found that, at maximum BMIs of 29 or more, weight losses of 5% to 14% appeared to be protective for men but not for women. Among men and women whose maximum BMI was less than 29, the risk for death increased with increasing weight loss; among participants who had been moderately overweight (maximum BMIs between 26 and 29), those who lost 15% or more had more than twice the mortality risk of those losing less than 5%. Additional Analyses This report used several more rigorous exclusionary criteria to test the consistency of these findings. We first examined the effect of excluding early death by estimating relative risks associated with weight loss for the full cohort (2453 men and 2739 women), and for persons surviving for 5 and 8 years after the baseline examination, respectively. Within each stratum of maximum BMI, adjusted risk estimates for death from all causes, cardiovascular disease (ICD 9 codes 401 to 459 and 798), and noncardiovascular disease (all other ICD 9 codes except those for external injury) [17] were calculated relative to persons who had lost less than 5% of their maximum weight. We compared these results with those obtained by limiting the analysis to persons with no preexisting medical conditions except for hypertension or diabetes. Because weight loss may have implications for the elderly that are different than those for younger persons [9, 10], we also estimated adjusted mortality risks for persons who were 45 to 64 years old at baseline. The variables for smoking status included in the model may not have allowed adequate adjustment for confounding. We repeated the analysis of all-cause mortality risk for persons who, at baseline, reported that they had never smoked. Results The mortality risks associated with weight loss in men are shown in Table 1. If loss from maximum weight were a marker for occult illness, we would expect the relative risk estimates associated with weight loss to be reduced after excluding persons who died within the first 5 years after baseline and perhaps to be reduced even further after excluding deaths occurring in the first 8 years. Among men in this study, however, extension of the exclusionary period did not produce this type of consistent effect on the relative risk estimates. Table 1. Relative Risk for Death among Men 45 to 74 Years Old at Baseline, by Maximum Body Mass Index and Percentage of Maximum Weight Lost* After excluding deaths occurring in the first 8 years after baseline, the risk for death from noncardiovascular disease increased with the amount of weight lost among men with maximum BMIs of less than 26. Among men whose maximum BMI was between 26 and 29, weight losses of 5% to 14% were associated with an increased risk for death from cardiovascular disease, and weight loss of 15% or more was associated with a more than twofold mortality risk for both cardiovascular and noncardiovascular diseases. For men whose maximum BMI was 29 or more, however, weight losses of 5% to 14% appeared to reduce the risk for death from cardiovascular disease by approximately 30%. The risk for death from cardiovascular disease was not reduced among men who lost 15% or more, and the risk for death from noncardiovascular disease appeared to be moderately increased; however, this result was not statistically significant. The results for women are shown in Table 2. The exclusion of early death had little effect on the risk for death from cardiovascular disease. After limiting the analysis to women who survived at least 8 years after baseline, we continued to find a strong, direct association between weight loss and risk for death from cardiovascular disease among women whose maximum BMI was less than 29. We found a moderate, but not statistically significant, association for those with a maximum BMI of 29 or more. Extension of the exclusionary period, however, reduced the association between weight loss and death from noncardiovascular disease for women in the lowest and highest strata of maximum BMI. Table 2. Relative Risk for Death among Women 45 to 74 Years Old at Baseline, by Maximum Body Mass Index and Percentage of Maximum Weight Lost* We repeated the analysis after excluding all persons with previously diagnosed medical conditions except for hypertension and diabetes and after excluding deaths that occurred within the first 5 years after baseline. For both sexes, the relative risk estimates were similar to those obtained by excluding persons who died within the first 8 years (data not shown). The estimated relative risks for persons 45 to 64 years old at baseline were either the same as or higher than those estimated for the entire group (data not shown). Figures 1 and 2 show the relative risks for death due to all causes for participants who had never smoked at baseline. Because fewer than one third of the men in the study cohort had never smoked, we preserved sample size by excluding only men who died in the first 5 years after baseline. The results are consistent with those in Table 1, although the relative risk is not significantly elevated for men with maximum BMIs between 26 and 29 who lost 5% to 14% of their maximum weight (see Figure 1). Relative risk estimates for women who never smoked excluded deaths that occurred within the first 8 years after baseline. Compared with the results in Table 2, the relative risk for death associated with weight loss was only slightly lower for women who never smoked and only if their maximum BMI was less than 29. Figure 1. Relative risk for death among men who never smoked, by maximum body mass index and percentage of maximum weight lost. Figure 2. Relative risk for death among women who never smoked, by maximum body mass index and percentage of maximum weight lost. Discussion Observational studies have produced inconsistent results regarding the association between weight loss and risk for death. These studies have differed substantially in design and definition of weight loss and have not directly assessed the reason for the weight loss. Studies that have found an elevated risk for death among persons who have lost weight have generally assumed the finding to result from involuntary weight loss associated with illness [5, 6, 810]. An adverse effect of weight loss has also been found, however, in studies that excluded participants with known medical conditions [11, 12, 14]. Because weight loss may disproportionately benefit persons with conditions such as coronary heart disease, hypertension, or diabetes, exclusion of these participants may have obscured a positive effect of weight loss on death. The exclusion of participants with known medical conditions may not fully control for the effect of illness-associated weight loss on the risk for death because some illnesses may not have been diagnosed. The procedure usually used to remove the effect of subclinical illness involves the exclusion of death occurring within 2 to 5 years after baseline [15]. We showed that, among women, extension of the exclusionary period consistently attenuated the adverse association between weight loss and risk for death from noncardiovascular disease. This effect was strongest for women in the lowest and highest strata of maximum BMI. For both sexes, the relative risk estimates for persons who survived for at least 8 years after baseline were similar to those estimated after exclusion of persons with diagnosed illnesses other than hypertension and diabetes in addition to exclusion of those who died in the first 5 years after baseline. It therefore seems plausible that this attenuation resulted from removal of the influence of illness-associated weight loss. We should also consider

Dietary calcium and hip fracture risk: The NHANES I Epidemiologic Follow-Up Study

Although weight loss increases bone loss and hip fracture risk in older women, little is known about the relation between weight loss in middle-aged women and subsequent hip fracture risk. The objective of this study was to determine the association between weight loss from reported maximum body weight in middle-aged and older women and the risk of hip fracture. Data were from a nationally representative sample of 2180 community-dwelling white women aged 50–74 years from the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey (NHEFS). In this prospective cohort study, incident hip fracture was ascertained during 22 years of follow-up. The adjusted relative risks associated with weight loss of 10% or more from maximum body weight were elevated for both middle-aged (RR 2.54; 95% CI 1.10–5.86) and older women (RR 2.04; 95% CI 1.37–3.04). For both ages combined, women in the lowest tertile of body mass index at maximum who lost 10% or more of weight had the highest risk of hip fracture (RR 2.37; 95% CI 1.32–4.27). Weight loss from maximum reported body weight in women aged 50–64 years and 65–74 years increased their risk of hip fracture, especially among those who were relatively thin. Weight loss of 10% or more from maximum weight among both middle-aged and older women is an important indicator of hip fracture risk.

Modification of the relationship between the Quetelet index and mortality by weight-loss history among older women

The effect of dietary calcium on hip fracture risk was examined prospectively using the NHANES I Epidemiologic Follow-Up Study cohort, which is derived from a nationally representative sample of the United States population. A cohort of 4342 white men and postmenopausal women ages 50–74 years at baseline (1971–1975) were observed through 1987 for up to 16 years of follow-up. Quantitative estimates of calcium intake were obtained at baseline from a 24-h recall, while weekly frequency of dairy food consumption was obtained from a qualitative food frequency. By 1987, 44 men and 122 women had experienced a hip fracture according to hospital records or death certificates. In the total sample of women the risk of hip fracture was only slightly lower for the highest quartile compared with the lowest. However, although not statistically significant, the age-adjusted risk of hip fracture was approximately 50% lower in the highest quartile of calcium intake compared with the lowest quartile in the subgroup of women who were at least 6 years postmenopausal and not taking postmenopausal hormone. The low relative risk observed among men, although interesting, must be interpreted cautiously due to small sample size. Adjusting for other risk factors did not appreciably change the results for either sex. The pattern of relative risks for calcium quartiles and by selected cutpoints was not consistent with a dose-response effect of calcium. Our results suggest that calcium may lower hip fracture risk in late menopausal women.