Age at natural menopause in Spain and the United States: results from the DAMES project.

Our research was undertaken to determine the median age of natural menopause and correlates of the timing of menopause in Spain and the United States (U.S.). A population-based sample of 300 women from Madrid, Spain and a random sample of 293 women from Fallon Community Health plan (FCHP), a health maintenance organization (HMO) in central Massachusetts, were interviewed using a semi-structured questionnaire. Logit analysis and logistic regression were used to estimate the median age at menopause and identify factors associated with it. The median age of natural menopause in Spain is estimated at 51.7 years, and in the U.S., it is 52.6 years. In Spain, women with any children (OR = 0.58, 95% CI: 0.25, 1.36) and a lower body mass index (BMI) (OR = 0.45, 95% CI: 0.27, 0.78) had later ages at menopause while current smokers (OR = 5.51, 95% CI: 1.82, 16.7) had earlier ages of menopause in a multivariate model. A multiplicative interaction between smoking status and parity was identified, and an interaction term included in the multivariate model (OR = 0.58, 95% CI: 0.35, 0.94). In the U.S., household income, marital status, and education level were statistically associated with age at natural menopause in bivariate models. These factors were no longer statistically significant after adjustments in a multivariate model. Oral contraceptive use, cycle length, and cycle regularity were not statistically associated with the age of menopause in either country. The ages of natural menopause in Spain and the U.S. are comparable to other industrialized nations. The factors associated with the timing of natural menopause, in particular smoking and BMI, are consistent with those identified in previous studies.     

Age at natural menopause in Beirut,Lebanon: the role of reproductive and lifestyle factors

Summary. Primary objective: To determine the median age of natural menopause and factors associated with the timing of menopause in Beirut, Lebanon. Research design: A population-based sample of 298 women were interviewed using a semistructured questionnaire. Methods and procedures: Logit analysis and logistic regression were used to estimate the median age and identify correlates of menopausal status. Main outcomes and results: The median age of natural menopause in Beirut, Lebanon is estimated to be 49.3 years. Not being currently married (odds ratio (OR)=4.19, 95% CI: 1.53, 11.51) and smoking (OR=1.02 for each year of smoking, 95% CI: 1.00, 1.05) are significantly associated with an earlier age at menopause. Women with menstrual bleeding longer than 5 days have later ages at menopause (OR=0.50, 95% CI: 0.26, 0.97). Age at menarche, parity, education and socio-economic status are not statistically associated with the age at menopause. Conclusions: The age at natural menopause in Lebanon is comparable to median ages reported for women in industrialized countries (49.3-51.4). Our results emphasize the role of smoking in determining an earlier age at menopause and indicate that reproductive characteristics affect the timing of menopause.     

Correlates of the age at natural menopause in Morocco

Primary objective : To determine the median age of natural menopause and factors associated with the timing of menopause in Morocco. Research design : A population-based sample of 299 women from Rabat, Morocco were interviewed using a semi-structured questionnaire. Methods and procedures : Logit analysis and logistic regression were used to estimate the median age and identify factors associated with the age at menopause. Main outcomes and results : The median age of natural menopause in Morocco is estimated to be 48.4 years (95% CI: 36.9, 70.3). Women who reported the onset of menstruation at age 11 or younger (OR = 2.84, 95% CI: 1.00, 8.10) had an earlier age at menopause than women who started menstruating at age 12 or older. Women who had ever used oral contraceptives were more likely to have a later age at menopause (OR = 0.55, 95% CI: 0.30, 1.00). The length of time a woman used oral contraceptives influenced the timing of the menopause in unadjusted models but after adjusting for the age at menarche the effect was no longer statistically significant. Marital status, parity, education level, and social class were not statistically associated with the age at menopause. Conclusions : The estimated age at natural menopause in Morocco is 1-3 years earlier than the median ages reported in industrialized countries and some developing countries. Factors that alter the frequency of ovulation or rate of follicular atresia appear to be important in determining the age at menopause.     

Correlates of the age at natural menopause in Morocco

PRIMARY OBJECTIVE: To determine the median age of natural menopause and factors associated with the timing of menopause in Morocco. RESEARCH DESIGN: A population-based sample of 299 women from Rabat, Morocco were interviewed using a semi-structured questionnaire. METHODS AND PROCEDURES: Logit analysis and logistic regression were used to estimate the median age and identify factors associated with the age at menopause. MAIN OUTCOMES AND RESULTS: The median age of natural menopause in Morocco is estimated to be 48.4 years (95% CI: 36.9, 70.3). Women who reported the onset of menstruation at age 11 or younger (OR = 2.84, 95% CI: 1.00, 8.10) had an earlier age at menopause than women who started menstruating at age 12 or older. Women who had ever used oral contraceptives were more likely to have a later age at menopause (OR = 0.55, 95% CI: 0.30, 1.00). The length of time a woman used oral contraceptives influenced the timing of the menopause in unadjusted models but after adjusting for the age at menarche the effect was no longer statistically significant. Marital status, parity, education level, and social class were not statistically associated with the age at menopause. CONCLUSIONS: The estimated age at natural menopause in Morocco is 1-3 years earlier than the median ages reported in industrialized countries and some developing countries. Factors that alter the frequency of ovulation or rate of follicular atresia appear to be important in determining the age at menopause.     

Age at natural menopause in Beirut, Lebanon: the role of reproductive and lifestyle factors

PRIMARY OBJECTIVE: To determine the median age of natural menopause and factors associated with the timing of menopause in Beirut, Lebanon. RESEARCH DESGIN: A population-based sample of 298 women were interviewed using a semi-structured questionnaire. METHODS AND PROCEDURES: Logit analysis and logistic regression were used to estimate the median age and identify correlates of menopausal status. MAIN OUTCOMES AND RESULTS: The median age of natural menopause in Beirut, Lebanon is estimated to be 49.3 years. Not being currently married (odds ratio (OR)=4.19, 95% CI: 1.53, 11.51) and smoking (OR = 1.02 for each year of smoking, 95% CI: 1.00, 1.05) are significantly associated with an earlier age at menopause. Women with menstrual bleeding longer than 5 days have later ages at menopause (OR = 0.50, 95% CI: 0.26, 0.97). Age at menarche, parity, education and socio-economic status are not statistically associated with the age at menopause. CONCLUSIONS: The age at natural menopause in Lebanon is comparable to median ages reported for women in industrialized countries (49.3-51.4). Our results emphasize the role of smoking in determining an earlier age at menopause and indicate that reproductive characteristics affect the timing of menopause.     

Are the effects of risk factors for timing of menopause modified by age? Results from a British birth cohort study

OBJECTIVES: This study investigated the influence of mother's age at menopause, early life and adult behavioral factors on the timing of menopause until age 57 years, and whether these effects vary according to the women's age at menopause. DESIGN: A nationally representative cohort of 1,583 British women born in March 1946 with prospective data across the life course. For factors that vary with age at menopause, analyses were stratified by age at menopause younger than 50 years or 50 years or older. RESULTS: Cox regression models indicated that for women with earlier menopause, those who were heaviest at 2 years had a 59% lower hazard ratio for menopause than those who were the lightest (hazard ratio [HR]=0.41, 95% CI: 0.16-1.01), whereas this figure was 35% lower (HR=0.65; 95% CI: 0.42-1.00) for the later menopause group. For women in the earlier group with parental divorce during childhood, the HR was 6.5 (95% CI: 2.021.3) times higher than that of other women. This rate decreased to 2.5 (95% CI: 1.5-4.2) for those with later menopause. In both groups, increasing mother's age at menopause was associated with decreasing HR (P<0.0001). For all women, being breast-fed (P=0.05), increasing cognitive ability (P=0.009), and increasing parity (P=0.001) delayed menopause. CONCLUSIONS: This study found that the impact of weight at 2 years, parental divorce during childhood, and mother's age at menopause varied according to the women's age at menopause. There was further evidence that being breast-fed, higher childhood cognitive ability, and increasing parity delayed menopause. These results suggest the interaction of genetic and environmental factors in determining age at menopause.     

Profile of menopausal women in west Anatolian rural region sample

OBJECTIVES: The aim of this study was to evaluate age at menopause, climacteric symptoms and related factors in women living in west Anatolian rural region of Turkey. METHOD: This study included 761 menopausal women living in three rural towns. Questionnaires regarding to 10 climacteric symptoms, menopausal status, sociodemographic characteristics, parity, breastfeeding, presence of chronic illness, direct sun exposure, smoking, caffeine use and hormone replacement therapy (HRT) were filled out by face-to-face interview. Logistic regression analysis was used to assess confounding factors on the age of menopause and menopausal status. RESULTS: Mean age at menopause was 44.38+/-5.30 years. Breastfeeding more than one year, low level of direct sun exposure and mother's early age at menopause were associated with early onset of menopause. The most prevalent climacteric symptoms were urine leakage, decreased libido, lack of energy and poor memory in post-menopausal and hot flushes in peri-menopausal women. Somatic and psychological symptoms were associated with hot flushes. HRT and osteoporosis treatment usage were higher in surgical menopause group. Osteoporosis and Type 2 Diabetes Mellitus (DT) were more common in natural menopause group. No association was found with onset of menopause and smoking, excess caffeine use, BMI, marital status and presence of chronic illness. Cardiovascular risk factors such as hypertension (HT), diabetes and obesity were common in post-menopausal women. CONCLUSION: Onset of menopause in Turkish women living in rural region is earlier on average women living in western or industrialized countries. Hot flushes in peri-menopausal, and urogenital, and psychological in post-menopausal women are the most prevalent symptoms. Primary care services in rural districts should focus on cardiovascular risks of menopausal women.     

Correlates of hormone replacement therapy use in Italian women, 1992-1996

OBJECTIVES: we analyzed the determinants of hormonal replacement therapy (HRT) use in Italy for the period 1992-1996, using data from a framework of case-control studies of colon and rectal neoplasm. METHODS: a total of 1574 women aged 45-74 years were considered. This group comprised women with acute, non neoplastic, non-hormone-related diseases admitted to a network of hospitals in six areas of Italy. RESULTS: a total of 146 women (8.5%) reported ever HRT use. The multivariate odds ratio (OR) of ever use was 1.6 (95% CI 1.0-2.6) for women with 12 years of education or more, compared with those with < 7 years. The frequency of use of HRT tended to decrease with increasing parity: the OR was 0.6 for women with four or more children as compared to nulliparae (chi2 trend 3.5, P = 0.06). Ever HRT users were more frequently smokers. HRT use was more frequent in women reporting surgical menopause (OR = 2.7) than those with natural menopause. Among post menopausal women, HRT use was related with early age at menopause (chi2 trend 4.6, P = 0.03). HRT use was more common among women reporting lower body mass index (BMI) both at interview and at age 30 years and the difference between current BMI and BMI at age 30 years, was not related with HRT use. CONCLUSIONS: women of higher socioeconomic status or education reported more frequent HRT use and nulliparae and smokers were also more likely to use HRT. Further HRT use was directly associated with early age at menopause and surgical menopause and inversely related with measures of body weight.     

The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy

Randomised clinical trials find no protection against development of ischaemic heart disease by use of Hormone Therapy (HT) after the age of 50 years. Observational studies suggest that early menopause is a risk factor for ischaemic heart disease. Yet, a clinical very relevant question is whether HT reduces this risk associated with early menopause. OBJECTIVE: To analyse whether early menopause based on various causes are independent risk factors for ischaemic heart disease, and to investigate whether the risks are modified by use of HT. METHODS: In a prospective cohort study questionnaires were mailed to Danish female nurses above 44 years of age in 1993. Information on menopause, use of HT and lifestyle was obtained. In total 19,898 (86%) nurses fulfilled the questionnaire, among them 10.533 were postmenopausal with definable menopausal age, free of previous ischaemic heart disease, stroke or cancer. Through individual linkage to national register incident cases of ischaemic heart disease were identified until end of 1998. RESULTS: Menopause below both age 40 and 45 was associated with an increased risk of ischaemic heart disease, seeming most pronounced for women who had an early ovariectomy but also among spontaneous menopausal women. Generally HT did not reduce the risk except for the early-ovariectomised women, where no increased risk of ischaemic heart disease for HT users was found. CONCLUSION: We found an increased risk of ischaemic heart disease associated with early removal of the ovaries that might be reduced with HT. The present study need confirmation from other studies but suggests that early ovariectomised women could benefit from HT.     

Gene variants in PPARD and PPARGC1A are associated with timing of natural menopause in the general Japanese population

Objectives

Timing of menopause affects postmenopausal health risks. The objective of this study was to evaluate the associations of the single nucleotide polymorphisms (SNPs) in peroxisome proliferator-activated receptor (PPAR)-related genes (PPARD, PPARG, and PPARGC1A) and environmental factors with timing of natural menopause among the general Japanese population.

Study design

We analyzed cross-sectional data from 1758 women aged 40–69 years who were enrolled in the baseline surveys of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study.

Main outcome measures

Associations of timing of natural menopause with its probable covariates and with target gene variants were evaluated by univariate and multivariate Cox proportional hazards models.

Results

Lower body mass index and later age at menarche were significantly associated with earlier natural menopause. Women with minor alleles at T-48444C in PPARD showed a significantly higher adjusted hazard ratio of 1.57 (95% confidence interval: 1.18–2.10) for earlier natural menopause. In contrast, women with minor alleles at Thr394Thr in PPARGC1A showed a significantly lower adjusted hazard ratio of 0.86 (0.76–0.97) for earlier natural menopause. These associations did not substantially alter when re-analyzed after excluding the subjects who self-reported a history of diabetes or the subjects whose age was more than 65 years.

Conclusions

Gene variants in PPARD and PPARGC1A might be associated with timing of natural menopause, probably through direct actions on the ovaries, among the general Japanese population.     

The timing of natural menopause in Poland and associated factors

OBJECTIVES: The outcome of interest was the assessment of age at natural menopause and the variables hypothesized as covariates of age at menopause were indicators of demographic and social status, characteristics of the reproductive history and lifestyle behaviour. METHODOLOGY: Seven thousand one hundred and eighty-three women from all social strata of non-clinical population, and aged between 35 and 65 years were investigated in cross-sectional survey across Poland in 2000-2004. The demographic, social, lifestyle behaviour and reproductive history aspects of the menopause-specific questionnaire were examined. The non-parametric Kaplan-Meier cumulative survivorship estimates were used to assess the timing of natural menopause. Univariate and multivariate Cox proportional hazards regression models were used to assess the association of age at natural menopause with factors of interest and to estimate relevant relative risk (the hazard ratio) for earlier age at menopause. RESULTS: The overall median age at natural menopause was 51.25 years; 25th percentile 49; 75th percentile 54 years. Temporal changes in age at menopause were not demonstrated in the sample (p=0.9 for differences among age cohorts). Univariate Cox models were first fitted to the age at natural menopause for all covariates singly. The findings revealed that marital status, living environment, employment, BMI, age at first live birth delivered by a woman, breastfeeding, physical activity, smoking amount, and consumption of alcohol were not associated with age at menopause (p>0.05). The multiple Cox model revealed that early menarche, short menstrual cycle length, smoking cigarettes, a low level of education, and a negative health perception were associated with younger age at menopause (p<0.01). Use of oral contraceptives and parity were associated with later menopause (p<0.01). CONCLUSION: The present study provides an estimate of median age at natural menopause in Poland that may be used as a measure of health for the growing number of Polish women whose survival is calculated at 30 years after menopause. This study has revealed that the pattern of relationship between age at menopause and the study factors reflects its population-specific character for its social and cultural backgrounds, socio-economic status, and social behaviours.     

Season of birth influences the timing of menopause

BACKGROUND: Seasons may influence prenatal growth and future fertility. This study investigated whether season and month of birth influenced the timing of menopause in a group of women attending three Italian menopause clinics. METHODS and RESULTS: Age at menopause of 2822 post-menopausal women (>12 months of amenorrhoea) was stratified by month and season of birth. Mean age at menopause was 49.42 years (SEM: 0.78 years). Menopause occurred earlier for women born in the spring (age 49.04+/-0.15 years) than in the autumn (49.97+/-0.14 years). The earliest menopause was found in women born in March (48.9+/-0.25 years) and the latest in women born in October (50.3+/-0.25 years). The effect of season of birth on age at menopause remained even when considering factors that in our analysis were capable of significantly interfering with the timing of menopause, such as age at menarche, body mass index, smoking habit, level of education and type of job. CONCLUSIONS: Taking into consideration the retrospective design of the study, and a possible recall bias, the present data seem to suggest that environmental factors linked to seasons are capable of interfering with the timing of a woman's ovarian exhaustion by an action exerted in the prenatal period.     

Childhood cognitive ability and age at menopause: evidence from two cohort studies

OBJECTIVE: To investigate whether poorer cognitive ability in childhood is associated with an earlier menopause. DESIGN: Two cohorts were included: a nationally representative British birth cohort study of 1,350 women born in March 1946 and followed up to age 54 years, and an Aberdeen cohort study of 3,465 women born in Aberdeen from 1950 to 1956 and followed up to age 44 to 50 years. Both cohorts had prospective information on childhood cognitive ability at age 7 or 8 years. RESULTS: In both cohorts, women with lower cognitive scores in childhood reached menopause earlier than women with higher scores. With follow-up of menopause to 49 years, the hazard ratio (HR) for one standard deviation of the cognitive score was 0.80 (95% CI, 0.72-0.90) in the Aberdeen cohort and 0.84 (95% CI, 0.73-0.97) in the older 1946 birth cohort. The effect was still evident in the 1946 birth cohort with follow-up of menopause to 53 years (HR = 0.87; 95% CI, 0.79-0.95). These ratios were weakly attenuated by adjustment for potential confounding effects of lifetime socioeconomic circumstances, parity, and smoking. CONCLUSIONS: The association between early cognitive ability and timing of menopause only partially reflects common risk factors, although residual confounding remains a possibility. Alternatively, early environmental or genetic programming may explain this association, perhaps through setting lifelong patterns of hormone release or causing transient hormonal changes at sensitive periods of development. These findings have implications for the interpretation of studies investigating an association between age at menopause and adult cognitive function.     

Determinants of age at menopause in women attending menopause clinics in Italy

OBJECTIVE: We analysed the mean age at menopause and its determinants in 31,000 women attending menopause clinics in Italy. DESIGN: Between 1997 and 2003 we conducted a large cross-sectional study on the characteristics of peri- and post-menopausal women attending a network of first-level outpatient menopause clinics in Italy for general counseling or treatment of menopausal symptoms. Spontaneous menopause was defined as natural cessation of menses for 12 or more months. A total of 31,834 women with spontaneous menopause entered the study. RESULTS: The mean age at spontaneous menopause was 51.2. The age at menopause did not markedly changed with cohort of birth. Higher education was associated with lower age at menopause (51.1 in women with low education versus 51.3 for women with high school or university degree, p<0.05). A higher body mass index (BMI) was associated with later age at menopause. Smokers reported a lower age at menopause (51.2 in nonsmokers versus 51.1 in smokers, p<0.05). A later age at menarche was associated with a later age at menopause. Likewise, lifelong irregular menstrual cycles and higher parity were related with later age at menopause. No association emerged between ever oral contraceptive use and age at menopause. CONCLUSIONS: Low educational level, lower BMI, smoking, early menarche, nulliparity and regular cycles are independently associated with lower age at natural menopause in a large sample of women attending menopause clinics in Italy. However, in absolute terms the effect of these factors in our sample is very small.     

The age at menopause and associated factors at the health center area in Ankara, Turkey

OBJECTIVES: This study is performed in one health center area in Ankara, Turkey on a women population of 50-65 years in order to demonstrate menopausal status of women, age at menopause and factors related with the age at menopause. METHODS: This is a cross-sectional study which has been performed on a women population of 50-65 years. The local population was 17,153 in this area by 2001. All of the household determining forms are screened in order to detect the all of the women who were in 50-65 years group, then name and addresses of the these women's are listed. There were 1089 women aged 50-65 years who were constituting 7% of the population. After choosing the first name randomly from the list of the women, 1/3 systematic sampling method was used and, the number of the women in the sampling was 363 (95% C.I., +/-5% S.E.). The response rate among those eligible women who were contactable during the study was 99% (360/363). Data were collected by interviews through questionnaires. The questionnaire consisted of a series of questions concerning age at menopause, socioeconomic status, age at menarche, age at first pregnancy, regularity of menstrual cycles, parity, duration of breast feeding, use of OCs, BMI, smoking habit, age at menopause of the mother and the sister. Chi-square and t-test methods were used for statistical analyses. RESULTS: 4.2% of the women were in premenopause, 13.3% were in perimenopause, 72.8% were in natural menopause and 9.7% were in surgical menopause. Average age at natural menopause was 47+/-4.2 years. Education, age at menarche, smoking, age at menopause of the mother and the sister were found to be related with the age at menopause. CONCLUSIONS: Ninety-six percent of the women over age of 50 years, are at menopause or perimenopause. The results of this study suggest that, for factors of genetic and age at menarche, there are not many possibilities for the lifestyle changes that would modify age at menopause with the subsequent reduction in risk for chronic diseases, but daughters or sisters of women with an early menopause and women who smoked or less educated could be counselled with respect to family timing.     

Age at menopause and determinants of hysterectomy and menopause in a multi-ethnic community: The Hilo Women's Health Study

Objectives

A lifespan approach was used to evaluate age at menopause, and determinants of surgical and natural menopause, in the multi-ethnic community of Hilo, Hawaii.

Study design

Participants aged 40–60 years (n = 898) were drawn from a larger, randomly generated sample recruited by postal questionnaires. Median age at natural menopause was computed by probit analysis. Logistic regression analysis was applied to examine determinants of hysterectomy, and Cox regression analysis was used to examine risk factors for an earlier age at menopause.

Main outcome measures

History of hysterectomy, age at menopause.

Results

Frequency of hysterectomy was 19.2% at a mean age of 40.5 years. The likelihood of hysterectomy increased with older ages, lower education, mixed ancestry, having been overweight at age 30, and married 20 years prior to survey. Median age at natural menopause was 53.0 years. Smoking and not being married 10 years before survey were associated with an earlier age at menopause.

Conclusions

Median age at menopause was later than the national average. Ethnicity and education were determinants of hysterectomy, but not associated with age at natural menopause. Events later in the lifespan (e.g., smoking and not being married 10 years prior to the survey) were more important than earlier events (e.g., childhood residence) in relation to age at menopause. The timing of weight gain and marital status appear to be important in relation to surgical menopause, and the timing of marital status appears to be important in relation to the timing of natural menopause.     

Symptoms at pre- and postmenopause in rural and urban women from three States of Mexico

OBJECTIVES: We studied the possible influence of modern cultural conditions on symptoms at menopause in three distant populations, comparing urban vs. rural women from three different States of Mexico: Guanajuato, Coahuila and Yucatán. In these groups we compared the age at menopause and symptoms at pre- and postmenopause. METHODS: A total of 7632 volunteers were selected from Guanajuato, Coahuila and Yucatán. In house visits, an oral questionnaire was applied to women 45-60 years old, non-pregnant or lactating, without hysterectomy, chronic illness, or hormone treatment. We collected general and personal data, clinical, somatometric variables, and symptoms: hot flashes, vaginal dryness, dispareunia, and diminished sexual interest. Depressive mood and anxiety were evaluated with the Hamilton-Bech-Rafaelsen Scale. RESULTS: The mean age at menopause was 48.0 years. A logistic regression identified the association of age at menopause with urban or rural residence, and the State of origin. Scores for depression and anxiety were lower in Yucatán, and they were higher in rural women. Hot flashes, vaginal dryness and the diminished sexual interest were increased at postmenopause. Hot flashes varied from 73 to 32%, and were associated with menopause, low schooling, rural residence, body mass index (BMI), and State of residence. Similar factors were associated with vaginal dryness, dispareunia, and loss of sexual interest. Depressive mood was associated with rural residence, State of residence, menopause, high BMI, smoking habit, age, and schooling. Anxiety was associated with menopause, rural residence, low schooling, high BMI, and age. The loss of sexual interest was associated with age, BMI, menopause and number of pregnancies. CONCLUSIONS: The frequencies of symptoms at menopause have similar ranges to other countries. Ethic and socio-cultural and environmental factors are involved in the appearance or symptoms.     

The influence of Nos3 polymorphisms on age at menarche and natural menopause

OBJECTIVE: Deficiency of the gene encoding endothelial nitric oxide synthase, i.e. Nos3, has been reported to be associated with late menarche, reduced ovulation rates, fewer deliveries, and earlier onset of menopause in a mouse model. METHODS: We assessed the Glu298Asp and the T-786C polymorphisms of Nos3 in 87 consecutive healthy postmenopausal women by pyro- and capillary-sequencing, respectively. Results were correlated with age at menarche and natural menopause, number of miscarriages and live births, as well as body mass index (BMI) and smoking habits. RESULTS: Allelic frequencies of the Glu298Asp polymorphism of Nos3 were 121 (69.5%) and 53 (30.5%) for the wild-type G allele and the mutant T allele, respectively. Forty-one women (47.1%) were homozygote wild-type (G/G), 39 (44.9%) were heterozygote (G/T), and 7 (8.0%) were homozygote mutant (T/T). Allelic frequencies of the T-786C polymorphism of Nos3 were 105 (60.6%) and 69 (39.4%) for the wild-type T allele and the mutant C allele, respectively. Thirty-three women (38.0%) were homozygote wild-type (T/T), 39 (45.1%) were heterozygote (T/C), and 15 (16.9%) were homozygote mutant (C/C). Presence of at least one mutant allele of the Glu298Asp or the T-786C polymorphisms of Nos3 were not associated with age at menarche, natural menopause, and number of miscarriages and deliveries. BMI above 27 kg/m2 and smoking were associated with earlier onset of natural menopause (47.8 years versus 50.2 years (P = 0.01) and 46.8 years versus 49.8 years (p = 0.02)). CONCLUSIONS: Our data show that smoking and increased BMI, but not Glu298Asp or the T-786C polymorphisms of Nos3, are associated with an early onset of natural menopause.