Meta-analysis suggests that smoking is associated with an increased risk of early natural menopause

Sun, Lu MSc1; Tan, Lijun PhD1; Yang, Fang PhD2; Luo, Yi MSc1; Li, Xi PhD1; Deng, Hong-Wen PhD1,3; Dvornyk, Volodymyr PhD4
Free Access Article Outline

Author Information From the 1Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, China; 2Department of Epidemiology and Biostatistics, School of Public Health, Central South University, Changsha, China; 3Department of Biostatistics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA; and 4 School of Biological Sciences, University of Hong Kong, Hong Kong SAR. Received February 28, 2011; revised and accepted May 18, 2011. Funding/support: The study was supported by the Natural Science Foundation of China (NSFC; 30900810, 30771222, 31071097, 30600364), the NSFC-Canadian Institutes of Health Research (CIHR) Joint Health Research Initiative Proposal (30811120436), and the University of Hong Kong startup fund (to Volodymyr Dvornyk). Financial disclosure/conflicts of interest: None reported. Address correspondence to: Volodymyr Dvornyk, PhD, School of Biological Sciences, University of Hong Kong, Pokfulam Rd., Hong Kong SAR. E-mail: dvornyk@hku.hk

Abstract Objective: Age at natural menopause (ANM) is usually defined as the age at the last menstrual bleeding followed by the absence of menses for 12 consecutive months. Although many studies have suggested an association between smoking and early age at natural menopause, evidence remains conflicting because some studies reported inconsistent or contrasting results. To resolve this ambiguity and to quantitatively evaluate the effect of smoking on ANM, we conducted a meta-analysis of the available data about smoking and ANM. Methods: After extensive searching of public literature databases, a total of 11 studies were selected for this meta-analysis. Among them, the phenotype of the participants in five studies (dichotomous studies) was classified as early or late ANM, and odds ratio (OR) was used to evaluate the effect of smoking on early ANM. For the other six studies (continuous studies), mean and SD were provided for smoking and nonsmoking samples, and weighted mean difference (WMD) was used as the effect size.

Results: We found that smoking was significantly associated with early ANM in both dichotomous and continuous studies. The pooled effect was OR = 0.74 (95% CI, 0.60-0.91, P < 0.01) in the dichotomous studies. For the continuous studies, the pooled effect estimated by WMD was 1.12 (95% CI, 1.80 to 0.44, P = 0.04). After adjustment of the original data for heterogeneity, the pooled results changed only a little: OR = 0.67 (95% CI, 0.61-0.73, P < 0.01) for dichotomous studies and WMD = 0.90 (95% CI, 1.58 to 0.21, P = 0.01) for the continuous studies. Conclusions: The results of our study suggest that smoking is a significant independent factor for early ANM. Menopause marks the end of a womans menstrual cycle and reproduction period. It is usually defined as the absence of menses for 12 consecutive months. The normal process of menopause occurs when ovaries cease the production of estrogen and progesterone, and a womans lifetime supply of oocytes is depleted.1 The age at natural menopause (ANM) is closely related to womens physical and psychological health. Early ANM was associated with a higher risk of several complex diseases, such as osteoporosis,2-4 genital tract cancers,5-7 and cardiovascular diseases.8-10 For example, early menopause may increase the risk of venous thrombosis and association with cardiovascular diseases through changes in the concentration of female sex hormones such as estrogen and progesterone.11,12 On the other hand, late ANM may be a factor for an increased risk of breast cancer13,14 and endometrial and hepatocellular cancers.15-17 In summary, although early ANM may lower the risk of some disorders like breast cancer, overall mortality is increased by about 2% with each reducing year of age at menopause.18,19 Therefore, from a clinical point of view, determining the potential factors that influence ANM may contribute to the prophylaxis of these diseases. ANM is affected by various social, genetic, and environmental factors such as smoking,20,21 alcohol consumption,22 nutrition,23 race,24 maternal age at menopause,25 and others. Tobacco smoking is one of the factors accelerating the process of human senescence. Many studies suggested smoking as a potential factor for early menopause,26-28 but some studies did not support this view.29,30 Furthermore, the effect sizes of smoking on ANM varied greatly in these studies. So far, two reviews summarized the published reports on the association of smoking and ANM,31,32 but none used a systematic statistical technique to quantitatively analyze the aggregated data. A meta-analysis is a powerful tool that can sum up results of different studies and produce a single estimate of the major effect with increased accuracy.33-36 To systematically review the published data, we performed a meta-analysis from all eligible studies to quantitatively estimate the association between smoking and ANM.37 Back to Top | Article Outline METHODS
Study selection

We performed a literature search in Medline and Google Scholar from 1977 to 2009 to find articles that examined the association between smoking and ANM (Fig. 1). The search was limited to articles published in English. We used the terms menopause and smoking/cigarette/tobacco as the keywords. In addition, references from retrieved

publications were checked to find additional articles on the topic. This strategy returned 1,836 articles. After preliminary screening and reexamination, a total of 18 studies were identified as providing the appropriate data (please see details below in this paragraph) for the meta-analysis. Six studies that involved participants with nonnatural menopause were excluded from our research.9,14,19,38-40 Two studies28,41 used overlapping participants, so the study41 with the smaller sample size was excluded. Finally, a total of 11 studies were included in the meta-analysis; all of them were observational studies (seven cross-sectional studies,27,29,30,42-45 three case-control studies,26,46,47 and one cohort study28). We divided the studies into two groups according to their data on menopause (dichotomous studies and continuous studies, respectively). Participants in the five dichotomous studies26-28,30,42 were classified by smoking status (smoking and nonsmoking) and ANM categorization (such as 45, 46-50, 51-55, 56 y). The six studies with continuous outcomes29,43-47 reported the sample sizes of the subgroups (smoking and nonsmoking) and the mean (SD) ANM in each subgroup.

Fig. 1 Image Tools Back to Top | Article Outline

Data extraction

We used a standardized reporting form based on the Meta-analysis Of Observational Studies in Epidemiology statement48 to independently extract data from each study. Among the 11 articles selected, tobacco smoking status was classified as current smoking, past smoking, and nonsmoking in the four studies26-28,46 and as smoking and nonsmoking in the other seven studies.29,30,42-45,47 In the former, the participants with past smoking and current smoking habits were combined in a single group in this meta-analysis. One of the studies26 contained two independent sets of data, and we analyzed each set separately. The average ANM is about 50 years27,29,30,42-45,47; therefore, we used 50 years as the threshold of late and early ANM for all dichotomous studies but one,42 in which the age of 51 years was used. The following information was extracted from each study: first author, year of publication, country of origin, age distribution, ethnic background of the study sample (white, Asian, African, or mixed), and the number of eligible participants. The summary information about the selected studies is given in Tables 1 and 2.

Table 1 Table 2 Image ToolsImage Tools Back to Top | Article Outline

Statistical analysis

The Comprehensive Meta-Analysis software (version 2; Biostat, Englewood, NJ) was used for all statistical analyses. Only the tabular data were used. For the dichotomous studies, we used odds ratio (OR) to evaluate the risk of early ANM for each study using nonsmokers as a control group. The power of the study was estimated as the probability of finding a significant association between smoking and ANM at the 0.05 significance level; assuming that the OR was 0.9, the power of all studies was as high as 99.55%. For the studies with continuous outcome, weighted mean difference (WMD) was used to assess the effect size; it

directly reflects the variation of average ANM between the smokers and nonsmokers. Heterogeneity among the studies was evaluated using the Cochran Q test, and P < 0.10 was considered as the significance level.49 Because many factors like smoking dose may potentially influence ANM, random-effects model was used for the analyses in this study. To demonstrate the influence of between-study heterogeneity, we performed a sensitivity analysis. The sensitivity analysis is one of the commonly used approaches in evaluating the impact of heterogeneity on the results of a meta-analysis.50 It provides information on which study had a major effect on the heterogeneity and the influence for the final results after excluding the study from the meta-analysis.51,52 Publication bias was estimated using both a funnel plot and the approach proposed by Egger et al.53 The funnel plot is a simple scatterplot of the treatment effects estimated from individual studies against a measure of study size; it is a visual tool for evaluating publication bias in a meta-analysis.51 The Egger approach is based on the funnel plot, in which the standardized effect estimation is regressed on a measure of the precision (1/SE). The intercept of the regression significantly greater than zero indicated the existence of a publication bias among the studies.36,53 Back to Top | Article Outline RESULTS
Characteristics of studies

The characteristics of the eligible dichotomous and continuous studies are shown in Table 1 and Table 2, respectively. Most of the individuals were of white descent; only two studies used participants of mixed ethnicities. The sample size of these studies varied substantially (ranging from 721 to 31,163 individuals), and so did the statistical power (9.56%-95.27%) for the dichotomous studies. The power of the pooled sample was 99.55%. After exclusion of the studies by Parazzini et al30 from the set of dichotomous studies (as a source of heterogeneity, see Sensitivity analysis), the statistical power became 78.33% (Table 1). The total number of participants in the dichotomous studies was much larger than that in the continuous studies (43,155 vs 6,010). Back to Top | Article Outline
Sensitivity analysis

Many factors, such as smoking dose, the duration of smoking, and the identification criteria for smoking and nonsmoking, may potentially influence the results of association between smoking and ANM. However, such data were not provided in most of the studies used. The subgroup analysis and sensitivity analysis are two common methods to deal with heterogeneity in a meta-analysis. Because the subgroup analysis was limited due to the lack of related information, sensitivity analysis was used to examine the source of the heterogeneity. The Cochran test indicated statistically significant between-study heterogeneity for both dichotomous (Q = 50.54, P < 0.01) and continuous (Q = 19.74, P < 0.01) studies. We found that one dichotomous study30 and one continuous study47 were the main cause of the observed heterogeneity. After they were excluded, no heterogeneity was observed for either the dichotomous or the continuous studies (Q = 3.94, P = 0.41 and Q =

7.68, P = 0.10 for Figs. 2 and 3, respectively). For comparison purposes, we also performed the meta-analysis after adjustment for heterogeneity by excluding these two studies.30,47

Fig. 2 Fig. 3 Image ToolsImage Tools Back to Top | Article Outline

Meta-analysis

The results of the meta-analysis of the dichotomous studies are presented in Figure 2. All ORs for the association between smoking and ANM were less than 1 and varied from 0.63 to 0.96. Between-study heterogeneity was statistically significant; the meta-analysis under the random-effects model showed significant association between smoking and early ANM (OR = 0.74; 95% CI, 0.60-0.91, P < 0.01). Figure 3 shows the results of the meta-analysis of the studies with continuous outcomes. The WMDs were below 0 for all studies except for that of Ashrafi et al29 and ranged from 2.16 to 0.02. Heterogeneity was also detected in this case, and the pooled results showed a significant association between smoking and early ANM (WMD = 1.12; 95% CI, 1.80 to 0.44, P = 0.04). We also conducted the meta-analysis after adjustment for heterogeneity as described previously. The analysis showed a significant association between smoking and ANM for both dichotomous and continuous studies (OR = 0.67 and WMD = 0.90, P 0.01). Back to Top | Article Outline
Publication bias

Figure 4 presents the funnel plots for both dichotomous studies and studies with continuous outcomes. First, we performed the publication bias analyses including all studies. To exclude the effect of heterogeneity and for comparison purposes, similar analyses were also conducted after exclusion of the previously mentioned two studies.30,47 All of the plots (Fig. 4B-D) are roughly symmetric and suggest no publication bias. When all studies were included for analysis (Fig. 4A, C), some spots were beyond the region of the funnel because of the between-study heterogeneity. The publication bias was not significant for the dichotomous studies (intercept of the regression a = 1.21, t = 1.13, P = 0.34 for the total data set; intercept a = 3.45, t = 2.33, P = 0.07 after adjustment for heterogeneity) and for the continuous studies (intercept of the regression a = 1.47, t = 1.26, P = 0.27 for the total data set; intercept a = 3.04, t = 1.78, P = 0.17 after adjustment for heterogeneity).

Fig. 4 Image Tools Back to Top | Article Outline DISCUSSION

The present meta-analysis used the data of 11 observational studies (about 50,000 participants) to evaluate the effect of smoking on ANM. Midgette and Baron31 surveyed 14 studies, which all reported earlier ANM for smokers, and concluded that smoking is associated with an approximately double risk of early menopause for women from age 44 to 55 years. Parente et al32 provided a systematic review on the relationship between smoking and menopause. They collected nearly all the relevant studies and concluded that there is no clear evidence for association between ANM and the duration of smoking and the number of cigarettes smoked. In reviews, factors such as heterogeneity and publication bias are important and may affect the accuracy of the results. However, none of the two studies previously mentioned estimated the impact of these factors. In the present study, we used a meta-analysis, a systematic statistical method, to evaluate the effect of smoking on ANM. Our results suggested that the smoking habit is significantly associated with early ANM. For the dichotomous studies, the pooled OR was about 0.7, which means that smoking increased the risk of early menopause (below 50 y) by 43% (1/0.70 1). For the continuous studies, the pooled WMD was about 1, which suggested a difference of about 1 year in the ANM between smokers and nonsmokers. Our results give further evidence that smoking is significantly associated with earlier ANM and provide yet another justification for women to avoid this habit. Previous studies about smoking and menopause also support the results of this meta-analysis. Smoking is suggested to exert antiestrogen effects and, therefore, to promote earlier ANM.4 Possible molecular mechanisms for such earlier menopause may include, among others, smoking-induced expression of CYP1A2,54 decreased serum estrogen levels and increased concentrations of the metabolic 2-hydroxyestrogen in women who smoke.55 Many studies reported an association between smoking and early ANM, but evidence remains inconclusive. For example, 2 of the 11 studies used in this meta-analysis reported no association between smoking and ANM.29,30 This difference may be explained by several factors. First, most of the surveyed studies were cross-sectional. In some cases, the problems associated with cross-sectional studies, such as survival bias and recall errors, may reduce the observed differences.56,57 For example, selective survival bias may occur when a researcher tends to recruit participants with a higher smoking load or when smokers report late ANM because of recall errors. Second, the inappropriate classification of smoking habits and ANM because of human errors or lenient standards, small quantity of or short-time tobacco smoking in smokers, and some other factors that are not properly identified and documented would result in finding no association between smoking and ANM. To minimize the impact of these interference factors, we used strict inclusion criteria in the selection of articles and adopted a standard method to extract data from each study. With the increase in total sample size, statistical power also increased (Table 1), and the pooled effect size became more accurate and stable. For example, after adjustment for heterogeneity, the pooled effect size changed only a little for both dichotomous and continuous studies (from 0.74 to 0.67 and from 1.12 to 0.90, respectively). The between-study heterogeneity found in the meta-analysis may be caused by several potential reasons. False-positive or false-negative associations may result from survival bias and recall errors involved in cross-sectional studies.56,57 Another potential source of heterogeneity is the lack of a standardized classification for smoking habits and ANM. For example, the quantity of cigarettes or packs consumed has a significant effect on the

association results.24,26,27,58 Other possible sources of the observed heterogeneity are differences in the participants characteristics, including differences in age and ethnicity. In addition, the definitions of menopause and smoking status were lacking in most of the studies but three.30,43,44 For the sensitivity analyses, we found two studies30,47 as a source of the observed heterogeneity. Compared with other studies, the study by Parazzini et al30 had the largest deviation with the pooled effect size among the dichotomous studies as did the study by Chmara-Pawlinska and Szwed47 among the continuous studies. However, the conclusions of these two studies on the influence of smoking on ANM are inconsistent (Figs. 2 and 3). The two studies might have large differences with the other studies on some factors involved in heterogeneity. Both studies have large sample sizes (Tables 1 and 2) so that random factors and some other minor factors, such as age and ethnicity, are unlikely to be the main reason for the quite different results.31,32 In view of all factors, smoking status may be the main source of heterogeneity. Actually, smoking dose, the duration of smoking, and the definitions of smoking status have important influence on the ANM.24,26,27,32,58 However, because of the absence of the respective data in most of the 11 studies, this hypothesis is still speculative and needs further testing. Our analysis has some limitations to be acknowledged. First, accurate information about smoking and ANM is missing in many studies. For instance, the details on the duration of smoking for smokers were absent in all 11 studies, and only 3 studies30,43,44 reported their definitions of menopause status. Some studies, although providing the relevant data, do not have the standardization for the factors that are important in our meta-analysis. For example, the classification of smoking is different among these 11 studies (see details in Data extraction). Ideally, to avoid a bias, the effect size should be adjusted for all factors known to contribute to smoking and ANM. However, because some of the studies used in the current meta-analysis did not contain relevant data, the crude effect size was calculated using only the tabular data. This might potentially affect the overall accuracy of the meta-analysis. In addition, although a meta-analysis is a good method of obtaining a large sample size and increasing statistical power, heterogeneity and publication bias may bring some noise. Back to Top | Article Outline CONCLUSIONS The results of this meta-analysis further support the hypothesis that smoking is associated with earlier ANM. However, because of the previously mentioned inherent limitations and the absence of the standardized definition for smoking, our meta-analysis may not be sufficient to resolve the existing controversy on the effect of smoking on ANM. Back to Top | Article Outline REFERENCES 1. Col NF, Fairfield KM, Ewan-Whyte C, Miller H. In the clinic. Menopause. Ann Intern Med 2009; 150: ITC4-1ITC4-15; quiz ITC4-6. Cited Here...

2. Kritz-Silverstein D, Barrett-Connor E. Early menopause, number of reproductive years, and bone mineral density in postmenopausal women. Am J Public Health 1993; 83: 983988. Cited Here... 3. Falch JA, Sandvik L. Perimenopausal appendicular bone loss: a 10-year prospective study. Bone 1990; 11: 425428. Cited Here... 4. Harlow BL, Signorello LB. Factors associated with early menopause. Maturitas 2000; 35: 39. Cited Here... 5. Snowdon DA, Kane RL, Beeson WL, et al.. Is early natural menopause a biologic marker of health and aging? Am J Public Health 1989; 79: 709714. Cited Here... 6. Schildkraut JM, Cooper GS, Halabi S, Calingaert B, Hartge P, Whittemore AS. Age at natural menopause and the risk of epithelial ovarian cancer. Obstet Gynecol 2001; 98: 8590. Cited Here... 7. Cramer DW. Epidemiologic aspects of early menopause and ovarian cancer. Ann N Y Acad Sci 1990; 592: 363375. Cited Here... 8. van der Graaf Y, de Kleijn MJ, van der Schouw YT. Menopause and cardiovascular disease. J Psychosom Obstet Gynaecol 1997; 18: 113120. Cited Here... 9. van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996; 347: 714718. Cited Here... 10. Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total mortality and mortality from ischemic heart disease: the Adventist Health Study. J Clin Epidemiol 1999; 52: 303307. Cited Here... 11. Wessler S. Estrogen-associated thromboembolism. Ann Epidemiol 1992; 2: 439443. Cited Here... 12. Perry C, Berliner S. Progesterone and the risk of arterial and venous thrombosis [in Hebrew]. Harefuah 1998; 134: 633637. Cited Here... 13. Collaborative group on hormonal factors in breast cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 10471059. Cited Here...

14. Monninkhof EM, van der Schouw YT, Peeters PH. Early age at menopause and breast cancer: are leaner women more protected? A prospective analysis of the Dutch DOM cohort. Breast Cancer Res Treat 1999; 55: 285291. Cited Here... 15. Franceschi S, La Vecchia C, Booth M, et al.. Pooled analysis of 3 European case-control studies of ovarian cancer: II. Age at menarche and at menopause. Int J Cancer 1991; 49: 57 60. Cited Here... 16. de Graaff J, Stolte LA. Age at menarche and menopause of uterine cancer patients. Eur J Obstet Gynecol Reprod Biol 1978; 8: 187193. Cited Here... 17. Mucci LA, Kuper HE, Tamimi R, Lagiou P, Spanos E, Trichopoulos D. Age at menarche and age at menopause in relation to hepatocellular carcinoma in women. BJOG 2001; 108: 291294. Cited Here... 18. Mondul AM, Rodriguez C, Jacobs EJ, Calle EE. Age at natural menopause and causespecific mortality. Am J Epidemiol 2005; 162: 10891097. Cited Here... 19. Cooper GS, Sandler DP. Age at natural menopause and mortality. Ann Epidemiol 1998; 8: 229235. Cited Here... 20. McKinlay SM. The normal menopause transition: an overview. Maturitas 1996; 23: 137 145. Cited Here... 21. Gonzales GF, Villena A, De La Cruz D. Age of natural menopause among women in Lima City, Peru. Int J Gynaecol Obstet 1997; 57: 6972. Cited Here... 22. Torgerson DJ, Avenell A, Russell IT, Reid DM. Factors associated with onset of menopause in women aged 45-49. Maturitas 1994; 19: 8392. Cited Here... 23. Nagata C, Takatsuka N, Kawakami N, Shimizu H. Association of diet with the onset of menopause in Japanese women. Am J Epidemiol 2000; 152: 863867. Cited Here... 24. Kato I, Toniolo P, Akhmedkhanov A, Koenig KL, Shore R, Zeleniuch-Jacquotte A. Prospective study of factors influencing the onset of natural menopause. J Clin Epidemiol 1998; 51: 12711276. Cited Here... 25. Torgerson DJ, Thomas RE, Reid DM. Mothers and daughters menopausal ages: is there a link? Eur J Obstet Gynecol Reprod Biol 1997; 74: 6366.

Cited Here... 26. Jick H, Porter J. Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet 1977; 1: 13541355. Cited Here... 27. Adena MA, Gallagher HG. Cigarette smoking and the age at menopause. Ann Hum Biol 1982; 9: 121130. Cited Here... 28. Willett W, Stampfer MJ, Bain C, et al.. Cigarette smoking, relative weight, and menopause. Am J Epidemiol 1983; 117: 651658. Cited Here... 29. Ashrafi M, Ashtiani SK, Malekzadeh F, Amirchaghmaghi E, Kashfi F, Eshrati B. Factors associated with age at natural menopause in Iranian women living in Tehran. Int J Gynaecol Obstet 2008; 102: 175176. Cited Here... 30. Parazzini F. Determinants of age at menopause in women attending menopause clinics in Italy. Maturitas 2007; 56: 280287. Cited Here... 31. Midgette AS, Baron JA. Cigarette smoking and the risk of natural menopause. Epidemiology 1990; 1: 474480. Cited Here... 32. Parente RC, Faerstein E, Celeste RK, Werneck GL. The relationship between smoking and age at the menopause: a systematic review. Maturitas 2008; 61: 287298. Cited Here... 33. Langley K, Marshall L, van den Bree M, et al.. Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. Am J Psychiatry 2004; 161: 133138. Cited Here... 34. Thakkinstian A, Han P, McEvoy M, et al.. Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet 2006; 15: 27842790. Cited Here... 35. Ye Z, Parry JM. The CYP17 MspA1 polymorphism and breast cancer risk: a metaanalysis. Mutagenesis 2002; 17: 119126. Cited Here... | View Full Text | PubMed | CrossRef 36. Pei YF, Zhang L, Deng HW, Dvornyk V. CYP17 MspA1 polymorphism and age at menarche: a meta-analysis. Dis Markers 2008; 25: 8795. Cited Here... | PubMed

37. Rice JP. The role of meta-analysis in linkage studies of complex traits. Am J Med Genet 1997; 74: 112114. Cited Here... 38. Brinton LA, Barrett RJ, Berman ML, Mortel R, Twiggs LB, Wilbanks GD. Cigarette smoking and the risk of endometrial cancer. Am J Epidemiol 1993; 137: 281291. Cited Here... 39. Key TJ, Pike MC, Brown JB, Hermon C, Allen DS, Wang DY. Cigarette smoking and urinary oestrogen excretion in premenopausal and post-menopausal women. Br J Cancer 1996; 74: 13131316. Cited Here... 40. Ossewaarde ME, Bots ML, Verbeek AL, et al.. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 2005; 16: 556562. Cited Here... 41. Hu FB, Grodstein F, Hennekens CH, et al.. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999; 159: 10611066. Cited Here... 42. Meschia M, Pansini F, Modena AB, et al.. Determinants of age at menopause in Italy: results from a large cross-sectional study. ICARUS Study Group. Italian Climacteric Research Group Study. Maturitas 2000; 34: 119125. Cited Here... 43. Reis N, Pasinlioglu T, Dane S. The natural menopause age of women in Erzurum and factors influencing the age at menopause. Turk J Med Sci 1998; 28: 415418. Cited Here... 44. Dvornyk V, Long JR, Liu PY, et al.. Predictive factors for age at menopause in Caucasian females. Maturitas 2006; 54: 1926. Cited Here... 45. Fleming LE, Levis S, LeBlanc WG, et al.. Earlier age at menopause, work, and tobacco smoke exposure. Menopause 2008; 15: 11031108. Cited Here... 46. Cooper GS, Sandler DP, Bohlig M. Active and passive smoking and the occurrence of natural menopause. Epidemiology 1999; 10: 771773. Cited Here... 47. Chmara-Pawlinska R, Szwed A. Cigarette smoking and the age of natural menopause in women in Poland [in Polish]. Przegl Lek 2004; 61: 10031005. Cited Here... | PubMed 48. Stroup DF, Berlin JA, Morton SC, et al.. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 20082012. Cited Here...

49. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127: 820826. Cited Here... 50. Patsopoulos NA, Evangelou E, Ioannidis JP. Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol 2008; 37: 1148 1157. Cited Here... 51. Copas J, Shi JQ. Meta-analysis, funnel plots and sensitivity analysis. Biostatistics 2000; 1: 247262. Cited Here... 52. Riley RD, Sutton AJ, Abrams KR, Lambert PC. Sensitivity analyses allowed more appropriate and reliable meta-analysis conclusions for multiple outcomes when missing data was present. J Clin Epidemiol 2004; 57: 911924. Cited Here... 53. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629634. Cited Here... 54. Gunes A, Ozbey G, Vural EH, et al.. Influence of genetic polymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population. Pharmacogenomics 2009; 10: 769778. Cited Here... 55. Meek MD, Finch GL. Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcription. Environ Res 1999; 80: 917. Cited Here... 56. Giuffra LA, Risch N. Diminished recall and the cohort effect of major depression: a simulation study. Psychol Med 1994; 24: 375383. Cited Here... 57. Forsberg BC, van Ginneken JK, Nagelkerke NJ. Cross-sectional household surveys of diarrhoeal diseasesa comparison of data from the Control of Diarrhoeal Diseases and Demographic and Health Surveys programmes. Int J Epidemiol 1993; 22: 11371145. Cited Here... 58. Hardy R, Kuh D, Wadsworth M. Smoking, body mass index, socioeconomic status and the menopausal transition in a British national cohort. Int J Epidemiol 2000; 29: 845851. Cited Here... Keywords: Age at natural menopause; Meta-analysis; Smoking