Abstract

Considerable within and between-population variation exists in menopause timing. Different genetic and environmental factors have been contributing to this variability. Factors responsible for this observed variation are still not well recognized. The purpose of this mini-review is to outline the recent literature regarding the natural menopause timing, to explore contributing factors that may be involved in age at menopause inception.

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Introduction

Menopause, women’s important reproductive milestone, is defined as at least one year of amenorrhea based on a definition of the World Health Organization (WHO). As women go through the years, both the number and quality of the oocytes in the ovaries decrease, menstrual periods stop permanently, and consequently women will no longer be able to bear children (1).

Women typically experience menopause in their mid-40s to mid-50s at an average age of 51, however it ranges from 40 to 60 years and about 10% of women reach menopause by the age of 45 years (1). Menopause before 40 is known as early or premature menopause and Menopause after 55 or older is late-onset menopause. Natural early menopause and late-onset one has been associated with important clinical and health implications.  

Considerable within and between-population variation exists in menopause timing (2) and no set age when it should start. The mechanisms underlying menopause timing have not completely understood (3), however, different genetic and environmental factors have been contributed to the variability in menopause onset (4).

Genetic

Genetic seems to explain some, but not all of the variations that exist in the menopause age (5, 6).  The evidence is contradictory regarding the contribution degree of genetic factors versus environmental ones on menopause age change. Several X-chromosome changes and more than 50 genetic variations have been linked to the age when a woman reaches menopause (7). Some researchers estimate a huge variation due to genetics, as in monozygotic twins (8), however, epidemiological studies take another side of controversy as smoking accounts for about 5% of the risk of early menopause, which estimated to equal to the effect of the top 17 genetic variants together (9). An association was found between mothers’ and daughters’ ages at natural menopause, meanwhile, an interaction between genetic and environmental factors in determining the age at menopause has been suggested (10).  

Smoking

Smoking has been identified as a factor in cellular senescence. It leads to ovaries senescence too and the process consequently underlies the menopause timing. Most of the studies have suggested that smoking associated with early natural menopause (11-15), however, some studies do not report such association (16-18). Some studies assumed a dose-response and irreversible effects of smoking (13, 19, 20). The inconsistency has been contributed to the degree of exposure to smoking, the years since smoking contemplation, and the criteria for women classification into smoker or nonsmoker categories (21). Either, active and passive forms of smoking affect the age at menopause, however, data is spare on the effect of passive or secondhand smoking (15). A population-based study in Beirut found 1.02 odds of early menopause for each year of smoking. Exposed to prenatal smoke or current smoking raises the odds of experiencing earlier natural menopause by three times (22). A comprehensive review by Parente et al showed an inverse relationship between smoking and menopause. Based on the finding of this study, smoking had a reverse effect on the reduction in the age at the menopause as current smokers experience earlier menopause than formers. Also, a dose-response gradient was observed in most of the included studies. The higher the number of cigarettes smoked, the lower the age at menopause. The consistency of duration, quantity and time of smoking and the age of the menopause was on the debate (23).  In a meta-analysis by Sun et al., 11 studies were included. The studies were divided into two groups according to their data on menopause age. In five studies with dichotomous data, smoking increased the risk of early menopause by 43% and among six studies with continuous data, smokers undergone menopause one year earlier than non-smokers (21).

Reproductive factors

Many reproductive factors affect the timing of menopause consists of menstrual cycle patterns (length, variability, regularity), parity, childbearing, age at menarche, and contraceptive pill consumption. With the approach of menopause, menstrual cycle length and variability increase and serial irregularity decrease (24). Menstrual cycle length is a factor which determines the age at menopause, too. Studies show a consistent link between cycle length and age at menopause. The shorter mean cycle length, the fewer the age at menopause (13, 25). A longitudinal study indicated earlier menopause at 1.4 years among women with cycle length less than 26 days than women with cycle lengths between 26 and 32 (26). The findings of the cycle days variability are mixed. Cycle variability was seen among either woman with later and earlier menopause (26-28).  Den Tonkelaar et al. (29) and Whelan et al. (30) reported no relation between cycle length variability and age at menopause. Cycle length and regularity were not statistically associated with the age of menopause for Spanish and American women (31).

The higher number of parity was supposed to delay menopause (10, 20, 32, 33). Although women with any children have later menopause (31), some studies even reported a trend for increased age at menopause with an increased number of children ever born to a woman (25), however, little researches have noted an association between parity and age at menopause (13, 33). As a further matter, a study identified an association between multiple births and early menopause (34). The later birth was associated with later menopause (14). Age at last pregnancy has a significant positive association with menopause age (16).

Early life reproductive characteristics may shape later reproductive trajectories. Overall the evidence on the relation between age at menarche and menopause is mixed. Two recent reviews reveal no consistency in the association between age at menarche and menopause. The majority of the relevant studies shows null finding (35, 36). Some studies reported that early age at menarche is associated with premature or early menopause (34, 37). A study in Morocco found that menstruation below 11 years old increase chance of earlier age at menopause compared to menstruating at age 12 or older (33). Limited studies also have noted an inverse association for the relationship (38). There is complexity in studying the relationship between age at menarche and menopause timing. There is a large window between these two important milestones of a woman life course, and many epigenetic, genetic, and environmental factors work in combination and consequently underlie menopause timing. Despite this fact, most of the studies that examine the association have a cross-sectional design which makes the situation worse.

There is a hypothesis that taking Oral Contraceptive (OC) pills could postpone the age of natural menopause. Studies are not consistent with such a hypothesis. Most of studies either found delayed menopause (25) or no relation for OC users (14, 31). One study reported heterogeneous effects on timing of menopause among nine European countries (14). A population-based study by de Vries et al. contradicted the hypothesis. They reported that high-dose OCs use antedate menopause age by approximately 1.2 months for every year of OC-use compared with no OC-use. No effect was found for low-dose OC use.  There is a possibility of a fallacious positive relation between taking OC and menopause delay since OC has been prescribing for menopausal complications too and many studies were not able to exclude women who used OC. The OC obscure menstruation date.  

Obesity

Inconsistent findings have seen in the relationship between body mass and age at menopause. Most of the previous related studies found a positive association between overweight, obesity, abdominal adiposity or waist-to-hip ratio with later age at natural menopause (31, 39-41). Besides, the greater the BMI, the later the age at menopause as in a study, women with upper 25% BMI at 40 or 41 y compared to women in the lower 25% group reported higher age at menopause (42). Some studies have reported no significant association of BMI with age at natural menopause (20, 43-47). Results of studies on the relation between weight and age at menopause have yet to be inferred with caution. First, body weight or any similar measure such as BMI have time-varying feature, so, a single measurement at an age could not represent the true lifelong weight trend. No critical age for when BMI might have the greatest effects on age at menopause has determined. One longitudinal study reported the association between later menopause and higher BMI at the age of 18 y (48) and another detected the association among premenopausal women (49). Although a study investigated woman aged 15, 20, 26, 36, and 43 years and indicated no significant associations between BMI at any age and timing of menopause (50).  Second, many factors are considered to be confounding factors of BMI. Age and sedentary life eventuate weight gain around menopause age (51). A meta-analysis indicated that the confounding effect of smoking changes results markedly when comparing obese versus normal-weight women (41). Third, the association between obesity and age at menopause is a two-way one. Chronological aging lead to both menopause and weight gain and increased central body fat distribution (52). Therefore, any conclusion about whether obesity postpones the menopause could be a simplicity.

Early life contributors

Evidence indicates that events surrounding the birth and early life could impact the timing of menopause trough the size of the oocyte pool (34). Fetal Environment independently associates with the timing of menopause. Either low or high birth weight advances menopause (even after standardization of birth weight to the gestational age) (53).

Lower cognitive scores in childhood were hypothesized to cause earlier menopause than those with higher scores (54, 55). However, one study noted the association as partial one and reported that confounding is a serious possibility (55).

Unrecognized correlates of age at natural menopause

It has been suggested 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.  Menopause occurred earlier for women born in the spring than in the autumn (4).

Chemical exposures experienced by women alter the age at menopause. Higher tibia lead level was associated with younger age at menopause (56).

A study among 8,038 women living and working on farms in Iowa and North Carolina explored the association between use of pesticides and age at menopause. The median time to menopause increased by approximately 3 months for women who used pesticides (hazard ratio = 0.87, 95% confidence interval: 0.78, 0.97) and by approximately 5 months for women who used hormonally active pesticides (hazard ratio = 0.77, 95% confidence interval: 0.65, 0.92) (57).

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