Natural menopause refers to the natural permanent cessation of reproductive ability and menstrual cycle due to the decline of the ovarian function without secondary causes such as surgery, chemotherapy, administration of drugs, and diseases. Age at natural menopause is affected by genetic factors related to region and ethnicity and various environmental factors such as socioeconomic position, life style, and culture.^1,2,3) Postmenopausal women are constantly exposed to the risk of chronic diseases due to the reduction in the level of ovarian hormones such as estrogen and suffer from corresponding symptoms.^4,5,6) Therefore, age at natural menopause (ANM) is an important risk factor of morbidity and mortality, and women who had early menopause are more likely to develop osteoporosis,⁷⁾ obesity, metabolic syndrome,^8,9,10) and cardiovascular diseases.^11,12,13,14) Previous studies revealed that income level, occupation, marital status, age at menarche, parity, smoking, and stress might affect reproductive ability and age at menopause, but their results were inconsistent.^15,16,17)

Stress can be defined as the response of the body to internal and external threat factors and the consequences of this response. Stress exerts physiological effects on peripheral organs, starting from the central nervous system, via hormonal secretion.¹⁸⁾ The purpose of this process is to properly adapt to the changes in the surrounding environment. Although transient stress may accelerate adaptation, chronic stress may cause a variety of mental and physical problems. Therefore, stress has recently drawn attention as a cause and exacerbating factor of various diseases. Excessive stress in daily life is known to cause diabetes, hypertension, hyperlipidemia, cardiovascular diseases, cognitive disorders, depression, digestive diseases, and chronic fatigue. Hyperactive hypothalamic-pituitary-adrenal axis as activated by stress, and elevated levels of stress hormones such as glucocorticoids and catecholamines are thought to affect the development and progression of such diseases.¹⁹⁾ Moreover, elevated levels of stress hormones can cause gynecological diseases such as amenorrhea or early menopause. Nevertheless, a direct association between stress and ANM has not yet been demonstrated in Korea or abroad.

Therefore, we analyzed the association between level of stress in daily life and ANM in Korean women based on the data from the 5th Korean Health and Nutrition Examination Survey.

The basal characteristics of the subjects are presented in Table 1. The mean age (n=1,941) was 59.33±6.3 years, and the mean BMI was 24.3±3.3. The number of women who reported a high level of stress in daily life was 477 (24.6%), whereas the number of women who felt relatively little stress was 1,464 (75.4%). The number of women with regular menstrual cycle was 1,768 (91.1%), and the number of women with live birth(s) was 1,889 (97.3%). The number of smokers was 100 (5.2%). Personal income was expressed in quartiles (high, upper middle, lower middle, and low). Mean values of basal characteristics that might affect age at menopause are compared in Table 2. To compare mean levels of stress in daily life and ANM, the subjects were divided into 3 subgroups by age (40-49, 50-59, and 60-70 years). Although no statistically significant differences were found between the subgroups, all of them showed a persistent tendency of a higher stress level being linked to a lower ANM. A comparison with mean overall values revealed that a high level of stress in daily life was significantly associated with an ANM reduced by about 5 months (50.58±3.5 years vs. 50.17±3.7 years, P<0.05). BMI and menstrual cycle regularity significantly affected ANM (P<0.05 in both cases), whereas personal income, history of live births, and history of smoking had no effect. Women with lower BMI and more regular menstrual cycle were found to have earlier ANM. Table 3 shows changes in ANM after adjustment for each confounder. In model 1, only age was adjusted for, and a statistically significant correlation was detected (P<0.05). In models 2, 3, and 4 with additional adjustments for BMI, menstrual cycle regularity, and personal income level, respectively, statistically significant negative correlations were identified (P<0.05).

The present study demonstrated a significant association between level of stress in daily life and ANM. In addition, ANM was further reduced by low BMI in the presence of a high level of stress. Menopause is a time of very significant biological and social changes in a woman's life. Post-menopausal women may be constantly exposed to the risk of chronic disease. Although menopausal symptoms may occur during perimenopause, they are usually severe immediately after the onset of menopause. Post-menopausal women begin to feel a variety of mental and physical changes. Therefore, in the modern society where physical as well as perceived age becomes important, menopause is considered to be directly linked to the woman's quality of life. In the present study, a high level of stress was found to reduce the mean age at menopause by about 5 months from 50.58±3.5 years to 50.17±3.7 years (P<0.05). These results may be clinically significant because women with menopausal symptoms may visit an outpatient department and undergo examination to determine underlying diseases and receive treatment. As the mean age of women and their social engagement are increasing, studies investigating the variety of causes that can affect age at menopause become increasingly significant. Stress, one of these causes, may affect woman's reproductive ability, menstrual cycle, and ANM by altering the neuroendocrine system. However, despite a number of studies, the exact mechanism by which stress causes disease still remains uncertain. Allostatis is a good example of a relatively powerful model. In the late 1980s, Sterling and Eyer²¹⁾ introduced allostatis to describe physiological changes resulting from the adaptation process and aimed at maintaining the internal stability under stress conditions. It was found that, if daily stimulation is repeated for a long period of time or the level of stimulation is very high, allostatic overload can occur in the process of adaptation even though homeostasis is maintained, and this may result in health problems through a variety of mechanisms.²¹⁾

It has to be noted that, because in this cross-sectional study stress evaluation was limited to a single question ("What is your level of stress in daily life?"), it may be somewhat difficult to interpret the results.¹⁹⁾ Thus, although high body weight and smoking have been found to be major causes of decreased ANM in a number of previous studies, we did not detect such associations.^22,23) A possible explanation is that only presence of smoking was considered in the present study, without quantitative and temporal segmentation. Nevertheless, the existence of a direct association between stress and ANM in Korean women is an important finding. Therefore, the results of the present study may be used as a reference for similar future studies.

In summary, a high level of stress was found to be significantly associated with earlier natural menopause in Korean women between 40 and 70 years of age. This association was still present after adjusting for possible confounders.