Consistent with our original hypothesis, the longer duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, was positive related to lower risk of dementia in late life.
This population-based cross-sectional study of rural females with natural menopause, were generally consistent with previous studies that have examined the relationship of the reproductive period on cognitive profile [24, 25]. Traditionally, the duration of reproductive period was defined as the period extending from age at menarche to age at menopause in years. We found that the average age at menarche in rural old females was 16.36 (2.25), which was consistent with old women in Eastern China (16.8 ± 1.7 years old) [17]. While the age of menarche was younger in developed countries. French women showed younger age at first menses (13.1 ± 1.6 years old), older age at menopause (49.5 ± 5.4 years old), and average 36.6 (5.6) years of reproductive period [26]. The Japanese women with CI began menstruating at 14.4 (1.7) years old, which was later than normal women [14] whereas earlier than rural women in northern China. The international age at natural menopause was 44.6–55 years [27], several reports suggested the age was 54 in Europe, 51.4 in North America, and 48.6 in Latin America, and 51.1 in Asia [15]. In our study, the average age at menopause (49.33 ± 4.52 years of age) was consistent with previous studies in Eastern China (49.3 ± 4.2 years of age) and France (49.5 ± 5.4). It was reported that the mean age of natural menopause among Jordanian women was younger (48.5 ± 5.0) [28], with 7.8% of the women experienced early menopause (40–44 years of age), and 21.1% with late menopause (> 52 years of age). What’s more, later age at menarche and younger age at menopause were associated with poor cognitive performance [13, 16], and our findings were generally consistent with these studies.
Most previous studies had been conducted among Western females to investigate the relationship between reproductive periods with risk of cognitive function and dementia, while evidence among Asian populations is limited. Reproductive period, an indicator of endogenous estrogen exposure, lasted shorter in Chinese women (32.97 ± 5.03 in our study; 34.5 ± 4.3 in Guangzhou province; and 32.5 ± 4.7 in Zhejiang province) than those living in dependent countries (36.6 ± 5.6 in ESPRIT study from France, 35.1 ± 5.2 in the Rotterdam Study from Netherlands, and 34.9 ± 4.5 in the Prospective Population Study of Women from Gothenburg, Sweden). In other words, old females in rural northern China had shorter period of endogenous estrogen exposure, which might lead to poor cognitive performance and increase the risk of dementia. Three population-based studies had supported that shorter reproductive period was significantly associated with worse cognitive function among Chinese women [12, 16, 17]. The Japan Public Health Center-based Prospective Study also showed longer exposure to endogenous estrogen may have a protective effect against cognitive impairment. Women with a reproductive period ≥ 38 years had a significantly lower risk of cognitive impairment (OR = 0.62, 95% CI, 0.40–0.96) compared with those with ≤ 33 years [14].
The putative association between hormones and cognitive performance is controversial. An observational study in Switzerland, including 44 women receiving IVF, showed that estradiol didn’t have a significant short-term effect on cognitive function [29]. While in a retrospective analysis with 164 surgical-menopause women (the mean time since menopause was 11.3 ± 7.4 years) performed frontal lobe dysfunction and couldn’t be improved by hormone therapy usage [30]. A Cochrane systematic review of clinical trials concluded that hormone replacement therapy (HRT) did not prevent cognitive decline in postmenopausal women[31], and some observational studies also reported null or opposite [13, 32, 33] associations[34]. In a population-based prospective cohort (The Singapore Chinese Health Study), women with < 35 reproductive years were 1.28 (95% CI, 1.11–1.48) times to get cognitive impairment compared with women with 35–39 reproductive years (Ref.), whereas no significant findings among women with > 39 years. When comparing to women with 39–44 years reproductive period, women with 35–38 years had no significant difference on the increased risk of dementia [35]. In ESPRIT study, longer reproductive period had association with better verbal fluency, instead of better global cognition, though the age at first menses was negatively associated with visual memory and psychomotor speed performance [26]. Longer reproductive period was associated with increased risk of all-cause dementia and Alzheimer’s disease in all models, particularly in aging people [34].
We also found that more pregnancies and parities were associated with lower MMSE scores, especially among women with shorter duration of reproductive period. Previous studies indicated that parous women had shorter reproductive periods and lower level of estradiol than nulliparous women, and thus greater parity could lead to an overall lower levels of lifetime estrogen exposure [36, 37]. These findings had been proved in many studies [38–41]. Women with higher number of pregnancies had indirectly relate to higher estro-progestinic exposure. We proposed that it is the increase of progesterone or estrogens level – and not the estrogens decrease, in other words, the dramatic changes in estrogen and progesterone during and after parity, play a role in cognitive impairment. Women with greater parity might lead to lower circulating estrogen over lifetime than women with fewer parity or nulliparity. In our analysis of interaction among the number of pregnancies/parities, reproductive period and dementia, reproductive period positively predicted cognitive performance. And the number of pregnancies/parities, as part of a mediation model, played negative predictive role on cognition; that is, reproductive period would be mediated by the number of pregnancies/parities, had indirect effects of cognitive performance for older women. The shorter reproductive period could increase the risk of dementia by non-parous or greater pregnancies/parities in elderly women. Later age at menarche (≥ 17 years), earlier age at menopause (< 40 years), shorter reproductive span (< 30 years) increased the risks of fractures [42] and age-related hearing decline [43] as well.
The main strength of our study was the large population in rural northern China, and detailed collection of information on participants (demographic, dietary, lifestyle factors, and medical history) to investigate the association and interaction between reproductive and dementia. Nevertheless, several limitations should be noted. As research on reproductive factors and dementia continues, more and more risk factors needed to be investigated, including those affecting dementia and reproduction. The second is recall bias. Because of the self-report information was retrospective, the information of participants might be inaccurate due to their age, while previous studies suggested that age at menarche, age at menopause, the number of brain fast /parities could still be reliable over many years [44, 45]. Another is the lack of objective biomarkers. In this cross-sectional study, hormone levels and Aβ levels were not measured, and dementia was not classified as subtypes, which required further analysis and exploration of the data.