Academic Editor: Brian Tomlinson
Background: We aim to examine the relationship between age at menarche
and hyperhomocysteinemia in women in Hunan Province. Methods: Participants were
required to complete a questionnaire that included age at menarche, lifestyle
habits, other baseline information, and blood biochemical parameters in a
cross-sectional study. The association between hyperhomocysteinemia and age at
menarche was examined by Multivariable adjusted logistic regression. Results: A
cohort of 2008 women with a mean age of 60.11 years (aged from 18.0 to 88.0
years) was included in this study. After adjustment for confounding factors such
as age, the results showed that the risk of hyperhomocysteinemia among women
whose age at menarche were over 16 years was 2.543 (1.849, 3.469) times higher
than the risk among women whose age at atmenarche were less than 14 years, and
2.656 (1.882, 3.748) times more likely to have hypertension than women with
menarche at 14 years. Besides, the odds ratios of diabetes, hyperlipidemia, and
obesity were elevated in women older than 16 years of age at menarche (OR =
1.924, p
Hyperhomocysteinemia (HHcy) has been defined as an elevated serum concentration
of homocysteine exceeding 15
The participants of our study were selected from four departments (Cardiology, neurology, geriatrics, general practice) of Hunan Provincial People’s Hospital between 2018–2021. After excluding participants who were male, taking vitamin B6, vitamin B12, folic acid, using sex hormones (estrogen or progesterone) and other medications that affect estrogen, Hcy levels, lipid, cardiovascular function, blood pressure, fail to respond and age at menarche earlier than 8 years (n = 0) or later than 22 years (n = 4), 2008 female inpatients aged 18–88 were selected. All patients participating in the study were informed and consented to this study.
Information on baseline characteristics of participants (age, gender,
registration address, marital status, etc.) lifestyles (smoking status, drinking
status) was obtained. Patients were instructed to complete the questionnaire
face-to-face and one-to-one by well-trained investigators. Smoking at least one
cigarette a day for six months was defined as smoking, and drinking alcohol at
least 12 times per year was defined as alcohol consumption. Body mass index (BMI,
kg/m
Hypertension was defined as systolic blood pressure
The data were double-inputted with EpiData 3.1 (EpiData Association, The Kingdom
of Denmark), and SPSS 26.0 (IBM, Armonk, NY, USA) software package was used to
perform statistical analysis. We divided participants into five groups based on
the plural and quartiles of their age at menarche:
The categorical variables are presented as percentages and frequencies, while
the continuous variables are described as mean
The basic characteristics of the study participants stratified by age at
menarche are summarized in Table 1. We included 2008 study subjects, whose mean
age was 60.11
Characteristics | Total | Age at menarche, y | p | ||||
13 | 14 | 15 | |||||
N | 2008 | 180 | 560 | 700 | 314 | 254 | —— |
Age at enrollment, y | 60.11 |
58.54 |
57.74 |
59.17 |
63.38 |
65.00 |
|
Urban, n (%) | 1170 (58.3) | 103 (57.2) | 351 (56.3) | 400 (57.1) | 197 (62.7) | 155 (61.0) | 0.329 |
Menopause, n (%) | 1708 (85.1) | 148 (82.2) | 460 (82.1) | 580 (82.9) | 284 (90.4) | 236 (92.9) | |
Age at menopause, y | 49.62 |
49.66 |
49.76 |
49.53 |
49.53 |
49.65 |
0.818 |
Menstruation is regular, n (%) | 1861 (96.3) | 168 (93.3) | 512 (91.4) | 652 (93.1) | 300 (95.5) | 229 (90.2) | 0.004 |
Age at first delivery, y | 24.01 |
24.39 |
23.88 |
24.10 |
24.33 |
23.41 |
0.003 |
Age at last delivery, y | 27.14 |
27.25 |
26.72 |
27.22 |
27.51 |
27.15 |
0.102 |
BMI | 23.69 |
24.14 |
23.35 |
23.81 |
23.46 |
24.05 |
0.248 |
SBP, mm Hg | 135.52 |
136.52 |
133.58 |
134.29 |
139.19 |
137.94 |
0.001 |
DBP, mm Hg | 80.80 |
81.10 |
79.89 |
81.63 |
80.57 |
80.62 |
0.877 |
Hcy, |
13.19 |
13.41 |
12.68 |
12.71 |
13.83 |
14.66 |
|
FPG, mmol/L | 5.66 |
5.84 |
5.38 |
5.56 |
5.58 |
6.49 |
|
BUN, mmol/L | 65.82 |
67.60 |
90.18 |
69.91 |
44.76 |
25.74 |
|
UA, |
259.75 |
255.46 |
232.90 |
258.24 |
280.33 |
300.36 |
|
GFR, mL/min | 90.35 |
88.98 |
92.80 |
91.95 |
86.33 |
86.13 |
0.001 |
Scr, |
72.25 |
73.79 |
71.02 |
73.01 |
71.18 |
73.06 |
0.987 |
ALT, U/L | 21.37 |
20.14 |
21.45 |
21.07 |
21.64 |
22.49 |
0.772 |
TC, mmol/L | 4.60 |
4.44 |
4.59 |
4.59 |
4.56 |
4.82 |
0.013 |
TG, mmol/L | 1.82 |
1.85 |
1.79 |
1.81 |
1.80 |
1.91 |
0.802 |
LDL-C, mmol/L | 2.71 |
2.56 |
2.72 |
2.66 |
2.72 |
2.90 |
0.001 |
HDL-C, mmol/L | 1.25 |
1.20 |
1.27 |
1.23 |
1.26 |
1.28 |
0.035 |
E2, pg/mL | 24.26 |
29.49 |
24.62 |
24.06 |
23.40 |
20.83 |
0.049 |
When the study participants were grouped by birth cohort, it was found that women with an earlier birth date generally had later menarche and had a slightly later age of menopause than women with a later birth cohort. Women who were born earlier also had an earlier age at first delivery and a later age at final delivery. Lifestyle habits such as smoking and alcohol consumption did not differ between the three groups. These data are presented in Table 2.
Characteristics | Birth cohort | p | ||
1950–1970 | ||||
N | 557 | 1200 | 251 | — |
Age at enrollment, y | 74.04 |
57.56 |
41.42 |
|
Urban, n (%) | 397 (71.3) | 658 (54.8) | 115 (45.8) | |
Married (n%) | 380 (68.2) | 1130 (94.3) | 229 (91.2) | |
Age at menarche, y | 14.50 |
13.92 |
13.76 |
|
Age at menopause, y | 49.74 |
49.67 |
46.00 |
|
Age at first delivery, y | 23.53 |
24.17 |
24.44 |
|
Age at last delivery, y | 28.35 |
26.42 |
27.00 |
|
Smoking, n (%) | 12 (2.2) | 33 (2.9) | 99 (4.0) | 0.292 |
Alcohol, n (%) | 19 (3.4) | 38 (3.2) | 5 (2.2) | 0.618 |
Linear regression analysis showed that UA, TC, LDL-C, Hcy, and FPG were all positively correlated with age at menarche, which suggests that the later age at menarche, the higher risk of disease. These data are presented in Table 3.
Variable | Model 1 | Model 2 | Model 3 | |||
p | p | p | ||||
UA, |
14.175 | 6.862 | 0.004 | 5.411 | 0.020 | |
TC, mmol/L | 0.068 | 0.068 | 0.075 | |||
TG, mmol/L | 0.037 | 0.092 | 0.035 | 0.121 | 0.036 | 0.116 |
LDL-C, mmol/L | 0.057 | 0.056 | 0.060 | 0.031 | ||
HDL-C, mmol/L | 0.007 | 0.185 | 0.006 | 0.275 | 0.008 | 0.176 |
Hcy, |
0.416 | 0.218 | 0.023 | 0.208 | 0.032 | |
FPG, mmol/L | 0.154 | 0.105 | 0.012 | 0.104 | 0.014 | |
E2, pg/mL | –1.401 | 0.003 | 0.152 | 0.722 | –0.102 | 0.808 |
Model 1: we did not adjust any confounding factors.
Model 2: we adjusted the age. Model 3: we adjusted age, area of residence, marital status, age at menopause, age at first delivery, age at final delivery, smoking, and alcohol consumption. |
Multivariable logistic regression analysis showed that women with age at
menarche of 13 years had a lower risk of developing hypertension and diabetes
than women with age at 14 years (OR = 0.740, p = 0.009; OR = 0.597,
p = 0.003). Conversely, women with age at menarche older than 16 years
had the risk of HHcy 2.543-fold and hypertension 2.656-fold compared with women
with age at menarche 14 years. The odds of diabetes, hyperlipidemia, and obesity
were elevated in women older than 16 years of age at menarche (OR = 1.924,
p
Variable | Age at menarche, y | ||||||||
13 | 14 | 15 | |||||||
OR | p | OR | p | OR | OR | p | OR | p | |
HHcy | 1.164 (0.781, 1.174) | 0.455 | 1.017 (0.770, 1.343) | 0.906 | 1 | 2.046 (1.511, 2.770) | 2.543 (1.849, 3.469) | ||
Hypertension | 1.098 (0.783, 1.540) | 0.588 | 0.740 (0.591, 0.927) | 0.009 | 1 | 1.842 (1.373, 2.471) | 2.656 (1.882, 3.748) | ||
Diabetes | 0.925 (0.582, 1.471) | 0.743 | 0.597 (0.423, 0.844) | 0.003 | 1 | 1.164 (0.815, 1.662) | 0.403 | 1.924 (1.360, 2.724) | |
Hyperlipidemia | 0.755 (0.500, 1.140) | 0.181 | 1.186 (0.918, 1.532) | 0.191 | 1 | 1.364 (1.012, 1.839) | 0.041 | 1.491 (1.086, 2.047) | 0.014 |
Obesity | 1.264 (0.742, 2.152) | 0.388 | 0.820 (0.546, 1.232) | 0.339 | 1 | 0.725 (0.434, 1.210) | 0.218 | 1.670 (1.078, 2.586) | 0.022 |
The model was corrected for age, area of residence, marital status, menopause, smoking, and alcohol consumption. |
After stratifying the study population by birth cohort, women born before 1950
and 1950–970 cohorts had a higher risk of HHcy if they had later menarche (OR =
2.354, p
Variable | birth cohort | Age at menarche, y | ||||||||
13 | 14 | 15 | ||||||||
OR | p | OR | p | OR | OR | p | OR | p | ||
HHcy | 1.312 (0.634, 2.716) | 0.464 | 1.704 (1.042, 2.785) | 0.034 | 1 | 2.349 (1.432, 3.853) | 0.001 | 2.354 (1.445, 3.835) | 0.001 | |
1950–1970 | 1.357 (0.797, 2.311) | 0.261 | 0.891 (0.603, 2.318) | 0.564 | 1 | 1.671 (1.070, 2.609) | 0.024 | 1.829 (1.120, 2.987) | 0.016 | |
0.558 (0.116, 2.676) | 0.466 | 0.788 (0.292, 2.127) | 0.638 | 1 | 0.802 (0.209, 3.080) | 0.748 | 1.283 (0.250, 6.588) | 0.765 | ||
Hypertension | 1.023 (0.326, 3.210) | 0.969 | 1.073 (0.487, 2.367) | 0.861 | 1 | 1.607 (0.675, 3.829) | 0.284 | 2.595 (0.935, 7.199) | 0.067 | |
1950–1970 | 1.071 (0.706, 1.626) | 0.746 | 0.727 (0.550, 0.962) | 0.026 | 1 | 1.405 (0.970, 3.036) | 0.072 | 1.763 (1,146, 2.714) | 0.010 | |
1.846 (0.759, 4.491) | 0.177 | 0.702 (0.352, 1.397) | 0.313 | 1 | 2.349 (1.008, 5.474) | 0.048 | 2.517 (1.132, 7.341) | 0.011 |
The results of this study showed that compared to those who were born before 1950, women born after the 1970s had an earlier age at menarche from 14 to 13 years, and this decrease in the age at menarche was not exceptional. In a study based on data from the China Health and Nutrition Survey, the average age at menarche for Chinese women dropped dramatically from 14.35 to 12.60 years from 1973 to 2004 [15]. The decline in the age at menarche among women in developed countries has been slightly slower; for example, the average age at menarche among Japanese women of the same Asian ethnicity decreased from 13.8 to 12.2 years, a decline of 1.6 years over approximately 50 years [16]. The average age at menarche dropped from 12.75 to 12.54 years Over 25 years in the United States [17]. However, the current study shows that the decline in the age at menarche in Chinese women has not slowed down.
Previous studies have suggested that earlier age at menarche may lead to increased cardiovascular disease and mortality [18], including hypertension and poor glucose tolerance [19]. Earlier age at menarche leads to increased plasma cholesterol or adverse vascular changes in postmenopausal women [11]. In 2016, a study of the association between age at menarche and cardiovascular disease among 300,000 women in 10 regions of China found that this association varied between birth cohorts [20]. Women who are born in the early cohort usually had a later age at menarche. However, the present study found women generally have an earlier age at menarche, while a later age at menarche may be associated with a range of disorders in middle-aged and elderly women. The pattern of reproductive factors and their interaction with lifestyle factors may explain the increased risk of cardiovascular disease. The industrialization revolution in China in the 1970s allowed young women to receive better education, more time for exercise, a later age at first birth, fewer births, and less smoking and alcohol use than women born in the 1950s.
The results of this study showed that advancing within normal limits, an earlier
age at menarche is protective against diabetes and hypertension (OR = 0.740,
p = 0.009; OR = 0.597, p = 0.003). However, this protective
effect disappears when the age at menarche is less than 12 years. Most studies
from the West, Japan, and developed cities on the eastern coast of China have
shown that early menarche increases the risk of hypertension. Still, our study
demonstrated that late age at menarche is associated with an increased risk of
hypertension (OR = 2.656, p
It has been well established that early menarche leads to obesity in adolescents and young women [23], but very few studies have been conducted on postmenopausal women because confounding factors of age cannot be excluded. In the present study, after excluding the effects of age and reproductive factors, late menarche was still associated with obesity (OR = 1.670, p = 0.022). Furthermore, age at menarche was associated with a stronger relationship of cardiovascular disease in white women compared to black people, both in adolescents [24] and in mature women [21]. Considering that age at menarche also differs between Chinese and European women, we speculate whether there are also ethnic differences in age at menarche, and, at the same time, the association between age at menarche and disease.
As an independent risk factor for CVD, Homocysteine is of great importance for the prediction of CVD. For women in Asia, the health consequences of reproductive factors on CVD risks have not been well quantified. If possible, risk factors for HHcy can be identified and controlled early in the life course, and it will have significant implications for health in women’s middle and old age. Indeed, besides cardiovascular disease, HHcy has been suggested as a mediator of other diseases. Due to the adverse vascular effects and cytotoxicity of homocysteine, HHcy can affect almost all body systems. Such as dementia and Alzheimer’s disease [25], osteoporosis [26], diabetes mellitus [27], and diabetic retinopathy [28]. Therefore the relationship between age at menarche and HHcy needs to be urgently studied.
The underlying mechanism for the difference in the age at menarche is unclear. A
genome-wide association study in European women identified 106 genomic loci
associated with age at menarche [29, 30], but it is unknown whether this evidence
can be applied to Asian women. The decline in endogenous estrogen in
postmenopausal women is associated with the risk of cardiovascular disease [31].
In women born earlier than the 1950s, age at menarche remained negatively
associated with estrogen after age correction (
Our study has several limitations. First, our sample spanned a large age range (18–88 years), and although stratified analyses by corrected age and birth cohort were able to offset confounding factors to some extent, most participants were older, with a smaller number of participants born after 1970. Second, when baseline information on age at menarche was collected, there may have been recalling bias in the data for some participants due to age. Finally, the samples collected in this study were all from inpatients of Hunan Provincial People’s Hospital, which is located in Changsha, the capital of Hunan Province, and most of the samples collected were from Changsha and its surrounding cities, which may have caused the existence of some selection bias.
Our findings suggest that late menarche tends to be associated with a high risk of hyperhomocysteinemia and its associated set of diseases such as hypertension, diabetes, hyperlipidemia, and obesity in women in Hunan, China. This association tends to differ across birth cohorts. Therefore, adequate attention to menarcheal age may be able to predict diseases in older women.
These should be presented as follows: YY performed analytical work to organize the data and was a major contributor in writing the manuscript. SHD, YNZ, RX, TY, ZHD did the work of collecting data, XQH led the project and provided financial support. All authors read and approved the final manuscript. All authors contributed to editorial changes in the manuscript.
Ethical approval was obtained from the Ethics Committee of Hunan Provincial People’s Hospital, China. The study was conducted in the form of a questionnaire at Hunan Provincial People’s Hospital, the approval number is 2017 (034). And written informed consent was obtained from all individual participants included in the study before participants completed the questionnaire. In addition, all methods were performed in accordance with the relevant guidelines and regulations.
We thank all the women who participated in this study and the Hunan Provincial People’s Hospital for their support.
This study was sponsored by grants from the National Natural Science Foundation of China (No. 81773530), Hunan Provincial Natural Science Foundation of China (No. 2020JJ4047).
The authors declare no conflict of interest.
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