Original Article

Association between Age at Menarche and Metabolic Syndrome in Southwest Iran: A Population-Based Case-Control Study

Background

Menarche, which is the first menstrual period in a woman’s life, is a marker of female puberty, as well as the onset of ovarian and other endocrine functions related to reproductive capacity.^1,2 In recent decades, the mean age of menarche has decreased.¹ Early menarche is often defined as menarche ≤ 11 years old; nonetheless, some investigators base definition on menarche at ≤ 12 years.³ Numerous factors, including race, genetics, geographical location, climate, lifestyle, socioeconomic status (SES), physical activity, and nutrition, affect the early or late age of menarche.⁴ Bratke et al proposed a downward trend in the mean age at menarche resulting from an increase in the prevalence of overweight and obesity.⁵

Age at menarche affects women’s health outcomes⁶; however, the conducted studies have yielded contradictory results. Moreover, different reports have been presented on the average age of menarche in many countries. Some studies demonstrated that age at menarche could be a risk factor for such diseases as metabolic syndrome (MetS),⁷ ovarian cancer,⁸ blood pressure,⁹ type 2 diabetes (T2D),¹⁰ gestational diabetes mellitus,¹¹ and cardiovascular disease (CVD).¹² Nevertheless, menarche age showed no statistically significant relationship with diabetes⁶ and MetS² in other studies.

The MetS components include hypertension, hyperglycemia, elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and abdominal obesity, a major predictive variable for CVDs.² Over the past two decades, the prevalence of MetS has increased significantly, especially in developing countries.¹³ A systematic review reported the overall prevalence of MetS at 29% in Iran.¹⁴ The results of the Hoveyzeh cohort study (HCS) demonstrated that the prevalence of MetS was 39.1% (29.3% in men vs. 45.7% in women).¹⁵ Age, weight, menopause, age at menarche, and genetic factors might be the risk factors for MetS development.¹⁶ Previous studies have yielded inconsistent results regarding the relationship between age at menarche and MetS. A thorough understanding of this association can be of great help in the development of therapeutic and preventive interventions, as well as the reduction of MetS and other CVDs. In light of the present study, the present study aimed to assess the association of age at the onset of menarche with MetS and its components in women aged 35-70 years in HCS.

Methods

Study design and participants

This unmatched case-control study was conducted on women aged 35-70 years who entered the enrolment phase of the HCS, which is a population-based cohort study conducted in Hoveyzeh county. This study assesses NCDs in the Arab ethnicity in southwest Iran in 10 009 adults (age 35-70 years) that were recruited from May 2016-August 2018.¹⁵ The HCS center is one of the sites of the Prospective Epidemiological Research Studies in Iran (the PERSIAN Cohort Study), including 180 000 Iranian adults. All the registration, implementation, and quality control steps of this study have been performed according to the PERSIAN protocol.¹⁷

In this study, we selected all participants in the HCS (n = 5983). The participants were asked about their age at the first menstrual. The women who did not have information about menarche age (n = 6) or whose MetS criteria were not measured (n = 147) were excluded from the study. Finally, 5830 women entered into the analysis. The participants were assigned to two groups: MetS as cases (n = 2660) and without MetS as controls (n = 3170). Thereafter, the relationship between the presence or absence of MetS and the age at menarche in the two groups was evaluated. Outcome and exposures were measured equally in the two groups. Informed written consent was obtained from the participants on the day of registration.

Metabolic syndrome definition

Based on the National Cholesterol Education Program-Adult Treatment Panel III guidelines (NCEP ATP3),¹⁸ participants with three or more of the five below criteria were diagnosed as MetS: Abdominal obesity (waist circumstance ≥ 102 in men and ≥ 88 in women), serum TG ≥ 150 mg/dL, take hypertriglyceridemia medications, HDL < 40 mg/dL in men and < 50 in women, taking drugs for low HDL-C, blood pressure (BP) ≥ 130/85 mm Hg, or taking hypertension drugs, fasting blood sugar (FBS) ≥ 100 mg/dL, and taking hyperglycemia drugs.

Assessment of confounders and covariates

Three lifestyle measurements were evaluated in the present study. The participant’s physical activity levels by the International Physical Activity Questionnaire (IPAQ)¹⁹ based on the metabolic equivalent of the task (MET Index). One MET is the energy cost of sitting quietly, equivalent to a caloric consumption of one kcal/kg/h. The person who has smoked at least 100 cigarettes during a lifetime is defined as a smoker.²⁰ Another lifestyle measurement was the use of alcohol (yes/no). The wealth index is one of the socioeconomic indexes calculated on interview day according to the information on households’ assets, including freezer, TV, motorbike, cell phone, car, vacuum cleaner, internet access, washing machine, computer, as well as household utilities consisting of house ownership and the number of rooms per capita. These scores were converted into 5-ordered categories, including poorest, poor, moderate, rich, and richest, based on the quintiles.²¹ The assessment of anthropometric measurements was performed while the participants were wearing light clothes and no shoes. Height was measured to the nearest 0.5 cm by a stadiometer (Seca 206), and weight was measured to the nearest 1 kg using a standing scale (Seca 755). Seca locked tape meters measured waist, hip, and wrist circumferences (cm). The body mass index (BMI) was calculated as weight (kg) divided by squared height (m²). BP was measured by Riester sphygmomanometers twice (10 minutes intervals) on each arm based on the PERSIAN cohort protocol.¹⁷Other anthropometric measurements were waist circumference (cm), hip circumference (cm), and wrist circumference (cm).

Assessment of biological measurements: In the HCS, 25 cc fasting blood was collected from each participant. Blood samples were centrifuged (Sigma, Germany) at 3000 rpm for 10 minutes to separate the serum. Thereafter, the required serum levels were measured by BT 1500 autoanalyzer (Biotecnica Instruments, Italy). The hematology autoanalyzer did a complete blood count (CBC) (Nihon Kohden 6510-k, Japan). Urine tests (urine pH, specific gravity) and analysis were also performed.¹⁷ Other confounders used contraceptives (yes/no), gravity, parity, and liver enzymes, such as alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP).

Statistical analysis

The mean and standard deviation (SD) for continuous variables, as well as the number and percent for categorical variables, were used to describe the variables. The chi-square test compared the categorical variables. The independent t test was used to compare continuous variables between the two groups. Multiple logistic regression was used to assess the association between age at menarche and MetS by controlling confounder factors. The analyses were carried out in SPSS software (version 23). A P value was less than 0.05 was considered statistically significant.

Results

In this study, we recruited 5830 female participants of the HCS. The mean age at menarche was 12.60 ± 1.76. The mean age at menarche slightly differed in Urban and rural women (12.58 ± 1.71 and 12.63 ± 1.83 years, respectively). Based on the wealth index, the prevalence of early menarche ( ≤ 11 years) in the poorest groups is more than that in the richest groups (22.1% vs. 16.6%). The overall prevalence of MetS in the enrollment phase in women aged 35-70 years in the HCS was 45.62%.¹⁵ The characteristics of women with or without MetS were reported in Table 1.

Participants with MetS were older than those without MetS. Women with MetS had a less-than-mean age at menarche and HDL level. On the contrary, women with MetS had a greater mean BMI, weight, waist circumference, hip circumference, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), TG, pulse rate (PR), FBS, ALK, AST, and ALT levels. The chi-square test results pointed to the significant relationship of MetS with wealth index, smoking, education, and contraceptive use (P < 0.0001). Furthermore, the results demonstrated that the groups with and without MetS were significantly different in the mean age of menarche, mean weight, waist circumference, hip circumference, waist circumference, SBP, DBP, PR, TC, TG, FBS, ALK, AST, ALT, gravity, and parity (P < 0.0001) (Table 1). The MetS and its components were significantly associated with age at menarche (Table 2).

Table 3 displays the odds ratio (OR) and 95% confidence interval (CI) for MetS according to age at menarche of the women in the four groups ( ≤ 11 years, 12-13 years, 14-15 years, ≥ 16 years), using age at menarche 12-13 years as the reference category. Model 1 depicts crude ORs of MetS for four menarche age groups so that the odds of MetS at menstrual age of ≤ 11 years is 1.14 (95% CI: 1.00, 1.30) more than the reference group. Model 2 is adjusted for demographic variables (age, education), lifestyle (smoking and physical activity), and BMI. The odds of having MetS at menstrual age of ≤ 11 years was 1.04 (95% CI: 0.90, 1.20) more than the reference group. Model 3 is adjusted for biological measurements (FBS, TG, TC, HDL, AST, ALT, and ALK), as well as DPB, SPB, and PR.

The odds of having MetS at menstrual age of ≤ 11 years was 1.33 (95% CI: 1.10, 1.60) more than the reference group. Moreover, after adjustment for reproductive variables (gravidity, parity, gestational diabetes, pregnancy hypertension, use of oral contraceptives, and use of hormone replacement therapy), model 4 demonstrated the odds of having MetS in groups with menstrual age ≤ 11 years (95% CI: 1.02, 1.35) was 14% higher than that in the reference group (Table 3). Adjusted Model 2, Model 3, and Model 4 reported in model 5, the odds of having MetS at menstrual age of ≤ 11 years was 1.23 (95% CI: 1.01, 1.51) more than the reference group.

Discussion

Based on previously conducted studies, the age of menarche affects health outcomes in the later years of women’s lives. In the current study, the age of menarche was not much different from the average age of girls in Iran. The age at menarche in this study was lower than that in a previous study in Khuzestan province, and this downward trend can be due to the increase in obesity and hormonal changes in children.²² The mean age at menarche has been reported differently in studies conducted across the globe. The result of the present study demonstrated that the mean age at menarche in Iran is similar to that in some countries, such as the United States and Turkey, and less than that in Indian and Chinese women.^12,23-25

The warm climate of Hoveyzeh in southwestern Iran might be the reason for the lower mean age of menarche in this area than that in women who live in cold regions.²⁶ This study demonstrated that the mean age at menarche in urban regions is slightly lower than that in rural areas. Different studies almost confirmed this result and pointed to the association of the urban/rural setting with early menarche. This difference in menarche age can be attributed to overnutrition, obesity, and overweight in urban girls.^27,28

In the current study, rich women experienced menarche earlier. In line with our results, other studies in Mexico reported that women with high SES reached menarche the earliest and those with low SES the latest. The historical decline in age at menarche for high and medium SES groups occurred relatively early, whereas it was observed later in low SES groups. Moreover, the US study found income status related to the timing of menarche over time when the proportion of girls experiencing early menarche ( < 11 years old) increased over 50 years only for those girls of a low socioeconomic position.²⁹ On the contrary, another study in the United Kingdom spanning 85 years found a decline in the timing of menarche across all socioeconomic groups.³⁰

The results of the current study pointed to a relationship between MetS and the age of menarche at the age of below 11 years; nonetheless, different studies have yielded inconsistent results. This discrepancy might be due to differences in the study area and participants, assimilation in confounding variables, study design, and sample size.²² The results of studies on the relationship between menarche age and MetS are not definite.^31,32 In agreement with the present research, some studies demonstrated an association between age at menarche in women with and without MetS.^33,34 The most suggested explanation is that early menarche in adolescents and MetS in adulthood are the consequences of childhood obesity.³² A study conducted on Chinese women reported that the age at menarche was inversely associated with the total number of MetS components.³⁵ Cho et al showed no association between age at menarche and MetS.³¹

Lee et al suggested that the risk of MetS was significantly increased at ≤ 12 years of age at menarche (OR = 1.91, P < 0 05).¹ Glueck et al indicated that menarche age had a curvilinear (‘U’ shaped) relationship with MetS in adulthood. Late and early menarche are risk factors for MetS and cardiometabolic abnormalities in adults.³⁶ Moreover, Hwang et al reported that early or late menarche was not associated with an increased risk of MetS in premenopausal Korean women.²

The present study illustrated a statistically significant relationship between the component of MetS and menarche age groups. Janghorbani et al showed a strong association between younger age at menarche and an increased risk of T2D.³⁷ A study in Brazil pointed to a relationship between menarche age (less than 11 years) and a high risk of diabete.³⁸ Sumi et al, in a retrospective cohort study on the relationship of menarche age with obesity and glycemic control in T2D demonstrated that age at menarche was inversely correlated with BMI and abdominal circumference.³⁹ Yang et al reported that menarche age has a linear and inverse relationship with the incidence of diabetes for each year of delay.⁴⁰ Another study by Qiu et al found no significant association between menarche age and diabetes. Nonetheless, there was a significant relationship between late menarche age (18 years) and lower CVD risk.⁶ Lee et al reported that women with age at menarche ≤ 12 years had significantly higher levels of triglycerides. Furthermore, hypertriglyceridemia was significantly increased at early menarche.¹

A major strength of the present study is the large study population. Another advantage was the use of high-reliability cohort study data. A limitation of our study is the absence of actual menarche dates of the girls and the use of self-reporting that may be prone to recall bias. However, previous studies pointed out that self-reporting for menarche dates is reliable. Furthermore, we conducted this study on Arab ethnicity, and the results of our study may have low external validity.

Conclusion

As evidenced by the obtained results, the odds of having MetS were higher in women whose menarche age was ≤ 11 years. Moreover, the association between MetS components and age groups at menarche was statistically significant. Although determining the average age of menarche can effectively identify people with the risk of MetS, cohort studies are needed to clarify this relationship

Acknowledgments

The ethics committee approved this project of Ahvaz Jundishapur University of Medical Sciences (Ethical code: IR.AJUMS.REC.1398.272). This study was performed in accordance with the Helsinki Declaration. Informed consent was obtained from all participants.

Conflict of interest

None to declare.

Funding

The Iranian Ministry of Health and Medical Education has contributed to the funding used in the Persian Cohort through Grant number 700/534 and the Vice-Chancellor for Research at Ahvaz Jundishapur University of Medical Sciences grant number HCS-9809.

References

1. Effect of interaction between early menarche and genetic polymorphisms on triglyceride. Oxid Med Cell Longev 2019; 2019:9148920. doi: 10.1155/2019/9148920 [Crossref]
2. Relationship between age at menarche and metabolic syndrome in premenopausal women: Korea national health and nutrition examination survey 2013-2014. Korean J Fam Med 2018; 39(5):300-6. doi: 10.4082/kjfm.17.0022 [Crossref]
3. Early menarche: a systematic review of its effect on sexual and reproductive health in low- and middle-income countries. PLoS One 2017; 12(6):e0178884. doi: 10.1371/journal.pone.0178884 [Crossref]
4. Age at menarche and risks of all-cause and cardiovascular death: a systematic review and meta-analysis. Am J Epidemiol 2014; 180(1):29-40. doi: 10.1093/aje/kwu113 [Crossref]
5. Timing of menarche in Norwegian girls: associations with body mass index, waist circumference and skinfold thickness. BMC Pediatr 2017; 17(1):138. doi: 10.1186/s12887-017-0893-x [Crossref]
6. Associations between age at menarche and menopause with cardiovascular disease, diabetes, and osteoporosis in Chinese women. J Clin Endocrinol Metab 2013; 98(4):1612-21. doi: 10.1210/jc.2012-2919 [Crossref]
7. Association of age at menarche with metabolic syndrome and its components in rural Bangladeshi women. Nutr Metab (Lond) 2012; 9(1):99. doi: 10.1186/1743-7075-9-99 [Crossref]
8. Age at menarche and risk of ovarian cancer: a meta-analysis of epidemiological studies. Int J Cancer 2013; 132(12):2894-900. doi: 10.1002/ijc.27952 [Crossref]
9. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab 2009; 94(12):4953-60. doi: 10.1210/jc.2009-1789 [Crossref]
10. Duration of reproductive life span, age at menarche, and age at menopause are associated with risk of cardiovascular disease in women. J Am Heart Assoc 2017; 6(11):e006713. doi: 10.1161/jaha.117.006713 [Crossref]
11. Age at menarche and risk of gestational diabetes mellitus: a population-based study in Xiamen, China. BMC Pregnancy Childbirth 2019; 19(1):138. doi: 10.1186/s12884-019-2287-6 [Crossref]
12. Age at menarche and risk of major cardiovascular diseases: evidence of birth cohort effects from a prospective study of 300,000 Chinese women. Int J Cardiol 2017; 227:497-502. doi: 10.1016/j.ijcard.2016.10.115 [Crossref]
13. Surgical menopause versus natural menopause and cardio-metabolic disturbances: a 12-year population-based cohort study. J Endocrinol Invest 2015; 38(7):761-7. doi: 10.1007/s40618-015-0253-3 [Crossref]
14. Prevalence of metabolic syndrome among Iranian population: a systematic review and meta-analysis. Iran J Public Health 2017; 46(4):456-67.
15. Cohort profile: the Hoveyzeh Cohort Study (HCS): a prospective population-based study on non-communicable diseases in an Arab community of Southwest Iran. Med J Islam Repub Iran 2020; 34:141. doi: 10.34171/mjiri.34.141 [Crossref]
16. Is there any association between age at menarche and risk of metabolic syndrome? The Tehran Lipid & Glucose Study. Arch Iran Med 2019; 22(9):495-500.
17. Prospective epidemiological research studies in Iran (the PERSIAN Cohort Study): rationale, objectives, and design. Am J Epidemiol 2018; 187(4):647-55. doi: 10.1093/aje/kwx314 [Crossref]
18. The US national cholesterol education programme adult treatment panel III (NCEP ATP III): prevalence of the metabolic syndrome in postmenopausal Latin American women. Climacteric 2007; 10(2):164-70. doi: 10.1080/13697130701258895 [Crossref]
19. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 2003; 35(8):1381-95. doi: 10.1249/01.mss.0000078924.61453.fb [Crossref]
20. Profile and preliminary results of Iranian sub cohort chronic obstructive pulmonary disease (COPD) in Shahrekord PERSIAN cohort in southwest Iran. BMC Pulm Med 2021; 21(1):105. doi: 10.1186/s12890-021-01469-8 [Crossref]
21. The international wealth index (IWI). Soc Indic Res 2015; 122(1):65-85. doi: 10.1007/s11205-014-0683-x [Crossref]
22. Menarche age in Iran: A meta-analysis. Iran J Nurs Midwifery Res 2014; 19(5):444-50.
23. Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. J Pediatr Endocrinol Metab 2014; 27(1-2):47-51. doi: 10.1515/jpem-2013-0286 [Crossref]
24. Trends in menarcheal age between 1955 and 2009 in the Netherlands. PLoS One 2013; 8(4):e60056. doi: 10.1371/journal.pone.0060056 [Crossref]
25. A Prospective cross-sectional study to assess the association of age of menarche with body mass index in adolescent girls of urban and rural schools of Vijayapura, North Karnataka. J Krishna Inst Med Sci Univ 2020; 9(3):72-80.
26. A systematic literature review of factors affecting the timing of menarche: the potential for climate change to impact women’s health. Int J Environ Res Public Health 2020; 17(5):1703. doi: 10.3390/ijerph17051703 [Crossref]
27. Knowledge of peri-menarcheal changes and a comparative analysis of the age at menarche among young adolescent school girls in urban and rural Cameroon. BMC Public Health 2020; 20(1):1661. doi: 10.1186/s12889-020-09787-y [Crossref]
28. Secular trends in age at menarche in 20th century Mexico: differences by ethnicity, area of residency, and socioeconomic status. Am J Hum Biol 2020; 32(6):e23404. doi: 10.1002/ajhb.23404 [Crossref]
29. Age at menarche: 50-year socioeconomic trends among US-born black and white women. Am J Public Health 2015; 105(2):388-97. doi: 10.2105/ajph.2014.301936 [Crossref]
30. Secular trends in age at menarche in women in the UK born 1908-93: results from the Breakthrough Generations Study. Paediatr Perinat Epidemiol 2011; 25(4):394-400. doi: 10.1111/j.1365-3016.2011.01202.x [Crossref]
31. Association of age at menarche with metabolic syndrome and components of metabolic syndrome in premenopausal women, Korea National Health and nutrition examination survey VI. Int J Diabetes Dev Ctries 2016; 36(3):345-51. doi: 10.1007/s13410-016-0488-3 [Crossref]
32. Early menarche is associated with metabolic syndrome and insulin resistance in premenopausal Korean women. Eur J Pediatr 2016; 175(1):97-104. doi: 10.1007/s00431-015-2604-7 [Crossref]
33. A cutoff for age at menarche predicting metabolic syndrome in Egyptian overweight/obese premenopausal women. Diabetes Metab J 2017; 41(2):146-9. doi: 10.4093/dmj.2017.41.2.146 [Crossref]
34. Age of menarche and the metabolic syndrome in China. Epidemiology 2007; 18(6):740-6. doi: 10.1097/EDE.0b013e3181567faf [Crossref]
35. Effects of age at menarche, reproductive years, and menopause on metabolic risk factors for cardiovascular diseases. Atherosclerosis 2008; 196(2):590-7. doi: 10.1016/j.atherosclerosis.2007.06.016 [Crossref]
36. Early and late menarche are associated with oligomenorrhea and predict metabolic syndrome 26 years later. Metabolism 2013; 62(11):1597-606. doi: 10.1016/j.metabol.2013.07.005 [Crossref]
37. Systematic review and meta-analysis of age at menarche and risk of type 2 diabetes. Acta Diabetol 2014; 51(4):519-28. doi: 10.1007/s00592-014-0579-x [Crossref]
38. Earlier age at menarche is associated with higher diabetes risk and cardiometabolic disease risk factors in Brazilian adults: Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Cardiovasc Diabetol 2014; 13:22. doi: 10.1186/1475-2840-13-22 [Crossref]
39. Impact of age at menarche on obesity and glycemic control in Japanese patients with type 2 diabetes: Fukuoka Diabetes Registry. J Diabetes Investig 2018; 9(5):1216-23. doi: 10.1111/jdi.12839 [Crossref]
40. Age at menarche and incidence of diabetes: a prospective study of 300,000 women in China. Am J Epidemiol 2018; 187(2):190-8. doi: 10.1093/aje/kwx219 [Crossref]