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<article article-type="review-article" dtd-version="1.0" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">CEP</journal-id>
<journal-title-group>
<journal-title>Clinical and Experimental Pediatrics</journal-title><abbrev-journal-title>Clin Exp Pediatr</abbrev-journal-title></journal-title-group>
<issn pub-type="epub">2713-4148</issn>
<publisher>
<publisher-name>Korean Pediatric Society</publisher-name></publisher></journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3345/cep.2019.00353</article-id>
<article-id pub-id-type="publisher-id">cep-2019-00353</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Review Article</subject>
<subj-group subj-group-type="heading">
<subject>Endocrinology</subject>
</subj-group></subj-group></article-categories>
<title-group>
<article-title>Early menarche and its consequence in Korean female: reducing fructose intake could be one solution</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Kim</surname><given-names>Ji Hyun</given-names></name>
<degrees>MD</degrees>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="af1-cep-2019-00353"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-9560-8921</contrib-id>
<name><surname>Lim</surname><given-names>Jung Sub</given-names></name>
<degrees>MD</degrees>
<degrees>PhD</degrees>
<xref ref-type="corresp" rid="c1-cep-2019-00353"/>
<xref ref-type="aff" rid="af2-cep-2019-00353"><sup>2</sup></xref>
</contrib>
<aff id="af1-cep-2019-00353">
<label>1</label>Department of Pediatrics, Dongguk University Ilsan Hospital, Goyang, <country>Korea</country></aff>
<aff id="af2-cep-2019-00353">
<label>2</label>Department of Pediatrics, Korea Cancer Center Hospital, Seoul, <country>Korea</country></aff>
</contrib-group>
<author-notes>
<corresp id="c1-cep-2019-00353">Corresponding author: Jung Sub Lim, PhD, MD. Department of Pediatrics, Korea Cancer Center Hospital, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea E–mail: <email>limjs@kcch.re.kr</email></corresp>
</author-notes>
<pub-date pub-type="collection">
<month>1</month>
<year>2021</year></pub-date>
<pub-date pub-type="epub">
<day>14</day>
<month>5</month>
<year>2020</year></pub-date>
<volume>64</volume>
<issue>1</issue>
<fpage>12</fpage>
<lpage>20</lpage>
<history>
<date date-type="received">
<day>17</day>
<month>4</month>
<year>2019</year></date>
<date date-type="rev-recd">
<day>27</day>
<month>12</month>
<year>2019</year></date>
<date date-type="accepted">
<day>28</day>
<month>2</month>
<year>2020</year></date>
</history>
<permissions>
<copyright-statement>Copyright &#x000a9; 2021 by The Korean Pediatric Society</copyright-statement>
<copyright-year>2021</copyright-year>
<license>
<license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions>
<abstract><p>The mean age at menarche (AAM) of Korean females has been rapidly decreasing over the last 50 years; currently, the prevalence of early menarche (&lt;12 years) is 22.3%. Female adolescents who experience early menarche are known to be at greater risk of psychosocial and behavioral problems along with several physical health problems such as menstrual problems. They also tend to achieve a shorter final height and develop obesity. Population-based Korean studies have shown a strong association between early menarche and the risk of obesity, insulin resistance, metabolic syndrome, nonalcoholic fatty liver disease, diabetes, breast cancer, and cardiovascular disease in adulthood. Although the exact mechanism of how early menarche causes cardiometabolic derangement in later adulthood is unknown, childhood obesity and insulin resistance might be major contributors. Recent studies demonstrated that an excessive consumption of fructose might underlie the development of obesity and insulin resistance along with an earlier AAM. A positive association was observed between sugar-sweetened beverages (a major source of fructose) intake and obesity, metabolic syndrome, insulin resistance, and cardiometabolic risk in Korean females. In pediatrics, establishing risk factors is important in preventing disease in later life. In this regard, early menarche is a simple and good marker for the management of cardiometabolic diseases in adulthood. Decreasing one&#x02019;s fructose intake might prevent early menarche as well as the development of obesity, insulin resistance, and cardiometabolic diseases. </p></abstract>
<kwd-group>
<kwd>Menarche</kwd>
<kwd>Metabolic disease</kwd>
<kwd>Fructose</kwd>
<kwd>Insulin resistance</kwd>
<kwd>Obesity</kwd>
<kwd>Pathophysiology</kwd>
</kwd-group>
</article-meta>
<notes>
<title>Key message</title>
<boxed-text>
<p>In Korea, the average age of menarche has declined sharply. Early menarche is associated with psychosocial and behavioral problems and cardiometabolic disease. Excess fructose intake has been suggested as one cause of early menarche in recent studies, so reducing fructose intake may be one solution.</p>
</boxed-text>
</notes>
</front>
<body>
<sec sec-type="intro">
<title>Introduction</title>
<p>Menarche, defined as a young woman&#x02019;s first menstrual period, is a landmark of pubertal development in females. Age at menarche (AAM) is a key maturity indicator of a female&#x00027;s healthy transition from childhood into young adulthood and an important clinical indicator of her physical, nutritional, and reproductive health &#x0005b;<xref ref-type="bibr" rid="b1-cep-2019-00353">1</xref>&#x0005d;. AAM is influenced by several factors, including genetics, ethnicity, geography, socioeconomic status, and nutritional status &#x0005b;<xref ref-type="bibr" rid="b2-cep-2019-00353">2</xref>-<xref ref-type="bibr" rid="b4-cep-2019-00353">4</xref>&#x0005d;.</p>
<p>AAM has decreased continuously and rapidly in Asian countries, including Korea, probably because of improvements in nutrition &#x0005b;<xref ref-type="bibr" rid="b5-cep-2019-00353">5</xref>&#x0005d;. In Korea, AAM has declined from 15&#x02013;17 years in the 1960s to around 14 years in the 1980s and 12.6 years in the 1990s &#x0005b;<xref ref-type="bibr" rid="b5-cep-2019-00353">5</xref>&#x0005d;. Thus, the proportion of females with early menarche, commonly defined as an AAM &lt;12 years old, has also increased in Korea &#x0005b;<xref ref-type="bibr" rid="b6-cep-2019-00353">6</xref>&#x0005d;.</p>
<p>Female adolescents who experience early puberty and early menarche are known to be at a greater risk of psychosocial problems such as delinquency and risky sexual behavior &#x0005b;<xref ref-type="bibr" rid="b7-cep-2019-00353">7</xref>&#x0005d;. Furthermore, they achieve a shorter final height and develop obesity and several physical health problems such as menstrual problems, compared to adolescents who experience menarche at a later age &#x0005b;<xref ref-type="bibr" rid="b8-cep-2019-00353">8</xref>,<xref ref-type="bibr" rid="b9-cep-2019-00353">9</xref>&#x0005d;. Furthermore, early menarche is a well-known risk factor of chronic cardiometabolic disease and related early mortality in adulthood &#x0005b;<xref ref-type="bibr" rid="b10-cep-2019-00353">10</xref>&#x0005d;. Population-based Korean studies also showed an association between early AAM (&lt;12 years) and the risk of obesity, insulin resistance (IR), metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), diabetes, breast cancer, and cardiovascular disease (CVD) in adulthood &#x0005b;<xref ref-type="bibr" rid="b10-cep-2019-00353">10</xref>-<xref ref-type="bibr" rid="b13-cep-2019-00353">13</xref>&#x0005d;.</p>
<p>In pediatrics, establishing risk factors is important in disease prevention in later life. An early AAM can be a good marker for predicting future metabolic problems. Therefore, this review aimed to: (1) review the secular trend of AAM and early menarche in Korean females; (2) review the factors and conditions related to AAM; (3) find proof of whether early menarche is a risk factor for obesity, IR, MetS, NAFLD, diabetes, and cancer in adult Korean females; and (4) address how to prevent early menarche and discuss its consequences by reviewing its proposed mechanism. To this end, we reviewed the literature, particularly meta-analyses and prospective studies, regarding menarche in Korean female. We hope this review will help pediatricians comprehensively understand the lifetime health problems of women due to early menarche and in preventing early menarche and its complications.</p>
</sec>
<sec>
<title>Secular trends in pubertal timing and AAM</title>
<p>Breast budding is the herald of puberty in girls. The age at the onset of breast development seems to have declined markedly over the last two decades &#x0005b;<xref ref-type="bibr" rid="b14-cep-2019-00353">14</xref>&#x0005d;. Before the 1980s, the mean age at the onset of breast development was approximately 11 years in American and European countries &#x0005b;<xref ref-type="bibr" rid="b15-cep-2019-00353">15</xref>&#x0005d;. However, the mean age at puberty onset in girls was &lt;10 years from the 3rd National Health and Nutrition Examination Survey (NHANES III), 1988&#x02013;1994 &#x0005b;<xref ref-type="bibr" rid="b16-cep-2019-00353">16</xref>&#x0005d;.</p>
<p>A gradual decline in AAM was reported over the past few decades in Western countries &#x0005b;<xref ref-type="bibr" rid="b17-cep-2019-00353">17</xref>&#x0005d;. In Europe, the AAM decreased from approximately 17 years in the early 19th century to approximately 13 years by the mid-20th century and stayed relatively stable with a variation of 0.5 years depending on study population since the 1960s &#x0005b;<xref ref-type="bibr" rid="b18-cep-2019-00353">18</xref>&#x0005d;. However, this secular trend is rapid and ongoing in Asian countries, including Korea. In China, the AAM has fallen 0.7 years per decade over a 40-year period; most recently, it was 12.76 years &#x0005b;<xref ref-type="bibr" rid="b19-cep-2019-00353">19</xref>&#x0005d;.</p>
<p>In Korea, the mean AAM for females born in 1925&#x02013;1929 was 16.59&#x000b1;1.82 years. The AAM decreased to 13.11&#x000b1;1.52 years for those born in 1980&#x02013;1984 and to 12.60&#x000b1;1.14 years for those born in 1990&#x02013;1994 (<xref rid="f1-cep-2019-00353" ref-type="fig">Fig. 1</xref>) &#x0005b;<xref ref-type="bibr" rid="b5-cep-2019-00353">5</xref>&#x0005d;. Young Korean women aged 18&#x02013;30 years now have a mean AAM of 12.7&#x000b1;1.6 years, which is 1.5 years earlier than that of their mothers. Furthermore, the prevalence of early menarche (&lt;12 years) is 22.3%, while the percentage of subjects&#x02019; mothers with early menarche was only 2.5% &#x0005b;<xref ref-type="bibr" rid="b8-cep-2019-00353">8</xref>&#x0005d;. This trend might be due to changes in the socioeconomic environment, possibly acting through changes in nutrition and exercise patterns. South Koreans rapidly accepted Western culture, especially the Western diet, after the 1988 Olympic Games. On the contrary, North Korean refugees still showed an AAM around 16.0&#x000b1;2.1 years &#x0005b;<xref ref-type="bibr" rid="b20-cep-2019-00353">20</xref>&#x0005d;.</p>
</sec>
<sec>
<title>Determinants and risk factors of early menarche</title>
<p>The AAM can be determined by genetic and environmental factors and their interactions. However, the observed secular trend in AAM in this ethnicity may suggest that environmental rather than genetic factors are the major contributors to increasing rates of early menarche. The factors and conditions related to early menarche are listed in <xref rid="t1-cep-2019-00353" ref-type="table">Table 1</xref>.</p>
<sec>
<title>1. Genetic determinants of menarche</title>
<p>Twin and familial studies of AAM indicated a 57%&#x02013;82% of variance in the timing of puberty could be explained by heritable factors &#x0005b;<xref ref-type="bibr" rid="b21-cep-2019-00353">21</xref>,<xref ref-type="bibr" rid="b22-cep-2019-00353">22</xref>&#x0005d;. Racial differences in pubertal maturation might reflect genetic factors.</p>
<p>Genome-wide association studies on AAM performed in Caucasian females confirmed associations at two loci: 6q21 (in or near the LIN28B gene) and 9q31.2 &#x0005b;<xref ref-type="bibr" rid="b23-cep-2019-00353">23</xref>,<xref ref-type="bibr" rid="b24-cep-2019-00353">24</xref>&#x0005d;. Effect sizes were estimated at only 0.12 years earlier per effect allele for <italic>LIN28B</italic> and 9q31.2. Menarche signals were enriched in imprinted regions, with three loci (<italic>DLK1-WDR25</italic>, <italic>MKRN3-MAGEL2</italic>, and <italic>KCNK9</italic>) &#x0005b;<xref ref-type="bibr" rid="b25-cep-2019-00353">25</xref>&#x0005d;.</p>
<p>Recently, a woman&#x02019;s AAM has been suggested as a likely contributor to earlier pubertal development and early menarche in her female offspring &#x0005b;<xref ref-type="bibr" rid="b26-cep-2019-00353">26</xref>&#x0005d;. In our study of Korean mother-daughter pairs, the correlation between the AAM of mothers and their daughters was 0.245, comparable to figures of 0.23&#x02013;0.39 in other countries &#x0005b;<xref ref-type="bibr" rid="b27-cep-2019-00353">27</xref>,<xref ref-type="bibr" rid="b28-cep-2019-00353">28</xref>&#x0005d;. Furthermore, the daughters of mothers with an earlier AAM (&lt;13 years) were more likely to experience early menarche (&lt;12 years) themselves (earlier, 35.6%; reference, 25.8%; <italic>P</italic>&lt;0.05). The odds ratio (OR) for early menarche of such daughters compared with reference was 1.56 after the adjustment for confounders (under review).</p>
</sec>
<sec>
<title>2. Nongenetic determinants of menarche</title>
<p>Despite the major role of genetic factors in AAM, environmental factors have gained increasing attention due to their potential for control. It is well-known that AAM is related to obesity, nutrition (especially fructose), endocrine-disruptor channels (EDCs), and physical activity. Furthermore, small for gestational age (SGA) and precocious puberty are risk factors for early menarche.</p>
<sec>
<title>1) Obesity (body fat)</title>
<p>The &#x0201c;critical weight hypothesis&#x0201d; suggested by Frisch-Revelle states that the onset of menarche is associated with increased body fat, 22% or 48 kg of body weight, in pubertal girls &#x0005b;<xref ref-type="bibr" rid="b29-cep-2019-00353">29</xref>&#x0005d;. Leptin conveys information about fat mass and distribution to the hypothalamus during puberty &#x0005b;<xref ref-type="bibr" rid="b30-cep-2019-00353">30</xref>&#x0005d;. It stimulates the pul satile release of gonadotropin-releasing hormone (GnRH) in the hypothalamus, which serves as a signal for the onset of menarche &#x0005b;<xref ref-type="bibr" rid="b31-cep-2019-00353">31</xref>&#x0005d;. Most studies showed the association between high-fat content in infancy (or prepuberty or puberty) and earlier AAM. A higher subcutaneous fat levels and a high prepubertal body mass index (BMI) are associated with an increased likelihood of early (&lt;11 years) menarche &#x0005b;<xref ref-type="bibr" rid="b3-cep-2019-00353">3</xref>&#x0005d;.</p>
</sec>
<sec>
<title>2) Nutritional habits</title>
<p>An increased energy intake was associated with early menarche. Food quality also influences puberty. Formula feeding during early infancy might promote weight gain and earlier AAM in Asians and Caucasians &#x0005b;<xref ref-type="bibr" rid="b32-cep-2019-00353">32</xref>,<xref ref-type="bibr" rid="b33-cep-2019-00353">33</xref>&#x0005d;, whereas breastfeeding may decrease the risk of early puberty. However, recent studies found no association between milk consumption, breastfeeding duration (more than 3 months), and pubertal timing in Chinese children &#x0005b;<xref ref-type="bibr" rid="b34-cep-2019-00353">34</xref>&#x0005d;. Berkey et al. &#x0005b;<xref ref-type="bibr" rid="b35-cep-2019-00353">35</xref>&#x0005d; demonstrated that a high animal versus vegetable protein ratio at the ages of 3&#x02013;5 years is associated with early menarche after controlling for BMI. Dietary fiber might prevent early AAM through its effect on estrogen metabolism &#x0005b;<xref ref-type="bibr" rid="b36-cep-2019-00353">36</xref>&#x0005d;. Dietary fiber might reduce estrogen reabsorption and deconjugation in the gut.</p>
</sec>
<sec>
<title>3) Sugar-sweetened beverages</title>
<p>Sugar-sweetened beverages (SSBs) include sodas and soft drinks as well as other beverages with added sugars such as fruit-flavored drinks, sports and energy drinks, and sweetened coffees and teas. SSBs comprise approximately 30% of the fructose consumed in the US diet &#x0005b;<xref ref-type="bibr" rid="b37-cep-2019-00353">37</xref>&#x0005d;. SSBs caused early AAM in a prospective study of US girls &#x0005b;<xref ref-type="bibr" rid="b38-cep-2019-00353">38</xref>&#x0005d;. Girls consuming &gt;1.5 SSBs per day had an estimated 2.7-month younger AAM. The National Heart, Lung, and Blood Institute Growth and Health Study recruited 2,379 girls aged 9&#x02013;10 years and followed them for 10 years. The incidence of early menarche (menarche age &lt;11 years) occurred in 8.3% of the girls. After the adjustment for confounders and premenarcheal percentage body fat, a greater consumption of SSBs was associated with a higher risk of early menarche &#x0005b;<xref ref-type="bibr" rid="b39-cep-2019-00353">39</xref>&#x0005d;. The relative risk (RR) for one serving/day was 1.47.</p>
</sec>
<sec>
<title>4) Exercise</title>
<p>Some physical activities, in combination with a nutritional deficiency, may influence the onset of puberty &#x0005b;<xref ref-type="bibr" rid="b40-cep-2019-00353">40</xref>&#x0005d; and lead to a mean 1-year delay in AAM in Caucasians &#x0005b;<xref ref-type="bibr" rid="b41-cep-2019-00353">41</xref>&#x0005d;. AAM was positively associated with physical activity (at least 2 hours daily) in a group of Colombian university women &#x0005b;<xref ref-type="bibr" rid="b42-cep-2019-00353">42</xref>&#x0005d;. Menarche tends to occur later in athletes, including ballet dancers, then in the general population, but not in swimmers, suggesting that intense exercise delays puberty &#x0005b;<xref ref-type="bibr" rid="b43-cep-2019-00353">43</xref>&#x0005d;. The most probable explanation for the lack of a pubertal delay in swimmers is that the normal body fat composition of swimmers balances the negative hypothalamic effect on GnRH pulsatile exerted by intensive exercise.</p>
</sec>
<sec>
<title>5) Endocrine-disruptor chemicals</title>
<p>EDCs are a group of hormonally active agents. People are directly or indirectly exposed to EDCs every day because EDCs are widely used in the industry for almost a century &#x0005b;<xref ref-type="bibr" rid="b44-cep-2019-00353">44</xref>&#x0005d;. EDCs are used as industrial solvents/lubricants (polychlorinated biphenyls &#x0005b;PCBs&#x0005d;, polybrominated biphenyls, dioxins), plastics (bisphenol A &#x0005b;BPA&#x0005d;), plasticizers (phthalates), and pesticides (dichlorodiph enyltrichloroethane) &#x0005b;<xref ref-type="bibr" rid="b45-cep-2019-00353">45</xref>&#x0005d;. Phthalates and PCBs are associated with earlier breast development and menarche, respectively &#x0005b;<xref ref-type="bibr" rid="b46-cep-2019-00353">46</xref>&#x0005d;. BPA is well-known for its molecular estrogen-like actions and showed a close relationship between urinary BPA, body weight, and early puberty &#x0005b;<xref ref-type="bibr" rid="b47-cep-2019-00353">47</xref>&#x0005d;. Low doses of lead may be associated with the earlier onset of menses, whereas high-dose exposure may delay AAM &#x0005b;<xref ref-type="bibr" rid="b41-cep-2019-00353">41</xref>&#x0005d;. Some personal care chemicals, such as hair care products, used every day during childhood, can also lower AAM &#x0005b;<xref ref-type="bibr" rid="b48-cep-2019-00353">48</xref>&#x0005d;.</p>
</sec>
<sec>
<title>6) SGA and rapid early weight gain</title>
<p>Girls born SGA showed early pubertal onset and menarche by about 5&#x02013;10 months &#x0005b;<xref ref-type="bibr" rid="b49-cep-2019-00353">49</xref>&#x0005d;. A lower postnatal weight gain has a stronger association with earlier AAM in females with intrauterine growth retardation. A rapid early infancy weight gain from birth to age 2 months as well as 2&#x02013;9 months predicted subsequent greater adiposity and earlier AAM in girls &#x0005b;<xref ref-type="bibr" rid="b32-cep-2019-00353">32</xref>&#x0005d;.</p>
</sec>
<sec>
<title>7) Precocious puberty</title>
<p>Precocious puberty is defined as the development of secondary sexual characteristics before 8 years of age in girls. Premature activation of the hypothalamic&#x02013;pituitary&#x02013;gonadal axis in central precocious puberty stimulates the production of sex steroids that stimulate linear growth and accelerate bone age advancement and result in early menarche. In untreated children with central precocious puberty, early growth acceleration and premature fusion of the epiphyseal growth plates result in an impaired final height &#x0005b;<xref ref-type="bibr" rid="b50-cep-2019-00353">50</xref>,<xref ref-type="bibr" rid="b51-cep-2019-00353">51</xref>&#x0005d;.</p>
</sec>
</sec>
</sec>
<sec>
<title>Early menarche and its adverse consequences in later life</title>
<p>Several studies have established an association between early menarche and the risk of cardiometabolic diseases in adulthood. The adverse consequences in later life (including late adolescents, young adults, and adults) associated with early menarche are listed in <xref rid="t2-cep-2019-00353" ref-type="table">Table 2</xref>.</p>
<sec>
<title>1. Short adult height</title>
<p>Early menarche increased the risk of adult short stature in young Korean women. According to the European Prospective Investigation into Cancer and Nutrition study, based on 286,205 women, their final height was 0.35 cm (range by country, 0.13 to 0.50 cm) shorter when menarche occurred 1 year earlier &#x0005b;<xref ref-type="bibr" rid="b52-cep-2019-00353">52</xref>&#x0005d;. Furthermore, a 1-year decrease in AAM decreased the standing height and leg length by 0.76 and 0.41 cm, respectively, in the USA birth cohort &#x0005b;<xref ref-type="bibr" rid="b53-cep-2019-00353">53</xref>&#x0005d;.</p>
<p>In Korea, we found that 1-year decrease in the AAM was associated with a 0.445 cm final height loss in young Korean women &#x0005b;<xref ref-type="bibr" rid="b8-cep-2019-00353">8</xref>&#x0005d;. We also found that young women with early menarche had a 10.5% chance of having a short adult stature (&#x02264;153 cm), which was 2.62-fold higher than those with later menarche. These findings are due to the earlier closure of epiphyseal growth plates due to the increase in ovarian estrogens &#x0005b;<xref ref-type="bibr" rid="b54-cep-2019-00353">54</xref>,<xref ref-type="bibr" rid="b55-cep-2019-00353">55</xref>&#x0005d;. A high dose of estrogen binding to its receptors in the growth plate cartilage might cause early epiphyseal fusion by advancing growth plate senescence &#x0005b;<xref ref-type="bibr" rid="b55-cep-2019-00353">55</xref>&#x0005d;.</p>
</sec>
<sec>
<title>2. Obesity</title>
<p>Obesity in adulthood is closely related with early menarche. Several studies observed an inverse relationship between AAM and adult BMI &#x0005b;<xref ref-type="bibr" rid="b56-cep-2019-00353">56</xref>-<xref ref-type="bibr" rid="b59-cep-2019-00353">59</xref>&#x0005d;. Although the causal relationship between AAM and obesity remains unclear, earlier menarche and obesity are strongly associated with chronic cardiometabolic diseases in adulthood.</p>
<p>Freedman et al. &#x0005b;<xref ref-type="bibr" rid="b57-cep-2019-00353">57</xref>&#x0005d; advocated that increasing childhood obesity rates result in both early menarche and adulthood obesity. Girls with early menarche, including Koreans, reportedly have greater body fat content in childhood &#x0005b;<xref ref-type="bibr" rid="b20-cep-2019-00353">20</xref>,<xref ref-type="bibr" rid="b57-cep-2019-00353">57</xref>&#x0005d;. However, Pierce and Leon &#x0005b;<xref ref-type="bibr" rid="b58-cep-2019-00353">58</xref>&#x0005d; stressed that earlier menarche in itself might cause obesity in adults rather than be a proxy marker of sexual maturation. The secular change of AAM was also found in normal-weight girls &#x0005b;<xref ref-type="bibr" rid="b59-cep-2019-00353">59</xref>&#x0005d;. Menarche is accompanied by a rapid increase in body weight &#x0005b;<xref ref-type="bibr" rid="b60-cep-2019-00353">60</xref>,<xref ref-type="bibr" rid="b61-cep-2019-00353">61</xref>&#x0005d;. High plasma estradiol levels and low sex hormonebinding globulin (SHBG) levels due to puberty are associated with adiposity &#x0005b;<xref ref-type="bibr" rid="b62-cep-2019-00353">62</xref>&#x0005d;. In our study based on Korea National Health and Nutrition Examination Survey (KNHANES), a younger AAM is associated with current BMI of adults after control for age. The OR of obesity in women with early menarche was 1.845 times higher than that in those who experienced menarche after 12 years &#x0005b;<xref ref-type="bibr" rid="b5-cep-2019-00353">5</xref>&#x0005d;.</p>
</sec>
<sec>
<title>3. Metabolic syndrome</title>
<p>MetS is the combination of central obesity, increased blood pressure (BP), glucose intolerance, and dyslipidemia &#x0005b;<xref ref-type="bibr" rid="b63-cep-2019-00353">63</xref>&#x0005d;. MetS is a main target for CVD prevention, as MetS is prospectively associated with an increased risk of CVD-related morbidity and mortality in European and Asian subjects &#x0005b;<xref ref-type="bibr" rid="b63-cep-2019-00353">63</xref>,<xref ref-type="bibr" rid="b64-cep-2019-00353">64</xref>&#x0005d;.</p>
<p>Early menarche is associated with MetS in most Western studies &#x0005b;<xref ref-type="bibr" rid="b65-cep-2019-00353">65</xref>-<xref ref-type="bibr" rid="b67-cep-2019-00353">67</xref>&#x0005d;. The Bogalusa Heart Study found that early menarche is characterized by excess body fat content and insulin in early childhood and a higher prevalence of MetS in young adulthood &#x0005b;<xref ref-type="bibr" rid="b65-cep-2019-00353">65</xref>&#x0005d;. The KORA F4 (Cooperative Health Research in the Region of Augsburg, South Germany, 2006&#x02013;2008) also showed that early menarche is associated with MetS in women aged 32&#x02013;81 years; after the adjustment for age and additional confounders, including lifestyle and reproductive history &#x0005b;<xref ref-type="bibr" rid="b67-cep-2019-00353">67</xref>&#x0005d;, that association was partially mediated by weight gain and increased BMI after 25 years of age. In our study based on KNHANESIV data, females with early menarche had a higher prevalence of central obesity, elevated fasting glucose, and elevated BP in the 20&#x02013;30 years group. The OR for MetS was 3.54 in premenopausal Korean women after the adjustment for age and another confounder &#x0005b;<xref ref-type="bibr" rid="b10-cep-2019-00353">10</xref>&#x0005d;.</p>
</sec>
<sec>
<title>4. Insulin resistance</title>
<p>The role of early menarche in the development of MetS in later adulthood is uncertain. The most likely explanation is that early menarche in adolescents and MetS in adulthood are consequences of IR. Hyperinsulinemia, usually but not always accompanied by obesity, is thought to play a mediating role in the development of early puberty &#x0005b;<xref ref-type="bibr" rid="b68-cep-2019-00353">68</xref>&#x0005d;. Hyperinsulinemia or IR independently increased the risk of MetS and coronary heart disease (CHD) risk after the adjustment for other confounders in the Helsinki Policemen Study &#x0005b;<xref ref-type="bibr" rid="b69-cep-2019-00353">69</xref>&#x0005d;. Among Koreans, premenopausal females over 30 years of age with early menarche had a higher prevalence of central obesity and IR &#x0005b;<xref ref-type="bibr" rid="b10-cep-2019-00353">10</xref>&#x0005d;. The OR for IR was 2.98 after the adjustment for confounders.</p>
<p>In pediatrics, the best example is children born SGA. In a longitudinal cohort study, SGA children had greater adiposity and IR during catch-up growth &#x0005b;<xref ref-type="bibr" rid="b70-cep-2019-00353">70</xref>&#x0005d;. SGA girls had early puberty and a lower AAM &#x0005b;<xref ref-type="bibr" rid="b64-cep-2019-00353">64</xref>&#x0005d;. After menarche, SGA girls also showed hyperinsulinemia, higher androgen levels, and lower SHBG levels &#x0005b;<xref ref-type="bibr" rid="b71-cep-2019-00353">71</xref>&#x0005d;.</p>
</sec>
<sec>
<title>5. Nonalcoholic fatty liver disease</title>
<p>NAFLD is a spectrum of disease activity that ranges from simple hepatic steatosis to nonalcoholic steatohepatitis &#x0005b;<xref ref-type="bibr" rid="b72-cep-2019-00353">72</xref>&#x0005d;. Epidemiological studies have shown that NAFLD may precede MetS onset and its complications and is associated with an increased risk of future CVD-related morbidity and mortality &#x0005b;<xref ref-type="bibr" rid="b73-cep-2019-00353">73</xref>,<xref ref-type="bibr" rid="b74-cep-2019-00353">74</xref>&#x0005d;.</p>
<p>Mueller et al. &#x0005b;<xref ref-type="bibr" rid="b75-cep-2019-00353">75</xref>&#x0005d;. first reported that earlier menarche is positively associated with NAFLD in the CARDIA study. They suggest that a 1-year earlier AAM is associated with a 10% increased the risk of NAFLD and visceral ectopic fat deposit in middle adulthood (43&#x02013;55 years of age) after the adjustment for other confounders. In our study, the OR for NAFLD in Korean women with early menarche compared to reference was 3.04. Further adjustment of mediators, like obesity or IR, attenuated the association to 1.91 and 2.17, but the results remained significant &#x0005b;<xref ref-type="bibr" rid="b11-cep-2019-00353">11</xref>&#x0005d;.</p>
</sec>
<sec>
<title>6. Type 2 diabetes mellitus</title>
<p>Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by a high blood glucose in the context of IR, a key factor in its development &#x0005b;<xref ref-type="bibr" rid="b76-cep-2019-00353">76</xref>&#x0005d;. Prospective studies showed that IR, based on Homeostatic Model Assessment of Insulin Resistance, persists for and is a powerful independent predictor of T2DM &#x0005b;<xref ref-type="bibr" rid="b77-cep-2019-00353">77</xref>&#x0005d;. A 2.2-time increase in fasting insulin concentration was linked to a 2-fold increase in the future incidence of T2DM over a 24-year follow-up &#x0005b;<xref ref-type="bibr" rid="b78-cep-2019-00353">78</xref>&#x0005d;.</p>
<p>Several studies, including ours, reported that an early menarche is associated with a higher risk of T2DM &#x0005b;<xref ref-type="bibr" rid="b79-cep-2019-00353">79</xref>-<xref ref-type="bibr" rid="b82-cep-2019-00353">82</xref>&#x0005d;. In the Nurses&#x02019; Health Study I &amp; II, the RR of T2DM in the young female cohort (40&#x02013;50 years) with early menarche was 1.40 versus 1.18 in the old cohort &#x0005b;<xref ref-type="bibr" rid="b79-cep-2019-00353">79</xref>&#x0005d;. In the Atherosclerosis Risk in Communities study, the OR for diabetes was 1.41 after adjustment for adiposity and lifestyle &#x0005b;<xref ref-type="bibr" rid="b80-cep-2019-00353">80</xref>&#x0005d;. In our study, the OR of diabetes was 3.61-fold after the adjustment for age in Korean women aged 20&#x02013;50 years &#x0005b;<xref ref-type="bibr" rid="b12-cep-2019-00353">12</xref>&#x0005d;. Thus, some authors insist that the history of early menarche was a more influential factor than the current BMI or adiposity &#x0005b;<xref ref-type="bibr" rid="b81-cep-2019-00353">81</xref>,<xref ref-type="bibr" rid="b82-cep-2019-00353">82</xref>&#x0005d;.</p>
</sec>
<sec>
<title>7. Cardiovascular diseases</title>
<p>CVD are the number one cause of death worldwide &#x0005b;<xref ref-type="bibr" rid="b83-cep-2019-00353">83</xref>&#x0005d;. In Korea, around 22% of deaths are attributable to CVD &#x0005b;<xref ref-type="bibr" rid="b84-cep-2019-00353">84</xref>&#x0005d;. In the past, many studies showed an association between AAM and the risk of CVD; increasing year of AAM lowers the risk of CVD &#x0005b;<xref ref-type="bibr" rid="b85-cep-2019-00353">85</xref>-<xref ref-type="bibr" rid="b87-cep-2019-00353">87</xref>&#x0005d;. The UK Million Women Study and Chinese birth cohort recently reported a significant increase in CHD risk for both early and late menarche &#x0005b;<xref ref-type="bibr" rid="b88-cep-2019-00353">88</xref>,<xref ref-type="bibr" rid="b89-cep-2019-00353">89</xref>&#x0005d;. In the UK Million Women Study, the risk of CHD was lowest at a menarcheal age of 13 years, and the risk was highest in a woman who experienced menarche at &#x02264;10 years of age with a RR of 1.27. In Korea, a 51% reduction in mortality associated with CHD was reported in women with early menarche (&lt;17 years) in a Kangwha cohort study &#x0005b;<xref ref-type="bibr" rid="b90-cep-2019-00353">90</xref>&#x0005d;. The prevalence of women with a &#x02265;10% or &#x02265;20% 10-year Framingham Coronary Heart Disease Risk Point Scale score was higher in those with early menarche (&lt;13 years) than in other groups after the adjustment for confounding factors &#x0005b;<xref ref-type="bibr" rid="b91-cep-2019-00353">91</xref>&#x0005d;. The results were consistent with the previous meta-analysis, which reported a 3% higher probability of death of all causes for each decreasing year of AAM &#x0005b;<xref ref-type="bibr" rid="b13-cep-2019-00353">13</xref>&#x0005d;.</p>
</sec>
<sec>
<title>8. Cancer risk</title>
<p>Breast cancer is a hormone-related cancer like ovarian and endometrial. In Korea, the incidence of breast cancer increased rapidly from 24.5 in 1999 to 50.7/100,000 in 2012 and 2nd most prevalent female cancer &#x0005b;<xref ref-type="bibr" rid="b92-cep-2019-00353">92</xref>&#x0005d;. A meta-analysis of 117 epidemiological studies showed that the breast cancer incidence risk increased by 5% when menarche occurred 1 year earlier &#x0005b;<xref ref-type="bibr" rid="b93-cep-2019-00353">93</xref>&#x0005d;. In a meta-analysis of eight prospective endometrial cancer studies, the risk of the highest AAM was 32% lower than that of the lowest AAM and showed that the cancer risk decreased by 4% when AAM was delayed by 2 years &#x0005b;<xref ref-type="bibr" rid="b94-cep-2019-00353">94</xref>&#x0005d;. In Korea, women with early menarche (&#x02264;12 years) were at increased risk of developing breast cancer with a hazard ratio of 1.57 in the Korean Heart Study &#x0005b;<xref ref-type="bibr" rid="b95-cep-2019-00353">95</xref>&#x0005d;. Among a cohort of British women, those with early menarche (&lt;12 years) had a 1.25-times higher cancer mortality rate and a 1.22-times higher all-cause mortality rate after the adjustment for age, BMI, and other confounders &#x0005b;<xref ref-type="bibr" rid="b96-cep-2019-00353">96</xref>&#x0005d;.</p>
</sec>
</sec>
<sec>
<title>Proposed mechanism of early menarche</title>
<p>The exact mechanism of how early menarche contributes to the development of cardiometabolic derangement (obesity, IR, MetS, NAFLD, diabetes, breast cancer, CVD) in later adulthood is not known.</p>
<p>The most popular and simple explanation is that early menarche in adolescents and cardiometabolic derangement in adulthood are consequences of childhood obesity. Childhood adiposity is known to trigger puberty and, as a result, early menarche by adipocytes and related hormones &#x0005b;<xref ref-type="bibr" rid="b71-cep-2019-00353">71</xref>,<xref ref-type="bibr" rid="b97-cep-2019-00353">97</xref>&#x0005d;. Childhood obesity progresses to adult obesity &#x0005b;<xref ref-type="bibr" rid="b97-cep-2019-00353">97</xref>&#x0005d;. Obesity is well-known to be closely related to IR, MetS, NAFLD, diabetes, breast cancer, and CVD &#x0005b;<xref ref-type="bibr" rid="b73-cep-2019-00353">73</xref>,<xref ref-type="bibr" rid="b98-cep-2019-00353">98</xref>,<xref ref-type="bibr" rid="b99-cep-2019-00353">99</xref>&#x0005d;.</p>
<p>The other more complex and fine explanation is that early menarche in adolescents and metabolic derangement in adulthood are consequences of IR or hyperinsulinemia. Hyperinsulinemia, which is usually but not always accompanied by obesity, is thought to play a mediating role in the development of early puberty &#x0005b;<xref ref-type="bibr" rid="b66-cep-2019-00353">66</xref>&#x0005d;. Furthermore, hyperinsulinemia or IR, accompanied by inflammation, independently increased the risk of MetS, NAFLD, T2DM, breast cancer, and CVD &#x0005b;<xref ref-type="bibr" rid="b69-cep-2019-00353">69</xref>,<xref ref-type="bibr" rid="b77-cep-2019-00353">77</xref>&#x0005d;. Hyperinsulinemia reduces SHBG levels, which in turn leads to greater bioavailability of the sex steroids &#x0005b;<xref ref-type="bibr" rid="b100-cep-2019-00353">100</xref>&#x0005d;. Decreased serum SHBG levels are associated with early puberty &#x0005b;<xref ref-type="bibr" rid="b101-cep-2019-00353">101</xref>&#x0005d;. SHBG is also a strong predictor of MetS, IR, and independent of total fat mass during puberty and might persist into adulthood &#x0005b;<xref ref-type="bibr" rid="b102-cep-2019-00353">102</xref>&#x0005d;.</p>
</sec>
<sec>
<title>Decreasing fructose intake to prevent early menarche</title>
<p>The next question is what causes obesity or IR. The Westernized lifestyle is associated with an increasing prevalence of obesity worldwide. The Westernized lifestyle is characterized by sedentary behavior or low physical activity and a Western pattern diet (WPD). The WPD is a modern dietary pattern that is generally characterized by high intakes of processed meat, pre-packaged foods, fried foods, high-fat dairy products, eggs, refined grains, potatoes, corn (and high-fructose corn syrup), and high-sugar drinks &#x0005b;<xref ref-type="bibr" rid="b103-cep-2019-00353">103</xref>&#x0005d;. In contrast, a healthy diet has higher proportions of unprocessed fruits, nuts, vegetables, whole-grain foods, poultry, and fish.</p>
<p>In Korea, as a result of the rapid economic growth and the adoption of a more Western lifestyle over the past four decades, the food content shifted from a traditional Korean diet (wholegrain rice, vegetables, and kimchi) to WPD (sugar, eggs, and oil) &#x0005b;<xref ref-type="bibr" rid="b104-cep-2019-00353">104</xref>&#x0005d;. Between 1998 and 2010, the consumption of sugar, sugar with coffee, and fruit intake were significantly and continuously increased. Strangely, energy intakes were significantly decreased by approximately 13% in adults over 20 years. During that period, the prevalence of obesity (BMI &#x02265;25 kg/m<sup>2</sup>) among South Korean adults also increased from 25.7% in 1998 to 37.9% in 2013 &#x0005b;<xref ref-type="bibr" rid="b105-cep-2019-00353">105</xref>&#x0005d;. Furthermore, according to the Korea Health Statistics, the percentage of obese adolescent boys and girls has increased considerably from 17.0% and 10.2% in 2005 to 19.1% and 14.3% in 2016, respectively &#x0005b;<xref ref-type="bibr" rid="b106-cep-2019-00353">106</xref>&#x0005d;.</p>
<p>A recent KNHANES study reported that SSB consumption increased dramatically from 58 g/day in 2008 to 101 g/day in 2011, and beverages including soda, coffee, and fruit and vegetable drinks are the major source of sugar intake from processed foods in the Korean population &#x0005b;<xref ref-type="bibr" rid="b107-cep-2019-00353">107</xref>&#x0005d;. For Korean adolescents, carbonated beverages is the number one source of sugar and the consumption of SSBs is on the rise &#x0005b;<xref ref-type="bibr" rid="b107-cep-2019-00353">107</xref>,<xref ref-type="bibr" rid="b108-cep-2019-00353">108</xref>&#x0005d;. For Korean children aged 6&#x02013;11 years, the mean daily total sugar intake was 79.31 g/day (boys, 80.00 g/day; girls, 78.57 g/day). Children with a beverage intake &#x02265;200 mL/day had a higher total sugar intake (107.97&#x000b1;3.24 g/day vs. 69.13&#x000b1;1.52 g/day) &#x0005b;<xref ref-type="bibr" rid="b109-cep-2019-00353">109</xref>&#x0005d;. Furthermore, 47.9% of children consuming more than 10% of their energy intake from total sugar in processed foods. It must be corrected considering the World Health Organization recommendation that the intake of free sugars be less than 10% of one&#x02019;s total energy intake due to its deleterious health effects &#x0005b;<xref ref-type="bibr" rid="b110-cep-2019-00353">110</xref>&#x0005d;. The excessive consumption of fructose and sucrose is associated with deleterious effects on the metabolism and an increased risk of visceral adiposity, MetS, NAFLD, IR, and cardiometabolic risk &#x0005b;<xref ref-type="bibr" rid="b111-cep-2019-00353">111</xref>-<xref ref-type="bibr" rid="b115-cep-2019-00353">115</xref>&#x0005d;. No study has directly assessed the association between dietary components and early menarche. However, a meta-analysis suggested that early menarche and insulin resistance are significantly associated &#x0005b;<xref ref-type="bibr" rid="b116-cep-2019-00353">116</xref>&#x0005d;; thus, it can be inferred that dietary components and early menarche are indirectly related.</p>
<p>Positive associations were also observed between SSB intake and obesity, MetS, NAFLD, insulin resistance, and cardiometabolic risk in Korean women. The OR for obesity in Korean children with a beverage intake of &#x02265;200 mL/day significantly increased by 1.83 times versus that of children with a beverage intake of &lt;200 mL/day after the adjustment for confounding variables &#x0005b;<xref ref-type="bibr" rid="b109-cep-2019-00353">109</xref>&#x0005d;. Korean women who consumed &#x02265;4 servings/week of SSBs were at a significantly higher risk of MetS than infrequent consumers &#x0005b;<xref ref-type="bibr" rid="b117-cep-2019-00353">117</xref>&#x0005d;. Another Korean cohort study reported that subjects in the highest SSB consumption group were at a significantly greater risk (21%) of developing hypertension &#x0005b;<xref ref-type="bibr" rid="b118-cep-2019-00353">118</xref>&#x0005d;.</p>
<p>We previously postulated that an excessive consumption of fructose might underlie the development of NAFLD, IR, and MetS &#x0005b;<xref ref-type="bibr" rid="b119-cep-2019-00353">119</xref>&#x0005d;. Fructose is consumed either as sucrose (50% fructose) or as high-fructose corn syrup (42% or 55% fructose). Although both glucose and fructose are categorized as carbohydrates, the hepatic metabolism of fructose is very different to that of glucose in that it is insulin-independent, bypasses the process of glycolysis, and increases de novo lipogenesis to a greater extent; metabolically, fructose is similar to ethanol &#x0005b;<xref ref-type="bibr" rid="b120-cep-2019-00353">120</xref>&#x0005d;. SSB consumption was recently reported to be associated with a risk of earlier menarche dose-dependently or -independently of childhood BMI &#x0005b;<xref ref-type="bibr" rid="b38-cep-2019-00353">38</xref>,<xref ref-type="bibr" rid="b39-cep-2019-00353">39</xref>&#x0005d;.</p>
</sec>
<sec sec-type="conclusions">
<title>Conclusions</title>
<p>In pediatrics, establishing risk factors is important in planning the prevention of disease in later life. In this review, we showed that early menarche increases the risk of a shorter final height and the development of obesity, IR, MetS, NAFLD, T2DM, breast cancer, and CVD in Korean women as with other ethnicities. Furthermore, a female adolescent with early menarche may suffer from various psychosocial problems and show delinquency and risky sexual behaviors. Although the above mentioned chronic cardiometabolic diseases might occur in adults and should be managed by all physicians, the pediatrician is an advance guard to recognize the problems correlated with early menarche and should take action to prevent its consequences.</p>
<p>We also reviewed the probable mechanism of early menarche: a high fructose intake, in the form of SSB and fruit juice (foods containing no fiber), is one of the major causes of early menarche, obesity, and IR.</p>
<p>A health education program that stresses a healthy diet composed mainly of unprocessed fruits (with much fiber like vegetables) and whole grains, should be implemented. Early menarche might be prevented by lifestyle changes, including regular exercise and a healthy diet (fructose-free and fiber-rich) during infancy and childhood. The secondary prevention of cardiometabolic disease in a female experiencing early menarche involves exercise and a healthy diet in line with obesity management.</p>
<p>We hope that this review will help pediatricians comprehensively understand the lifetime health problems associated with early menarche and to participate in preventing early menarche and its complications.</p>
</sec>
</body>
<back>
<ack><p>We thank Sanghui Kweon from the Division of Health and Nutrition Survey for her technical support in analyzing the data of the Korea National Health and Nutrition Examination Survey.</p></ack>
<fn-group>
<fn fn-type="conflict"><p>No potential conflict of interest relevant to this article was reported.</p></fn>
</fn-group>
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<sec sec-type="display-objects">
<title>Figure and Tables</title>
<fig id="f1-cep-2019-00353" position="float">
<label>Fig. 1.</label><caption><p>Secular trend of mean age at menarche and body mass index for women born between 1904 and 1995. Adapted from Ahn et al. Ann Pediatr Endocrinol Metab 2013;18:60-4 &#x0005b;<xref ref-type="bibr" rid="b5-cep-2019-00353">5</xref>&#x0005d;.</p></caption>
<graphic xlink:href="cep-2019-00353f1.tif"/></fig>
<table-wrap id="t1-cep-2019-00353" position="float">
<label>Table 1.</label>
<caption><p>Factors and conditions related to early menarche</p></caption>
<table rules="groups" frame="hsides">
<thead><tr>
<th align="left" valign="middle">Genetic</th>
<th align="center" valign="middle">Nongenetic</th>
</tr></thead>
<tbody>
<tr>
<td valign="top" align="left"><italic>Race</italic></td>
<td valign="top" align="left">Obesity</td>
</tr>
<tr>
<td valign="top" align="left"><italic>LIN28B</italic></td>
<td valign="top" align="left">Sugar-sweetened beverages (fructose)</td>
</tr>
<tr>
<td valign="top" align="left"><italic>DLK1-WDR25</italic></td>
<td valign="top" align="left">Low intake of fiber</td>
</tr>
<tr>
<td valign="top" align="left"><italic>MKRN3-MAGEL2</italic></td>
<td valign="top" align="left">Decreased physical activity</td>
</tr>
<tr>
<td valign="top" align="left"><italic>KCNK9</italic></td>
<td valign="top" align="left">Endocrine-disruptor chemicals</td>
</tr>
<tr>
<td valign="top" align="left">Mother&#x02019;s earlier menarche</td>
<td valign="top" align="left">Small for gestational age</td>
</tr>
<tr>
<td valign="top" align="left"></td>
<td valign="top" align="left">Rapid early weight gain</td>
</tr>
<tr>
<td valign="top" align="left"></td>
<td valign="top" align="left">Precocious puberty</td>
</tr>
</tbody></table>
</table-wrap>

<table-wrap id="t2-cep-2019-00353" position="float">
<label>Table 2.</label>
<caption><p>Adverse consequences of early menarche in later life</p></caption>
<table rules="groups" frame="hsides">
<tbody><tr>
<td valign="top" align="left">Risk&#x02010;taking behaviors</td>
</tr>
<tr>
<td valign="top" align="left">Psychologic problems</td>
</tr>
<tr>
<td valign="top" align="left">Short adult height</td>
</tr>
<tr>
<td valign="top" align="left">Obesity</td>
</tr>
<tr>
<td valign="top" align="left">Metabolic syndrome</td>
</tr>
<tr>
<td valign="top" align="left">Insulin resistance</td>
</tr>
<tr>
<td valign="top" align="left">Nonalcoholic fatty liver disease</td>
</tr>
<tr>
<td valign="top" align="left">Type 2 diabetes mellitus</td>
</tr>
<tr>
<td valign="top" align="left">Cardiovascular diseases</td>
</tr>
<tr>
<td valign="top" align="left">Breast cancer</td>
</tr>
<tr>
<td valign="top" align="left">Mortality</td>
</tr>
<tr>
<td valign="top" align="left">Others</td>
</tr>
</tbody></table>
</table-wrap>
</sec>
</back></article>